YAM TAN TAOS TL LE aL Mae D Mevtcat Students Linary | OfECCKMA Pee aeAI. Gozhenko LP. Gurkalova LV. Savitsky PATHOPHYSIOLOGY Recommended by the Central methodical study relating to Higher Medical Education of Ministry of Public Health of Ukraine as a textbook for students of Higher Medical Educational Establishments of the IVth level of accreditation using English Odessa The Odessa State Medical UniversityBBK 52.52173 UDS 616-092(075.8) Authors. Professor A.I. Gozhenko, M.D. Honored Seiece and Technique Worker of Ukraine, D.M. Science LP. Gurkalova, Candidate of Medical Science, Senior Lecturer LV. Savitsky, D.M. Science ~ Reviewers: Professor Yu.V. Byts, M.D., the Head of the Pathophysiology Department of the Kiev National Medical Academy name after A.A. Bogomolets, Honored Science and Technique Worker of Ukraine; Professor A.V. Kubischkin, M.D., the Prorector on International Communication of the Crimea State Medical University named after S.I, Georgievsky This textbook presents the data about General and Systemic Pathophysiology for medical students according to the Program of Ministry of Public Health of Ukraine. The first part deals with the questions on general nosology and typical pathological processes. The second part is devoted to the General regularities disturbances of different organs and systems so that rational therapy can be devised. Towenxo AL, Fypkasosa LIL, Casnnpkuii 1B. 159 Marodisionoria: Miapyuuax. —Oneca: Onec. ep. Me. yH-T, 2014. — 382 c. —(B-Ka cryjjenTa-Mequka). — Mosa anra. ISBN 966-7733-69-6 Y oniapysnuky enknaqeio ani mpo 3arambHy a cuctemny natopisiosorio Ana crytentis-MeaHkis 3riqHo 3 mporpamow MO3 Yxpaixn. Y nepwitt Yactuni itmersca mpo saranby, Ho30n0riNo Ta tmoRi naropisiozorigHi mpoyecu. J[pyra yactuHa NpHcBAveHa 3aralbHAM MpaBiaM: npopedenua pauionameHoi Tepanit npH Nopyiiennax opranis i cuctem. Ta6a. 21. Puc. 45 BBK 52.5273 ISBN 966-7733-47-5 © ALL Foxerxo, LIT. Fypxanona, 1.B. Casunpxni, 2014 ISBN 966-7733-69-6 © Onechkult nepxapnait Meainnit ynisepentet, 2014PREFACE. According to the Program of the Ministry of Public Health of Ukraine this book is divided into 33 chapters organized parallel to most standard texts. The first 16 chapters cover general or basic pathology, presenting the major concepts of disease processes viewed as manifestations of a common set of mechanisms of injury. The second part is devoted to systemic pathology, paveane the principal disorders of each organ system. The last part is devoted to the Comprehensive Examination can be used both as a pretest and as a post test to help identify areas that merit further attention in the chapters or in standard text. The present edition continues the traditions of the previous edition, continuing and developing Ukraine pathophysiological school of N.Zaiko, Yu.Byts who created a text-book for Ukrainian and Russian speaking students. We express our gratitude and acknowledgment to them.I. FOUNDATION CONCEPTS OF PATHOPHYSIOLOGY UNIT 1 i THE SUBJECT, METHODS AND AIM OF PATHOPHYSIOLOGY. THE GENERAL TEACHING ABOUT DISEASE ETIOLOGY AND PATHOGENESIS Pathophysiology should form the basis of every physician's thinking about a patient. The study of the nature of a disease, pathological processes, pathological conditions, which form general pathology may be used by the genetist, biochemist, clinical diagnostician, etc., and it is difficult function of the pathologist to attempt to bring about a synthesis, and present diseases in as whole or as true an aspect as can be done with present knowledge. Pathophysiology — it is the study of the mechanism underlying a disease, the main laws of the development and complications of the disease. The final aim is to discover the laws of the disease development so that rational therapy can be devised. Pathophysiology analyzes the general processes for all the diseases or for some groups of disease syndromes that's why pathophysiology is a transition stage between the main theoretical biological and clinical disciplines. The main aims of pathophysiology are: 1) to define the external and internal causes of disease, the effect of pathological factors of environment upon the human organism; 2) to learn the general laws of patient resistance, adaptation re- actions and mechanisms of convalescence; 3) to form the student's conception about the disease, pathological process, pathologic state and its mechanisms; 4) to learn the typical pathological processes such as inflammation, tumor, fever, hypoxia, allergy, shock and others; 5) summarizing all these conceptions will be used in creating the moder medical technologies. Pathophysiology can use the following methods: 1) the modeling of various forms of pathologic processes, protective 6and adaptive reactions of humans; 2) experimental therapy as an important method of studying and introducing the new ways of treatment; 3) clinical studying of various diseases with functional, biochem- ical, immunological and other tests due to pathophysiology groun- dation therapy. General pathophysiology includes a very important part of nosology or the general teaching about etiology and pathogenesis of the disease and such terms as the "health", "tiorm'", "disease", "pathological process", and "pathological condition". Traditionally, the study of pathophysiology is divided into two general disciplines: the General Pathophysiology and Special or Systemic and Clinical Pathophysiology. The General Pathophysiology focuses on the injurious stimuli undergoing in the cells, tissues, organs and the whole organism (eti- ological factors) and also on the mechanisms of the development of pathological process, its conditions and diseases (pathogenesis), the role of self defense mechanisms (heredity, constitution, reactivity, immunity, sex and age), the general studies of disease, the determination of "the disease". Special and clinical pathophysiology has to leam morphological, biochemical, functional disorders in different organs and systems (pathophysiologic alterations). THE GENERAL TEACHING ABOUT THE DISEASE _ The disease and the health are the main forms of living process. It is necessary to determine what normal healthy life means to understand the essence of the disease. The normal condition of the organism is characterized by: a) the balance of the organism and environment; b) organism integrity; c) ability to work. The health is a condition of total physical, mental and social well- being, but not only the absence of the disease and physical defects (World Health Organisation, 1946). Health is the normal condition of a human, who is able to work and adapted to the changes of environment (1. Petrov). According to N. Zaiko, health is the organism's normal condition, 7when its structure and functions conform to each other and its regulatory systems are able to maintain homeostasis. The norm is the biologic optimum of functioning and developing of the organism. ‘The disease is the abnormal activity of the human organism un- dur the influence of injurious agents, it is characterized by the limitation of adaptability to work, leading to harm to the life of the organism. The disease is a complicated process in the organism with the two quite opposite processes: 1) “a measure against the disease” (by L P. Pavlov) — which means the compensatory reactions; 2) “pathologic process proper" with functional, morphological, biochemical and other disorders. So, the disease is a unity of opposites, which always contend (law of dialectics). The doctor must find out the pathologic process proper and stimulate the protective processes. There are four stages of disease: 1) latent period (incubation period of the infectious diseases); 2) prodromal period; 3) period of expressed manifestations; 4) the outcome of the disease. Tlie disease includes (a) pathologic process, (b) pathologic condition. A pathologic process is a combination of pathologic and protective reactions in the damaged organs or organism. The simplest form of the pathologic process is called "pathologic reaction" (hyperemia, ischemia and others). Pathologic condition is reflected in the dynamic development of pathologic process. It develops slowly (for example condition after amputation of foot, resection of the stomach). THE GENERAL ETIOLOGY Etiology is a study about the causes and conditions of the disease, which provoke the disease and determine its specific features. Etiologic factors may be ‘divided into two groups: external and internal. According to nature there are: 1) biological (microbes, viruses, parasites); 2) mechanical (trauma); 3) physical (atmosphere pressure, electric current, ionizing ra- diation, X-rays, space flight factors and others); 84) chemical (drugs, narcotics, alcohol, acids and others), 5) mental (emotional stress). Endogenous factors are heredity, constitution, sex, age (Down's syndrome, diathesis). ‘There are internal and external conditions, which favour the disease, for example, old age, early childhood, poor nutrition, overcooling, overheating, oxygen and clean water deficit and others. Pathogenesis (from Greek "pathos" — suffering, "genesis" — origin) is a study on mechanisms of the development and outcome of the disease. Pathogenesis of every diszase depends on the cause and resistance (reactivity) of the human organism. There are four periods of pathogenesis: 1) the latent (incubation) period; 2) the prodromal period; 3) the period of expressed manifestations; 4) the outcomes. The outcomes of every disease may be: — recovery (complete, incomplete); — the turning to chronic course or the pathologic condition; — preagony, agony, clinical death and biological death What is the connection between the cause and the pathogenesis? There are three variants of interconnection of the cause and pathogenesis: 1. The etiologic factor initiates the pathologic process and then disappears, so pathogenesis develops without etiological factor (trauma, radiation). 2. The cause continues its action throughout all the period of the development of the disease (infectious disease), as a consequence, the etiological factor penetrates into pathogenesis, exists in it and influences it. 3. Persistence of the cause agent, which causes the clisease, is delayed in the organism (healthy bacilli-carrier). Causes and consequences constantly change their places. The cause (etiological factors) causes the pathologic reactions (process) and then these reactions retum to the first agent (ctiological factor) and intensify it. So "vicious circle" is formed in pathogenesis. For example, if arterial pressure decreases it causes hypoxia and then yasomotor center is depressed. It leads to the prolonged decrease of 9arterial pressure. What is "the main stage" in pathogenesis? The main stage of pathogenesis is the process, which initiates the development of others. The time of elimination of the main stage is the time of elimination of the whole process. So, in diabetes mellilus "the main stage" of pathogenesis is lack of insulin. Its elimination (introduction of the hormones) leads to the disappearance of other manifestation of the disease (hyperglycemia, ketosis, coma). COMPREHENSION CHECK Try to answer the following questions. 1. What is pathophysiology? 2. Why is pathophysiology important? 3. Name the methods and aim of pathophysiology. 4. Give the definition of the term "disease". 5. Characterize differences between "pathological process", “pathological condition" and "disease". 6. Define "etiology", "pathogenesis" and the connection between them. 10UNIT 2 PATHOGENIC EFFECT OF ENVIRONMENTAL FACTORS: ATMOSPHERIC PRESSURE, ELECTRIC CURRENT, IONIZING RADIATION, SPACE FLIGHT FACTORS NEGATIVE EFFECT OF CHANGES OF ATMOSPHERIC PRESSURE Pe A man feels the effect of decreased atmospheric pressure during ascent on plane, or in mountains. The pathologic changes, occurring in it, are caused by two main factors: decrease of partial pressure of oxygen in inspired air and decrease of atmospheric pressure (decompression). Lack of oxygen in inspired air causes state, described in the unit "Hypoxia". Range of phenomena, connected with decrease of atmospheric pressure, is called decompression syndrome. It is known, that some physical characteristics of gases and liquids (volume and solubility of gases in liquids, point of boiling of liquids) depend on atmospheric pressure. Decrease of atmospheric pressure leads to expansion of internal gases of the organism. That's why their solubility in liquid medium decreases. Point of boiling of blood and other liquids is so low, that they can begin to boil at body temperature. The degree of manifestation of these phenomena depends on velocity of decompression and its degree. Pilots, flying in nonhermetically sealed cabin, can have some symptoms, caused by decompression: expansion of air in intestines, pain in ears and frontal sinuses because of expansion of air in these cav- ities, nasal bleeding because of bursts of small vessels. Liquids begin to boil at body temperature at the height of 19,000 m. Explosive decompression syndrome develops when quick change of atmospheric pressure. The main cause is barotrauma of lungs, heart and big vessels is quick increase of pulmonary pressure. Rupture of alveoli and vessels of the lungs causes the gas bubbles to penetrate into circulatory system (gas embolism). In case of depressurization of a space ship or high-altitude plane momentary death occurs because of boiling, of blood and other liquids of the organism, and also because of quick form of hypoxia. A man feels effect of increased atmospheric pressure in water during diver's or caisson works. One can have pain in ears because of pressing tympanic membranes. Rupture of lung alveoli is possible at quick increase of atmospheric pressure. But the most important is the fact that 11in conditions of hyperbaria the man breathes with air or other gas mixture under increased pressure. That's why additional quantity of gases dissolves in blood and tissues of the organism (saturation). Nitrogen is the most important in breathing with compressed air. It was considered for a long time, that nitrogen, as inert gas, didn't make a biological effect, and only experience of underwater medicine has showed another thing. Nitrogen causes syndrome of specific changes in people, working under increased pressure. The nitrogen quantity of the organism can increase sometimes, especially in organs, containing a lot of lipids. It's known, that nervous tissue contains a lot of lipids, so it is mostly affected. The first manifestation of it is a light excitement, like euphoria. The next are phenomena of narcosis and intoxication. Oxygen-helium mixtures are used in underwater mechanisms for avoiding these phenomena (helium is dissolved less than nitrogen). But not only nitrogen is toxic at increased pressure. Surplus of oxygen (hyperoxia) exerts a favorable effect only in the beginning, improving processes of tissue respiration. But oxygen gas realizes its toxic effect later. Optimum concentration of oxygen in inspired air exists for every depth of immersion. For example, concentration of oxygen in gas mixture is about 2% in immersion at the depths of 100 m. MECHANISM OF TOXIC EFFECT OF OXYGEN UNDER INCREASED PRESSURE At first those reactions of the organism develop, which are directed to maintenance of optimum oxygen regime in the brain tissue and limitation of excessive increase of oxygen concentration in it. Decrease of excitability of blood channel chemoreceptors has great importance in formation of these protective reactions, breath and pulse are rare, circulating blood volume is decreasing, and brain vessels are narrow. Suffocation can develop later. The cause of it is that hemoglobin molecule is blocked by oxygen and losses ability to take out carbon dioxide. It can be explained as follows: tissues use oxygen physically dissolved in plasma, it encourages dissociation of oxyhemoglobin. Content of dissoluble in blood oxygen is increased at increased pressure. The quantity of dissolved oxygen corresponds to normal con- sumption of oxygen by tissues. The result is that oxyhemoglobin 12practically doesn't dissociate and carbon dioxide isn't taken out. Toxic effect of high concentration of oxygen is similar to that one of radiation. In both cases formation of free radicals and peroxides with strong oxidative abilities causes affection of DNA and tissue enzymes. Sensitivity of the organism to toxic action of oxygen is defined by level of tissues antioxidants (tocopherols, glutathione, and others), which suppress free-radical oxidation. They can be used for treatment and prophylaxis at oxygen action on the organism under high pressure. Desaturation (excretion of excessive quantity of dissolved gases via blood and lungs) develops at return of men into conditions of normal atmospheric pressure (decompression). Decompression must be done slowly, so that speed of gas formation doesn't exceed excretory opportunity of lungs. In an opposite case bubbles of air cause occlusion of blood vessels press on cells and irritate receptors (gas embolism). Clinical picture of this disease is defined by location of gas bubbles. The most often signs are pain joints, skin itch. In serious causes — disorder of vision, paralysis, loss of consciousness and other signs of brain affection and spinal marrow. This syndrome is called decompression (caisson) disease. PATHOGENIC INFLUENCE OF ELECTRIC CURRENT Person is exposed to effect of natural (lightning) or technical elec- tricity. Lightning influences like transitory (part of a second, seconds) penetration through the human body of current with high tension (to millions of volt). Death results from cardiac arrest and (or) respiratory standstill (Ju. R. Petrov). In consequence of light- ning thermoeffect, burns, haemorrhages like special branch figures, blackening and necrosis of tissues remain on the body; there may be mechanical influence — tearing off of the tissues and even part of the body. Pathogenic effect of technical electricity (electrotrauma) depends on kind of current (constant, variable), strength, tension, direction and duration of penetration through the body and also of tissue resistance and condition of the body reactivity. Current strength, At the same strength alternating current is more dangerous than direct current. Current with strength of 100 mA is mortally dangerous. Alternating current of 50-60 Hz with strength of 12-25 mA causes cramps ("unleaving"). Its basic danger is "chaining" 13of the person to the electric object. Tissue resistance. Full resistance of the human body to alternating current is called impedance. The most resistant to electric current is external epidermal layer of the tissue (to 2,000,000 Om), after that tendons, bones, nerves, muscles, blood come, The least resistant is the cerebrospinal fluid. General resistance of the human body is on the average 100,000 Om (from 1,000 to a million Om). The dry skin is more resistant than the wet skin. Direction of electric current through the human body. Ascending direct current (anode is lower -— cathode is higher) is more dangerous than descending, one (opposite localization of electrodes) in the same direction. With ascending current in the sinus node of the heart is under exciting influence of cathode, and the apex-under- suppressing influence of anode. Frequency of alternating current. \t is considered, that alternating current with frequency of 40-60 Hz has steady effect (arise of ventricle fibrillation). Alternating current frequency of 1,000,000 Hz and more isn't pathogenic, but in high tension Tesl's, d'Arsonval’s, diametric currents exert the thermal effect and are used for treatment. Condition of the organism reactivity. Tiredness, weakening of light or moderate alcohol intoxication, hypoxia, overheating, thyrotoxicosis, cardiovascular insufficiency decrease the reaction of electrotrauma. Severity of defect decreases significantly in emotional exertion, which is a result of waiting for current influence, necrosis or a condition of deep intoxication. Mechanisms of the injurious effect of electrical current, Elec- trotrauma may cause local (current marks, burns) and general changes in the organism. Local reaction of the organism to electrotrauma. Current marks, burns arise in outlet and inlet points current in consequence of trans- formation of electrical energy into thermal (Joul-Lens' warmth). Current marks arise on the skin, if the temperature in the place of penetration isn't more than 120 °C; they are small formations of white-gray color ("parchment” skin), of hard consistency, bordered by dilating eminence. When the temperature in the penetrative place of current is more than 120 °C, bums arise: contact due to heat — production with current penetration through the tissues and thermal — in consequence of flame effect of volt arch. The latter are more dangerous. General reactions of the organism to electrical current. Penetrating 14through the body current causes an excitement of the nervous receptors and conductors, smooth and skeletal muscles, glandular tissues. It results in tonic cramps of the muscles that may be accompanied by abruptive fractures, extremity dislocation, spasm of the vocal cords. Arrest of breathing, increase of blood pressure, involuntary urination and defecation. Excitement of the nervous system and organs of the internal secretion leads to "ejection" of catecholamines (adrenaline, noradrenaline), changes many somatic and visceral functions of the organism. a The main significance in the mechanism of current injurious effect has" its electrochemical effect (electrolysis). Having got over skin resistance, electric current causes disbalance in different cells, changes their biological potential and results in polarization of the cell membranes; at some areas of tissues positively charged ions (acid reaction) are concentrated at the cathode, negatively charged ions (alkaline reaction) are concentrated at the anode. In consequence functional condition of the cells is changed significantly. Coagulation of protein is a result of motion of albuminous molecules under the anode (coagulation necrosis) in alkaline areas under the cathode — swelling of colloids (colliquative necrosis). The processes of electrolysis in the cardiac synticium may cause the shortening of refractor phase of the cardiac cycle, which causes development of circular increase of its thythm. Injury of the respiratory and vasomotor centers in electrotrauma is brought about by injury of the nervous cells due to depolarization of their membranes and protoplasm coagulation. In non-normal electrotrauma cramping muscle contraction occurs with temporary loss of consciousness, cardiac activity disorder and (or) respiratory disorder, clinical death (imaginary) may come. In timely rendering of medical care the patient feels vertigo, headache, photophobia, nausea; disorders of skeleton muscles may persist. Immediate cause of death in electrotrauma are respiratory standstill and cardiac arrest. Respiratory standstill may depend on: — injury of the respiratory center; — spasm of the vertebral arteries, which bring blood to the res- piratory center; — spasm of the respiratory musculature; — disorder of potency of airways due to laryngospasm. 15Cardiac arrest may arise due to: — ventricle fibrillation; spasm of the coronary vessels; injury of the vasomotor center; increase of the nervous vagus tension. THE EFFECT OF IONIZING RADIATION — Etiology The general property of ionizing radiation is the ability to penetrate into the radiated environment and produce ionization. The rays of high energy (X- and y-rays) and a- and P-particles (radionuclides) possess this ability. There are the external radiation when the source of it is outside the organism and the internal one when radioactive substances get into the organism. The latter is called incorporated radiation. This kind of radiation is considered to be more dangerous. Corabined radiation is possible. The character and degree of radiation injury depend on radiation dose. However there is direct dependence on the dose only for high and median doses. The effect of low doses of radiation is subject to other laws and it will be clarified while studying pathogenesis of radiation injuries (Table 1). Pathogenesis Physical, Chemical and Biochemical Disturbances Energy of ionizing radiation exceeds energy of the intramolecular and intraatom bonds. Absorbed by macromolecule, it may migrate in the cell realizing in the most vulnerable places. It results in ionization, excitation, and break of less stable bonds, tearing off of radicals, which are called free. It is a direct effect of radiation. The primary target may be a highly molecular compound (proteins, lipids, nuclear acids, and molecules of complex proteins —_ nucleoprotein complexes, lipoproteins). In the molecule of DNA is a target genetic code may be disturbed. Ionization of water molecules is the most significant of all primary radiochemical transformations. Ionization of water molecule results in formation of free radicals (OH-, H ), which begin to interact with excited water molecule, tissue oxygen and produce additional hydrogen peroxide, radical of hydroperoxide, atomic oxygen (H202, H,, 0). More active reduction agents catch energy of free radicals. The products of water radiolysis have a very big biochemical activity and are capable of causing oxidation reaction by any bonds including stable ones in 16usual oxidation — reduction transformation. The effect of ionizing radiation conditioned by products of water radiolysis is called indirect effect of radiation. Tabie |. Biologic significance of a single whole-body exposure to various doses of ionizing radiation on a man Dose (roentgens) Biologic response 10 ‘0 detectable somatic effects. Detectable morpho- logic and functional alterations in specific populations of lymphocytes; probable hromosonial abnormalities. radiation sickness in some persons with nausea d vomiting, decrease in mitotix index of bone ow and transient leukopenia. . 1,000 xtensive damage to bone marrow with leukopenia, | ombocytopenia and anemia; necrosis of | ‘intestinal mucosa; severe radiation sickness; Bl 100 jeath within 30 days. | 10,000 Intermediate disorientation or coma; death within hours. 8 100,000 fAcute death of most types of mammalian cells. Free radicals and peroxides are capable of changing chemical structure of DNA. Radiation of chemical oxidation of pyrimidine and desamination of purine bases are observed in radiation of solutions of nuclear acids. Unsaturated fatty acids and phenols are oxidized resulting in formation of lipids (LRT) (lipid peroxides, epoxids, aldehydes, ketones) and quinone radiotoxins (QRT). Radiotoxins inhibit synthesis of nucleic acids, influence upon the molecule of DNA as chemical mutagens, change the enzyme activity, and react with lipid- protein and intracellular membranes. Thus, primary radiochemical reactions consist of direct and indirect (through the products of water radiolysis and radiotoxins) injury of the most important biochemical cell components — nucleic acids, proteins, and enzymes, Later on, fermentative reactions are violently changed — fermentative lysis of proteins and nucleic acids is increased, synthesis of DNA is decreased, biosynthesis of proteins and enzymes is disturbed. 17Disturbance of Biological Processes in the Cells The above-described physical, chemical and biochemical changes lead to disturbance of all manifestations of the cell vital activity. We can see signs of radiation injuries of the nucleus in the electronic and light microscope. There are observed chromosome aberration (breakdowns, reconstruction, fragmentation), Chromosome mutations and more subtle disturbances of the genetic apparatus (gene mutations) lead to disturbance of hereditary properties of the cell, inhibition of synthesis of DNA and specific proteins. Cell division is inhibited or has an abnormal course. The cell may be destructed at the moment of division as well as the interphase. All cell organoids are injured. lonizing radiation injures the in- tracellular membranes — membranes of the nucleus, mitochondria, lysosomas, and endoplasmatic reticulum. The injured lisosomas release ribonuclease, desoxiribonuclease and catepsins having an injurious effect on nucleic acids, cytoplasmatic and nuclear proteins. Oxidative phosphorillation is disturbed in mitochondrion membranes. Disturbance of cell energy metabolism is one of the most probable cause of cessation of synthesis of nucleic acids, nucleic proteins and mitosis inhibition. So, radiation injury of the nucleus is connected not only with direct effect of ionizing radiation of the DNA molecules and chromosome structure, but also with processes in other organelles. Summing up the above given findings of pathogenesis of the cell's iadiation injury, it may be concluded that the most typical manifestation, namely the nuclear damage, inhibition of division or destruction of the cells is a result of impairment of the genetic apparatus, disturbance of the cell energy metabolism in injury of mitochondria and release of lytic ferments from the injured lysosomas. The cell's nucleus has especially high radiosensitivity in comparison with cytoplasm, disturbance of the nuclear structures influences more significantly on the viability and vital activity of the cell. Therefore it is easy to understand the phenomenon revealed during the comparison of radiosensitivity of the tissues: the highest radiosensitivity have those tissues where processes of cell division is more intensively marked, and in radiation even by low doses there is their mitotic destruction. First of all they are the thymus, sexual glands, hemopoietic lymphoid tissue where renewal of the cells is constant. Then comes the epithelial tissue, especially glandular epitheliura in the digestive and sex glands, 18pegment epithelium of the skin and the endothelium of the vessels. Cartilaginous, osseal, muscular and nervous tissues are radioresistant. The nervous cells are not able to divide and that's why they are de- stnucted only in high over-dose radiation (interphase destruction). Mature lymphocytes are the exception; they are destructed even in radiation by 0.01 Gy. Dysfunctions of the Organism and Common Symptoms In lethal and superlethal radiation doses interphase destruction of the cells prevails and death comes within first minutes (hours) after radiation. In median radiation doses the life is possible but in all functional systems without exception there are pathologic changes, which are marked depending on comparative radiosensitivity of the tissues. The most characteristic are disturbances of hemopoiesis and blood system. There is decreased amount of all formed blood elemeats as well as their functional deficiency. During first hours after radiation there is lymphopenia, later — deficit of granulocytes, thrombocytes and at least — erythrocytes. Loss of the bone marrow is possible. Immune reactivity decreases. Phagocytosis is reduced, formation of antibodies is inhibited or corapletely suppressed. Therefore, infection is the earliest and severe complication of radiation. Tonsillitis is of necrotic character. Frequently the cause of the patient's death is pneumonia. Infection develops violently in the intestines. Pathology of cle- mentary canal is one of the causes of death. The barrier function of the mucus membrane of the intestines is disturbed that results in absorption of toxins and bacteria in blood. Dysfunction of the alimentary glands, intestinal autoinfection, severe condition of the oral cavity leads to exhaustion of the organism. The characteristic sign of the radiation disease is hemorrhagic syndrome, The most important for pathogenesis of this syndrome is reduction of thrombocytes containing biological factors of blood coagulation. The cause of thrombocytopenia is disturbance of thrombocyte maturation in the bone marrow rather than their de- struction. Disturbance of thrombocyte ability to adhesion is of great significance as biological factors of blood coagulation are released in aggregation of thrombocytes. Probably, disturbance of thrombocyte ability to aggregation is connected with changes of their membrane 19ultrastructure. Besides, thrombocytes play an important role in maintaining integrity of the vascular wall, its elasticity and mechanical resistance. There is reduction of ability of fibrin fibers to contractility and blood clot to retraction. The activity of fibrinolysis and anticoagulation system increases. Anticoagulants appear in blood, for example, heparin, which is released in degranulation of tissue basophiles (mast cells). Synthesis of proteins of eédgulation system of blood decreased in the liver. The changes of the vascular wall, mainly of small vessels are very important in pathogenesis of the hemorrhagic syndrome im radiation disease. The endothelium becomes pathologically changed end peels off; the ability of its cells to produce polysaccharide-protein complexes to construct basal membrane is disturbed. The perivascular connective tissue, which is the mechanical base of the vessel, undergoes great destructive changes. The tension and resistance of the vessels are disturbed. The injured cells release biologically active substances (BAS) — proteolytic ferments from the injured lysosomas, kinines, hialuronidase, which aggravate damage of the vascular wall inereasing its permeability Destructure of the vascular wall leads to functional deficiency ef the vessels and disturbance of blood circulation in those vessels v/here there is metabolism between blood and cells. The hereditary properties of the cell are changed if the cell isn't destructed due to chromosome injuries. The somatic cell may have malignant regeneration, and chromosome aberration in the sex cells leads to development of hereditary diseases. Pathogenesis of Nervous System Disorders Severe structural changes and destruction of the nervous cells occur in higher doses of radiation. However, structural changes do not always correspond to the functional ones, so the nervous tissue is very sensitive to any influences, including radiation. In the few seconds after radiation the nervous receptors are stimulated by products of radiolysis and tissue disintegration. The impulses come into the nervous centers changed by direct radiation, disturbing their functional condition. The changes of the bioelectrical activity of the brain can be registered within first minutes after radiation. Thus, neuroreflex activity is disturbed before appearance of other typical symptoms of radiation disease. At first functional and then deeper dysfunctions of the organs and systems are connected with it. 20Tn the organs of the endocrine system the initial signs of increased activity are replaced by inhibition of the function of the endocrine glands. Similar to other pathologic processes, compensatory-adaptive reactions are observed in radiation injury. They develop at all levels of the organism organization. At the molecular level the pathologic changes are compensated by natural antioxidant systems. These are compensated by natural antioxidant systems. These are captors of free radicals, inactivators of peroxides (catalase), of sulfhydrilic group (glutathione). The ferments of reparation of the injured DNA, inhibitors and inactivators of BAS function in the cell. Correction of radiation injury includes a number of measures directed at prevention of infection, intoxication and hemorrhagic signs. The preparations of symptomatic therapy are variable and include correction of dysfunction of the endocrine glands, nervous and alimentary system. Restoration of hemopoiesis is of special importance. In its respect transplantation of the bone marrow is the most effective measure. Hypothermia, hypoxia increase radiostability of the animals in experiment. There is a special group of preparations of antiradiation chemical protection. These are substances blocking the development of chain of radiation chemical reactions by capture of active radicals, antioxidants creating tissue hypoxia (methemoglobin producers). Acute Radiation Disease All the described disturbances of hemopoiesis, function of the nervous and alimentary systems are marked in all forms of radiation injury. But the degree of changes, development rate and prognosis depend on the absorbed dose of total radiation. Medullar Form (dose 0.3-10 Gy) There are four clinical periods: (1) the period of initial reactions, (2) the latent period, (3) the period of marked clinical signs and (4) the outcome of the disease. The first period, duration of which is several hours to | -2 days is reactions of the nervous and hormonal mechanisms to radiation: excitation, instability of the vegetative functions, lability of the arterial pressure and pulse, dysfunctions of the inner organs ("X-ray hangover"). Disturbance of the alimentary canal motility is manifested in yomiting and diarrhea. The body temperature may increase due to central disturbance of thermoregulation. There is shot- term 21redistribution leukocytosis, which is accompanied by lymphocytopenia. In severe cases radiation shock is possible in this period. Pituitary- adrenal! system becomes activated. The second period is a period of alleged health. The signs of over- exertion of the nervous system, dyspeptic disorders disappear but still there are some signs of the disease: instability of arterial pressure, lability of the pulse, leukopenia (progressing of lymphocytopenia, development of granulocytopenia). The third period is characterized by marked manifestations of radiation disease. There are leukopenia, thrombocytopenia and anemia in blood. There are inevitable infectious complications, which are the main cause of the patient's sufferings. Development of autoinfections of the oral cavity is typical of this period. They are inflammation of the tongue and gums, necrotic tonsillitis. Intake of food becomes difficult. Radiation disease may be complicated by pneumonia, which is very severe on the background of decreased immunologic reactivity and may become the cause of the patient's death. The appearance of the patient is quite typical — the skin is covered with numerous hemorrhages. There is blood in urine, feces and sputum. At the height of the disease the patient may die. The signs of recovery are improvement of health, normalization of blood picture and young blood cells. However, residual signs may persist for a long time, they are asthenia, fatigue, general weakness, instability of hemopoiesis, sexual dysfunction, weakening of immunity, trophic disorders leading to premature aging and marasmus. The follow-up consequences are tumors. The intestinal form develops in the dose of 10-20 Gy. The toxemic form is obscrved in radiation of 20-80 Gy. In these forms of injury there are stopping of mitotic division of cells of the intestinal epithelium and their mass interphase destruction, loss of proteins, electrolytes and tissue dehydratation. The surface of the mucous membrane of the intestines becomes bare that promotes penetration of infection. Shock is possible due to the effect of toxic substances of microbe and tissue origin. : The clinical picture is characterized by vomiting, anorexia, flaccidity, blood in feces, increased body temperature and pain in the intestines. There develops paralytic obstruction of the intestines, Peritonitis due to disturbance in the barrier function of the intestinal wall. Lethality is 100%. 22The cerebral form is observed in radiation dose over 80 Gy. The fatal outcome may occur during radiation or in a few minutes (hours) after it. The most severe changes are observed in the nervous system due to direct injury of ionizing radiation of the nervous tissue. There are significant structural changes and even destruction in the nervous cells of the brain cortex and hypothalamus, severe damage of the vessels endothelium. Severe and irreversible disorders in the central nervous system lead to development of spasm-paralytic syndrome, disturbance of the vascular tension and thermoregulation. “The Pathogenic Effect of the Factors of Space Flight There are such factors, which influence on the human organism in space flight: 1. Acceleration and overloads at the active parts of flight (in taking- off the space ship at the time of descent). 2. Weightlessness. 3. Stressor action. The Acceleration, Overloads The acceleration is marked at the beginning of the flight in taking- off the space ship and at the end of flight in descent of the ship from the orbit and at the end of flying under lowering of ship from orbit (entering the compact strata from the atmosphere and landing). The acceleration is a vector quantity size, which is characterized by the quickness of exchange of movement speed. In movement with acceleration in the opposite direction the inertion strength acts. For its determination we usually use such a term as ‘overload". In the aviational and cosmic medicine the overloads are differ- entiated by some indices, including quantity and duration (long — more than 1 s, shock — less than I s), speed and character of increasing (even and pick). As to relation of the vector of overload to the longitudinal axis of the human body we have a positive (from head to legs) and longitudinal negative (from legs to head), transversal positive (back — chest), lateral positive (right — left) and lateral negative (left -— right). The significant overloads condition redistribution of blood mass in the vessel flow, the disturbances of lymphatic outflow, displacement of the organs and soft tissues and then the disturbance of blood circulation, respiration and condition of the central nervous system. The displacement of great mass of blood is accompanied with overfilling of the vessels of some region of the organism and blood deficiency of 23other organs. The recurrence of blood to the heart and of the amount the cardiac output change, the reflexes from baroreceptor zones are realized, that take part in the regulation of the heart work and vessel tonus. A healthy man endures the transversal positive overloads (back — chest) easier. Most of healthy men endure easily the even overloads at this direction for one minute with quantity to 6-8 units. In short pick overloads their endurance increases. In transversal overloads (above the level of individual endurance) the function of the external respiration is disturbed, the blood circulation changes in the vessels of the lungs and the contractions of the heart increase. In increasing of the quantity of the transversal overloads the mechanic compression of some parts of the lungs becomes possible. The longitudinal overloads are more difficult to endure. In positive longitudinal overloads (heart — legs) the recurrence of blood to the heart becomes more difficult; the blood supply of the cavities becomes decreased (and consequently the ejection cardiac), the blood supply of the cranial parts of the body and brain is reduced. The receptor apparatus of the sinocarotid zone reacts on decrease of the arterial pressure. Tachycardia appears, and sometimes we can see the disturbances of the cardiac rhythm. In increasing of the level of individual stability we can see marked arrhythmia of the heart, the disturbances of vision and respiration. The longitudinal negative overloads are more difficult to endure (pelvis — head). The vessels of the head are overfilled with blood. The increase of the arterial pressure in the reflexogenic zones of the carotid arteries cause reflex slowing down of the contractions of the heart. In increase of the levels of individual stability the headaches. vision disturbances, arrhythmia of the heart appear, the respiration is disturbed, prefaint condition arises and then the man loses consciousness. As to weightlessness, we can say that at present we have enough experience of the long space flights, which proved the possibility of the human adaptation to that condition. The adaptation to weightlessness is based on active reorganization of some systems on the new level of functioning. The significant changes can be noted in the system of blood circulation. As a result of going out of the hydrostatic component of the arterial pressure, we can see the redistribution of blood with increased blood supply of the vessels of the upper part of body. The stimulation of. the volumoreceptors and inhibition of excretion of vasopressin and aldosterone result in 24reorganization of hydroelectrolytic metabolism (the increased excretion of Na’ and H,O through the kidneys). The volume of circulative blood decrease, the overloads with H-ion leads to decrease of heart activity. This is an unloading reorganization. The decrease of energy expenditures promotes it (because there are no muscular effects to overcome the strengths of Earth gravity), In weightlessness we can sce intensified excretion of K*, Cl, Fe”. The negative asotic balance and loss of water explain the decrease of body mass, which we can see in cosmonauts. The changes in the locomotor apparatus deserve a great attention. Ca” and Ph are excreted; the structure of the bones changes, osteoporosis appears. The mass of the skeleton muscular tissue clecreases, the signs of atrophy appear. The changes in the muscles and bones result from hypokinesia, decrease of gravitation overload on the locomotor apparatus, decrease of mechanic compression of the bones. For prophylaxis we recommend the physical trainings, muscular electrostimulation, vibromassage. In the pathogenesis of the changes in the muscular and bone tissues the nervous trophicity takes place. The adequate afferentation is the necessary link of the trophic reflex and in weightlessness the locomotor apparatus is in the condition of the functional diafferentation. The appeared changes of the muscles are not only atrophy without action but also neurogenic dystrophy, and prophylactic measures are aimed at keeping and imitating the locomotor function and maintaining the afferent link of the trophic reflex. Evaluating the influence of weightlessness on the organism we must remember, that new level of functioning of blood circulation system and Jocomotor apparatus, and energy and hydro-electrolyte metabolism for conditions of weightlessness, may be more adequate but it is unfavorable for conditions of Earth life, and to these conditions a cosmonaut must return. After coming back to the Earth we can see the decrease of functional possibilities of the systems opposing to the gravity. Under the conditions of flight the pathogenesis factors act not isolately, but in the different combination and sequence. We must remember that the final effect may be different from the expected. In particular it was shown in that overloads the reactivity of the organism changes and so the course of other pathologic processes changes too (hypoxia, overheating, intoxication and cooling). It is known, that the organism having had the overloads reacts differently on the medicine 25for curative aim. In the long stay under the weightlessness the organism condition also sharply changes and makes the i eee for the action of other pathogenic factors of flight. COMPREHENSION CHECK Try to answer the following questions. 1. What is the pathologic action of decreased atmospheric pressure? 2. Characterize hyperbaria, hyperoxia, caisson disease as the effect of increased atmospheric pressure. 3. Describe pathogenic action of electric current, its manifestations and mechanisms. 4. Describe the effect of ionizing radiation, dysfunctions of the organism and common symptoms. 5. What is acute radiation disease? 6. Characterize the pathogenic effect of the factors of the space flight. 26UNIT 3 CELLINJURY Knowledge of the structural and functional reactions of cells and tissues to injurious agents, including genetic defects, is the key for the understanding of disease processes. Currently diseases are defined and interpreted in molecular terms and not just in general descriptions of altered structure. Altered cellular and tissue biology can be the result of adaptation, injury, neoplasia, aging, or death. Adaptation occurs in response to both normal, or physiologic, conditions and adverse, or pathologic, conditions. For example, the uterus adapts to pregnancy — a normal physiologic state — by enlarging. Enlargement occurs because of increase in the size and number of uterine cells. In an adverse condition, such as high blood pressure, myocardial cells are stimulated to enlarge by the increased work of pumping. Like most of the body's adaptive mechanisms, however, cellular adaptations to adverse conditions are usually only temporarily successful. Severe or long-term stressors overwhelm adaptive processes, and cellular injury or death ensues. Cellular injury can be caused by any factor that disrupts cellular structures or deprives the cell of oxygen and nutrients required for sur- vival. Injury may be reversible (sublethal!) or irreversible (lethal) and is classified broadly as chemical, hypoxic (lack of sufficient oxygen), free radical, or infectious. Cellular injuries from various causes have differ- ent clinical and pathophysiologic manifestations. Cellular death is confirmed by structural changes seen when cells are stained and examined under a microscope. No biochemical indicators of cellular death are universally applicable because we still do not know precisely what biochemical functions must be compromised before a cell dies, Cellular aging causes structural and functional changes that eventually lead to cellular death or a decreased capacity to recover from injury. Mechanisms explaining how and why cells age are riot known, and distinguishing between pathologic changes and physiologic changes which occur with aging is often difficult. Aging clearly causes alterations in cellular structure and function, yet senescence is both inevitable and normal. First of all it is necessary to recall prerequisite knowledze. The intact, normally functioning plasma membrane is selectively permeable to substances; it allows some substances to pass and excludes aeothers. Water and small, uncharged substances move through pores of the lipid bilayer by passive transport, which requires no expenditure of energy. This process is driven by the forces of osmosis, hydrostatic pressure, and diffusion. Larger molecules and molecular complexes are moved imo the cell by active transport, which requires the expenditure of energy, or ATP, by the cell. In active transport, materials move from low concentrations to high concentrations. The largest molecules and fluids are ingested by endocytosis and expulsed by exocytosis after cellular synthesis of smaller building blocks. When t tie plasma membrane is injured, it becomes permeable to virtually everything and substances move into and out of the cells in an unre- stricted manner. Notably, such substances may affect (a) the nucleus and its genetic information or (b) the cytoplasmic organelles and their varied functions; then, there is altered cellular physiology and pathology (Table 2), Homeostasis is the concept of a dynamic steady state, turnover of bodily substances that maintains physiologic parameters within narrow limits. Stressors cause reactions that alter this dynamic steady state or homeostasis. Deviations from normal values, or homeostasis, cause disease (Fig, 1). DESCRIPTION OF THE CELLULAR ADAPTATIONS OCCURRING IN ATROPHY, HYPERTROPHY, HYPERPLASIA, DYSPLASIA, AND METAPLASIA At first we identify conditions under which everybody can occur, When confronted with stresses that discupt normal structure and fimetion, the cell undergoes adaptive changes that permit survival and maintain function. An adapted cell is neither normal nor injured — it is somewhere between these two states. These changes may lead to atrophy, hypertrophy, hyperplasia, metaplasia, or dysplasia. These adaptive responses occur in response to a need and appropriate stimulus. Once the need is no longer present, the adaptive response ceases. Cellular atrophy decreases the cell substance and results in cell shrinkage. The size of all the structural components of the cell usually decreases as the cell atrophies. Causes of atrophy include difuse, denervation, lack of endocrine stimulation, decreased nutrition, or ischemia. Difuse atrophy is seen in muscles that are not used, Denervation atrophy occurs in the muscles of paralyzed limbs. Lack of endocrine ‘stimulation causes changes that may occur in reproductive structures during menopause. During prolonged periods of malnutrition, the body may undergo a generalized wasting of tissue mass. Ischemia 28teduces blood flow and delivery of oxygen and nutrients to tissues. Table 2. Cellular Accumulations Accumulation) Causes Injury 120 lular H,O shifts into {Cellular swelling, ell, reduced ATP and vacuolation, hydropic ‘TPase, sodium accumulates degeneration in cell ‘ ipids, balance in production, [Vacuolation, displaced {carbohydrates jutilization, or mobilization of \nucleus and organelles, | ‘arbohydrates llead to fibrosis and scarring | |Glycogen netic disorders, diabetes [Cytoplasmic acuolation Hitus [Proteins mzymes digest cellular [Disrupted function and) elles, renal disorders, _ [intracellular lasma cell tumor jcommunication, displaced, cellular organelles tic defects, bruising and morthaging increases osiderin, liver lysfunction Pigments xogenous particle ingestion, light stimulates melanin juction, malignancy, loss f hormonal feed-back, Membrane injury leading to xeretion of H* *, endocrine disturbances \Hardening of cellular istructure, interferes with lfunction bscence of enzymes Calcium tered membrane rmeability, influx of xtracellular calcium, jore OH- which precipitates rate 29 (Crystal inflammationHomeoresis Hypertrophy Hyperplasia Cell death Forcible (from injury) [oe Aatophagocytosis ni Ca Ne jecrosis | (programmed) Apoptosis ] Fig 1. Types of the cell injury Hypertrophy increases the amount of functioning mass by increas- ing cell size. This allows the cell to achieve an equilibrium between demand and function. Hypertrophy usually is seen in cardiac and skele- tal muscle tissue. These tissues cannot adapt to increased workload by mitotic to form more cells. The increase in cell components is related to limitations in blood flow. Hypertrophy may be either physiologic or pathologic. In myocardial hypertrophy, initial enlargement is caused by dilation of the cardiac chambers in response to valvular disease or hypertension. This adaptation is short-lived and is followed by increased synthesis of cardiac muscle proteins that allows cardiac muscle fibers to do more work. Ultimately, advanced hypertrophy becomes pathologic and can lead to heart failure. Hyperplasia is an increase in the number of cells of a tissue or organ. It occurs in tissues where cells are capable of mitotic division, Hyperplasia is a controlled response to an appopriate stimulus and ceases once the stimulus has been removed. Breast and uterine enlargement during pregnancy are examples of a physiologic hyperplasia that is hormonally regulated. A pathologic hyperplasia occurs when the endometrium enlarges because of excessive estrogen production. Then, the abnormally thickened uterine layer may bleed excessively and frequently. Compensatory hyperplasia enables certain 30organs, like the liver, to regenerate after loss of substance. Dysplasia is deranged cell growth that results in cells that vary in size, shape, and appearance of mature cells and is related to hyperplasia. Minor degrees of dysplasia occur in association with chronic irritation or inflammation in the uterine cervix, oral cavity, gallbladder, and respiratory passages, Dysplasia is potentially reversible once the irritating cause has been removed. Dysplastic changes may progress to neoplastic disease. This makes dysplasia a phenomenon of importance. Metaplasia is a reversible conversion from one adult cell type to another adult cell type. It allows for replacement with cells tha: are better able to tolerate environmental stresses. In metaplasia, one type of the cell may be converted to another type of the cell within its tissue class (ie., an epithelial cell cannot change to a connective tissue cell). An example of metaplasia is the substitution of stratified squamous epithelial cells for ciliated columnar epithelial cells in the airways a habitual cigarette smoker. THE MAIN CAUSES AND MECHANISMS OF CELLULAR INJURY pices acti. There are different causes of the cell injury: hypoxia, chemicals, infectious agents, immunological and inflammatory responses, genetic factors, nutritional imbalances, ionizing radiation, and physical trauma. Hypoxia Hypoxia deprives the cell of oxygen and interrupts oxidative metabolism and the generation of ATP, as oxygen tension within the cell reverts to anaerobic metabolism. One of the earliest effects of reduced ATP is acute cellular swelling caused by failure of the sodium- potassium membrane pump, intracellular potassium levels decrease and sodium and water accumulate within the cell. As fluid and ions move into the cell, there is dilation of the endoplasmic reticulum, increased membrane permeability, and decreased mitochondrial function as extracellular calcium accumulates in the mitochondria. If the oxygen supply is not restored, there is continued loss of essential enzymes, proteins, and ribonucleic acid through the very permeable membrane of the cell. Hypoxia can result from inadequate oxygen in the air, tespiratory disease, decreased blood flow due to circulatory disease, anemia, or inability of the cell to use oxygen. An important mechanism of membrane damage is causzd by free radicals, especially by activated oxygen species. A free radical is an atom or group of atoms with an unpaired electron, The unpaired electron makes 31the atom or group unstable. To gain stability, the radical gives up an electron to another molecule or steals an electron. These radicals can bond with protein, lipids, and carbohydrates, which are key molecules in membranes and nucleic acids. These reactive species cause injury by (1) lipid peroxidation, which destroys unsaturated fatty acids, (2) fragmentation of polypeptide chains within proteins, and (3) alteration of DNA by breakage of single strands. Free radicals ‘are difficult to control, and they are initiated within cells by the absorption of ultraviolet light or X- rays, oxidative reactions that occur during normal metabolism, and enzymatic metabolism of exogenous chemicals or drugs. Toxic Chemical Agents Toxic chemical agents can injury the cell membrane and cell structures, block enzymatic pathways, coagulate cell proteins, and disrupt the osmotic and ionic balance of any cell. Chemicals may injure cells during the process of metabolism ot elimination. Carton tetrachloride, for example, causes little damage until it is metabolized by liver enzymes to a highly reactive free radical and then it is extremely toxic to liver cells. Carbon monoxide has a special affinity for the hemoglobin molecule and reduces its ability to carry oxygen. Alcohol (ethanol) is the favorite mood-altering drug in the United States and other countries. Liver and nutritional disorders are serious consequences of alcohol abuse. The hepatic changes, initiated by ethanol conversion to acetaldehyde, include deposition of fat, enlargement of the liver, interruption of transport of proteins and their secretion, increase in intracellular water, depression of fatty acid oxidation, increased merabrane rigidity, and acute cell necrosis. In the CNS, alcohol is a depressant initially affecting subcortical structures. Consequently, motor and intellectual activity become disoriented. At high blood alcohol levels, respiratory med- ullary centers become depressed. Lead acts on the central nervous system ‘by interference with neurotransmitters; this may cause hyperactive behavior. Manifestations of brain involvement include convulsions and delirium. Peripheral nerve involvernent may cause wrist, Finger, and foot paralysis. Lead inhibits enzymes involved in hemoglobin synthesis; anemia is seen in lead toxicity. Infectious Agents They produce injury by invading and destroying cells, producing toxins, or inducing hypersensitivity reactions. Immunologic and Inflammatory Injury It is an important cause of cellular injury. Cellular membranes are 32injured by direct contact with cellular and chemical components of the immune and inflammatory responses. Such mediators are lymphocytes and macrophages and chemicals such as histamine, antibodies, lymphokines, complement, and proteases. Complement, a serum protein, is responsible for many of the membrane alterations that occur during immunologic injury. Membrane alterations are associated with rapid leakage of potassium out of the cell and rapid influx of water, Antibodies can interfere with membrane function by binding to and occupying receptor molecules on the plasma membrane. Genetic Disorders Genetic disorders may alter the cell nucleus and the plasma membrane structure, shape, receptors, or transport mechanisms. Nutritional Imbalances They are important because cells require adequate amounts of proteins, carbohydrates, lipids, vitamins, and mineral substances nor- mally. If inadequate or excessive amounis of nutrients are consumed and transported, pathophysiologic cellular effects can develop. Proteins are the major structural units of the cell and participate in many enzymatic and hormonal functions. With lowered plasma proteins, particularly albumin, fluids move into the interstitium and produce edema. Children suffering from protein malnutrition are very susceptible to and often die fromm infectious diseases, Glucose is the major carbohydrate obtained from the breakdown of starch. Hyperglycemia, excessive glucose in the blood, if caused by excessive carbohydrate intake may lead to obesity. Deficiencies of glucose result from starvation or from inadequate use, as in diabetes. In both of these conditions, the body is compensated by metabolizing lipids to obtain cellular energy. In lipid deficiency, the body is compensated by mobilizing fatty acids from adipose tissue. This causes an increase in the production and circulation of acidic ketone bodies. Severe increases in ketone bodies can cause coma or death. Hyperlipidemia, or an increase of lipoproteins in the blood, results in deposits of fat in the heart, liver, and muscle. Vitamins are involved in many reactions including metabolism of visual pigments (vitamin A), calcium and phosphate metabolism (vitamin D), prothrombin synthesis (vitamin K), and antioxidation reactions (vitamin E), Vitamin B affects amino acid transfer reactions; FAD, FMN, and NAD help transfer electrons. Deficiencies in vitamin C cause poor wound healing and scurvy. Vitamin D deficiency causes 33rickets and problems with healing of fractures. Folate deficiency is associated with plasma and membrane changes of the red blood cell and is particularly a problem in individuals with severe liver dysfunction. Vitamin deficiencies are associated with several other disease states including cancer. Injurious Physical Agents They include temperature extremes, changes im atmospheric pressure, radiation, illumination, mechanical factors, noise, and pro- longed vibration. Physical injury is often environmental. The temperature extremes of chilling or freezing of cells cause hypothermic injury directly by creating high intracellular sodium concentration. This results from the formation and dissolution of ice crystals. Indirect forms of injury like vasoconstriction paralyze vasomotor control and vasodilation follows with increased membrane permeability. This causes cellular and tissue swelling. Hyperthermic injury, from excessive heat, varies depending on the nature, intensity, and duration of the heat. Burns cause extensive loss of fluids and plasma proteins. Also, intense heat damages temperature-sensitive enzymes and the vascular endothelium and causes coagulation of the blood vessels. Sudden increases or decreases of atmospheric pressure cause blast injury. In air blast or explosive injuries, tissue injury is due to com- pressed waves of air against the body. The pressure changes may collapse the thorax, rupture solid internal organs, or cause widespread hemorrhage. In increased pressure caused by immersion blast, water pressure is applied suddenly to the body, and the body is forced up out the water. The positive pressure compresses the abdomen and ruptures hollow internal organs such as the spleen, kidneys, and liver. With sudden decreases in pressure, carbon dioxide and nitrogen normally dissolved in the blood leave solution and form tiny bubbles, gas emboli, which obstruct blood vessels. This is seen in rapidly ascending deep sea divers and underwater workers. At low atmospheric pressure, such as occurs at altitudes above 15,000 feet, there is a decrease in available oxygen; this causes hypoxic injury. The compensatory vasoconstriction shunts the blood from the peripheral circulation to the visceral organs including the lungs. The combination of increases in pulmonary blood flow and systemic hypoxic cause pulmonary edema, interstitial water excess. Jonizing radiation It is any form of radiation capable of removing orbital electrons from atoms. Ionizing radiation is emitted by X-rays, gamma rays, and the 34process of radioactive decay. Radiant energy from sunlight can also injury cells. DNA is the most vulnerable target of radiation, particularly the bonds within the DNA molecule. Inadiation during mitosis produces chromosome abberation, and other cell injury and enzymes are also damaged by radiation. Radio- sensitivity depends on the rate of mitosis and cellular maturity. The more numerous the mitotic figures, the greater the sensitivity; more maturity, less sensitivity. Particularly vulnerable cells of the bone marrow, intestinal, and ovarian follicles are susceptible to injury because they are always undergoing mitosis. “IDENTIFICATION OF THE MAJOR TYPES OF CELLULAR NECROSIS Neerosis is local cell death and involves the process of ce'lular self- digestion known as autodigestion or autolysis. As necrosis progresses, most organelles are disrupted, and karyolysis, nuclear dissolution from the action of hydrolytic enzymes, becomes evident. There are four major types of necrosis: coagulative, liquefactive, caseous, and fat. Gangrenous necrosis is not a distinctive type of cell death but refers to large areas of tissue death. Coagulative necrosis occurs primarily in the kidneys, heart, and adrenal glands and usually results from hypoxia caused by severe ischemia. Protein denaturation causes ccagulation. An increased intracellular level of calcium may be a critical event in coagulation necrosis. Liquefactive necrosis is common following ischemic injury to r eurons and glial cells in the brain. Because brain cells are rich in digestive hydrolytic enzymes and lipids, the brain cells are digested by their own hydrolases. The brain tissue becomes soft, liquefies, and is walled off from healthy tissue to form cysts. Liquefactive necrosis can also result from bacterial infections. Here, the hydrolases are released from the lysosomes of phagocytic neutrophils that are attracted to the infected area to kill the bacteria; these hydrolases also destroy brain tissue. The accumulation of pus is; present in liquefaction necrosis. Caseous necrosis is commonly seen in tuberculosis pulmonary infection and is a combination of coagulative and liquefactive necrosis. The necrotic debris is not digested completely by hydrolases, so tissues appear soft, granular, and resemble clumped cheese. A granulomatous inflammatory wall may enclose the central areas of caseous necrosis. Fat necrosis found in the breast, pancreas, and other abdominal structures is a specific cellular dissolution caused by lipases. Lipases break down triglycerides and release free fatty acids that then combine 35with calcium, magnesium, and sodium ions to create soaps, or saponification. The necrotic tissue appears opaque and chalk white. Gangrenous necrosis refers to death of tissue, usually in con- siderable mass and putrefaction. It results from severe hypoxic injury subsequent to arteriosclerosis or blockage of major arteries followed by bacterial invasion. Dry gangrene is usually due to a coagulative necrosis, and wet gangrene develops when neutrophils invade the site and cause liquefactive necrosis. Gas gangrene, a special type of gangrene, is due to bacterial infection of injury tissue by a species of Clostridium. These anaerobic bacteria produce hydrolytic enzymes and toxins that destroy connective tissue and the cellular membrane; bubbles of gas likely form in the muscle cells, DESCRIPTION OF THE MECHANISMS OF APOPTOSIS Apoptosis is an important, distinct type of cell death that differs from necrosis. it is an active process of cellular self-destruction in both normal and pathologic tissue changes. Apoptosis likely plays a role in deletion of cells during embryonic development and in endocrine-dependent tissues that are undergoing atrophic change. It may cecur spontaneously in malignant tumors and in normal, rapidly proliferating cells treated with cancer chemoiher-apeutic agents and ionizing radiation. Unlike necrosis, apoptosis affects scattered, single cells and results in shrinkage of a cell; whereas in necrosis, cells swell and lyse (Fig. 2). THE MAIN THEORIES OF AGING There are two general theories of aging: (1) aging is caused by the accumulations of injurious events, sometimes termed damage- accumulation theories, or (2) aging is the result of a genetically controlled developmental program. In support of these two categories, the mechanisms of aging have emerged: the cells of the endocrine, immune, and central nervous systems, are responsible for aging; and (3) degenerative extracellular and vascular alterations cause aging. Regardless of injurious environmental factors, some believe that each cell may have a finite life span during which it can replicate. Fibroblasts have been demonstrated to be limited to 40 to 60 cell doublings. Alternatively, an intrinsic program within the human genome progressively slows or shuts down mitosis. Alterations of cellular control mechanisms include increased hor- monal degradations, decreased hormonal synthesis and secretion, and decreased receptors for hormones and neuromodulators. This suggests 36that a genetic program for aging is encoded in the brain and relayed through hormonal and neural agents because of shared common receptors within these systems. Weak action lof necrosogenic ‘agents Moderated long-living RNA of cytoplasm blockator mn of cytoplasmatic Accumulation of Catt in cytoplasm Binding of apoptosis proteins with RNA. Fragmentation of nucleus and cytoplasm’ ‘Apoptotic bodies ‘Autophagocytosis Fig 2 Mechanisms of apoptosis Immune function declines with age and the number of autoanti- bodies that attack body tissues increases with age. These observations implicate the immune system in aging. A degenerative extracellular change that affects the aging process is collagen cross-linking, which makes collagen more rigid and results in decreased cell permeability to nutrients. Free radicals of oxygen are believed to damage tissues during aging. These reactive species not only permanently damage cells but also may lead to cell death. Damage accumulates over time and reduces the body's ability to maintain a steady state. COMPREHENSION CHECK Try to answer the following questions. 1. Describe the cell responses on various injurious factors (hypoxia, chemicals, infectious agents, physical trauma). 2. Explain what atrophy, hypertrophy, hyperplasia, dysplasia and metaplasia mean. 3. Identify the major types of cellular necrosis. 4. Describe the mechanisms of apoptosis. 37UNIT 4 REACTIVITY AND ITS ROLE IN PATHOLOGY REACTIVITY. The characteristic of the organism to react in a certain way on the influence of the environment. It is as important as growing up, feeding, metabolism. * Reactivity is formed in the process of evolution in phylogenesis and ontogenesis, reflects specific, group and individual peculiarities of reaction. Reactivity is one of the forms of relations and interactions of the organism as a united system with the environment, which is basically of the defensive, adaptive and adjustive nature. The notion of reactivity got into practical medicine and gives more clear view of the patient's condition. Any pathological process in one or another degree changes the reactivity of the organism and the changing of reactivity exhausts compensatory mechanisms of the organism and predisposes to the disease development. That's why, the study of reactivity and its mechanism is of great value for understanding of pathogenesis of the diseases and their purposeful treatment. Types of Reactivity Biological or specific reactivity is defined as hereditary and ex- presses the ability of all representatives of the given species to react in the same way, which is the de‘ensive-adaptive nature due to different changes of the environment. This reactivity is also called primary. It defines specific immunity to infectious diseases, for example: hibernation of animals, seasonal migration offish and birds. Gophers infected in winter hibernation by pests and tuberculosis do not get sick, sleep raises stability to strychnine and other poisons. On the base of the specific reactivity group and individual reactivity is formed. Group reactivity is possessed by people who have some hereditary constitutional peculiarities: such as constitutional type, blood group, antigens of leukocytes and others. It is known that the people from the firs: blood group are more often fall ill with peptic ulcer of the stomach, but people who have antigen HLA-B; have high risk to get diabetes mellitus. Individual reactivity is stipulated by heredity and obtained by factors, depending on the conditions of the external environment, in which the organism develops, for example, climate, contents of oxygen in the atmosphere, nature of feeding and others. Reactivity depends on the sex. In the female organism reactivity changes in connection with menstrual cycle, pregnancy. The women are 38more stable to hypoxia, blood loss, starvation. Age peculiarities play a significant role in reactivity. In babies the form of reaction is simple, as a rule, with low reactivity. This is connected with the incomplete development of the nervous, endocrine and immune system, imperfection of the external and internal barriers. Higher and more complex reactivity is observed in maturity and it is gradually decreasing due to old age. In old age the barrier function is reduced in the organism and the immune reaction is also reduced. Therefore purulent infection of skin and mucous, inflammatory processes in the lungs occur rnore often. Individual reactivity can be specific and non-specific. Specific reactivity reflects immune reactivity, which consists of the abilities to form antibodies +o irritating antigen. It ensures immunity, reaction of biological tissue incompatibility, Non-specific reactivity reveals itself by the reaction of different external factors on the organism, and it's realized with the help of different mechanisms like parabiosis, stress, changes of functional candition of the nervous system, the biological barriers, phagocytes and others. Specific and non-specific reactivity can be physiologic and pathologic. Physiological reactivity covers the reactions of the healthy or- ganism in normal circumstance of existence, for example, immunity (specific reactivity), and also reactions of the organism on the action of the different factors of the external environment, which do not change homeostasis (non-specific reactivity). Pathologic reactivity reveals itself in the action of the pathogenic factors on the organism. Examples of specific pathologic reactivity are: allergy, immune deficit condition. Example of non-specific pathologic teactivity can be change of reactivity under traumatic shock, narcosis (phagocytosis, sensitivity to medicines). By the forms of manifestations we distinguish: increased (hyperergia), lowered (hypoergia) and perverted (dysergia) reactivity. In the development of pathologic process (allergy, inflammation) it's possible to observe the change of reactivity on different levels: molecular, cellular, systems of the organs and the organism on the whole. RESISTANCE. TYPES. INTERACTION WITH REACTIVITY Resistance Resistance is the stability of the organism due to the action of the 39pathogenic factors, During the evolution the organism has gained mechanisms: of adaptation which ensure its existence in conditions of non-stop-actions connected with the environment, but many factors can cause impairment of vital activity and even death in the absence of these mechanisms. The resistance of the organism is connected with reactivity. Ability of the organism to withstand harmful influences determines its reactions as a whole so that's why resistance is one of the main effects and manifestations of the activity. Resistance can be active and passive. e resistance is connected with the anatomic-physiological peculiarities of the organism: aging of the skin, mucous layers. bone tissue, thick coverings. Active resistance is stipulated by switching on defensive-adaptation mechanism. So, stability to hypoxia is connected with the activation of the ventilation of the lungs, acceleration of the blood circulation, increase of the quantity of erythrocytes and hemoglobin in the blood, stability to infectious influence-immunity — is connected with the formation of antibodies and the activation of phagocytosis. Resistance can be primary which is connected with hereditary factors and secondary, which is acquired. Usually reactivity and resistance are changed in the same way. But other correlation can be possible, so in conditions of hibernation the reactivity of the animals falls but their resistance increases . Under two or more kinds of (extreme) stimuli the organism often responds to only one, staying "deaf to the action of the others. Such a form of reactions cannot be named resistance, because the organism reacts only when it's vital activity is deeply affected. Such form of reactivity is named tolerance. I: is usually observed in less developed organisms, when transmission to more ancient and resistant though economic way of release of energy — "glycolysis". Reactivity as contrasted with tolerance ensures active protection of the organisra from the pathogenic factors due to protective-adaptive mechanisms, which help the organism to maintain homeostasis. Reactivity by Bogomolets The study of A. Bogomolets shows a great role of connective tissue in specific and non-specific reactivity. He proposed the tem — physiological system of connective tissue (PhSCT), as an important system of the defense. This system includes: a) endothelium of vessels; b) lymphocytes and lymph nodes; c) cells of bone marrow; 404) reticular cells of the liver, spleen, kidneys, lungs; ) micro- and macrophages, as such cells of blood as neutrophils, monocytes, lymphocytes (moving phagocytes), histiocytes of con- nective tissue. There are protective-adaptive mechanisms, which help the organs to maintain homeostasis. Bogomolets created antireticular cytotoxic serum. Introduction of this serum in the organism stimulates all elements of reticuloendothelial system and then reactivity increases. According to Selye, adaptation insufficiency causes adaptation diseases. The Selye's theory (cne of the achievement of modern medicine) is the important role of the endocrine glands, in particular, the system of the pituitary-adrenal cortical substance. It is known that after introduction of large doses of desoxicorticosterone (DOCS) to the experimental animals it was observed elevation of blood pressure, development of hypertension, nephrosclerosis, hyalinosis of the organs, intensification of the inflammatory reactions, Introduction of glucocorticoids (anti-inflammatory hormones) to the animals inhibits inflammation but at the same time they depress immune reaction and cause impairment of the stomach and duodenum, create conditions for myocardial necrosis. Insufficiency of glucocorticoid secretion promotes hyperergic course of the pathogenic effects. Seley considers rheumatism, bronchial asthma, some diseases of the kidneys. heart and vessels, a number of skin diseases and others to he diseases of adaptation. Such condition factors as overcooling, overheating, physical overstrain, aggravated heredity, excess intake of salt are of great significance. Combined introduction of corticosteroids and sodium chloride creates the background for development of necrotic changes of the myocardium by different stimuli. W. Cannon and L. Orbelly created a study of adaptational- trophic tole of the sympathetic part of the vegetative nervous system in the protective compensatory reactions. Reactivity and Biological Barriers Biological barriers are special tissue structures, which protect the organism or its separate parts from pathogenic influence of the environment and preserve homeostasis. There are two types of the barriers: external and internal. External barriers include the skin, the mucous layer which protect the organism from pathogenic influence of the environment, the respiratory 41organs which hold back harmful materials pressure in atmosphere, the digestive organs (antibacterial action of gastric juice, deprivation of rutrients of antigenic properties), the liver has desintoxicating function, the spleen and the lymph nodes, as well as other organs also have the same function, including mononuclear cells of phagocytes. Interna] barriers are the necessary energetic material, preventing the penetration of the foreign and poisonous material arriving from the blood to the organs and tissues. In 1929 L. S. Stern made a supposition that there was a defence mechanism between the blood and the liquid of the tissue, which she named histo-hematic barriers. Each organ has its own medium because the blood does not contact with the cells of the organs. The functional characteristics of the barriers depend on the morphological and physiological peculiarities, corresponding to the organs and tissues. The peculiarity of each barrier is its selective permeability. Special barriers are a particular group which defend certain organs which are in need of its own strictly constant media. They are hematoencephalic, hematoophthalmic, hematotesticular, hematoplacentar barriers. The structural elements of the barriers are capillaries, whose endothelium in different organs possesses their own distinctive pe- culiarities, and that is the principal morphological selective permeability. In different organs in respect of different materials the barrier function may not be alike. In the study of the penetration of serum proteins into the organs, several types of barriers were shown. Hematoencephalic barrier is mainly present in the vascular walls, the barrier of the thyroid gland has an organisation on the tissue level and with the help of the paranchymatous cells divides the organs into zones where protein does not penetrate. The sarcolemma acts as a barrier in the muscles. Hematoencephalic barrier has the most difficult organization. Besides endothelium and basal membrane, it has also argirophil material, the brain layers and glia with astrocytes, It is known that microorganisms, toxins, medicines, antigens, antibodies do not penetrate into the brain. As to metabolites, hormones, biologically active materials, these barrier acts selectively, with respect to them regulating the penetration of these materials into the cells of the brain. The main function of the barrier is the mechanism of dialysis, ultra- filtration, osmosis, as well as the metabolic function of the cells, which are included in the structure of the barrier. 42Biological barriers, executing protective and adjusting function, support an optimum composition of medium for the organ and promote a conservation homeostasis to maximum. Intensive transport through the barrier depends on the functional needs of the organ, hemodynamic, hormonal and nervous effect and also presence and absence of morphological and functional disturbances. The function of the barrier may change depending on the age, sex, nervous and hormonal effects and many influences of external and internal media. The functional state of the barrier may change when in sleep and staying awake, tiredness, trauma irradiation with infra-red, ultraviolet and X-rays, influence of ultrashort and high-frequency waves, ultrasound. Introduction of alcohol, acetylcholine, histamine, kinines, hialuronidase, agitating the central nervous system, increases the permeability of the barrier in the organism. Materials, with an opposite effect of lowering permeability include catecholamines, salts, calcium, vitamin PP, sleeping medicines. Permeability of barriers is changed under different pathologic processes, such as trauma, inflammation, alcoholic intoxication, virus infection and others. Increase of permeability makes the organ more sensitive to poisons, intoxications, intensifies tum6r growth. In impairment of permeability of the barriers there is possibility of autoimmune damage of the organs (for instance the thyroid gland, the brain). Particular value for developing fetus has the hematoplacental barrier, which defends the fetus in the period of pregnancy. Impairment of permeability of this barrier (virus infection, alcoholic intoxication) can be harmfully reflected in the embryonal development of the fetus, which results in the development of different types of postnatal pathology. COMPREHENSION CHECK Try to answer the following questions. 1, Define reactivity an its types. 2. What is specific and non-specific reactivity? 3. Explain the term "physiological system of connecting tissue" and name elements of this system by Bogomolets. What is the role of this system in maintenance of organism's homeostasis? 4, Characterize biological histohematic barriers as protecting and adjusting mechanism in reactivity. 43UNIT 5 THE ROLE OF HEREDITY AND CONSTITUTION IN PATHOLOGY We should remember, that the disease and its pathogenesis depend on etiologic ("extreme") factors and such properties of the organism as heredity, constitution, reactivity. et The most important questions are when and how hereditary diseases appear. Depending on the scope of the damage of hereditary apoaratus in reproductive cells (genetic or chromosomal mutations) molecular and genetic and chromosomal diseases are distinguished. ETIOLOGY The factors that cause mutation are called mutagens. They are physical, chemical and biological. Among the physical mutagens ionizing and ultraviolet radiation are on the first place. Radiation may change hereditary substance of the reproductive cells and cause mutation in such a minimal dose of radiation, that doesn't :ause death. But the posterity of a person, who underwent radiation, is at risk of developing this disease There are hereditary diseases, hereditary predisposition and con- genital diseases. Hereditary diseases are caused by mutation of the reproductive cells. Their manifestations doesn't depend on exogenic (etiological) factors. Hereditary predisposition is connected with genetic damage of regulatory apparatus. Their manifestations depend on etiological factors. Without injurous factors hereditary predisposition doesn't izurn into disease. For example, the development of diabetes mellitus depends on the interaction of genetic factors and the environment. Congenital (innate) diseases are caused by the mother's diseases during pregnancy (tuberculosis, alcoholism, syphilis, toxoplasmosis). They imitate hereditary diseases, such as deaf-mutism, microcephaly, cataract and others. Harmful mutation causes diseases and anomalies, which may be lethal and non-lethal for the carrier. The hereditary disease manifestation sometimes depends on age. Hemophilia, ichthyosis, hereditary deaf-mutism are manifested at birth, Hungtington's chorea is found at 30-35 years of age, gout — at the old age, There are following ways of inheritance: 44Inheritance of a dominant type means that hereditary traits or anomalies are transmitted directly from parents to children and are manifested at the first generat‘ on. Inheritance of a recessive type is manifested only in that case when the children get the pathological gene from both parents. The recessive type is connected with X-chromosome — it means that in women who have X-chromosome pathology it may be com- pensated by another normal one. So the disease is manifested only in males, while the females remain healthy (conductor), being, however, the carriers of this trait. The juvenile defects as microcephaly, deaf mutism, deafness and dumbness, blindhess, some psychiatric diseases, phenylketonuria, retinitis pigmentosa, enzymopathies and others belong to a recessive type. Hemophilia, albinism transmitted by a recessive type is linked with the sex chromosome. To anomalies inherited by a dominant type belong skeletal and other anomalies (sex digital, shot finger, Polydactyly, horse foot, brachydactyly, accreted fingers, muscular atrophy, otosclerosis, progressive Huntington's chorea, Marpaan's syndrome, achonéroplasia), They don't impair reproduction, don't shorten the life span and hence they undergo selection to a lesser extent. The most dangerous diseases of this group are polyposis of flie rectum that tends to malignance and neurofibromatosis. Chromosomal Diseases Klinefelter's Syndrome Klinefelter's syndrome is a genetic disorder in which there are three sex chromosomes, XXY. Total number of chromosomes 47, 48, 49. Affected individuals are apparently male, but they are: (1) (all and thin, (2) have small testes, with failure of normal sperm production, (3) azoospermia, (4) enlargement of the breasts — gynaecomastia, absence of facial and body hair, (5) less intelligence, (6) insufficient physical and genetical development. When X-chromosome more than two (three, four) —- XXXY, XXXXY — oligofrenia may be present; when Y-chromosome more than one (KYY, XXYYY)— increase of aggressiveness. Down's Syndrome Most individuals with Down's syndrome have 47 chromosomes (i.¢., one extra chromosome 21, or trisomy 21) and are born to parents with normal karyotypes. This type of aneuploidy is usually caused by non- 45disjunction during meiotic segregation, which means the failure of two homologous chromosomes to separate, or disjoin, from each other at anaphase. In contrast, aneuploid conditions that affect part of an autosome or sex chromosome must, at some point, involve DNA breakage and reunion. DNA rearrangements are an infrequent but important cause of Down's syndrome and are usually evident as a karyotype with 46 chromosomes in which one chromosome 21 is fused via its centromere to another acrocentric chromosome. This abnormal chromosome is described as the Robertsonian translocation and can sometimes be inherited from a carrier parent, Thus, Down's syndrome may be caused by a variety of different karyotypic abnormalities, which share in common a 50% increase in gene dosage for nearly all of the genes on chromosome 21. IV 1 2 s 4 Fig. 3. Scheme of the generation with X-associated mental retardation syndrome Clinical manifestations. Down's syndrome occurs approximately once in every 700 live births and accounts for approximately one third of all cases of mental retardation. The likelihood of conceiving a child with Down's syndrome is related exponentially to increasing of maternal age. However, screening programs detect most Down's syndrome pregnancies in pregnant women over 35 years of age. The condition is usually suspected in the perinatal period from the presence of characteristic facial and dysmorphic features such as brahycephaly, epicanthal folds, small ears, transverse palmar creases, and hypotomia. Approximately 50% of affected children have congenital heart defects that come in the immediate perinatal period because of cardiorespiratory problems, Strong suspicion of the condition on clinical grounds is usually confirmed by 46karyotyping within 3 4 days. ‘The natural history of Down's syndrome in childhood is characterized mainly by developmental delay, growth retardation, and immunodeficiency. Developmental delay is usually apparent by 3- 6 months of life as a failure to attain age-appropriate developmental milestones and affects all aspects of motor and cognitive function. The mean IQ is between 30 and 70 and declines with the age. However, there is a considerable range in the degree of mental retardation in adults with Down's syndrome, and many affected in- dividuals can live semi-independently. In‘general, cognitive skills are more limited than affective performance, and only minorities of affected individuals are severely impaired. Retardation of linear growth is moderate, and most adults with Down's syndrome have the heigt shorter than the most of the general population. In contrast, weight growth in Down's syndrome exhibits a mild proportionate increase compared with that of the general population, and most adults with Down's syndrome are overweight for height. Although increased susceptibility to infections is a common clinical feature at all ages, the nature of the underlying abnonmality is not well understood, and laboratory abnormalities can be detected in both humoral and cellular immunity. One of the most prevalent and drarnatic clinical features of Down's syndrome — premature onset of Alzheimer’s disease — is not evident until adulthood. Although fraok dementia is not clinically detectable in many adults with Down's syndrome, the incidence of typical neuropathologic changes — senile plaques and neurofibrillary tangles — is nearly 100% by the age of 35. The major causes of morbidity in Down's syndrome are congenital heart disease, infections, and leukemia. Prognosis depends to a large extent on the presence of congenital heart disease. Survival to the age of 10 and 30 years is approximately 60% and 50%) respectively for individuals with congenital heart disease, and approximately 85% and 80% respectively for individuals without congenital heart disease. Fragile-Associated Mental Retardation Fragile X-associated mental retardation syndrome produces a unique combination of phenotypic features that affect the central nervous system, testes, and cranial skeleton. In some respects, fragile X-associated mental retardation syndrome is similar to other genetic conditions caused by X-linked mutations — affected males are impaired more severely than affected females, and the condition is never transmitted from father to son. 47Penetrance of fragile X-associated mental retardation syndrome. This artificial pedigree of the syndrome shows the each individual will manifest phenotypic features of the condition (penetrance). Penetrance increases with each successive generation owing to the progressive expansion of a triplet repeat element. Expansion is dependent on maternal allele; thus, daughters of normal transmitting males (indicated with T in I-4) are non-penetran: (Fig. 3). a PATHOPHYSIOLOGY OF SELECTED GENETIC DISEASES Osteogenesis Imperfecta Osteogenesis imperfecta is a condition inherited in a mendelian fashion that illustrates many principles of human genetics. It is a heterogeneous and pleiotropic group of disorders characterized by a tendency toward fragility of the bone. More then 100 different mutant alleles have been described for osteogenesis imperfecta: the relationships between different DNA sequence alterations and the type of disease (genotype-phenotype correlations) illustrate _ several pathophysiologic principles in human genetics (Table 3). Phenylketonuria Phenylketonuria presents one of the most dramatic examples of how the interrelationship between genotype and phenotype can depend on environmental variations. Phenylkefonuria was firstly recognized as an inherited cause of mental retardation in 1934, and systematic attempts to treat the condition were initiated in 1950-s. Treatment outcomes have been hailed, perhaps prematurely, as the pinnacle of success in applying biochemistry and molecular biology to social problems that stem from inherited disease. The term "phenylketonuria" denotes elevated levels of urinary phenylpyruvate and phenylacatate, which occur when circulating phenylalanine levels, normally between 0.06 and 0.1 mmol/L, rise above 1.2 mmol/L. Thus, the primary defect in pheny|ketonuria is hyperphenylalaninemia, which itself has a number of distinct genetic causes. Clinical Manifestations The incidence of hyperphenylalaninemia varies among different populations. In American blacks it is about 1:50,000; in Yemenite Jews — about 1:5,000; and in most Northern European population, about 1:10,000. Postnatal growth retardation, moderate to severe mental retardation, recurrent seizures, hypopigmentation, and eczematous skin rashes constitute the major phenotypic features of untreated phenylketonuria. 48Table 3. Pathophysiological characteristics of the types’of osteogenesis imperfecta Genetics _[ Molecular pathophysiology | little or no leformity, blue cleras, premature aring loss i \Autosomal dominant Loss-of function mutation i pro al (1) chain resulting id \decreascd amount of mRN. quality of collagen is normal: juantity is reduced twofold ‘Type [Perinatal lethal: 2 |severe prenatal fractures, abnormal me formation, se- vere deformities, lue scleras, and onnective tissue fragility lominant) sporadic —s autosomal Structural mutation in pro a 1) or pro a2 (1) chain that lows heterotrimer assembly; quality of collagen ii abnormal; quantity ne reduced also. | ‘Type Progressive B leforming: prenat fractures, defor- mities usual: resent at birth, ver short stature, usuall jonambulatory, blug eras, hearing loss wutosomal lominant (7 ASeS tutosomal cessive) rei) or pro a.2 (1) chain that Structural mutation in pro al has mild or no effect on) iheterotrimer assembly; jquality of collagen is mildly, abnormal; quantity can bd pormal [Type |Deforming will scleras: 4 ormal stnatal fractures, ild to moderat leformities, remature hearin; lloss, normal or gra leras, dentinogene- ‘Autosomal dominant sis imperfecta Structural mutation in pro a2 (1) chain that has little or n effect on _heterotrimer, lassembly; quality of collagen| is mildly abnormal; quantity, can be normal Metabolic Fates of Phenylalanine Because catabolism of phenylalanine must proceed via tyrosine, the absence of phenylalanine hydroxylase leads to accumulation of phenylalanine. Tyrosine is also a biosynthetic precursor for melanin and 49certain neurotransmitters, and the absence of phenylalanine hydroxylase causes tyrosine to become an essential amino acid. ‘The different genetic forms of phenylketonuria illustrate two important pathophysiologic mechanisms by which inbom errors of metabolism can cause disease: end-product deficiency and substrate accumulation The mental retardation in phenylalanine hydroxylase is caused not by deficiency of tyrosine or its metabolites but instead by aecunmulat ion of the substrate for phenylalanine hydroxylase. In contrast, the progressive hypotonia and developmental regression seen in disorders of BH4 metabolism are caused by a decrease in the metabolic products of tryptophan hydroxylase and tyrosine hydroxylase. Finally, a thorough understanding of the pathophysiology of phe- nylketonuria is a prerequisite for the development of gene therapy. For example, since most phenylalanine hydroxylation occurs in the liver, attempts to deliver a normal phenylalanine hydroxylase gene to affected individuals have focused on strategies to express the gene in hepatocytes. However, since individuals with —_ benign hyperphenylalaninemia have phenylalanine hydroxylase activities that may be as low as 5% of normal, successful gene therapy of phenylketonuria might be accomplished by expressing phenylalanine hydroxylase in only a small proportion of hepatic cells. THE ROLE OF BODY CONSTITUTION IN PATHOLOGY __ The constitution, or the make up of the body is a unified complex of morphological, functional, psychological peculiarities of the body. These peculiarities are quite stable; they define the body reactivity, being formed on the hereditary basis under the influence of the environmental factors. Constitution determines the individual reactivity of the body, its adaptational peculiarities, the distinctive waits of physiological and pathological processes, and pathological predisposition to certain dis- eases. The course of any disease, its prognosis and treatment depend not only on the character and severity of the pathogenic activity, but also on the individual peculiarities of the human body. In constitution it is extreracly important to see the ratio of the inherited and acquired peculiarities. The environment is a source of condition of existence and manifestation of inherited peculiarities, which can be termed as potential possibility of a body. At the same time 50the environment may promote the formation of new peculiarities having, constitutional significance. It is well known for instance, that infection and/or intoxication, avitaminosis and radiation can considerably change the make up of the body, its reactivity and resistance. Such pathological influence is especially harmful at the stage of intrauterine development and in childhood. Beyond doubt, the sovial and hygienic factors, as every day conditions, work-site conditions, food habits, etc. have a special significance for a man. Hippocrates offered the first constitutional classification He at- tracted his attention at the differences existing in various people, which reflected peculiarities in temperament and social behavior. Precisely these observations were assurned by Hippocrates as the basis for his classification. They were choleric, sanguine, phlegmaiic and melancholic types according to Hippocrates’ terminology, this ancient typology exists up to the present time. Choleric personality is impetuous, easily irritated and angered, sometimes uncontrollable. His workability is high, but not constant. Sanguine personality is communicable, vivacious, lively, active, and emotional. Phlegmatic personality is calm, apathetic, unexcitable, but stable. Melancholic personality is unsociable, sometimes depressed, and hesitating, The ancient doctors have in general noted some predispositions of one or the other personality type to certain diseases and tried to give people recommendations as to the rational behavior and life style. The sanguine personality has a predisposition to fullbloodedness apoplexy, headache and diabetes mellitus. It is useful for such type to have bloodletting, which was so popular among the ancients. One of the most, popular morphological classifications was made by Sigaud. Basing upon the pronounced development of one or the other physiological feature he differentiated the following four constitutional types: respiratory, digestive, muscular and cerebral. Sigaud belonged to the group of scientists who believed that main constitution is forming throughout his life, but mainly in the childhood and the process of training. Kretschmer's classification is widely spread. He singled out three constitutional types: athletic, asthenic and pyknic. Kretschmer, being a psychiatrist by profession, attempted to connect the morphological peculiarities of a man not only with the specific character traits, psyche and temperament, but also with the mental disease morbidity. Among the schizophrenics one can meet the asthenic type more often than other 51ones, while epileptics are encountered mainly among individuals of an athletic constitution; the pyknic type is spread among those patients who suffer from manic-depressive psychosis. In the clinical practice M. V. Chernorutsky's classification has received acknowledgement in this country. Each of the constitutional type (hyposthenic, hypersthenic and normosthenic types) was given a characteristic from the standpoint of the main functions and metabolism. Thus, he indicates that a hyposthenic type has a low blood pressure and absorptive intestinal function, but metabolism is elevated. High blood pressure, slower metabolic processes, lower carbohydrate tolerance, slow matabolic waste excretion are characteristic for the hypersthenic type. This type also has a predisposition to obesity. A. A. Bogomolets, a Ukrainian physician described leading sig- nificance to the connective tissue physiological system in the structural and functional peculiarities of the human body. Henee, he laid the active mesenchymal peculiarities as a basis for his classification of constitutional types. According to A. A. Bogomolets, the asthenic type is characterized by predominantly thin, tender connective tissue, the fibrotic type has a denser and more fibrillar connective tissue; the lipomatous type has an abundant adipose tissue, his mesenchymal elements have a leniency to fatty infiltration and to various decomposition of a lipoid character, and pastly type (from latin pastosus) has a predominantly edematous, loose (friable) connective tissue. J, P. Pavlov in classifying the humans and animals into consti- tutional types leaned upon the idea that the inner unity of all bodily parts, body reactivity and balance with the environment are insured by the central nervous system. The higher nervous activity. as it is known, is characterized by the following main peculiarities: the intensity of the stimulating and inhibiting processes, their agility and the balancing ability. From this stand point L P. Pavlov singled out the following constitutional types: the strong, unstable excitable type, or unrestrained ‘one (with intensive stimulation and inhibition processes, but with a relative prevalence of stimulation), the strong, stable lively (agile); strong, stable, composed or slow (inertia of the main nervous processes); weak (weakness of both stimulation and inhibition processes with a relative prevalence of inhibition). For humans |. P. Pavlov suggested one more classification where he indicated the prevalence of the 1st or 2nd signal system. Depending on this prevalence there are discerned the reasoning and the artistic types. 52When studying the constitutional types it becomes evident that the minority of people can be referred to pure types, the majority present transitional types. There were attempts to describe those transitional constitutional types, but up to the present the issue did not find its solution. The significance of constitution was well understood by the ancient doctors. They knew of the stronger and weaker peculiar traits of every constitutional types. They have discovered, for instance, that the tall type had a predisposition to respiratory diseases, while the short stature type had a predisposition to apoplexy (status apoplexicus). For instance, in tuberculosis the primary infection does not depend on constitution, but for asthenics the course of the disease is more severe and lethal outcomes Occur more offen. Atherosclerosis and coronary disease are more often observed in pyknics. While gastric ulcer, hypertension, neurasthenia is characteristic of people with excitable type of the nervous system. It has also been noticed that the specificity of neurotic symptoms is connected with the constitution. For example, hysteria and depression are more common among the athletic pyknic types, while fear and anxiety are more cornmon for asthenics. At present the aim of the science is to study the nature of the established connections, which is probably genetically conditioned. Evidently one chromosomal locus controls simultaneously « group of features, which are morphological, functional and psychic. The mechanisms of environmental influence on constitution formation necessitate their investigation too. The study of the most vulnerable sides of constitution makes it possible to prognose their traumatic consequences, to determine the disease predisposition, to prognose the disease course, to have an individual approach to the treatment course. COMPREHENSION CHECK Try to answer the following questions. 1. Define hereditary disease, hereditary predisposition and con- genital (innate) disease, 2. Characterize different ways of the inheritance. 3. Describe chromosomal abnormalities and the main syndromes. 4. What is the role of constitution in pathology? 5. Name different types of constitution and their role in deter- mination of disease predisposition, and prediction of the disease course. 53UNIT 6 é PATHOPHYSIOLOGY OF THE PERIPHERAL BLOOD CIRCULATION Circulation in the peripheral vessels (small arteries, arterioles, metarterioles, capillaries, preferential channels, posteapillary yenules and small veins) provides an exchange of water, electrolytes, gases, essential nutrients and metabolites in the system "blood — tissue — blood". The most common forms of the local disturbances of microcirculation are arterial and venous hyperemia, ischemia, stasis, thrombosis and embolism. ARTERIAL HYPEREMIA_— Arterial hyperemia means increasing of an organ blood supply due to excessive blood inflow from arterial vessels. It is characterized by the following functional changes and signs: — spread redness; — dilatation of small arteries, arterioles, veins, capillaries; pulsation of small veins and capillaries; — increasing of the number of function vessels; — local hyperthermia, — increasing of the volume of the region with hyperemia; — increasing of the tissue turgor; — increasing of the pressure in arterioles, capillaries and yeins; — speeding up of blood flow and intensifying of metabolism and organ function. Pathogenesis There are two types of arterial hyperemia recognized according to pathogenesis: neurogenic (of neurotonic and neuroparalytic type) and caused by local metabolic (chemical) factors. Neurogenic arterial hyperemia was first reproduced by Clod Bemard by stimulation of chorda tympani — the branch of the facial nerve, containing parasympathetic vasodilating fibers. In a case if vessels don't have parasympathetic stimulation, hy- peremia is caused by the sympathetic (cholinergic, histaminergie and p-adrenergic) system. Sympathetic cholinergic nerves dilate small arteries and arterioles of skeletal muscles, facial muscles, mucous membrane of the cheeks, intestine. Their mediator is also acetylcholine. 54