Pathological physiology Part 1 (topic #1-8) Content.
№ Name topic Page Introduction. Pathophysiology as a science and medical disciplines. 1. 3 Subject, tasks and methods of studying pathological physiology. 2. HEALTH AND DISEASE. General nosology. GENERAL pathogenesis. 6 3. Pathological reactions, pathological process, pathological condition 14 4. Sanogenesis. 22 5. Environmental factors 26 6. The damaging effect of mechanical factors 27 7. Pathogenic effect of low temperatures. Hypothermia 29 8. Pathogenic effects of heat. Overheating. Heatstroke. 30 9. Sunstroke. The cause and pathogenesis of sunstroke. 31 10. Action barometric pressure 33 11. Poisoning with oxygen, nitrogen. 35 12. Pathogenic action of electric current 37 13. The damaging effects of ionizing radiation 40 14. The damaging effect of rays of the solar spectrum 45 15. The action of chemical factors 47 16. The action of biological factors 48 17. Action space flight factors. Gravity Pathophysiology. 49 18. The role of psychogenic factors in the pathology 54 19. Pathogenic action of sound and noise 55 20. The damaging effect of laser radiation 57 TYPES OF DAMAGE ON DIFFERENT LEVELS OF MULTICELLULAR 21. 58 ORGANISMS 22. DAMAGE TO CELLS 61 23. GENERAL MECHANISMS OF CELL DAMAGE 63 24. CHARACTERISTICS TYPICAL FORMS OF CELL DAMAGE 71 25. The death of cells 75 26. ADAPTATION OF CELLS IN THEIR DAMAGE 79 27. REACTIVITY OF THE BODY 85 28. The Resistance 88 29. Carbohydrate metabolism disorders 94 30. HYPOGLYCEMIA 99 31. HYPERGLYCEMIA 103 32. Diabetes 105 33. Pathophysiology of metabolism. Disturbance of the water-salt metabolism 119 34. Hypohydration 120 35. HYPERHYDRATION 123 36. EDEMA 125
2 Introduction. Pathophysiology as a science and medical disciplines. Subject, tasks and methods of studying pathological physiology.
Pathophysiology - the doctrine of the bodily functions of the patient (pathos - injury, illness). Pathophysiology - is a medical discipline that studies the most general laws of occurrence, development and outcome of the disease and the pathological process that studies the principles of their treatment, as well as the problems of methodology obtained about the disease or pathological process knowledge. Pathophysiology refers to medical and biological sciences, combining biological sciences (biology, biochemistry, anatomy, histology, physiology, etc.) With clinical disciplines (internal medicine, pediatrics, surgery, neurology, etc.). Pathophysiology - this section of the medicine - a science that has as its main task, on the one hand, maintaining and promoting human health and on the other - the prevention of diseases and treatment of patients. The very same medicine arose at the intersection of the natural and social sciences (disciplines) and consists of health sciences and the science of the disease (pathology). Below is a chart showing the pathophysiology place among other medical and biological and clinical disciplines. Natural Sciences Social Sciences ↓ ↓ Medicine ↓ ↓ Science Health Sciences diseases (anatomy, physiology, (pathological anatomy, pathophysiology, histology, hygiene), surgery, pediatrics)
Pathological physiology exists in two related conditions. I. Pathological physiology as a science. The study of pathological physiology as a science by scientists pathophysiology. Tasks Pathophysiology as a science. 1. The study etiology of disease. Etiology (aitia - reason) - is the study of the causes and conditions of the disease. 2. The study of the pathogenesis of the disease. Pathogenesis - a mechanism of the disease (the mechanism of injury and the mechanism of protection at illness). 3. The study of mechanisms of disease outcome (recovery mechanisms, mechanisms of dying). 4. Development of the principles of treatment of the disease (etiotropic, pathogenetic, sanogenetic, symptomatic). 5. Prevention of diseases, as well as the methodology, obtained knowledge about the disease (disease of comprehension received knowledge from the standpoint of philosophy: the formation of hypotheses, theories, concepts of illness, etc.).
II. Pathological physiology as a medical discipline The object and purpose of pathophysiology as a medical discipline. 1. General nosology - the general doctrine of the disease (the general laws of occurrence, development and outcome of the disease). Topics included in the first section: - The introduction, the subject methods; - A disease in historical terms; - General nosology; - Disease-causing environmental factors; - Common pathogenesis; - The doctrine of the reactivity of the organism, allergic reactivity, immunological reactivity, heredity and disease.
3 2. General typical pathological processes (inflammation, fever, tumor process, extreme conditions, etc.). Topics included in the second section: - Standard peripheral circulatory disorders; - Inflammation, - Fever, - Extreme condition (shock, collapse, coma) - Lack of oxygen (hypoxia) - Typical metabolic disorders, - Stress and distress, - Neoplastic process. 3. Typical pathological processes of organs and systems (heart arrhythmia, heart failure, respiratory failure, anemia, kidney failure and others.). Topics included in the third section: - Typical disorders of the nervous system, - Typical disorders of the endocrine system, - Typical disorders of the cardiovascular system, - Typical disorders of the blood system, - Typical disorders of the respiratory system, - Typical digestive disorders, - Typical of the liver, - Typical renal impairment.
Sometimes artificially first two sections are combined together and called "general pathophysiology," the third section is even more artificial (formally) called "private pathophysiology." However, in all three sections examine general patterns of disease.
The challenges facing students in the study of the pathophysiology of both medical disciplines. 1. To study the general laws of occurrence, development and outcome of the disease. 2. Prepare yourself to the perception of the disease process in the hospital - at the bedside. 3. Remember - every disease always has: its specific causes and conditions, its pathogenesis, knowledge of which is necessary for an accurate diagnosis for proper treatment of any disease. 4. Remember that effective treatment can only be based on the principles of causal, pathogenetic, sanogenetic and symptomatic treatment of the disease. 5. Remember - the doctor all their knowledge, their experience, should devote a lifetime to the service of the interests of the sick person's health.
The basic method of pathophysiology - method pathophysiological experiment.
Its essence - the modeling of disease or pathological process in an experiment to study. Types pathophysiological experiments: 1. Method pathophysiological experiment - modeling of human disease in animal experiments. 2. Method pathophysiological experiment on humans ("natural experiment" - on volunteers),
Pathophysiological features of the experiment is that it consists of three phases: 1. Physiological phase - study of healthy body functions. 2. Pathophysiological phase - modeling of disease or pathological process and the study of functions on the background of the disease. 3. Phase experimental therapy - the use of experimental therapy and follow-up restoration functions.
Auxiliary research methods in pathophysiological experiment: 1. Physiological,
4 2. Morphological, 3. Biochemical, 4. Immunological, 5. Physico-chemical, 6. Physical, 7. Mathematical, 8. Clinical, 9. Comparative evolutionary method, 10. The method of studying isolated organs and tissues in culture in vitro.
Clinical Pathophysiology - learning clinically in patients.
5 HEALTH AND DISEASE Health and disease are two major forms of life. The states of health and disease can often replace each other over the individual life of the animal and the human. Aristotle considered health and illness qualitatively different categories. Norm and health To understand the nature of the disease it is important to define what a normal, healthy life (normal, health), beyond which there is a disease. There are different views on the concepts of "normal" and "health". It should be emphasized that these concepts are very closely related to each other. Norm - the more general concept that defines many of the processes and phenomena of living organisms. It expresses particular qualitative state of a living organism as a whole in every single moment of his existence. Norma (from the Greek norm - a way of knowing) is a term that is very close to the concept of "health", but not exhaustive, the term altogether. In medical practice very often use the expression "normal temperature", "Normal electrocardiogram", "normal weight and height", "normal composition of blood," etc. In this case, it refers to the rate as a statistical mean value of the measurement data from a large number of healthy individuals (average rate). The average rate takes into account race, age and gender characteristics, but it can not take into account all possible genotypes. You can be healthy on the basic parameters of the structure and functions of the body, but have a deviation from the norm for some individual characteristics, such as growth, mental abilities, peculiarities of behavior in society, and others. On the other hand, you can be patient and at the same time have outstanding intellectual abilities. All this speaks of the relativity of the terms "normal" and "health" and some conventions of the scope of their assessment for each individual. By definition, GI Tsaregorodtsev "rate - is a set of harmonic ratio and structural and functional data of the body, adequate its environment and provide the body with optimal ability to live." For example, in conditions of low oxygen content on the mountain heights to be considered a normal increase in red blood cells in the blood against that of sea level. Thus, the norm - this is the optimal state of life of the organism in a given environment for the person. The rate varies with the variability of species and their populations, it is different for individuals of different species, different populations, different ages, different genders and individuals. It is determined genetically and at the same time depends on the environment surrounding living organisms. Who it is considered usual, when the doctor asks the patient: what his blood pressure is normal, what is its sensitivity to a particular drug, what is his tolerance of certain nutrients, climatic and geographical conditions of existence. World Health Organization (WHO) adopted the following definition: "Health - a state of complete physical, mental and social well-being of a person, and not merely the absence of disease or infirmity." Being part of the phenotype, health changes due to aging and the effects of the accumulation of life of the individual's potential disease-causing factors. There are women's, children's diseases with the features of their origin, course and outcomes. There was science - gerontology, the object of which is to study the features of the occurrence, course and outcome of disease in old age. The problem of individual reactivity of healthy and sick person currently occupies a central place in medicine. A plurality of individual differences in the structure, chemical composition, metabolism and energy, the functioning of organs and systems in healthy and sick person. Therefore, the conclusion of the doctor "healthy» (sanus) put in some degree is always conditional. Certain concessions in the estimates of the individual characteristics of healthy and sick person is to use a special expression of "practically healthy". This expression emphasizes that at some near point in time a person can be healthy and able to work, but it is not guaranteed on the capabilities of the disease when changing the conditions around him at home and at work. It is now well known that the existence of any living organism is possible only in the presence of mechanisms that support the non-equilibrium state of the cells, tissues and body as a whole with
6 their environment. This, for example, the work of many membrane "pump", is the strength ("reliability") structure of organs and tissues of the skeleton, muscles, ligaments, etc., And their resistance to various injuries. This is the work of various systems (nervous, immune, endocrine, etc.), Maintaining the integrity and soundness of the organism in the environment. Damage to these systems lead to violations of their functions to a disease, illness, and sometimes death. One can agree with the definition of "health" as a kind of "optimal" state of the body, bearing in mind primarily the adaptive significance of the health of the human or animal to ever-changing environmental conditions. It should also specify that person as being a social norm or health - is the existence of admitting more fully participate in different kinds of social and working life.
General nosology Nosology - teaching about the disease, including biological and medical bases of diseases, as well as issues of etiology, pathogenesis, classification and nomenclature. General nosology develops the structure and provisions of general teaching about disease.
Defining the essence of the disease "The disease - it is a complex overall reaction to the damaging effects of environmental factors; this is a new process of life, accompanied by structural, metabolic and functional changes as a destructive and adaptive nature in tissues and organs, leading to a decrease in the body's adaptability to ever-changing environmental conditions and to limit disability "AD Ado (2009). Modern views on the nature of the disease It can be argued that primary and basic processes in the development of each disease is the damage, destruction, disruption of structures and functions of the diseased organism. All reactive, defensive, compensatory, adaptive processes are always secondary, developing after the damage when exposed to disease-causing factors on the body. It should be emphasized that in the development of any disease adaptive and compensatory processes can be harmful to the patient and seriously affect its condition. As an example, the allocation of gastric mucosa and skin urea (sweat glands) in uremia, fever and other severe conditions. Hans Selye emphasized that overstrain the adaptive systems of the body when the disease is harmful and may worsen its course. Thus, the essence of the disease can not be reduced only to the device, though adaptive, compensatory processes involved in the life of a patient's body and are required for healthy living beings in all its forms. An example of a simplified interpretation of the nature of the disease in terms of molecular pathology can be called Pauling Lyaynus concept of "sick molecules." In fact, no patients molecules, and there are diseases in which the molecules appear unusual for a healthy body composition and properties. Broadly speaking, all diseases are molecular, but the patterns of molecular processes are mediated by the animals in the biological plan, and biological processes in humans - and socially. In humans, as social beings, the most important and essential element in maintaining the health and development of the disease is the mediation of biological (physiological) processes of social factors. A significant influence on these processes has a labor activity of man that distinguishes him from the animals. The crucial role of social factors in the development of pathological processes becomes apparent when studying the causes of action of any pathogens in the human body. Essentially, they act on the human body indirectly through the surrounding social processes. Indeed, it is well known the influence of social factors on the occurrence of epidemic processes (eg, hospital, water, war, famine epidemic). There are many professions, social mediating the possibility of occurrence of various diseases, which are a warning requires special protection measures and working conditions for workers. A severe form of social mediation of mass mortality and morbidity are men of war. Action on the human physical and chemical pathogenic factors (heat,
7 cold, electricity, poisonous substances, etc.), With a few exceptions (lightning stroke, poisoning, poisonous mushrooms, freeze motionless man in the cold, and the like), as mediated by social factors - clothing, housing, appliances, etc. at the same time a number of sources of ionizing radiation, electricity, etc., can cause severe damage in the body, it is created by human labor. Resulting damage of pathological processes mediated are also socially. It is important to emphasize that the disease - it is a new standard process by which though and saved functions inherent in a healthy body, but there are new changes. For example, in a healthy person the number of newly formed cells in the body are strictly equal to the number of dead (resulting ended life cycle) cells. In patients with tumors there is a clone of cells with high potential for reproduction, but at the same time preserved and properly functioning cellular system. At the level of the whole organism new quality - a reduction of adaptability and ability to work. Summarizing all the above, we can give the following definition of the disease: the disease - it is a complex overall reaction to the damaging effects of environmental factors, it is a new process of life, accompanied by structural, metabolic, destructive and adaptive nature of the functional changes in tissues and organs, leading to a decrease in adaptability organism to the ever-changing environmental conditions and disabilities.
Criteria disease There are subjective criteria of the disease - a patient's complaints (malaise, pain, various functional disorders, and others.), Which do not always accurately reflect the condition of the body. In some cases, people with increased suspiciousness and superficially, but is widely knowledgeable about specific symptoms of a disease and their causes, may misinform the doctor, telling him about his ailments and linking them with the specifics of the profession (eg, work with sources of radiation ) or a specific place of residence (for example, in areas in their opinion, environmental distress, and others.). Medical students, starting the study of clinical disciplines and are familiar with the symptoms of certain diseases, often "projecting" them over, checking written in the pages of textbooks with their own well-being ("third-year disease"). Decisive are the objective criteria for disease - are the results of patient studies involving laboratory and instrumental methods to identify those or other deviations from the norm and establish the characteristic symptoms (signs) of the disease. Disease are the most important criteria, as already indicated, reduction of adaptability and disability limitation. To identify the reduction of adaptive abilities of the body are carried out so-called functional test, when the body (organ, organ system) artificially placed in conditions in which he is forced to show an increased ability to function. As an example, a test with a load of sugar in diabetes, various functional loads to detect abnormalities on the ECG and others.
General principles of disease classification There are many, based on different principles of disease classification. Diseases are divided on the causes of their occurrence: hereditary, infectious, radiation sickness, injuries, etc. According to another principle of the disease are classified, based on the characteristics of their pathogenesis:. Metabolic diseases, allergic diseases, shock, etc. Very popular is the principle organ classification of diseases: heart disease, lung, kidney, liver, etc. An important place in the classification of diseases occupy the principles based on age and gender differences in the human body. There are disease of the newborn (neonatologist), childhood diseases (pediatrics), diseases of old age (geriatrics). Special sections of medicine are women's diseases (gynecology).
General etiology The term "etiology" (from the Greek aitia -. Reason, logos - teaching) was introduced by the ancient Greek materialist philosopher Democritus. In ancient times, the word signified the doctrine of diseases in general (Galen). In the modern understanding of the etiology of disease - knowledge,
8 the doctrine of causes and conditions of the particular, of the disease. General etiology - the doctrine of the causes and conditions of diseases and pathological processes as a branch of general nosology.
Causes disease Despite the fact that from ancient times to the present day the question of why people got sick, was one of the main medicine, unfortunately, and now the etiology remains, in the words of IP Pavlov, "the weakest department of medicine." Meanwhile, it is obvious that without revealing causes of the disease is impossible to determine the correct path for its prevention and treatment. Serious scientific development of the etiology of problems began only in the late XIX century. thanks to the rapid development of biology and medicine in general and microbiology in particular. The main impetus for this was the "cellular pathology," R. Virchow, settling material nature occurring in diseases and functional disorders prompted investigators to search for specific material causes of these disorders. A revolutionary breakthrough in microbiology was connected with the discovery of a number of microorganisms - causative agents of human infectious diseases (P. Ehrlich, R. Koch, L. Paster et al.). According to idealistic notions about the causes and nature of disease has been dealt a blow, entrenched materialistic principles of determinism. In the future, become identified more and more causes of disease. In this case a long time it was believed that the presence of the cause (pathogenic factors) is equivalent to the presence of the disease, while the body to play the role of passive object under the influence of this factor. This period in the development of the theory of the etiology of the period referred to as mechanical determinism. Soon, however, it became evident that not always the presence of the pathogenic factors leading to the emergence of the disease. It has been proven that an equally important role in this play the condition of the body (reactivity, gender, age, constitution, individual anatomical and physiological characteristics, heredity), various kinds of socially constructed (unsanitary living conditions, poor nutrition, poor working conditions, bad habits and etc.), and many other factors that either contribute to or, conversely, prevent the occurrence of disease. So there are two diametrically opposing views in the interpretation of the etiology of problems: monocausalism and conditionalism. Representatives monocausalism argued that defining value in the occurrence of the disease has only its basic (ie, one) reason (from monos - one, causa - the cause), and all the other factors do not play a significant role. Supporters conditionalism (from conditio - condition) believed that the disease is caused by a complex of conditions, they are all equal (equipotential) and select any one (main) cause of the disease is not possible. Conditionalism ancestor was a German physiologist and philosopher Max Verworn (1863-1921), who claimed that "the concept of cause is a mystical of concept" subject to expulsion from the exact sciences. Concept conditionalism to some extent adhered to the largest domestic pathologists VA Oppel, SS Bathrobe, NN Anichkov, IV Davydovsky and others. With today's point of view, both positions can not be regarded as correct: monocausalism, quite rightly highlighting the main cause of the disease, completely denies the role of the environment in which it occurs; conditionalism, on the contrary, denies the leading role of the primary (main) cause of the disease, completely equating it to the other conditions, thus making it impossible to study specific diseases factors and conducting a causal therapy. Modern understanding of causality in pathology are three main provisions: - All the phenomena in nature have a cause; no unreasonable phenomena; the reason is material, it exists outside and independent of us. - The reason interacts with the organism and changing it changes itself. - The reason for the process according to a new quality, ie, among the many factors that affect the body, it gives it a pathological process of a new quality. The disease is caused by a complex of factors unequal. It is necessary to highlight the main etiological factor (producing, specific) - is the factor, with the absence of which can not develop the disease under any circumstances. For example, lobar
9 pneumonia arises not only under the influence of human infection with pneumococcus. The disease also contributes to cold, fatigue, negative emotions, malnutrition and others. It is easy to understand, however, that without pneumococcal infection all of these reasons will not be able to cause lobar pneumonia. Therefore, the main causative agent of this disease should be considered as pneumococcus. However, sometimes it is difficult to identify the cause of the disease (some tumors, mental illness). It was believed, for example, that a stomach ulcer develops due to irregular and improper diet, in connection with the neurosis, functional disorders of the autonomic nervous system, endocrine disorders. These and many other observations gave rise to ideas about polyetiology disease. The position is wrong. It arose as a result of our lack of knowledge about the causes of certain diseases and their variants. Thus, recently it has been proven that the principal causative agent of the disease is peptic ulcer bacterium Helicobacter pylori. As mentioned, each disease has its own, peculiar only to her cause. With the accumulation of knowledge about the causes of all types and subtypes of disease will improve their prevention and treatment. Many diseases as ascertain their real reasons fall into a new sub-species, each of which has a separate cause. For example, earlier there was a disease of "bleeding" (hemorrhagic diathesis). With the establishment of the causes of some symptoms of the disease, identify new, completely independent form of the disease characterized by bleeding (scurvy, hemophilia, hemorrhagic purpura, etc.). Similarly, the split into separate diseases with their causes neuro-arthritic diathesis (gout, rheumatism, non-infectious arthritis, and others.). The reasons (the main etiological factors) disease are divided into external and internal. The external causes include mechanical, physical, chemical, biological and social factors to the internal - in violation of the genotype. The disease can also be caused by a deficit in the environment or in the body of the substances (factors) required to ensure the normal life (beriberi, starvation, immunodeficiency states, etc.). In the body the main etiological factor may be affected indirectly: - Through the nervous system - reflex, changing the functional state of the nervous system, as well as by the occurrence of a pathological condition or parabiotic dominant. Parabiosis with prolonged action of the pathogenic agent takes place in several stages: a) leveling - when a strong and a weak stimulus is the same reaction; b) The paradox - when a weak stimulus response higher than that of the strong; c) the brake - the lack of response to a stimulus; - Via humoral and endocrine system. Mediators of this action are products of decay of damaged tissue, inflammatory mediators, and various biologically active substances and hormones released into the blood. In other cases, the causative factor has a direct damaging effect, acting as a trigger, and then disappearing (mechanical injury, radiation); or it remains in the body and determine the pathogenesis of the disease on its individual stages or in its entirety, it is observed in infections, poisoning, parasitic infestations. It should be noted that the presence of the main etiological factor and its effect even on the body does not always lead to the emergence of the disease. This is facilitated by, or, on the contrary, prevents a whole range of conditions.
Terms of occurrence and development of diseases Factors that influence the emergence and development of the disease, called the conditions of the disease. Unlike the causal factor conditions are not required for the development of the disease. If there is a causal factor of the disease can develop without the participation of some of the conditions of its origin. For example, lobar pneumonia, pneumococcal virulence strong, and can develop without a cold, no power and deterioration al. Conditions. There are conditions that predispose to the disease or contribute to its development and prevent the occurrence of disease and its development. All of these can be internal and external. The internal or predisposing conditions include hereditary predisposition to the disease, a pathological constitution (diathesis), early childhood, adolescence and old age.
10 The external conditions conducive to the development of diseases that include eating disorders, fatigue, neurotic states, previously borne diseases, poor patient care. The internal conditions, hindering the development of diseases include hereditary, racial and constitutional factors, such as the species of human immunity to certain infectious diseases of animals. The man does not suffer from a plague of cats and dogs, cattle pneumonia and many other infectious diseases of animals. People with sickle cell disease do not get sick with malaria. The external conditions, preventing the development of disease, carry a good and balanced diet, proper organization of the working day regime, physical education, and in the event of illness - good patient care. Establishing the main (producing, specific) etiological factor, the selection conditions predisposing to the disease or contribute to its development, and conditions that prevent the emergence of the disease and its development, it is imperative for the development of effective disease prevention, reducing morbidity and recovery.
GENERAL pathogenesis The definition of "pathogenesis" General theory of pathogenesis (from the Greek pathos -. Suffering, genesis - the origin) - section of pathological physiology, studying general regularities of the origin, development, course and outcome of disease or mechanisms of disease development. It is based on pooled data study of certain types of diseases and groups (private pathology and clinical sciences), as well as on the results of experimental reproduction (modeling) of diseases or their individual traits in humans and animals. This sets the sequence of changes in the body for each disease, identify causal relationships between the different structural, metabolic and functional changes. In other words, so-called pathogenic factors of the disease - the changes in this body, which arise in response to the main etiological factor in the future (even disappearance of the disease agent), dictate the disease. Thus, if the study of etiology allows you to answer the question: "Why is there disease", the final result of the study of the pathogenesis has to be an answer to the question: "How is it developing?" Main (specific) etiological factor acts as a trigger of the disease. The pathogenesis of the disease begins with any primary damage (Virchow) or "destructive process" (Sechenov), "damage" (Pavlov) of the cells in a particular part of the body (a pathogenetic factor of the first order). In some cases, the initial damage can be rough, well distinguishable to the naked eye (injuries, burns, wounds, etc.). In other cases the damage unnoticeable without special methods of detection (damage at the molecular level). Between these extremes there are all sorts of transitions. The initial link of pathogenesis - development of mechanisms of damage every disease starts with the effects of the damaging environmental factor (the cause of the disease), which causes initial damage to the body portion. This leads to the development of subsequent damage mechanisms - pathogenetic factors. Changes occurred first, immediately after exposure to the causative agent, are pathogenetic factors of the first order. In the future, products of tissue damage become sources of new violations in the course of the disease, so there pathogenetic factors of the second, third, fourth ... order and formed the causal relationships between them. The cause - effect relationship pathogenetic factors, where each prior is like a "cause" of the following (the "investigation"). Defining a coherent chain of cause-and-effect relationship with the disease it is essential to carry out a rational symptomatic and pathogenetic therapy. By their nature, pathogenetic factors are divided into humoral (such mediators damaged as histamine, serotonin, proteolytic enzymes), physical and chemical changes (blood pH shift toward acidosis or alkalosis, decreased oncotic pressure, hyper hypoosmia), violation of the neuroendocrine regulation of functions organism (pathological reflexes, neuroses development, hormonal imbalances), and others.
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The main link and the "vicious circle" in the pathogenesis of diseases In the study of the mechanism of the disease it is extremely important to identify the basic, most important link in the chain occurring disorders - the change in the body (one of the pathogenic factors), which determines the development of the remaining stages of the pathological process. The main link of pathogenesis - a mechanism that eliminated with the help of therapeutic measures can stop the development of the following mechanisms of damage and lead to recovery of the sick person. For the rational pathogenetic therapy is necessary to assess the value of each of the pathogenic factors, among them how to identify major and minor changes. Pathogenetic therapy - a set of measures designed to interrupt the chain of cause-and-effect relationship between the different structural, metabolic and functional disorders that occur in the body due to the impact of the main etiological factor by eliminating the main component of the pathogenesis. Removing the main violation leads to recovery of the body. For example, stenosis of the left atrioventricular opening is the main link in the chain of many subsequent violations: enlargement of the left atrium, the blood stagnation in a small circle, dysfunction of the right ventricle, and then stagnation in the systemic circulation, oxygen starvation circulatory type, dyspnea, etc. The removal of this link. by mitral commissurotomy eliminate all such violations. Encountered during the development of the disease or organ dysfunction system itself often becomes a factor (cause) that supports this violation, in other words, the causal relationships are reversed. This provision in medicine called "vicious circle." The vicious circle in which the subsequent pathogenetic factor ("investigation") can amplify the previous pathogenetic factor ("cause"), and the previous follow-up may intensify again. For example, the sharp deterioration in the transport of oxygen in blood loss leads to heart failure, which further impairs the transport of oxygen. There is a "vicious circle". Under normal conditions, the regulation of any process based on the fact that the deviation of a controlled parameter is an incentive to return it to normal. In the pathology appeared deviation level of functioning organ or system can, on the contrary, to maintain and strengthen itself.
Local and general, specific and non-specific reactions in the pathogenesis In the complex chain of cause-and-effect relationships in the development of the disease was isolated, local and general changes. At the same time it should be stressed that it is absolutely local (LAN) processes in the whole organism does not happen. Practically any seemingly local pathology (boil, pulpit, felon, etc.) In the pathological process of the disease involves the entire body. Nevertheless, the role of local and general effects in the pathogenesis of very different. There are 4 variants of the relationship of local and general processes in the pathogenesis: 1. In response to the local damage to an organ or tissue as a result of the general reactions of the organism are mobilized tissue adaptive mechanisms aimed at the delimitation of lesion (eg, granulating shaft in inflammation, the barrier function of the lymph nodes). As a result, the basic parameters of homeostasis (body temperature, white blood cell count and leukocyte formula, erythrocyte sedimentation rate (ESR), metabolism) can not be changed. 2. The local process through the receptor apparatus and entry into the blood and lymph systems of biologically active substances cause a generalized reaction, and certain changes in the main parameters of homeostasis. In this case, includes adaptive reactions aimed at preventing the development of the common pathological changes in the body. 3. Generalization of local process in severe cases can lead to failure of adaptive and protective reactions, and ultimately - to the general intoxication, sepsis, or death. 4. Local pathological changes in organs and tissues may develop secondarily on the basis of primary generalized process (such as boil in a patient with diabetes, leykemidy in the skin in some types of leukemia, and others.).
12 With the development of almost any disease can distinguish specific and nonspecific mechanisms of its formation. For nonspecific mechanisms include typical pathological processes such as inflammation, disorder lymphocirculation, fever, thrombosis, et al., As well as the generation of reactive oxygen species increase membrane permeability and so forth. Specific mechanisms include activation of systems of cellular and humoral immunity, which provides specific protection in the fight against once ingested foreign object.
Protective and compensatory processes An important manifestation of each disease are reactive changes in the cells, organs and systems, which always arise again, in response to the damage caused by the pathogenic factors. These include inflammation, fever, swelling, etc. These reactive changes in the body are referred to as protective and compensatory processes, or "physiological measure" of protection (IP Pavlov), as a "pathological (or emergency) regulation function" (VV Pidvysotsky, NN Anichkov) "the healing powers of the body" (II Mechnikov). During the development of the disease processes of damage and recovery are in close interaction, and as pointed out, IP Pavlov, it is often difficult to separate from one another. Compensatory devices - an important part of the adaptive response of the body to injury. They can be expressed in the development of both functional and structural changes in some way liquidating disorders of organs and systems caused by damage. Compensation thus becomes one of the main factors of clinical recovery. In addition to the compensatory process, an important role is played in the recovery and other adaptive reactions of the body of the patient to ensure the removal of the causative agent (antibody production, phagocytosis, protective inhibition). Thus, compensatory process is not to be confused with the whole complex of protective and adaptive reactions on the part of the body. Compensatory processes can evolve and take place at various levels, from the molecular and ending with the whole organism sick person. At the beginning of the disease compensatory processes develop at the molecular and cellular levels. If the action of pathogenic causes of mild and short-lived, and the disease can not develop. This happens in cases falling not too virulent germs, poisons in small doses at low doses of ionizing radiation, weak trauma, etc. Significant damage caused stronger responses on the part of regulators and their systems. Initial responses to injury are to mobilize the relevant functional reserves, providing adaptation, and can be implemented on intraorganic, intra and intersystem level as follows: - Reserve stocks include diseased organ (it is known that only 20-25% of the lung surface respiratory used in healthy organism, 20% of the capacity of the heart muscle, kidney glomerular 20-25% vehicle, 12-15% of the liver parenchymal cells, etc.). Under load, this percentage increases that can be used to assess the state of a functional organ samples. For example, the destruction of the kidney nephrons occurs intraorganic compensation due to the fact that the surviving nephrons increase their function and hypertrophy; - Developing vicarious hyperactivity. This type of compensation is carried out in case of damage of any of the paired organs, with the possible full implementation of the remaining body of the function with the loss of one. Thus, after the removal of or turning off of the work light (or a single kidney) arises compensatory hyperfunction of the remaining light (or other kidney). Mobilization of all the functional reserves of a single working body at first is imperfect, but as a result of the subsequent increase in the mass of its cell body again regains its activity almost to normal; - Increases the intensity of the organs and systems, similar in function to a damaged organ or tissue, which in some degree disturbed homeostasis restores and extends the life of the organism. An example of such inter-system of compensation - allocation of nitrogenous wastes through the sweat glands, the mucous membrane of the digestive tract and respiratory tract, strengthen the liver detoxification function in kidney damage. When you remove the stomach implemented internal system compensation, which provides increased secretory function of the lower parts of the digestive system.
13 It is important to emphasize that only the appearance of functional compensation does not provide a sustainable adaptation to the effects of the damaging agent. If hyperfunction of any organ or system enough to eliminate the defect, then it may be a compensatory process and limit. However, if homeostasis violations persist, the compensatory reactions continue to evolve. Long term compensatory hyperfunction organ systems entails the activation of the synthesis of nucleic acids and proteins in the cells of these organs and results in the formation of corresponding structural changes. There are the following compensation structure: 1. Hypertrophy - an increase in body weight by increasing the amount of its constituent functional units. An example is the hypertrophy of the heart, skeletal muscle, kidney etc. 2. Hyperplasia - increase in body by increasing the number of its functional units. They are prone to hyperplasia lymphoid tissue, the tissue of the mucous membranes. 3. Regeneration - the recovery process of organ or tissue after injury (Can be physiological and pathological, see Section 13.2.2), is carried out by: a) restitution, ie, filling defect by dividing parenchymal cells of damaged tissue; b) substitution when healing damage is due to the division of the connective tissue cells. 4. Compensatory distortion - for example, changing the location of the chest with a pronounced scoliosis of the thoracic spine, or kyphosis, as well as the expansion of the esophagus above the narrowing section with achalasia. 5. Development of collaterals in violation of blood flow in the major blood vessels that feed the body. In the process of compensating structural changes occur not only in the cells of the executive body, which accounts for increased load, but also at all levels of the compensation system. This is the basis of the transition from emergency to long-term adaptation.
Pathological reactions, pathological process, pathological condition Pathological response - short-term, an unusual reaction to any impact. For example, a transient increase in blood pressure under the influence of negative emotions, allergies, inadequate psycho-emotional and behavioral reactions, abnormal reflexes (reflexes Rossolimo, Babinski et al.). The pathological process - a combination of (complex) pathological and protective-adaptive reactions in the affected tissues, organs or body, manifested in the form of morphological, metabolic and functional disorders. Formed and fixed in the process of evolution permanent combination or combinations of various pathological processes and pathological reactions of individual cells and tissues are called typical pathological processes. These include inflammation, fever, hypoxia, edema, and other tumor growth. Pathologic process underlies the disease, but it is not.
Differences between the pathological process of the disease: 1. The disease is always one main reason (producing a specific etiological factor), the disease process is always polyetiological. For example, inflammation (disease process) may be caused by the action of a variety of mechanical, chemical, physical and biological factors, and malaria can not occur without the action of Plasmodium falciparum. 2. One and the same pathological process might result in different patterns of disease, depending on the location, in other words, a place of localization of the pathological process determines clinic disease (pneumonia - pneumonia, inflammation of the meninges - meningitis, an inflammation of the heart muscle - myocarditis, etc.). 3. The disease usually - a combination of several pathological processes. For example, when there is a lobar pneumonia combination (in relation) of pathological processes such as inflammation, fever, hypoxia, acidosis, and others. 4. The pathological process is not accompanied by a decrease in the body's adaptability and ability to work limitation (warts, lipoma, atheroma, etc.).
14 Pathological state - slowly (sluggish) current pathological process. It may be as a result of past illnesses (eg, narrowing of the esophagus scar after burn injury, false joints, condition after kidney resection, amputation, etc.) or as a result of violations of fetal development (clubfoot, flat feet, a defect of the upper lip and palate and etc.). It's kind of ended up the process, which resulted in persistently changed body structure having atypical replacement in certain tissues or parts of the body. In some cases, a pathological condition may go again in the pathological process (illness). For example, pigmented skin (birthmark) when exposed to a number of mechanical, chemical and physical (radiation) factors can be transformed into a malignant tumor melanosarkoma.
Forms and stages of disease development Each disease has progressed for some, more or less, time. Some diseases occur very quickly, others slowly. In terms of the rate of disease development are acute - to 4 days, sharp - about 5-14 days, subacute - 15-40 days, and chronic, lasting months or years. The division is somewhat arbitrary, but the term "subacute", "acute" and "chronic" disease are widely used. The development of the disease can be distinguished 4 stages: 1. Start the disease - latent (incubation) period. It lasts from the moment of impact on the body disease agent until the first signs of the disease. During this period included numerous protective reaction aimed at removing the causes of diseases and compensation for damages incurred 2. Prodromal period during which the first signs of the disease (first non-specific) followed by deployment of clinical manifestations characteristic of the disease. 3. Stage demonstrations of specific signs of the disease (actually a disease). 4. The outcome of the disease. Onset or "prediseases" expresses the process of the primary etiological factors impact on the body and its protective reactions. Protective reactions can stop in many cases, the occurrence of disorders and prevent the development of clinical signs of disease. The period from infection to onset of the disease to infectious diseases is called the incubation. . For radiation sickness, defeat chemical warfare agents and other is called the latent period for cancer - the state of pre-disease ("precancer", etc.). The initial period for different types of the disease may be very short (for example, mechanical trauma, acute) or very long (metabolic diseases, tumors, certain infections). However, for the majority of currently known diseases the time of onset and duration of pre- disease is difficult to determine. It can be changed individually at the same disease (e.g., hypertension, myocardial infarction), with some viral (rabies et al.) Diseases, varying widely. Stage the actual disease is characterized by the most prominent general and local manifestations, typical for each specific disease. Their study - the task of clinical disciplines.
Disease outcome There are the following outcomes of the disease: 1) complete or incomplete recovery; 2) the transition to a chronic form; 3) death. Recovery Recovery - the restoration of disturbed functions of the patient's body, its adaptation to the environment and livelihood (for a person) a return to work. In this sense, healing is called rehabilitation (from the Latin re -. Again and abilitas - suitability). This refers to the return of the recovered person to the same employment and vocational training in connection with the change of state (new quality) health. When a full recovery in the body does not remain traces of those disorders that have been in the disease. Not by chance before full recovery called «restitutio ad integrum» (restoration to the whole, intact). Incomplete recovery is stored in various degrees of dysfunction of individual organs
15 and their regulation. One of the expressions of incomplete recovery is a recurrence (return) of the disease, as well as its transition into a chronic condition.
Mechanisms of recovery. There are 3 main ways sanogenesis: 1. Urgent (unstable, "emergency"), protective and compensatory reactions that occur in the first seconds and minutes after exposure and which are mostly defensive reflexes by which the body is freed from harmful substances and removes them (vomiting, coughing, sneezing, etc. .d.). This type of reactions should also include the release of adrenaline and glucocorticoid hormones of the adrenal cortex during stress reaction, and the reaction aimed at maintaining the arterial blood pressure, blood sugar and other so-called hard constants. 2. Relatively stable protective and compensatory mechanisms (adaptation phase by H. Selye) operate throughout the illness. These include: - inclusion of reserve capacity or replacement of damaged strength and healthy bodies; - the inclusion of numerous devices regulatory systems, such as switching to a higher level of thermoregulation, increasing the number of red blood cells, etc .; - processes neutralize toxins (poisons the blood binding proteins neutralize them by oxidation, reduction, alkylation, methylation and others.); - response from the active system of the connective tissue (AA Bogomolets), which plays a very important role in wound healing mechanisms, inflammation, immune and allergic reactions. 3. Resistant protective and compensatory reactions: immunity, compensatory hypertrophy, reparative regeneration and other structural compensation are stored for many months and years recovering from illness.
Pathophysiology terminal states The life of any organism is inconceivable without its opposite - death. Consequently, dying as a transition from a state of life in the state of death in nature is a natural process where the body's vital functions, first broken and then stops as a result of the inevitable aging. Death comes as a result of the natural aging of tissues and cells, called natural, or physiological. Unfortunately, natural death, due to aging, rare, because in the course of life of the organism to it are a variety of damaging factors that determine the onset of premature death. Death occurs as a result of exposure to pathogenic factors, called premature or pathological. In the course of evolution nature has developed a system of protective (compensatory) reaction, enabling the body to fight for the preservation of life, allowing to divide the process of dying to a number of successive steps, called a terminal state. Terminal state - is reversible fading functions of the body prior to biological death, when the complex of protective and compensatory mechanisms are insufficient to eliminate the consequences of the action of pathogenic factors on the body. The main stages of dying (terminal state) are: - preagonia (preagonic state); - terminal pause; - agonia; - Clinical death; - biological death. The first four terminal states are reversible stages of dying, of which the body by providing appropriate assistance can be derived. Preagonia (preagonic state) is characterized by the development of inhibition in the higher parts of the central nervous system, confusion, decreased blood pressure, lack of pulse in the peripheral arteries, the sharp increase of breath, pallor or cyanosis of the skin. Gradually progressing depression of consciousness, the electrical activity of the brain and reflex activity. The duration of this period is from tens of minutes to several hours. Preagonic state ends terminal pause, characterized by cessation of breathing and a sharp slowing of cardiac activity until time of asystole. Sleep apnea is temporary and may last from a few
16 seconds to 3-4 minutes. It is believed that the increasing cerebral hypoxia possible sharp increase in the activity of the vagus nerve, which can cause the development of sleep apnea. Sometimes pause terminal may be omitted for example in case of shock. Clearly expressed the terminal pauses dying from blood loss and asphyxia. After a pause, the terminal comes agonia. Agonia (from the Greek ugonia - relax) - terminal condition prior to clinical death and is characterized by a profound violation of the functions of the higher parts of the brain, particularly the cerebral cortex of the brain, with simultaneous excitation of the medulla oblongata. Consciousness is not (sometimes briefly clears), disappear eye reflexes and reaction to external stimuli. There is a relaxation of the sphincter, involuntary release of feces and urine. The main symptom is the appearance after the agony of terminal pause first independent breath. Breathing initially weak, then amplified in depth and reaching a maximum, gradually weakened again and stops at all. The breath auxiliary muscles involved - the muscles of the neck and face, ie, It appears "gasping" - breathing (from the English gasping -. convulsive, spasmodic). "Gasping" - breathing - a pathological breathing, characterized by rare, short and deep breathing jerky movements. Recent agonal breaths resemble the act of swallowing. Agonal breathing inefficiently - alveolar ventilation when it does not exceed 20% of the due importance. On the part of the cardiac activity after bradycardia (sometimes temporary asystole) and a significant reduction in blood pressure observed a slight increase in its (30-40 mm Hg) as a result of renewed and increased heart rate. However, these symptoms are often short-lived and quickly extinguished. In some cases, these "flash" strengthening of life can be repeated many times, and during the agony - delayed for a long time (several hours). In cases where there is no terminal pause, rhythmic breathing preagonic period gradually transformed into agonal. The emergence of agonistic breathing - evidence of severe cerebral hypoxia and lack of inhibitory effect of the cortex on the subcortical centers, intermediate and stem parts of the brain that leads to temporary activation of the vital functions. During the agony abruptly changed metabolism, catabolic processes prevail over synthesis, decreases the amount of glycogen, a sharp increase in glycolysis and increased lactic acid content in tissues and organs, greatly enhanced the decay of high-energy phosphates and elevated levels of inorganic phosphate. From the senses before just fading smell, then taste and sight. Reduced body temperature (hypothermia). The agony of the dying as a reaction of the body is compensatory in nature and aimed at maintaining life, but how each compensatory reaction, it is limited in time due to the depletion of functional metabolic reserves. In the final stages of agony develops paresis of vessels, the blood pressure is reduced to almost zero, heart sounds muffled or tapped. Determined only carotid pulse. Characteristic view of the patient: "Hippocratic face" - sunken eyes and cheeks, pointed nose, gray and earthy complexion, corneal opacity, pupil dilation. Then the agony goes into clinical death. Clinical death (mors clinicalis) occurs after the cessation of cardiac activity and respiration, and continues until the onset of irreversible changes in the higher parts of the central nervous system. During clinical death outward signs of life (consciousness, reflexes, respiration, heart rate) are missing, but the body as a whole has not died, in its tissues ongoing metabolic processes, so you can recover under certain influences as the initial level and orientation of metabolic processes, and therefore - to restore all body functions. The duration of clinical death is determined by the time it is going through the cortex at the termination of blood circulation and respiration. Moderate destruction of neurons, synapses begins from the moment of clinical death, but after 5-6 minutes of clinical death of damage are still reversible. This is due to the high plasticity of the CNS - function dead take on other cells that retain viability. Under normal conditions, the duration of clinical death in humans does not exceed 3.4 m, maximum - 5.6 min. In animals, it sometimes reaches up to 10-12 minutes. The duration of clinical death in each case depends on the duration of dying, age, ambient temperature, specific features of an organism, the degree of excitation processes activity during dying. On the duration of clinical
17 death affect resuscitation techniques. The use of heart-lung machine allows the body to revive and restore the function of the central nervous system, and after 20 minutes of clinical death. In the process of dying and death experience revealed the following changes in the body: 1. Stop breathing, so that stops blood oxygenation, develop hypoxemia and hypercapnia. 2. Asystole or fibrillation of the heart. 3. Violation of metabolism, acid-base status, the accumulation in the tissues and blood of unoxidized products and the development of carbon dioxide gas and non-gas acidosis. 4. Termination of the central nervous system (originally arises excitation stage, then depression of consciousness and the development of deep coma, reflexes disappear and the bioelectric activity of the brain). 5. Fading functions of all internal organs. Biological death - irreversible cessation of life of the organism, which is the inevitable final stage of his individual existence. By the absolute grounds of biological death include: 1. Rigor cooling - lowering the temperature of the corpse to the level of the ambient temperature. 2. The emergence of cadaver skin patches. They are formed as a result of post-mortem blood drip in the lower divisions, overflow and expansion of vessels in the skin and soaking with blood vessels surrounding tissue. 3. Rigor mortis - the process of post-mortem seal skeletal muscle and smooth muscles of internal organs. 4. Rigor decomposition - the process of destruction of organs and tissues of a corpse by its own proteolytic enzymes and enzymes produced by microorganisms. The pathophysiological bases of resuscitation. The desire to return life to the dying, to resurrect, revive the deceased person is as old as humanity itself. In 1902 Tomsk University Professor AA Kulyabko revived and forced to work isolated heart of a child, who died on the eve of pneumonia. In 1908, AA Kulyabko revived isolated dog's head through the introduction to the brain saline solutions. But the science of resuscitation (resuscitation) appeared only in the 30-40-ies of XX century, when they were offered effective methods of recovery. The set of measures to revive the developed VA Negovsky and his colleagues, provides a complete and long-lasting restoration of vital functions of the body, when the benefits begin resuscitation provided no later than 4-5 minutes from the moment of clinical death. This complex includes mechanical ventilation in combination with intra-arterial injection with epinephrine blood toward the heart, cardiac massage and optionally its electrical defibrillation. Initially the complex was tested on dogs, and later used in the revitalization of soldiers during World War II. Behind these developments Academician VA Negovsky was twice awarded the USSR State Prize (1952 and 1970).
Essence and resuscitation equipment is as follows: 1. The victim is placed on a hard surface, unbutton clothes (cut) and remove. 2. In the area of the lower third of the sternum produce rhythmic tap with two juxtaposed hands to the rhythm of 40 to 60 minutes. These should be pressed jerky - squeezing the chest is not so much due to arm strength, but rather because of the severity of the body. In the closed chest massage should flatten by 5-7 cm; the duration of the push - to 0.7-0.8. Each pressure on the sternum of the heart contraction occurs between the sternum and the spine, resulting in expulsion of blood into the aorta and pulmonary artery. Thus, it is possible to maintain long-term recirculation of blood, enough to preserve the viability of the body, if it is possible to maintain blood pressure at the level of not less than 70 mm Hg If chest compressions ineffective hearts, then move to direct that requires opening the chest, so it carried out medical specialists in well-equipped operating rooms, where there are ventilators, defibrillators, etc. 3. An essential component of resuscitation is intraarterial (toward the heart) injection of blood glucose, and epinephrine, hydrogen peroxide and vitamins. This provides angioreceptor reflex irritation and helps restore the heart rate. Furthermore, recovering coronary blood flow and nutrients
18 to the myocardium, also promotes resumption of cardiac contractility. Once the heart is running, intra-arterial blood pumping stops. If necessary fill blood volume in order to eliminate its blood injected deficit. 4. In the case of atrial defibrillation is performed by passing an electric for 0.01 with electric voltage from 2 to 7 thousand. (Essentially a capacitor discharge, which is between the patient plates) that synchronizes the heart rate, eliminating fibrillation. 5. All these activities should be combined with the artificial lung ventilation (ALV) "mouth to mouth" or "mouth-to-nose", which gives the oxygen supply, and stretching reflex lung tissue contributes to the restoration activity of the respiratory center. Performance criteria resuscitation: 1. The appearance of the pulse in the carotid and radial arteries. 2. Reduction of the degree of cyanosis. 3. Narrowing of dilated pupils before. 4. Increased blood pressure 60-70 mm Hg How long should be the resuscitation? The literature describes cases of successful revitalization of the body after 3-8 hours of continuous cardiac massage and artificial respiration. Extras can be recommended suppressants hypermetabolism caused hypercatecholaminemia; antioxidants to prevent the degradation products of lipid peroxidation (LPO) membranes; reduction in intra- and extracellular brain edema and reducing intracranial pressure. It is necessary to prevent and suppress seizure activity. P. Safar (USA) recommends the use of large doses of barbiturates (90-120 mg / kg) to reduce the amount of brain damage and the degree of neurological deficit, however, expressed hepatotoxic effects of these drugs greatly limits their application in the terminal states.
Postresuscitation disorder. In postresuscitative identified: - violation of the system and peripheral hemodynamics, hemostasis disorders, disorders of all types of rough metabolism; - Violation of gas exchange function of the respiratory system; - failure of the liver and kidneys; - violation of the functions of the brain (encephalopathy). This naturally occurring complex set of changes, often prone to progression, growing in all systems, organs and tissues, called postresuscitation disease.
Pathogenesis postresuscitative disease. Pathogenesis postresuscitative disease. Leading pathogenetic factors postresuscitational sickness (hypoxia, giperkateholaminemii, reoxygenation, acidosis, LPO activation, the deficit of circulating blood volume, impaired microcirculation, etc.) decided to analyze depending on the timing postresuscitative period. There are several periods during postresuscitative disease: I period - postresuscitative earlier (in the experiment, he takes the first 6-8 hours; in the clinic - 10-12 h), is characterized by the rapid dynamics of the restoration of the vital organs and systems, combined with the instability of many bodily functions; restored heart function, blood flow resumes, there are breathing, signs of brain electrical activity on an electroencephalogram. Thus, cardiac output first increases and then decreases, hypovolemia develops, increasing the total peripheral vascular resistance, blood pressure instability observed. Characterized by a violation of regional circulation and microcirculation blood flow in the form of bypass, increasing the viscosity of the blood, the centralization of blood circulation in the peripheral tissue hypoperfusion background. Hypermetabolism are growing and the consumption of oxygen to vital organs. Despite the growing volume blood flow, oxygen debt organism persists though blood oxygenation in the lungs during this period has not suffered. Due to the ongoing hypoxia accumulate oxidized products of metabolism, which enhances metabolic acidosis, which then goes into respiratory alkalosis; identified hyperenzymemia (sign of generalized membranodestructive caused by excessive activation of free radical processes),
19 hormone imbalance, hypercatecholaminemia, endotoxemia, expressed hemostatic disorders (bleeding, microtrombi), violation of water and electrolyte balance. Death can occur from repeated circulatory disorders, heart failure, coagulopathic bleeding, pulmonary edema and brain. With proper treatment and the absence of irreversible disorders in organs and tissues of the first period into the second. II period - the period of time and the relative stabilization of the main functions of the body and improve the overall condition of the patient. It lasts for a few hours. The patient regains consciousness, his condition improved, regardless of the forecast. There a temporary stabilization of the main functions, as evidenced by a constant level of blood pressure, increased cardiac output, increased kidney function. There has been improvement in regional blood circulation, microcirculation disorders but not completely eliminated. Saved metabolic disorders (hypokalemia, slow fibrinolysis, increased lipolysis, the tendency to hypercoagulability), blood volume deficit and widespread violations of the acid-base status. In any case (favorable or unfavorable) trends postresuscitative disease II period passes in III. III period - stage re-deterioration. It begins with the end of the first - the beginning of the second day. For circulatory and anemic hypoxia joins pulmonary (respiratory), which is largely due to the increase of microtrombosis pulmonary vascular disorders due to blood aggregation and leaching mikrotrombosis and fat emboli from the systemic circulation, as well as 3-4-fold increase of shunting in the pulmonary circulation, which leads to a sharp decrease in the oxygen partial pressure in arterial blood. Clinically it is manifested by shortness of breath. There persistent and progressive arterial hypoxemia. There are radiological signs of "shock" lung, pulmonary hypertension is growing due to increased formation of thromboxane. Observed re-development of hypovolemia, the deterioration of peripheral circulation, oliguria, metabolic acidosis, an increase of catabolic processes, the development of a pronounced slowdown of fibrinolysis and hypercoagulability. Critical severity reach lesions of parenchymal organs. However, in many patients the reversibility of these changes still possible (with a favorable course of the recovery period). When unfavorable course postresuscitative period in this stage are formed by a variety of complications (shock kidney, shock lung), which are the main cause of mortality in the period after the data recovery. IV period - completion stage (second or third day after the revival). During this period, possibly as a further improvement to the recovery and deepening functional metabolic disorders and structural abnormalities that occur in the III period. Appear pyoseptic complications of immunosuppression in the background, re-grow human peripheral blood circulation, decreases blood oxygen capacity by deepening anemia, potassium increases the excretion of urine (due to hypoxic cell damage). Usually develops complete failure of spontaneous breathing occurs or deepening coma. In the case of a favorable course of the recovery period the effects of suffering a terminal state can be observed for a long time (autoimmune damage to the brain, encephalopathy, etc.), so the patient must be in a year or more to be under a doctor's supervision. Reanimatologists should remember that the outcome of resuscitation is significantly affected by the level of perfusion during resuscitation. Excessively high blood pressure leads to enhanced extravasation of fluid extravasation, which threatens the possibility of the development of brain edema and lung. Too low blood pressure (less than 100 mm Hg), the dynamics of delays recovery and normalization of metabolic processes. It is a long time to maintain ventilation, as in the early period of revitalizing a lot of energy is spent on the work of the respiratory muscles. After the restoration of circulation recommended pH- normalizing treatment (sodium bicarbonate) used anticoagulants and drugs that improve the rheological properties of blood, which is confirmed by experimental studies. To minimize brain damage by hypoxia, ischemia reoxygenation and acidosis used craniocelebral hypothermia (lowering the temperature to 30-32 ° C in the external auditory canal), which stopped after the appearance of signs of stable positive dynamics of neurologic and electroencephalographic (but not less than 2-3 days).
20 During resuscitation and intensive therapy complex in postresuscitative used glucocorticoids, antihypoxants, antioxidants, β-blockers receptor antagonists of calcium ions, means detoxification (plasmapheresis, exchange transfusion, etc.). The primary objective of the means (such as intensive care and benefits) is to protect the neurons of the cerebral cortex from the action of pathogenic factors that could deepen postresuscitation damage. Postresuscitation brain damage depends on: - hypoxia acting at dying and after resuscitation; - Group postresuscitation intracerebral pathogenic factors (unreduced flow phenomenon); - Group postresuscitation extracerebral factors associated with primary hypoxic changes in the internal organs (the impact of product activation free radical processes, endotoxins, etc.). It must be emphasized that the treatment postresuscitative disease should be carried out in accordance with its staging through a set of specific therapeutic interventions. Prevention, active and timely treatment of the disease make it possible to save the lives of many patients, even suffered a near-death.
21 Sanogenesis. Sanogenesis term derived from the Latin sanitas (health) and the Greek genesis (origin) and meaning literally "the origin of health", one of the youngest in the pathophysiological science. The doctrine of sanogenesis dates back to 1966, when the definition of this concept was formulated by SM Pavlenko. Sanogenesis - a dynamic complex of protective and adaptive mechanisms of physiological and pathophysiological nature, developing as a result of effects on the body of an extreme irritant, operating throughout the pathological process (from pre-disease until recovery) and aimed at restoring the disturbed self-regulation body. Sanogenesis - a dynamic complex mechanisms. In this part of the definition emphasizes that sanogenetic mechanisms are not something constant. They change throughout the disease process. If a malicious agent has not yet penetrated into the interior of the body Wednesday, sanogenesis mechanisms will prevent its penetration, if the agent has already penetrated into the body, they will seek to bring it or break if the pathogenic stimulus has already caused in the body any "floor" that sanogenetic mechanisms are directed to the compensation or restoration of the lost function. In other words sanogenesis - is constantly changing (more dynamic) set of protective and adaptive mechanisms. Sanogenesis - a complex physiological and pathophysiological mechanisms of nature. It highlights the fact that in sanogenesis involves not only the mechanisms that have emerged in the course of the disease, but the physiological reactions that occur in the intact organism, and only under the influence of pathogenic factors come into play sanogenetic. Sanogenesis develops when exposed to the body of an extreme irritant, ie only when there is (or may be) disease. The body normally has a number of mechanisms that are specific function (providing excretion, selection, etc.). In a normal body, they do not perform any safety functions and only when exposed to the body of an extreme irritant transformed into sanogenetic. Sanogenesis - a complex mechanism of action throughout the pathological process (from pre- disease until recovery). A characteristic feature of sanogenetic forces is that their mechanisms begin to function at a time when the body acted extraordinary stimulus and finish its function only when the body has recovered. In other words sanogenesis and pathogenesis - two parallel proceeding, closely related, but the opposite process for its biological orientation. Sanogenesis aimed at restoring the disturbed self-regulation body. Self-regulation of the body - is its ability to rebuild their functions with a view to adapt to changing environmental conditions. In the pathology of this ability of the organism to an adequate self-regulation is violated, that is, the body can not fully adapt to environmental changes. The whole complex sanogenetic reactions and is aimed at the restoration of the self-regulation of disturbed relationships.
Classification sanogenetic mechanisms. Firstly, mechanisms sanogenetic divided into primary and secondary. The difference between these two groups from each other is as follows. The primary (physiological) mechanisms sanogenesis exist in a healthy body, and only when exposed to the body of an extreme irritant into play sanogenetic. Secondary (pathophysiological) sanogenetic mechanisms occur in the body in the development of a pathology that is generated based on the problems in the body "floor." Primary sanogenetic mechanisms. Adaptation mechanisms. The term "adaptation" means adaptation to the changing conditions of the external and internal environment. In the normal body functions are a number of mechanisms. For example palpitations on exertion, sweating when the ambient temperature increases, increased urination when receiving large quantities of liquid. However, these arrangements can not be called sanogenetic as they carry out adaptation within the physiological regulation of functions. Adaptation is sanogenetic mechanisms are the only ones that adapt the body to the action of an extreme irritant, preventing the development of disease (for example, a sharp spasm of peripheral blood vessels when exposed to body low temperatures,
22 the opening of the blood depot and release into the bloodstream an additional amount of red blood cells in insufficient oxygen in the inspired air etc.). Thus, the primary sanogenetic adaptation mechanisms - are mechanisms to adapt the body to function normally when exposed to extreme irritant. If coping mechanisms are effective, the disease does not occur. Protective mechanisms. The second group of primary sanogenetic mechanisms designed to prevent the organism or pathogen to quickly put out of his body, to prevent development of pathological process. For example, in each organism are normal antibody; in saliva and tears has bactericidal factor - lysozyme; trachea and bronchi mucous membranes cells are provided with fibers that do not allow light to get into the fine alien bodies. These mechanisms prevent the penetration into the body of the pathogenic agent. If it has penetrated into the body (or formed in it), the protective organisms may destroy or remove it from the body before the agent will have time to initiate the disease process. For example, in the liver are destroyed some toxic substances, or caught in the body, or formed in it. By the protective mechanisms excretory nature include, for example, cough, vomiting, ie complex reflex acts aimed at the removal of the respiratory tract (cough) or stomach (vomiting), foreign bodies or harmful to the body. Thus, the primary defense mechanisms sanogenetic - are mechanisms or inhibit penetration into the body of a pathogenic agent or destroy it, or deducing it from the body until it causes the development of the pathological process. Compensatory mechanisms, if the primary adaptation and protective mechanisms are not able to prevent the development of pathological process, however, the disease process can not occur if the initial turn on the compensatory mechanisms that can adequately replace the impaired function. For example, the weakening of the contractile function of its ear auricle may be an additional pump, thereby compensating for a drop of atrial contractility. Thus, the primary sanogenetic compensatory mechanisms - these are processes, complementary function, impaired pathogenic agent, and not giving manifest the pathological process. It turns out that is successfully functioning primary sanogenetic mechanisms, there is no disease, but can only be a state of pre-disease which either disappears or goes into a state of disease in the event that the primary sanogenetic mechanisms overstrained, exhausted and can not be to the extent necessary to fulfill its function. Secondary mechanisms sanogenetic If there was a pathological process, then begin to function sanogenetic secondary mechanisms, developing on the basis formed in the body, "Paul." These mechanisms may be protective, compensatory and terminal. Adaptation mechanisms in this group are not available, because if I have a pathological process, adapting the body is no longer held. Safety mechanisms prevent the progression of the pathological process: either neutralize or destroy a pathogenic agent, or impede its spread throughout the body, or remove it from the body. For example, antibodies produced by the microbe caught in the body can be destroyed or neutralized; inflammatory process, creating around taken root pathogen powerful barrier, including edema, leukocyte shaft, prevents the dissemination of the agent; diarrhea resulting from intestinal mucosal inflammation removed malicious factor from the digestive tract. Thus, the secondary protective sanogenetic mechanisms - is the localization mechanisms, destruction or removal from the body, penetrated into it pathogenic agent. Compensatory mechanisms. If the pathogen entered the body, it usually causes damage to organs and tissues and thus leads to a loss of a particular function that can cause serious disorders of vital activity. But this often does not happen, as the secondary compensatory mechanisms include processes, replacing impaired function. A classic example of such mechanisms is a compensatory hypertrophy of the heart muscle, which occurs when a significant and prolonged increase of the incident heart hemodynamic load (for example, valvular heart disease). If the increased load on the heart is the myocardium to cope with it in cardiomyocytes is to increase energy production. This leads to additional energy supply not only the contractile act and protein synthesis in cardiac cells. As a result, increased myocardial mass, and load per unit of its weight returns to normal.
23 Secondary sanogenetic compensatory mechanisms - mechanisms to fill this disturbed as a result of pathological process functions. Terminal (extreme) arrangements. This group of mechanisms included in the critical (extreme) situations for the body and is the last reserve, allowing at least delay his death. Since these mechanisms are activated in the closing periods of the disease, they tend themselves associated with severe disease. There is a seemingly paradoxical situation - a severe pathological changes are beginning to play a protective role for the body. For example, when developing a massive myocardial infarction, heart failure, protects the heart muscle: the weakening of the contractile function of the heart can prevent his break on the background myomalacia (melting necrotic) by 5-9 hours from the time of heart attack. The result of increased activity of the terminal bulbar centers is occurring in a period of agony clarification of consciousness in the dying. Although in this case, death still occurs, however - this is an example of action of the terminal sanogenetic mechanism associated with increased activity of regulatory centers in a critical situation. Thus, the terminal (extreme) secondary sanogenetic mechanisms come into play at the final stage of the organism protection from exposure to pathogenic agents and develop most commonly as a result of coming in critical conditions of gross violations of the structure and function of organs and tissues. As mentioned above, the sano - and pathogenetic mechanisms developed in the dynamics of the disease process in parallel and often pathogenic changes in the body begin to play a role, and vice versa sanogenetic inclusion of some sanogenetic mechanisms may lead to the weighting and the progression of the pathological process. Sanogenetic role of pathogenetic mechanisms. In medicine, there are many examples where the pathological process can bring the body to use. For example, such a serious disease like sickle-cell anemia, resulting from a hereditary defect in hemoglobin synthesis, plays a role in malaria sanogenetic. A patient with sickle cell anemia, along with normal hemoglobin A, A2 and F hemoglobin has pathological S, the reduced form of which has a much lower solubility than that of normal hemoglobin. As a result, in the venous part of the capillary bed, where the oxygen partial pressure is sharply reduced hemoglobin enters the semi-crystalline state and takes the form of so-called tactoids having the form of a crescent. This leads to distortion of the shape of red blood cells (a type of sickle), their destruction and the emergence of severe hemolytic anemia. However, if the hemoglobin S concentration in the blood does not exceed 45% of the total hemoglobin. These changes will occur only if the inhaled air dramatically decrease the partial pressure of oxygen (mountain climbing, diving, etc.). In ordinary conditions, this disease is reduced to asymptomatic carriage of hemoglobin S. Sickle-cell anemia is common in so-called "malarial" zone of the Earth. And I noticed that her ill have an increased resistance to the malaria parasite. The fact is that the malaria parasite for their development requires a large amount of oxygen. In connection with what in erythrocytes, which is Plasmodium, hypoxia. In these circumstances, there is loss of hemoglobin in the form of tactoids, red blood cells die, and with them and die of malaria. Thus, in this case there is a genetically fixed sanogenetic role pathogenetic mechanism. The phenomenon sanogenetic role of pathogenetic mechanisms can give the following explanation. On the body in a number of pathogenic factors affect the course of his life. What if he had not developed in the evolution of sufficiently reliable mechanisms of adaptation and protection, he could not have survived. In the event of sickness claims increased sharply in the body protection reliability. Since starting to operate in unusual conditions for him. In order not to die body has developed over the evolution of the ability to use even appearing in it "Paul" in their own interests. Sanogenetic role pathogenetic mechanisms - is the highest reflection of the body's ability to adapt to the environment.
Pathogenic role sanogenetic mechanisms.
24 Quite often there is a reverse pattern when sanogenetic mechanisms play a pathogenetic role, that is a situation where the protection of the other party turns itself leads to the progression of the disease process or the death of the organism. This may occur, for example, in the following situations. The reaction of the protective systems are not the cause, but one of the consequences of exposure to a pathogenic factor. In this case, the point is. What is most different in etiology of disease processes can have a common pathogenetic link, and such, which can initiate the reaction sanogenetic standard, whereby sanogenetic enters pathogenetic mechanism, such as in reducing blood flow in the renal vascular spasm and enhance production of renin. Lack of differentiation sanogenesis mechanisms. When exposed to the pathogenic organism antigenic variation factor structures of some proteins can occur, causing them to destroy their produced antibodies. However, due to the fact that the antigenic structure modified and normal protein has a lot in common, antibodies raised to the modified proteins can react with and destroy them unchanged. Develop the autoimmune process, which is based on the transition sanogenetic pathogenetic mechanism. Local development sanogenetic mechanisms. In acute focal ischemia (infarction) of the myocardium in the area of the heart muscle, deprived of blood flow, hence, oxygen, compensatory enhanced glycolysis, which is undoubtedly sanogenetic character, because it allows the muscle fibers of the ischemic area of the heart to receive a certain amount of energy. However, this gain in glycolysis areas of cardiac muscle ischemia surrounding area occurs. Consequently, the area between and surrounding ischemic tissue there is a high electrical potential difference, which may lead to the development of cardiac arrhythmias, including inevitably leading to death ventricular fibrillation. Thus, local development sanogenetic mechanism caused the violation of the functions of the body as a whole system can lead to the eventual death of the organism. Genetically determined deficiency of protective mechanisms. This type of transition sanogenesis mechanisms in the pathogenesis can be illustrated by the so-called "storage diseases" associated with genetic defects in lysosomal system. One of the main functions of lysosomes is the implementation of intracellular digestion and the cells get rid of ballast substances. This process is carried out mainly through the formation of intracellular digestive vacuoles, which merges with a lysosome: the latest releases in the cavity of the vacuole corresponding enzymes that perform splitting and got in the vacuole of the substrate. In that case, if the substrate is not subjected to cleavage, it remains in the cavity of the digestive vacuoles and eventually all the vacuole (lysosome merged with it) is filled with this substrate. If you have a genetically based lysosomes lack of a particular enzyme, is trying to carry out their inherent function of digesting foreign substrates for cell lysosomes die, turning into "bags" with uncleaved substrate. These "bags" filled the entire cell, which also killed. It is in this way develops a number of serious diseases (mucopolysaccharidosis), in which the central nervous system cells are filled with undigested mucopolysaccharides. The same mechanism underlies the development of atherosclerosis, and (as a result of genetically determined defect of enzymes that break down the cholesterol in the lysosomes of cells of the vascular wall). Thus, as a result of a genetic defect in defense mechanism becomes a severe pathology. These are just some of the reasons for the transition sanogenetic pathogenetic mechanisms.
25 Environmental factors
Classification of environmental factors in character: 1. Mechanical factors - injury, sprain, break, blow, compression, compression. 2. Physical factors - all kinds of solar energy, ionizing radiation, ultraviolet radiation, visible rays of the sun, high and low ambient temperatures, the effect of an electric current, high and low barometric pressure, gravity, cosmic energy, vibration and more. 3. Chemical factors - organic and inorganic compounds. 4. Biological factors - micro and maсropredator. Micropredator - bacteria, viruses, fungi. Maскщpredator - worms, insects. 5. Social factors - social system, the media, psychogenic factors, iatrogenic factors, stress.
The role of environmental factors in the origin of diseases. 1. The enviromental factor may be the cause of the disease. For example, the cause of the disease pneumonia biological enviromental factor is Streptococcus pneumoniae. 2. The enviromental factor may be a condition of the disease. For example, the social environmental factor of the stress is a condition for the occurrence of diseases as gastric ulcer. The cause of gastric ulcer is a biological environmental factor - Helicobacter pylori. 3. The same environmental factors may be the cause and condition of disease. For example, the physical factors of the environment reduced the ambient temperature can cause diseases such as hypothermia, freezing, frostbite, cold shock. Reduced ambient temperature may be a predisposing condition for the development of diseases such as angina, influenza, pneumonia. Reduced ambient temperature may be a condition for preventing the development of diseases, when the procedure hardening.
26 The damaging effect of mechanical factors Mechanical factors can have both local and general damaging effect on the body. The effect of the pathogenic action determined by the strength of this action (tension, compression) or in the form of kinetic energy mass moving at a certain speed (shock, drop, bullet or other gunshot wound). The damaging effect of mechanical factors also depends on the state of reliability, durability or resistance of damaged structures. The strength of biological structures (tendons, bones, blood vessels, muscles, etc.) Is their ability to resist the deforming effects of mechanical damaging agents. Tensile strength is the ratio of the applied load to the cross-sectional area of the material. This value characterizes the voltage at which under the influence of the deformation fabric is destroyed. Stretching and tearing. The action of mechanical forces can cause stretching of living structures. Stretching - the inverse of the elasticity or the elasticity of the tissue (resistance to deformation and the ability to restore the initial state), shows which part of the original length possible to stretch the test object. An indicator of the extensibility is elongation. The effect of the applied force depends on the mechanical strength of the structures, which in turn is determined by the limit load required for a complete rupture of the test body. The highest tensile strength have a bone (tearing strength - 800 kg / cm2) and tendon (625 kg / cm2). Tearing force for vessels equal to 13-15 kg / cm2 for the muscles - 4-5 kg / cm2. Combinations of individual tissues constituting the body structure have a greater tear resistance than each of them individually. With age, the tissues strength and elasticity decrease. In this regard, in the elderly and elderly fractures often occur, cracks, stretching and deformation of tissues. Various pathological processes also affect the elasticity of the tissues. For example, inflammation of the lower elasticity and extensibility increase risk of tendon rupture, ligaments, muscles and other structures. The result of applying the fracturing force also depends on the initial tissue state. Thus, the muscle, which is in a state of rest, more extensible than cutting. Repeated long extension at the same load alter the structure and properties of stretch fabrics. Their elongation increases and the elasticity recovery after cessation of stretching reduced. It is observed in repeat sprains ligament apparatus of the joints, skin, aorta and other organs. Stretchable tissue atrophy, impaired their function. For example, on a long stretch of the stomach more food develop atrophy of its walls and its decrease motor and contractile activity. Stretching the bladder contents with difficulty urinating accompanied by atrophy of its walls and the weakening of the contractile ability. Stretching pulmonary emphysema, asthma brochial reduces their elastic properties and makes it difficult to breath. When stretched, a change of the functional state of tissues. So, for example, distension of the intestines is reduced bad. Compression. The greatest resistance to compression of the bone and have musculoskeletal system. For example, for femoral compression deformation is required by load 685 kg / cm2. Skull bone tissue withstand pressure up to 500 kg / cm2, while the pressure resistance of 1,000 times the impact resistance. The soft tissues are significantly more sensitive to compression. So, if their short-term small compression results in reversible local circulatory disorders and food, even small in strength, but the long-acting factors of compression can lead to tissue necrosis. When compression of the tissue growing their growth slows down or stops completely (eg, artificially caused by atrophy of the feet of girls in Ancient China and Japan by "swaddling" legs or wearing special shoes). Growing tumors cause atrophy (pressure) of the surrounding tissues. Particularly serious violations are the result of long-term pressure on the body of a man caught in the rubble in earthquakes, bombings, etc. Shortly after exemptions the dam (decompression) arise pervasive functional and morphological disorders - "crush syndrome" characterized by shock symptoms, progressive renal failure with symptoms of oligo- and anuria, the development of edema, increasing the general intoxication of the organism. Hit. This set of mechanical phenomena occurring during the collision of moving solids (or moving body with an obstacle), and the interaction of a solid body with a liquid or gas (blow jets of the body, a body hitting the surface of the liquid blast effect or the shock to the body, etc.).. Shot
27 time is usually very small (a few ten-thousandths to millionths of a minute), and developing on contact area forces are very great. As a result of strike violated the integrity of the fabric: there are fractures, breaks the skin, soft tissues, blood vessels, bleeding, damage to the subcutaneous tissue and internal organs. Character-induced shock trauma depends on the nature of the traumatic factor (blunt or sharp object, cold or fire-arms, hydraulic shock, the shock wave, and so on. D.), Rate of motion of bodies and the value of the kinetic energy, the contact area of the traumatic agent with the living body surface, the state of the traumatized tissue and organism as a whole. For example, the nature of the gunshot wound depends on the manpower wounding projectile, its shape and the type of tissue that it hurts. Living force (impact force) the greater, the larger the mass of the projectile and its speed at the moment of contact with the tissue lying in his path; its effect extends far beyond the wound channel. Small-arms bullet released from a distance of 1000 m, has the force of impact of about 80 kg / m2, inflicting wounds with extensive changes in the surrounding tissues. With the reduction of the distance of its living force increases with increasing distance - decreases with decreasing speed of a bullet. When blows with a blunt object and a relatively large area of contact with the body surface can damage internal organs while preserving the integrity of the outer skin. Traumatology well- known cases of bleeding in the lungs after a strike to the chest across the board or other items. When you hit the chest with a closed larynx appears to be easily rupture. Strikes in the lumbar region of kidney damage, blows to the abdominal wall can cause bleeding in the brain. Action impact is not limited to local lesions of organs and tissues. In cases of damage to extensive receptor zones or a large number of nerve fibers is the failure mechanisms of emergency regulation and urgent protective and compensatory reactions (spasm of blood vessels, the release of adrenal hormones, increased blood clotting and others.). There is a common reaction to mechanical injury - traumatic shock.
28 Pathogenic effect of low temperatures. Hypothermia Effect of low temperature on the body can lead to a decrease in body temperature and the pathological process development - hypothermia. In developing hypothermia distinguish two stages. First, despite the low ambient temperature, the body temperature does not decrease, and maintained at the initial level thanks to the inclusion of compensatory reactions, causing the restructuring of thermoregulation. This cooling period is called the stage of compensation. From a wide variety of thermoregulatory devices primarily include physical thermoregulation mechanisms to limit heat transfer. Giving warmth to the environment is known to be effected by radiation, convection, and evaporation of. In cold conditions, heat transfer is limited due to spasm of blood vessels of the skin and reduce sweating. In animals, it plays an important role wool (the hairs are raised, and the heat insulating air layer is formed). In man, this reaction is preserved in rudimentary form ( "gooseneck" leather) and, of course, not important in the maintenance of body temperature, but only indicates the voltage of the thermoregulatory mechanisms. It is characterized by changes in the animal's posture, which in the cold "rolled up in a ball." These reactions, to reduce the impact of heat can be sufficient to maintain body temperature. With more intensity and duration of action of the cold included mechanisms of chemical thermoregulation, to increase heat production. It appears muscle tremors, increased metabolism, increased breakdown of glycogen in the liver and muscles, increases blood glucose. Oxygen consumption increases, strongly functioning systems to ensure the delivery of oxygen to tissues. Metabolism is not only increased, but also rebuilt. Dopolnitёlny energy output in the form of heat is provided both by increasing oxidative processes, and by separation okis¬leniya and associated phosphorylation. This mechanism contributes to warming of emergency, however, known to be associated with decreased amount macroergs necessary to perform the functions. Consequently, the oxidation and phosphorylation uncoupling can not provide long-term adaptation to cold and thus more active in cold conditions. The latter can be achieved by increasing the capacity of the mitochondrial system. Experimentally proved that the animals adapted to cold, increased enzyme activity of Krebs cycle and respiratory chain, and electron microscopy revealed an increase in the number of mitochondria. The biogenesis of these organelles is associated with activation of the genetic apparatus of the cell, an increase in the synthesis of nucleic acids and proteins (F. Meerson). Complicated rearrangement in the body, which provides constancy in body temperature under cold conditions occurs involving neurohumoral regulatory mechanisms which can be represented schematically as follows. Thermoreceptors perceive skin irritation cold and sensitive ways of sending impulses to the hypothalamus, which is the center of thermoregulation, and in the higher parts of the central nervous system. Hence, in the reverse direction to receive signals to various organs and systems participating in maintaining body temperature. According to the motor nerves pulses are delivered to the muscles, which develops thermoregulatory tone and tremor. According to sympathetic nerve stimulation reaches the adrenal medulla, which increases the secretion of adrenaline. Adrenaline helps narrowing the peripheral blood vessels and stimulates the breakdown of glycogen in. liver and muscle. An important factor is the inclusion in the thermal regulation of the pituitary, and through its tropic hormones - thyroid gland and the adrenal cortex. Thyroid hormone increases metabolism, splits oxidation and phosphorylation, and also activates the mitochondrial biogenesis. Glikokortikoitsy stimulate the formation of carbohydrates from protein. In conditions of prolonged or intense action possible cold stress and exhaustion of the thermoregulatory mechanisms, after which the body temperature drops, and comes second cooling stage - the stage of decompensation, or actually hypothermia. In this period, in addition to lower body temperature, there is a decrease metabolism and oxygen consumption; vital functions are depressed. Respiratory disorders and. circulation causes oxygen deficiency, inhibition of the central nervous system, reduction of immunological reactivity. In severe cases, possible irreversible changes in tissue, entailing death.
29 In the second stage of hypothermia are intertwined phenomena of pathological and adaptive. Moreover, the same shifts, as, on the one hand, pathological, on the other can be evaluated as adaptive. For example, depression of the central nervous system functions can be called protective, because it decreases the sensitivity of nerve cells to the lack of oxygen and further decrease body temperature. Reduced metabolism in turn reduces the demand for oxygen. Extremely interesting is the fact that in a state of hypothermia, the body becomes less sensitive to a variety of adverse environmental effects - lack of oxygen and food poisoning, infection of an electric current, overload, etc.
Pathogenic effects of heat. Overheating. Heatstroke. The action of heat can cause burns, burn disease and hyperthermia. Burns (thermal) - Local (local) damage to tissues by increasing their temperature within 45- 50 °C and higher as a result of the action of flame, hot liquids, steam, heated solids. Depending on the depth of tissue damage are four degrees of burns: 1) skin redness (erythema); 2) the formation of bubbles; 3a) a partial or complete necrosis of the Malpighian (sprout) layer of the skin; Zbigniew) complete necrosis of the skin during the whole of its thickness; 4) necrosis of the skin and deeply lying tissues. The mechanism of burns associated with an inflammatory response at the site of action of thermal agent and coagulation proteins, leading to cell death and tissue necrosis. Burn disease - versatile functional disorders of the internal organs and systems of the whole organism, caused extensive (more than 10-15% of the body surface) and deep burns. In the development of burn disease is divided into four periods: 1. Burn shock; 2. General toxemia - the result of auto-intoxication decomposition products tissue formed at the site of burn (denatured protein, biologically active amines, polypeptides, and others). And the production of specific autoantibodies burn. Additionally, in animal and human skin burn autoantigen was found absent in healthy people and in other tissues character the damage; 3. Septic (accession infection); 4. Convalescence (recovery). Overheating (hyperthermia) - passive temporary increase in body temperature due to the accumulation of excess heat in the body (with a loss of heat transfer processes and a high ambient temperature operation environment). To maintain the normal body temperature at the maximum level of heat (work) and enters the body of 100-150 kcal / hr of heat by thermal radiation heat transfer is required in the total environment of about 500-600 kcal / hr. When aligning the skin and the ambient temperature (average 33 ° C), the heat output from the body surface due to convection and heat radiation stops. At higher ambient temperature, the heat output is only possible due to the evaporation of sweat from the skin surface. Termination of office or evaporation of sweat (high humidity, water-resistant clothing, etc.) can lead to overheating even at 33-34 ° C. Overheating contribute to water shortages in the body and lack of replenishment of its losses through sweat. Increased body temperature is accompanied by a dramatic increased frequency of respiratory movements, caused by irritation of the respiratory center of the heated blood (PN Veselkin), shortness of breath develops heat. Further notes quickening heart rate and increased blood pressure. Due to the loss of water through sweating occurs blood clots, disturbed electrolyte metabolism, increased hemolysis, there are phenomena of intoxication decay products of hemoglobin. Damage to the various tissues is also accompanied by the accumulation of toxic products of their decomposition. In connection with the destruction VII, VIII, X and other plasma clotting factors is disrupted. Overvoltage mechanisms of thermal regulation leads to their depletion, accompanied by inhibition of the central nervous system, respiratory depression, cardiac function, blood pressure reduction, and ultimately - to the profound hypoxia.
30 Acute hyperthermia with a rapid rise in body temperature and prolonged exposure to high ambient temperatures can cause heat stroke. Death at a heatstroke occurs from paralysis of the respiratory center. I stage II stage
Stimulation of the cerebral Inhibition of the cerebral cortex (delusions, cortex, loss of hallucinations) consciousness Stop breathing movements. Excitation of the bulbar Thermal shortness of The paralysis of the
etiological factor respiratory center breath respiratory center The excitation of the heart
muscle and its sympathetic Tachycardia innervation Inhibition of the vasomotor 50 ° C Excitation of the Reducing arterioles Ambient center, lowering blood temperature vasomotor center (hypertension) pressure, collapse Violation of The sharp increase in thermoregulation, The continuation of heat blood temperature increased heat production and fever after death (up to 41-43 ° C) and heat Increased blood viscosity, Concentration of of blood humidity 80% albuminosis, Temperature ° 40 C, Hyperthermia blood body and polycythemia
Sunstroke. The cause and pathogenesis of sunstroke. Sunstroke, as a form of hyperthermia states, it has some differences from hyperthermia both because of, and in the mechanisms of development. Cause. The cause of sunstroke sunstroke is a direct effect of solar radiation on the body. Most pathogenic effect, among others, provides the infrared part of solar radiation, i.e. radiative heat. Last, unlike the conductive and convective heat-foot, and heats both superficial and profound tissue. In addition, the infrared radiation acting on the whole body, and rapidly heats the tissue of the brain in which neurons are located the center of thermoregulation. In this regard, sunstroke developing fleeting and fraught with fatal. Pathogenesis. The pathogenesis of sunstroke sunstroke - a combination of hyperthermia and the actual mechanisms of sunstroke. Leading are the various CNS. 1. Increasing arterial hyperemia of the brain. Causes: - An increase in temperature of the brain under the influence of infrared (heat) radiation from sunlight. - BAS produced directly in the brain tissue: kinins, adenosine, acetylcholine, and others. Long term effects of heat and various vasodilators reduces neuronal and myogenic tone of the walls of the arterioles to the development of pathological (!) Form of arterial hyperemia neyromioparaliticheskomu mechanism. Arterial hyperemia leads to an increase in blood supply to the tissue. For the brain, located in the confined space of the skull bone, which means its compression. 2. Increase (in terms of arterial hyperemia), and lymph formation of filling excess lymph lymphatic vessels, which leads to an increase in compression of the brain substance. 3. Progressive venous congestion of the brain. Its cause is the compression of the brain, including the occupants of the veins and sinuses. In turn, venous congestion leads to the development of
31 cerebral hypoxia, cerebral edema and small focal brain hemorrhage. The result is a focal symptoms in a variety of neurogenic disorders of sensitivity, movement and autonomic functions. 4. Growing errors of metabolism, energy supply and plastic processes in the neurons of the brain. It potentiates decompensation mechanisms of thermoregulation, disorders of the cardiovascular system, respiratory, endocrine glands, blood and other organ systems. In severe changes in the brain of the victim loses consciousness, coma develops. Given the intensive growth of hyperthermia and disturbances of vital activity, sunstroke is fraught with a high probability of death (due to the dysfunction of the CVS and the respiratory system), as well as development of paralysis, nervous disorders, sensitivity and trophism.
32 Action barometric pressure Action reduced barometric pressure. The mountain (altitude) sickness The term "altitude sickness" describes mostly cerebral and pulmonary syndromes that can develop in people non acclimatization shortly after ascent to high altitude. Man experiences a low barometric pressure (hypobarium) while climbing in the mountains, with the rise to a height of hermetically aircraft, in special pressure chambers. Emerging with pathological changes caused by two main factors - a decrease in atmospheric pressure (decompression) and a decrease in the oxygen partial pressure in the inhaled air. The nature of the violations arising from hypobarium and their degree of severity depends on the magnitude of the fall in barometric pressure. The general condition of the body at altitude sickness, depending on the atmospheric pressure and partial pressure of oxygen in the inspired air (pO2)
Atmospheric pressure, PO2, Height, m Condition of the body mm Hg. Art. мм рт. ст. 0-2500 760-560 159-117 Good 2500-4000 560-462 117-97 Without changes 4000-5000 462-405 97-85 The first symptoms of altitude sickness 5000-6000 405-354 85-74 Significantly expressed altitude sickness 6000-8000 354-267 74-56 Very severe altitude sickness Over 8000 Less 250 Less 52 Without oxygen devices stay incompatible with life
When the barometric pressure drops to 530-460 mm Hg, which corresponds to the rise in the height of 3000-4000 m, there is an expansion of gases and the relative increase of the pressure in the closed and semi-enclosed body cavities (paranasal nasal cavity, frontal sinuses, middle ear cavity, pleural cavity, gastrointestinal tract). By stimulating receptors of these cavities, the gas pressure causes pain, which is especially pronounced in the tympanic cavity and inner ear. At an altitude of 9,000 m (225.6 mm Hg) or more in the 10-15% of the flights in hermetically cabins (but with oxygen devices) having symptoms of decompression, which is associated with the transition to the gaseous state of dissolved nitrogen in the tissues and the formation of bubbles of free gas. Nitrogen bubbles enter the bloodstream and spread blood into various areas of the body, causing ischemia and vascular embolism tissues. Especially dangerous embolism, coronary and cerebral vessels. Physical activity, hypothermia, obesity, local blood circulation disorders of lower body resistance hypobarium action. At an altitude of 19,000 m (47 mm Hg) and above there is a "boiling" liquid body fluids at body temperature, a so-called altitude tissue emphysema. Mountain (altitude) disease is caused by a decrease in the partial pressure of oxygen in the inspired air during ascent to high altitude. Risk factors for altitude sickness are: high speed lift, permanent residence at an altitude below 900 m, physical stress, the presence of underlying cardiopulmonary disease, age older than 50 years, genetically mediated individual sensitivity. The spectrum of disorders ranging from mild disorders to pulmonary edema and brain, which often are the cause of death. Disease incidence in children is the same as that of adults; women are less susceptible to the development of high-altitude pulmonary edema than men. The cold temperature is an additional risk factor, as the cold increases the pressure in the pulmonary artery and stimulates the sympathetic nervous system, so a high-altitude pulmonary edema occurs bowl in the winter. At climbers and skiers who already have these episodes sudden relapse can occur at high altitude. In this high-altitude edema lungs fast turn (down enough to lower height), which distinguishes it from acute respiratory distress syndrome. In the pathogenesis of high-altitude pulmonary edema is not cardiogenic. those. not associated with heart weakness, it develops due to increased pressure in the pulmonary artery. Hypoxia
33 increases the excitability of the sympathetic nervous system, which causes constriction of the pulmonary veins and increasing the capillary pressure. Capillary permeability increases under the influence of inflammatory mediators, vascular endothelial growth factor, interleukin (IL-1) and tumor necrosis factor (TNF), released from the pulmonary stromal cells, alveolar macrophages and neutrophils. Hypoxia can disrupt the removal of water and sodium from the alveolar space, as it reduces the expression of genes encoding subunits of sodium channels and Na+ / K + - adenosintriphosphate (Na+/K+ - ATPase). Sensitivity to the development of pulmonary edema may be genetically determined (increased release of endothelin-1 and decreased production of nitric oxide (NO), the deterioration of the water and transepithelial sodium clearance in the lungs). Pulmonary edema may develop on the second night's stay at the altitude. High-altitude cerebral edema (the final stage of acute altitude sickness) manifest violation of coordination of movement, and impaired consciousness, drowsiness or even stupor, convulsions, rarely, it can be accompanied by retinal hemorrhage, paralysis of cranial nerve due to increased intracranial pressure. With the rise to great heights in almost all people in varying degrees of brain swelling occurs. As in the high-altitude pulmonary edema, hypoxia in the brain leads to the activation of the sympathetic nervous system and the appearance of neurohumoral and hemodynamic changes that increase perfusion in the microcirculation and the hydrostatic pressure in the capillaries and increase their permeability. As a result, oxygen starvation changes the status of the blood-brain barrier in the endothelial cells produce more nitric oxide and dilate blood vessels of the brain, hence the headache, nausea and vomiting. Activators may be bradykinin endothelium activated by NO-synthase, endothelial growth factor. In the classical experiments of Paul Beer modeling of altitude sickness, it was found that the main factor in its ethnological is not vacuum the air itself, and the lack of oxygen caused by this hypoxemia (decreased oxygen in the blood) and hypoxia (oxygen starvation of tissues). In our country, the study of altitude sickness a lot of attention paid NN Sirotinin. He and his colleagues had found that the cause of respiratory failure at altitude sickness are hypocapnia and gas alkalosis caused by hyperventilation and removal of CO from the alveolar air. In the pathogenesis of altitude sickness allocate two stages: stage adaptations and stage decompensation. Stage adaptations. At an altitude of 1000-4000 m as a result of stimulation of the chemoreceptors hypoxemic blood vessels of the carotid sinus and aortic arch (the most sensitive to oxygen deficiency) occurs reflex stimulation of the respiratory and vasomotor centers, and other centers of the autonomic system. There is shortness of breath, tachycardia, increases (slightly) blood pressure, increases the number of red blood cells in the peripheral blood (up to (6-8) 1 012 / l) due to the reflex "release" them from the spleen and other organs depot. At an altitude of 4000-5000 m there are signs of release and excitation of cortical cells: people become irritable, exposed latent traits (in the mountains easier to get to know each other better). Violation of cortical processes can be detected by "writing sample" - changing handwriting, writing skills are lost. As a result of increasing renal hypoxia activated erythropoietin production, which leads to the activation process of erythropoiesis in the bone marrow and an increase in the number of reticulocytes and erythrocytes in peripheral blood. Stage of decompensation (actual disease). This step usually develops at an altitude of 5000 m or more. The result of hyperventilation and reduce the formation of CO2 in tissues (tissue hypoxia due to the oxidation of carbohydrates and fats is not completed by the formation of water and carbon dioxide) gas evolving hypocapnia and alkalosis, reducing the excitability of the respiratory centers and other central nervous system. The euphoria and excitement give way to depression, depression. Develop fatigue, drowsiness, stiffness. There is a differential braking reflexes, then ischezayutpolozhitelnye food and other reflexes. Breathing becomes more scarce and intermittent (such as Cheyne-Stokes and Biota). Progressive hypocapnia and alkalosis at an altitude of 6000 - 8000 m can cause death by paralysis of the respiratory center.
34
The action of high barometric pressure. caisson disease Pathogenic action of high atmospheric pressure (hyperbaric) are subjected when submerged under water while diving and caisson work. With the rapid transition from a medium with a normal atmospheric pressure in a pressurized environment (compression) may eardrum impression that the obstruction of the Eustachian tube causes severe pain in the ears, intestinal gas contraction, increased blood supply to internal organs. At very fast (sharp) dive to great depths can occur rupture of blood vessels and pulmonary alveoli. However, the main causative effect in hyperbaric compression period is associated with an increased gas dissolution in body fluids (saturation). There is a correlation between the amount of dissolved gas in the blood and tissues of the body and its partial pressure in the inhaled air. When immersed in water every 10.3 m the pressure increases at I atm, respectively, and increased the amount of dissolved nitrogen. Particularly active saturated nitrogen organs rich in fat (adipose tissue dissolves 5 times more nitrogen than blood). Due to the high content of lipids primarily affects the nervous system, light excitation ( "profound admiration") quickly replaced Narcotic and then the toxic effect - weakening of concentration, headaches, dizziness, impaired neuromuscular coordination, possible loss of consciousness. To prevent these complications in diving operations appropriate to use an oxygen-helium mixture as helium worse (the nitrogen) dissolved in the nerve tissue and is indifferent to the body. In the transition from the area of high barometric pressure to the normal atmospheric pressure (decompression) are developing the main symptoms of the bends (decompression) disease caused by a decrease in the solubility of gases (desaturation). Liberated from the tissues in excess of nitrogen does not have time to diffuse from the blood through the lungs outwards and forms gas bubbles. If the diameter of the bubbles exceeds the lumen of the capillaries (over 8 m), there is a gas embolism, warrant the main manifestations of decompression sickness - the muscle-joint and chest pain, blurred vision, itchy skin, vascular and brain disorders, lesions of the peripheral nerves. Hyperbaric oxygen therapy - breathing oxygen under increased pressure. Using Hyperbaric oxygenation in medical practice (to increase oxygen capacity) based on the increase in the soluble fraction of oxygen in the blood. The excess oxygen in the tissues (hyperoxia) by inhalation of its pressure 303.9 kPa (3 bar) has a beneficial effect, activating the processes of tissue respiration and detoxification. Increasing the pressure of the inhaled oxygen to 810,4-1013 kPa (8-10 atm) is the phenomenon of severe intoxication due to the activation of free radical oxidation, formation of free radicals and peroxide compounds.
Poisoning with oxygen.
It is a pathological condition that develops as a consequence of the toxic effect of oxygen and manifested swelling of the lung tissue, or convulsive disorders. Poisoning occurs when breathing pure oxygen or gas mixtures with an increased partial pressure of the gas. By oxygen poisoning can cause: Excessive descent depth or time of stay under water while breathing pure oxygen; use gas mixtures with a high oxygen partial pressure not corresponding to the depth and length of the shutter. Oxygen toxicity contribute to: excess carbon dioxide content in the inspired gas mixture is more than 1%; hypothermia; overheating; heavy exercise. Clinic. There are two clinical forms of oxygen poisoning - convulsive and pulmonary. Cramping form. During this form distinguish 3 stages: stage of the precursors, convulsive stage, comatose stage. In one stage, the decrease in sensitivity and numbness in the tips of the fingers and toes may be shortness of breath, fatigue, nausea, ringing in the ears. There pale skin, sweating, involuntary contraction of facial muscles. Cramping stage begins with twitching actively working muscles. Then there are attacks of clonic convulsions with loss of consciousness, which are becoming longer is, and the pause between them shorter. Clonic seizures are moving in the tonic
35 and occurs opisthotonos. Comatose stage is characterized by seizures and progressive weakening of respiratory disorders which lead to its stop. The pulmonary form is manifested retrosternal pain, shortness of breath, cough. The examination found hard breathing and crackles. Gradually developing pulmonary edema and hypoxia phenomenon. Sometimes develops collapse. With the normalization of oxygen develops acute oxygen starvation. Complication - pneumonia. Treatment. When convulsive form is first necessary to normalize the content of oxygen in the inspired mixture. When seizures are administered anticonvulsants (2.5% solution of chlorpromazine 1 ml, 2% solution dimedrol 1 ml, 2% solution promedola 1 ml of 0.5% solution seduxen 1-2 mL). To prevent recurrent seizures victim is placed in a warm shady area with good sound insulation. When the pulmonary form is necessary to clear the airways and carry out activities aimed at reducing pulmonary edema and hypoxia elimination. Carry inhalation ethanol vapor can be introduced 3 - 4 ml of alcohol / in. Assign diuretics in / injected 10 ml of a 10% solution of calcium chloride.
Poisoning nitrogen Toxic effects of nitrogen occurs when breathing compressed air at a depth of 60 m or shallower with breathing gas mixture with a high content of carbon dioxide. The first signs of nitrogen actions appear as wanton gaiety, excessive talkativeness. In the future, there is a clear violation of coordination, impaired orientation, lost the ability to critically assess the situation. Sharply reduced working capacity. Status resembles the action of drugs. In marked nitrogen poisoning and lost consciousness comes a deep sleep. At the first signs of toxic action of nitrogen a diver stops the descent. If this does not help, divers raised to the surface and at the same time signs of nitrogen narcosis disappear.
36 Pathogenic action of electric current The electric current is called an ordered motion of charged particles. Man is exposed to natural (lightning) or technical electricity. Lightning strikes act as a short (fractions of a second, seconds), passing through the human body a huge current-voltage (up to millions of volts). Death occurs from heart failure and (or) breathing. As a result, the heat lightning effect on the body still burns, bleeding in the form of special branched "figures" blackening and necrosis; possible mechanical effect - separation of tissues and even parts of the body. Pathogenic action of technical electricity (electrotrauma- damage caused by exposure to an electric current or electric arc). Depending on the type of current (constant or variable) and its power, voltage, direction and duration of action as well as the tissue resistance state and reactivity in general electrical accident may occur in the range from minor pain and tissue charring to death. Current. At the same strength alternating current (periodically changing their direction in the circuit) is more dangerous than DC. The current strength of 100 mA is deadly. 50-60 Hz AC power 12-25 mA causes convulsions ("non release"); main danger here is "chaining" affected them to a captured object busbar. Tension - a value that is numerically equal to the work done when moving a single positive charge on the site of an electrical circuit. Tension acting on the body of the power supply to 40 V fatal injuries does not cause, at a voltage of 1000 V mortality rate reaches 50%, with a voltage of 30 000 - 100%. Danger alternating current at a voltage of 42.5 is the risk of direct current at a voltage of 120 V. However, the direct current is less dangerous than AC, only to a voltage of 450-500 V. At higher voltage DC is more dangerous than AC.
Effects of electric current on the human body at the position of the electrode arm-hand or hand-foot (by Kulebakin, Morozov) Amperage The nature of perception мА AC (59-60 Hz) DC
0,6-1,5 Start feeling slight trembling fingers not felt 2-3 Severe trembling fingers not felt 5-10 movement disorders Pruritus, sensation of heat Hands difficult to tear away from the 12-15 electrodes, severe pain in the fingers, hands. strengthening heating Tolerant state with 5-10 sec The hands are paralyzed immediately, "non release" current. Very severe pain. Difficulty Even more heat gain. A slight decrease 20-25 breathing. State tolerated no more than 5 in arm muscle seconds A strong sense of heat. Reduction of the Respiratory paralysis. Home ventricular 50-80 hand muscles. Seizures. Shortness of fibrillation of the heart breath Respiratory paralysis. When the duration of 3 90-100 respiratory paralysis to heart failure or sustained ventricular flutter
Paralysis of breathing and heart under the 3000 and influence of more than 0.1 s. The destruction respiratory paralysis more of body tissue formed by Joule heat
The resistance of the tissues (quantity characterizing opposition to the body portion to the electric current) is caused by the conversion of electrical energy into other forms of energy. Total 37 (full) body resistance to the alternating electric current is called impedance and is made up of active (resistive) and reactive (capacitive) tissue resistance. The greatest resistance to the electric current has an outer epidermal layer of the skin (to 2 000 000 ohms), followed by further descending tendons, bones, nerves, muscles, blood. Of least resistance has the cerebrospinal fluid. The total resistance of the human body is on average 100,000 ohms (1000 to millions of ohms). Skin resistance decreases when it is wetted and at higher power and voltage. Current voltage is 10-40 in the breakdown of the epidermis; by increasing the voltage to 220 V resistance decreases sharply, approaching the resistance of the skin, devoid of the outer epidermal layer. The direction of flow of electric current through the body. Rising DC is more dangerous than downward, because the excitement coming from the sinus node, is facing oncoming wave of electric current, which causes cardiac arrest or ventricular fibrillation. When descending current wave excitation emanating from the sinus node, increasing the electric current at the same time in the open-circuit may cause ventricular fibrillation. Asynchronous excitation of the muscle fibers is because after fading outages electromagnetic field source is scattered in the space will induce currents of different strength in cardiomyocytes. In areas of the heart, at the center of the magnetic lines will be induced by a strong current, and its direction is the same as it was at the time of opening the circuit. Time factor. With increasing time of passage through the body of the pathogenic effect of an electric current increases. So, if the effect of the current 1000 V BB for 0.02 s not accompanied by the development expressed violations, with an exposure of 1 s, it inevitably leads to death. AC frequency. It is believed that the pathogenic effect (occurrence of ventricular fibrillation) has an alternating current frequency of 40-60 Hz. Alternating currents frequency 1,000,000 Hz and above are not dangerous, but at high voltage (Tesla currents, D'Arsonval, diathermic currents) they have a heating effect and are used for therapeutic purposes. Status reactivity. Fatigue, weakening of attention, light and moderate alcohol intoxication, hypoxia, hyperthermia, hyperthyroidism, heart failure reduces the body's resistance to electrical accident. The severity of electrocution is greatly reduced with the emotional stress caused by waiting for the current action in the state of anesthesia and deep (close to anesthesia) intoxication. The mechanisms of the damaging effect of an electric current. Electric shock can cause local (current marks, burns), and general changes in the body. Local reactions to electrocution. current signs, burns occur mainly in the field input and current output as a result of the conversion of electrical energy into thermal energy (heat Joule). current signs appear on the skin, if the temperature at the point of passage of the current does not exceed 120 ° C, and are small education grayish-white ( "Butter" skin), solid consistency, bordered by an undulating elevation. In some instances, damaged tissue by circumferential drawing emerges branched red blood vessel due to paralysis. When the temperature at the point of current flow in excess of 120 ° C, there are burns: contact - from the evolution of heat by passing a current through the tissue, providing resistance, and thermal - when exposed to the flame of a voltaic arc. The latter are the most dangerous. Common reactions to electrocution. When passing through the body of the electric current causes the excitation of nerve receptors and agents, skeletal and smooth muscles, glandular tissue. This gives rise to tonic seizures, skeletal and smooth muscle, which may be accompanied by a tear fracture and dislocation of limbs, spasm of the vocal cords, stop breathing, increased blood pressure, involuntary urination and defecation. The excitation of the nervous system and organs of internal secretion leads to the "release" of catecholamines (epinephrine, norepinephrine), alters many somatic and visceral functions of the body. Of great importance in the mechanisms of the damaging effect of an electric current has its effect electrochemical (electrolysis). Overcoming the resistance of the skin, an electric current causes an imbalance in the cells of various tissues, alters their biological potential, leads to polarization of cell membranes: on some tissue sections - at the anode - accumulate negatively charged ions (there is an alkaline reaction) at the cathode accumulate positively charged ions ( It appears acid reaction). As a result, significantly changes the functional state of the cells. Due to the
38 movement of protein molecules in the cathode under acidic sites occurs coagulation proteins (coagulative necrosis) in areas under alkaline anode - the swelling of colloids (liquefactive necrosis). Electrolysis process causing a shortening of cardiomyocytes refractory phase of the cardiac cycle, which leads to increasing tachycardia. When there non-fatal electrical accident convulsive muscle contractions with the temporary loss of consciousness, disturbance of cardiac activity and (or) breathing; Clinical death can occur. With timely assistance to victims feel dizziness, headache, nausea, photophobia; may persist disorders of skeletal muscle functions. The immediate causes of death are at the electrical accident respiratory arrest and cardiac arrest. The defeat of the respiratory and vasomotor centers due to the depolarization of the cell membrane and cytoplasm protein coagulation. Respiratory arrest may be due to: 1) defeat of the respiratory center; 2) spasm of the vertebral arteries, which supply blood to the respiratory center; 3) spasm of the respiratory muscles; 4) violation of the airway due to laryngospasm. Heart failure can be caused by: 1) ventricular fibrillation; 2) coronary artery spasm; 3) defeat vasomotor center; 4) increase the vagal tone.
39 The damaging effects of ionizing radiation General characteristics of the damaging effects of ionizing radiation Acting on the body ionizing radiation sources may be both external and internal. Man is exposed to ionizing radiation in the working environment, working with X-ray equipment, nuclear reactors and particle accelerators (Betatrons, cyclotrons, synchrotrons, linear accelerators), with radioactive isotopes, mining and processing of radioactive ores. In clinical practice, patients receive radiation therapy for therapeutic purposes. Finally, radiation may be due to the use of nuclear weapons and accidental releases of nuclear technology product companies in the environment. The source of internal radiation can be radioactive substances entering the body with food, water, through the skin. Perhaps the combined effect of external and internal exposure. Ionizing radiation, having the ability to cause ionization of atoms and molecules that are characterized by high biological activity. By their nature, all ionizing radiation is divided into electromagnetic (X-rays and gamma rays that accompany the radioactive decay) and corpuscular (charged particle: a helium nucleus - a-rays, electrons - p-rays, protons, pions and neutrons, do not carry an electrical charge). The damaging effect of different types of ionizing radiation depends on the value of the ionization density in the tissues and their penetrating power. The shorter path of photons in the tissues and particles, the more they caused ionization density and stronger damaging effect.
Penetration and density of ionization of various types of radiation with an energy of 2 MeV
Type radiation Length, m Density radiation, ions/mkl α-radiation 0.01 6000 β-radiation 10 6 γ-radiation about 600 0,1 Most ionizing power at the a-rays having a run length of biological tissues a few tens of micrometers, the lowest - in the y-rays have great penetrating power. The biological effects of ionizing radiation of different types are not only determined by the total amount of absorbed energy, but also its distribution in the tissues. For comparative quantitative assessment of the biological effect of various types of radiation determined by their relative biological effectiveness (RBE). The greatest biological efficiency characterized as radiation, protons, fast neutrons, the RBE for which equals 10. As a criterion for determining the RBE used mortality rates, the degree of hematological and morphological changes in tissues and organs, the effect on the sex glands and OE in this regard, RBE is not constant.
The values for the relative biological effectiveness of different types of radiation
Type radiation RBE γ-wave and X-ray beam 1 β-particle and electron 1 α-particle and proton 10 thermal neutron 3 fast neutron (to 20 MeB) 10 Multiply charged ions and nuclear recoil 20
The biological effects are determined not only by the type and the amount of absorbed radiation dose, but also its capacity. The unit dose is the gray (Gy), and for comparative biological assessment of various types of radiation, a special unit - rem. The higher dose rate, the greater biological activity. The damaging effect of ionizing radiation for short irradiation is more pronounced than in long-term irradiation in the same dose. Irradiation can be single, fractional and time-consuming. When fractional (fractionated) and long-term exposure of the body damage caused by higher total doses. The severity of ionizing radiation also depends on the area of the exposed
40 surface of the body (general and local), especially individual reactivity, age, sex and the functional state of the body prior to irradiation. It is believed that exercise, changes in body temperature and other influences affecting the metabolism, have a significant impact on the radioresistance. Young and pregnant animals are more sensitive to ionizing radiation. Even in a variety of body tissues and cells differ in radiosensitivity. Along with radiosensitive tissues (bone marrow hematopoietic cells, reproductive glands, small intestinal mucosal epithelium) are stable, radioresistant (muscle, nerve and bone).
The mechanisms of action of ionizing radiation on living organisms. Common pathogenesis Biological effects of ionizing radiation is reflected in the development of local radiation reactions (burns and cataracts) and special generalized process - radiation sickness. In the process of the damaging effect of radiation can be roughly divided into three stages: a) the primary action of ionizing radiation; b) the impact of radiation on cells; c) the effects of radiation on the whole organism. The primary action of ionizing radiation on living tissue is manifested by ionization, excitation of atoms and molecules and thus the formation of free radicals, HO, HO2 and hydrogen peroxide (H2O2), the existence of which does not exceed 105-106 with (direct effect of radiation). The ionization and excitation of atoms and molecules of the irradiated tissue cause the trigger biological effects of radiation. Free radicals cause chain reactions, react with the most reactive protein structures of enzyme systems (SH-groups) and translate them into inactive disulfide group (S = S). Indirect (indirect) effects of radiation due to the radiation-chemical changes in the structure of DNA, enzymes, proteins, etc., caused by the water radiolysis products or substances dissolved in it, has a high biochemical activity and capable of causing an oxidation reaction on any links. The oxidation of unsaturated fatty acids and phenols form lipid (peroxides, epoxides, aldehydes, ketones) and quinone primary radiotoxins that inhibit the synthesis of nucleic acids, which suppress the activity of various enzymes that increase the permeability of biological membranes, and alter the diffusion processes in the cell. This results in a violation of metabolic processes, functional and structural damage to the cells, organs and body systems.
The effect of ionizing radiation on cells Ionizing radiations cause various cell responses - from the time delay breeding until their death. Even in 1906, L.Bergonie and I.Tribondeau noted that the radiosensitivity of tissues proportional to proliferative activity and inversely proportional to the degree of differentiation of its constituent cells. Radiosensitivity tissue cells can be arranged in the following descending order: lymphoid organs (lymph nodes, spleen, thymus), bone marrow, testes, ovaries, mucous membrane of the gastrointestinal tract, the skin and other epithelia. The radiosensitivity of cells depends on the amount of genetic material, the activity of power station systems intensity metabolic enzyme activity and ratio providing repair cells, the stability of biological membranes and their reparation, as well as the presence in the cell radiotoxins precursors. At the core of radiation damage to cells are a violation of the ultrastructure of organelles and related metabolic changes. Small doses of ionizing radiation cause reversible, nonlethal changes cells. They appear immediately or within a few minutes after exposure (inhibition of nucleic acid metabolism, changes in the permeability of cell membranes, occurrence of stickiness of chromosomes, formation of grains and lumps in the nuclear matter, the delay of mitosis) and over time disappear. At high doses of radiation in cells occur lethal changes that lead to their death before the entry into mitosis (interphase death) or at the time of mitotic division (mitotic or reproductive, death). Interphase death is preceded by changes in the permeability of nuclear, cytoplasmic and mitochondrial membranes. Changing the membranes of lysosomes results in the release and activation of DNase, RNase, cathepsins, phosphatase enzyme hydrolysis of mucopolysaccharides, and others. Inhibits the cellular respiration, there is degradation of deoxyribonucleic complex in the
41 nucleus. The main reason for the death of reproductive cells are structural chromosomal damage (structural aberrations) occurring under the influence of radiation. It is believed that significantly higher radiosensitivity nucleus than cytoplasm. It also plays a crucial role in the outcome of cell irradiation. Cell death leads to the devastation of tissue disruption of their structure and function.
The effect of ionizing radiation on the body The effect of ionizing radiation can be local (radiation burns, necrosis, cataracts) and common (radiation sickness). Local effects of ionizing radiation (exposure of tissues during radiation therapy, dermal radioactive isotopes) most often manifested in the form of radiation burns. Soft X and p-radiation penetrating the tissue at a small depth to cause burns to the skin; high-energy bremsstrahlung and neutrons, which have a greater penetrating power, can affect and deep-lying tissue. Course radiation burns characterized by the development in series of successive periods (early radiation reaction, latent, acute inflammation, restoration), the duration and severity of symptoms depend on the severity of the lesion (1 degree - 8-12 Gy - light; II degree - 12-20 Gy - moderate severity ; III degree - more than 20 Gy - severe). When irradiated with doses of 20 Gy kills not only the skin but also the subcutaneous tissue, fascia, muscles and even bones. Patients develop fever, high leukocytosis, severe pain. Radiation sickness. When an external uniform irradiation of the body, depending on the dose of ionizing radiation arise from lesions subtle reactions of the individual systems to the acute form of radiation sickness. Upon irradiation at doses of 1-10 Gy develops the typical form of acute radiation sickness in which most clearly manifested major pathogenetic patterns of clinical formation of its individual periods, there is a preferential bone marrow (bone marrow syndrome). In the dose range 10-20 Gy there is intestinal, at doses of 20-80 Gy - toxemic (vascular) and at doses above 80 Gy - cerebral form of radiation sickness. A typical form of acute radiation sickness on the severity of determined by the absorbed radiation dose, divided into four groups: I - mild (1-2 Gy); II - moderate (2-4 Gy); III - severe (4-6 Gy); IV - extremely severe (more than 6 Gy). In its current is divided into four phases: 1) initial acute reaction; 2) an imaginary clinical well-being (latent phase); 3) the height of the disease; 4) Recovery. Initial acute phase response in the human body develops a dose dependent manner in the first minutes or hours after the irradiation. There are some agitation, headache, general weakness. Then come dyspepsia (nausea, vomiting, loss of appetite), in the blood - a short-term leukocytosis with a left shift, the absolute lymphocytopenia. The clinical manifestations of the disease are a consequence of both the direct damaging effects of ionizing radiation, and indirectly (through the neurohumoral regulation violations). Observed an increase in the excitability of the nervous system, vegetative lability functions - blood pressure fluctuations. heart rate, etc. Activation of the pituitary- adrenal system leads to increased secretion of adrenal hormones, which in this situation may have adaptive value. At doses of 8-10 Gy observed the development of shock-like state with a fall in blood pressure, transient loss of consciousness, fever, development of diarrhea. The duration of the primary phase of acute reaction 1-3 days. Phase imaginary clinical well-being characterized by the inclusion of a protection- compensatory reactions. Therefore patients feel becomes satisfactory tested clinically visible signs of illness. The duration of the latent phase depends on the radiation dose and ranges from 10-15 days to 4-5 weeks. With a relatively small doses (up to 1 Gy) initial light functional responses not go into a detailed clinical picture of the disease is limited and damped phenomena initial reactions. In very severe defeat latent phase is absent. However, at that time loss increases blood system: peripheral blood lymphocytopenia progressing against the background of leukopenia lowered content reticulocytes and platelets. In the bone marrow develops devastation (aplasia). There may be atrophy of the gonads, the suppression
42 of the early stages of spermatogenesis, atrophic changes in the small intestine and skin. Neurological symptoms gradually smoothed out. The phase height of the disease is characterized by the fact that the health of patients once again deteriorating sharply, growing weakness, increased body temperature, there is bleeding and hemorrhages in the skin, mucous membranes, gastrointestinal tract, brain, heart and lungs. As a result of metabolic disturbances and dyspeptic disorders (anorexia and diarrhea) is sharply reduced body weight. In total irradiation at a dose of 1 Gy, acute radiation sickness occurs in typical form, which is sometimes called bone marrow. Bone marrow form of acute radiation sickness occurs in four clinical periods: the primary reactions, the latent period, the period of extensive clinical evidence, the outcome of the disease. The first period, the duration of which varies from a few hours to a day or two, is a reaction of the nervous system to irradiation: agitation, headache, instability of autonomic functions, labile blood pressure and pulse rate, functional disorders of the internal organs ("X-hangover»). Dysmotility alimentary canal manifested by vomiting and diarrhea. Body temperature may rise as a result of the central thermoregulation disorders. There intermittent leukocytosis, accompanied by lymphopenia. In severe cases, this period of possible radiation shock. The second period got clinicians called "period of imaginary well-being." The phenomena associated with overexcitation nervous system, disappear, and other painful symptoms appear later. There is still some signs of the progression of the disease: leukopenia and lymphopenia progression. The third period is characterized by severe symptoms of radiation sickness. From the blood - a significant leukopenia, thrombocytopenia and anemia. Inevitably there are infectious complications, which constitute the main cause of the patient's suffering. Typically the development of auto- infection in the oral cavity (inflammation of the tongue and gums, necrotic angina). Eating is difficult. A common complication of radiation disease is pneumonia, which is against the background of reduction of immunological reactivity proceeds very seriously and may result in death of the patient. The appearance of the patient is characteristic - the skin is covered with numerous punctate hemorrhages. It appears in the urine, feces, sputum. Signs of recovery are feeling better, the normalization of the blood picture, the emergence of young blood formed elements. However, long after the disease can persist residual effects - fatigue, tiredness, weakness, instability of hematopoiesis, sexual dysfunction, hair loss, weakening of the immune system, trophic disorders, leading to premature aging. The intestinal form of acute radiation sickness occurs when irradiated laboratory animals at doses of 10-20 Gy, causing death 3-5 days after exposure. At autopsy the animals always ascertain the death of the bulk of the intestinal epithelium, denudation of villi, their flattening and destruction. In humans, at an irradiation dose of 10-20 Gy in death bowl comes on the 7-10th day. The main signs of illness are nausea, vomiting, bloody diarrhea, fever, can be observed complete paralytic ileus and bloating. Develop a deep hemorrhage and leukopenia with a complete absence of lymphocytes in peripheral blood, as well as a picture of sepsis. The cause of death in the intestinal form of acute radiation sickness is dehydration, accompanied by a loss of electrolytes and protein, the development of irreversible shock associated with the action of microbial toxins and tissue origin. Toxemic form is characterized by severe hemodynamic disturbances mainly in the intestine and liver, vascular paresis, tachycardia, hemorrhage, severe intoxication and meningeal symptoms (swelling of the brain). Observed and hyperasotemia oliguria due to renal disease. Death occurs in the 4-7 th day. Cerebral form of acute radiation sickness occurs when irradiated with doses above 80 Gy. Death in this case comes in 1-3 days after exposure, and the action of very high doses (150-200 Gr) death may occur even during the actual irradiation (death under the ray), or in a few minutes - hours after exposure, as well as local irradiation of the head at doses of 100-300 Gy. This form of radiation injury is characterized by the development of convulsive, paralytic syndromes, disorders of blood and lymph circulation in the central nervous system, vascular tone
43 and thermoregulation. Later, there are functional disorders of the digestive and urinary systems, there is a progressive decrease in blood pressure. The cause of death in cerebral form of acute radiation sickness is severe and irreversible damage of the central nervous system, characterized by significant structural changes, the death of cells of the cerebral cortex and hypothalamus neurons. The defeat of the nervous system plays a major role directly damaging effects of ionizing radiation on the fabric, as well as primary radiotoxins as H2O2 and other substances produced by oxidation of unsaturated fatty acids and phenols. Individual monitoring the effects of human exposure to doses exceeding 100 Gy indicate the occurrence of disorders in which the regulation of higher nervous activity, blood circulation and respiration. Chronic radiation sickness occurs when the body's long-term exposure to low, but higher than the permissible dose. There are two main variants of the disease: - Due to external irradiation (general or local); - Due to internal exposure (due to intake of radioactive nuclides). The disease is characterized by the gradual development of a long and undulating course, the timing of the origin and nature of the changes at the same time determined by the intensity and the total radiation dose. The initial period of the disease is characterized by unstable development of leukopenia, symptoms of asthenia, vegetative-vascular instability, and others. Open period of the disease characterized by failure of physiological regeneration of the most radiosensitive tissues in combination with functional changes in the nervous and cardiovascular systems. The recovery period is characterized by smoothing destructive and distinct predominance of reparative processes in the most radiosensitive tissues. According to the severity of chronic radiation sickness caused by common external irradiation, divided into three groups: mild (I), medium (II) and severe (III) degree. Chronic radiation sickness 1 degree (mild) characterized by mild pronounced neuro-regulatory disturbances in the activity of various organs and systems, unstable moderate leukopenia and thrombocytopenia. In chronic radiation sickness II degree (middle) joined gravity functional disorders of the nervous, cardiovascular and digestive systems. Progressing leukopenia and lymphopenia, reduced platelet count; in the bone marrow - the phenomena of hypoplasia of hematopoiesis. In chronic radiation sickness III degree (severe) anemia, the phenomena of severe hypoplasia of hematopoiesis, atrophic processes in the mucosa of the gastrointestinal tract, joining infectious- septic complications, hemorrhagic syndrome and circulatory disorders. Extremely uncommon severe, with patients developing diarrhea and cachexia. The clinical picture of chronic radiation sickness caused by internal exposure, generates a loss of one or more critical organs, which are deposited in the body received radioactive nuclides. Long-term effects of radiation may develop after the general and local exposure of the body after a number of years and are non-tumor or tumor character. For non-tumor forms in the first place include a reduction in life expectancy, hypoplastic state in hematopoietic tissue, the mucous membranes of the digestive system, the respiratory tract, the skin and other organs; sclerotic processes (cirrhosis, nephrosclerosis, arteriosclerosis, cataracts, and other radiation.) and dishormonal state (obesity, hypophysial cachexia, diabetes insipidus). One of the most common forms of long-term consequences of radiation injury is the development of tumors in critical organs during irradiation incorporated emitters (a- and radiation), a radiation and leukemia.
44 The damaging effect of rays of the solar spectrum The action of ultraviolet radiation Ultraviolet (UV) radiation to penetrate skin and conjunctiva of the eye to a depth of several tenths of a millimeter. Nevertheless, its effect is not limited to local variations, but extends to the entire body. Biological properties of UV radiation different in wavelength dependence. In this regard, the entire UV range is divided into three areas: area A (longwave) - 400-320 nm; area B (medium wave) - 320-280 nm; аrea C (short-wave) - 280-200 nm. Area A also called fluorescence (for ability to cause luminescence of some substances, such as in fluorescent lamps), or in connection with suntan chromogenic effect: under the influence of UV radiation generated from the amino acid tyrosine melanin, which organism is a protective agent against excessive UV radiation. Area B (after brief exposure to UV light in small doses) is characterized by a strong general stimulating effect. General stimulating mechanism of the photochemical action of UV radiation is associated with the ability to initiate its atoms to increase their reactivity. In general this leads to increased activity of chemical reactions in the cells, which stimulates the metabolic and trophic processes. Ultimately, the enhanced growth and tissue regeneration, increases the body's resistance to the action of infectious and toxic agents, improves physical and mental performance. UV radiation in the range 315-265 nm region in have vitamin formation antirachitic action: under its influence from the 7.8-dehydrocholesterol synthesized vitamin D3 (cholecalciferol). Area C has a strong bactericidal effect, the maximum of which is at the wavelength of 254 nm. Disposable excessive UV exposure causes skin absent suntan its photochemical burns, accompanied by the development of erythema and Blistering skin reactions, fever, headache, a common painful condition. It may be the conjunctiva eye disease (photoelectric ophthalmia) manifested its redness and swelling, burning sensation, and "sand" in the eyes, watery eyes, pronounced photophobia. Photoelectric ophthalmia phenomena can be observed both from direct sunlight and from the scattered and reflected (from snow, sand in the desert), as well as when working with artificial sources of UV radiation, such as welding. The pathogenic effect of excess disposable UV irradiation (photochemical burn) associated with the activation of free radical (superoxide) oxidation of lipids, resulting in damage to the membranes, the disintegration of the protein molecules, cell death in general. Excessive UV radiation can provoke the exacerbation of certain chronic diseases (rheumatism, gastric ulcer, tuberculosis and others.). With intensive UV irradiation due to increased melanin formation and degradation of proteins in the body increases the need of essential amino acids, vitamins, and other calcium salts. Excessive exposure to UV radiation in the range of wavelengths 280-200 nm (region C) may cause inactivation cholecalciferol to its conversion into indifferent (suprasterine) and even harmful (toxisterin) substances that must be taken into account when preventive UV irradiation. Prolonged excessive UV exposure can promote the formation of peroxide compounds and epoxy substances having a mutagenic effect, and induce the occurrence of basal cell and squamous cell skin cancer, particularly in people with fair skin. UV radiation is enhanced by so-called photosensitizing. These include dyes (methylene blue, rose bengal), cholesterol, and porphyrins, as well as contact photosensitizing (perfumes, lotions, lipsticks, creams and other cosmetics). There have been cases of hypersensitivity to UV radiation – photoallergy. For example, in people with high blood porphyrins due to violation of hemoglobin transformations (for example, hematoporphyria) even after short-term exposure to the sun can cause burns and severe state of intoxication toxic products irradiated porphyrin. Especially high sensitivity to UV radiation have xeroderma pigmentosum patients. The resulting effect of UV irradiation on the skin burns open areas of these patients in the 50% pass in carcinoma.
45 The general effect of UV radiation in conjunction with the thermal effect of the sun's rays (infrared rays heats the deeper tissues) manifests itself in the form of so-called heat stroke. The action of UV radiation on the nervous system is mediated through the skin capillaries in the irradiated blood cholesterol and proteins. There is the excitement of the autonomic centers of the hypothalamus and basal ganglia, increased body temperature, increased blood pressure and continue to fall, drowsiness, collapse and death from paralysis of the respiratory center. Sunstroke often occurs with prolonged stay on the beach.
46 The action of chemical factors Human Environment contains a large number of chemical factors, which may cause a pathological condition. Among these industrial poisons, pesticides used in agriculture, household poisons, and so on. D. Medications taken in large doses or in case of intolerance, could also lead to poisoning. In the clinical picture of poisoning distinguish the following groups of poisons - suffocating, irritating (cauterizing), blister agents, narcotics, seizure, blood, cardiac, vascular (capillary), renal, hepatic, psychotomimetic and others. In terms of biochemistry, chemical poisons can be divided for electoral effects on enzyme systems (oxidative phosphorylation poisons, toxins that block the functional groups of proteins and enzymes, enzyme inhibitors, biosynthesis, and so on. D.). Chemical poisons have both local and general effect. In terms of pathophysiology, we can speak of hypoxic poisons with different mechanisms of action; poisons predominantly central or peripheral action; poisons selectively affecting choline - and adrenergic transmission, and so forth. The study of the mechanism of poisoning is extremely important for the development of the most effective means of pathogenetic therapy. In the pathogenesis of poisoning has a number of specific features, due to the chemical characteristics of the poison. The study and identification of these features help to formulation of a differential diagnosis and the use of specific therapies. Furthermore, as a trigger, chemical poisons include pathophysiological complex system shifts up to allergic condition, shock, collapse, coma, hypoxia. For example, if a chemical poison effect accompanied by severe pain, the clinical picture of poisoning takes the form of a painful shock, and that is what is dictated by the medical tactic. Hemolytic poisons give a picture of acute oxygen starvation, capillary - collapse. Kidney and liver poisons in severe cases, cause a coma. The substances of protein nature, plant and animal origin, and certain medications can cause anaphylactic shock. Furthermore exogenous toxins, causes poisoning substance can be endogenous, ie. E. Natural metabolic products accumulated in excess. This is very important violation of neutralizing function of the liver and a violation of renal excretion of metabolic products. The intestines are home to removal of metabolic products and the formation of rotting food, it accumulates intestinal microflora and digestive enzymes are active. In violation of gut mucosal barrier function, such as ileus occurs severe poisoning organism intestinal contents. Poisoning caused by chemical poisons are content specific area of medicine - Toxicology.
47 The action of biological factors The flora and fauna surrounding the person, contains a large number of pathogenic biological agents. Many plants and their fruits are poisonous to humans (mushrooms, ergot, henbane, wolfberries). Some substances of plant origin are allergens, causing severe disease (asthma, dermatitis, etc.). Poisonous to humans are also representatives of the animal world (poisonous snakes, insects, etc.). The most extensive group of pathogenic biological agents comprise microorganisms - bacteria, viruses, rickettsia, protozoa. Penetrating into the body and multiply, they cause it to different pathological processes. In the occurrence of infectious diseases in addition to pathogen often have value and other biological objects-vectors (flies, mosquitoes, lice, ticks, etc.). Worms, multiply in the human body, poisoning it with their decay products and waste. In addition, worms contribute to sensitization of the organism. Parasites, even if they themselves do not cause severe pathological changes, can contribute to the implementation of the body other, more pathogenic agents. Microorganisms, parasites on the skin and mucous membranes of man and does not cause him any harm normal conditions are called saprophytes. However, in the case of reducing the barrier properties of the tissues, and the general immunological reactivity saprophytes can cause pathological changes. As a source of toxic substances, plants and products of animal origin may have a therapeutic effect and (ergot, a snake venom).
48 Action space flight factors. Gravity Pathophysiology. The factors that have the most significant impact on the human body in space flight include: 1) accelerate and they cause an overload on the active sites of the flight (take-off the spacecraft during descent); 2) weightlessness; 3) action stressor, particularly emotional. In addition, the condition of the astronauts is influenced by changes in the rhythm of daily periodicals, in varying degrees, expressed in sensory isolation, closed habitat with climate characteristics, some dust periodically artificial atmosphere spacecraft, noise, vibration, etc. Exposure to ionizing radiation is taken into account while ensuring the spacecraft radiation protection, in the planning of human spacewalks. Acceleration, handling. Acceleration expressed in the beginning of the flight during takeoff spacecraft and at the end of the flight during the descent of the ship from orbit (entry into the dense layers of the atmosphere and landing). Acceleration - vector quantity that characterizes the rate of change of speed or direction. The acceleration rate is expressed in meters per second squared (m/s2). "Overload" - is a force of inertia that occurs when driving with the acceleration acts in the opposite direction. The values are expressed in congestion in relative terms, indicates how many times a given acceleration increases body weight compared to the weight in a normal Earth gravity. The acceleration and overload denoted by the letter G - the initial letter of the word "gravity" (attraction, gravitation). The magnitude of the Earth's gravity is taken as a relative one. In free fall of the body in a vacuum, it causes an acceleration of 9.8 m / s2. In the conditions of the Earth's gravity force with which the body presses on the support and experience opposition from her, it is designated as the weight. In aviation and space medicine congestion are distinguished by a number of parameters, including the amount and duration (long - more than 1 second, the shock - less than 1 second), the speed and nature of growth (uniform, spiked, etc.). From the ratio of the vector to the longitudinal body axis distinguish overload longitudinal positive (in the direction from the head to feet), the longitudinal negative (from the legs to the head), lateral positive (chest-back), transverse negative (back-chest), the side positive (right left) side and negative (from left to right). Significant value for overload cause a redistribution of the blood supply in the bloodstream, a violation of lymphatic drainage, mixing organs and soft tissues, which primarily affects the circulatory, respiratory, central nervous system. Moving a large mass of blood vessels accompanied by the overflow of some regions of the body and other bleeding. Accordingly modified blood return to the heart and the amount of cardiac output, realized with reflexes press sensitive areas involved in the regulation of the heart and vascular tone. A healthy person most easily transfers positive transverse overloading (direction-to-back). Most healthy people freely transferred for one minute in this overload uniform direction of up to 6.8 units. When short-term peak overloads their tolerance increases significantly. When transverse accelerations exceeding the limit of individual tolerance, impaired lung function, blood flow changes in the vessels of the lungs, frequent sharp contraction of the heart. With increasing magnitude of transverse accelerations possible mechanical compression of individual light areas, poor circulation in the small circle, decrease in blood oxygenation. At the same time in connection with the deepening of hypoxia quickening heartbeats replaced slowdown. More difficult than cross-tolerated longitudinal overload. Positive longitudinal accelerations (in the direction from the head to the feet) hampered the return of blood to the heart, reduced blood supply of the heart cavities and thus cardiac output, decreased blood circulation in the vessels of the cranial parts of the body and brain. On the reduction of blood pressure in the carotid arteries responds receptor apparatus sinocarotid zones. As a result, there is tachycardia, in some cases, there are cardiac arrhythmias. If increase individual resistance limit the expressed cardiac arrhythmia, impairment in the form of veil, respiratory disorders, pain in the epigastric region. Tolerability longitudinal accelerations positive in most cases is within 4.5 units. However, in case of overload 3 units occur in some cases expressed cardiac arrhythmia.
49 Another negative longitudinal overload heavier transferred (in the direction of feet-head). In these cases, an overflow occurs in blood vessels of the head. Increased blood pressure in the reflex zones of the carotid arteries is a reflex slowing of the heart rate. With this type of overload cardiac arrhythmias in some cases, already marked at accelerations magnitude 2 units, and prolonged asystole - the acceleration value of 3 units. If you exceed the limit of stability of an individual having a headache, visual disturbances in the form of a veil before the eyes, heart arrhythmia, impaired breathing, lightheadedness occurs, then there is a loss of consciousness. Portability overload depends on many factors, including the magnitude, direction and duration of the acceleration, the nature of their growth, the position of the human body and its fixation, exercise, a reactivity of an individual, etc. Weightlessness (the state of "zero gravity"). Weightlessness occurs under certain conditions. According to Newton's law of gravity, any two material particles are attracted to each other with a force (F), is directly proportional to the product of their masses (m1 m2) and inversely proportional to the square of the distance (d) between them: F = G x (m1 x m2 / d2) KE Tsiolkovsky defined as a state of weightlessness, in which the forces of gravity 'does not act on the observed body or act on them is very weak ... ". Static weightlessness occurs in different situations, such as being in a space at a great distance from Earth; the body does not feel the Earth's gravity. Dynamic weightlessness arises in circumstances where the force due to gravity is balanced by the oppositely directed centrifugal forces. The orbital space flight body moves mainly under the influence of inertial forces (except during engine operation, correcting the flight path). In orbital flight inertial force is balanced by the force of Earth's gravity. It determines the state of weightlessness and spacecraft of all moving objects with him. In the absence of gravity in weightlessness disappear stress and pressure on the own weight of the body structure. Accordingly, it changes the load on the musculoskeletal system: the blood disappears weight and, consequently, the hydrostatic pressure of the fluid in the blood vessels; there are conditions for a substantial redistribution of blood in the bloodstream and body fluids; feeling disappears support; changing conditions of operation responsive to the direction of gravity analyzer systems; there is disagreement among the various departments of the vestibular analyzer. Changes in blood flow in zero gravity caused by several factors. Under the conditions of the Earth's gravity transport of fluid through the capillary walls under the Starling equation is determined by the relations of hydrostatic and colloid osmotic pressure in the capillaries and surrounding tissues. As the hydrostatic pressure decreases in the direction from the arterial to venous end of the capillary, the liquid from the filtration vessel in the tissue is replaced by its reabsorption into the vessels of the tissue. In weightlessness ratio of filtration and reabsorption changes. This is reflected in the increase in fluid absorption at the level of capillaries and venules and is one of the factors causing the increase in the beginning of the flight volume of circulating blood and tissue dehydration in certain regions of the body (especially the legs). fluid column height stops to influence on the pressure in the small and large blood vessels. In microgravity, it depends on the suction and discharge functions of the heart, the elastic properties of the pressure vessel walls and surrounding tissue. In weightlessness differences venous pressure in the vessels of the forearms and legs are smoothed. The disappearance of the weight of the blood facilitates the movement of the veins of the lower half of the body to the heart. The outflow of blood from the veins of the head, makes it easier on the Earth gravity in weightless conditions is difficult. This causes an increase in blood volume in the blood vessels of the head, swelling of the soft tissues of the face, and distension also sensation head, sometimes a headache in the early days of flight (the period of acute adaptation). In response to these violations occur reflexes, altering the tone of cerebral vessels. Redistribution of blood in the bloodstream, changing venous return, the disappearance of such a significant factor as the hydrostatic pressure, reduced overall energy consumption of the body - all affect the heart. In weightlessness changes the load ratio on the left and right side of the heart. As a
50 result of changing the phase of the cardiac cycle, the bioelectric activity of the myocardium, diastolic blood filling of heart cavities, tolerance of functional tests. Due to the redistribution of blood in the bloodstream of the body's center of gravity is shifted in the cranial direction. In the early period of stay in weightlessness substantial redistribution of blood in the bloodstream and the change of blood filling of heart cavities are seen afferent systems of the body as the information on the increase in blood volume and cause reflections aimed at liquid discharge. Changes in water-electrolyte metabolism in the early period of stay in weightlessness explained mainly a decrease in the secretion of antidiuretic hormone and renin, aldosterone, and then, as well as an increase in renal blood flow and an increase in glomerular filtration rate and decrease canalicular reabsorption. In experiments on animals for modeling of weightlessness noted that the water content decreases in the body, the muscles and increases in sodium reduced potassium content, which may be a consequence of changes in the microcirculation. In zero gravity disappears load on the spine, stops the pressure on the intervertebral cartilage, become unnecessary static force of antigravity muscles that counteract the forces of the Earth's gravity and allow the world to hold the position of the body in space, reducing the overall tone of the skeletal muscles, reduces stress on the body movement and objects vary coordination movements and the nature of stereotyped motor acts. Prolonged exposure to weightlessness can cause changes in the structure and function of the musculoskeletal system. It is known that bone has a high plasticity and susceptibility to the effects of regulatory changes and loads. One of the factors affecting the bone structure is a mechanical load. When compression and tension in her bone structure appears a negative electrical potential that stimulates the process of bone formation. By reducing the load on the bone occurring disorders depend on the generalized violations of metabolic and regulatory processes. With no load on the bones of the skeleton is reduced mineral saturation of bone observed calcium out of the bones and the general loss of calcium, there are generalized changes of protein, phosphorus and calcium metabolism, etc. Long load reduction of skeletal muscles (in the absence of preventive measures) causes atrophic processes, as well as the impact on the energy exchange, the general level of metabolic processes and state regulatory systems, including tone higher autonomic centers of the brain. It is known that muscle relaxation is accompanied by a decrease in the tone of the autonomic centers of the hypothalamus. Under the influence of weightlessness decreases tissue oxygen consumption, muscle decreases the activity of enzymes of the Krebs cycle and oxidative phosphorylation of the pairing process, increases the content of glycolysis products. After space flight marked decrease in red blood cell mass. Recovery hematological parameters occurs within 1.5 months after the end of the flight. These shifts are explained compensatory decrease in the circulating blood volume in the flights and significantly more rapid recovery of blood plasma volume than the red blood cell mass following operations. Furthermore, these changes in the weightlessness associated with the expectation of muscle mass and decrease body compensatory response aimed at increasing the oxygen request tissues. Stress effect. In the context of spaceflight person is exposed to stress, which are based on a combination of factors: changes in the effects of gravity, tension attention, heavy loads, etc. The period of acute adaptation to weightlessness can be characterized as a stress reaction, which arose in response to a set of specific (zero gravity) and nonspecific factors (emotional and physical stress, altered circadian rhythms, circulatory disorders). Space form of motion sickness, which has similarities with seasickness, manifested during the early days of flight. With quick movements of the head observed dizziness, pale skin, drooling, selection of cold sweat, change in heart rate, nausea, vomiting, change in condition of the central nervous system. These disorders primarily due to changes in the microcirculation of the brain vessels. The genesis of the cosmic form of movement of the disease play an important role partial loss of information coming from the various analyzer systems that provide spatial orientation. For example, information from the different structures of the vestibular apparatus mismatched (in weightlessness preserved function of the semicircular canals respond to angular acceleration caused
51 by rapid movements of the head, and falls function otoliths). Current information from the sensors in weightlessness does not correspond to the stereotypes that are stored in non-volatile memory of the central nervous system. In most cases, the astronauts relatively quickly adapt to factors that cause motion sickness, and her symptoms disappeared after the first three days of flight. In the early stages of flight status changes of sensory systems may be accompanied by disorders of spatial orientation, illusory sensations inverted body position, movement coordination difficulties. The immunological reactivity of the organism. After spaceflight exceeding 30 days, usually marked decrease in the functional activity of cell populations related to immune T-system, and in some cases there are signs of sensitization to microbial and chemical allergens. These changes increase the risk of infectious and allergic diseases, and may be a consequence of the restructuring of the immune system in the process of adaptation to a range of flight factors. The flow of the processes of adaptation can clearly be seen in ground-based studies, simulating the effect of space flight factors on the body. In terms of strict bed rest (hypokinesia) antiorthostatic in a position in which the head end of the bed lowered 4°C angle to the horizontal plane, there are changes that have similarities to arise in weightlessness. Manifestations of hypokinesia (in the absence of preventive measures are more pronounced than in space flights): 1) changes in systemic hemodynamics, reducing the burden on the myocardium, de-conditioning of the cardiovascular system, the deterioration of portability orthostatic tests; 2) changes in regional blood flow (in the basins of the carotid and vertebral arteries), which is caused by obstruction of venous outflow from the blood vessels of the head and the corresponding compensatory changes in the regulation of vascular tone; 3) changes in blood volume and a decrease in red blood cell mass; 4) changes in water and electrolyte metabolism (loss of potassium); 5) changes in the central nervous system and the state of autonomic cardiovascular changes, and autonomic dysfunction phenomenon asthenia; 6) partial atrophy of the muscles and neuromuscular disorders; 7) the regulatory imbalance systems. In terms antiorthostatic hypokinesia changes microcirculation. For example, in the blood vessels of the conjunctiva eyes reduced the number of perfused capillaries, varies the ratio of the diameter of arterioles and venules; in the vessels of the fundus observed stagnation. Unlike systemic hemodynamics compensatory changes in the microcirculation system arise at a later date hypokinesia. Under the influence of hypokinesia significantly increased predisposition to emotional stress and severity of autonomic manifestations - heart (arrhythmias) and vascular (hypertensive reaction). In space flight the emergence of these changes is possible to prevent using a system of preventive measures. However, while reducing the requirements for astronauts health or attention to the implementation of preventive measures is clearly a risk factor increases. Readaptation. At the conclusion of the flight transition from zero gravity to overloading during descent and return to Earth's gravity after landing, combined with significant emotional stress and are, essentially, the combined stress occurring in conditions of intense adaptation reactions. The changes reflect the state of the body's adaptive dynamics and stress reactions. During the period of re-adaptation will cease factors causing dehydration in weightlessness, redistribution of blood flow line, etc. At the same time there is a need to mobilize urgent adaptation mechanisms to ensure the normal functioning of the body in conditions of the Earth's gravity. Soon after completion of the flight manifest cardiovascular de-conditioning system, residual impairment of microcirculation in the vessels of the head, the body changes the reactivity and the state of its regulatory systems. Circulation quickly adapt to Earth's gravity. In particular, after months of flight stagnation in the fundus and signs peripapillary retinal edema disappear within the first week after the end of the flight. After space flights lasting up to 14 days observed increased activity of the hypothalamic- pituitary axis and sympathoadrenal systems. After the flight, which lasted from 2 to 7 months, found increased activity sympathoadrenal system in the absence of signs of increased activity of the hypothalamic-pituitary system. So, after months of flight is characterized by an increase in the secretion of adrenaline (the most in the first day) and norepinephrine (a maximum of 4-5 days after
52 landing) at a fixed concentration of ACTH, thyroid and growth hormone, cyclic nucleotides in the blood and reduce the concentration of prostaglandins and pressor group plasma renin activity in these terms. Relations hormonal and mediator exchanges are one of the indicators of a certain imbalance in the regulatory systems of the body. In connection with the reduction of orthostatic stability and changing stereotypes motor acts astronauts in the first hours after landing hard in an upright position and walk without assistance. As a result, the adaptive adjustment is quickly restored stereotype motor acts, normalize metabolic processes, state regulatory and executive body systems. Problems developed modern space medicine, cover a wide range of issues, including clarification of the mechanisms of human adaptation to the effects of weightlessness in flight factors, mechanisms of reintegration upon return to the conditions of the Earth's gravity, improving the efficiency of management of these processes.
53 The role of psychogenic factors in the pathology Diseases in which the occurrence of the leading role played by emotional stress or other disturbances of higher nervous activity, called neurogenic or psychogenic. Any trauma is accompanied by pronounced autonomic disorders, which in severe cases may be in the nature of psychogenic shock. Much more often than acute trauma, it is a chronic overstrain of nervous activity. This is usually less noticeable, but the consequences will inevitably appear. Trauma and mental fatigue reduces the ability of the nervous system to mobilize the defense mechanisms, violate her functional mobility, limit its flexibility to adapt to ever-changing environmental conditions and internal environment. Chronic trauma of the nervous system decreases the body's resistance to disease. Emotional stress can become unfavorable background against which any pathological stimulus causes the disease. The emotional state can determine the outcome of the pathological process. It should be said about the meaning of words. By definition, Pavlov, is "strongly conditioned stimulus is not included in any quantitative and qualitative comparisons with other stimuli." We describe the facts of sudden death from posts, joyful or tragic. Particularly exposed to sick people words. The authoritative word of the doctor should be, so it is particularly careful. Section of medicine dealing with the influence of psychogenic factors in the course of the disease, called the medical deontology.
54 Pathogenic action of sound and noise Noise - an unpleasant or unwanted sound or set of sounds to break the silence, irritating effect on the human body and reduce its efficiency. The area of high pressure and follows her area of low pressure to form sound waves. Spreading in the air at a speed of about 340 m / s, they carry a certain amount of energy. The human ear perceives sound vibrations with a frequency of 16 to 20,000 Hz (Hz 1 - is one in 1 wobble). High frequency sounds (up to 4000 Hz) are perceived by man as louder when the same intensity. When the sound intensity exceeds 1 mW / cm2, it may be damaging effect on the auditory analyzer. When the sound intensity of more than 3 kW / cm2 lead to abnormalities in the overall condition of the body: possible convulsions, complete loss of consciousness, paralysis. Pathogenic effect of noise is determined by the volume and frequency response, while the greatest harm generate high-frequency noise. Normally constant acceptable level of noise (intensity of which varies by no more than 5 dB in time) is considered to 40-50 dB. This is the level of ordinary human speech. Harmful border volume of 80 dB. The conversation in a raised voice can cause auditory stress. In areas of even a short stay banned from the sound volume in excess of 135 dB. In today's concert rock music sound volume may exceed 120-140 dB, which corresponds to the level of jet noise. Even a 40-minute stay in the room with the sound volume can cause a concussion. A case where the lake is located near the outdoor concert venue, while «PinkFloyd» the concert emerged stunned fish. An interesting table leads the German magazine «Stern».
Noise levels of different sources Type of noise Noise level, db leaves rustling 10 car, traveling at normal speed 50 freight train 98 motorcycle 104 a jet plane at an altitude of 600 m 105 thunder 112 concert rock band «LedZeppelin» 123 shelling 130
From this table it is clear why so many rock musicians, long subjected to the action of his music (where the noise level is close to the threshold of pain sensitivity - 130 dB), suffer from persistent hearing impaired. Long sound volume 155 dB causes severe violations of human activity; volume of 180 dB is deadly for him. In ancient China, there was a penalty music, and some African tribes killed sentenced drumbeats and shouts. There are specific and non-specific effect of noise on the human body. The specific effect of the noise associated with impaired function of the auditory analyzer, which is based on a long spasm of sound-system, leading to disruption of metabolic processes and as a result - to degenerative changes in the endings of vestibulo-cochlear nerve cells and the organ of Corti. Noise level 80-100 dB and above fairly quickly cause hearing loss and hearing loss development. Strong short-stun (concussion) can cause temporary (reversible) hearing loss. The initial stages of hearing impairment manifest bias threshold of hearing. Damaging action noise on the audio analyzer depends on individual sensitivity of the body and is more pronounced in the elderly, when the structure of anomalies and diseases of the organ of hearing. Non-specific effects of noise on the human body due to the excitation enters the cerebral cortex of the brain, the hypothalamus and spinal cord. In the initial stages of developing protective inhibition of the central nervous system with impaired mobility and balance of excitation and inhibition. The resulting in further depletion of nerve cells is the basis of increased irritability, emotional instability, memory impairment, reduced attention, and performance.
55 The response of the body's hypothalamic arousal is realized by stress reaction type. On admission to the spinal cord excitation is switched him to the centers of the autonomic nervous system, which causes a change in the functions of many internal organs. As a result of prolonged exposure to intense noise develops noise disease - a common disease of the body with a primary violation of the organ of hearing, central nervous and cardiovascular systems, organs of the gastrointestinal tract. Ultrasound - inaudible to the human ear elastic waves whose frequency exceeds 20 kHz. The main physical characteristics as the ultrasonic acoustic radiation are frequency, intensity (power density or - W / cm2) and the pressure (Pa). In recent years, ultrasound found use in medical practice for therapeutic and diagnostic purposes. Unequal propagation velocity of ultrasonic vibrations, as well as varying degrees of absorption and reflection in different media biologic and tissues can detect the shape and location of the brain tumor and the liver and other internal organs formations, set the fracture site and bone fusion, to determine the size of the heart over time and etc. Methods of extracorporeal lithotripsy (shock wave focused on the impact of kidney stones and gall bladder) also have ultrasonic nature. Also useful result (destruction of hard stones), these effects lead to undesirable consequences in the form of internal bruising in the soft tissues adjacent to concretions and are in shock radiation focus zone. The biological effects of ultrasound due to its mechanical, thermal, physical and chemical action. sound pressure ultrasonic wave can vary ± 303.9 kPa (3 atm). Negative pressure promotes the formation of microscopic cavities in the cells, followed by rapid slamming them, which is accompanied by intense hydraulic shocks and discontinuities - cavitation. Cavitation leads to depolarization and destruction of molecules, causing their ionization that activates chemical reactions, normalize and accelerates processes of tissue metabolism. The thermal effect of ultrasound is mainly due to the acoustic energy absorption. When the ultrasound intensity of 4 W / cm2 and its exposure for 20 seconds temperature tissues a depth of 2-5 cm is increased by 5-60 ° C. The positive effect of the biological tissue causes ultrasound small (up to 1.5 W / cm2) and medium (1.5-3 watts / cm2) intensity. Ultrasound of high intensity (3-10 W / cm2) has a damaging effect on individual cells, tissues and the organism as a whole. Exposure to high intensity ultrasonic waves gives capillary blood flow, causing destructive changes in cells, leading to local overheating tissues. High sensitivity to the action of ultrasound is characterized by nervous system: selectively affects the peripheral nerves, impaired transmission of nerve impulses in the synapses. This results in a vegetative polyneuritis and paresis, increase the threshold of excitability of the auditory, vestibular-cochlear and visual analyzers, sleep disorders, irritability, fatigue. Compared with the noise of high frequency ultrasound has little effect on the function of the auditory analyzer, but is more pronounced changes in the functions vestibular-cochlear organ, increases pain sensitivity violates thermoregulation. It should be noted that in modern ultrasound scanners, manufactured in Russia, the maximum intensity of the emitted oscillations does not exceed 50 mW / cm2. In this study of the effects of ultrasound on biological structures (blood cells, bone tissue, reproductive organs) show that the average level of ultrasound intensity up to 100 mW / cm2 (used in diagnosis) are any significant changes in the tissues are not detected.
56 The damaging effect of laser radiation Lasers - devices for narrow beams of monochromatic light of high intensity energy have been used successfully for the treatment of a variety of diseases (diseases of the eye, the tumor growths and others.). The action of the laser radiation is measured in hundreds of thousand of a second, so, despite the fairly deep penetration of the laser beam into the body (20-25 mm), pain sensation does not arise. The greatest sensitivity to laser radiation have pigmented tissue. The mechanism of action of the damaging laser radiation has not been studied. Direct laser damaging effect on the cell associated with the excitation of atoms and ultimately damage to protein molecules. An important role in the laser damaging effect plays free radical mechanism. The formation of free radicals under the action of a laser beam was detected in tissues and black melanin skin of mice and also in pigmented areas of skin of guinea pigs. Laser radiation has a thermal and cavitation effects. The thermal effect is due to the absorption of energy cloth infrared part of the spectrum of radiation and heat inactivation of the protein. Cavitation effect due to rapid increase in temperature to a level at which the vaporization of the cell fluid. There is a "blast effect" (cavitation) due to the instantaneous formation of a cavity with high pressure (up to tens and hundreds of atmospheres) and extending from her shock wave tearing tissue. This effect is the basis of the laser scalpel. One mechanism for the damaging action of the laser radiation can also be caused by inactivation of enzymes, or they change their specific activity. Intensity of the damaging effect of laser radiation depends on the type of the optical maser, density and output power, physical, chemical and biological characteristics of irradiated tissues (the degree of pigmentation, blood filling, and thermal conductivity).
57 TYPES OF DAMAGE ON DIFFERENT LEVELS OF MULTICELLULAR ORGANISMS Damage - violation of biological structure, leading to disruption of the structure features resulting from interaction with the damaging factor. Damage - the initial link in the pathogenesis (development mechanism) of disease; Pathogenic factors can cause damage by acting directly on the biological structure of the organism (primary) and indirectly - as a result of the launch of responses, many of which are themselves capable of causing an additional, secondary damage. The action of various pathogenic factors can lead to damage at various levels of organization of life: molecular, subcellular, cellular, tissue, organ, system and organism. The interaction of structures of any of the above levels capable entail either reversible, able to be restored, or irreversible, not able to heal the injury. Two main types of damage can be distinguished at the molecular and subcellular levels: - A destruction - irreversible destruction of biomolecules to their components or simple inorganic substances - Modification - reversible change in the structure of protein molecules without destroying them. For example, non-specific toxic chemicals (strong oxidizers acid. Alkalis, etc.), high doses of ionizing radiation, high temperature, causing coagulation of protein, lead to the destruction of all living structures irreversibly destroying components of biomolecule. On the contrary, "a modification of a protein receptor molecule to molecule acetylcholine muscle relaxant ditilina leads to its reversible change, making it impossible to the normal response of the receptor to acetylcholine. Although this structure does not fracture the receptor occurs, resulting in impaired transmission of electrical pulse at the neuromuscular synapse, resulting in paralysis of muscles, including respiratory. As a result, the body can die from lack of oxygen due to reversible changes in the structure of only one of the proteins. Thus, there are specifically toxic chemicals, including many drugs and poisons. Thus, damage (alteration) - a comprehensive term, it includes the destruction - destruction, and any change in the biological structure at all, violating its function. Damage at the cellular level. Cell - an elementary biological system capable of self-renewal, self-reproduction and development. Interaction between cells and the external environment is a necessary condition for maintaining the operating life of the organism. In this cell, although subject to the general correlative influences and links from other cells and the organism as a whole, but also works by its own laws and in Rada cases may go out of control these common correlative influences. Normal cells respond to the constantly changing demands and external influences. The cell is capable of changing the structure and function in a fairly narrow range. If it is excessive impact or are pathological factors, it can be adapted, reaching a steady state, in order to maintain adequate cell activity in the changed circumstances. If the cell can not be adapted or adaptable possibilities have been exhausted, there is damage that is reversible to a certain point, but if the effect of excessive or prolonged, irreversible changes and the cell is doomed. The term equivalent death as irreversible damage we may apply to biological structures, since their level of cellular organization. Irreversible damage at the cellular level have her death, which can be violent (murder) - necrosis and non-violent (suicide) - apoptosis. You can draw an analogy with the free-standing tree in the wind: it bends and sways to a certain point, but quickly regains its original position when a gust of wind ceases. The stronger the wind can blow the leaves and broken branches, but the damage is not fatal, the hurricane can also pull out a tree by the roots, resulting in irreversible damage, in which survival is impossible, It involves whether for a specific effect of adaptation or damage (reversible or irreversible), depends not only on the nature and intensity of the current factor, but also from the many conditions that occur in these cells and their microenvironment, such as the degree of differentiation that preceded the impact of the state of the cell, blood supply, supply of nutrients, and you can find the following general rule: the faster the cells divide and the more oxygen consumed (ie, the higher the intensity of metabolism in the cells), the more they are susceptible to damage by the action of various factors and changing conditions of existence. The validity of this statement we can still
58 repeatedly seen by considering hypoxic, and other types of radiation damage to the cells of various organs and tissues. The problem of studying the sequence of events when damaged cells at the molecular level is rather complicated. Cell damage can be caused by various reasons, and will likely have a specific pathway leading to cell death. Many macromolecules, enzymes, organelles inside the cell interact so closely that it is impossible to identify a primary object damage. The boundary separating the reversible and irreversible changes, and has not yet been determined. However, there are certain structures and processes, it is absolutely necessary for the life of the cell, the violation of which leads to her death: - The integrity of the cell membrane structure and its receptor system, which is necessary for the normal processes of cell metabolism and cell interaction with the environment; - Oxidative phosphorylation and ATP production, taking place in the mitochondria, and necessary for the implementation of energy-dependent functions; - The synthesis of enzyme and structural protein; - The integrity of the genetic apparatus of the cell. Let's try to systematize the factors that can disrupt the normal life of a multicellular organism cells. Violation of cell activity may be the result of: 1) deficit that it needs to produce energy in the form of ATP, an update of its own structures and maintaining internal homeostasis: - Oxygen; - For the oxidation of substrates (primarily glucose) structural elements (amino acids, fatty acids, etc.), аnd vitamins; 2) destruction in nonbiological action of high energy factors causing any degradation of the cells: - Physical (high temperature and low temperature, ionizing radiation, electrical current, etc.); - Mechanical; - Chemicals - non-specific toxic substances; 3) cell specific disorders structure hormone receptors and neurotransmitters, ion channels, due to intracellular enzymes joining them specifically toxic chemical and biological toxins; 4) the immunological destruction of antibody labeled cells, such as proteins of the complement system, or phagocytes. Separately, it should be said about the micro-organisms as a factor that damage cells. It is known that about 90% of all clinical entities caused by microorganisms. Many micro-organisms do not cause harm to a multicellular organism cells that live on the surface of the mucous membranes and skin, and even benefit, not allowing to multiply pathogenic microbes. Some of the pathogens of infectious agents (viruses, intracellular bacteria) are able to enter cells, replicate them and immediately destroy. Other penetrating into the tissue or populating mucous membranes and skin, causing damage to the tissue level (extracellular bacteria, fungi, protozoa, helminths). At the same time they use the body as a medium for their habitat, often with their pathogenicity factors (enzymes, toxins, metabolic products) destroying cells and extracellular matrix. These toxins may exhibit specific toxicity by binding to specific receptor or enzyme proteins or cellular organelles and disrupting their activities. For example, diphtheria toxin binds to a ribosomal subunit and gives thus broadcast - beam synthesis based on the messenger RNA. The process of introducing infectious agents in the macro-organism (colonization), highlight their pathogenicity factors, dissemination of Macro-Organism effects on the host and transfer to another macroorganism is called infection and is one of the standard forms of pathology. More, this phenomenon is seen in the course of microbiology. Damage to the tissue level. In most cases, the introduction of infectious agents causing damage to a group of cells - tissue site. Similarly, the effect of damaging factors with high energy (mechanical trauma, high and low temperature, non-specific toxic chemicals), as well as the acute shortage of oxygen supply of cells can lead to irreversible damage to many local cells in the tissue
59 site, their violent death - necrosis. It is usually accompanied by the introduction of infectious agents and produces stereotypical response of the body - a typical pathological process at the tissue level: inflammation. During his leukocytes and plasma proteins exit the blood vessels in the tissue for phagocytosis of dead cells and infectious agents infiltrated. Later in the place of necrosis formed coarse-fibered connective tissue - shaped scar. Damage at the organism level. Irreversible damage to the organism level is determined by the possibility of restoring the vital functions. With regard to human (social and philosophical aspects) death is the loss of higher cognitive (cognitive, mental) functions depending on the cerebral cortex. Therefore, irreversible damage to the organism level in relation to the person is the death of the cerebral cortex, which is proved by the data of electroencephalography, magnetic resonance imaging, and others. In all cells of our body, particularly the brain cells are critically dependent on the ATP content, which is determined by the delivery of oxygen through the blood. For this reason, it is the oxygen deficiency is the most common factor causing violation of the functioning of cells and reversible and irreversible damage. It is an acute shortage of oxygen protects the cells most vulnerable vital organs (brain and heart) complex non-specific adaptation reactions called stress. It aims to mobilize all the functional resources of the body, blood flow redistribution and metabolic resources to the brain and heart.
60 DAMAGE TO CELLS The doctrine of the damaged cells in modern medicine has a special meaning. This is due, at least three reasons: First, it is closely linked to the development issues of the origin, development and outcome of diseases, since any pathological process is accompanied by damage to cells; Secondly, more intensive introduction into clinical practice different ways of restoring livelihoods damaged organs and tissues has set a target for the study of mechanisms for eliminating or reducing the degree of alteration, as well as the development of methods for the activation of protective, compensatory and adaptive reactions in the cells in order to optimize the recovery process; Third, understanding the molecular pathology of many discoveries of recent times, it is possible only under condition of determining their place and importance from the standpoint of cell pathology and cell-cell interactions. The cell is a self-regulating elementary structural and functional unit of tissues and organs. It flow processes underlying the energy and plastic provide varying structures and levels of functioning of tissues and organs. Various pathogenic agents acting on a cell, it can cause damage. Damage to cells - is genetically determined or acquired changes in metabolism, physical and chemical parameters, the conformation of macromolecules, cell structures, leading to disruption of its function and activity. Cell damage underlies any disease or pathological process. Damage to cells is a general law of the disease The doctrine of the damaged cells are conventionally divided into three sections: 1) the whole cell pathology; 2) the pathology of individual subcellular structures and components; 3) The pathology of intercellular interaction and cooperation.
CAUSES DAMAGE TO CELLS Cell damage may result from exposure to the plurality of agents. These agents are divided into different groups depending on their nature and origin.
Types by their nature causes cell damage 1. Mechanical effects: strokes, stretching (for example, distension of the muscle tissue or organs); compression (in particular tumor, hematoma, scar, exudate), gravitational overload, etc; 2. Physical factors. The most frequent causes of damage to the physical nature of the cells include the following: - Fluctuations in temperature. Increasing the temperature of the medium in which the cell, to 45 - 50° C and more can lead to protein denaturation, the nucleic acids of lipoprotein complexes decompose, increasing the permeability of cell membranes and other changes. A significant reduction in temperature can cause a significant slowdown or irreversible cessation of metabolic processes in the cell, the crystallization of intracellular fluid and rupture of the membranes; - Varying the osmotic pressure in the cell, for example, due to accumulation therein of incomplete oxidation products of organic substrates or excess ions. The latter, usually accompanied by the flow of liquid into the cell by osmotic pressure gradient, swelling and stretching it (up to fracture) plasmolemma membranes and organelles. Conversely, a decrease in intracellular osmotic pressure or an increase in the extracellular medium it will result in loss of cell fluids, its shrink (pyknosis) and often to death; - Exposure to ionizing radiation, causes the formation of free radicals and peroxides lipoperoxide activation processes, products that damage the membrane and denature the enzymes of cells. Pathogenic effects on cell can also provide electromagnetic and other physical factors. 3. Chemical factors. Among the factors the chemical nature of cell damage include a variety of ingredients: organic and inorganic acids, alkalis, salts of heavy metals and products of disturbed metabolism. For example, cyanides inhibit the activity of cytochrome oxidase. Ethanol and its metabolites to inhibit many enzymes cells. Substances containing arsenic salts inhibit piruvatoxidase. Improper use of drugs may also lead to cell damage. Eg, overdose strofantina
61 causes significant inhibition activity of K +, Na + -ATPase activity of sarcolemma myocardial cells, which leads to an imbalance of intracellular ions and fluid content. An overdose of insulin can cause rapid use of glucose, depletion of its reserves in the form of glycogen and a violation of the energy supply cells. Importantly, the cell damage may be due to excess and deficiency of the same agent. For example, an excess of oxygen in the tissues activates the process of free-radical lipid peroxidation (FRPOL), products which damage cell membranes and enzymes. On the other hand, the reduction of oxygen content causes a violation of oxidation processes, the reduction of ATP and, consequently, cell function disorder. 4. Biological factors. a large number of factors included in this group the causes cell damage. The most significant among them - viruses, rickettsia, bacteria, parasites, fungi. The products of their life or cause degradation of cell function disorders, during the break in her metabolic reactions, permeability or integrity of membranes, inhibit the activity of cellular enzymes. Damaged cells are often determined by factors of immune and allergic disorders. They may be caused by, in particular, antigen affinity, such as microorganisms and cells. For example, some types of hemolytic streptococcus and the proteins of the basement membrane of renal glomeruli have similar antigenic composition. Once in the body, they cause the formation of antibodies that damage as streptococci and nephrons. Endo - and exotoxins, and structural components of bacteria, viruses and parasites can change the composition of antigenic cells, which leads to the production of antibodies or immune T-lymphocytes, damaging its own cells, causing may develop autoimmune disease process. Damage can also be the result of antibody or T-lymphocytes acting against unmodified organism cell due to mutations in the genome - or T lymphocytes of the immune system. An important role in the maintenance of metabolic processes in the cell play physiologically active substances and factors coming from neuron endings, in particular enzymes, proteins, lipids, adenine nucleotides, trace elements and other. Their deficiency or excess can cause metabolic disorders in cells violations their functioning and development of various pathological conditions. Cell damage is often due to significantly enhance the function of organs and tissues. For example, when long-term excessive exercise may develop heart failure as a result of violations of cardiomyocytes life.
Types of causes of damage to cells according to their origins The origin of the causative factors of cell damage is divided into 2 subgroups: - Exogenous and endogenous; - Infectious and non-infectious. Exogenous factors. These include the physical effects: mechanical, electricity, heat, cold; chemical agents; Biological: viruses, rickettsia, bacteria, parasites, etc. Endogenous factors. These agents include physical nature: a cell or in an excess of free radicals extracellular environment, considerable variations in osmotic pressure; chemical factors deficit or excess ions (H +, K +, Ca2 +, etc.), oxygen, carbon dioxide, organic peroxide compounds and inorganic nature, metabolites, etc .; biological nature of factors deficit or excess of a physiologically active substance (catecholamine hormones, prostaglandins, etc.); of life or decay products of viruses, bacteria, parasites, rickettsiae; Products released from other damaged or dead cells. Infectious factors. Examples of these microorganisms can be toxins, parasites themselves. Factors of non-infectious origin. These factors include physical, chemical or biological nature of non-microbial origin. The action of damaging factors on the cells is carried out directly or indirectly. In the latter case we are talking about the formation of the chain of secondary reactions, the formation of substances-intermediaries implementing the damaging effect of the so-called "primary" pathogenic factor. Its effect may be mediated by changes in neuronal or endocrine effects on cells (eg, under stress, shock); violation of the circulatory system (heart failure); deviation of the physico-chemical
62 parameters (for conditions involving acidosis, alkalosis, the formation of free radicals, FRPOL products, imbalance of ions and fluids); immunoallergic reactions in autoimmune diseases; the formation of an excess or deficiency of biologically active substances (histamine, kinins, prostaglandins). Many of these and other agents involved in the development of various forms of pathology of cells were called mediators or mediators (e.g., inflammatory mediators, allergies, etc. carcinogenesis.), damage.
GENERAL MECHANISMS OF CELL DAMAGE The specific mechanisms of cell damage. The first event, which ultimately leads to cell damage - is damaging agent interaction with target-molecules. Thus, targets may be UV aromatic groups of proteins, enzymes and receptors or nucleotides in the DNA and RNA molecules. The target for carbon monoxide are various heme- containing enzymes. The target of the action of hypoxia are the mitochondria, which are no longer store energy in the form of ATP, etc. Interaction target damaging factor c can lead to damage of the target itself that occurs, for example, under the action of ultraviolet rays on the cells. In other cases, the target is not damaged by the actions of agents, but temporarily ceases to function. That is, this leads ultimately to cell damage in general. For example, turn off the function of cytochrome oxidase, which in this case serves as a target for the action of the poison cyanide. But the enzyme is not damaged: if you remove cyanide from the environment, cytochrome oxidase function is restored. The cause of cell death is subsequent damage to cell structures, caused by prolonged cessation of power supply. Thus, between the point of interaction with the target damaging agent and certain process damage cell structures may occur entire chain of events.
Acting agents The main target Primary process Toxins Active center enzymes and Inactivation of enzymes, receptors and receptors ion channel blockade Ionic channel Ultraviolet radiation Nucleic acids and proteins nucleotides and amino acids of certain photochemical reactions Microwave millimeter water molecules Accelerating, limited diffusion in an wave aqueous medium hypoxia Mitochondria Reduced ATP synthesis hyperkalemia cell membranes The decline in membrane potential, excitement
Non-specific mechanisms of cell damage I. Violation of energy supply of the processes occurring in the cell: - Reduction of intensity and (or) the efficiency of ATP resynthesis process. - Violation of the transport of ATP energy. - Violation of using the energy of ATP. II. Damage to the membrane device and enzyme systems of the cell: 1. Excessive intensification of free radical reactions and FRPOL. 2. Significant activation of hydrolases (lysosomal, membrane-free). 3. Introduction of amphiphilic compounds in the lipid phase of membranes and their detergent effect. 4. Slowdown of resynthesis of damaged membrane components and (or) the synthesis of them again. 5. Violation of the conformation of protein molecules, lipoproteins, phospholipids. 6. Hyperextension and rupture of the membranes swollen cells and (or) their organelles. III. Ions and fluid imbalance, change of electrophysiological properties of cells: - Changes in the ratio of individual ions in hyaloplasm.
63 - Changes in transmembrane ion ratio. - Hyperhydration cells. - Dehydration cells. IV. Violation of the genetic program of cells and (or) the mechanisms for its implementation: A. Violation of the genetic program: - Changes in the biochemical structure of genes. - De-repression of pathogenic genes. - Repression "vitally important" genes. - Introduction of foreign DNA into the genome fragments with the pathogenic properties. B. Violation of the implementation of the genetic program: 1. Breakdown of mitosis: a) damage to chromosomes, b) damage to structures providing the mitotic cycle, c) violation of the cytokinesis process. 2. Violation of meiosis. V. The breakdown of intracellular mechanisms regulating cell functions: - Violation of reception of regulatory impacts. - Violation of the Second Education intermediaries. - Violation of protein phosphorylation.
I. Violation of the energy supply of the processes occurring in the cell. The energy supply of cells at the expense of ATP produced mostly in the mitochondria. Among the many functions performed by mitochondria are the most important oxidation in the Krebs cycle, electron transport phosphorylation of ADP, conjugation of oxidation and phosphorylation. Oxidation in the Krebs cycle. Unlike the anaerobic glycolysis in which one molecule of glucose form two molecules of pyruvate, Krebs cycle requires the involvement of oxygen. Glycolysis occurs in the cytosol and the resulting pyruvate is supplied via its carrier to the mitochondria in exchange for OH. The matrix of the mitochondria contain enzymes that oxidize acetyl-CoA to CO2. The end products of the tricarboxylic acid cycle (CO2, leaving the cells and NADH) - an electron source portable respiratory chain. Transport of electrons. Electrons move through the respiratory chain localized in the inner mitochondrial membrane and containing four large enzyme complex (mainly cytochrome) chain electron transport. Chemiosmotic conjugation. Pairing electron transport and ATP synthesis provides a proton gradient. The inner mitochondrial membrane is impermeable to the anions and cations. But with the passage of electrons in the respiratory chain H + ions are pumped from the matrix into the intermembrane space. The energy used by the electrochemical proton gradient for ATP synthesis and transport of inorganic ions and metabolites in the matrix. The phosphorylation of ADP. Christa mitochondria contain ATP synthase, conjugating oxidation in the Krebs cycle, and phosphorylation of ADP to ATP. ATP synthesized by the reverse current of protons into the matrix through the channel in the ATP-synthesizing complex. Pair of oxidation and phosphorylation. As a result, coupling of these processes the energy released by the oxidation of substrates stored in the energy-rich bonds of ATP. The liberation of the energy stored in ATP, further ensures that numerous cell functions (e.g., muscle contraction, flagellum motility of the sperm, pumping H + out of the parietal cells in the gastric glands to maintain acidic conditions). The efficiency of oxidative phosphorylation in mitochondria higher effectiveness of glycolysis in the cytosol. From one molecule of glucose formed in the first case 38 ATP molecules, and only two in the second. Violation of re-synthesis of ATP. Resynthesis of ATP is disturbed as a result of oxygen deficiency and (or) substrate metabolism, reducing the activity of enzymes of tissue respiration and
64 glycolysis, mitochondrial damage and destruction, in which the reaction of the Krebs cycle and the electron transfer to molecular oxygen, coupled with phosphorylation of ADP. Disorders of energy transport. Encased in a high-energy bonds of ATP energy is normally delivered from places of its synthesis (from mitochondria and hyaloplasm) to effector structures (myofibrils, membrane ion "pumps" and OE) with the participation of the enzyme systems: ADP - ATP translocase (adeninnukleotidtransferazy) and creatine phosphokinase (CPK). Adeninnukleotidtransferaza provides energy transportation macroergic phosphate bond of ATP from mitochondrial matrix across their inner membrane and CPK - Creatine further to form creatine phosphate, which enters the cytosol. CK effector cell structures transports creatine phosphate group to ADP to form ATP, which is used in the processes of cell activity. Enzyme energy transport systems can also be damaged by a variety of pathogenic agents, in connection with which, even against the background of the high total content of ATP in the cell, can develop its deficit energoraskhoduyuschih structures. Breakdown of energy utilization. Violation of energy cells and their metabolic disorder can develop in conditions of sufficient production and normal transport of ATP energy. This damage can result from recycling energy mechanisms mainly by reducing the ATPase activity (actomyosin ATPase, K +, Na + - dependent ATPase plasmolemma, Mg2 + -dependent ATPase "calcium pump" etc. sarcoplasmic reticulum.). Therefore, disorder of cell activity can occur even under conditions of normal or high content of ATP in the cell. Violation of energy supply, in turn, may be a factor in disorders of cell membrane device functions, their enzyme systems, the balance of ions and fluid, and cell regulation mechanisms.
II. Damage to the membrane device and enzyme systems of the cell. This mechanism plays an important role in the breakdown of cell activity, as well as reversible transition changes in it irreversible. This is because the basic properties of cells depend to a large extent on the condition and its membrane enzymes. According to the model of the cell membrane, and the proposed S.Singer G.Nicolson (1972), it is a viscous semi-liquid mosaic pattern. Its basis molecules comprise phospholipids (lipid phase of the membrane), polar (ionic) "head" which is directed to an aqueous environment, i.e. hydrophilic membrane surfaces and non-polar parts ( "tails") - inside them (hydrophobic zone). Phospholipid suspended in medium protein molecules, some of which are fully immersed in the membrane and penetrates its thickness (so-called integral proteins) located on a portion of their surface ("peripheral" proteins). Peripheral proteins do not penetrate into the thickness of the membrane and are retained at the surface mainly by electrostatic forces. Protein molecules can change the positions they hold in the lipid phase of the membrane, which affects the intensity and character of the catalyzed reactions. In addition, the membrane lipids often provide optimal conditions for the enzymatic processes. For example, oxidative phosphorylation requires anhydrous environment that prevents "spontaneous" ATP hydrolysis. In recent years the idea of the structure of membranes complemented position that its components (proteins, glycoproteins, glycosaminoglycans, glycolipids) interact with each other and with the microfilaments, microtubules, epitheliofibril cytoplasm of cells, forming a complete dynamic system - tverdoelastichny frame. This frame "mounted" in the liquid phase of the lipid membranes. Having frame provides a relatively stable position on (in) membrane antigens, receptors, enzymes, and other components, and prevents aggregation of the membrane proteins, which would be unavoidable with the free movement of the molecules in the liquid lipid environment.
65
Elements of biological membranes, damage-prone: 1 - lipid bilayer; 2 - a monolayer of lipid molecules; 3 - glycolipids; 4 - glycoproteins; 5 - microfilaments; 6 - microtubules; 7 - an ion channel; 8 - ion pump
The main mechanisms of cell membrane damage include: 1) excessive intensification of free radical reactions (FRR) and free-radical lipid peroxidation (FRPOL) membranes; 2) a significant activation of hydrolases (lysosomal, membrane-free); 3) introduction of amphiphilic compounds (mainly FRPOL products and lipolysis) in the lipid membranes and detergent phase (destructive) action; 4) inhibition processes resynthesis of damaged membranes and components (or) their re- synthesis (de novo); 5) violation of the conformation of macromolecules; 6) hyperextension and rupture of the membranes swollen cells and (or) their organelles. It is important that all of these mechanisms directly or indirectly cause damage conformational change and (or) the kinetic properties of the cell enzymes, many of which are associated with membranes. Free-radical reactions. One of the most important mechanisms of enzymes and membrane damage is excessive activation of free radical reactions and FRPOL. These reactions occur in the cells and in normal, being a necessary element of vital processes, such as electron transport chain respiratory enzymes, the synthesis of prostaglandins and leukotrienes, proliferation and maturation of cells, phagocytosis, catecholamine metabolism and others. Reactions FRPOL involved in the processes of the lipid composition of the regulation biomembranes and enzyme activity. The latter is a result of both the direct products lipoperoksidnyh reactions to enzymes and indirectly - through a change in the state of membranes, which are associated with many enzymes. FRPOL intensity is regulated by the relation of factors, activating (pro-oxidants) and suppress (antioxidants), this process. Among the most active pro-oxidants are easily oxidized compounds inducing free radicals, such as naphthoquinones, vitamins A and D, reducing: NADFH2, NADH2, lipoic acid, products of metabolism of prostaglandins and catecholamines. The peroxidation reaction may involve the connection of different biochemical composition: lipids, proteins, nucleic acids. However, the leading role among them are phospholipids. This is determined by the fact that they are a major component of membranes and readily undergo oxygenase reaction. FRPOL process can be divided into three stages: 1) initiation of oxygen ("oxygen" stage) 2) formation of free radicals of inorganic and organic ("free radical" stage) 3) formation of lipid peroxides and other compounds ("peroxy" stage). An initial link peroxy free radical reactions in the cell is damaged, as a rule, in the formation of so-called oxygenase reaction of active oxygen species: singlet (O2), oxygen radical superoxide (O2-, hydrogen peroxide (H2O2), hydroxyl radical (OH-).
66 Superoxide radical O2- generated leukocytes (especially intense during phagocytosis) in mitochondria during oxidative reactions in tissues in metabolic transformation catecholamine synthesis of prostaglandins and other compounds. H2O2 is produced by reacting (dismutation) O2 hyaloplasm radicals in cells, and mitochondrial matrix. This process can be catalyzed by the enzyme superoxide dismutase (SOD) O2 + O2 + 2H + → H2O2 + O2 O2 and H2O2 have a damaging effect in and of themselves. However, under the influence of iron ions present in hyaloplasm cells and in biological fluids (extracellular blood plasma, lymph) O- and H2O2 may be "transformed" into a very "aggressive", which has a high pathogenic action of hydroxyl radical OH-: H2O2 + Fe2 → Fe3 + + OH + OH-; O2 + H2O2 → O2 + OH + OH. OH active radicals react with organic compounds, mainly lipids and nucleic acids and proteins. As a result, formation of active radicals and peroxides. This reaction can buy Chain "avalanche" character. However, this does not always happen. Excessive activation of free-radical reactions and peroxide factors inhibit antioxidant protect cells. Antioxidant protection of cells. The cells flow processes and are factors that limit or even stop free radical and peroxide reactions, ie, has an antioxidant effect. One such process is, in particular, radicals and interaction between a lipid hydroperoxide that leads to the formation of a "non-radical" compounds. The leading role in the antioxidant defense system cells play mechanisms of enzymatic and non-enzymatic nature.
Links antioxidant system and some of the factors
Links antioxidant system Factors Mechanisms of action I. «Antioxigen» Retinol, carotenoids, Decrease O2 content in the cell, for riboflavin example, by activation of its utilization, increase conjugation of oxidation and phosphorylation II. «Antiradical» Superoxide dismutase, Translation of active radicals in the "non- tocopherols, mannitol radical" compounds, "quenching" free radicals with organic compounds III. «Antiperoxide» Glutathione peroxidase, Inactivation of lipid hydroperoxides, for catalase, serotonin example by restoring
Excessive intensification of free radical and peroxide reactions is one of the main factors of damage to membranes and cell enzymes. The leading role in this process are the following: 1) a change of physicochemical properties of lipid membranes, reducing the content of phospholipid, cholesterol, fatty acids. This conformation causes a violation of lipoprotein complexes and therefore decrease in activity of proteins and enzyme systems providing reception humoral effects transmembrane transport of ions and molecules, the structural integrity of the membrane; 2) changing the physical and chemical properties of the protein micelles performing structural and enzymatic functions in the cell; 3) the formation of structural defects in the membrane - the so-called elementary channels (clusters) due to the introduction of products in them FRPOL. In particular, the accumulation of lipid hydroperoxides in the membrane leads to their association in micelles creating transmembrane channels permeability, which is possible uncontrolled current cations and other organic and inorganic molecules in the compounds and from the cage. Increased education FRPOL products and in parallel with these clusters may lead to fragmentation of the membrane (this process is known as detergent action FRPOL products), and cell death. These processes, in turn, are responsible for the
67 violation of important vital processes of cells - excitability and generation of the nerve impulse, metabolism, perception and implementation of control interventions, intercellular interaction and others. Activation of hydrolases. Normally, the composition and condition of the membranes are modified not only lipoperoxide and free radical processes, but also membrane-bound, free (solubilized) and lysosomal enzymes, lipases, phospholipases, proteases. Under the influence of pathogens or their activity hyaloplasm content in cells can be significantly increased (in particular, due to the development of acidosis, enzymes promoting increased yield of lysosomes and their subsequent activation). In this regard, intensive and glycerophospholipids undergo hydrolysis of membrane proteins, enzymes and cells. This is accompanied by a significant increase in membrane permeability and a decrease in the kinetic properties of enzymes. The detergent effects of amphiphiles. As a result of the activation reactions and lipoperoxide hydrolases (especially the lipases and phospholipases) are accumulated in the cell lipid hydroperoxides, free fatty acid, lysophospholipids, especially glycerophospholipids, phosphatidylcholines, phosphate diletanolaminy, phosphatidylserines. These compounds are called amphiphilic due to their ability to penetrate into and be fixed on both (as in the hydrophobic or in the hydrophilic) environments cell membranes (from the Greek. Ampho «two", "two", in two ways). With a relatively small level in the cell amphiphilic compounds are penetrating into the biological membrane, alter the normal sequence of glycerophospholipids, violate the structure of lipoprotein complexes, increased permeability, as well as changing the configuration of the membrane due to the "wedge-shaped" form lipid micelles. Accumulation of a large number of amphiphiles is accompanied by massive introduction of a membrane, as well as lipid hydroperoxides and excess, it leads to the formation of clusters and micro-breaks in them. Disorders reactions membranes updates. Potentiation of damage to cell membranes due to braking processes update their components and elimination of defects in them also contributes to the disorder of energy "security" of plastic processes in the cell. This is due to a violation of reparative reactions resynthesis of damaged or lost lipid, protein, lipoprotein, glycoprotein and other membrane molecules, as well as their re-synthesis. Violations of the conformation of macromolecules. Significant changes in physical and chemical state of cell membranes can be caused by a modification of the conformation (spatial structure, shape) of protein macromolecules, lipoproteins, glycoproteins, and other compounds. The reason for this may be the dephosphorylation ("deenergization"), these molecules are mainly due to the violation of the processes of power supply cells. At the same time there is a change of the secondary and tertiary structure of proteins, conformation of lipoproteins, as well as suppression of catalytic activity of enzymes. Hyperextension and rupture of membranes. membrane damage causes cell swelling (including their organelles) in connection with their overhydration. A significant increase in cell volume and subcellular structures (mitochondria, endoplasmic reticulum, nucleus, and others.) Causes hyperextension and often breaks their membranes. The latter is the consequence of increasing the oncotic and osmotic pressure in the cells. This in turn is due to an excess of hydrophilic molecules are organic compounds (lactic acid, pyruvic acid, albumin, glucose, etc.), As well as ions. Thus, it is seen that the membrane damage and cell enzyme is one of the most frequent causes of disturbances and the major cell activity.
III. Ions and fluid imbalance, change of electrophysiological properties of cells. Ions and water imbalance in the cell, usually develops after or simultaneously with disorders of energy supply and damaged membranes and enzymes. As a result, significantly changed the transmembrane transport of many ions. To the greatest extent it relates to K +, Na +, Ca2 +, Mg2 +, Cl-, ie ions, which are involved in such vital processes as arousal, conduct action potentials (AP), electro-mate and others.
68 Ion imbalance characterized by the change in the ratio of individual ions in the cytosol and the violation of the transmembrane ion ratios on both sides of a plasmolemma and intracellular membranes. Manifestation of ion imbalance. Manifestations of ion imbalance are varied. Most important for the functioning and existence of cell changes in the ionic composition, determined by different membrane ATPase and membrane defects. Cations. Due to the disruption of Na +, K + -ATPase plasmolemma occurs: - Cytosolic accumulation of excess Na + cells; - The loss of the cell K +. Because disruption of Na + -Ca2 + -ionoobmennogo plasmolemma mechanism (sharing two Na +, outside the cell, one of Ca2 + exiting from it), and Ca2 + -ATPase is an increase in the content of Ca2 + in the cytosol. Anions. Violations of the transmembrane distribution of cations soprovozhdaetmya change the content in the cell and anions Cl-, OH-, HCO3-, and others. The effects of ion imbalance. Important posldstviyami ionic imbalances are changes in cell volume and cell oragnoidov (hypo- and hyperhydration), as well as violations electrogenesis in excitable cellular elements (eg, cardiomyocytes, neurons, skeletal muscle fiber, smooth muscle cells - MMC). Hyperhydration cells. The main cause of fluid overload - increase in the content of Na + and Ca2 + in damaged cells. This is accompanied by an increase in their osmotic pressure, and water accumulation. Cells with the swell, their volume increases, combined with stretching and often with micro- breaks tsitolemmy and organelle membranes. Hypohydratation cells. Hypohydratation cells is observed, for example, fever, hyperthermia, polyuria, infectious diseases (cholera, typhoid, dysentery). Such conditions lead to loss of body water, accompanied by fluid exiting the cells and dissolved therein proteins (including enzymes), as well as other water-dissolved organic and inorganic compounds. Intracellular hypohydration often combined with the wrinkling of the core, the disintegration of mitochondria and other organelles. Violation electrogenesis. Violation electrogenesis as changes in membrane potential and action potential characteristics are essential, as they are often one of the most important signs of the existence and nature of cell damage. Examples include changes in ECG at myocardial cell injury, an electroencephalogram in violation of the structure and function of brain neurons, electromyogram with changes in muscle cells.
IV. Violation of the genetic program of cells and (or) the mechanisms for its implementation. The main processes, leading to changes in the cell genetic information, are changing the biochemical structure of genes (mutations); derepression of pathogenic genes (e.g., oncogenes); suppression of vital activity of genes (for example, programming the synthesis of enzymes); introducing into the genome a foreign DNA fragment encoding the pathogenic properties (e.g., DNA oncogenic viruses, abnormal area other cell DNA). In addition to changes in the genetic program, an important mechanism of cell metabolism disorder is a violation of the implementation of this program, mainly in the process of cell division during mitosis or meiosis. Data about the pathology of meiosis (during germ cell development) to date is not enough. This is due, in particular, the difficulty of obtaining biopsies of testicles or ovaries. More questions are designed mitosis pathology. There are three groups of disorders of mitosis: 1) change in the chromosomal apparatus; 2) damage to structures for mitosis process; 3) violation of the division of the cytoplasm and cytolemmy (cytokinesis). For group 1 mitosis disorders include changes in the structure and number of chromosomes. Examples of group 2 disorders may be multipolar or formation monocentric mitosis at metaphase chromosomes dispersion, that is, in particular, a consequence of the spindle abnormalities. Violations of the cytoplasm and plasmolemma fission appear premature or delayed cytokinesis, and the lack of it (group 3 mitosis disorders).
69 Action on the genetic apparatus of the cell-damaging factors, the different nature of very high intensity can cause the death of her. Among the most important processes causing cell death are as follows: 1) the destruction of the structure of DNA by direct action of a superstrong pathogens, most chemical or physical nature (in particular, high doses of ionizing radiation, alkylating agents, free radicals, hydroperoxides lipids); 2) by hydrolytic cleavage of the DNA with nucleases significant activation (pre-existing or synthesized de novo), 3) activation transferases, causing degradation of the DNA by transfer from a phosphoric acid residue the carbon atom of ribose its mononucleotide one to another, which is accompanied by rupture of the internucleotide bond; 4) changes in the structure of DNA. It is believed that the cells have a special program, which leads to irreversible destruction of genetic material and cell death. It is believed that the cell death program is linked to the presence in its genome of gene specific "killer." These genes were formed in the early stages of the evolution of multicellular organisms to eliminate irreversibly damaged and (or) abnormally functioning cells that represent a real or potential danger for the life of the whole organism. Thus eliminate normal cells were replaced in connection with the division of neighboring cells intact. This ensured the stability of the structure and functioning of tissues, organs and generally in a multicellular organism as a system. The presence of the genetic program of cell death explains many phenomena: regular change of cells during embryogenesis; physiological death "grown old" cells as the final stage of their differentiation needed to change their "young" cells; removal of damaged and (or) of abnormal cells that threaten the existence of the whole organism (eg, tumor cells)
V. The breakdown of intracellular mechanisms regulating cell function. Disorders of cell activity may be a result of disorders of one or more levels of implementation of regulatory mechanisms. Intercellular information signals. All kinds of information described in the cell-cell interactions within the concept of "response signal", which laid the foundations of Paul Ehrlich. Intercellular informational interactions fit into the following scheme: Signal → receptor → (second intermediary) → answer. Signals. Signaling from cell to cell signaling molecule is performed (first intermediary) generated in some cells and specifically affecting the other - of a target cell. The specificity of the effects of signaling molecules determine the receptors of the target cell binding ligands only their own. All signaling molecules (ligands) - depending on their physical and chemical nature - divided into polar (or rather - hydrophilic) and apolar (fat-soluble). Hydrophilic molecules (e.g., neurotransmitters, cytokines, peptide hormones, antigens) can not penetrate the plasma membrane and bind to receptors plasmolemma (membrane receptor). The fat-soluble molecules (for example, thyroid hormones and steroilnic) plasmolemma penetrate and bind to intracellular receptors (nuclear receptor). Receptors. Three classes of cellular receptors are described: membrane, nuclear and orphans. Membrane receptors - glycoproteins. They control the permeability plasmolemma by changing the conformation of the ion channel proteins (eg, N-acetylcholine receptor). Regulates the flow of molecules into a cell (e.g., using LDL cholesterol receptors), extracellular matrix molecules bind to cytoskeletal components (e.g., integrins). Record the presence of information signals (e.g. neurotransmitters light quanta olfactory molecules. Antigens, cytokines, peptide hormones). Membrane receptors recorded arriving to cell signal and transmit it to the intracellular chemical compounds mediating the final effect (second messengers). Functional membrane receptors are divided into catalytic associated with ion channels and operates through G - protein. Nuclear receptors - proteins of steroid hormone receptors (mineral and glucocorticoids, estrogen, progesterone, testosterone), retinoids, thyroid hormone, bile acids, vitamin D3. Each receptor has a ligand-binding domain and a portion that interacts with specific DNA sequences. In other words, the nuclear receptor - ligand-activated transcription factors.
70 Orphan receptors. The human genome has more than 30 nuclear receptors, ligands which are on the identification step. Second intermediaries. The intracellular signaling molecules (second messengers) transmit information with the membrane receptors on the effectors (actuators molecule) mediating cell response to the signal. Stimuli such as light, the molecules of different substances, hormones and other chemical signals (ligands) initiate a response of the target cell, changing it in the intracellular level (second) mediators. Second mediators presented numerous class of compounds. These include cyclic nucleotides (cAMP and cGMP), inositol triphosphate, diglycerol Ca2 +. Responses target cells. cell function are the result of realization of genetic information (e.g., transcription, post-translational modification) and highly diverse (e.g., changes in the nature of the operation, the stimulation ilipodavlenie activity reprogramming syntheses, etc.). Disorders BAS interaction with receptors. Intercellular signals in the form of character information BAS (hormones, neurotransmitters, cytokines, etc.) Implement regulatory effects of BAS after interaction with cellular receptors. The reasons are diverse regulatory signal distortion. The most important are: - Changes in receptor sensitivity; - Deviation of the number of receptors; - Violations of the receptor conformation of macromolecules; - Changes in the lipid environment of membrane receptors. These deviations can significantly modify the nature of the cellular response to the control stimulus. Since the accumulation of toxic products when Spolli myocardial ischemia alters the physical and chemical properties of the membranes. It is associated with the cardiac responses to norepinephrine and atsitilholin, perceives the corresponding receptors of the plasma membrane of cardiomyocytes. Frustration at the level of the second mediators. At the second level of intracellular mediators (messengers) - cyclic nucleotides: adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) and other generated in response to the primary intermediaries - hormones and neurotransmitters that numerous disorders. An example would be a violation of the formation of the membrane potential of cardiomyocytes with excess accumulation of cAMP in them. This is one of the possible causes of cardiac arrhythmias. Frustration at the level of response to the signal. At the level of metabolic processes regulated second messengers, or other intracellular factors are also capable of numerous disorders. For violation of the activation of cellular enzymes, for example in connection with a deficit of cAMP or cGMP, can greatly change the intensity of metabolic reactions, and as a result - lead to the breakdown of cell activity.
CHARACTERISTICS TYPICAL FORMS OF CELL DAMAGE Damage to cells is characterized by the development of a variety of complex changes in them. However, they can be grouped into several groups. The main groups of typical forms of cell damage 1. Dystrophy. 2. Dysplasia. 3. Typical violations of subcellular structures and components. 4. Necrosis
Dystrophy Under dystrophies (from the Latin dys -. Breach + Greek trophe - I feed) understand the metabolism in the cells, accompanied by disturbances of their functions, processes and plastic structural changes, leading to disruption of their livelihoods. The main mechanisms dystrophies are: - The synthesis of abnormal substances in the cell, such as protein-polysaccharide complex amyloid;
71 - Excessive transformation of some compounds in others, such as fats and carbohydrates into proteins, carbohydrates into fat; - Decomposition (Phanerozoic), for example, protein-lipid membrane complexes; - Infiltration of the cells (intercellular substance and) organic and inorganic compounds such as cholesterol and its esters arterial wall in atherosclerosis. The main cell types of dystrophies, depending on the species mainly disturbed metabolism include: 1) protein (disproteinos); 2) fat (lipidoses); 3) carbohydrate; 4) pigment; 5) mineral. 1. Disproteinos. They are characterized by a change in physico-chemical properties of proteins, cells, and as a consequence of a violation of their enzymatic and structural functions. Most often disproteinozy appear as granular, hyaline droplet and hydropic dystrophy. Often they represent successive stages metabolic disorders cytoplasmic proteins, leading to cell death. When granular dystrophy appear in the cytoplasm granules (grains) protein. They are formed as a result of infiltration (penetration) it from the interstitial fluid, the transformation of carbohydrates and fats in the proteins decay (decomposition) and lipoprotein cytoplasmic membrane. One of the main reasons for the general granular dystrophy is a violation of the energy cells. Hyaline degeneration is characterized by the accumulation of the protein in the cytoplasm of acidophilic mostly hyaline inclusions ("drops"). Simultaneously revealed signs of degradation of cellular organelles. Signs of hyaline degeneration observed in conditions that increase the permeability of cell membranes. Hydropic (hydropic, vacuolar) degeneration is the result of such changes in the physicochemical properties of cytoplasmic proteins, which is accompanied by an increase in oncotic pressure cell hydration and excess protein micelles. The cytoplasm of cells formed vacuoles filled with liquid and containing no lipid or glycogen. Electron microscopy shows signs of intracellular organelle swelling and edema. The most common causes are hydropic dystrophy hypoxia, exposure to ionizing radiation, toxins, microbes and parasites, malnutrition. 2. Lipidosis. To include various lipids on the chemical composition of substance, insoluble in water. Lipidoses manifested either by increasing intracellular lipid content, or the appearance of cells, where they are normally absent or abnormal formation of the chemical composition of lipids. Lipidoses, as well as disproteinozy most frequently observed in the cells of the heart, liver, kidney, brain and have corresponding names (fatty degeneration of the heart, liver, kidney, brain). 3. Carbohydrate dystrophy. Characterized by impaired metabolism of polysaccharides (glycogen, mucopolysaccharides) and glycoproteins (mucin mucoids). "Polysaccharide" dystrophy appear: 1) reduction of their content in the cell (e.g., glycogen diabetes); 2) the lack of, or a significant reduction (aglikogenozy) or 3) the accumulation of excess (glycogen infiltration cells glycogenoses). The reason carbohydrate dystrophies are often endocrinopathies (eg, insulin deficiency), or fermentopathy (no or low activity of enzymes involved in carbohydrate synthesis and decay processes). Carbohydrate dystrophy, metabolic disorders related glycoproteins are characterized as typically accumulation and mucins mucoids with mucous consistency. In this regard, they are called mucous dystrophies. The reasons most often serve their endocrine disorders (eg, insufficient production, or low activity of the thyroid gland hormones) as well as direct damaging effects on the cells of pathogenic factors. 4. Pigment dystrophy (dispigmentos). Pigments of the human body and animal cells are involved in the implementation of many functions: synthesis and catabolism substances, reception of various influences, protection from damaging factors. Cell pigments are hromoproteidov, ie compounds composed of protein and dye. Depending on the biochemical structure of the endogenous cellular pigments separated as follows: 1) gemoglobinogennye (ferritin, hemosiderin, bilirubin, hematoidin, hematin, porphyrin);
72 2) proteinogenic, tirozinogennye (melanin adrenochrome, pigments ochronosis and enterochromaffin cells); 3) lipidogennye, lipoproteinogennye (lipofuscin, gemofustsin, ceroid, lipochromes). All dispigmentozy are divided into several groups depending on their origin, development mechanism, the biochemical structure of the pigment, manifestations and prevalence. Types dispigmentosis I. By origin: - Primary (hereditary, congenital). - Secondary acquired (occurring under the action of pathogenic agents during postnatal life of the organism). II. On the mechanism of development: - Caused by defects in enzymes (fermentopathy) pigment metabolism and (or) changes in their activity. - Related to the changes in the content and (or) activity of transport enzymes, pigments across the cell membrane. - Cause damage to cell membranes. - Caused by an excess accumulation of pigments in the cells which have the property of phagocytosis. III. According to biochemical structure of the pigment: - Hemoglobinogenic "iron dependent". - Proteinogenic, tirosinogenic. - Lipidogenic, lipoproteinogenic. IV. As manifestations: - The appearance of pigment cell that is not in its normal. - Accumulation of excess pigment formed in the cell as normal. - Reducing the amount of pigment formed in the cell as normal. V. By the prevalence of: - Local (regional). - General (common). Hemoglobinogenic dispigmentosis include hemosiderosis, hemochromatosis, hemomelanosis, porphyria, excess accumulation of direct bilirubin in the hepatocytes. Most hemoglobinogenic pigments are products of hemoglobin catabolism. Some (ferritin, hemosiderin) are formed with iron absorbed from the intestine. Part hemoglobinogenic dispigmentosis is the result fermentopathia. These include, in particular, primary hemochromatosis and porphyria. Primary Hemochromatosis - a disease caused by a genetic defect (transmitted by autosomal dominant) of enzymes involved in the processes of iron transport from the gut cavity. In this case, the blood enters the excess iron that accumulates in the form of ferritin and hemosiderin in the cells of various tissues and organs (liver, myocardium, skin, endocrine glands, salivary glands, and others.). Similar changes are also observed in secondary hemochromatosis. It is the result or acquired deficiency of enzymes that ensure the exchange of dietary iron (alcoholism, intoxication), or - high iron organism revenues from iron-containing foods or drugs, or a consequence of excessive red blood cell hemolysis. Porphyria is characterized by the accumulation in the cells uroporphyrinogen I, porfobilina, porfirinogenov. One of the common causes of porphyria is the lack of or low kinetic activity of enzymes of porphyrin metabolism (eg, uroporphyrinogen-W-kosintetazy) hereditary or acquired nature. Most other species hemoglobinogenic dispigmentosis (hemosiderosis, hemomelanosis) are the result of excessive accumulation of pigments in the cells due to increased hemolysis of red blood cells of various origins (for infections, intoxications, inogrupp transfusion of blood, Rh-conflict, and others.).
73 Proteinogenic (tirosinogenic) dispigmentosis manifest enhancement or suppression of pigmentation of tissues (local or general) products of tyrosine metabolism. Increased pigmentation is often the result of excess melanin in the cells (melasma, from the Greek, melas - dark, black). Observed in adrenal insufficiency caused by a decrease in their weight, for example when they are tuberculous or neoplastic lesions; a pituitary adenoma, hyperthyroidism, ovarian tumors. It is believed that an excess of melanin in the cells is a result of its increased synthesis of tyrosine instead of adrenaline. Process melanin formation potentiated ACTH level is elevated in a shortage of adrenaline in the blood. Accumulation of pigment ochronosis (from the Greek ochros -. yellow, yellow) in cells is observed in the primary (hereditary) fermentopathy characterized by deficiency of enzymes of metabolism of phenylalanine and tyrosine. This hyperpigmentation is local or widespread in nature. The pigment accumulates in the cells of the tissues of the nose, ears, sclera, trachea, bronchi, tendons, cartilage, etc. Attenuation tissue pigmentation, or lack of pigment in their cells (albinism, lat albus -. White) may also be a primary or secondary origin. In albinism Melania absent from the skin cells of the iris eye, hair. The reason for this is most often a hereditary lack of the enzyme tyrosinase in cells. In the case of a local reduction of pigmentation, such as the skin (leukoderma, vitiligo) is essential secondary violation exchange of melanin due to neuroendocrine disorders of its regulation (at hypoinsulinism, reducing the level of parathyroid hormone), due to the formation of antibodies to melanin or as a result of increased destruction of melanocytes in inflammation or tissue necrosis. Lipidogenic dispigmentosis characterized most often increase the amount of pigment in the cells of the lipid and lipoprotein nature (lipofuscin, hemofuscina, lipochromes, ceroid). All these pigments are very similar on basic physical and biochemical properties. In humans, usually there are various options for local lipofuscinosis hereditary (rarely) or acquired (usually) origin. It is believed that the main causes are acquired lipofuscinosis tissue hypoxia, a deficiency in the body of vitamins, protein and certain types of lipids. Lipofuscinosis most commonly develops in middle and old age people on chronic "metabolic" disorders. Hereditary and congenital lipofuscinosis characterized by excess accumulation of lipofuscin in the cells, usually combined with fermentopathy (ie these are an option lipofuscinosis storage diseases). Examples of these diseases may be neuronal lipofuscinosis (excess deposition of lipofuscin in neurons, combined with a decrease in intelligence, vision, hearing, development of seizures); lipofuscinosis liver, combined with bilirubin metabolism disorders caused by inherited defects of enzymes and transport glucoronisation bile pigments. 5. Mineral dystrophy. Shows a significant decrease or increase in the mineral content in the cells. The most important are violations of exchange of calcium compounds, potassium, iron, zinc, copper. Their ionized fraction and molecular processes involved in the regulation of cell membrane permeability, enzyme activity, and the formation of peace-building activities, the implementation of the action of hormones and neurotransmitters, the electromechanical coupling in myocytes and many others. Mineral dystrophy characterized by the accumulation of excess in the cells of the molecular or ionized cations fractions (such as calcifications, siderosis, deposition of copper at hepatocelebral dystrophy) or a decrease in their content. One of the most common species in the human cell is a mineral dystrophies calcification - accumulation ("deposition") of excess calcium in the cells. Calcification may be general or local. On the "territory" of the cell to the greatest extent calcium salts accumulate in mitochondria, lysosomes (phagolysosomes) in the tubules of the sarcoplasmic reticulum. The main reason is to change cellular calcification physicochemical properties hyaloplasm cell (e.g., intracellular alkalosis), combined with calcium absorption. The most frequently observed calcification of myocardial cells, renal tubular epithelium, lung, gastric mucosa, the walls of arteries. Among dystrophy refers also thesaurismosis (from the Greek thesauriso - accumulation, absorption, float). They are characterized by an excess accumulation of various substances in the
74 cells, which is accompanied by breach of their structure and function, and - the intensity and nature of the plastic and metabolic processes in them. Almost all tesaurismosis - the result of a hereditary pathology of enzymes, transmitted, as a rule, an autosomal recessive manner. Inheritable change in the genetic program are responsible for a defect of enzymes (lysosomal, membrane-free). The result is a metabolic disorder in the cell that makes the accumulation of excess in it products of incomplete or abnormal cleavage of substrates. Depending on the structures of biochemical substances accumulate in the cells tesaurismosis separated into lipid (lipidoses), glycogen (glycogenoses), amino acid, nucleoprotein, mucopolysaccharide, mucolipid. The most common varieties are tesaurismosis lipid and glycogen.
Dysplasia Dysplasia (from dys - disorder disorder Greek plasis + -. The image) - the common name of disturbances of development (differentiation, specialization) of cells exhibiting persistent changes in their structure and function, which leads to the breakdown of their life. The causes of dysplasia are factors of physical, chemical or biological nature, damaging the genome of the cell. In this case it violated the genetic program of cells or the mechanisms of its implementation. That is what makes resistant and, as a rule, inherited from cell to cell changes unlike dystrophies, which often are temporary, reversible and can be eliminated at the termination of the causal factor. The main mechanism of dysplasia is a disorder of the differentiation process, which is to form the structural and functional specialization of cells. Cellular differentiation is mainly determined by genetic program. However, the implementation of the program to a large extent depends on the complex interactions of the nucleus and the cytoplasm, the cell microenvironment, influence on it of biologically active substances and many other factors. That is why even if the same change in the genome of different manifestations of dysplasia cells can be different character. Dysplasia manifest changes in the size and shape of cells, their nuclei and other organelles, the number and structure of chromosomes. Typically, cells are increased in size, have irregular, bizarre shape ("monster cells"), the ratio of different organelles in them disproportionately. Often in such cells are found various inclusions, symptoms of degenerative processes. Examples of cellular dysplasia can be called education megaloblasts in the bone marrow with pernicious anemia, sickle-shaped red blood cells in the presence of abnormal hemoglobin, the major neyronov- "monsters" in the defeat of the cerebral cortex (tuberous sclerosis), polynuclear giant cells with bizarre arrangement of chromatin in neurofibromatosis (illness Recklinghausen). Cellular dysplasia is one of the manifestations of atypism tumor cells.
The death of cells Development of multicellular organisms, the formation of tissues and their functioning assume a balance between cell proliferation, differentiation and cell death. They are killed in different situations, both physiological and pathological. Mass death of cells in the early ontogenesis called programmed. Cells that have fulfilled their function die within the entire life of the organism. They are killed during tissue injury and necrosis, as well as various diseases selectively infect certain types of cells (degeneration). We know two qualitatively different versions of cell death: necrosis and apoptosis.
NECROSIS Necrosis - the actual death of the damaged cell, accompanied by the irreversible cessation of its activity. Necrosis is the final stage of cell dystrophies or due to a direct effect on the cell- damaging factors significantly (destructive) force. Necrosis is typically accompanied by an inflammatory response.
Paranecrosis and necrobiosis
75 Necrosis preceded paranecrosis (metabolic and structural changes still reversible) and necrobiosis. At necrobiosis pathogenic changes become irreversible and result in necrosis. The basic pathogenesis of necrosis are the same as in the damaged cells, but with the development of necrosis are the most intensified and developed against the background of failure of adaptive mechanisms (protection and regeneration of damaged structures, compensation of disturbed processes in the cell).
Lysis and autolysis Necrotic cell destruction (lysis) by lysosomal enzymes and free radicals. 1. Hydrolysis of intracellular components and intercellular substance is influenced by lysosomal enzymes alterirovannyh cells. The release of lysosomal enzymes, contributes to the development of intracellular acidosis. 2. Destruction of damaged cell components is carried out with the participation of reactive oxygen species and free radicals. Known facts of intensification of free radical and lipoperoxide reactions in acute inflammation, mechanical damage, at certain stages of a heart attack (private form of necrosis that develops as a result of circulatory disorders of tissue), tumor growth (accompanied by the loss of a large number of both malignant and surrounding normal cells) and other pathological processes. These two mechanisms provide a self-destruct cell structures (autolysis). The destruction of damaged and necrotic cells occurs and the participation of other cells - phagocytes, as well as microorganisms. Unlike autolytic decay, the latter mechanism is referred to as heterolytic.
Apoptosis Apoptosis is another embodiment of cell death. Apoptosis - a form of death of individual cells, arising under the influence of extra- or intracellular factors, carried out by specialized activation of intracellular processes, controlled by certain genes. Thus, apoptosis - the programmed cell death. This is its fundamental difference from necrosis. Another fundamental difference apoptosis from necrosis is that triggers apoptosis program information signal, whereas cell necrosis develops under the influence damaging agent. In the final necrosis occurs the cell lysis and the release of its contents into the extracellular space, whereas apoptosis completed phagocytosis fragments damaged cells. Necrosis - always pathology, whereas apoptosis observed in many natural processes, as well as adaptation of cells to disturbing factors. Apoptosis - unlike necrosis – energy dependent and requires RNA and protein synthesis.
The manifestations of apoptosis In the cytoplasm of apoptotic cells is compacted, condensed chromatin, the nucleus undergoes pycnosis followed karyorhexis. The fragmentation of the nucleus precedes internucleosomal ordered degradation of nuclear DNA to form successively smaller fragments up to 180 bp. The disintegration into individual nucleosome DNA fragments with the nucleotide chain breaks leads to the appearance of DNA fragments of different lengths. In the final stage of fragmentation of apoptotic cells exposed themselves to the formation of the so-called apoptotic bodies - surrounded by a membrane cell fragments, including the remnants of organelles cytolemma, cytoplasm, chromatin. Cells included in apoptosis and apoptotic bodies are phagocytosed by macrophages and granulocytes; phagocytosis is not accompanied by local inflammation.
Examples of apoptosis Programmed cell death - a natural process of massive cell death and elimination of entire clones during embryonic development, morphogenesis and histogenesis bodies. In this case we are talking about cell death have not reached the state of terminal differentiation. An example is the programmed death of neuroblasts (from 25 to 75%) at certain stages of brain development.
76 Cell death, fulfilled its function, observe the removal of clones of immunocompetent cells in the immune response. Eosinophils are killed after degranulation. The cells perform their function, die by apoptosis. The mechanism of cell death, reached terminal differentiation state and perform its function has not been studied, but it is clear that it is genetically determined. Thus, the expression of fos gene is a marker of terminal differentiation and cell death precedes simultaneously. Degeneration. Under certain pathological conditions there is a relatively selective destruction of cells, for example, in the nervous system in amyotrophic lateral sclerosis (Lou Gehrig's disease) and disease Altshaumera. Congenital form of amyotrophic lateral sclerosis due to mutation of Cu / Zn-1 gene product superoxide dismutase defective gene is not able to inhibit IL-lp-converting enzyme and the resulting IL-1p affects motor neurons and causes apoptosis. Elimination of auto-aggressive T cells in the development of the thymus or delete lymphocytes after the implementation of the immune response; tissues elimination of cells exposed to cytotoxic T lymphocytes or natural killers. Aging (eg, hormone-dependent involution by cells of the endometrium and ovarian follicle atresia in menopausal women, prostate and testicular tissue in older men). Transfection. Introduction of viral nucleic acid in the cell (e.g. from viral hepatitis, myocarditis, encephalitis, AIDS). Damage to the cells. Exposing the cell to agents that damage it, but not leading to necrosis (e.g., heat, radiation, cytotoxic drugs, hypoxia). The increase in the intensity of these influences leads to necrosis as usual. Tumor growth (apoptosis is emerging as a node in the formation of tumor, and during its degradation).
The mechanism of apoptosis With the implementation of apoptosis can be roughly divided into four stages: 1. Initiation 2. Programming 3. Implementation of the program 4. Removal of dead cells
Initiation stage At this stage, the cell data signals rehearsed. The pathogenic agent or it is a signal, a signal causes the generation of the cell and it’s holding to intracellular regulatory structures and molecules. Initiating apoptosis stimuli may be transmembrane or intracellular. Transmembrane signals are divided into negative, positive, and mixed. - Negative signals: absence or cessation of cell exposure to growth factors, cytokines that regulate cell division and maturation, as well as the hormones that control cell growth. The normal action of the above-mentioned groups of biologically active substances on the membrane receptors provides suppression of the cell death program and normal their livelihoods. On the contrary, their absence or reduction of the effects of "free" apoptosis program. So, you need a permanent presence of neurotrophic factors for the normal functioning of a number of neurons. Their elimination or reduction of effects on nerve cells may lead to the inclusion of the program neuron death. - Positive signals are generated as a result of the apoptosis program. Thus, the binding of TNF 77 Among the intracellular apoptotic stimuli registered excess H +, lipid free radicals and other substances, fever, hormones and intracellular viruses realizing their effect via the nuclear receptors (e.g., glucocorticoids). Stage programming At this stage the implement specialized proteins or signal to apoptosis by activation of the agent (its effectors are cysteine protease - caspases and endonucleases) or blocking potentially fatal signal. There are two (not mutually exclusive) embodiment of the programming stages: 1) by direct activation of effector caspases and endonucleases (bypassing the genome of the cell) and 2) mediated by signal transduction gene on the effector caspases and endonucleases. Direct transmission of the signal through adapter proteins, cytochrome C and granzymes - Adapter proteins. The protein acts as an adapter, for example, caspase-8. Since implementing its action cytokines T-lymphocytes-killers against foreign cells, TNF and other ligands of CD95. - Standing out Cytochrome C from mitochondria cytochrome C with the protein Apaf-1 and caspase-9 activation complex shapes (apoptosomu) effector caspases. Caspase-8 and caspase-9 is activated effector caspases (e.g. caspase-3), which are involved in the proteolysis of proteins. - Granzyme. These proteases isolated cytotoxic T-lymphocytes, proteases enter the target cell cytoplasm through pores preformed perforin. Granzymes aspartate activated cysteine proteases specific target cells undergoing apoptosis. Direct transmission of the signal is usually observed in the non-nuclear cells, eg erythrocytes. Mediated signal transduction includes the repression of genes encoding inhibitors of apoptosis, and activation of genes encoding apoptosis promoters. Inhibitors of apoptosis proteins (e.g., anti-apoptotic gene expression products of Bcl-2, Bcl- XL) block apoptosis (for example, by reducing the permeability of the mitochondrial membrane, thereby reducing the likelihood of access to the cytosol of one of the triggers apoptosis factors - cytochrome C). Promoters of apoptosis proteins (e.g., proteins, whose synthesis is controlled by genes Bad, Box, or anti-oncogenes Rb / T53) activate effector caspases and endonucleases. Stage of implementation of the program The stage of implementation of the program of apoptosis (executive, effector) is actually cell death, carried out by activation of proteolytic and nucleolytic stages. Implementing direct process "devitalization" cells are Ca2 +, Mg2 + -dependent endonuclease (decay catalyze nucleic acids) and effector caspases (subjected to proteolytic cleavage various proteins, including cytoskeletal proteins, nucleus proteins and regulatory enzymes). As a result of the destruction of proteins and chromatin in the cell undergoes apoptosis destruction. It formed, and from it bud fragments containing residues of organelles, the cytoplasm, chromatin and cytolemma - apoptotic cells. The step of removing fragments of dead cells On the surface of apoptotic cells expressed ligands that interact with receptors of phagocytic cells. Phagocytes rapidly detect, absorb and destroy the apoptotic cells. Due to this the contents of the destroyed cells misses in the extracellular space, and when no inflammatory reaction apoptosis. This feature distinguishes apoptosis from necrosis, which is accompanied by the development perinecrotic inflammation. Manifestations of damaged cells Any damage causes cells in her complex specific and nonspecific changes, detectable by various methods: biochemical, physico-chemical, morphological and others. Under the specific properties of the cells to understand the changes that are typical of this factor under the action of its various cells or characteristic only this type of cells when exposed to 78 damaging agents of various kinds. Thus, an increase in any cell osmotic pressure, accompanied by her overhydration, stretching membrane, a violation of their integrity. Influenced releasers process of oxidation and phosphorylation is reduced or blocked by pairing these processes and decreases the effectiveness of biological oxidation. The high concentration in the blood of one of adrenocortical hormones - aldosterone - causes accumulation of different cells in excess of sodium ions. On the other hand, the effect of damaging agents to specific cell types is specific to them (cells) changes. For example, the impact of the various (chemical, physical, biological) of pathogenic factors on muscle cells accompanied by the development of contracture of myofibrils, neurons - the formation of the so-called potential damage to the red blood cells - hemolysis and their exit from their hemoglobin. Damage to the cells is always accompanied by a complex and non-specific, stereotypical, standard changes in them. They are identified in the various cell types of the action of various agents. Among the frequent non-specific manifestations of alterations in the cells are acidosis, excessive activation of free radical and peroxide reactions, denaturation of the protein molecules, increased permeability of cell membranes, ion imbalance and fluid, changing the parameters of the membrane potential, increase the sorption properties of the cells. Detection of the complex specific and nonspecific changes in the cells of organs and tissues makes it possible to judge the nature and potency of the pathogenic factors, on the extent of damage, as well as on the effectiveness used for the treatment of drug and non-drug means. For example, to change the activity in the blood plasma of specific cell myocarditis MB-isoenzyme of creatine kinase, and the content of myoglobin in comparison with the level of potassium ions dynamics (emerging from the damaged cardiocytes), ECG changes, indicators of contractile function of different parts of the myocardium can be judged on the degree and extent of damage heart when a heart attack. ADAPTATION OF CELLS IN THEIR DAMAGE Action on the cell pathogens naturally accompanied by the activation (or inclusion) of reactions aimed at eliminating any decrease in the degree of damage and its consequences. The complex of these reactions provide a device (adaptation) of the cell to change its conditions of life. The major reactions include adaptive compensation mechanisms, recovery of lost or damaged substitution patterns and impaired functions, protect cells from the effects of pathogenic agents and functional decline in their regulatory activity. All complex adaptive responses can be divided into two groups: the intracellular and intercellular. Intracellular adaptive mechanisms in case of damage. The following can be attributed to one of them. Mechanisms of adaptation of cells when they are damaged 1. Payment of violations energy supply of cells: - Intensification of re-synthesis of ATP during glycolysis and tissue respiration in intact mitochondria - Activation of ATP energy transport mechanisms - Activation of ATP energy recovery mechanisms. 2. Protection of cell membranes and enzymes: - Increase in the activity of antioxidant defense system factors - Activation of the buffer systems, - Increase in the activity of detoxification enzymes microsomes - Activation of the mechanisms of repair components of membranes and enzymes. 3. Reducing or eliminating the imbalance in ion and fluid cells: - Reducing the degree of disturbance of energy, - Reduction of the degree of damage to the membranes and enzymes, - Activation of the buffer systems. 4. Fix Violations cell genetic program: - The elimination of gaps in the strands of DNA, 79 - The elimination of (block) the modified DNA segments, - Synthesis of normal DNA fragment instead of damaged or lost. 5. Payment disorders mechanisms regulating intracellular processes: - Changes in the number of "functioning" of the cell receptors, - Change the cell receptor affinity to regulatory factors, - Changes in activity of adenylate - and (or) guanylate cyclase systems and other "intermediary" systems, - Change in the activity and (or) the content of intracellular metabolism regulators (enzymes etc. cations.). Reducing the functional activity of the cells. 1. Regeneration. 2. Hypertrophy. 3. Hyperplasia. Compensation violations energy supply of cells. If damaged cells tend to be more or less affected mitochondria and reduced ATP resynthesis in tissue respiration process. It serves as a signal to increase the ATP "products" in the glycolysis system. With a weak or moderate damage to the activation of ATP re-synthesis can be achieved by increasing the activity of enzymes involved in the processes of oxidation and phosphorylation. Some contribution to the compensation of disturbances of intracellular processes of power supply in case of damage makes the activation of enzymes transport and utilization of ATP energy (creatine kinase, ATPase), and also limit the functionality of cell activation. The latter contributes to a substantial reduction of energy consumption of ATP. Protecting cell membranes and enzymes. One of the most important mechanisms of damage to the membrane unit cells and enzymes is the intensification of free radical and peroxide reactions. The intensity of these reactions is limited mostly antioxidant enzymes - superoxide dismutase (inactivating O2 radicals), catalase and glutathione peroxidase that break down hydrogen peroxide, respectively, and lipids. Another mechanism of protection of the membrane and the damaging action of enzymes, in particular lysosomal enzyme can be activated cell buffer systems. This causes a decrease in the degree of intracellular acidosis and as a result of excessive activity of the hydrolytic lysosomal enzymes. An important role in protecting cell membranes and enzymes from damage play microsomal enzymes (primarily endoplasmic reticulum), providing a physical and chemical transformation of pathogenic agents by oxidation, reduction, demethylation, etc. Alteration of cells may be followed by derepression of genes and thus activating the synthesis and repair of membrane components (proteins, lipids, carbohydrates) to replace damaged or lost. Reducing or eliminating the imbalance in ion and fluid cells. If damaged cells eliminate the imbalance of ions and fluid can be achieved by activating the mechanisms of energy supply ion "pumps", as well as the protection of membranes and enzymes involved in ion transport. A role in reducing the degree of ionic imbalance plays a character change in the intensity of metabolism, as well as the effect of intracellular buffer systems. Thus, increased glycolysis, coupled with the collapse of glycogen, accompanied by the release of its molecules of potassium ions, the content of which in damaged cells is lowered due to the increase of membrane permeability. Activation intracellular buffer system (carbonate, phosphate, protein) can contribute to restoring the optimum ratio in the distribution of the transmembrane and hyaloplasm ions K +, Na +, Ca2 +, etc., In particular by reducing the content of hydrogen ions in the cell. Reducing ion imbalance in turn may be accompanied by normalization of the intracellular contents and circulation of the liquid volume of cells and their organelles, and electrophysiological parameters. Solving Problems in the genetic program of cells. Changes in the structure of DNA, leading to cell damage, can be detected and eliminated with reparative DNA synthesis enzymes. These enzymes provide the detection and removal of the modified DNA region is (they are called 80 endonucleases or restriction enzymes), synthesis of normal nucleic acid fragment for the deleted region (by DNA polymerases) and insertion of the newly synthesized fragment to a remote location (with ligase). In addition to these complex enzyme systems of DNA repair in cells have enzymes that remove the "small-scale" biochemical changes in the genome. These include demethylase, removing methyl groups; ligase eliminating breaks in DNA strands that are caused by the action of ionizing radiation or free radicals, and others. Compensation disorders mechanisms regulating intracellular processes. Among the responses, effectively compensating disturbances of perception mechanisms regulating cell influences include changes in the number of hormone receptors, neurotransmitters and other physiologically active substances on the surface of the cell and its organelles, as well as sensitivity (affinity) receptors to these substances. The number of receptors may vary, in particular due to the fact that their molecules can be immersed in the cell membrane, or cytoplasm and rise to the surface thereof. From the number and sensitivity of receptors, which receive regulatory incentives are largely dependent nature and severity of the response to them. The excess or deficiency of neurotransmitters and hormones, as well as significant variations in their activity level may be so-called second implementation nerve stimulus mediators, in particular of cyclic nucleotides. It is known, for example, that the ratio of cAMP and cGMP is changed not only as a result of regulatory extracellular stimuli, intracellular factors but also, in particular phosphodiesterase, and calcium ions. Violation of regulatory effects on the implementation of the cell can be compensated to some extent on the level of intracellular metabolic processes, since many of them on the basis of flow rate regulation of metabolism amount of the enzyme reaction product (the principle of positive or negative feedback). Reducing the functional activity of the cells. The importance among the adaptive mechanisms of damaged cells is controlled, controlled reduction of their functional activity. This causes a decrease in consumption of ATP energy substrate metabolism and oxygen needed to implement the functions and provide plastic processes. As a result, the degree and extent of damage to the cells by the action of pathogenic factors are significantly reduced, and after its termination is marked more intensive and complete recovery of cellular structures and their functions. Among the main mechanisms that explain the temporary lowering of cell function, may include a decrease in effector (incentive function) impulses from the nerve centers, reduction in the number or sensitivity to cell surface receptors, intracellular regulatory suppression of metabolic reactions, the repression of the activity of individual genes. Adapting cells under injury occurs not only on metabolic and functional level. Prolonged repeated or serious damage causes substantial structural changes in the cell that have adaptive value. They are achieved through the processes of regeneration, hypertrophy, hyperplasia. Regeneration (from the Latin regeneratio -. Regeneration, restoration). It means cell compensation and (or) their structural elements instead of dead, damaged, or have completed their life cycle. Regeneration structures is accompanied by the restoration of their functions. There are so-called cellular and intracellular (subcellular) forms of regeneration. The first is characterized by the multiplication of cells through mitosis or amitosis. Intracellular Regeneration manifested by reduction of organelles: the mitochondria, nucleus, endoplasmic reticulum and other instead of damaged or dead. Hypertrophy (from the Greek hyper -. Excessively, increasing + Greek trophe -. Food). It represents an increase in an organ or part due to an increase of volume and mass of the structural elements, in particular cells. Hypertrophy of the intact cell organelles compensates breach or failure the functions of its corrupt elements. For example, tissue cell hypertrophy mitochondria undergoing repeated influence of moderate hypoxia, can provide adequate intracellular energy process even in conditions of reduced oxygen delivery and significantly reduce or prevent damage. Hyperplasia (from the Greek hyper -.. Overly + Greek plasis - formation, formation). Characterized by increasing the number of structural elements, in particular in cell organelles. Often in the same cell and there are signs of hyperplasia and hypertrophy. Both processes provide not only compensation for a structural defect, but also the possibility of increased cell functioning. 81 Intercellular (system) cell adaptation mechanisms when they are damaged. Within tissues and organs are not separated cells. They interact with each other by exchanging metabolites, physiologically active substances, ions. In turn, the interaction of the body in general, cells and organs functioning ensured lymph and circulatory systems, immunobiological surveillance, endocrine and nervous influences. Thus, a decrease in the oxygen content in the blood (which causes or can cause damage to cells, especially the brain) through reflex irritation chemoreceptors stimulate the neurons of the respiratory center. This increases the volume and alveolar ventilation eliminates or reduces the extent of lack of oxygen in blood and tissues. Damage to the cell under conditions of hypoglycemia can be reduced by increasing the production of hormones that increase in blood glucose level and its transport into cells: adrenalin, glucocorticoids, growth hormone, and others. An example of an adaptive response such as circulatory can be increased inflow of blood through the collateral (bypass) vessels at the closing of the lumen of the main artery of an organ or tissue. Immune mechanisms of supervision and protection are included under the influence of pathogen antigen nature. System involving immunocompetent phagocytes, and antibodies (or) inactivates T lymphocytes endo - and exogenous antigens that can damage the cells of an organism. Normally, the above and other systems provide adequate response of the whole organism to various influences endo - and of exogenous origin. In pathology, they are involved in the regulation and implementation mechanisms for the protection, compensation and rehabilitation of damaged structures and functions of cells and damaged tissues. A characteristic feature of the intracellular mechanisms of adaptation is that they are implemented mainly with the participation of cells that have not been directly exposed to the pathogenic factor (eg, hyperthyroidism cardiomyocyte necrosis outside the zone of myocardial infarction). In terms of implementation at the intercellular cell damage response adaptation can be divided into organ-tissue, intra, inter-system. An example of the reaction of organ and tissue levels may be activation of the function of damaged cells of the liver or the kidney is damaged part of the body cells. This reduces the load on the cell, subjected to pathogenic effects, reduces the degree of alteration and implementation of reparative processes. Among intra-arteriolar narrowing relates reactions with a decrease of the heart (e.g. myocardial infarction), which maintains a high level of tissue perfusion pressure and prevents (or reduces power) of cell damage. Involvement in adaptive responses observed in several physiological systems, such as general hypoxia. This activates the breathing work systems, circulation of blood and tissue metabolism, which reduces the lack of oxygen and metabolic substrates to the tissues, increasing their utilization and thereby reduces the degree of cell damage. Activation of intracellular and intercellular mechanisms of adaptation in case of damage, usually prevents cell death, ensures that their functions and contributes to the elimination of the consequences of the action of pathogenic factors. In this case we speak of reversible changes in the cells. If the power is high pathogenic agent and (or) the protective and adaptive mechanisms are not sufficient, develop irreversible damage to the cells and they die. PRINCIPLES AND METHODS OF INCREASING THE STABILITY intact cells to the action of pathogenic factors and stimulation of adaptive mechanisms in them at DAMAGE Impact is designed to protect intact cells from damage (prevention) or to the stimulation of adaptive mechanisms in case of damage (medical), conventionally divided into two groups: non- drug and drug. Drug-effects are mainly used for the purpose of preventing damage to cells, medications - for activation of adaptive mechanisms in cell damage. The greatest effect is achieved when the combination effects of both groups. 82 And drug and non-drug exposure can be directed to 1) the removal, termination, reduction in force and (or) the duration of action of pathogenic factors on the cells, as well as addressing the conditions conducive to the implementation of this action. Such effects are called etiotropic; 2) activation of compensatory mechanisms, protection, recovery and cell adaptation to the changed conditions. These effects are referred to as sanogenetic (from the Latin sanus - healthy.); 3) break the links of the mechanism (pathogenesis) of the pathological process. These effects are referred to as pathogenic. As indicated by the experimental animal studies and testing of their results on the person, the body training in a specific pattern, such as intermittent moderate hypoxia, stress factors, physical exertion, cooling, increases the resistance of the cells of organs and tissues and the organism as a whole, a number of pathogenic factors: to significant hypoxia, ischemia, cold, ionizing radiation and other agents. In this regard, training and other actions specified is used to prevent tissue damage and organ cells in various diseases and pathological processes, as well as a method of stimulation of reparative processes in cells. The basis of increasing the resistance of tissue cells and organs to pathogenic influences in training named above, as well as other impacts is improving the reliability and capacity of regulatory systems, mechanisms of energy and plastic to ensure the cells, their compensatory, restorative and protective reactions. This in turn is the result of the activation of the genetic apparatus, and as a consequence of necessary protein synthesis, formation of subcellular structures and the formation of other changes that enhance cell resistance to damaging agents. The majority of pharmacological agents appointed in various diseases and pathological processes, is used to causal or pathogenic therapy. The main principles of the actions that aim to reduce the effect of pathogenic effect on the cells and (or) to block the mechanism of development of the pathological process, include: 1) the degree of decline or elimination of infringements of processes of energy supply of cells; 2) protection of cells and membrane enzymes; 3) correction and protection mechanisms of transmembrane transport and intracellular distribution of the ions, to control the volume and electrophysiological parameters of the cells; 4) prevention of the factors that cause changes in the genetic apparatus of cells; 5) regulation of correction mechanisms and the integration of intracellular processes. Below are some of the principles of pathogenetic therapy of damaged cells of various tissues and organs. In order to reduce or eliminate the extent of violations of the processes of energy supply of the cells used drugs, regulating or influencing the activity of the synthesis process, transport or assimilation of ATP energy. These include agents which provide the following effects: - An increase in cell transport and absorption of oxygen and metabolic substrates (e.g., substances that cause dilation of arterioles, antihypoxants, agents facilitating transmembrane transport of the substrates); - Protection and correction of re-synthesis mechanisms of intracellular transport and assimilation of ATP energy (for example, antioxidants, Membrane, agents that stimulate the metabolic processes); - Reduction of energy consumption in the cells (e.g., reduction means the functional activity of the cells or the load on them, the drugs or blockers of neurotransmitter action, peptides, inhibitors of the calcium channel activity of cell membranes). Protection of membranes and enzymes, cells from the action of damaging factors is achieved by using tools that determine: - Reduction in the intensity of free radical and peroxide reactions (antioxidants); - Stabilization of the lysosomal membranes and prevent the release of these hydrolytic enzymes (Membrane preparations); - Inhibition of the activity of hydrolases, destroying phospholipids and membrane proteins (antiadrenergic agents, inhibitors of calcium channel activity and other drugs, either directly or indirectly prevent activation of hydrolases). Correction and protection mechanisms of transmembrane transport and intracellular distribution of the ions, to control the volume and electrophysiological parameters of the cells are carried out with the help of drugs that regulate the transport of ions through the cell membrane, such 83 as membrane calcium channel blockers; means changing the activity of K, Na- ATPase and others. Given that the transmembrane transport and intracellular distribution of ions is largely dependent on the physical and chemical state of the membranes and the energy supply of cells, ion imbalance correction can be largely achieved thanks to the normalization of the synthesis process, transportation and energy utilization of ATP, and by protecting the membrane device enzymes and cells (see. above). Eliminating the ion imbalance in the cell, usually accompanied by normalization of its content of liquid and electrophysiological parameters (values resting potential, action, etc. of the amplitude.). However, a number of diseases applied drugs that reduce the total liquid content in the body, including intracellular, e.g. diuretics. In recent years intensively developed measures aimed at preventing the factors that cause changes in the genetic apparatus of cells. To this end, in addition to carrying out special organizational and hygienic measures (overalls shielding radioactive sources) are used as drugs that increase resistance of body cells to the action of mutagenic agents (mainly ionizing radiation) by protecting or reduce the degree of damage to nucleic acids and other macromolecules . These substances are called radiation protectors (radioprotective or radioprotective agents). Radioprotectors conventionally divided into two groups depending on their origin and mechanism of action: 1) biological and 2) pharmacochemical. The first increase radioresistance of cells in the body due to the activation of non-specific mechanisms and reduce the sensitivity of the cells to ionizing factors. Therefore they are mainly used as a prophylactic measure. As biological radioprotective used vitamins C and P, hormones, coenzymes, adaptogens (Eleutherococcus extracts and tinctures, ginseng, Chinese magnolia vine, etc.). Troubleshooting and mutations also contribute to exposure, to protect cell membranes and enzymes, including enzymes reparative DNA synthesis. Correction mechanisms regulating intracellular processes and integration is achieved by using drugs hormones, neurotransmitters, cyclic nucleotides and other enzymes. Methods and applications different schemes depending on the nature of the damage and the developing concerning the pathological process. The above-mentioned principles and methods aimed at increasing cell resistance to pathogens, and stimulation of adaptive responses in damaged cells, as well as preparation examples of groups do not exhaust the whole arsenal of approaches and drugs used today in medical practice. These principles are modified with the deepening of knowledge about the causes and conditions of disease, as well as the mechanisms of their development. 84 REACTIVITY OF THE BODY Reactivity of the body (from Latin "reactio" -opposition) - is ability to react to the exogenous influence by changing of vital activity. This property is developed in the course of evolution as the highest form of irritability and has a mainly protective and adaptive nature. Reactivity - a manifestation of a biological reflection of matter, socially mediated in humans. A well – known pathophysiologist N.Sirotinin studied the problem of the body’s reactivity for over 30 years. Reactivity is a characteristic of all living beings. The ability of a human being or an animal to adapt to the environment, to maintain homeostasis largely depends on the reactivity. It is the reactivity that determines the occurrence and the progress of an illness. Therefore, the study of reactivity and its mechanisms is so important for understanding a disease pathogenesis and its purposeful prevention and treatment. Different species of animals change their vital activity under endogenous influence differently; different groups of people react to the same influence in different ways, and every individual has his own peculiar ways of reacting. The types of reactivity: 1. Species (biological). 2. Group. 3. Individual: (physiological, pathological, non-specific, specific). Species (biological) reactivity Species (biological) reactivity is the reactivity typical of particular species of animals. Species reactivity is aimed at preserving the species in general, and has an adaptive character. We can cite animals’ seasonal behaviour as an example of the species’ reactivity (hibernation, migration of birds and fish, etc.), specific features of pathologic processes in different species (inflammation, fever, allergy, the response of an acute stage, etc.) Vertebrates’ reactivity is manifested stronger and more varied than invertebrates’ reactivity. All warm – blooded species can produce special antibodies, and this ability of different species is expressed differently. In an experiment one can easily reveal the specific features of the reactions of different species to mechanic, chemical and thermal exposures, ionic radiation (dogs, guinea-pigs and people are the most sensitive, and unicellulars and worms are the least sensitive), hypoxia. Susceptibility or unresponsiveness to infection is a vivid symptom of the species’ reactivity and resistance: dogs’ distemper and foot – and – mouth disease are not dangerous for people; tetanus is dangerous for people, monkeys and horses and it is not dangerous for cats, dogs, hedgehogs, tortoises, crocodiles; sharks are never ill with this disease and their wounds never fester; rats and mice can’t have diphtheria, dogs and cats – botulism. Group reactivity Group reactivity is the reactivity of separate groups of people (or animals) sharing a common sign which determines the reaction specifics of all the representatives of this group to external exposure. Group reactivity is property of a specific group of animals or humans to react by change of vital activity to response of environmental factors. This reactivity is aimed at preserving certain group of people or animals due to protective and adaptive responses. The group was formed in the process of evolution, and during the life of animals or humans of a certain group. Such signs are: age, sex, constitution type, race, blood group, higher nervous activity type, group of people with the same illness, etc. E. g.: Men are often affected by such diseases as gout, spondylarthritis; pyloric stenosis, ulcer, cancer of the head of pancreas, coronarosclerosis, alcoholism; and women rather have rheumatoid arthritis, cholelithiasis, cancer of cholecyst, myxedema, hyperthyreosis, purpura hemorrhagica; dark-skinned people are not very sensitive to ultraviolet rays. The risk of getting a 85 peptic ulcer is as much as 35% as high for people sharing the 1st blood group, these people died more often in time of epidemics of plague; and people sharing the 2nd blood group more often get stomach cancer, a coronary disease, they are more sensitive to grippe, but they are more resistant to enteric fever. Individuals of phlegmatic, sanguine, melancholic and choleric types respond differently to a social and emotional stress (their reactivity depends on their temperament). Children and old people have special reactivity. This fact has resulted in the development of special branches in medicine – pediatrics and geriatrics. Any age is characterized by certain morphological and functional characteristics which determine the character of a body response to external exposures. Children under 1 month never suffer from mumps, scarlet fever, since they have received their mothers’ antibodies; newborn babies are very sensitive both to over-cooling and overheating as a result of their imperfect mechanisms of thermoregulation. They need a special diet because of morphofunctional specifics of their gastrointestinal tract and digestive glands, a special water intake schedule, due to the high intensity of their water metabolism. The period of involution is characterized by weakened protective mechanisms, limited adaptability to the environment, weakened regeneration and immune protection, hormonal reorganization. Such people are more subjected to oncological and infectious diseases. Individual Reactivity Individual reactivity is the property of the individual to react by change of vital activity to response of adequate or extreme stimuli of the environment. Individual reactivity is aimed to preserve or restore of homeostasis and to maintain the health and save the life of the individual. Every human being or animal possesses a range of reactions typical of a certain group or species. Therefore, they respond to external agents changing their vital activity, in their own, particular way. For example, some people have low resistibility to influenza, others have higher resistibility, and there are people who don’t get this disease at all, however, the virus can be found in their body (they can be virus carriers). Individual reactivity of every organism accounts for this fact. The diseases may advance individually for every particular patient. Every case should be treated individually. A particular disease has to be treated (etiologically, pathogenetically, and symptomatically) in a particular patient considering their individual reactivity. Individual physiological reactivity Physiological reactivity is the property of the individual to react by change of vital activity to response of adequate stimuli of the environment. This reactivity is aimed to preserve of homeostasis and maintain of the health of the individual. Physiological reactivity means a change of the bodily vital activities, definite forms of reaction to the influence of external agents that don’t disturb its homeostasis; it is the reactivity of a healthy person (or an animal) to non-pathogenic stimulants (e. g. adaptation to moderate physical strain, processes of thermoregulation, secretion of hormones and peptic enzymes, natural emigration of leucocytes, etc.). Individual pathological reactivity Pathologic reactivity is the property of the individual to react by change of vital activity to response of extreme stimuli of the environment. This reactivity is aimed to restore of homeostasis and save the life of the individual. Pathologic reactivity manifests itself when an organism is exposed to pathogenic factors causing lesions of the body and disturbing its homeostasis. Individual non-specific and specific reactivity 86 Specific reactivity is related to certain factor. Specific reactivity is the ability of an organism to respond to the influence of an antigen by producing antibodies or with a complex of cell reactions, that are specific to this antigen, i.e. it is the reactivity of the immune system (immune reactivity). Its types are as follows: active specific immunity, allergy, autoimmune diseases, immunodeficiency and immunosuppressive conditions, immunoproliferative diseases. Immunological tolerance is a condition of a specific immunological non-reactivity to a particular antigen caused by the previous contact with this antigen. Immune reactivity to other antigens is preserved. Immunological tolerance is an active process when the contact with an antigen (tollerogen) causes specific elimination or inactivation of the antigen- reactive clones of lymphocytes (e.g. by means of antibody complexes) or formation of suppressor-cells inhibiting immunocompetent lymphocytes. The types of immunological tolerance are as follows: congenital or natural, acquired (immunological paralysis or high doses, small doses, drug-induced). Runt disease (homologous disease) is conditioned by the immunological reaction of a transplant to a host. It is usually observed in case of transplanting allogenic immunocompetent lymphocytes of a donor to an adult recipient whose immune system is considerably impaired as a result of earlier roentgeno- or chemotherapy. Non-specific reactivity. Non-specific reactivity is related to many factors. All changes in the body occurring in response to the influence of external agents and not associated with the immune reaction, are the signs of nonspecific reactivity. For example, the changes in the body in response to the hypovolemic or traumatic shock, hypoxia, acceleration or overstrain are the signs of nonspecific reactivity. In infectious, allergic, autoimmune diseases the mechanisms of both specific (production of antibodies) and nonspecific reactivity (inflammation, fever, hypercytosis, changes of function of damaged organs and systems, etc.) are involved. Both the whole organism and its separate systems, organs, cells may have reactivity. When an environmental agent affects the whole organism, its main regulatory systems – nervous and endocrine – get involved in response to it, when metabolism, blood circulation and respiration change, we can witness the reactivity of the whole organism. If a patient with an ischemic heart disease develops a stenocardial attack as a result of physical exertion, in this case we mainly deal with cardiac reactivity with affected coronary vessels. Criteria of individual reactivity in disease (criteria of pathological individual reactivity): 1. Quantitative (rate of occurrence of the reaction, the amplitude, the duration of the reaction). 2. Qualitative (protective potential of the organism, its passive and active resistance). Quantitatively is distinguished forms of reactivity: - normergy; - hyperergy; - hypoergy; - disergy. Normal reactivity – normergy, increased – hyperergy (hyper – more, ergon – act), decreased – hypoergy, perverted – disergy. The lack of reaction to any influence is called anergy. If a disease (pneumonia, tuberculosis, dysentery, etc) takes an intensive, rapid course, with clearly marked symptoms, high fever, sharp acceleration of erythrosedimention rate, high leucocytosis, etc., the course of this disease is considered to be hyperergical. On the contrary, if the symptoms of a disease are poorly marked and the course of the disease is inactive without manifestations of the acute phase, they speak about the hypoergical course of the disease. A perverse (atypical) reaction of the patient to a drug, vasodilation and excessive sweating at low temperatures in patients with disorders of the vegetative nervous system are the examples of disergy. Anergy is a condition when the body 87 doesn’t respond to the presence of pathogenic microorganisms in it (carriers), or when the central nervous system is either deeply depressed or inhibited (coma, shock, anesthesia, inhibitory stage of parabiosis). The condition of immunological tolerance to an antigenic stimulus can be also classified as anergy. Reactivity should be estimated in relation to a particular intervention. Quite often high reactivity to one agent is coupled with low reactivity to another (for example, reactivity to hypoxia and acceleration, overheating and over-cooling, to physical overstrain and starvation, reactivity to different infective agents, etc.). During prenatal development an embryo doesn’t respond to enteric fever and jail fever infection but responds to diphtheria, staphylococcus and streptococcus. A newborn has low reactivity to hypoxia but high reactivity to overheating. Sometimes when two or several agents affect the body, it can respond only to one of them ignoring the others. Qualitative characteristics of reactivity: 1. Resistance – basic qualitative indicator. 2. Irritability - a general property of all living things, defines the most basic reaction. 3. L ability (functional mobility) - the rate of elementary reactions. 4. Excitability - ability of the nervous, muscular, glandular tissues to respond to stimulation by occurrence of the excitement. 5. Sensitivity - The ability of the whole organism to determine the location, strength and quality of the stimulus. The Resistance Resistance is the body insusceptibility to pathogenic effects. Forms of resistance: 1. Primary resistance: -active; -passive; 2. Secondary resistance; 3. Passive resistance; 4. Active resistance; 5. Specific resistance; 6. Non-specific resistance; 7. Local resistance; 8. General resistance; The resistance of the body to pathogenic effects manifests itself in different forms: for example, skin and mucous membranes are the structures preventing the penetration of microorganisms and many poisonous agents into the body. They perform the so-called barrier function. Subcutaneous fat tissue has poor thermal conductivity, while bones and other tissues of the locomotor apparatus are characterized by high resistance to deformation under the influence of mechanical agents. These examples testify to the resistance of tissues and the whole body depending on their inherited structure and properties. This is the so-called primary resistance. Primary and Secondary resistance Primary resistance is hereditary. It is based on the morphofunctional specifics of the body owing to which an organism is resistant to the action of extreme factors (unicellular organisms and worms are resistant to radiation, cold-blooded animals – to hypothermia, etc.). Due to hereditary immunity people are not subjected to many infections typical of animals, and in the period of epidemics of smallpox and plague some people who were directly in contact with sick people didn’t catch the infection. Hereditary resistance (immunity in particular) may be absolute and relative. 88 Gonorrhea is a human disease. Animals cannot be infected with gonococcus. It is possible to infect hens with anthrax only by exposing them to cold, however, they are resistant to it in ordinary conditions. Secondary resistance is acquired (for example, immunity develops after some infectious diseases, after the administration of vaccines and sera). Resistance to non-infectious interventions can be acquired through exercising resitance to physical exertion, to acceleration and overstrain, hypoxia, low and high temperatures, etc. Passive and Active resistance Passive resistance of the body is provided by its barrier systems (skin, mucous membranes, hematoencephalic barrier, etc.), the present bactericidal agents (hydrochloric acid in the stomach, lysozyme in the saliva) and hereditary immunity. Active resistance is provided by the activation of its protective-adapting and compensatory mechanisms, such as production of leukocytes, phagocytosis, production of antibodies, neutralizition and excretion of toxins, secretion of stress hormones, changes of blood circulation and breathing, fever, synthesis of acute phase proteins by the liver, increase of leuco- and erythropoiesis, etc. Reactivity and resistance relationship Reactivity and resistance are interrelated but not always unidirectional For example, reactivity in breast-fed babies under 3 months is low but resistance to some infections is high as they have received some antibodies from their mothers. A newborn animal has low reactivity and high resistance to hypoxia, while in a mature animal it is opposite. In surgery anesthesia is used to reduce the patient’s reactivity and at the same time to boost their resistance to trauma. In animals which are dormant in winter reactivity is low but the resistance to many external agents is high. At the same time old people have a hypoergic course of most diseases and their resistance is low. Factors of individual reactivity of organism: 1. Heredity. 2. Age. 3. Sex. 4. Life story. 5. Constitution type of the body. Role of heredity factor in the individual reactivity: Heredity - individual reactivity factor. Human genotype determines how to respond to environmental factors - its norm of reaction. Reaction norm - is determined by genotype range of adaptive reactions of the organism - its adaptation in time and space. Role of the age factor in the individual reactivity of organism: in process of development man from the state of infancy to adulthood - reactivity is improved (its resistance increases to various environmental factors). Persons at any age have their own morphological and functional peculiarities and the body response to external intervention depends on them. The adaptability to environmental temperature changes is weaker in newborns than in adults as a result of immaturity of their thermoregulatory system. Children aged 1 – 3 years are highly susceptible to different infections (measles, scarlet fever, whooping-cough, diphtheria) due to functional immaturity of their immune system (inability to produce the required amount of their own antibodies) and the exhaustion of antibodies received from their mothers through placenta and breast milk as well as as a result of immaturity of their barrier systems. The incidence of malignant tumors, atherosclerosis, ischemic heart disease increases in elderly people. It may be conditioned by age-specific peculiarities of the activity of regulatory systems, their rearrangement in the process of individual development. Owing to decreased function of the nervous system, weakened barrier systems as well 89 as ability to develop an immune reaction in senile people, the susceptibility to infections, especially to coccal bacteria, increases again. Role of the sex factor in the individual reactivity of organism: the norm of reaction of the female body as a result of homozygosity for 23 pair of chromosomes is wider. Wide norm of reaction leads to greater life expectancy of women. Men are often affected by such diseases as miocardium infarction, coronarosclerosis, spondylarthritis, pyloric stenosis, ulcer, cancer of the head of pancreas, alcoholism. Women are often affected by such diseases as autoimmune disorders, cholelithiasis, myxedema, hyperthyroidism , purpura hemorrhagica. History of life - individual reactivity factor of human: history of life may leave trails former biologically important stimuli of the environment. This can affect the body's reactions to a given stimulus (including the aggressor). Constitution type of the body - individual reactivity factor. The constitution type of the body - a combination of structural, biochemical, functional characteristics of the organism of hereditary and acquired genesis affecting on its individual reactivity. This is an important internal condition that promote or hinder the emergence of the disease (with the causes of disease). Classification of constitution type by Chernorutskii: 1. normosthenic 2. asthenic 3. hypersthenic. Index of Pine (IP): growth (cm) – (chest (cm) + weight (kg)) IP = 10-30 - normosthenik IP ›30 - asthenik IP ‹ 10 – hypersthenic. Asthenic characterized by slender body, weak development of the muscular system, dominated (as compared to normostenic) longitudinal body size and the size of the chest over the size of the stomach. High level of metabolical processes. The tendency to ptosis of the organs, stomach ulcer, severity of pulmonary tuberculosis, hypotension, pathological amenorrhea. Normosthenic characterized by proportional body size and harmonious development of the musculoskeletal system. Predisposition to diseases of the upper respiratory tract and musculoskeletal system. Hypersthenic characterized by long body and short limbs, a relative predominance of the transverse dimensions of the body, the size of the stomach over the size of the chest. Low metabolism. Tendency to hyperlipidemia, hyperglycemia. Predisposition to diseases of the cardiovascular system (atherosclerosis, myocardial infarction, hypertension), diabetes mellitus, obesity, gallstones. Mechanisms of physiological reactivity: 1. Humoral mechanism. 2. Reflex mechanism (more often). 3. Neurohumoral mechanism. Mechanisms of physiological reactivity is characterized by the formation of negative feedback. Mechanisms of pathological reactivity: 1. Humoral mechanism. 2. Reflex mechanism. 3. Neurohumoral mechanism (more often). Mechanisms of pathological reactivity may with negative feedback, without negative feedback, with the positive feedback. The mechanisms of nonspecific protection: 90 1. The cellular. Phagocytosis is phylogenetically oldest and most stable protective and adaptive cellular response of the organism. Phagocytic cells are: -macrophages (alveolar, peritoneal macrophages of the liver, etc.); -monocytes (macrophage precursors); -neutrophil granulocytes and macrophages. 2. Humoral: - lnhibitors of viral activity (heat-labile, thermostable); - Complement system - heat-labile enzyme system; - Lysozyme (muramidase); - Properdin - high molecular weight protein that provides antibacterial, hemolytic, antiviral property of serum; - Leukins - thermostable antibacterial factors which are able to inactivate gram (+) bacteria; - Interferons - having antiviral activity. American psychophysiologist and physiologist Walter Cannon (1871-1942) emphasized the importance of sympathetic nervous system in the development of protective and compensatory mechanisms. L.A. Orbeli in 1935 formulated the theory about the adaptive-trophic role of the sympathetic nervous system. It has been shown that the damaging effects it is through the sympathetic nervous system activates the higher parts of the central nervous system, there is a mobilization of energy, stimulates the cardiovascular system, increasing efficiency of muscles are activated immunological mechanisms and other processes. Great contribution to the study of stress brought Canadian pathologist Hans Selye.Selye merit is that he investigated in detail and showed a critical role in the development of the general adaptation syndrome, pituitary-adrenal axis. Damaging factors when acting on the body caused by two types of reactions: specific, related to the quality of the factors and non-specific, general. This set of characteristics, stereotypical general response of the body to the action of stimuli of various nature is called "stress" or "general adaptation syndrome." Such reactions are primarily the protective and aimed at adaptation of the body to the new conditions, the alignment of the changes that are caused by damaging factors. Stress is the nonspecific response of the body that occurs under the influence of various extreme factors that threaten the disruption of homeostasis, and is characterized by stereotypical changes in the nervous and endocrine systems. Irritant causing a stressful situation, called a stressor. Stressor in origin may be of any factor. The damaging effect of a stressor depends on the intensity (power), and the duration or frequency of its impact. Selye noted that despite the variety of stressors, they all lead to the same changes in the thymus, adrenal glands, lymph nodes, blood composition and metabolism. In experiments on rats, he observed the typical triad: 1. Hypertrophy of the adrenal cortex. 2. Involution lymphoid system (thymus). 3. Hemorrhage in the mucosa of the stomach and duodenum. General adaptation syndrome, according to Selye, in its development goes through three stages: 1. First stage - "alarm reaction“. 2. Second stage - stage of resistance. 3. Third stage of the adaptation syndrome - the stage of exhaustion. First stage. Antihock phase is characterized by changes in the opposite direction (increased blood pressure, muscle tone, blood glucose), leading to the development of the next stage - the stage of resistance. The main pathogenetic link of antyshok phase - is a persistent increased secretion of corticotropin and corticosteroids. 91 Second stage. In the second stage, the stage of resistance - developed hypertrophy of the adrenal cortex with a steady increase in the formation and secretion of corticosteroids. They increase the amount of circulating blood, increases blood pressure, have an antihistamine effect,increase gluconeogenesis. These effects are related both to the direct action of corticosteroids, and to a large extent with the ability to activate the effects of the sympathetic nervous system and its adaptive-trophic influence. At this stage usually increases the body's resistance to the action of some of extraordinary stimuli, although there are cases increase of sensitivity. If the action of the stressor stops or it is insignificantly, the changes caused by them, gradually normalized. Third stage. If the effect of the pathogenic factor is extremely strong and lengthy develop depletion of adrenocortical function and death of the organism occurs. This third stage of the adaptation syndrome - the stage of exhaustion. Pathogenesis of stress The impact of the stressor Central and peripheral nervous system Hypothalamus Pituitary Adrenal cortex Thyroid gland catecholamines, glucocorticoid, thyroxine, glucagon, TSH, stress limiting factors and others -↑ blood pressure, metabolism stimulation, CNS stimulation; -gluconeogenesis, the involution of the thymus, lymph nodes, inhibition of inflammation, immune responses, development of gastrointestinal ulcers; -limit the damaging effects of glucocorticoids and catecholamines. Adaptive effects of glucocorticoids to the stress exposure: - Mobilization of energy resources. - The delay Na (↑ blood volume) - ↑ blood pressure. - ↑ sympathetic influences (↑ blood pressure, ↑ cardiac output, ↓ blood flow to the kidneys, ↓ peripheral blood flow). - A powerful anti-inflammatory effect. - Activate erythropoiesis neutropoiesis, thrombocytopoiesis, ↓ eosinophils and lymphocytes (on the periphery). Adaptive effects of catecholamines to the stress exposure: - Acceleration and increased of cardiac activity. - Regulation of blood pressure (noradrenaline). - Centralization of blood flow. - Dilation of coronary vessels (epinephrine). - ↑ rate and depth of breathing, bronchodilation. - Stimulation of lipolysis. - Mobilization of psychic activity. 92 - Blunting of pain. Functional system of preservation of life (FSPL) is set of all hereditary and acquired adaptive reactions (protective, compensatory, homeostatic), emerging in response to the emergency (damaging) stimulus (the aggressor) of the environment - causes of the disease. Formation of FSPL goes through the individual reactivity factors (heredity, age, sex, history of life, the constitution). They create the initial functional state of regulatory and executive body systems. Example embodiments of forming the results of the response FSPL: 1. Absolutely optimal functional system of preservation of life with negative feedback (favorable outcome of the general stress, the favorable outcome of the meeting with the pathogens) - the disease does not occur. 2. Optimal functional system of preservation of life with negative feedback (illness with complete recovery). 3. Relatively optimal functional system of preservation of life with negative feedback (a disease with a chronic course, with incomplete recovery). 4. Nonoptimal functional system of preservation of life without negative feedback (sudden death in acute pneumonia, acute myocardial infarction, etc.). 5. Nonoptimal functional system of preservation of life with positive feedback (severe course of the disease with complications - infections sepsis, severe mechanical trauma with traumatic shock of II - III stages, etc.). Possible death. 93 Carbohydrate metabolism disorders Carbohydrates - compulsory and most significant component of food. The day a person consumes 400-600 grams of different carbohydrates. As a necessary participant in the metabolism of carbohydrates are included in almost all types of metabolism: nucleic acid (as ribose and deoxyribose), proteins (e.g., glycoproteins), lipids (e.g., glycolipids), nucleosides (such as adenosine), nucleotides (such as ATP ADP, AMP), ions (for example, providing energy transfer their transmembrane and intracellular distribution). As an important component of cells and the intercellular substances, carbohydrates included in the structural proteins (e.g., glycoproteins), glycolipids, and other glycosaminoglycans. As one of the main sources of energy, carbohydrates are necessary to ensure the life of the organism. Most carbohydrates are important for the nervous system. Brain tissue uses approximately 2/3 of glucose entering the bloodstream. Exchange of carbohydrates includes several stages: 1) Digestion of polysaccharides originating from food in the duodenum and upper small intestine to monosaccharides and their absorption into blood. 2) Deposition of carbohydrates. 3) An intermediate carbohydrate metabolism: - Aerobic and anaerobic degradation of glucose; - Mutual transformation of hexoses; - The process of gluconeogenesis (glucose synthesis from non-carbohydrate precursors). 4) Isolation of glucose by the kidney glomerular apparatus with primary (provisionally) in urine and its complete reabsorption in the renal tubules. Disorders of digestion and absorption of carbohydrates Carbohydrate absorption occurs primarily in the duodenum and jejunum with intestinal epithelial microvilli only in the form of monosaccharides. Hydrolysis of starch and glycogen food begins in the mouth under effect salivary α-amylase. Monosaccharides can be absorbed already in the mouth. In the stomach, no enzymes, performing the hydrolysis of carbohydrates. The intestinal cavity under the influence of α-amylase pancreatic juice before they hydrolyze dextrins and maltose (cavitary digestion). On the surface of the microvilli of enterocytes enzymes are localized: sucrase, maltase, isomaltase and lactase other, splitting and disaharaidy dextrins to monosaccharides (parietal digestion). Monosaccharide absorption in the small intestine - mentioned active transport process of molecules through the membrane of epithelial cells, which requires energy. The driving force of glucose transport into the epithelial cell is an ATP-dependent sodium pump, and the transport occurs by means of specific transporter, physically independent of the sodium pump. This is an example of secondary active transport, in which to transfer a single connection (glucose) using the energy of the electrochemical gradient generated by another substance (sodium ions). Considered glucose transport mechanism also operates in epithelial cells of renal tubules. Receipt of the glucose into the red blood cells is carried out by a different mechanism. The process of absorption of the individual monosaccharides occurs at different rates. The highest speed of the process is characterized by glucose. Apparently, this is due to the difference in specific monosaccharide transport mechanisms through the mucosa of the small intestine. Violation of the breakdown of carbohydrates. Among the most common problems include the lack of enzymes - disaccharidases: sucrase and isomaltase manifested always a combination. As a result of this disaccharide sucrose and isomaltose are not split and not absorbed by the body. Accumulating with intestinal lumen disaccharides osmotically bind significant amounts of water, causing diarrhea (diarrhea). Under these conditions, it is also possible absorption of a certain amount of epithelial cells disaccharides. However, they are metabolically inactive and unaltered rather quickly excreted in the urine. When defects activity disaccharidases disaccharides load does not cause hyperglycaemia in the range of 30-90 minutes, as is the case in healthy people. 94 Monosaccharides (galactose, glucose, fructose, and pentose) from food or vacated by hydrolysis and poly disaccharides absorbed microvilli of epithelial cells of the small intestine. Causes of disorders of the process of absorption of carbohydrates are: 1) The inflammation of the small intestine mucosa. 2) The action of toxins that block the process of phosphorylation and dephosphorylation (phloridzin, monoyodatsetat). 3) Lack of ions Na +, for example, when adrenocortical hypofunction. 4) Violation of the blood supply to the intestinal wall. In addition, in neonates and infants insufficiency active as digestive enzymes and enzymatic systems phosphorylation and dephosphorylation of carbohydrates, whereby their absorption is slowed down. Lactose intolerance syndrome without deficiency of lactase enzyme. Malignant syndrome manifests in the first days after birth as severe diarrhea, vomiting, acidosis, lactosuria often and proteinuria. Also revealed atrophy of the adrenal glands and liver, renal tubular degeneration. Congenital lactase deficiency. The enzyme hydrolyses the disaccharide lactose into glucose and galactose. Newborn babies usually get 50-60 grams of lactose (milk) a day "The most characteristic expression of lactase deficiency - diarrhea after taking milk. Undigested lactose enters the lower parts of the small intestine, which is fermented by intestinal microflora to produce gases (which causes flatulence) and acid "Their osmotic action in the gut lumen attracts a large amount of water that causes diarrhea. Here Cal has acidic pH and contains lactose laktosuria sometimes observed. Over time, the child develops malnutrition. This syndrome should be distinguished from the acquired lactase deficiency (enteritis, inflammatory diseases of the colon, sprue) and intestinal lactase deficiency from occurring in adults. Violations of the synthesis and breakdown of glycogen In body tissues, glucose can enter cells both from food exogenous and endogenously formed from a deposited glycogen (glycogenolysis as a result), or other substrates such as lactate, glycerol, amino acids (resulting in gluconeogenesis). Sucked into glucose enters the small intestine via the portal vein to the liver and into the hepatocytes. For glucose transport in cells respond transport proteins - GluT, which are able to transfer glucose through the membrane against a concentration gradient and enhance passive transport. In cells, glucose is phosphorylated in the hexokinase reaction, turning into glucose 6-phosphate (G-6-P), G-6-P is a substrate for multiple pathways: this molecule begins glycogen synthesis, the pentose phosphate cycle, the glycolytic breakdown to lactate or aerobic total degradation to CO2 and H2O. In cells capable of gluconeogenesis (liver cells, kidney, intestinal), G-6-P and may be dephosphorylated as the free glucose in the blood flow and transported to other organs and tissues. Especially important is the glucose to the brain cells. Cells of the nervous system depends on glucose as the main energy of the substrate "At the same time, the brain glucose have stocks, there is not synthesized, neurons can not consume power other substrates besides glucose and ketone bodies. Glycogen. From G-6-P as a result of the combined action of glycogen and "branching" enzyme synthesized glycogen - a polymer-like in appearance wood. In the molecule of glycogen can contain up to a million of monosaccharides. Thus there is a sort of crystallization of glycogen, and it does not have an osmotic effect. This form is suitable for storage in the cell. If this amount of glucose molecules have been dissolved, then due to osmotic forces would blow the cage. Glycogen is a form of glucose deposited. It is found in almost all tissues; cells of the nervous system in its minimum quantity, and in the liver and muscles it particularly much. Glycogen contains only two types of glycosidic bonds: and (1 → 4) -type and a (1 → 6) -type. Communication and (1 → 4) - type is formed every 8-10 residues of D-glucose. Glycogenolysis. It is a way of splitting of glycogen. Glycogen in the body mainly retained by the liver and skeletal muscle. Muscle glycogen is used as an energy source during intense exertion. Hepatic glycogenolysis activated in response to a decrease in the concentration of glucose in the 95 meal intervals or in response to stress factors. The main hormones activating glycogenolysis are glucagon, adrenaline (epinephrine) and cortisol. Reduced glycogen synthesis. Reduced synthesis of hepatocytes occurs in lesions (hepatitis, phosphorous poisoning, carbon tetrachloride, etc.) Of hypoxia when oxygen deficit inevitably leads to a significant decrease in efficiency of ATP necessary for the synthetic processes; lowering the tone of the parasympathetic nervous system; hypovitaminosis B1 and C; endocrine diseases - diabetes, thyrotoxicosis, adrenal insufficiency (Addison's disease). Increased glycogen breakdown. Hepatic glycogenolysis Amplification occurs during excitation of the central nervous system. Nerve impulses are conducted of the sympathetic nervous system to the depot of glycogen and activate the process of decay, providing a flow of glucose into the bloodstream. Increased glycogenolysis is also observed with an increase in hormone production - glycogenolysis stimulants (adrenaline, glucagon, growth hormone and thyroxine) and intense muscular work, which is due to an increase in muscle glucose uptake. In addition, the breakdown of glycogen increases in shock, fever, emotional stress. When failure of glycogen (due to decreased synthesis or decreasing its degradation) Energy fabric proceeds for use as substrates for oxidation of fats and proteins. The result is excessive formation of ketone bodies and develops intoxication. Using cell proteins as an energy source causes enzymatic disorders and various plastic processes. Violations of the intermediate metabolism of carbohydrates Causes of disorders of intermediate metabolism of carbohydrates can be: 1. Hypoxia caused by circulatory failure, respiratory and other. Developing a deficiency of oxygen cell metabolism switches from aerobic to anaerobic type, in which the main source of energy becomes anaerobic glycolysis. The decay of glucose in these circumstances an excess of lactic and pyruvic acids. Lactic acid enhances tissue oxyhemoglobin dissociation and expansion of the coronary vessels, compensating thus hypoxia phenomena. In normal tissues of lactic acid, which is glycolysis (e.g., muscle), blood enters the liver (Cori cycle), where it is converted by the enzyme lactate to pyruvate. Pyruvate is partially oxidized in the liver and is partially converted to glucose (gluconeogenesis). Thus, lactate returned to metabolic pool of carbohydrates. Prolonged existence of excess lactic acid in the tissues leads to deficiency of substrate oxidation - glucose, which causes a further decrease in the efficiency of ATP synthesis. Macroergs deficiency underlies disorders transmembrane ion transport membrane and increase permeability. Ultimately, this leads to significant structural and functional damage in tissues until cell death. 2. Violations of the liver. The lactic acid hepatocytes part resynthesis normal glucose and glycogen. If it affects the liver, this process is disrupted, lactic acid goes into the blood, develops acidosis. 3. Hypovitaminosis B1. Vitamin B1 (thiamine) as a result of phosphorylation process is converted into cocarboxylase - prosthetic group of some enzymes of carbohydrate metabolism. When failure occurs deficiency of vitamin B1 cocarboxylase, which leads to suppression of the synthesis of acetyl-CoA from pyruvic acid, and the latter is accumulated partially converted into lactic acid, the content of which in this connection is increased. pyruvic acid oxidation braking reduces the synthesis of acetylcholine, which causes violation of transmission of nerve impulses. With increasing concentration of pyruvic acid by 2-3 times compared with the norm there are violations of sensitivity, neuritis, paralysis and others. Hypovitaminosis B1 also leads to disruption of the pentose phosphate pathway of oxidation due to the lower activity of the enzyme transketolase. Glucose regulation Blood glucose is a crucial factor in homeostasis. It is maintained at a certain level of intestines, liver, pancreas, kidney, adrenal gland, adipose tissue, and other organs. There are several types of carbohydrate metabolism regulation: the substrate, the nervous, renal, hormonal. Substrate regulation. The main factor determining glucose metabolism, is the level of blood glucose. Border glucose concentration at which the production in the liver is equal to its 96 consumption by peripheral tissues is 5,5-5,8 mmol / l. At a level of less than this, liver supplies glucose to the blood; at higher levels, on the contrary, it dominates glycogen synthesis in the liver and muscles. Nervous regulation. Stimulation of sympathetic nerves leads to the release of adrenaline from the adrenals, which stimulates breakdown of glycogen in the glycogenolysis process. Therefore, the stimulation of the sympathetic nervous system is observed hyperglycemic effect. Conversely, stimulation of the parasympathetic nerve fibers accompanied by increased release of insulin by the pancreas, glucose enters the cell and hypoglycemic effect. Renal regulation. In the glomeruli of the kidneys, glucose is filtered and then reabsorbed in the proximal tubules volatile mechanism. The amount of tubular reabsorption is relatively constant with age there is a tendency to decrease. Exceeding the serum level of 8.8 - 9.9 mmol / l of glucose excreted in urine. Glycemic index, in which there is glycosuria, called the renal threshold. On the excretion of glucose in the urine affect glomerular filtration rate, which normally is about 130 ml / min. By reducing the filtering in renal failure or reduction of blood supply to the kidneys, glucose is absent in the urine, even when glucose is significantly higher than the renal threshold, since less glucose is filtered and reabsorbed all she can in the proximal tubules of the kidney. In the case of nephropathy with impaired reabsorption of glucose in the urine may occur even when normoglycemia. Therefore, the level of glucose in the urine can not diagnose diabetes. Hormonal regulation. On blood glucose level affects a wide range of hormones with virtually only causes insulin hypoglycemic effect. Contrinsular action with increased blood glucose levels have glucagon, adrenaline, glucocorticoids, growth hormone, ACTH, TTT. Effects of insulin and hormones kontrinsulyarnyh normal control fairly stable blood glucose levels. At low concentrations of insulin, in particular during fasting, amplified hyperglycemic effects of other hormones, such as growth hormone, glucocorticoids, epinephrine and glucagon. This occurs even if the concentration of these hormones into the systemic circulation is not increased. The metabolism of glucose after a meal. Glucose sucked into the intestine to the liver. The liver maintains a constant delivery of energy substrates to other organs, particularly the brain. Glucose uptake in the liver and the brain is not dependent on insulin in muscle and adipose tissue - insulin-dependent. In the first step of all the cells in glucose metabolism - the formation of glucose- 6-phosphate. In the liver, insulin stimulates the enzyme glucokinase, converting glucose 6- phosphate into glycogen, an excess of glucose-6-phosphate is converted to fatty acid with subsequent formation of triglycerides, which are released from the liver as very low-density lipoproteins (VLDL). In muscle glucose stored as glycogen enters triglycerides, glucose in the cerebral tissue is used as an energy substrate in adipose tissue. Physiologically in the regulation of glucose metabolism are the most important two hormones - insulin and glucagon. Insulin - a polypeptide consists of two chains: the A-chain contains 21 amino acid B-chain - 30 amino acids. Circuit 2 are interconnected by disulfide bonds. Insulin is similar phase in mammalian species: for example, the A-chain is identical in humans, pigs, dogs, sperm whale; B- chain is identical to the bull, goat and pig. In fact, human insulin and porcine differ only in that the carboxyl end of the B-chain is at the amino acid alanine, porcine and human threonine. Therefore, the commercial "human insulin" is produced by replacing alanine to threonine in pig insulin. Insulin is synthesized as inactive polypeptide chains of the proinsulin, so it is stored in granules of β-cells of pancreatic islets of Langerhans. Activation of proinsulin peptide is a partial proteolysis pas Arg31 and Arg63. As a result, in an equimolar amount produced insulin and C- peptide (connecting peptide). Insulin in the blood is in free and protein-bound state. Degradation of insulin occurs in the liver (80%), kidney and adipose tissue. C-peptide is also subjected degradation in liver but much slower. The basal concentration of insulin is determined radioimmunologically is healthy 15-20 uU / ml after an oral glucose load level of 1 hour is increased 5-10 times as compared with the original. Fasting insulin secretion rate of 0.5-1 U / hr after ingestion is increased to 2.5-5 U / hr. In healthy people, there are two phases of insulin secretion - early peak (in 3-10 min after glucose load) and 97 peak late (after 20 minutes). Early release of insulin inhibits a sharp rise in glucose levels during its absorption. Hormones that control of glucose homeostasis Hormone Mechanism of action Tissue Insulin Increases: glucose uptake by cells Muscle, fat glycogen synthesis Liver, muscle protein synthesis Liver, muscle synthesis of fatty acids and triglycerides Liver, adipose tissue decreases: gluconeogenesis Liver ketogenesis Liver lipolysis fatty tissue proteolysis Muscles glucagon Increases: glycogenolysis Liver gluconeogenesis Liver ketogenesis Liver lipolysis fatty tissue Adrenalin Increases: glycogenolysis Liver, muscle lipolysis fatty tissue growth hormone Increases: glycogenolysis Liver lipolysis fatty tissue Cortisol Increases: gluconeogenesis Liver glycogen synthesis Liver proteolysis Muscles Reduces: glucose uptake by cells Muscle, fat Stimulated insulin secretion, in addition to hyperglycemia, glucagon and intestinal polypeptide hormones including gastrointestinal hormone-dependent insulinotropic polypeptide, amino acids, free fatty acids, stimulation of the vagus. Complex metabolic effects of insulin, it includes direct effects on lipid metabolism, proteins, and especially in connection with diabetes - D-glucose. Insulin increases membrane transport of glucose and amino acids K +, activates many intracellular enzymes. At the same time, the insulin polypeptide molecule is not able to penetrate through the cell membrane, so that all the effects of insulin are made through specific membrane receptors on the cell surface. Insulin receptor complex, it consists of α- and β-subunits linked by disulfide bridges. High levels of insulin in the blood have anabolic and low - catabolic effects on metabolism. Insulin resistance may develop, acute resistance associated with infections or inflammation. Resistance can be determined by the appearance of circulating antibodies to insulin (IgG) and tissue insensitivity, which is often observed in obesity. The affinity (affinity to insulin receptor) and / or the number of receptors is dependent on a number of factors; This sulfonylurea drugs, pH, cAMP, physical activity, and the nature of the food composition, antibodies and other hormones. Glucagon - polypeptide consisting of 29 amino acids secreted by α-cells of the islets of the pancreas, secretion decreases with increasing concentration of glucose in the blood. Basically its opposite effects of insulin action. Glucagon stimulated glycogenolysis and gluconeogenesis in the liver and promotes lipolysis and ketogenesis. Epinephrine is synthesized in the adrenal medulla, it stimulates hepatic glycogenolysis and gluconeogenesis, skeletal muscle - glycogenolysis and lipolysis, enhances lipolysis in adipose tissue. hyperproduction of adrenaline is observed at pheochromocytoma, while blood can be transient hyperglycemia. Glucocorticoids are produced by the adrenal cortex, increase gluconeogenesis, inhibit glucose transport, inhibit glycolysis and the pentose phosphate cycle reduces protein synthesis, potentiate 98 the action of glucagon, catecholamines, growth hormone. Excessive production glucocorticoid hydrocortisone characterized Cushing syndrome - Cushing in which hyperglycemia occurs due to excessive formation of glucose from the proteins and other substrates. Thyroid hormones increase the rate of glucose utilization, accelerate its absorption in the gut activated insulinase increase the basal metabolic rate, including glucose oxides summer. Thyroid hormone has metabolic effects through thyroid stimulation. STH has a metabolic effect, has hyperglycemic action in adipose tissue - lipolytic effect. With an excess of growth hormone in children education is developed gigantism, adult - acromegaly. High blood glucose feature of this disease. Adrenocorticotropic hormone directly and through the stimulation causes the release of glucocorticoids pronounced hyperglycemic effect. TYPICAL FORMS OF VIOLATIONS Many carbohydrate metabolism disorders conditionally combined into several groups: hypoglycemia, hyperglycemia, glycogenoses, hexoses - and pentozemia, aglicogenosis. These disorders are considered as typical forms of carbohydrate metabolism disorders. Stages of violations of carbohydrate metabolism. Glucose of blood plasma - 3,58 - 6,05 mmol / l. I. Violation of the bioavailability of carbohydrates: 1) Violation of carbohydrate intake: - fasting - excess of income 2) Violation of digestion of carbohydrates: - change in pancreatic function - changes in the production of enzymes by the intestine 3) Impaired absorption of carbohydrates: - violation of enzymatic maintenance of glucose absorption - membronopathia II. Disturbance of metabolism, metabolism and assimilation of glucose 1) Change in glucose uptake and consumption: - change in the load on the central nervous system - change in physical activity 2) Change in the metabolism of carbohydrates: - changes in liver function - violation of the transition from glycogen to glucose and from glucose to glycogen - disorders of gluconeogenesis 3) Endocrinopathies: - disorders of the pituitary gland - disorders of the adrenal glands - Pancreatic disorders III. Disorders of glucose and metabolites: The threshold level of glucose in plasma is 10 mmol / l. 1) Disturbance of enzymatic maintenance of glucose reabsorption: - fermentopathia - Enzymopathia 2) Change in permeability of membranes: - membronopathia HYPOGLYCEMIA 99 Hypoglycemia - conditions characterized by reduction in plasma glucose level below the normal (less than 65 mg% or 3.58 mmol / l). The normal fasting glucose level is in the range 65-110 mg%, or 3,58-6,05 mmol / l. Causes hypoglycemia 1. Pathology of the liver. - Braking glycogenesis - Lack of glycogenolysis 2. Disorders of digestion in the intestine. - Cavernous - The near-wall ( "membrane") 3. Long-term significant physical activity. 4. Pathology of the kidney. - Reduction of glucose reabsorption in the proximal tubule 5. Carbohydrate starvation. 6. endocrinopathies. - Lack of hormones hyperglycemic - Hyperinsulinism Pathology liver Hereditary and acquired pathology of the liver - one of the most frequent causes of hypoglycemia. Hypoglycemia is characteristic of chronic hepatitis, liver cirrhosis, hepatodystrophy (including immunoagressive origin) for acute toxic liver lesions, for a number of fermentopathia (eg, hexokinase glycogen, glucose-6-phosphatase) and membranopaty hepatocytes. To cause hypoglycemia transport glucose from the blood into hepatocytes disturbances, decreased activity glycogenesis in them and the absence (or low maintenance) deposited glycogen. Hypoglycemia also develops with prolonged fasting, and may also occur with significant activation of the body's vital functions (such as during exercise or stress). Eating Disorders Eating Disorders - cavitary digestion of carbohydrates and their parietal digestion and absorption - lead to hypoglycemia. Hypoglycemia is also being developed for chronic enteritis, alcoholic pancreatitis, pancreatic tumors, malabsorption syndromes. 1. The causes of violations of cavity digestion of carbohydrates: - Lack of α-amylase of the pancreas (eg, pancreatitis in patients with tumors or cancer). - Lack of maintenance and / or amylolytic activity of intestinal enzymes (eg, chronic enteritis, bowel resection). 2. Causes of violations of parietal digestion and absorption of carbohydrates: - Lack disaccharidases that break down carbohydrates to monosaccharides - glucose, galactose, fructose. - Lack of enzymes transmembrane transport of glucose and other sugars (phosphorylase), as well as protein - glucose transporter GLUT5. Pathology kidney Hypoglycemia develops in violation of glucose reabsorption in the proximal tubules of the kidney nephron. Causes: - Deficit and / or low activity of enzymes (fermentopathy, enzimopaty) involved in glucose reabsorption. - Violation of the structure and / or physico-chemical state of the membranes (membranopathy) due to deficiency or defect of membrane glycoproteins involved in glucose reabsorption. The above factors lead to the development of the syndrome, characterized by hypoglycemia and glucosuria ("diabetes kidney"). 100 Endocrinopathy The main causes of hypoglycemia when endocrinopathy: lack hyperglycemic factors or excess insulin. 1. Hyperglycemic factors include corticosteroids, iodine-containing thyroid hormones, growth hormone, glucagon and catechol amines. - Glucocorticoid insufficiency (eg, when hypocorticism due to malnutrition, and hypoplasia of the adrenal cortex). Hypoglycemia is caused by inhibition of gluconeogenesis and glycogen deficiency. - Lack of thyroxine (T4) and triiodothyronine (T3) (for example, when myxedema). Hypoglycemia in hypothyroidism is the result of inhibition of glycogenolysis process in hepatocytes. - Lack of growth hormone (for example, malnutrition adenohypophysis, the destruction of his tumor, hemorrhage in the pituitary gland). Hypoglycemia thus develops due to the inhibition of glycogenolysis and glucose transmembrane transport. - Lack of catecholamines (eg for tuberculosis with the development of adrenal insufficiency). Hypoglycemia with a deficit of catecholamine is a consequence of the reduced activity of glycogenolysis. - Lack of glucagon (e.g., degradation in α-cells of the pancreas as a result of immune autoaggression). Hypoglycemia develops in connection with the braking glycogenetic and glycogenolysis. 2. An excess of insulin and / or its effects Causes of hypoglycemia with hyperinsulinism: - Activation of the body's utilization of glucose by cells, - Inhibition of gluconeogenesis, - Inhibition of glycogenolysis. These effects are observed at insulinoma or overdose of insulin. Carbohydrate starvation Carbohydrate starvation occurs due to the long total starvation, including carbohydrate. Deficiency in nutrition not only of carbohydrate leads to hypoglycemia due to gluconeogenesis activation (formation of non-sugar carbohydrates substances). Continued significant hyperactivity of the body during physical work Hypoglycemia develops with prolonged and significant physical work as a result of the depletion of the glycogen deposited in the liver and skeletal muscle. Clinical manifestations of hypoglycemia Possible consequences of hypoglycemia: hypoglycemic reaction - a sharp reduction in glucose concentration to 80-70 mg% (4,0-3,6 mmol / l), a syndrome - persistent reduction in glucose concentration to 60-50 mg% (3.3-2.5 mmol / l) and coma - reduced glucose to glucose concentration to 40-30 mg% (2.5-1.5 mmol / l). Hypoglycemic reaction Hypoglycemic reaction - a sharp temporary decline in the CPC to the lower limit of normal (usually up to 80-70 mg% or 4,0-3,6 mmol / l). Causes: - Acute excessive, but transient insulin secretion in 2-3 days after the onset of starvation. - Acute excessive, but reversible secretion within a few hours after the glucose load (for diagnostic or therapeutic purposes, eating sweets, especially in elderly persons). Implication: - Low glucose level. - Easy hunger, 101 - Muscle tremors, - Tachycardia. These symptoms are mild, rarely missing and more identified with exertion or stress. Hypoglycemic syndrome Hypoglycemic syndrome - persistent reduction in the CPC is below normal (up to 60-50 mg%, or 3.3-2.5 mmol / l), in keeping with the life of the organism disorder. Manifestations hypoglycemic syndrome can be both adrenergic (caused by excessive secretion of catecholamines) and neurogenic (due to CNS disorders). 1. Adrenergic - Hunger - Muscle tremors - Sweating - Anxiety, fear of dying - Tachycardia, cardiac arrhythmia 2. Neurogenic - Headache - Dizziness - Confusion - Breach of - Mental retardation. Hypoglycemic coma Hypoglycemic coma - a condition characterized by falling glucose level below normal (usually less than 40-30 mg% or 2,0-1,5 mmol / l), loss of consciousness, significant disturbances of vital activity. Mechanisms development 1. Violation of the energy supply of neurons, as well as other organs due to cell: - Lack of glucose. - Deficit of short free fatty acid metabolites - and β-acetoacetic hydrooxibutyric acid which effectively oxidize in neurons. These neurons can provide energy even under conditions of hypoglycemia. However ketonemia develops only after a few hours and in case of acute hypoglycaemia may be a mechanism to prevent energy shortages in neurons. - Violations of transport ATP and ATP use disorders effector structures of power. 2. Damage to membranes and enzymes neurons and other cells. 3. An imbalance of ions and water into the cells: the loss of K + accumulation H +, Na +, Ca2 +, water. 4. Violations electrogenesis. Principles of therapy of hypoglycemia Principles eliminate hypoglycemic symptoms and coma: etiotropic, pathogenetic and symptomatic. Etiotropic Causal principle is aimed at the elimination of hypoglycaemia and treatment of the underlying disease. The elimination of hypoglycaemia Administering to glucose: - Intravenous (for acute hypoglycemia simultaneously removing 25-50 g as a 50% solution in a subsequent infusion of glucose at the concentration continues until the patient's recovery of consciousness). - With food and drinks. This is necessary due to the fact that the on / in a glucose can not be restored depot of glycogen in the liver. 102 Treatment of the underlying disease causing hypoglycemia (liver disease, kidney, gastrointestinal tract, endocrine glands, and others.). Pathogenetic Pathogenetic therapy principle is aimed at: - Blocking of the main pathogenetic links hypoglycemic coma or hypoglycemic syndrome (disorders of energy supply, damage membranes and enzymes electrogenesis disorders, imbalance of ions, AAR, liquids, etc.). - The elimination of disorders of functions of organs and tissues caused by hypoglycemia and its consequences. Removal of acute hypoglycemia usually leads to a rapid "off" its pathogenetic links. However, chronic hypoglycemia requires individualized targeted pathogenic therapy. Symptomatic Symptomatic treatment principle is aimed at addressing the symptoms, exacerbating the patient's condition (eg, severe headache, fear of death, sudden fluctuations in blood pressure, tachycardia, etc.). Glycogen storage disease Glycogen - the standard form of carbohydrate metabolism pathology of hereditary or congenital origin, characterized by excess accumulation of glycogen in the cells, which leads to disruption of the body's vital functions. Glycogen storage disease develops as a result of mutations in the genes coding for the synthesis of cleavage enzymes (at least - education) glycogen. This leads to a lack of or low activity of enzymes glycogenolysis, at least - glycogen synthesis (e.g., glycogenosis type IV). Almost all glycogenoses inherited in an autosomal recessive manner. Enzyme defect Type glycogen storage disease Glucose-6-phosphatase 1 type - Gierke's disease Alpha-1,4-glucosidase Type 2 - Pompe disease Amilo-1,6-glucosidase Type 3 - Corey disease 1,4-D-glucan-α-glucosyltranspherase 4 type - Andersen's disease glycogen phosphorylase myocytes 5 type - McArdle's disease hepatocyte glycogen Type 6 - Girs disease phosphoglucomutase Type 7 - Thompson's disease Phosphofructomutase 8 type - Tarui disease Phosphorylase kinase in hepatocytes Type 9 - Haga's disease Hexosemia Hexosemia - conditions characterized by an increase in blood hexoses above normal (more than 6.4 mmol / L or 1.15 g / l). The greatest clinical significance have galactosemia and fructosemia. Galactosemia The most common galactosemia, galactose diabetes or hereditary or congenital origin, observed in children in a few days or weeks after birth. Fructosemia Fructosemia (including fructose intolerance due congenital deficiency of aldolase B) leads to accumulation of cells in fructose-1-phosphate, fructosuria, liver failure and kidney failure. HYPERGLYCEMIA Hyperglycemia - conditions characterized by an increase in glucose level above normal (more than 120 mg%, or 6.05 mmol / l on an empty stomach). Causes hyperglycemia 103 Causes of hyperglycemia: endocrinopathies, neurological and psychogenic disorders, overeating, liver pathology. Endocrinopathy Endocrinopathies - the most common cause of hyperglycemia. The main reasons for the development of hyperglycemia in endocrinopathy: excess hyperglicemic factors (or their effects) and insulin deficiency (or its effects). By hyperglycemic factors include corticosteroids, iodine- containing thyroid hormones, growth hormone, glucagon and catechol amines. Excess hyperglicemic factors (or their effects) - Glucagon (e.g., Langerhans islet hyperplasia resulting α-cells) stimulates gluconeogenesis (of amino acids in hepatocytes) and glycogenolysis. As a result of hyperglycemia develops. - Glucocorticoids (for example, hypertrophy, or tumors of the adrenal cortex - corticosteroma, Cushing's disease) activate gluconeogenesis, and inhibit the activity of hexokinase. - Catecholamines (eg, in pheochromocytoma - hormone-active tumors of the adrenal medulla) lead to hyperglycemia by activating glycogenolysis. - Thyroid hormones (for example, in diffuse or nodular goiter hormonally-active) cause hyperglycemia due to: enhance glycogenolysis glycogenesis inhibition of glucose and MK, stimulation of gluconeogenesis, the activation of glucose absorption in the intestine. - STG (for example, hormone-active tumors of the anterior pituitary adenoma, or). Hyperglycemia in conditions of excess growth hormone is mainly the result of the activation of glycogenolysis and inhibition of glucose utilization in a number of tissues. Lack of insulin and / or its effects (hypoinsulinism). The most frequently observed hyperglycemia in diabetes. Hyperglycemia at hypoinsulinism is the result: - Reduce the utilization of glucose by cells, - Activation of gluconeogenesis, - Enhance glycogenolysis. Neurological disorders and psychogenic Neuro- and psychogenic disorders (for example, the state of mental excitement, stress reaction, causalgia), characterized by activation of the sympathetic-adrenal, hypothalamic-pituitary- adrenal and thyroid systems. Hormones these systems (catecholamines, glucocorticoids, T4 and T3) cause a number of effects (activation of glycogenolysis, glycogenesis inhibition, stimulation of gluconeogenesis) leading to a significant hyperglycemia. Binge eating Overeating (including prolonged and excessive consumption of sweet food digestible carbohydrates) - one of the causes of hyperglycemia. Glucose is rapidly absorbed in the intestine. GIC increases and exceeds the capacity of hepatocytes to include it in glycogenesis process. In addition, excess carbohydrate food in the intestine promotes glycogenolysis in hepatocytes potentiating hyperglycemia. Pathology liver When liver failure may develop transient hyperglycemia due to the fact that the hepatocytes are not able to convert glucose into glycogen. Usually this occurs after a meal. CLINICAL MANIFESTATIONS HYPERGLYCEMIA Possible consequences of hyperglycemia: hyperglycemic syndrome and hyperglycemic coma. 1. hyperglycemic syndrome. Persistent increase of glucose concentration to 190-210 mg% (10.5- 11.5 mg / dL) 2. hyperglycemic coma. Increased glucose concentration to 400-600 mg% (22,0-28,0 mmol / l) or more, the loss of consciousness. 104 Hyperglycemic syndrome Hyperglycemic syndrome - a condition characterized by a significant and sustained increase in the Code of Civil Procedure regarding the above rules (up to 190-210 mg%, ie 10.5-11.5 mmol / l or more), in keeping with the life of the organism disorder. Manifestations 1 is the result of hyperglycemia, glycosuria. 2. polyuria - increased urination and urine formation as a result of: - Increase urine osmolality, - Increase concerning glomerular filtration - Reduce tubular reabsorption of water. 3. Polydipsia - increased fluid intake, caused by increased thirst, - is due to a significant loss of body fluids. 4. hydropenias the body - reduction of fluid in the body due to polyuria. 5. Hypotension due to: - Hypovolemia - a decrease in circulating blood volume (CBV) due hydropenia organism; - A decrease in cardiac ejection of blood due to hypovolemia. Hyperglycemic coma Hyperglycemic (hyperosmolar) coma discussed the topic of diabetes complications. Principles control of hyperglycemia The basic principle of the effective control of hyperglycemia is etiotropic. It is aimed at eliminating the causes of hyperglycemia. Achieving this and as a consequence - the normalization of HPA usually lead to the elimination of other manifestations of hyperglycemia. Diabetes Diabetes mellitus (DM) - one of the most serious diseases, fraught with severe complications, disability and death cases, characterized by disorders of all types of metabolism and life of the organism as a whole. The reported incidence varies in different countries from 1 to 3% (in Russian about 2%), and individuals with varying degrees of obesity reaches 15-25%. Obesity and diabetes, on the one hand, and hypertension and coronary heart disease, on the other, constitute the so-called metabolic syndrome, "deadly quartet". According to WHO experts, diabetes increases the overall mortality of patients 2-3 times. At about 3 times more likely to have identified cardiovascular disease and stroke cases, 10 times - blindness, 20 times - gangrene of the extremities. DM - one of the causes of renal lesions leading to death of patients. Diabetes decreases the average life expectancy in 7% of its overall average. Diabetes - a disease that is characterized by impaired metabolism, and all kinds of vital activity disorder; hypoinsulinism develops as a result (i.e., absolute or relative insulin deficiency). CLASSIFICATION OF DIABETES WHO Expert Committee on DM has developed a classification that is constantly updated and refined. It is isolated primary and secondary forms of diabetes. The primary forms of diabetes The primary form of diabetes characterized by the absence of the patient any certain diseases secondarily lead to the development of diabetes. There are two primary kinds of diabetes: - Insulin-dependent diabetes mellitus (IDDM); - Insulin dependent diabetes mellitus (NIDDM). The concept of "IDDM" means: - The absolute insulin deficiency. - The need for constant use of insulin. - A real threat to the development of ketoacidosis. 105 Patients with IDDM prescribe a dose of insulin, which is needed to maintain an optimum level of CPC. Cancel or insulin deficiency causes them ketoacidosis. The term "NIDDM" refers to forms of diabetes due to insulin deficiency effects under normal or even elevated levels of the hormone in the blood. - The function of the pancreatic β-cells partially or fully preserved. - The majority of patients do not require a mandatory introduction of insulin. - Disorders of the body's vital functions develop relatively slowly. - NIDDM is at least 80% of all diabetes cases. Secondary forms of diabetes Secondary forms of diabetes are characterized by the presence of the patient to any underlying disease or condition that damage the pancreas, as well as the effect on her physical or chemical factors. This leads to the occurrence of diabetes. Such diseases, pathological conditions and factors include: - Diseases affecting pancreatic tissue (eg, pancreatitis). - Other disorders of the endocrine system (eg, multiple endocrine adenomatosis family). - The impact on the pancreas to chemical or physical agents. Diabetes mellitus type I and II In earlier classifications isolated diabetes types I and II. These designations initially used interchangeably with IDDM and NIDDM, respectively. Modern experts believe this approach is not entirely correct. This is because, for example, patients with NIDDM can also be purchased from insulin dependency. With its lack they develop ketoacidosis, coma-prone (eg, it is observed in many patients without obesity, with blood on the AT to the β-cells of the islets of Langerhans). - The term "Type I diabetes" is used to refer to those variants main pathogenetic link of which was immune (immunoagressive) mechanism. Type I diabetes is seen in 10-15% of patients suffering from diabetes. - The term «II diabetes Type" recommended the use of that form of diabetes, the pathogenesis of which is not included as a cause of the immune mechanism. Type II diabetes diagnosed in more than 85% of patients with diabetes. Thus, diabetes is caused by a deficiency of insulin (i.e., resulting hypoinsulinism or absolute insulin deficiency) or insufficient effects of insulin in its normal, or even elevated levels in blood plasma. ETIOLOGY OF DIABETES Diabetes develops due to a deficiency of insulin (IDDM), or failure of its effects (NIDDM). Causes I. Insulin deficiency can occur under the influence of biological factors, chemical, physical nature, as well as in inflammatory processes of the pancreas 1. Biological factors a) Genetic defects in β-cells of the islets of Langerhans. There is a pronounced dependence of frequency hypoinsulism in patients with IDDM of expression of certain Ag HLA. These include Ar glycoproteins encoded by alleles HLA-DR3, HLA-DR4, HLA-DQ, B1. Genetic defects cause inclusion autoaggressive immune mechanisms of pancreatic injury (due to occurrence of the immune system to foreign Ar) and low insulin synthesis (for example, when repression of genes encoding enzymes synthesizing insulin). b) Immune factors: Ig, cytotoxic T lymphocytes and cytokines produced by them damaging β-cells and the immune reaction autoaggression implement. In patients with insulin deficiency detect several types of specific AT: - To the cytoplasmic Ag - ICA (from the English islet cell autoantibody - autoantibodies to islet cell proteins.); 106 - A protein with a molecular mass of 64 kDa, detectable in the cytoplasmic membrane of β-cells. AT These often show before the other signs of diabetes. In this regard, they are referred to the number of initiators of the immune response of anti-β-autoaggression cell; - Molecules of insulin. c) Viruses, tropic to the β-cells:. Coxsackie B4, hepatitis B, measles, chicken pox, mumps, rubella, etc. For example, in intrauterine rubella diabetes develops in about 20% of newborns. Viruses are responsible for: - Direct cytolytic activity against β-cells, - Initiation of immune processes against β-cells, - The development of inflammation in the areas of location of β-cells of the islets of Langerhans - insulitis. g) endogenous toxic substances that damage the β-cells, the most "aggressive" of them - allokean. It is formed in excess as a result of a pyrimidine metabolism and insulin blocks the formation. The latter is associated with a low content of SH-groups (required for inactivation of alloxan) in β-cells. 2. Chemical factors alloxan, high doses of ethanol, cytostatics and other drugs (e.g., anticancer agent streptozocin). 3. Physical factors: ionizing radiation, initiating activation lipoperoxide processes, mechanical trauma of the pancreas, tumor compression. These and other factors lead to the physical nature of the death of islet β-cells. a) Inflammation Inflammatory processes occurring in the pancreas by the action of biological factors (mainly of microorganisms), chemical and physical nature. Chronic pancreatitis is about 30% of cases the cause of insulin deficiency. II. Effects of insulin deficiency develops under the influence of the causes of neuro or psychogenic nature contrinsular factors, as well as due to defects in insulin receptors and postreceptor violations in target cells. 1. Neuro - and / or psychogenic factors: - Activation of the neurons of the posterior hypothalamus nuclei, leading to an increase in tone of the sympathetic-adrenal and hypothalamic-pituitary-adrenal system. This results in a significant and sustained increase in blood contrinsular hyperglycemic hormones: epinephrine, norepinephrine (adrenal origin), glucocorticoids, and therefore, the relative lack of insulin effects. - Re-development of protracted stress reactions. These include activation of the sympathetic-adrenal and hypothalamic-pituitary-adrenal system. This leads to an increase in blood levels of catecholamines, glucocorticoids, thyroid hormones. All of them are functional antagonists of insulin. 2. Contrinsular factors: - Excessive activation insulinase hepatocytes. This protease hydrolyzes insulin molecule. - AT to endogenous insulin. - Increase in blood levels of contrinsular (hyperglycemic) hormones: catecholamines, glucagon, glucocorticoids, growth hormone, T3 and T4. Hyperproduction these hormones can be observed in the corresponding tumors of the endocrine glands or prolonged stress. - Increased concentration in blood plasma proteins, insulin binding molecule. 2. Factors causing blockage, destruction or decrease the sensitivity of insulin receptors: - Ig, imitating the structure of the insulin molecule. Such Ig receptors interact with insulin, block them, thus preventing access of insulin to the receptor molecules. - Ig, destroying the insulin receptor and / or zone perireceptors target cells. - Prolonged excess insulin causes hypoconcaveation target cells to the hormone. - Hydrolases released from lysosomes and activates the inside and outside of the damaged or decaying cells (for example, a total of hypoxia, disorders of external respiration and circulation). - Free radicals and products Spolli (for example, when re-prolonged stress, atherosclerosis, cardiovascular disease). 3. Factors that violate implementation of the effects of insulin in target cells: 107 - The damaging of the membrane and / or cell receptors to the insulin. - A denaturing and / or disrupting cellular enzymes. The most common causes of damage to cell membranes and enzymes are over-activity of lysosomal enzymes, excessive formation of reactive oxygen species, free radicals and lipid hydroperoxide. These and other pathogenic agents inhibit the transport of glucose into the cells, the formation of cAMP, the transmembrane transport of Ca2 + ions and of Mg2 +, necessary for the implementation of intracellular effects of insulin. Risk factors A large number of risk factors for diabetes. 1. Overweight. Obesity is detected in more than 80% of patients with NIDDM. This increases hepatic insulin resistance, adipose and other tissues - targets insulin. 2. Persistent and significant hyperlipidemia. Both factors stimulate the production of contrinsular hormones and hyperglycemia. This in turn activates insulin synthesis of β-cells, leading to their "depletion" and damage. 3. Hypertension, leading to disruption of the microcirculation in the pancreas. 4. Hereditary or congenital predisposition. It is believed that patients with diabetes immunoagressive predisposition to the disease determine HLA genes. Patients with NIDDM a predisposition to diabetes has polygenic character. In the presence of diabetes in a parent ratio of their sick children to healthy can be 1: 1. 5. Female gender. 6. Repeated stress reaction. They are accompanied by a persistent increase in blood levels of contrinsular hormones. 7. The combination of several risk factors increases the risk of diabetes in the 20-30 times. PATHOGENESIS OF DIABETES The following are the links of the pathogenesis of diabetes with insulin deficiency (resulting in developing IDDM) and with insufficient effects of insulin (and therefore developing NIDDM). Insulin deficiency The main pathogenesis. Exposure to pathogenic factors causing damage to the pancreatic β-cells. This action leads to the suppression of the processes: - Biosynthesis proinsulin - Splitting of proinsulin to insulin - Transport of proinsulin to the Golgi apparatus - Devesiculationi and release insulin into the bloodstream - Vesiculation insulin When insulin deficiency occurs: - Damage and loss of β-cells of the islets of Langerhans, - Reduction of the total β-cell mass, - Inhibition of the synthesis and release of insulin into the blood from damaged β-cells. In most cases (possibly even all) of the pathogenesis of insulin deficiency is common link: immunoagressive development process. This process typically takes several years and is accompanied by the gradual destruction of β-cells. Diabetes Symptoms usually appear at break of about 75-80% β-cells (which can be detected earlier on a different background, "precipitating" states - diseases, intoxications, stress, glucose metabolism disorders, binge eating and other endocrinopathy). The remaining 20-25% of cells usually destroyed during the subsequent 2-3 years. In the dead of diabetes patients pancreas weight is an average of 40 g (80-85 g norm). The mass of β-cells (healthy individuals about 850 mg) is negligible or not is determined. 108 Key links immunoagressive version of the pathogenesis of diabetes mellitus. 1. The introduction of the organism is genetically predisposed to diabetes people of foreign Ar carrier. The most common are viruses, at least - other microorganisms. 2. Absorption of foreign antigen presenting cells Ag, Ag processing and presentation of it in conjunction with the Ag HLA (presentation) helper T lymphocytes. 3. The formation of immune AT and activated lymphocytes against specific foreign Ag. 4. Action AT and activated lymphocytes: - Foreign Ag: its destruction and elimination from the body, with the participation of phagocytes; - Antigenic structures β-cells having a similar structure to the alien Ag (assume that such an endogenous Ag, like an alien, may be a protein with Mr 64 kDa); - Cells containing such Ar, are attacked by the body's system of immunobiological surveillance, perceiving their own Az for alien. This phenomenon is referred to as "cross-immune response." During this reaction, β-cells are destroyed and the individual proteins are denatured and autoantigens. 5. Absorption, processing and presentation of both the lymphocytes alien Ar and newly formed β- cell autoantigens monocytes / macrophages. The process of the immune autoaggression potentiated the synthesis and transport to the surface of damaged β-cells Ag HLA class I and II. Said Ar stimulate helper T cells and consequently - specific Ig production and differentiation of cytotoxic T-lymphocytes. Immune autoaggression against their β-cells increases. Increasing scale islet damage the appliance. 6. Migration in regions of damaged and destroyed by the pancreatic β-cells phagocytes. 7. cytolytic effect on leukocyte β-cells by lysosomal enzymes, generation of large amounts of reactive oxygen species, free radicals of organic substances, the activation process lipoperoxide cytokines (γ-IFN, TNF-β, IL-1). 8. The destruction of β-cells is accompanied by the release of these "foreign" to the immune system proteins (normally they are only intracellularly and in the blood does not fall): heat shock, cytoplasmic ganglioside, proinsulin. 9. Absorption macrophages said cytoplasmic proteins β-cells, its processing and presentation to lymphocytes. This causes the next episode of the destruction of the immune attack of additional β-cells. By reducing their weight to 75-80% of normal "suddenly" appear clinical signs of diabetes. Signs in relation to the activation of β-cells of the immune surveillance system may disappear with time. With the death of β-cells decreases and the stimulus to the immune response autoaggression. So, AT level in Ag β-cells is significantly reduced by 1-1.5 years after their first detection. Pathogenesis of absolute insulin deficiency caused by the action of chemical pancreatic factors. Chemical pancreatropic agents cause direct damage to the β-cells, damage to the membranes and enzymes, and as a result to the denaturation of proteins and the appearance of autoantibodies. The same process can cause a chain and other mechanisms - the action of the primary chemical pancreatropic agent stimulates the formation of an excess of reactive oxygen species and activation of lipid peroxidation. The result is a destruction of β-cells and insulin deficiency. The mechanism of absolute insulin deficiency caused by the influence of physical pathogenic factors. Pathogenic agents physical nature ↓ Damage and destruction of β-cells ↓ The emergence of autoantigens ↓ Education and cytotoxic effect on β-cells and lymphocytes AT autoaggressive ↓ The destruction of β-cells 109 ↓ insulin deficiency Lack of insulin effects The implementation of various embodiments of the pathogenesis of diabetes with insulin deficiency effects occur with normal or even elevated its synthesis and incretion in the blood (the developing NIDDM). Contrinsular factors 1. insulinase. Mechanisms of activation insulinase: - An increase in the blood of glucocorticoids and / or growth hormone (which is often observed in patients with diabetes); - Deficiency of zinc and copper ions, reducing the normal activity insulinase; Since insulinase begins to rapidly synthesized by hepatocytes in puberty, this mechanism is an important pathogenesis of juvenile diabetes. 2. The proteolytic enzymes. They can come from extensive foci of inflammation and destroy the insulin (for example, cellulitis, peritonitis, infection of burn surface). 3. AT to blood insulin. 4. Substances insulin molecule binding and thereby block the interaction with the insulin receptor. These include: - Plasma insulin inhibitors of protein nature (eg, the individual fractions α- and β-globulin). Insulin bound to plasma proteins does not show activity in all tissues except the fat. The final conditions for the cleavage of the protein molecule, and contact with specific insulin receptors. - Β-lipoproteins. The synthesis of β-LP in increased amounts indicated in patients with overproduction of growth hormone. β-form LP large - molecular complex with insulin, insulin in the composition is not able to interact with its receptor. The elimination or reduction of the effects of insulin on target tissues The elimination or reduction of the effects of insulin on target tissues is achieved owing to the effect of excess hormones hyperglycemic insulin metabolic antagonists. These include catecholamines, glucagon, glucocorticoids, growth hormone, and iodine-containing thyroid hormones. Long-term and significant hyperglycemia stimulates increased production of β-cell insulin. However, this may not be sufficient to normalize HPA, as long hyperactivation pancreatic islets leading to damage of β-cells. Insulin resistance Violation implement the effects of insulin at target cells known as insulin resistance. Known receptor and postreceptor mechanisms of this phenomenon. The receptor mechanisms 1. "Screening" (closing) insulin receptor Ig. Recent specifically react with the receptor proteins themselves and / or perireceptors zone. Ig molecule thus make it impossible interaction of insulin and its receptor. Under these conditions, the receptor itself and the cell membranes are not damaged. 2. Hypoconcaveation target cells to insulin. It is caused by prolonged increase in insulin concentration in blood and the interstitium. - Hypoconcaveation cells is the result of increasing the number of low-affinity on the surface of cells to insulin receptor and / or decrease the total number of insulin receptors. - Hypoconcaveation observed in individuals suffering from overeating, which causes overproduction of insulin. 3. The destruction and / or modification of the conformation of the insulin receptor are determined by: - Antireceptors the AT, is synthesized by changing the structure of the receptor (eg, as a result of acceding to it in the form of the hapten drug or toxin); 110 - An excess of free radicals and products at process lipoperoxide hypoxia deficiency antioxidants - tocopherol, ascorbic acid, etc; - Defects in genes encoding the synthesis of the insulin receptor polypeptides. postreceptor mechanisms - Violations of protein phosphorylation of target cells, which disrupts intracellular processes "recycling" of glucose. - Defects in the target cells transmembrane glucose transporters. They are mobilized in time insulin interaction with its receptor on the cell membrane. Transmembrane glucose transporters failure is detected in patients with diabetes in conjunction with obesity. PRESENTATION OF DIABETES DM is shown two groups of related disorders: metabolic disorders and abnormal tissues, organs, systems. This disorder leads to life of the organism as a whole. In patients with diabetes revealed signs of disorders of all types of metabolism, not only of carbohydrate as its name implies. Metabolic disorders 1. Carbohydrate - Hyperglycemia - hyperlactatemia - glycosuria - Acidosis 2. The protein - hyperasotemia - Improving the levels of residual nitrogen in the blood - azoturia 3. Adipose - Hyperlipidemia - ketonuria - ketonemia - Acidosis 4. Liquids - polyuria - Polydipsia Carbohydrate metabolism Disorders of carbohydrate metabolism clinically manifested by hyperglycemia, glycosuria and hyperlactacedemic. 1. Hyperglycemia Glucose level patients with diabetes exceeds the norm. If the content is constantly fasting glucose above 140 mg% (7.7 mmol / l), it is considered a sign of impaired glucose tolerance; above 200 mg% (11 mmol / l) - possible symptom of diabetes. In untreated patients HPA can be increased to an average of 500 mg% (22 mmol / l), and in states precoma - 1000 mg% or more. Causes of hyperglycemia: - The lack of or absence of insulin effects in target cells: as a stimulant (transport of glucose into the cells, the synthesis of glycogen from glucose, glucose oxidation in the citric acid cycle and pentozomonofosfatnom, liponeogenez from carbohydrates) and inhibitory (gluconeogenesis and glycogenolysis). - Violation of renal excretory function, including glucose excretion (as a result of diabetic nephropathy). 2. Glucosuria Normally urine glucose not detected. It appears only after exceeding its physiological renal threshold of around 180 mg% (9.9 mmol / L). This threshold is subject individual variations with age it rises. Therefore glucosuria test is only a guide for admission hyperglycemia. 111 Reasons glucosuria: - Hyperglycemia, exceeding the threshold for glucose; - Violation of glucose reabsorption in the renal tubules. 3. Hyperlactacedemic Hyperlactacedemic - increase in blood MK concentration above normal (more than 16 mg%, or 1.3 mmol / l). Causes: - Inhibition of the oxidative catabolism of lactate in the Krebs cycle, - Violation of glycogen re-synthesis of lactate. Protein metabolism Disorders of protein metabolism in diabetes characterized hyperasotemia, increased residual nitrogen in the blood, azoturia. 1. Hyperasotemia Hyperasotemia - Increase in blood levels of nitrogenous compounds (protein products of metabolism) above normal. Nitrogen protein normally is 0.86 mmol/l, total nitrogen - 0.87 mmol/l. Causes: - Increased protein catabolism, - Activation of the process of deamination of amino acids in the liver because of the intensification of gluconeogenesis. 2. The residual nitrogen In DM elevated blood levels of non-protein nitrogen (residual nitrogen) higher than normal (over 30 mmol / l). Non-protein nitrogen represented urea nitrogen, amino acids, uric acid, creatinine, ammonia. Reason: increased protein degradation, mainly in the liver and muscles. 3. Azoturia When DM in the urine increased content of nitrogen compounds (azoturia). Reason: increasing the blood concentration of nitrogen-containing products and their excretion in urine. Fat metabolism Disorders of lipid metabolism in diabetes appear hyperlipidemia, ketonemia, ketonuria. 1. Hyperlipidemia For typical DM hyperlipidemia - increase in blood total lipids levels above normal (more than 8 g / l). Causes of hyperlipidemia: - Activation of lipolysis in tissues - Inhibition of lipid cells waste, - The intensification of the synthesis of cholesterol ketone bodies - Vehicle deceleration higher fatty acids in cells - Reduction LPLase activity. 2. Ketonemia Ketonemia - increase in blood concentration of CT above normal (more than 2.5 mg%). By CT include acetone, acetoacetic and β-hydroxybutyric acid. Ketonemia usually develops in IDDM. The total content of CT in the blood may exceed 30-50 mg%. Causes: - Activation of lipolysis, - Intensification of the oxidation of IVH in the cells, - Inhibition of lipid synthesis, - Suppression of the oxidation of acetyl-CoA in the hepatocytes with the formation of CT. 3. Ketonuria Ketonuria - excretion ketone bodies is excreted in the urine - is considered to be a symptom of an unfavorable course of diabetes. Reason ketonuria - high concentration in the blood ketone bodies, which is well filtered in the kidney. 112 Water metabolism Metabolic water in diabetes appear polyuria and polydipsia. 1. Polyuria Polyuria - education and urine in excess of the norm (in normal conditions of 1000-1200 ml per day). In DM daily urine output reaches 4000-10000 ml. Causes: - Hyperosmia- urine due to excretion of excess glucose, nitrogenous compounds, ketone bodies, ions and other osmotically active substances. This stimulates the fluid filtration in the glomeruli and inhibits its reabsorption in the renal tubules. - Violation fluid excretion and reabsorption in the kidney caused by diabetic neuropathy. 2. Polydipsia Polydipsia - an increased fluid intake as a result of abnormal thirst. Causes: - Hydropenia the body as a result of polyuria. - Blood hyperosmia- due to hyperglycemia, azotemia, ketonemia, hyperlactacedemic increase in the content of individual ions. The osmolality of serum exceeds the norm. Usually it is more than 300 mOsm / kg. - Dryness of the mouth and throat caused by the suppression of the function of the salivary glands. The pathology of tissues, organs and systems When diabetes affects all the tissues and organs, although to varying degrees. To the greatest extent damaged by the heart, blood vessels, nervous system, kidney, eye tissue, the NBI system. This is evident cardiopathy, angiopathy, neuro- and encephalopathy, nephropathy, reduction of visual acuity and blindness, comas and other disorders. They are referred to as diabetes complications. COMPLICATIONS OF DIABETES Complications of diabetes - pathological processes and conditions are not binding for him, but due to any cause diabetes or disorders occur with diabetes. Complications of diabetes is divided into acute and chronic. 1. Acute - Diabetic ketoacidosis, coma acidotic - Hypoglycemic coma - Hyperosmolar coma 2. Chronic - angiopathy - Reduction factors IBN activity - Neuropathy - Encephalopathy - Retinopathy - nephropathy Acutely occurring ("acute complications of diabetes"): diabetic ketoacidosis, fraught with the development of acidotic coma; hyperosmolar (non ketoacidotic) and hypoglycemic coma. Duration (chronic) proceeding ("late complications of diabetes"): angiopathy, neuropathy, encephalopathy, nephropathy, reduced activity IBN factors other complications (osteo - arthropathy and cataracts). Acutely occurring complications These complications usually occur under the influence of any provoke factors. The most frequent reasons - improper insulin (violation of calculating the required amount of insulin), stress reaction, the development of other diseases. 113 Diabetic ketoacidosis Diabetic ketoacidosis is characteristic of IDDM. Ketoacidosis ketoacidotic and coma are among the main causes of death in patients with diabetes. Not less than 16% of patients with these complications are killed in a coma. Causes - Insufficient blood levels of insulin and / or its effects. - Increase the concentration and / or severity of effects contrinsular hormones (glucagon, catecholamines, growth hormone, cortisol, thyroid). Risk factors Most often diabetic ketoacidosis seen in patients with the administration of therapeutic impossibility (replacement) of the dose of insulin or insufficient dose of stress reactions, surgery, trauma, substance abuse, pregnancy, the occurrence of other diseases. Development Mechanism consists of several units: a significant activation of gluconeogenesis, which runs on the background of stimulation of glycogenolysis, proteolysis and lipolysis; violation of glucose transport into the cells, leading to an increase of hyperglycemia; ketogenesis stimulation to the development of acidosis. Activation of gluconeogenesis is the result: 1. The lack of effects of insulin; 2. Effects of glucagon excess. The latter leads to: - Reduction of fructose-2,6-diphosphate and as a consequence - the inhibition of glycolysis reactions and activation of gluconeogenesis; - An increase in glucose level. Impaired glucose transport into the cells as a result hypoinsulinism. The result of the activation and inhibition of gluconeogenesis assimilation of glucose into cells is increasing hyperglycemia. Stimulation of ketogenesis. Stimulation ketogenesis due to: - Activation of lipolysis (especially in adipose tissue). As a result, increases in the blood level of IVH and liver. - Activation karnitinatsiltransferazy I hepatocytes (increases when excess glucagon) significantly accelerates ketogenesis. This process contributes to an increase of liver carnitine content (especially in the context of activation of glucagon effects). Carnitine stimulates transport of fatty acids into the mitochondria of hepatic cells, where they undergo β-oxidation with the formation of CT: acetoacetate and β-hydroxybutyrate. Effects: - Increasing acidosis due to excess CT. This leads to a characteristic pronounced ketoacidosis and acidotic coma smell of acetone in the breath of a patient. - Polyuria caused ketonemia, hyperglycemia, and azotemia. - Withdrawal from the body in the urine Na +, K +, C1, with the development of bicarbonate ion imbalance blood. - Hydropenia cells. - Hypovolaemia (resulting polyuria) hyperosmolarity combined with plasma. - Reduction of renal blood flow, which leads to an increase of azotemia, urinary disturbance Ca2 +, Mg2 +, phosphates, bicarbonate formation inhibition in the kidney, inhibition acido- ammoniogenesis and kidney epithelial cells. - Violation of circulation with the development of hypoxia. - Development of a rapidly progressing ketoacidotic coma. Hyperosmolar coma Hyperosmolar non ketoacidotic (hyperglycemic) coma is most common in elderly patients with NIDDM. Hyperosmolar coma develops much more slowly than ketoacidotic. However, mortality in it above. 114 Hypoglycemic coma Causes of hypoglycemic coma - Overdose of insulin. - Delay the next meal or fasting (involuntary or deliberate, in the latter case there is an attempt at suicide). - Excessive and / or prolonged physical activity. - Contrainsular hormone deficiency and / or their effects. This is one of the common causes of hypoglycemic coma because of glucagon and catecholamine synthesis in these patients is usually reduced. - All of the above causes (especially if they are combined) cause significant hypoglycemia. Mechanisms development 1. The causative factor of pathogenesis - hypoglycaemia. It causes: - Reduced oxygen consumption of brain neurons. Therefore Substrate "starvation" of nerve cells compounded oxygen. - Acute violation of ATP re-synthesis in neurons of the central nervous system. - Activation of the sympathetic-adrenal system. Catecholamines in this situation hamper the development of severe hypoglycemia by stimulating glycogenolysis and causing tachycardia, arrhythmias, tremors, muscle weakness, discomfort in the heart, sweating, forcing the patient to take immediate glucose. 2. Insufficient supply of brain neurons causes a change in GNI and mental disorders: the increasing drowsiness, confusion and loss, headache, speech disorder, convulsion. 3. Violation function of the heart (arrhythmia, heart failure). 4. Respiratory disorders, hypoventilation of the lungs, frequently - the cessation of breathing. 5. Circulatory failure manifested disorders of the central, organ-tissue and microcirculation. In patients developing severe hypotension (collapse). Late complications Symptoms of late complications of diabetes most often appear 15-20 years after the detection of hyperglycemia. However, in some patients, or they may occur before, or not at all occur. The basis late complications of diabetes are mainly metabolic disorders in the tissues. Angiopathy There are microangiopathy and macroangiopathy. Microangiopathy - pathological changes in the blood vessels of the microvasculature. Mechanisms of: non-enzymatic glycosylation of proteins of the basal membrane of the capillaries under conditions of hyperglycemia and activation of the conversion of glucose into sorbitol by aldose reductase influence (normally in transformed sorbitol 1-2% less than the intracellular glucose, and diabetic hyperglycemia level conversion is increased by 8-10 times). Excess sorbitol in the vascular wall leading to its thickening and compaction. This violates: - The flow of blood in the vessels of the microvasculature with the development of tissue ischemia; - Transcapillary exchange metabolic substrates, metabolites and oxygen. The effects of glycosylation of proteins of the basal membrane and the accumulation of sorbitol in the walls of microvessels: - Violation of the structure of vascular wall cells (swelling, thickening, development dystrophies). - Changing the structure of the proteins of the intercellular substance of the vascular walls and the acquisition of antigenic properties. AT education to them leads to the formation of immune complexes, together with AT potentiating damage microvessel walls. - Tissue ischemia. To a large extent ischemia is the result of reducing the formation of N0, causing dilation of arterioles. 115 These changes lead to disruption of the permeability of vascular wall, the formation of microaneurysms, microtrombi formation, expansion and venules postcapillaries, neoplastic microvascular microbleeds, education, seals and scarring in the perivascular tissue. Macroangiopathy are characterized by an early and intensive development of sclerotic changes in the walls of arteries of medium and large caliber in patients with diabetes, one of the main risk factors (fast!) atherosclerosis. Causes - Glycosylation of proteins of the basal membrane and interstitial vessel walls. Modification of protein molecules promotes atherogenesis. - Sorbitol accumulation in the arterial wall. - Increasing the level of atherogenic LDL and decrease HDL antiatherogenic. - Activation of the synthesis of thromboxane A2 by platelets and other formed elements of blood. It potentiates the vasoconstriction and platelet adhesion to vessel walls. - Stimulation of the proliferation of arterial vessels of smooth muscle cells. Effects These (and certain other) changes lead to earlier and accelerated atherosclerosis, including: - Calcification and ulceration of atherosclerotic plaques, - Blood clots, - Occlusion of the arteries, - Circulatory disorders of the myocardial tissue with the development (including infarction), stroke, gangrene (most soft tissues of the foot). Neuropathy The symptoms of diabetic neuropathy can occur in the early stages of the disease in any part of the nervous system. They are one of the most common causes of disability in patients. Neuropathies are most pronounced in older patients with chronic diabetes and hyperglycemia significantly. Development Mechanisms. At the heart of the development of neuropathies are metabolic disorders and intraneural blood supply. Key links in the pathogenesis of diabetic neuropathy: - Excessive glycosylation of proteins of the peripheral nerves. - antibody formation to modified proteins of immune reactions with the development towards autoaggression antigen nervous tissue. - Activation of neurons and Schwann cells of the transformation of glucose into sorbitol, catalyzed by aldose reductase. - Reduction of intraneural blood supply with the development of chronic ischemia and hypoxia neural structures. The main factor ishemizirovaniya nervous tissue believe N0 deficit. Last normally causes relaxation and vasodilation of arterioles MMC. In turn, causes neuronal deficit N0 are: reduction of protein kinase C activity caused by hyperglycemia; NADFN2 deficit. - Competitive inhibition of myo-inositol transport in nerve cells with excess GIC. This leads to the development of three effects: impaired synthesis of myelin and demyelination of nerve fibers; activity decrease Na +, K + -ATPase activity of neurons that potentiates decrease Na-dependent transport in nerve tissue myoinositol; the speed of nerve impulses slowdown. Types and symptoms of diabetic neuropathies 1. The peripheral polyneuropathy. They are characterized by a primary lesion of a few peripheral nerve trunks and feet appear paresthesia, rarely - hand; soreness of feet and legs; pain and loss of vibration sensation, often in the distal lower extremities; decrease the severity of reflexes, especially stretching; neuropathic ulcers, erosions, necrosis of the tissue stop (diabetic foot syndrome). 2. Autonomic neuropathy. It affects mainly the structure of the autonomic nervous system, often combined with peripheral neuropathy and shows: - Disorders of GI function (difficulty swallowing, emptying of the stomach and bowel, constipation, diarrhea), caused by a violation of its regulation, mainly cholinergic. 116 - Dystrophy bladder (urinary retention) in connection with damage to the neurons of the pelvic plexus. - Impaired regulation of neurogenic vascular tone walls. This is manifested positional (postural) hypotension or syncope (a sharp decrease in blood pressure when rising from a lying or sitting position). - Disorders of the nervous regulation of cardiac activity, often leading to sudden death. - Impaired regulation of sexual function (especially in men, which is manifested impotence, decreased libido and other disorders). 3. Radiculopathy. Due to changes in the spinal cord and roots are characterized by pain in the course of one or more spinal nerve (usually in the chest and abdomen), and increased sensitivity in these areas. 4. Mononeuropathy. Hit the individual cranial and / or proximal motor neurons, manifested transient flaccid paralysis hand or foot and reversible paresis III, IV or VI pairs of cranial nerves. Encephalopathy Causes - Dystrophic and degenerative changes in the brain neurons. Caused by repeated hypoglycemic states, violation of the energy supply of neurons and cerebral ischemia areas, developing as a result of micro - and angiopathy. - Stroke (ischemic and / or hemorrhagic). Due to angiopathies. Manifestations - Violation of mental activity in the form of memory disorders, irritability, tearfulness, apathy, sleep disorders, fatigue. - Signs of an organic brain damage as a result of hemorrhage or ischemia of its separate areas: sensitivity disorders, neurogenic movement disorders, neurodistrophy. Retinopathy The defeat of the retina in diabetes is the main cause of loss of visual acuity and blindness. Retinopathy found in approximately 3% of patients at the onset of the disease in 40-45% after 10 years, 97% after 15 years of disease. Causes - Microangiopathy in the tissues of the eye. - Hypoxia eye tissues, especially the retina. Types and symptoms 1. Nonproliferative (background, simple) is more than 90% of diabetic retinopathy. It manifests itself: - An increase in microvascular permeability of the walls with the development of exudates; - The formation of microaneurysms arterioles and venules; - Microbleeds in the retina and / or vitreous humor (it can cause blindness); - Development mikrotrombi vascular occlusion. 2. Proliferative retinopathy is observed in 10% of patients. She characterized: - Formation of new microvessels (stimulated by hypoxia), germinating in the vitreous; - The formation of scarring at the site of bleeding; - Detachment of the retina in regions of major hemorrhage. Nephropathy Impaired renal function - one of the common causes of disability and death in diabetes. The latter is the outcome of renal failure. Diabetic nephropathy is the second leading cause of death in patients with diabetes. Nephropathy identified in approximately 40% of patients with IDDM and NIDDM with 20%. Diabetic nephropathy is characterized by: - Signs of micro - and macroangiopathy. - Thickening of the walls and the seal of afferent and efferent glomerular arterioles. 117 - Thickening of the basement membrane of the glomeruli and tubules with filtering violations, reabsorption, secretion and excretion. - The development of interstitial nephritis and glomerulosclerosis. - Increase in blood pressure as a result of the activation of "renal ischemic" and "renoprival" hypertension development mechanisms. - The development of the syndrome Kimmelshtilya-Wilson, who appears sclerosis renal tissue (diabetic glomerulosclerosis), severe proteinuria, nephrogenic edema, hypertension and uremia. Immunological defeat For diabetes is characterized by decrease in NBI system efficiency. This is evidenced by data on the development of more frequent and severe course in patients with diabetes: 1. Infectious skin lesions (with the development of furunculosis, carbuncle), urinary tract, lungs. 2. Infections typical for diabetes: - External otitis caused by Pseudomonas aeruginosa. - Rhinocerebral mukorosis. The disease is caused by fungi such as Mucor, it can be completed necrosis of the mucous membrane of the nasal passages, and underlying tissues, the internal jugular vein thrombosis and cerebral sinuses. - Cholecystitis. The reason for it are clostridia and other microorganisms. The reasons for reducing the activity of the immune system and protect the body's non- specific factors are: - Hypoxia caused by blood circulation, breathing, changes in the state of hemoglobin (due to its glycosylation) enzymes and mitochondria. - Metabolic disorders, characteristic of diabetes. Other complications In patients with diabetes there are many other complications (cardiomyopathy, cataracts, triglyceridemia, violations of ion exchange, osteo - and arthropathy). This is because the abnormalities in diabetes developed in all tissues and organs. PRINCIPLES OF TREATMENT OF DIABETES 1. The causal principle is aimed at eliminating the causes of diabetes and conditions conducive to the development of the disease. This approach is most rational at the initial stage of the disease. 2. Pathogenetic principle aims to break the pathogenetic LED units. In the framework of the principle objectives: - Control and correction level of the glucose level. Normalization of glucose over time, tend to reduce the severity or eliminate the main metabolic and functional and structural abnormalities in a number of body. - Correction of the water and ion exchange, shifts the acid-base status. - Prevention of acute complications of diabetes (ketoacidosis, coma). - Prevent or reduce the extent of chronic complications (angio -, neuro -, encephalopathy -, nephropathy, and others.). 3. Symptomatic principle is aimed at elimination and prevention of conditions and symptoms, aggravating for diabetes and patient well-being: furunculosis, hyper - or hypotensive reactions, reduction of visual acuity, severe headaches, changes in the skin and mucous membranes, neuropathic pain, digestive disorders. 118 Pathophysiology of metabolism. Disturbance of the water-salt metabolism Water is universal environment, and an indispensable structural component of any living system. Total water in the body : 1. intracellular water sector (30-35%); 2. extracellular water sector (20-24%): -plasma fluid (plasma water) - 3,5-5%; -interstitial fluid - 15-18%; -transcellular fluid - 1-1.5%. Regulation of water balance The water metabolism regulation system is sophisticated structure. The adaptive objective of this system is to maintain the optimal fluid volume in the organism. Being affected by pathogenic factors and/or with the modified concentration of fluid and salts in the organism this system either eliminates the abnormalities or reduces their influence. Water metabolism regulation system is closely connected with the systems of salt metabolism and osmotic pressure control. Water metabolism regulation system includes the central, afferent and efferent parts. The central part of the water metabolism control system is thirst centre (regulating water level). Its neurons are mainly in the front section of hypothalamus. This centre is connected with the areas of great brain cortex which make possible to experience the feelings of thirst and water comfort. The afferent part of the system includes sensory nerve endings and nerve fibres from different organs and tissues of the organism (oral mucosa, vascular channel, stomach, intestine and tissues), distant receptors (mainly optic and acoustic ones). The afferent impulses from the receptors of various types (chemoceptors, osmoceptors, baroceptors, thermoreceptors and possibly some others) reach hypothalamic neurons. Regulatory stimuli from the thirst centre neurions (nerve and humoral) are transmitted to affector structures. The efferent part of the water metabolism regulation system includes kidneys, sweat glands, intestines and lungs. These organs (kidneys to a greater extent and lungs to a smaller extent) are responsible for eliminating disturbances of water and salt balance in the organism. Being affected by pathogenic factors and/or with the modified concentration of fluid and salts in the organism the system of water metabolism regulation either eliminates these abnormalities or reduces their influence. Insufficient efficiency of this system gives rise to a number of water metabolism disturbances. TYPICAL WATER BALANCE DISTURBANCES. All kinds of water exchange disturbances (dyshydria) are classified into hypohydration (water loss) and hyperhydration (hyperhydria), including the clinically important form of hyperhydration, i. e. edema. Each typical form of dyshydria can be characterized by means of two basic criteria, the first being the osmolality of extracellular fluid. On the basis of this criterion three forms of dyshydria are singled out: 1. hypoosmolalic (with plasma osmolality under 280 mosm/kg H2O); 2. hyperosmolalic (with plasma osmolality above 300 mosm/kg H2O); 3. isoosmolalic. The second criterion is the sector of the organism in which dyshydria predominantly develops. On the basis of this criteria dyshydria can be classified: -cellular -extracellular -mixed forms. 119 Hypohydration. The characteristic feature of all kinds of hypohydration is the negative fluid balance: the predominance of water loss over its intake by the organism. Hypohydration causes. The causes of hypohydration may be either insufficient water supply of the organism or its increased loss. Insufficient water supply of the organism may occur in time of the so-called water “water starvation”, i. e. the deficient intake of liquid with food and drink by the organism (e. g. in time of forced starvation, or when there is no opportunity to secure the regular drinking regime in time of acts of God or hostilities). The other possible causes may be mental disorders or traumas, reducing or eliminating the feeling of thirst (for example, in concussion of the brain; when the neurons of the thirst centre have been damaged due to hemorrhage, ischemia, tumor growth as well as in hysteria and neurosis), somatic diseases, hampering food and liquid intake (for example, in impaired swallowing, esophageal occlusion, in the trauma of the facial part of the skull). Increased water loss by the organism may occur in continuous polyuria (for example, in patients with renal failure, diabetes mellitus or when diuretics are not properly administered), gastrointestinal disorders (for example, in continuous profuse salivary discharge, recurrent vomiting, chronic constipation), heavy blood loss (for example, caused by blood vessel and/or heart injury), pathological processes, causing the heavy loss of lymph (for example, in case of extensive burns, lymphatic trunks damaged or injured by a tumour), prolonged or profuse sweating (for example, in the conditions of hot dry climate or industrial processes involving increased air temperature and decreased humidity in the workshop), hyperthermal states of the organism including fever. 1° C body temperature increase results in the discharge of 400-500 ml of liquid daily as a result of sweating. According to the osmolality of extracellular fluid three types of hypohydration are singled out: hypoosmolalic, hyperosmolalic and isoosmolalic. Hypoosmolaric hypohydration. In hypoosmolalic hypohydration the organism’s salt losses are predominant as compared to water losses and the decrease in extracellular fluid osmolality. Causes: -hypoaldesteronism. It is associated with decreased reabsorption of Na+ ions in the kidneys, decreased osmolality of blood plasma and water reabsorption which results in the organism’s hypohydration. -continuous profuse sweating involving the discharge of a great amount of salts. -recurrent or uncontrollable vomiting (for example, in case of poisoning or pregnancy) causing Na+ and K+ losses. -diabetes mellitus or diabetes insipidus (for example, when ADH is deficient) combined with the excretion of K+ salts, Na+ glucose, albumins. -profuse diarrhea (for example, in cholera or malabsorption syndrome) associated with the loss of intestinal juice containing K+, Na+, Ca2+ and other cations. -improper or unjustified implementation of dialysis procedures (hemodialysis or peritoneal dialysis with low osmolality of dialyzing solution. This results in the diffusion of ions from blood plasma and the fluid for dialysis. -the correction of isoosmolalic hypohydration with the help of solutions with decreased salt concentration. The extracellular form of hypoosmolalic hypohydration is conditioned mainly by the organism’s predominant fluid loss. However, its severe and/or continuous varieties are associated with fluid transport into the cell (according to osmolality Gradient). Alongside with that intracellular hyperhydration (cell swelling) determining the extent of extracellular hypohydration may be registered. 120 Consequences and manifestations. Mucous and cutaneous dryness, decreased salivary secretion (hyposalivation), decreased elasticity and tension (turgor) of skin, muscles, recession and softening of eyeballs, reduced amount of daily excreted urine. All these manifestations result from the organism’s hypohydration, the reduced volume of intercellular fluid and the volume of circulating blood, decreased perfusion and hemodymanic pressure in arterioles and precapillaries. It should be noted that patients with hypoosmolalic hypohydration do not feel thirst due to low blood plasma osmolality and cell hyperhydration. Hyperosmolaric hypohydration. In hyperosmolalic hypohydration the organism’s water losses are predominant as compared to salt losses. Increased osmolality of intercellular fluid leads to water transport from the cells into extracellular space. Under such conditions general (cellular and intracellular) hypohydration may develop. Causes: - Insufficient water intake (for example, in the so called “dry starvation” when a person refuses to drink water; when there is lack of drinking water supply in time of hostilities, acts of God, emergency situations). - Hyperthermal states (including fever), associated with heavy prolonged sweating. - Polyuria (for example, in diabetes insipidus (nephritic) involving the loss of a great amount of liquid with low concentration of osmotically active substances: ions, glucose, nitrous compounds by the organism; in diabetes mellitus due to osmotic polyuria in combination with high hyperglycemia). Prolonged artificial lung ventilation (ALV) with insufficiently moistened gaseous mixture. - Drinking sea water in the conditions of the organism’s hypohydration. - Parenteral infusion of solutions of increased osmolality (for example, in treating disturbances of acid base equilibrium; in artificial feeding of patients with dystrophy). Consequences and manifestations: - Decreased volume of circulating blood; - Increased Ht resulting in blood viscosity; - Systemic disturbances of blood circulation (central, organ-tissular, microcirculatory); - Disturbed acid base equilibrium (mainly acidosis) resulting from impaired hemodynamics, respiration and metabolism; - Hypoxia. As is seen the manifestations of hyperosmolalic hypohydration are quite similar (but not identical) to those of hypoosmolalic hypohydration. However, considerable cell hypohydration as well as the death of some of the cells in hyperosmolalic hypohydration results in a more aggravated course of this pathology. This accounts for the fact that some other signs may occur in hyperosmolalic hypohydration. - Fever due to the release of pyrogen from injured cells. - Mental disorders (psychomotoric agitation, anxiety, fear of death, and mental confusion and loss of consciousness). - excruciating unquenchable thirst due to extra- and intracellular hypohydration. It makes the patient drink any liquid (sea water and other water unfit for drinking, sewage, etc., which is aggravating his condition even more.) In children hyperosmolalic hypohydration develops at a higher rate and its course is more aggravated. This is conditioned by higher intensity of fluid excretion from the organism by kidneys, lungs, through the skin as compared to that of adults (when calculated per unit of body surface). 121 Isoosmolaric hypohydration. Isoosmolalic hypohydration involves an approximately equivalent reduction of water and salt concentration in the organism. Causes: - Acute heavy blood loss at its initial stage (i.e. before the emergency compensatory mechanisms are brought into action). - Profuse recurrent vomiting. Profuse diarrhea. Extensive burns. Polyuria caused by bigger doses of diuretics. Consequences and manifestations. Consequences and manifestations of isoosmolalic hypohydration are conditioned by the reduced volume of extracellular fluid resulting in blood circulation disturbances: - Reduced volume of circulating blood; - Increased blood viscosity; - Disturbances of central, organ-tissular and microhemocirculation; - Disturbances of acid base equilibrium (for example, acidosis in profuse diarrhea and heavy blood loss, alkalosis in recurrent vomiting); - Hypoxia (especially after heavy blood loss). The prompt action of compensatory mechanisms, as a rule, eliminates or considerably decreases the extent of hypohydration and severity of its manifestations. The mechanisms of hypohydration compensation. The general mechanisms of dehydration compensation include the activation of the neurons of the hypothalamic thirst centre and the activation of the system “renin - angiotensin – aldosteron”. In the first case the increased amount of antidiuretic hormone (ADH or vasopressin) is secreted into the blood and diuresis decreases. In the second case the mineraloicorticoid hormone aldosteron increases the renal reabsorption of Na+, which results in water staying in the organism. Thirst. The feeling of thirst emerges when there is 1-2% deficit of water. It considerably increases in the conditions of excess sodium in the blood plasma – hypernatremia (hyperosmolality). 2,5-4 % water deficit causes a painful, excruciating feeling of thirst. This feeling sometimes makes people take a liquid which is unfit for drinking (for example, sea or dirty water), which aggravates the condition of the organism even more. Causes of thirst: Increased osmolality of extracellular fluid (mainly that of blood plasma being more than 285 mosm/kg H2O). Decreased amount of water in the cells. Decreased level of angiotensin II in blood plasma, which immediately stimulates the thirst centre neurons. Antidiuretic hormone The activation of ADH (vasopressin) synthesis in the neurons of supraoptic and paraventricular hypothalamic nuclei and its secretion into blood from the posterior lobe of hypophysis result in decreased diuresis and vasoconstrictive effects. Compensatory reactions are efficient in the organism’s hypohydration of a mild degree, when water deficit does not exceed 5 % as compared to the norm. In hypohydration of more severe degrees special medical aid is necessary. The principles of hypohydration elimination. Etiotropic principle involves eliminating or decreasing the severity and the length of the causal factor action . This therapy is individual for each patient. Pathogenetic principle implies: 122 1. Eliminating water deficit in the organism which is achieved by infusing the lacking amount of liquid. 2. Decreasing the degree of ion disbalance. This must be preceded by the analysis of their concentration in blood plasma as well as osmolality. Having taken into consideration these factors the liquid containing the required number of ions is prepared or chosen. 3. Eliminating acid base equilibrium disturbances. 4. Normalizing central, organ-tissular and microhemocirculation. The particular measures are determined to a great extent by the degree of blood circulation disturbances, the major pathology, the degree of hypoxia and its consequences. A symptomatic principle is aimed at eliminating or decreasing the severity of the symptoms, aggravating the condition of hypohydration. Pain-relieving and sedative drugs as well as drugs for relieving a headache and cardiotropic drugs are administered. The particular therapeutic measures must be strictly individual. HYPERHYDRATION. Hyperhydration is characterized by the positive fluid balance: predominant water intake by the organism as compared to water excretion and losses. According to the osmolality of extracellular fluid hypoosmolalic, hyperosmolalic and isoosmolalic hyperhydration are singled out. Hypoosmolalic hyperhydration. Hypoosmolalic hyperhydration is characterized by excess extracellular fluid of low osmolality in the organism. Hypoosmolalic hyperhydration involves a fluid volume increase both in the extra- and intracellular sector, as excess extracellular fluid according to the gradient of osmotic and oncotic pressure enters the cells. Causes: - Excessive infusion of fluids with low concentration of salts or lacking salts into the organism. Most frequently this occurs in the course of repeated enteric infusion of water into the organism. This state is designated as “water poisoning”. Such a situation may arise when patients with mental disorders repeatedly consume a great amount of water or drinks, when water is infused into the gastrointestinal tract through a catheter or a fistula (for example, for gastric or intestinal lavage). The development of “water poisoning” is alleviated with the excretory hypofunction of the kidneys. - Increased concentration of ADH in blood as a result of its hyperproduction in the hypothalamus (for example, in Parhon’s syndrome). - Renal failure (with considerable excretory hypofunction of the kidneys). - Marked circulatory insufficiency involving edema development. Consequences and manifestations: - Increased volume of circulating blood (hypervolemia) and hemodilution. - Hypervolemia and hemodilution are conditioned by water transport into the vascular channel due to higher osmotic and oncotic blood pressure as compared to that of intercellular fluid. - Polyuria is increased urination due to higher filtration pressure in renal corpuscles. Polyuria may not occur at the hypo- or anuria stage of renal failure. - Erythrocyte hemolysis. - The emergence of intracellular components in blood plasma (for example, enzymes and other macromolecules) due to the injure or death of cells of different tissues and organs. - Vomiting and diarrhea due to the organism’s intoxication (as a result of the release of excess ions, metabolism products, enzymes and other substances from injured or dead cells.) - Psychoneurological disorders: flabbiness, apathy, disturbed consciousness, frequent convulsions. The listed disorders result from brain cell injury as a result of their swelling. Hypoosmolalic syndrome. It develops when blood plasma osmolality decreases up to 280 mosm/kg H2O or even lower, as a rule, as a result of hyponatremia (this syndrome may occur both 123 in hypo- and hyperhydration of the organism). Blood plasma osmolality decrease under 250 mosm/kg H2O may result in irreversible changes in the organism and its death. Hyperosmolalic hyperhydration. Hyperosmolalic hyperhydration is characterized by increased osmolality of extracellular fluid, which is higher than that in the cells. Causes: - Forced intake of sea water. It happens when there has not been fresh water for a long time (for example, during sea and ocean catastrophes, when flying vehicles fall down into seas or oceans). - Infusion of the solutions with increased concentration of salts into the organism without controlling their concentration in blood plasma (for example, in running remedial measures in patients with iso- or hypoosmolalic hypohydration, acid base equilibrium disturbances). - Hyperaldosteronism, causing the excessive reabsorption of Na+ in the kidneys. - Renal failure associated with salt excretion decrease (for example, in “renal tubulo- and/or enzymopathy”. The above-mentioned causes (as well as some others) account for the increase in the volume and the osmolality of extracellular fluid. The latter leads to cell hypohydration (as a result of fluid escape from the cell into extracellular space according to the osmotic pressure gradient). Thus, mixed (associated) dyshydria develops: extracellular hyperhydration and intracellular hypohydration. Consequences and manifestations: - Hypervolemia. - Increased volume of circulating blood. - Increased cardiac output, followed by its decrease in case of cardiac insufficiency development. - Increased arterial blood pressure. Increased central venous blood pressure. All the above- mentioned signs of hyperosmolalic hypohydration result from the blood plasma volume increase. - Brain edema. - Pulmonary edema. The last two manifestations develop as a result of intracellular hyperhydration as well as the increased volume of intercellular fluid (edema) due to cardiac insufficiency. - Hypoxia caused by cardiac insufficiency development, blood circulation disturbances and respiratory disorders. - Mental disorders, caused by brain injury due to its edema, increasing hypoxia and intoxication of the organism. - Powerful thirst developing as a result of blood plasma hyperosmolality and cell hypohydration. The additional supply of the organism with water under these conditions aggravates the patient’s state. Hyperosmolalic syndrome. It occurs when blood plasma osmolality increases (most often due to excess Na+ and/or glucose) above 300 mosm/kg H2O (both in hyper- and hypohydration of the organism). This reveals the signs of cell hypohydration. Isoosmolalic hyperhydration. Isoosmolalic hyperhydration is characterized by the increased volume of extracellular fluid of normal osmolality. Causes: - Infusion of a great amount of isotonic solutions (for example, sodium chloride, potassium chloride, sodium hydrocarbonate). 124 - Insufficient blood circulation, resulting in the increased volume of extracellular fluid due to increased hemodymanic and filtration pressure in arterioles and precapillaries; decreased efficiency of liquid reabsorption in postcapillaries and venules. - Increased permeability of microvessel walls which facilitates fluid filtration in precapillary arterioles (for example, in intoxication, some infections, toxemia of pregnancy). - Hyperproteinemia, in which fluid is transported from the vascular channel into intercellular space according to the oncotic pressure gradient (for example, in general or protein starvation, hepatic insufficiency, nephritic syndrome). - Chronic lymphostasis, in which the drainage of intercellular fluid into lymph vessels is slowed down. The listed factors alongside with some others cause the increase of circulating blood volume and intercellular fluid. The developing hyperhydration may be easily eliminated if the system of water metabolism regulation is in optimal condition. Consequences and manifestations: - Increased blood volume; its general and circulating fractions (oligocytemic hypervolemia). - Increased arterial blood pressure, caused by hypervolemia, increased cardiac output and peripheral vascular resistance. - Cardiac insufficiency development especially in prolonged hypervolemia. The latter causes cardiac overload (both with blood volume and increased vascular resistance). - Edema development. Edema development may considerably aggravate the patient’s state if edema develops in the lungs or in the brain. The mechanisms of hyperhydration compensation. The general mechanism of hyperhydration compensation first of all appears to be diuresis stimulation, which is achieved in various ways including decreasing vasopressin (ADH) synthesis and secretion. Compensatory reactions activated in hyperhydration are efficient in mild and moderate hyperhydration conditions. In its more severe forms drastic remedial measures are required. The principles of hyperhydration elimination. Etiotropic principle, most commonly applied in hyperhydration treatment, consists in eliminating or decreasing the severity and the length of the causal factor action (for example, the excessive infusion of fluid into the organism, renal failure, endocrine disorders, blood circulation insufficiency) and in many cases liquidates the signs of the organism’s hyperhydration . Pathogenetic principle implies the disruption of the main links of hyperhydration pathogenesis. To achieve this: - Excess fluid is excreted from the organism. For this diuretics of different action are commonly administered. - Either the disturbed ion balance is eliminated or its degree is decreased. This is based on the analysis of ion concentration in the patient’s blood plasma as well as its osmolality. Having taken into consideration these factors, liquids containing the required concentration of particular ions are infused. - Blood circulation is normalized by optimizing cardiac activity , vascular tone, blood volume and its rheological properties. For this cardiotropic and vasoactive drugs, blood plasma and plasma substitutes are administered. Symptomatic therapy involves eliminating the organism’s changes which cause more severe hyperhydration (for example, pulmonary edema, brain edema, cardiac arrhythmia, attacks of angina, hypertensive reactions). EDEMA. Edema - typical form violation of water balance, which is characterized by fluid accumulation in the tissues. Edema is one of the most common forms of hyperhydration. 125 According to the theory of E. Starling exchange of water between capillaries and tissues is determined by the following factors (1896): - hydrostatic pressure of the blood in the capillaries and interstitial fluid pressure; - colloid osmotic pressure of blood plasma and tissue fluid; - permeability of capillary wall. The hydrostatic pressure within the vascular system and the colloid osmotic pressure in the interstitial fluid tend to promote movement of fluid from the vascular to the extravascular space. The filtration pressure can be calculated according to the following equation: FP = CHP + ICOP - (CCOP + IHP) In contrast, the colloid osmotic pressure contributed by the plasma proteins and the hydrostatic pressure within the interstitial fluid, referred to as the tissue tension, promote the movement of fluid into the vascular compartment. The reabsorption pressure is calculated as following: RP = CCOP + IHP - (CHP + ICOP) Arterial hydrostatic pressure is three-folds venous hydrostatic pressure whereas blood colloid osmotic pressure does not change. In most tissues interstitial hydrostatic pressure is slightly negative, about 3 mm Hg. But cerebral and renal interstitial hydrostatic pressures are slightly positive. Interstitial colloid osmotic pressure depends on capillary permeability and therefore it is varied in different tissues. Consequently there is a movement of water and diffusable solutes from the vascular space at the arterial end of the capillaries. Fluid returns from the interstitial space into the vessels at the venous end of the capillary. The lymphatic system controls the concentration of proteins in the interstitial fluid, the volume of interstitial fluid and the interstitial fluid pressure. The development of edema then depends on one or more alterations in the Starling forces so that there is a net movement of fluid from the vascular system into the interstitium or into a body cavity. Edema classification. Edemas are classified according to their localization, the extent of their spread, the rate of their development and the basic pathogenetic factor of edema development. According to the origin, edema can be classified into congestive(due to cardiac insufficiency), renal, inflammatory, liver, endocrine, toxic, neurogenic. According to edema localization general edema (anasarca) and dropsy are singled out. Anasarca is the edema of subcutaneous cellular tissue. Dropsy is the edema of a body cavity (accumulation of transudate in it). Ascites is the accumulation of excess transudate in the abdominal cavity. Hydrothorax is the accumulation of transudate in the chest. Hydropericardium is excess fluid in the pericardum cavity. Hydrocele is the accumulation of transudate between the folia of the testicular serous membrane. Hydrocephaly is excess fluid in the brain ventricles (inner dropsy of the brain) and/or between the brain and the skull - in subrachnoid or subdural space (outer dropsy of the brain). Depending on the composition: - exudate - inflammatory fluid containing more than 4% protein and blood cells; - transudate - contains little protein and cells. According to the extent of their spread local and general edemas are singled out. Local edema (for example, in the tissue or organ at the point of inflammation or allergic reaction development). General edema is the accumulation of excess fluid in all organs or tissues (for example, hypoproteinemic edemas in hepatic insufficiency or nephritic syndrome). According to the rate of edema development instantaneous and acute development or chronic development are singled out. 126 Instantaneous edema develops within a few seconds after being affected (for example, after being bitten by insects or snakes). Acute edema normally develops within an hour after the causal factor action (for example, pulmonary edema in acute myocardial infarction). Chronic edema develops within several days or weeks (for example, nephrotic edema in time of starvation). According to the basic pathogenic factor: hydrodynamic, lymphogenic, oncotic, osmotic and membranogenic edemas are singled out. Pathogenic factors of development. Hydrodynamic factor. Hydrodynamic (hemodynamic, hydrostatic, mechanical) factor is characterized by increased efficient hydrostatic pressure. 1. Increased venous blood pressure. General venous blood pressure increases in cardiac insufficiency due to its decreased contractile and pumping functions. Local venous blood pressure increases when there is obturation of venous vessels (for example, with a thrombus or embolus) or when veins or venules are squeezed (for example, by a tumour, a scar, edematous tissue). 2. Increased volume of circulating blood (for example, in hypervolemia, polycythemia, water poisoning). 3. Tissue turgor decreases. Turgor decrease is an important factor, potentiating the mechanism of fluid filtration from the vessel into the tissue. Lymphogenous (lymphatic) pathogenetic factor. Mechanisms of action of lymphogenous (lymphatic) pathogenetic factor of edematization are different in dynamic and mechanical lymph insufficiency. Dynamic lymph insufficiency. This mechanism of lymphatic edematization is caused by a considerable increase of lymphization. In this case lymph vessels seem to be unable to trasport considerably increased volume of lymph into general blood supply. The same features can be observed in hyperproteinemia in patients with nephrosis or hepatic insufficiency. Mechanical lymph insufficiency. It is the so-called mechanical protection against the drainage of lymph through the vessels caused by their squeeze or obturation. In such cases one can observe considerable tissue edematization accompanied by an increase in size and mass. Edematization in the lower extremities is usually referred to as elephantiasis. In elephantiasis a leg can increase in size and mass considerably (up to 40-50 kg). The same process can occur in the upper extremities, genital organs and some other, quite often large parts of the human body. It is necessary to note that lymphogenous (lymphatic) edemas can cause accumulation of fluid rich in proteins (up to 3-4 g). One can also observe excessive formation of collagenous fibers and other elements of connective tissue that can cause deformation of organs and tissues. Oncotic factor. The main peculiarities of the oncotic factor (hyperalbuminemic, hyperprogeinemic) are a reduction of oncotic blood pressure or/and an increase of oncotic pressure in the intercellular fluid. Hyperproteinemia (mainly due to hyperalbuminosis as albumins are 2.5 times more hydrophilic than globulins) is often caused by: 1) Insufficient intake of proteins during starvation or protein deprivation; 2) Disorders related to cavity or/and membrane digestion (e.g. in cases of resection of intestinal fragments, dysbacteriosis, malabsorption); 3) Reduced synthesis of albumins in the liver (e.g. under the influence of hepatotropic poison, advanced cirrhosis); 4) Excessive loss of proteins in the body (e.g. in case of nephrosis excreted with urine, in extensive burns with plasma, in intestinal and stomach disorders with feces); 127 The factors which can cause increased oncotic interstitial fluid pressure are regional and they usually produce or potentiate local edematization. Hyperoncia of interstitial fluid can be caused by: 1. Excessive transport of blood proteins into intercellular space. It can be associated with increased permeability of the walls of small vessels 2. Escape of proteins of the cells into intercellular fluid in case of cell damage or destruction (e.g. in the focus of inflammation, ischemia, allergic reactions); 3. Increased hydrophility of protein micella in interstitial fluid. - accumulation of excessive amounts of some ions in interstice (e.g. H+, K+, Na+); - insufficient amounts of the ions of Ca2+; - excessive amounts of such as histamine, serotonin; - deficient amounts of thyroid hormones containing iodine. Mechanism of action of the oncotic factor consists in reducing efficient oncotic absorptive force (as a consequence of hyperproteinemia or/and hyperoncia of the tissues). As a result, the volume of filtrated water from small vessels into interstitial fluid according to the gradient of oncotic pressure increases, whereas resorption of fluid from intercellular space into postcapillaries and venules decreases. Osmotic factor. The osmotic factor of edematization consists either in increasing osmolality of interstitial fluid or in decreasing osmolality of the plasma, or in combining both processes. Mechanism of action of the osmotic factor consists in excessive trasportation of water from the cells and vessels of the microcirculatory channel into intercellular fluid according to the gradient of osmotic pressure (higher in interstice). This mechanism is considered a component of pathogenesis in cardiac, nephritic, hepatic and other edemas. In the above-mentioned edemas the volume of extracellular fluid increases. The membranogenic factor is characterized by a considerbale increase in the permeability of the vessel walls in the microcirculatory channel for water, fine-molecular and macromolecular substances (proteins are most significant). Membranogenic factor. Mechanisms of action of the membranogenic factor of edematization. 1. Facilitation of water filtration. In this relation the drainage of fluid from the blood and lymph into interstitial space increases. On the other hand, this mechanism is balanced with increased water reabsorption in the venous part of capillaries related to thinning of their walls. 2. Increased amounts of protein molecules from small capillaries into interstitial fluid. On the one hand, it can lead to decreased oncotic pressure of the plasma and lymph but, on the other hand, it leads to the development of hyperoncia of intercellular fluid. Due to the increased permeability of the walls of small capillaries the fluid passes into intercellular space according to the gradient of oncotic pressure. It is this process that underlies edematization of the tissues in case of inflammation, local allergies, stings, poisonings, effect of pure oxygen, and especially when atmospheric pressure is high. In practice, edematization which developed under the influence of one of the mentioned pathogenetic factors is not very common. In other words, there are no monopathogenetic edemas. Thus, in each case of edematization one can distinguish: - initial (primary) pathogenetic factor in the patient; - secondary pathogenetic factors. Edemas due to cardiac insufficiency Systemic edema occurs in congestive heart failure (cardiac insufficiency) affecting right ventricular cardiac function or both ventricular. Pulmonary edema result from cardiac insufficiency both left ventricular and general (right and left). Cardiac insufficiency, i.e. state in which a person´s heart does not supply organs and tissues with the amount of blood necessary for their functioning 128 and maintaining plastic processes, is characterized by lower (compared with normal) of cardiac output and primary circulatory hypoxia. This type resulting from increased capillary pressure. The hydrostatic capillary pressure depends on the arterial blood pressure, the arteriolar resistance, the state of the precapillary sphincters, and, most importantly, the venous pressure. An increase in the venous pressure within the microvessels results in increased filtration of fluid from the capillaries and an accumulation of fluid in the tissues. Although increased venous hydrostatic pressure is important, the pathogenesis of cardiac edema is more complex. Thus, initial pathogenetic factor is a hydrodynamic factor. Sequence and significance of pathogenetic factors of edematization are different depending on the dynamics of blood circulation disorders and their complications. Pathogenesis of a cardiac edema includes all of the mentioned factors: - Decreased cardiac output. - Reduced volume of circulating blood - Activation of baroreceptors in the walls of blood vessels. - Narrowing of the arterioles of the cortical substance of kidneys. - Increased blood supply in the medullary substance of kidneys. - Increased reabsorption of Na+ in venal tubules of kidneys which can lead to hyperosmia of the blood. - Activation of osmoreceptors. - Increased synthesis and release of antidiuretic hormone in the blood. - Increased water reabsorption in kidneys. - Increased efficient hydrodynamic pressure. - Activation of water filtration in the arterial part of the capillaries accompanied by inhibition of water reabsorption in the venous part of small capillaries. Reduced flow of blood in the vessels of kidneys. The main cause is decreased cardiac output. - Activation of the system renin-angiotensin-aldosteron. - Increased reabsorption of Na+ in the venal tubules of kidneys. - Systemic increase of the venous blood pressure both in great and peripheral venous blood vessels. - Slackened drainage of lymph from tissues which results in developing mechanical lymph insufficiency. - Increased volume of interstitial fluid, i.e. rate of edematization. - Disorders related to the drainage of osmotically active substances (e.g. ions, inorganic and organic compounds) caused by venous hemostasia (i.e. venous hyperemia) and lymph insufficiency. - Increased amounts of metabolites (e.g. lactic acid, pyroracemic acid, peptides, amino acids) caused by metabolism disorders in case of hypoxia. - Activation of non-enzymic hydrolysis of the components of basement membrane in the walls of the vessels. It can also lead to an increase of their permeability. - Increased formation and activation of which provide the increase of permeability in the walls of small vessels (e.g. histamine, serotonin, kinin, separate factors of the complement). - Increased escape of proteins from the blood into interstitial space. - Disorders related to synthesis of protein function of the liver which can lead to hyperalbuminosis. - Reduced efficient oncotic absorptive force. - Increased outflow of water from small capillaries into intercellular space according to the increased gradient of oncotic pressure. Hence, edematizaton occuring in case of cardiac insufficiency is the result of a combination of all pathogenetic factors such as hydrodynamic, osmotic, oncotic, membranogenic and lymphatic ones. 129 Kydney edemas. Various forms of kidney pathology are usually accompanied by more or less marked edematization. Initial pathogenetic factors are different in patients with nephrotic and nephritic syndrom. Edemas developing in nephrotic syndrome . The causes of nephrotic syndrome can be related to - primary impairment of kidneys (e.g. focal glomerulosclerosis, lipid nephrosis); - secondary modification of nephritic tissue (e.g. tuberculosis, allergic reactions). Nephrotic syndrome is characterized by diffuse destruction of the parenchyma of kidneys and severe proteinuria (> 3.5 g/day). The initial pathogenetic factor of edematization is oncotic factor, which result from: 1) Increased permeability of the membranes of nephritic glomerules for the proteins. In this case, the blood loses not only albumins but also globulins, transferrin, haptoglobin, peruloplasmin and some other proteins. 2) Disorders related to reabsorption of proteins in venal tubules of kidneys. All of the above mentioned blood disorders lead to considerable changes in the content of proteins in the body. Main links of pathogenesis Protein losses with urine (i.e. proteinuria). Daily protein losses in patients with nephrosis can reach 35-55 g/l (normally, utilization is no more than 50 mg). Reduced concentration of proteins in the plasma (i.e. hypoproteinemia).. Decrease of efficient oncotic absorptive force. Increase of water filtration in small vessels and accumulation of excessive water in intercellular space and body cavities (i.e. edema). Squeeze of lymph vessels by edematous tissues caused by the development of mechanical lymph insufficiency and increase of edematization. Reduced volume of circulating blood (i.e. hypovolemia). Activation of vascular baroreceptors which provide increased Na+ reabsorption in venal tubules of kidneys. Reduced flow of blood in kidneys caused by hypovolemia which activates the system “renin-angiotensin-aldosteron”. It potentiates reabsorption of Na+ in kidneys. Increase of Na+ in the plasma (i.e. hypernatriemia). It activates osmoreceptors. Stimulation of synthesis in neurons of hypothalamus and excretion of antidiuretic hormone into the blood. Activation of water reabsorption in renal tubules. Increase of efficient hydrostatic pressure in small vessels of tissues which potentiates accumulation of trasudate in interstitial space. Besides, transportation of water from the vessels of the microcirculatory system into interstice provides intensive hypovolemia and lymph insufficiency. Thus, during nephrotic edematization pathogenetic factors potentiating edematization are combined. In nephrotic edematization oncotic, hydrostatic and lymphatic pathogenetic factors usually participate. Edemas developing in patients with nephritis. Nephritic syndrome can be caused by: disorders of blood circulation in kidneys (more often ischemia) in patients with inflammatory or immunoinflammatory diseases such as chronic diffuse glomerulonephritis. In this case, nephritic tissues (including vessels of kidneys) can be squeezed by inflammatory exudate. The rigid capsule of the kidney is. Therefore, even small amounts of exudate can cause the squeeze of its parenchyma. It can result in the disorders of blood supply of kidneys including the cells of juxtaglomerular apparatus. The initial pathogenetic factor is a hydrostatic factor (due to reduced blood supply of the cells of juxtaglomerular apparatus) and formation of ducts between rounded impaired cells of endothelium. Links of pathogenesis Stimulation of synthesis and excretion of renin into the blood by the cells of juxtaglomerular apparatus. Production of angiotensin in the blood under the influence of renin which is converted into angiotensin II with the help of angiotensin-converting enzymes. This process usually takes place in the lungs and walls of the vessels. A small portion of angiotensin II converts into 130 angiotensin III. Stimulation of angiotensin II and, to some extent, angiotensin III provides excretion of aldosteron by the cells of glomerular zone of the adrenal cortex. Increased reabsorption of Na+ in venal tubules of kidneys is associated with the development of hypernatremia. Activation of osmoreceptors is usually accompanied by excretion of antidiuretic hormone into the blood. Increased water reabsorption in renal tubules is associated with the development of hypervolemia. Increased efficient hydrostatic pressure which can cause increased fluid filtration in the arterial part of capillaries and inhibition of water reabsorption in the venous part of capillaries. Edema develops Edema is an accumulation of excessive interstitial fluid. Reduced volume of glomerular filtration accompanied by potentiating hypervolemia can result in a decrease in the number of functioning nephrons damaged during glomerulonephritis. The most common increased permeability of the walls of vessels is usually referred to as generalized capillaritis. It makes the process of transportation of proteins and water into interstice as well as reabsorption of fluid in kidneys much easier. Increased permeability of glomerular filter for proteins (i.e. proteinuria). Development of hyperproteinemia. Reduced efficient oncotic absorptive force which can provide the enlargement of edema. Thus, in nephritic edematization one should take into consideration the following factors: hydrodynamic, oncotic, membranogenic ones. Pulmonary edemas Pulmonary edema refers to excess accumulation of fluid in the extravascular spaces of the lung. Pulmonary edema can be classified based on the etiology into cardiogenic pulmonary edema and noncardiogenic pulmonary edema. Microscopically, pulmonary edema reveals the alveoli to be filled with pale pink fluid. Cardiogenic pulmonary edema results from abnormalities of hemodynamic (Starling) forces. Initial and basic pathogenetic factors are hemodynamic factors. They are characterized by: - Reduced contractility of the myocardium of the left ventricle. - Increased systolic residual volume of the blood in the left ventricle. - Increased end-diastolic volume and pressure in the left ventricle of the heart. - Increased blood pressure in the vessels of the pulmonary circulation (higher than 25-30 mm Hg). - Increased efficient hydrodynamic pressure. If it exceeds efficient oncotic absorptive force, transudate passes into intercellular space of the lungs (interstitial edematization may develop). Noncardiogenic pulmonary edema results from cellular injury. Edema may be the result of either endothelial injury (infections, disseminated intravascular coagulopathy, or trauma) or alveolar injury (from inhaled toxins, aspiration, drowning, or near drowning). Pulmonary edemas developing under the influence of toxic substances. The causes can be such toxic substances as poisonous substances like phosgene, high concentration oxygen. 1 The initial and basic pathogenic factors Membranogenic factors which can be associated with increased permeability of the walls of small vessels are regarded as the initial and basic pathogenic factors Factors which can lead to the increase of permeability of the walls of the vessels under the unfluence of toxic substances are as follows: - Acidosis which can cause non-enzymic hydrolysis of the ground substance in the basement membrane of small vessels; - Increased activity of hydrolytic enzymes. Pathogenic and adaptive role of edemas. Pathogenic role of edemas includes 131 1) The mechanical squeeze of the tissues which result in squeeze of the vessels and disorders of blood formation and lymphization. The flow of blood and lymph is impaired mainly in the vessels of microcirculatory channel (it is usually accompanied by the development of ischemia, venous hyperemia, blood stasis, lymphostasis), though in case of accumulation of edematous fluid in some cavities of the body (e.g. in ascites, hydrothorax, in pericardial cavity) great vessels and even the heart can be squeezed. 2) Emergence of painful sensations due to extension or/and displacement of the tissues and nerve endings. 3) Metabolism disorders in blood and cells accompanied by the development of dystrophy. The causes of metabolism disorders are as follows: 1) Increase of the distance between the capillary and the cells caused by excessive water in intercellular space; 2) Thickening of the walls of vessels (in case of edematization). 4) Excessive growth of cellular and noncellular elements of the connective tissue in the area of edematization (sclerosis) result from/ The causes are as follows: - Influence of growth factors excreted by the damaged and nondamaged cells of the tissues in the area of edematization; - Influence of metabolites which are released from alternating cells of the edematous tissue. Mechanisms of development Proliferation of fibroblasts of the connective tissue in the area of edematization. - Increased synthesis of collagen by the cells.. - Frequent infections in the area of edematization. 5) Frequent infections can be caused by: ischemia of the tissue in the area of edematization (squeezed arterioles) and venous hyperemia in the edematous tissue (compression of veins and venules). Ischemia and venous hyperemia can often lead to hyperoxia, disorders of energy supply of the functioning and plastic processes occuring in the edematous tissues. Mechanisms of realization Inhibition of immune mechanisms and nonspecific protective factors of in edematous tissues. 6) Psychoneurological disorders (e.g. in case of brain edema). 7) Fever. 8) Acid-base equilibrium disorders. 9) Hypohydration of cells. Causes of disorders Metabolic disorders of salts and ions of Na+, K+, Cl, HCO3 in the cells and intercellular fluid. For example, the development of secondary aldosteronism in cardiac and renal edematization can lead to accumulation of excessive Na+ in the cells. Such cells usually develop alkalosis. 10) Functioning disorders of separate vital organs. Disorders which can be fatal. For example, brain edemas, pulmonary edemas, renal edemas, hydropericardium and hydrothorax have a deleterious effect on the functioning of the respective organs, and they can be fatal for the patients. Adaptive role of edemas. The adaptive role or adaptive significance of some reactions or processes developing in edematization consists in: 1) Reduced content of pathogenic substances in the blood as they are transported into edematous fluid (e.g. excessive ions, normal metabolic-waste products and abnormal metabolic- waste products, toxins in case of kidney, hepatic and cardiac edemas). 2) Low concentration of toxic substances which can damage the cells in edematous fluid (e.g. in allergic, inflammatory and toxic edemas). Edematous fluid dissolves toxic substances. 3) Prevention from the spread of toxic substances from the area of pathologic process or reaction throughout the body. Good examples are edemas developing in the focus of inflammation, local allergies, toxic substances. In this case edematous fluid causes the squeeze of lymph vessels and venous blood vessels. Thus, it prevents from the spread of pathogenic agents, toxins, metabolic- waste products and microorganisms throughout the tissues, organs and in the human body. 132 Treatment of edemas The main methods of treating edemas include etyotropic, pathogenetic and symptomatic principles of managing edemas. The pathogenetic method of managing edemas consists in blocking initial and some other factors of edematization. Efficient hydrostatic pressure can be normalized by reducing increased venous blood pressure (e.g. diuretics, cardiotropic drugs, venous blood dilators) as well as by reducing the volume of circulating blood (e.g. diuretics, bloodletting). One can treat blood hyperosmia and hypervolemia with some drugs blocking the system “renin-angiotensin-aldosteron”. For this purpose one should use ß-adrenoblockers which provide a decrease of secretion of renin by kidneys; spinolactones which inhibit the effect of mineralocorticoids; blockers preventing excess aldosteron. Lymph insufficiency can be treated by: 1) normalization of lymph levels (e.g. reduced volume of circulating blood). It can lead to reduced mechanical lymph insufficiency. Preventing the drainage of lymph (e.g. thrombuses, cicatrices, tumors, stenosed lymph vessels). It can also lead to eliminating mechanical lymph insufficiency. Efficient oncotic absorptive force is normalised by: 1) managing hyperproteinaemia (e.g. parenteral administration of solutions containing proteins, management of hepatic insufficiency or malabsorption). Excessive oncotic pressure of interstitial fluid can be decreased by: 1) decreasing permeability of the walls of vessels for proteins with the help of steroid hormones; 2) elimination of inflammatory, allergic and other unfavourable reactons accompanied by the escape of proteins from damaged cells and/or an increase in their hydrophylity. Efficient osmotic factor of edematization can be eliminated or alleviated by: 1) Managing tissue hyperosmia (e.g. normalization of the drainage of intercellular fluid through small vessels; management of pathological processes accompanied by the escape of osmotically active substances from damaged or destroyed cells; elimination of hypoxia and acidosis). Normalization (increase) of osmolality of the plasma is usually treated by: 1) administration of physiological saline solutions of sodium (Na), potassium (K) and some other ions; 2) administration of the plasma and plasma substitutes. Permeability of the walls of small vessels mainly for proteins and fluid, can be normalised by: 1) Eliminating or reducing hypoxia (e.g. management of cardiac, hepatic or pulmonary insufficiency, anemias). Management of anemias. Anemia is usually treated either with buffered solutions or by managing hepatic or renal insufficiency. It can also be achieved by blocking the factors which damage the cells of endothelium and/or extending the walls of small vessels (e.g. reducing venous blood hyperemia, lymphostasis, vasculitis). The symptomatic factor is aimed at managing pathological processes, symptoms and reactions which make the patient feel even worse. It can be achieved by: 1) reducing hypoxia in pulmonary edematization; 2) liquidation of ascitis in cardiac insufficiency or portal hypertension; 3) elimination of excessive edematous fluid from pleural or articular cavities. 133