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General Nosology - Complete Study Guide

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1. Pathological Process, Pathological Reaction, Pathological Condition, and Disease; Typical Pathological Processes

• Inflammation
• Fever
• Hypoxia
• Thrombosis and DIC
• Edema
• Tumor growth
• Atrophy
• Dystrophy (degeneration)
• Stress response

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2. Etiology - the Concept; Role of Causes and Conditions; Classification of Etiological Factors

• Favorable (promoting): malnutrition, immunodeficiency, stress, hypothermia
• Unfavorable (protective): good nutrition, prior immunity, physical fitness

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3. Pathogenesis - Definition; Main Mechanisms of Action of Pathogenic Factors

1. Direct cell and tissue damage - the pathogenic factor directly destroys membrane integrity, denatures proteins, or breaks chemical bonds (e.g., burns, acids, ionizing radiation).
2. Disturbance of energy supply - blockade of oxidative phosphorylation or substrate supply (e.g., cyanide poisoning, ischemia → ATP depletion).
3. Disruption of genetic programs - mutations, chromosomal breaks alter the information encoded in DNA.
4. Membrane damage - alteration of lipid bilayer via lipid peroxidation, phospholipases, or mechanical forces changes ion gradients and signaling.
5. Dysregulation of functional systems - pathogenic factors may act on receptors, neuronal pathways, or hormonal axes, triggering cascades that ultimately injure tissues (e.g., excess catecholamines in stress → cardiomyocyte damage).
6. Immunopathological mechanisms - immune complexes, autoreactive T cells, or complement activation damage host tissues.

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4. Pathogenetic Factors; Their Types; Pathogenetic Therapy; Main Pathogenetic Factor; Vicious Cycles

• Pathophysiological - disturbances in physiological regulation (e.g., hypoxia in shock driving further vasoconstriction)
• Biochemical - metabolic imbalances (lactate accumulation, free radical excess)
• Morphological - structural changes (cell swelling, necrosis)
• Immunological - activation of complement, cytokine storm

• Example in shock: decreased cardiac output → ischemia of myocardium → further decrease in cardiac output → worsening ischemia.
• Example in cell injury under hypoxia: ATP depletion → membrane pump failure → intracellular Na⁺/Ca²⁺ accumulation → mitochondrial damage → further ATP depletion.

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5. Outcomes of Disease; Mechanisms of Recovery; Protective-Adaptive Reactions; Structural and Functional Compensation

1. Complete recovery - full restoration of structure and function
2. Incomplete recovery / remission - functional restoration with residual structural defects
3. Transition to chronic form - persistence of pathological process with periodic exacerbations
4. Pathological condition - stable residual defect (scar, amputation)
5. Death - cessation of vital functions

• Reflexive protective reactions: coughing, sneezing, vomiting, pain withdrawal
• Release of stress hormones (adrenaline, cortisol) - mobilize energy, cardiovascular response
• Hemostasis activation after bleeding

• Inflammation and immune response - eliminate the injurious agent and its products
• Regeneration - replacement of lost cells by division of surviving cells
• Hypertrophy - increase in functional capacity of remaining cells
• Metaplasia - adaptation of epithelial differentiation to altered demands

• Protective reactions prevent or minimize injury (pain reflex, mucus secretion, fever)
• Compensatory reactions maintain function despite structural loss (cardiac hypertrophy in valve disease, renal compensation in nephrectomy)
• Substitution (vicarious) reactions - one organ takes over the function of another (e.g., left kidney hypertrophying after right nephrectomy)

1. Emergency (urgent) stage - existing reserve capacity is maximally utilized (tachycardia, increased stroke volume)
2. Stable compensation stage - structural remodeling (hypertrophy) sustains function at a new equilibrium
3. Decompensation stage - exhaustion of reserves, structural breakdown, failure of compensation

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6. Pathogenic Action of Mechanical Factors; Crush Syndrome (Etiology and Pathogenesis)

• Contusion, laceration, fracture, compression
• Blast wave injury (barotrauma, rapid pressure change)
• Acceleration/deceleration forces

• Mechanical disruption of myocytes
• Local ischemia under pressure → ATP depletion → membrane pump failure → intracellular Na⁺ and Ca²⁺ accumulation

• Massive release into circulation of: myoglobin, potassium, phosphate, creatine kinase, lactic acid, thromboplastin
• Myoglobin precipitates in renal tubules (especially in acidic urine) → tubular obstruction + direct tubular toxicity → acute kidney injury (AKI)
• Hyperkalemia → cardiac arrhythmia, potential cardiac arrest
• Hypovolemia - fluid shifts into damaged muscles create a "third space" → shock
• DIC - released thromboplastin activates coagulation → consumptive coagulopathy
• Metabolic acidosis - lactic acid and phosphate load

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7. Shock - Definition, Types, General Pathogenesis, Leading Pathogenetic Factors

• Baroreceptor reflex → sympathetic activation → tachycardia, vasoconstriction, redistribution of blood to brain and heart
• Renin-angiotensin-aldosterone axis activation → Na⁺ and water retention
• ADH release → water conservation
• Tissue perfusion maintained in vital organs

• Prolonged ischemia → anaerobic metabolism → lactic acidosis
• Acidosis impairs vasomotor tone → peripheral pooling
• Ischemic endothelium activates coagulation → DIC
• Vicious cycle: reduced perfusion → myocardial depression → further reduction in cardiac output

• Multi-organ failure (kidney, liver, lung, brain)
• Profound mitochondrial dysfunction
• Intestinal barrier breach → bacterial translocation → septic complications
• Death

• Hypovolemic: decreased preload → low cardiac output
• Cardiogenic: reduced contractility → low cardiac output (vicious cycle: myocardial ischemia → further dysfunction) - Goldman-Cecil Medicine
• Septic: cytokine storm (TNF-α, IL-1, IL-6) → vasodilation, capillary leak, myocardial depression, microvascular thrombosis

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8. Pathogenic Action of Low Temperature; Hypothermia

• Vasoconstriction → ischemia → ice crystal formation in cells → membrane damage
• On rewarming: reperfusion injury, edema, thrombosis
• Grades: I (erythema), II (bullae), III (necrosis of skin), IV (deep necrosis to bone)

1. Mild (35-32°C) - Compensatory stage: Shivering thermogenesis, vasoconstriction, tachycardia, elevated blood pressure, elevated metabolic rate - organism actively fights cooling
2. Moderate (32-27°C) - Adynamic stage: Shivering stops (muscle rigidity), CNS depression, bradycardia, hypotension, respiratory rate decreases, reflexes diminish
3. Severe (<27°C) - Paralytic stage: Loss of consciousness, absent reflexes, ventricular fibrillation risk, respiratory arrest

• Cold reduces enzyme activity (every 10°C drop roughly halves metabolic rate)
• Initial sympathetic surge (compensatory) transitions to direct cardiac membrane effects (arrhythmias)
• Paradoxical undressing is a pre-terminal neurological phenomenon
• Therapeutic hypothermia (32-34°C) is protective for cardiac arrest and neonatal hypoxic-ischemic encephalopathy - illustrating the dose-dependent nature of cold effects

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9. Pathogenic Action of High Temperature; Overheating; Heat Stroke; Burn Disease

1. Compensation: Vasodilation, sweating, tachycardia, increased cardiac output maintain normothermia at metabolic cost
2. Decompensation: Core temperature rises - proteins begin to denature above 42°C, enzyme kinetics disrupted, cell membranes lose fluidity

• Classic (non-exertional): elderly, anhidrotic patients in heat waves
• Exertional: young athletes or soldiers; often with sweating still present

• High temperature directly denatures proteins and disrupts membrane lipids
• Splanchnic ischemia → gut barrier disruption → endotoxin translocation → systemic inflammatory response resembling sepsis
• DIC, rhabdomyolysis, acute hepatic failure, AKI

1. Burn shock (1-3 days): Massive fluid shift from vascular to interstitial and burn wound spaces → hypovolemia → decreased cardiac output; accompanied by intense pain, catecholamine surge; massive release of arachidonic acid metabolites, cytokines
2. Acute toxemia (3-10 days): Absorption of burn wound toxins and bacterial products → fever, organ dysfunction
3. Septicotoxemia (weeks): Wound infection → bacteremia → sepsis
4. Recovery/Cachexia: Hypermetabolic state, protein catabolism, weight loss, slow healing

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10. Pathogenic Action of Low Barometric Pressure; Altitude Sickness

• Decreased PO₂ → stimulation of peripheral chemoreceptors (carotid bodies) → hyperpnea → respiratory alkalosis
• Sympathetic activation → tachycardia, increased cardiac output
• Hemoconcentration (fluid shifts)
• Days later: Erythropoietin (EPO) release from renal peritubular cells → increased erythropoiesis

• Hypoxic pulmonary vasoconstriction → High-altitude pulmonary edema (HAPE): heterogeneous vasoconstriction creates areas of overperfusion, breaking capillary integrity
• Cerebral vasodilation from hypoxia + breakdown of autoregulation → High-altitude cerebral edema (HACE): vasogenic edema
• Headache, nausea, ataxia, altered consciousness (severe HACE)

• Polycythemia (hematocrit up to 60%)
• Right ventricular hypertrophy (due to chronic pulmonary hypertension)
• Increased 2,3-BPG in erythrocytes → rightward shift of O₂-Hb dissociation curve → better O₂ unloading in tissues
• Increased capillary density in muscles
• Increased mitochondrial density

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11. Pathogenic Action of High Barometric Pressure; Caisson Disease (Decompression Sickness)

• Increased PO₂ (hyperoxia) at high pressures → oxygen toxicity (pulmonary, CNS)
• Nitrogen narcosis ("rapture of the deep") at depths >30-40 m: nitrogen dissolves in neuronal membranes → narcotic effect

• Under high pressure, inert gases (mainly N₂) dissolve in blood and tissues (Henry's Law: gas solubility ∝ partial pressure)
• Rapid decompression → gas comes out of solution faster than it can be cleared via lungs → bubble formation in tissues and blood vessels
• Bubbles in joints → intense joint pain ("bends")
• Bubbles in CNS → neurological deficits, spinal cord ischemia, paralysis
• Bubbles in coronary vessels → myocardial ischemia
• Bubbles in lungs → "chokes": respiratory distress, pulmonary edema
• Vascular bubbles cause endothelial damage → platelet aggregation, coagulation activation, inflammatory response

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12. Pathogenic Action of Electricity; Factors Determining the Degree of Injury

• "Entry" and "exit" burns (current marks/metallization)
• Deep coagulative necrosis along the current path (especially in tissues of high resistance like bone)
• Electroporation of cell membranes → non-thermal cell death

1. Cardiac effects: Ventricular fibrillation (main cause of death in low-voltage electrocution), asystole, conduction disturbances
2. Neurological effects: Unconsciousness, retrograde amnesia, peripheral nerve damage, late-onset neurological complications
3. Respiratory: Respiratory muscle tetany → apnea; direct damage to respiratory center
4. Vascular: Vascular thrombosis along current path; delayed arterial rupture
5. Rhabdomyolysis and AKI (from deep muscle necrosis)

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13. Pathogenic Action of Sound, Noise, and Ultrasound

1. Mechanical: High-amplitude sound waves cause excessive displacement of the basilar membrane → mechanical disruption of stereocilia of outer hair cells
2. Metabolic/oxidative: Intense sound → excess glutamate release at cochlear synapses → excitotoxicity; plus mitochondrial overactivity → reactive oxygen species (ROS) generation → oxidative stress in hair cells
3. Vascular: Cochlear ischemia during noise (vasoconstriction of spiral arteriole)
4. Apoptosis of outer hair cells, beginning at the basal turn (3-4 kHz region)

• Noise-induced hearing loss (NIHL) - sensorineural, initially high-frequency
• Activation of the sympathetic nervous system and HPA axis → hypertension, tachycardia, increased cardiovascular risk
• Sleep disturbance → neuroendocrine dysregulation, immunosuppression
• Psychological: irritability, cognitive impairment

1. Cavitation: Formation and violent collapse of microbubbles → localized pressures of thousands of atmospheres → shockwaves → cell membrane disruption, DNA strand breaks, free radical generation
2. Thermal effect: Ultrasound energy absorbed in tissues → local heating → protein denaturation at focal point
3. Streaming: Unidirectional fluid movement near vibrating surfaces → shear stress on cells

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14. Pathogenic Action of Ionizing Radiation; Radiation Sickness; Chronic Radiation Sickness

1. Direct action: Ionization directly breaks covalent bonds in DNA (single-strand breaks, double-strand breaks) and proteins
2. Indirect action (radiolysis of water - dominant mechanism): H₂O + radiation → •OH (hydroxyl radical) + H• → these react with DNA and cell membranes; ~70% of all radiation damage is indirect
3. Lipid peroxidation of cell membranes
4. Protein oxidation - loss of enzyme activity

1. Functional stage: Fatigue, headache, sleep disturbance, labile vasomotor reactions, mild leukopenia, thrombocytopenia; reversible with removal from exposure
2. Organic stage: Persistent leukopenia and anemia, hemorrhagic syndrome, immunodeficiency, reproductive dysfunction, cataract formation, accelerated atherosclerosis
3. Severe/Late stage: Aplastic anemia, increased cancer risk (leukemia, solid tumors), premature aging phenotype

• Gradual accumulation of unrepaired DNA double-strand breaks leads to genomic instability and chromosome aberrations
• Persistent oxidative stress depletes antioxidant reserves
• Inhibition of bone marrow hematopoiesis → pancytopenia
• Neuroendocrine dysregulation (hypothalamic-pituitary axis)
• No acute radiation syndrome features; dominated by slowly progressive multisystem insufficiency

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15. Acute Radiation Sickness - Forms and Characteristics

1. Prodromal phase (hours 0-2 to day 3): Nausea, vomiting, fatigue, fever, headache (onset within minutes at high doses = poor prognosis); thought to result from direct radiation effects on CNS and gastrointestinal tract
2. Latent (subclinical) phase (days 3-28 at 2-4 Gy): Patient feels relatively well; bone marrow silently failing - mitotic death of stem cells; peripheral counts begin falling (lymphocytes drop first, within 24-48h - highly dose-predictive)
3. Manifest illness (peak hematopoietic syndrome, days 28-42):
   • Severe pancytopenia → bleeding (thrombocytopenia), infection (neutropenia), anemia
   • Hemorrhagic syndrome: purpura, mucosal bleeds, internal hemorrhage
   • Infectious complications: bacteremia, fungal sepsis
4. Recovery phase (if survived): Surviving stem cells repopulate marrow; counts recover over weeks to months

• Radiation kills rapidly dividing crypt cells of small intestinal epithelium → villous denudation within 3-5 days
• Loss of mucosal barrier → massive fluid/electrolyte loss, bacteremia, endotoxemia
• Fatal before marrow failure can manifest; combined bone marrow + GI lethality

• Direct radiation injury to cerebral vasculature → vascular leak, brain edema → coma, seizures
• Fatal within hours to days; no meaningful intervention possible

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16. Cell Injury - Definition; Classification

• Reversible injury - cell can return to normal if the injurious stimulus is removed; characterized by cellular swelling, lipid accumulation, slight mitochondrial swelling; EM: plasma membrane blebbing, ER swelling
• Irreversible injury - point of no return reached; committed to death; characterized by severe mitochondrial damage (amorphous densities), membrane disruption, lysosomal rupture

• Hypoxic/ischemic
• Physical (mechanical, thermal, radiation)
• Chemical and drug-induced
• Biological (viral, bacterial toxins)
• Immune-mediated
• Genetic/metabolic
• Nutritional deficiency

• Free radical-mediated
• Calcium overload-mediated
• ATP depletion-mediated
• Membrane damage-mediated
• Mitochondria-mediated

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17. Typical Manifestations of Cell Injury; Changes in Intracellular Metabolism

• Cellular swelling (hydropic change, vacuolar degeneration) - earliest and most common; results from failure of Na⁺/K⁺-ATPase
• Fatty change (steatosis) - abnormal intracellular lipid accumulation; seen in liver, heart, kidney in toxic or ischemic injury
• Plasma membrane changes - blebbing, loss of microvilli, loosening of intercellular attachments
• Mitochondrial changes - swelling, loss of cristae, formation of amorphous densities (irreversible sign)
• Endoplasmic reticulum changes - swelling, ribosome detachment
• Nuclear changes (sign of irreversibility): pyknosis (condensation), karyorrhexis (fragmentation), karyolysis (dissolution)

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18. Barrier Function of Cytoplasmic Membrane; Mechanical Stretching, Phospholipases, Lipid Peroxidation

• Excessive membrane stretch (from cell swelling due to osmotic forces or ATP depletion) → rupture of lipid bilayer and integral proteins
• Cytoskeletal attachments to membrane (spectrin, ankyrin, vinculin) detach → membrane blebs form
• Blebs can rupture → instant irreversible injury

• Rising intracellular Ca²⁺ activates phospholipase A₂ (PLA₂) and C (PLC)
• PLA₂ cleaves fatty acids from phospholipids → free fatty acids (including arachidonic acid) → eicosanoid storm; lysophospholipids accumulate (detergent-like, disrupt bilayer)
• Loss of phosphatidylserine asymmetry (normally inner leaflet) → flipping to outer leaflet signals macrophages to phagocytose (in apoptosis) or indicates loss of membrane polarity (in necrosis)

• Reactive oxygen species (ROS: O₂•⁻, •OH, H₂O₂) attack polyunsaturated fatty acids (PUFAs) in membrane phospholipids
• Chain reaction: initiating radical → lipid radical (L•) → peroxyl radical (LOO•) → new lipid radical → propagates until antioxidant (vitamin E, glutathione peroxidase) terminates the chain
• Products: malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) - these cross-link proteins and further disrupt membranes
• Consequences: increased membrane fluidity/permeability, loss of selective transport, receptor dysfunction

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19. Disturbances of Matrix (Structural) Functions of the Plasma Membrane

• Loss of glycocalyx components (after enzymatic cleavage or deficient synthesis)
• Disruption of integrin-extracellular matrix connections
• Damage to cadherins and tight junctions
• Cytoskeletal uncoupling from transmembrane anchors

1. Increased permeability: Disruption of tight junctions (e.g., by toxins like Clostridium perfringens alpha toxin, or by Ca²⁺ chelation) → paracellular leak → edema
2. Loss of cell polarity: Normally, membrane proteins (pumps, receptors, channels) are sorted apically vs. basolaterally; structural damage randomizes distribution → dysfunctional vectorial transport
3. Loss of adhesion: Detachment from basement membrane or neighboring cells → anoikis (apoptosis triggered by loss of matrix contact in non-cancerous cells); cancer cells evade anoikis → metastatic behavior
4. Impaired mechanotransduction: Integrins normally convert mechanical signals to intracellular responses (growth, differentiation); disruption contributes to aberrant tissue remodeling

• Edema (increased paracellular permeability)
• Tissue disintegration (loss of cell-cell adhesion)
• Impaired wound healing (loss of integrin signaling)
• Pathological cell migration (cancer)
• Organ dysfunction proportional to number of cells affected

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20. Necrosis and Apoptosis; Types of Necrosis

• Cell swelling → plasma membrane rupture
• Release of intracellular contents → triggers inflammation
• Affects groups of cells/tissues, not individual cells
• Not genetically programmed

• Ischemic (coagulative) - most common
• Toxic (chemical necrosis)
• Infectious (e.g., in bacterial abscess)
• Immune-mediated (fibrinoid necrosis in vasculitis)
• Traumatic

1. Coagulative necrosis: Protein denaturation dominates over enzymatic digestion. Architecture preserved for days (tissue remains firm and pale). Characteristic of ischemic infarcts in most organs (kidney, heart, spleen). Dead cells form "ghost outlines."
2. Liquefactive (colliquative) necrosis: Enzymatic digestion dominates. Tissue liquefies into creamy-white paste. Characteristic of: (a) brain infarcts (high lipid content, few structural proteins); (b) bacterial abscesses (neutrophil enzymes digest tissue). Pus is a form of liquefactive necrosis.
3. Caseous necrosis: "Cheesy" appearance - amorphous granular debris; characteristic of tuberculosis and some fungal infections. A combination of coagulative and liquefactive patterns surrounded by granulomatous inflammation.
4. Fat necrosis:
   • Enzymatic (pancreatic): Lipase release from injured pancreatic acini cleaves triglycerides in peripancreatic fat → free fatty acids → react with Ca²⁺ → calcium soaps (saponification, chalky white deposits)
   • Traumatic: Direct trauma to adipose (e.g., breast)
5. Fibrinoid necrosis: Immune complex deposition in vessel walls → complement and fibrin accumulation → bright pink amorphous material in walls; seen in malignant hypertension, polyarteritis nodosa, vasculitis
6. Gangrenous necrosis: Not a specific pattern but a clinical term - dry gangrene (coagulative + desiccation), wet gangrene (liquefactive + superimposed bacteria), gas gangrene (Clostridium infection + gas production)

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21. Signs and Mechanisms of Apoptosis

• Cell shrinkage (opposite of necrotic swelling)
• Chromatin condensation and margination (pyknosis) against nuclear envelope
• Nuclear fragmentation (karyorrhexis)
• Cell membrane blebbing
• Formation of apoptotic bodies - membrane-bound fragments containing organelles and chromatin fragments
• Phagocytosis of apoptotic bodies by macrophages and adjacent cells - no inflammation (hallmark distinguishing apoptosis from necrosis)
• Phosphatidylserine externalization (eat-me signal) - recognized by macrophage receptors (MFG-E8, TIM4)

• Internucleosomal DNA fragmentation (180-200 bp "ladder" on gel electrophoresis) by endonucleases
• Caspase activation (cysteinyl aspartate-specific proteases)

• FasL binds Fas (CD95) or TNF binds TNFR1
• Receptor trimerization → recruitment of FADD (Fas-associated death domain)
• FADD recruits and activates procaspase-8 → DISC (death-inducing signaling complex) forms
• Active caspase-8 cleaves and activates executioner caspases (3, 6, 7)

• Stimuli: DNA damage, oxidative stress, growth factor withdrawal
• Increased mitochondrial outer membrane permeability (MOMP)
• Pro-apoptotic BCL-2 family proteins (Bax, Bak) oligomerize → pores in outer mitochondrial membrane
• Cytochrome c released into cytoplasm
• Cytochrome c + Apaf-1 + procaspase-9 → apoptosome
• Apoptosome activates caspase-9 → executioner caspases
• Anti-apoptotic BCL-2, BCL-XL inhibit MOMP (their inhibition by BH3-only proteins like BIM, PUMA, NOXA drives apoptosis)

• DNA double-strand breaks → ATM/ATR kinases activate → phosphorylate and stabilize p53
• p53 transactivates pro-apoptotic genes: PUMA, NOXA (BH3-only BCL-2 family members) → engage mitochondrial pathway
• Also transactivates Bax and Fas/FasL → both intrinsic and extrinsic pathways
• p53 also directly interacts with BCL-2 family proteins at the mitochondrial membrane

• CTL/NK cell recognizes target → forms immune synapse
• Releases perforin (polymerizes in target membrane → pores) and granzyme B (serine protease)
• Granzyme B enters through perforin pores (also via receptor-mediated endocytosis)
• Granzyme B directly cleaves and activates caspase-3 (executioner)
• Also cleaves BID (BCL-2 family) → tBID → engages mitochondrial pathway

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22. Mechanisms of Cell Damage During Hypoxia; Role of Free Radical Oxidation; Vicious Cycle of Cellular Pathology

1. O₂ supply fails → aerobic respiration stops → ATP synthesis ceases
2. ATP depletion → failure of Na⁺/K⁺-ATPase → Na⁺, Cl⁻, H₂O enter → cell swelling; ER swelling with ribosome detachment
3. Switch to anaerobic glycolysis → lactic acid → intracellular pH falls → inhibits glycolytic enzymes → ATP synthesis further impaired
4. Ca²⁺ homeostasis failure: Ca²⁺/H⁺ antiporter works in reverse; PMCA and SERCA fail due to ATP depletion → cytosolic Ca²⁺ rises → activates phospholipases, proteases, endonucleases, ATPases (→ accelerates all forms of injury)
5. Mitochondrial permeability transition (MPT): Ca²⁺ overload + oxidative stress open the MPT pore → loss of mitochondrial membrane potential → no ATP production even if O₂ is restored → cytochrome c release → apoptosis initiation

• Reintroduction of O₂ to metabolically deranged cells
• Electron leakage from damaged respiratory chain → burst of ROS generation ("oxidative burst")
• Ca²⁺ overload worsens
• Neutrophil recruitment → secondary inflammatory injury
• Mitochondrial MPT: paradoxical worsening at moment of reperfusion

• Under normal conditions, mitochondrial electron transport generates small amounts of O₂•⁻ (superoxide), neutralized by superoxide dismutase (SOD), catalase, glutathione peroxidase
• In hypoxic/ischemic injury: depleted antioxidants + damaged ETC → massive ROS production
• •OH (most reactive) attacks: (1) membrane PUFAs → lipid peroxidation; (2) protein sulfhydryl groups → enzyme inactivation; (3) DNA bases and sugar-phosphate backbone → strand breaks

Hypoxia → ATP depletion
     ↓
Na⁺/K⁺-ATPase failure → Cell swelling
     ↓
Ca²⁺ influx → phospholipase activation → membrane damage
     ↓
Mitochondrial damage → more ATP depletion
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23. Mutations - Causes, Types, Role in Hereditary Disease; Classification of Hereditary Diseases

• Spontaneous: errors of DNA replication; spontaneous depurination/deamination
• Induced (mutagens):
  • Physical: ionizing radiation (double-strand breaks, base oxidation), UV radiation (pyrimidine dimers)
  • Chemical: alkylating agents (add groups to bases → mispairing); base analogs; intercalating agents; reactive oxygen species
  • Biological: viral insertion of DNA (retroviruses); transposable elements

• Gene (point) mutations: Single nucleotide changes
  • Missense: changes one amino acid (e.g., sickle cell: Glu→Val in β-globin)
  • Nonsense: creates premature stop codon → truncated, usually non-functional protein
  • Silent: same amino acid (redundant code) - usually harmless
  • Splice site mutations: alter intron-exon boundaries → aberrant splicing
  • Frameshift: insertion or deletion of non-multiples of 3 bases → shifts reading frame → nonsense protein
• Chromosomal mutations (rearrangements):
  • Deletion, duplication, inversion, translocation
• Genomic mutations:
  • Changes in chromosome number: aneuploidy (monosomy, trisomy), polyploidy

• Germline - present in all cells, heritable
• Somatic - present only in descendant clone of originally mutated cell (relevant to cancer)

1. Monogenic (single-gene) diseases - autosomal dominant/recessive, X-linked
2. Chromosomal diseases - numerical or structural chromosome abnormalities
3. Multifactorial diseases - interaction of multiple genes + environmental factors
4. Mitochondrial diseases - mutations in mtDNA (maternal inheritance)
5. Somatic genetic diseases - cancer, acquired somatic mutations

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24. Chromosomal Diseases - Etiology, Pathogenesis, Classification

• Failure of chromosomes to separate at meiosis I or II
• Risk factors: advanced maternal age (decreased meiotic spindle checkpoint fidelity), radiation, some chemicals
• Most common: trisomy 21 (Down syndrome) - 95% from non-disjunction in maternal meiosis I

• An extra chromosome means ~50% more gene product from genes on that chromosome
• Dosage imbalance of hundreds of genes → complex, pleiotropic developmental disruption
• Critical regions have been identified (e.g., Chr 21q22 critical region for Down syndrome features)
• Deletions/duplications cause haploinsufficiency or triplosensitivity of key developmental genes

• Trisomies: Down syndrome (47,+21): intellectual disability, characteristic facies, cardiac defects, increased leukemia risk, early Alzheimer's pathology
• Edwards syndrome (47,+18): severe, multiple organ defects, 95% die within first year
• Patau syndrome (47,+13): severe brain, heart, and face malformations, very poor prognosis
• Sex chromosome: Turner syndrome (45,X): short stature, gonadal dysgenesis, neck webbing, coarctation; Klinefelter syndrome (47,XXY): tall, hypogonadism, infertility, mild cognitive effects; Triple X (47,XXX)

• Deletions: Cri-du-chat (5p-); Williams syndrome (7q11.23 microdeletion)
• Translocations: Balanced (no clinical effect usually) vs. unbalanced (deletion + duplication effects); Robertsonian translocation (14;21) → familial Down syndrome
• Inversions: Usually no effect if balanced; inversion carriers at risk for unbalanced progeny
• Ring chromosomes

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25. Multifactorial Diseases; Genetic Diseases of Somatic Cells; Non-Traditional Inheritance

• Familial clustering without clear Mendelian pattern
• Concordance in monozygotic twins: higher than dizygotic, but <100%
• Risk increases with number of affected first-degree relatives
• Threshold model: genetic predisposition raises liability; environmental factors push over threshold

1. Mitochondrial (maternal) inheritance:
   • mtDNA mutations are transmitted exclusively through the mother (sperm have no mitochondria in the embryo)
   • All children of affected mother are at risk; no paternal transmission
   • Heteroplasmy: mixture of normal and mutant mtDNA; clinical severity depends on proportion
   • Examples: MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), Leber hereditary optic neuropathy (LHON)
2. Genomic imprinting:
   • Certain gene loci are methylated (silenced) in a parent-of-origin-specific manner
   • Loss of the active (non-imprinted) allele → disease
   • Same deletion of Chr 15q11-q13 causes Prader-Willi (if paternal allele deleted, maternal imprinted allele = only copy, silenced) or Angelman syndrome (if maternal allele deleted, paternal allele = only copy, silenced)
3. Trinucleotide repeat expansion (dynamic mutations):
   • Tandem repeats (CAG, CGG, CTG) are unstable and can expand during meiosis
   • Expansions above a threshold cause disease; larger expansions → earlier onset (genetic anticipation)
   • Examples: Fragile X syndrome (CGG in FMR1 5'UTR), Huntington disease (CAG in exon 1 of HTT), myotonic dystrophy (CTG in DMPK)
4. Uniparental disomy (UPD):
   • Both copies of a chromosome pair inherited from the same parent
   • If an imprinted region is involved → disease (e.g., maternal UPD15 → Prader-Willi)

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26. Monogenic (Single-Gene) Diseases - Etiology, Pathogenesis, Classification

• One mutant allele sufficient to cause disease
• 50% offspring risk from one affected parent
• Mechanisms:
  • Haploinsufficiency: One functional copy insufficient to maintain normal function (e.g., familial hypercholesterolemia - one LDLR allele insufficient)
  • Dominant negative: Mutant protein interferes with normal product (common in structural proteins and dimeric transcription factors, e.g., collagen disorders)
  • Gain-of-function: Mutant protein has novel toxic activity (e.g., Huntington disease - polyglutamine expanded huntingtin forms toxic aggregates)
• Examples: Marfan syndrome (FBN1), Huntington disease (HTT), neurofibromatosis type 1 (NF1), familial adenomatous polyposis (APC), achondroplasia (FGFR3)

• Both alleles must be mutant
• 25% offspring risk from two heterozygous carriers
• Heterozygotes typically unaffected (enough protein from one allele - dosage sufficient)
• Examples: Cystic fibrosis (CFTR - defective Cl⁻ channel), Phenylketonuria (PAH - phenylalanine accumulates, neurological damage), sickle cell disease (HBB), Tay-Sachs (HEXA - lysosomal enzyme defect → GM2 gangliosidosis), Wilson disease (ATP7B)

• Gene on X chromosome
• Males (XY) hemizygous → fully affected when they carry the mutation
• Females (XX) carriers: one normal allele compensates; may have mild features (Lyon hypothesis: random X-inactivation may be unfavorable)
• Examples: Duchenne muscular dystrophy (DMD), hemophilia A (F8) and B (F9), G6PD deficiency, fragile X syndrome

• Rare; affects both males and females; males often more severely affected or lethal in males
• Examples: Rett syndrome (MECP2), incontinentia pigmenti

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27. Reactivity - Concept, Kinds, Dependence on Internal and External Factors

1. Species (phylogenetic) reactivity - responses common to all members of a species (e.g., all humans develop fever with endogenous pyrogens; frogs are resistant to streptococcal infections)
2. Group reactivity - characteristic of a specific group within a species, defined by sex, age, constitution, or blood type
3. Individual reactivity - unique response of each individual, determined by genotype + life experience
4. Specific reactivity (immunological) - ability to produce a specific immune response to an antigen; involves T and B lymphocytes
5. Non-specific reactivity - responses to any damaging agent: inflammation, phagocytosis, fever, stress

• Physiological: Normal adaptive responses (exercise adaptation, immune response to vaccination)
• Pathological: Inadequate responses - hyperergic (exaggerated, e.g., anaphylaxis), hypoergic (insufficient, e.g., immunodeficiency), dysergic (misdirected, e.g., autoimmunity)

• Sex: Estrogens enhance humoral immunity and inflammatory responses; testosterone has mild immunosuppressive effect; women have stronger inflammatory and autoimmune responses; men have higher susceptibility to infections
• Age:
  • Neonates/infants: immature immune system (low IgA, complement), reduced fever capacity, vulnerable CNS; protective maternal IgG
  • Elderly: immunosenescence - decreased T cell diversity (thymic involution), reduced vaccine responsiveness, chronic low-grade inflammation ("inflammaging")
• Nutrition: Protein-energy malnutrition severely impairs T-cell immunity, phagocytosis, and complement synthesis; obesity associated with chronic inflammation, altered adipokine signaling
• Nervous system: The CNS modulates immune function via the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system. Psychological stress suppresses immune responses. Pavlovian conditioning can modulate immunological reactivity.
• Endocrine system: Glucocorticoids - anti-inflammatory, immunosuppressive; thyroid hormones - stimulate immune function; growth hormone - stimulates lymphocyte proliferation; insulin deficiency (diabetes) - impairs neutrophil function
• Immune system: The immune system IS a major reactivity system; its state (autoimmunity, immunodeficiency, allergy) fundamentally defines pathological reactivity

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28. Resistance - Concept, Kinds, Examples; Difference from Reactivity

1. Non-specific resistance - defense against various agents regardless of their nature:
   • Passive: Skin and mucosa as mechanical barriers; lysozyme in tears and saliva; low pH of stomach; normal microbiome competition; blood-brain barrier
   • Active: Phagocytosis, natural killer cells, complement system, interferons, fever
2. Specific resistance - defense against a particular antigen:
   • Immune memory (after infection or vaccination)
   • Antigen-specific T and B cells
3. Primary (innate) resistance - genetically determined, present from birth, does not require prior contact with agent (e.g., humans are resistant to canine distemper virus; specific blood group antigens confer partial resistance to certain pathogens)
4. Acquired resistance - developed during life through adaptation or immune experience

• Black rats are naturally resistant to plague (Yersinia pestis does not multiply in their macrophages)
• Sickle cell trait (HbAS) confers resistance to severe Plasmodium falciparum malaria
• Physical training increases resistance to hypoxia

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29. Stress - Definition, Etiology, Types; Selye's Triad; Stages of General Adaptation Syndrome

• Physical: cold, heat, pain, trauma, infection
• Chemical: toxins, heavy metals
• Biological: infection, surgery
• Psychological/social: fear, conflict, loss, chronic workload
• ANY factor producing sufficient deviation from homeostasis

• Eustress - moderate, manageable stress; beneficial, leads to adaptation (exercise stress, cognitive challenge)
• Distress - excessive, uncontrollable stress; leads to pathological changes
• Emotional (psychological) stress - limbic system-mediated, particularly potent in humans
• Physiological stress - direct physical/biological stressors

1. Adrenal cortex hypertrophy (hyperactivation of cortisol synthesis)
2. Thymic and lymphoid tissue involution (immunosuppressive effect of glucocorticoids)
3. Gastric and duodenal ulcers ("stress ulcers" - from reduced mucus, increased acid due to catecholamines + glucocorticoids)

• Organism recognizes the threat
• Shock phase (seconds to minutes): transient fall in blood pressure, temperature, blood glucose (initial "shock")
• Counter-shock phase (minutes to hours): HPA and sympatho-adrenomedullary axes activate; catecholamines and glucocorticoids surge; resistance rises above baseline
• Features: tachycardia, hypertension, hyperglycemia, lipolysis, anti-inflammatory suppression

• Continued exposure with ongoing HPA activation
• Organism adapted to stressor - can perform better than baseline against this stressor
• "Cross-resistance" - resistance to unrelated stressors may also increase
• Selye's triad lesions appear

• Prolonged or intense stress exhausts adaptation reserves
• Adrenal cortex depleted of glucocorticoid precursors
• Immune suppression becomes profound
• Stress ulcers progress, hemorrhage
• Return of alarm reaction symptoms
• Death if stress continues

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30. Pathogenesis of the General Adaptation Syndrome; Protective and Damaging Effects of Stress Hormones

STRESSOR
    ↓
Sensory pathways → Hypothalamus
    ↓                    ↓
Autonomic NS         CRH release
(Sympathetic)            ↓
    ↓               Anterior pituitary
Adrenal medulla         ACTH
    ↓                    ↓
CATECHOLAMINES    Adrenal cortex
(Adrenaline,         GLUCOCORTICOIDS
Noradrenaline)      (Cortisol)

• Increased cardiac output, blood pressure → maintains perfusion in hemorrhage/fight-flight
• Bronchodilation → improved O₂ delivery
• Hepatic glycogenolysis → hyperglycemia → energy for muscle and brain
• Lipolysis → free fatty acids → myocardial energy substrate
• Redistribution of blood to muscles and brain (vasodilation) from skin and gut (vasoconstriction)

• Gluconeogenesis → sustained glucose availability
• Protein catabolism → amino acids as gluconeogenesis substrates
• Lipolysis → energy substrate
• Potentiate catecholamine effects on vessels (permissive effect)
• Anti-inflammatory actions (short-term adaptive): suppress PLA₂, reduce cytokine production, reduce vascular permeability → limit tissue damage at injury site
• Immune suppression (short-term): prevents autoimmune collateral damage

• Sustained tachycardia and hypertension → myocardial hypertrophy, heart failure risk
• Coronary vasospasm → myocardial ischemia
• Platelet aggregation → thrombosis risk
• Oxidative damage to myocardium (direct catecholamine cardiotoxicity: "stress cardiomyopathy" / Takotsubo)
• Gut vasoconstriction → mucosal ischemia → ulcers

• Immunosuppression → increased susceptibility to infections and cancer
• Cushing-like syndrome: truncal obesity, muscle wasting, osteoporosis, skin thinning, impaired wound healing
• Hyperglycemia → increased risk of diabetes mellitus
• Hypertension (Na⁺ retention)
• Depression, cognitive impairment (hippocampal damage - glucocorticoid receptors in hippocampus; sustained cortisol → hippocampal neuron loss → impaired memory)
• Gastric ulcer formation
• Suppression of growth hormone and thyroid hormone (reduces anabolism)
• Adrenal insufficiency upon abrupt cessation of chronic stress

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