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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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General Nosology - Easy Memory Guide

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1. Pathological Process vs. Reaction vs. Condition vs. Disease

• Pathological reaction = a quick, temporary blip. Your heart races when scared. Done in minutes. (Short flash)
• Pathological process = a sequence of events the body runs like a program. Inflammation always follows the same steps no matter what caused it. (A script the body runs)
• Pathological condition = a permanent "frozen" leftover. A scar after a heart attack never changes. (A fossil of old disease)
• Disease = the whole package - a cause, a story of how it develops, symptoms, and an ending. It affects the whole person, including their ability to work and function socially. (The full movie)

Inflammation, Fever, Hypoxia, Edema, Thrombosis, Atrophy, Dystrophy, Stress, Tumor growth

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2. Etiology - Causes and Conditions

• Cause = the thing you absolutely need for the disease to exist. No TB bacteria = no TB. The cause gives the disease its identity.
• Conditions = things that help or prevent the disease. They don't cause it alone, but they decide if and how badly you get sick.

Think of it like a fire: the spark = cause, dry wood + wind + no fire extinguisher = conditions

• "Only the cause matters, conditions are irrelevant" ❌ (monocausalism)
• "All factors are equal, there's no single cause" ❌ (conditionalism)
• ✅ Correct: The cause is irreplaceable, but conditions decide whether disease actually develops.

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3. Pathogenesis - How Disease Develops

Etiology = WHY it started. Pathogenesis = HOW it unfolds.

1. Breaks things directly - burns your skin, smashes your cells
2. Cuts the power - blocks energy (ATP) production → cells starve
3. Corrupts the code - mutates DNA → wrong proteins made
4. Damages cell walls - punches holes in membranes → cells leak and die
5. Hijacks the controls - messes with nerves/hormones → cascading dysfunction
6. Turns your immune system against you - autoimmune damage

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4. Pathogenetic Factors, Main Factor, Vicious Cycles, Pathogenetic Therapy

Example: In Type 1 diabetes, the cause is autoimmune destruction of beta cells. The main pathogenetic factor = no insulin. Give insulin → glucose enters cells → all downstream problems (ketosis, dehydration) resolve.

Shock example: Low blood pressure → heart gets less blood → heart pumps even less → blood pressure drops further → repeat 🔄

• Etiological therapy = kill the bacteria (the cause)
• Pathogenetic therapy = reduce inflammation, give fluids, correct acidosis (the mechanisms)
• Symptomatic therapy = give painkillers (just mask the symptom)

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5. Disease Outcomes; Recovery Mechanisms; Protective Reactions; Compensation

1. ✅ Full recovery - back to normal completely
2. 🔶 Incomplete recovery - function OK but a scar/defect remains
3. 🔄 Becomes chronic - comes and goes, never fully resolves
4. 🪨 Pathological condition - stable permanent defect (like an amputation)
5. ☠️ Death

• Coughing/sneezing = physically expel the enemy
• Pain reflex = pull away from danger
• Adrenaline surge = mobilize energy fast

• Inflammation = clean up debris, fight infection
• Regeneration = grow new cells to replace dead ones
• Hypertrophy = surviving cells work harder to compensate
• Immune response = build specific defenses

1. Emergency stage - use what you have (e.g., speed up the heart)
2. Stable compensation - build new capacity (e.g., heart muscle hypertrophies)
3. Decompensation - reserves exhausted, system collapses (e.g., heart failure)

---

6. Mechanical Damage; Crush Syndrome

All the toxic garbage from dead muscle floods into the bloodstream at once:

• Myoglobin → blocks and damages kidneys → acute kidney failure
• Potassium → dangerously high levels → heart stops or fibrillates
• Fluid shifts into dead muscle → blood volume drops → shock
• Clotting factors released → blood clots everywhere → DIC
• Lactic acid → acidosis

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7. Shock - Definition, Types, Pathogenesis

1. Compensated - Body is fighting back. Heart races, vessels constrict, kidneys hold water. You look pale but OK. (Car sputtering but still moving)
2. Progressive (Decompensated) - Tissues are acidotic, vessels dilate, heart weakens, blood clots form. Vicious cycles kick in. (Car stalling)
3. Irreversible - Multiple organs fail. Gut bacteria cross into blood. Too far gone. (Car is totaled)

Weak heart → less blood to coronary arteries → heart gets even weaker → even less cardiac output 🔄

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8. Low Temperature - Hypothermia

Key fact: The body first fights the cold (stage 1), then gives up (stage 2), then dies (stage 3). Therapeutic hypothermia (32-34°C) is protective after cardiac arrest - cold slows damage.

---

9. High Temperature - Overheating, Heat Stroke, Burn Disease

• Above 42°C: proteins start denaturing = catastrophic.

Dangerous mechanism: gut becomes ischemic → bacteria leak from intestine into blood → looks like sepsis + high temperature → multi-organ failure.

---

10. Low Barometric Pressure - Altitude Sickness

• Breathe faster (but this causes respiratory alkalosis)
• Heart beats faster
• Days later: kidneys release EPO → more red blood cells are made

• More red blood cells (polycythemia)
• Right heart enlarges
• More 2,3-BPG in red cells → hemoglobin releases O₂ more easily to tissues
• More capillaries and mitochondria in muscle

• HAPE = High Altitude Pulmonary Edema: fluid floods the lungs (the most deadly)
• HACE = High Altitude Cerebral Edema: brain swells → headache, ataxia, coma

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11. High Barometric Pressure - Caisson Disease (The Bends)

Think of opening a soda bottle slowly vs. popping it - slow = safe, fast = explosion of bubbles.

• Joints → excruciating pain ("the bends")
• Spinal cord → paralysis
• Lungs → "the chokes" (breathing agony)
• Coronary arteries → heart attack
• Blood vessels → endothelial damage → clotting → inflammation

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12. Electrical Injury

• Heart → ventricular fibrillation (main cause of death)
• Brain → unconsciousness, memory loss
• Muscles → rhabdomyolysis → kidney failure
• Lungs → breathing muscle paralysis → suffocation

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13. Sound, Noise, and Ultrasound

1. Mechanical: Loud sound waves physically break the tiny hair cells in the cochlea (outer hair cells die first)
2. Chemical: Too much stimulation → hair cells produce excess free radicals (ROS) → oxidative self-destruction
3. Vascular: Noise causes vasoconstriction in the cochlea → local ischemia

• Stress response activation → high blood pressure, heart disease
• Poor sleep → hormonal disruption, immune suppression
• Psychological: irritability, reduced concentration

• Cavitation = microscopic bubbles form and violently collapse → like tiny bombs inside tissue → cell membrane destruction, DNA breaks, free radicals
• Thermal = focused heating → proteins cook at focal point (used therapeutically in HIFU)

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14. Ionizing Radiation - Chronic Radiation Sickness

1. Direct = radiation smashes DNA directly (breaks strands)
2. Indirect (most common ~70%) = radiation splits water → •OH radical → this attacks DNA

Most sensitive cells = ones that divide fastest: bone marrow, gut lining, skin, gonads Most resistant = neurons, muscle (rarely divide)

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15. Acute Radiation Sickness

1. Prodrome (first hours) = nausea, vomiting, fatigue. Speed of onset = dose indicator. (Vomiting in 1 hour = very high dose.)
2. Latent phase (days 3-28) = patient feels OK but bone marrow is silently dying. Lymphocytes already dropping - this is the best early dose indicator.
3. Manifest illness (weeks 3-6) = the crash:
   • Low neutrophils → infections (bacteremia, fungal sepsis)
   • Low platelets → bleeding everywhere (purpura, hemorrhage)
   • Anemia → fatigue, oxygen deprivation
4. Recovery (if survived) = remaining stem cells slowly repopulate marrow; counts recover over months.

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16 & 17. Cell Injury - Definition, Classification, Manifestations

ATP drops → pumps fail → Na⁺ floods in → cell swells → Ca²⁺ floods in → activates destructive enzymes (phospholipases eat membrane, proteases destroy structure, endonucleases cut DNA) → mitochondria fail → lysosomes rupture → cell dies

• Cellular swelling = earliest and most common (looks puffy/vacuolated)
• Fatty change = fat droplets accumulate (liver in alcoholism)
• Nuclear changes = signs of death: pyknosis (shrinks), karyorrhexis (fragments), karyolysis (dissolves)

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18. Membrane Damage - Three Mechanisms

The cell swells (from ion pump failure) → membrane is stretched beyond its limit → tears open like an overfilled balloon. Cytoskeleton anchors pull away → blebs form → rupture.

Ca²⁺ rises inside cell → activates phospholipase A₂ → it chews through the phospholipid bilayer → membrane falls apart. Also releases arachidonic acid → inflammatory cascade.

Free radical attacks a fatty acid in the membrane → chain reaction: one damaged lipid → creates another radical → attacks the next lipid → propagates until an antioxidant stops it. Products: MDA, 4-HNE → cross-link proteins, destroy more membrane. Antioxidants that stop this: Vitamin E, glutathione peroxidase, catalase.

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19. Structural Functions of the Membrane

1. Tight junctions break → paracellular leakage → edema
2. Cell polarity lost → transport proteins shuffle to wrong places → organ can't do vectorial transport (e.g., kidney can't properly reabsorb)
3. Integrins lose contact with ECM → cell gets signal to die (anoikis) - cancer cells learn to bypass this → invasion and metastasis
4. Mechanosensing lost → wrong signals for cell growth → abnormal remodeling

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20. Necrosis vs. Apoptosis; Types of Necrosis

1. Coagulative = proteins denature → tissue turns firm and pale, like cooked meat. Architecture preserved briefly. (Heart attack - "pale infarct")
2. Liquefactive = enzymes digest everything → tissue turns to liquid pus. (Brain infarct, bacterial abscess)
3. Caseous = "cheesy" crumbly white material. (Tuberculosis - the hallmark)
4. Fat necrosis = pancreatic lipases spill → fat breaks down → reacts with Ca²⁺ → chalky white calcium soap deposits. (Pancreatitis)
5. Fibrinoid = immune complexes in vessel walls → looks bright pink under microscope. (Vasculitis, malignant hypertension)
6. Gangrenous = dry (coagulative + desiccation) or wet (liquefactive + bacteria) or gas (Clostridium)

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21. Apoptosis - Signs and Mechanisms

• Cell shrinks
• Chromatin condenses and packs against the nuclear envelope
• Nucleus fragments
• Membrane blebs off
• Cell breaks into neat "apoptotic bodies"
• Macrophages eat them silently - NO inflammation
• Phosphatidylserine flips to outside (eat-me flag for macrophages)

Killer sends a "die" signal (FasL, TNF) → hits the receptor → recruits caspase-8 → activates executioner caspases 3/6/7 → cell dismantles itself.

Stress inside the cell (DNA damage, oxidative stress, no growth factors) → pro-death proteins (Bax, Bak) punch holes in mitochondria → cytochrome c leaks out → forms apoptosome with Apaf-1 + caspase-9 → activates executioner caspases. BCL-2 is the bodyguard that prevents this. When BCL-2 is overwhelmed → apoptosis.

DNA is broken → p53 is stabilized → acts like a judge deciding if damage is repairable. If not → activates PUMA, NOXA → engage mitochondrial pathway → apoptosis. p53 = "guardian of the genome." Lost in many cancers.

Cytotoxic T cell recognizes infected/cancerous cell → releases perforin (makes pores) + granzyme B (enters through pores) → granzyme B directly activates caspase-3 → apoptosis of target cell.

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22. Cell Damage During Hypoxia; Free Radicals; Vicious Cycle

No O₂ → No ATP
    ↓
Pumps fail → Na⁺ in, Ca²⁺ in
    ↓
Cell swells + enzymes activated
    ↓
Mitochondria damaged
    ↓
Even less ATP → worse Ca²⁺ overload → more enzyme damage
    ↓         ↑_________________________________↑
   CELL DEATH (vicious cycle)

• Damaged mitochondria suddenly get O₂ → produce a burst of free radicals
• Ca²⁺ overload worsens
• Neutrophils arrive → add more inflammatory damage

This is "ischemia-reperfusion injury" - the basis of why we do protective cooling, give antioxidants, etc.

1. Membrane fats → lipid peroxidation chain reaction → membrane destruction
2. Proteins → enzyme inactivation, structural collapse
3. DNA → strand breaks → mutations or apoptosis

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23. Mutations - Causes, Types, Role in Hereditary Disease

• Natural copying errors during cell division
• Physical mutagens: X-rays, UV light (UV makes thymine dimers → the reason sunscreen matters)
• Chemical mutagens: cigarette carcinogens, alkylating agents
• Biological: retroviruses inserting DNA

---

24. Chromosomal Diseases

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

Like needing both a fuel leak (genes) AND a spark (environment) for a fire.

• Examples: Type 2 diabetes, hypertension, asthma, schizophrenia
• Twins: identical twins both get it more often than fraternal twins, but not 100% - proving the environmental component.

Mitochondria come ONLY from mom's egg (sperm's mitochondria are discarded). So mitochondrial diseases pass only through mothers. All children of affected mother can get it.

• Examples: MELAS, LHON (visual loss)

Some genes are "muted" based on which parent they came from. So losing the same piece of chromosome 15 causes DIFFERENT diseases depending on which parent it came from:

• Delete from dad → Prader-Willi (obesity, intellectual disability)
• Delete from mom → Angelman (happy demeanor, seizures, no speech)

Sections of DNA that stutter (like a skipping record) get longer with each generation → worse disease = genetic anticipation.

• Fragile X: CGG repeats expand → intellectual disability (most common inherited ID)
• Huntington: CAG repeats → protein forms toxic clumps → brain death starting in 40s
• Myotonic dystrophy: CTG repeats → muscle disease

You get BOTH copies of a chromosome from ONE parent only (instead of one from each). If an imprinted gene is involved → disease.

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26. Single-Gene (Monogenic) Diseases

• ONE bad copy is enough to make you sick
• 50% chance of passing to children
• Why? Either the good copy can't compensate (haploinsufficiency), the bad protein fights the good one (dominant negative), or the bad protein does something new and toxic (gain-of-function)
• Examples: Marfan (connective tissue), Huntington (brain), Neurofibromatosis, Familial hypercholesterolemia

• Need TWO bad copies to be sick
• Carriers (one bad copy) are usually fine
• 25% risk when both parents are carriers
• Examples: Cystic fibrosis (bad Cl⁻ channel → thick mucus), PKU (can't break down phenylalanine → brain damage), Sickle cell, Tay-Sachs (enzyme deficiency → fat accumulates in brain)

• Males get sick (only one X, no backup)
• Females are carriers (two X chromosomes, one backup)
• Examples: Duchenne MD, Hemophilia A & B, G6PD deficiency

• Rare, affects females more (males often too severe or lethal)
• Example: Rett syndrome (girls lose speech and hand use after normal start)

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27. Reactivity - Concept, Kinds, Determinants

Think of it as the "sensitivity setting" of the body.

• Species: All humans react similarly to certain things (we all get fever from pyrogens; rats don't get chicken pox)
• Group: Based on sex, age, blood type
• Individual: Your unique response pattern
• Specific (immune): Response to ONE particular antigen
• Non-specific: Response to any irritant - inflammation, fever, stress response

• Normal: you get a fever from real infection ✅
• Hyperergic: you go into anaphylaxis from a peanut ❌ (overreaction)
• Hypoergic: you can't fight off a mild cold ❌ (underreaction)
• Dysergic: your immune system attacks your own joints ❌ (misdirected)

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28. Resistance vs. Reactivity

Think of it as the "armor rating" of the body.

• Non-specific passive: Skin barrier, stomach acid, normal bacteria on skin competing with pathogens
• Non-specific active: Phagocytes, NK cells, complement, fever, interferons
• Specific: Immune memory from past infection or vaccines

• Black rats resistant to plague bacteria (bacteria can't survive in their macrophages)
• Sickle cell trait (one copy) = resistant to severe malaria
• Athletes are more resistant to hypoxia

Reactivity = How strongly do you respond? Resistance = How well do you not get sick in the first place?

• A person with severe allergy is highly reactive (strong response) but has low resistance (the allergen makes them sick)
• An immunosuppressed person has low reactivity but may have some resistance via physical barriers

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29. Stress - Definition, Types, Selye's Triad, GAS Stages

• Stressor = the thing causing stress
• Stress = the body's response to it

• Eustress = good stress - challenges you just enough → adaptation and growth (exercise, learning)
• Distress = bad stress - too much, too long → damage
• Emotional stress = most powerful in humans (limbic system-driven)

1. 🫁 Adrenal cortex hypertrophy (overworked making cortisol)
2. 🫃 Thymus + lymphoid tissue shrink (cortisol suppresses immune tissue)
3. 🫀 Stomach ulcers (reduced mucus + increased acid from catecholamines)

Memory: "Fat adrenals, shrunken thymus, bleeding stomach"

• Body recognizes the threat
• Brief initial "shock" (brief drop in function)
• Then: adrenaline + cortisol surge - heart rate up, blood sugar up, blood pressure up
• Body is mobilized and ready to fight

• Body adapts to the stressor
• Hormones stay elevated but body copes
• Can now handle this stress better
• Ulcers start developing from Selye's triad

• Stress too prolonged or severe
• Hormone reserves depleted
• Immune system crashes
• Ulcers bleed
• All alarm symptoms return but now body can't compensate
• Death if not resolved

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30. GAS Pathogenesis; Protective vs. Damaging Effects of Stress Hormones

Stressor
    ↓
Hypothalamus → releases CRH
    ↓
Pituitary → releases ACTH
    ↓
Adrenal cortex → releases CORTISOL

Also simultaneously:
Hypothalamus → Sympathetic nerves
    ↓
Adrenal medulla → releases ADRENALINE + NORADRENALINE

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Adrenaline (Catecholamines):

Cortisol (Glucocorticoids):

The bottom line on cortisol: It's brilliant in a crisis (anti-inflammatory, energy-mobilizing, circulatory support) but toxic when chronically elevated (suppresses almost everything anabolic and immune-related while accelerating catabolic damage).

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General Nosology — Complete Easy Guide

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TOPIC 1: Pathological Process, Reaction, Condition, and Disease

First, understand the four terms separately

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🔹 Pathological Reaction

• Lasts only minutes to hours
• Disappears on its own
• Does NOT lead to disease by itself
• It is a brief, automatic body response

Think of it like a phone notification that pops up and disappears — it alerts you briefly, then it's gone.

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🔹 Pathological Process

1. Vasodilation (blood vessels widen)
2. Increased permeability (vessels become leaky)
3. White blood cells arrive
4. Healing begins

• Has a beginning and an end
• Follows a fixed biological script
• Can happen in any tissue or organ
• Can occur without necessarily becoming a full disease

Think of it like an app running on your phone — whether you open it from a notification, a shortcut, or a link, it runs the same way.

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🔹 Pathological Condition

• A scar on the heart after a heart attack
• A missing limb after amputation
• A healed but deformed bone after fracture

• Stable — does not get better or worse
• No tendency to develop further
• No active process happening
• Does not threaten life directly

Think of it like a pothole in a road — it's a permanent damage mark that doesn't spread, but it never repairs itself either.

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🔹 Disease

• Cause: TB bacteria
• How it develops: bacteria infect lungs → immune reaction → granuloma formation → tissue destruction
• Symptoms: cough, fever, weight loss
• Outcome: recovery with treatment OR death if untreated
• It limits the patient's ability to work and live normally

• Affects the WHOLE organism
• Has a definite cause
• Has a specific development pathway (pathogenesis)
• Has subjective symptoms (the patient feels them) and objective signs (doctor can measure them)
• Reduces quality of life and ability to work
• Has defined possible outcomes

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How they differ — Summary Table

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Typical Pathological Processes

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TOPIC 2: Etiology — Causes and Conditions of Disease

What is Etiology?

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The Cause of Disease

• Tuberculosis bacteria (Mycobacterium tuberculosis) is the CAUSE of tuberculosis. No bacteria = no TB, regardless of any other conditions.
• The HIV virus is the CAUSE of AIDS.
• Lack of insulin is the CAUSE of Type 1 diabetes symptoms.

1. It is absolutely necessary (without it, no disease)
2. It determines the TYPE and CHARACTER of the disease (TB bacteria cause TB, not pneumonia)

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Conditions of Disease

• Malnutrition
• Stress
• Immunodeficiency
• Cold environment
• Fatigue
• Poor hygiene

• Good nutrition
• Vaccination
• Physical fitness
• Strong immune system
• Sanitation

Think of starting a fire:

• The cause = the spark (without it, no fire, no matter what)
• Conditions = dry wood, wind, no water nearby You need the spark, but conditions decide whether the fire spreads into a big blaze or fizzles out.

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Modern Understanding: The Relationship Between Cause and Conditions

• The CAUSE is irreplaceable and determines the specific disease
• CONDITIONS determine whether and how severely the disease develops
• Both are necessary for a complete understanding of why someone gets sick

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Classification of Etiological Factors

• Exogenous = come from OUTSIDE the body (most infections, trauma, toxins)
• Endogenous = arise INSIDE the body (metabolic disorders, autoimmune attack, spontaneous mutations)

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TOPIC 3: Pathogenesis — How Disease Develops

What is Pathogenesis?

Simple definition: Etiology tells you WHY the disease started. Pathogenesis tells you HOW it develops step by step.

• Etiology = coronary artery blocked by a clot
• Pathogenesis = blockage → no oxygen → cells switch to anaerobic metabolism → ATP depletes → ion pumps fail → cells swell → membranes rupture → cell death → inflammatory reaction → scar formation

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The Main Mechanisms by Which Damaging Factors Act

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1. Direct Physical Damage

• Burns physically denature proteins
• Trauma ruptures cell membranes
• Radiation breaks DNA strands directly

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2. Disruption of Energy Supply

• Cyanide blocks mitochondrial electron transport → no ATP
• Ischemia (blocked blood supply) → no oxygen → no aerobic respiration → no ATP
• Without ATP, ALL cell functions fail simultaneously

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3. Disruption of Genetic Programs

• Radiation causes double-strand DNA breaks
• Chemical mutagens change nucleotide sequences
• Viruses insert foreign DNA
• Result: wrong proteins are made, or normal proteins aren't made at all

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4. Membrane Damage

• Toxins punch holes in membranes
• Free radicals destroy membrane lipids
• Ion gradients collapse → water floods in → cell swells and dies

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5. Dysregulation of Control Systems

• Some bacterial toxins mimic hormones → dysregulate metabolism
• Certain poisons block nerve signal transmission
• Stress hormones in excess → damage heart and blood vessels

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6. Immunopathological Mechanisms

• Autoimmune diseases: immune cells attack joints, kidneys, thyroid
• Immune complexes deposit in vessel walls → vasculitis
• Excessive immune response (cytokine storm) destroys lungs in severe infections

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TOPIC 4: Pathogenetic Factors, Vicious Cycles, and Pathogenetic Therapy

What Are Pathogenetic Factors?

A car crash (cause) injures you. The crash is over in seconds, but the bleeding, inflammation, shock, and infection that follow can kill you hours or days later. Those secondary processes = pathogenetic factors.

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Types of Pathogenetic Factors

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The Main (Leading) Pathogenetic Factor

• In Type 1 diabetes, the main pathogenetic factor = absolute absence of insulin
• Giving insulin → glucose enters cells → hyperglycemia stops → ketosis stops → acidosis stops → everything reverses
• One factor, fixed, everything else corrects

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Vicious Cycles (Circuli Vitiosi)

↓ Cardiac output
       ↓
↓ Blood flow to heart muscle
       ↓
↓ Heart function weakens further
       ↓
↓↓ Cardiac output (even worse)
       ↓
(back to the start, but worse)

No O₂ → no ATP → ion pumps fail → Ca²⁺ floods in
→ mitochondria damaged → even less ATP
→ more Ca²⁺ floods in → more mitochondrial damage
→ (loop until cell dies)

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Pathogenetic Therapy

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TOPIC 5: Outcomes of Disease, Recovery Mechanisms, Protective Reactions, Compensation

Possible Outcomes of Any Disease

1. ✅ Complete recovery — body fully restored, no trace of disease
2. 🔶 Incomplete recovery — function is restored but a structural defect remains (e.g., scar tissue after heart attack)
3. 🔄 Chronic disease — disease persists long-term, with periods of remission and relapse
4. 🪨 Pathological condition — permanent stable defect, no active disease but no recovery either (e.g., amputated limb)
5. ☠️ Death — irreversible cessation of vital functions

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Mechanisms of Recovery

Urgent (Emergency) Recovery Mechanisms

Delayed Recovery Mechanisms

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Main Types of Protective-Adaptive Reactions

• Examples: sneezing, coughing, vomiting, skin pigmentation (suntan), fever, mucus secretion

• Examples: cardiac hypertrophy in hypertension; bone marrow working harder during anemia; one kidney compensating for loss of the other

• Example: after one kidney is removed, the other kidney grows larger and filters almost twice as much blood

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Structural-Functional Compensation — 3 Stages

• Uses what is already available, immediately
• Example: Heart failure → heart beats faster (tachycardia) to maintain cardiac output
• No new structures are built yet — just working harder with existing capacity

• The body builds new structural capacity to handle the extra demand
• Example: Heart muscle fibers grow thicker (hypertrophy) → heart can now pump adequately at a normal rate
• The organ is now physically larger and stronger

• Compensatory capacity is exhausted
• The hypertrophied heart outgrows its blood supply → energy deficit
• Function collapses → organ failure
• This is when the person becomes clinically sick again

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TOPIC 6: Mechanical Factors and Crush Syndrome

Pathogenic Action of Mechanical Factors

• Blunt force: Contusion (bruise), concussion
• Sharp force: Lacerations, stab wounds
• Compressive force: Crush, compression fracture
• Blast wave: Barotrauma, lung contusion from explosion
• Deceleration: Whiplash, aortic tear in car accidents
• Repeated microtrauma: Stress fractures, tendinopathies

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Crush Syndrome (Traumatic Rhabdomyolysis)

What is it?

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Etiology (Causes)

• Prolonged compression of large muscle groups (legs, thighs most commonly)
• Limb tourniquet left too long
• Extreme exertion (very rare)
• Prolonged immobility in unconscious patients

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Pathogenesis Step by Step

• Muscle under pressure → blood supply cut off → ischemia
• Without oxygen → anaerobic metabolism → ATP depletes
• Cells can no longer pump Na⁺ out → Na⁺ and water flood in → cells swell
• Calcium enters cells → activates destructive enzymes
• Muscle cells begin to die silently (but are still contained within the limb)

• Myoglobin → Kidney failure
• Acidosis (lactic)
• Kalium (potassium) → Cardiac arrhythmia
• Anemia + DIC (coagulopathy)
• Dehydration → Shock

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Clinical Stages

1. Shock stage (hours 1-3): Hypovolemia, pain, pale/cold skin, cardiovascular instability
2. Acute kidney injury stage (days 2-5): Oliguria/anuria, rising creatinine, hyperkalemia
3. Recovery stage: Diuretic phase, gradual restoration of kidney function (if patient survives)

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TOPIC 7: Shock — Definition, Types, Pathogenesis

What is Shock?

Simple definition: Shock = the body's delivery system has failed. Tissues are not getting enough oxygen.

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Types of Shock

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General Pathogenesis of Shock — 3 Stages

Stage 1: Compensated Shock (Body is fighting back)

• Baroreceptors in the aorta detect low pressure → signal the brain
• Sympathetic nervous system activates → releases adrenaline + noradrenaline
• Heart: beats faster and harder (tachycardia)
• Blood vessels: constrict → blood is redirected from skin, gut, and kidneys to the brain and heart
• Kidneys: activate renin-angiotensin-aldosterone system → retain sodium and water
• Pituitary: releases ADH (vasopressin) → retain water

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Stage 2: Progressive (Decompensated) Shock (Body is losing the fight)

• Cells switch to anaerobic metabolism → massive lactic acid buildup → metabolic acidosis
• Acidosis weakens heart muscle and relaxes blood vessels (opposite of what you need)
• Vicious cycle begins: Weak heart → less perfusion → more acidosis → weaker heart
• Ischemic endothelium activates clotting → DIC (microclots form everywhere)
• Fluid leaks from damaged vessels into tissues → edema worsens hypovolemia

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Stage 3: Irreversible Shock (Too late)

• Gut wall becomes ischemic → intestinal bacteria cross into the bloodstream → septic component added to any shock type
• Multi-organ failure (kidney, liver, lungs, brain)
• Severe mitochondrial destruction across all tissues
• Cell death becomes irreversible even if circulation is restored

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Leading Pathogenetic Factors by Shock Type

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TOPIC 8: Low Temperature — Hypothermia

How Low Temperature Harms the Body

1. Local cold injury (frostbite) — affects exposed body parts
2. General hypothermia — whole-body core temperature drops

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Local Cold Injury (Frostbite)

• Blood vessels in cold tissues constrict → blood flow stops → ischemia
• Ice crystals form INSIDE cells → physically puncture cell membranes from within
• On rewarming: ischemia-reperfusion injury → burst of free radicals → additional damage + severe edema

1. Grade 1: Skin redness, tingling — fully reversible
2. Grade 2: Blisters form — mostly reversible
3. Grade 3: Skin dies — permanent skin loss
4. Grade 4: Deep tissues (muscle, bone) die — amputation may be needed

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General Hypothermia

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Three Stages of Hypothermia

• Shivering = involuntary muscle contractions that generate heat (thermogenesis)
• Vasoconstriction = blood vessels in skin and extremities clamp down to keep heat in the body core
• Tachycardia and high blood pressure = heart works harder
• Goosebumps = erects hairs to trap air (vestigial but still happens)
• Increased metabolic rate

• Shivering STOPS (muscles are exhausted and cold) — this is a very dangerous sign
• Muscles become rigid
• Heart rate slows (bradycardia)
• Blood pressure falls
• Breathing slows
• Reflexes diminish
• Consciousness becomes clouded (drowsy, confused)
• Paradoxical sensation of warmth (neurological phenomenon — leads some victims to remove clothing)

• Loss of consciousness
• All reflexes absent
• Ventricular fibrillation (chaotic heart rhythm) can occur at any moment
• Respiratory arrest
• Death

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Interesting Clinical Note

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TOPIC 9: High Temperature — Overheating, Heat Stroke, Burn Disease

How High Temperature Harms the Body

1. Denaturing proteins — above 42°C, proteins begin to lose their 3D shape and stop functioning
2. Disrupting enzyme activity — most enzymes stop working at temperatures above their optimal range
3. Damaging cell membranes — excess heat increases membrane fluidity → loss of selective permeability
4. Depleting energy — heat raises metabolic demand → energy reserves exhausted

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Overheating (Hyperthermia)

• Sweating (evaporation — most effective)
• Skin vasodilation (radiation/convection)
• Breathing (exhalation of warm air)

• High ambient temperature + high humidity (sweat won't evaporate)
• Dehydration (no sweat to produce)
• Physical exertion in a hot environment

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Heat Stroke

• Classic (non-exertional): Elderly people, infants, or those on medications that impair sweating, during heat waves
• Exertional: Young healthy people (athletes, soldiers) doing intense exercise in heat — they may still be sweating when they collapse

Gut wall loses integrity → bacteria from the intestine leak into the bloodstream (bacterial translocation) → triggers a systemic inflammatory response that looks exactly like sepsis → multi-organ failure, DIC, rhabdomyolysis, acute kidney injury, liver failure

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Burn Disease

Why burns cause a SYSTEMIC disease:

Four Stages of Burn Disease

• Massive fluid leaks from burned vessels into damaged tissue and surrounding areas
• Enormous "third-space" fluid loss → blood volume drops → hypovolemic shock
• Intense pain → sympathetic surge → adrenaline released → vasoconstriction
• Prostaglandins, leukotrienes, and cytokines released from burned tissue → increase vascular permeability everywhere
• Key danger: Hypovolemia and cardiovascular collapse

• Dead tissue in the wound starts to break down and is absorbed
• Toxic products (burn toxins, bacterial products) enter the bloodstream
• Fever spikes (often very high)
• Confusion, kidney and liver strain
• Key danger: Systemic toxicity from wound

• Burned skin is an ideal culture medium for bacteria
• Wound becomes infected → bacteria enter bloodstream → sepsis
• This is the most common cause of death in burn patients
• Key danger: Infection and multi-organ failure from sepsis

• Extremely high metabolic rate (hypermetabolism) → burns 2-3x normal calories just to maintain temperature and repair tissues
• Massive protein catabolism → weight loss, muscle wasting
• Slow wound healing, scarring, contractures
• Key challenge: Nutritional support and rehabilitation

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TOPIC 10: Low Barometric Pressure — Altitude Sickness

The Core Problem at High Altitude

At 5000m altitude, the partial pressure of O₂ is roughly half that at sea level. Each breath delivers half the oxygen.

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Body's Response — Compensation and Decompensation

Compensation Stage (body adapting)

• Peripheral chemoreceptors in the carotid bodies detect low O₂ → signal the brainstem → increase breathing rate and depth (hyperpnea)
• BUT: breathing out more CO₂ → blood CO₂ drops → respiratory alkalosis (blood becomes too alkaline)
• Alkalosis partially inhibits breathing drive (competing signal) — a temporary brake on compensation
• Sympathetic activation → heart rate and cardiac output increase → more blood circulates → more oxygen delivered per minute

• Kidneys excrete bicarbonate to compensate for the alkalosis → pH normalizes
• Erythropoietin (EPO) released from kidney peritubular cells → stimulates bone marrow → more red blood cells produced (polycythemia)
• More RBCs = more hemoglobin = more oxygen-carrying capacity

• Hematocrit rises (up to 55-60%)
• 2,3-BPG increases in red blood cells → hemoglobin releases O₂ more easily to tissues (rightward shift of oxygen-hemoglobin dissociation curve)
• More capillaries grow in muscles (increased capillary density)
• More mitochondria per cell → more efficient oxygen use
• Right ventricular hypertrophy (due to higher pulmonary vascular resistance at altitude)

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Decompensation Stage — Altitude Sickness

• Headache, nausea, fatigue, dizziness, poor sleep
• Due to mild cerebral vasodilation and early fluid shifts
• Self-limiting if the person stops ascending

• Hypoxic pulmonary vasoconstriction is uneven → some lung areas are overperfused → high pressure breaks capillary walls → fluid floods the air sacs (alveoli)
• Symptoms: breathlessness at rest, pink frothy sputum, crackling sounds in lungs
• Can be fatal within hours

• Cerebral vasodilation from hypoxia + breakdown of the blood-brain barrier → vasogenic edema → brain swells
• Symptoms: severe headache, ataxia (can't walk straight), confusion, hallucinations, coma
• Fatal if not immediately descended and treated with oxygen

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TOPIC 11: High Barometric Pressure — Caisson Disease (Decompression Sickness)

The Core Problem

Think of a can of fizzy drink. Under pressure (can sealed), CO₂ stays dissolved. Open it quickly → pressure drops → CO₂ bubbles violently. This is exactly what happens to nitrogen in your body during rapid decompression.

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Pathogenesis of Caisson Disease

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Treatment and Prevention

• High pressure re-dissolves the nitrogen bubbles
• Breathing 100% oxygen accelerates nitrogen removal from tissues
• Then slowly, according to decompression tables, pressure is reduced safely

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TOPIC 12: Electrical Injury — Factors and Mechanisms

What Makes Electrical Injury Worse or Less Severe

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1. Current Intensity (Amperes — most important)

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2. Type of Current (AC vs DC)

• Alternating current (AC) — used in homes (50-60 Hz) — is MORE dangerous at low voltages
• Why: 50-60 Hz frequency is exactly the right frequency to cause ventricular fibrillation AND it causes sustained (tetanic) muscle contraction, so victims can't let go of the source
• Direct current (DC) — causes a single violent muscle contraction (propels victim away from the source, which can paradoxically be safer)

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3. Voltage

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4. Resistance of the Body (Ohm's Law: R)

This is why working with electricity with wet hands is so much more dangerous — much more current flows.

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5. Path Through the Body

• Hand to hand or hand to foot — current crosses the chest → passes through the HEART → most dangerous for arrhythmia
• Foot to foot — current doesn't cross heart or vital organs — less dangerous

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6. Duration of Contact

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Local Disorders (What Happens at the Site)

• Entry wound and exit wound — current enters at contact point, exits at grounding point
• Both look like coagulative burns — the current enters/exits so rapidly it cooks the tissue
• Deep tissue along the current path is burned — especially where resistance is high (bone) — bone becomes intensely hot and can destroy surrounding muscle and nerve
• Electroporation — current punches holes in cell membranes directly, without heat

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General (Systemic) Disorders

1. Thermal (Joule heating): Electrical energy converts to heat (I² × R × t) → coagulative necrosis of tissues in the current path
2. Electrophysiological: Current directly changes transmembrane potentials → forces action potentials in excitable cells (heart, nerve, muscle) → fibrillation, tetanic contraction, neural disruption

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TOPIC 13: Sound, Noise, and Ultrasound

How Loud Noise Damages Hearing

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Three Mechanisms of Noise-Induced Cochlear Damage

• Very loud sounds create large-amplitude vibrations in the basilar membrane inside the cochlea
• These vibrations physically tear or distort the delicate stereocilia (tiny hair-like projections) on hair cells
• Once stereocilia are destroyed, the cell dies — and unlike skin or liver cells, cochlear hair cells do NOT regenerate in humans
• Damage starts at the base of the cochlea (which processes high frequencies: 3-4 kHz) — this is why high-frequency hearing loss appears first

• Intense sound forces hair cells to work at maximum capacity continuously
• Mitochondria work harder → produce excess reactive oxygen species (free radicals)
• These free radicals damage the hair cell's own membranes, proteins, and DNA → oxidative cell death
• Additionally, excess glutamate is released at hair cell synapses → excitotoxicity (nerve endings literally "overdose" on stimulation)

• Loud noise → sympathetic nervous system activation → cochlear artery vasoconstriction → reduced blood flow to the cochlea → ischemia
• This adds hypoxic damage on top of mechanical and oxidative damage

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General Body Effects of Chronic Noise

• Cardiovascular: Sympathetic activation → persistent hypertension, increased risk of heart disease (well-documented in studies of people near airports)
• Neuroendocrine: Cortisol and adrenaline chronically elevated → all the damaging effects of chronic stress
• Sleep disruption: Even quiet-ish nighttime traffic noise disrupts sleep architecture → impairs immune function, memory consolidation, hormonal regulation
• Psychological: Irritability, difficulty concentrating, anxiety, reduced work performance

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Pathogenic Action of Ultrasound (>20,000 Hz)

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1. Cavitation (Most Important Mechanism)

• Alternating pressure waves first pull the fluid apart → microscopic bubbles (cavities) form
• Then the compression phase causes these bubbles to violently collapse (implode)
• This implosion creates localized pressures of thousands of atmospheres, temperatures of thousands of degrees Celsius (locally, for microseconds), and powerful shock waves
• Effects: cell membrane rupture, DNA strand breaks, free radical burst, mechanical tissue destruction

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2. Thermal Effect

• Ultrasound energy is absorbed by tissues → converted to heat
• At high intensities and focused beams → local temperature can rise dramatically → protein denaturation at the focal point
• Used therapeutically in physiotherapy (low intensity → mild heating → increased blood flow, accelerated healing) or HIFU (high intensity → thermal ablation of tumors)

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TOPIC 14: Ionizing Radiation — Mechanisms; Chronic Radiation Sickness

How Ionizing Radiation Damages Cells

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Two Modes of Damage

• Radiation hits water molecules (most of the body is water) → splits them: H₂O → •OH (hydroxyl radical) + H•
• •OH is the most reactive and damaging free radical known
• It attacks DNA bases → modifies them or creates strand breaks
• It attacks membrane lipids → lipid peroxidation chain reaction
• It attacks proteins → enzyme inactivation

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Which Cells Are Most Vulnerable to Radiation?

• Divide frequently (high mitotic activity)
• Are immature (undifferentiated)
• Have high metabolic activity

1. 🔴 Bone marrow and lymphoid tissue — most sensitive (blood cell precursors divide constantly)
2. 🔴 Gonads (testes, ovaries) — germ cells are highly dividing
3. 🟡 GI epithelium — gut lining cells renew every 3-5 days
4. 🟡 Skin (epidermis)
5. 🟡 Lens of the eye (hence cataracts from radiation)
6. 🟢 Liver, kidney — moderate sensitivity
7. 🟢 Muscle — relatively resistant (rarely divide)
8. 🟢 Nervous tissue — most resistant (neurons don't divide at all in adults)

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Chronic Radiation Sickness (CRS)

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Three Stages of CRS

• Fatigue, headaches, difficulty sleeping, emotional instability
• Mild decreases in white blood cells and platelets (because bone marrow is affected first)
• If exposure stops at this stage → recovery is possible

• Persistent leukopenia (low white cells) → susceptibility to infections
• Persistent thrombocytopenia (low platelets) → spontaneous bleeding, bruising
• Anemia → fatigue, shortness of breath
• Impaired immune responses → common infections become life-threatening
• Cataracts begin (lens cells damaged)
• Reproductive dysfunction (damage to gonads → infertility)
• Accelerated atherosclerosis (radiation damages blood vessel walls)

• Aplastic anemia — bone marrow completely fails
• Greatly increased risk of leukemia and solid tumors (radiation is a carcinogen — accumulated DNA mutations lead to malignant transformation)
• Premature aging — accelerated telomere shortening, reduced tissue repair capacity
• Features similar to total body aging but occurring decades early

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TOPIC 15: Acute Radiation Sickness (ARS)

What is ARS?

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Three Forms of ARS Based on Dose

1. Bone Marrow (Hematopoietic) Form — 1 to 6 Gy

2. Gastrointestinal Form — 6 to 10 Gy

3. Cardiovascular / CNS Form — >10-20 Gy

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Four Phases of ARS (Bone Marrow Form — Most Teachable)

Phase 1: Prodromal Phase (Hours 0 to Day 3)

• Nausea, vomiting, diarrhea, fatigue, fever, headache
• Caused by radiation's direct effect on the GI tract and release of inflammatory signals
• Important diagnostic clue: The faster vomiting begins after exposure, the higher the dose:
  • Vomiting within 1 hour = very high, potentially lethal dose
  • Vomiting after 6+ hours = lower, potentially survivable dose
• Lymphocyte count drops within 24-48 hours — this is the earliest blood indicator of radiation dose. A count below 1.0 × 10⁹/L at 24-48h indicates severe exposure.

Phase 2: Latent (Apparent Well-being) Phase (Days 3 to 28)

• Patient feels relatively normal — the prodromal symptoms subside
• But silently: Bone marrow is failing. The radiation has killed the stem cells. The blood cells currently circulating were already made before the radiation hit — they are still doing their job, but no new ones are being made.
• Blood counts are slowly falling: white cells ↓, platelets ↓, later red cells ↓

• At 2 Gy: latent phase lasts ~3-4 weeks
• At 5 Gy: latent phase only ~1 week
• At 8 Gy: almost no latent phase (goes straight to manifest illness)

Phase 3: Manifest Illness Phase (Weeks 3 to 6 at 2-4 Gy)

Phase 4: Recovery (If Survived)

• Surviving bone marrow stem cells (even a few can repopulate the marrow if given time and support)
• Blood counts begin recovering — first white cells, then platelets, then red cells
• Recovery takes weeks to months
• Long-term risks: increased cancer risk, reproductive damage, possible late cataracts

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TOPIC 16 & 17: Cell Injury — Definition, Classification, Manifestations

What is Cell Injury?

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Classification of Cell Injury

By Severity (Most Important Classification)

• The damaging stimulus is not severe enough or long enough to cross the "point of no return"
• If the stimulus is removed, the cell fully recovers
• Signs: cellular swelling, fat accumulation, slight mitochondrial changes

• The damage has reached a critical threshold — the cell is committed to death regardless of whether the stimulus is removed
• Key irreversible signs: severe mitochondrial damage with calcium deposits, lysosome rupture

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By Cause

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Typical Manifestations of Cell Injury

What you see under the microscope:

• First and most common sign of cell injury
• Ion pumps fail → sodium and water flood into the cell → cell puffs up
• Looks like vacuoles (bubbles) in the cytoplasm
• Reversible if the stimulus stops

• Fat droplets accumulate inside cells
• Common in liver, heart, kidneys after toxic/ischemic injury
• The cell is struggling metabolically
• Classic in alcoholic liver disease

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Changes in Intracellular Metabolism When a Cell is Injured

• Na⁺/K⁺-ATPase pump fails → sodium floods in → chloride and water follow → cell swells
• Ca²⁺-ATPase pump fails → calcium floods into cytoplasm from outside AND from ER stores → Ca²⁺ overload

• Glucose → lactic acid (anaerobic) → intracellular pH drops (acidosis)
• Acidic pH inhibits further glycolysis → even less ATP (the emergency backup shuts itself down)

• Phospholipase A₂ → attacks and destroys cell membranes
• Proteases → destroy cytoskeletal proteins and structural proteins
• Endonucleases → cut DNA strands
• ATPases → destroy remaining ATP

• Calcium enters mitochondria → opens the mitochondrial permeability transition (MPT) pore → loss of mitochondrial membrane potential → no more ATP can be made even if oxygen returns → cytochrome c releases from mitochondria → triggers apoptosis pathway

• Lysosomes (bags of digestive enzymes inside cells) rupture → enzymes pour into the cytoplasm → autodigestion — the cell literally digests itself from inside

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TOPIC 18: Membrane Damage — Three Mechanisms

• Controls what enters and exits the cell
• Maintains the electrochemical gradient (difference in ion concentration)
• Houses receptors and communication molecules
• Separates internal machinery from the external environment

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Mechanism 1: Mechanical Stretching

• The lipid bilayer is stretched beyond its elastic limit → it tears open
• The cytoskeleton (which is attached to the inner surface of the membrane) becomes detached → the membrane loses structural support
• Blisters ("blebs") form on the membrane surface → they expand and eventually rupture
• Once the membrane ruptures → everything inside pours out → irreversible death

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Mechanism 2: Phospholipase Activation

• Releases arachidonic acid → converted to prostaglandins, leukotrienes → amplifies inflammation
• Releases lysophospholipids → these are detergent-like molecules that disrupt the membrane's structure from within → punch holes in the bilayer
• Loss of phospholipid content → membrane integrity collapses → cell cannot maintain ion gradients → immediate death

Think of it like cutting the threads of a woven fabric — PLA₂ cuts the molecular "threads" of the membrane until it falls apart.

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Mechanism 3: Lipid Peroxidation (Free Radical Chain Reaction)

1. •OH steals an electron from a PUFA → creates a lipid radical (L•)
2. L• reacts with oxygen → lipid peroxyl radical (LOO•)
3. LOO• steals an electron from the NEXT PUFA → creates another L•
4. This new L• continues the chain → and so on...

• Malondialdehyde (MDA) → cross-links proteins → stiffens the membrane
• 4-Hydroxynonenal (4-HNE) → toxic to proteins and DNA
• Both products are measurable in the blood → used as biomarkers of oxidative stress

• Vitamin E (in the membrane itself — the lipid-soluble antioxidant)
• Glutathione peroxidase (enzyme in the cytoplasm)
• Catalase
• Superoxide dismutase (SOD)

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TOPIC 19: Structural (Matrix) Functions of the Plasma Membrane

The Membrane Does More Than Just Be a Barrier

1. Cell shape and structure (via cytoskeletal connections)
2. Cell-to-cell adhesion (via cadherins and tight junctions)
3. Cell-to-matrix adhesion (via integrins connecting to collagen, fibronectin)
4. Polarity (different proteins on the top vs. bottom surface)
5. Mechanosensing (feeling physical forces and converting them to signals)

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Causes of Structural Membrane Dysfunction

• Physical damage: Trauma, osmotic shock
• Chemical: Detergents, solvents, bacterial toxins (e.g., Staphylococcal alpha-toxin punches holes)
• Immune attack: Complement system punches membrane attack complexes (MACs) through the membrane
• Genetic: Missing structural membrane proteins (e.g., dystrophin in Duchenne muscular dystrophy)
• Ischemia: ATP depletion → cytoskeletal detachment from membrane

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Pathogenesis — What Happens When Structural Membrane Functions Are Lost

1. Tight Junctions Break → Edema

• Fluid leaks between cells (paracellular leak)
• Tissue swells with excess fluid (edema)
• In the gut: bacteria and toxins leak from the intestinal lumen into the bloodstream (bacterial translocation — very dangerous in severe illness)

2. Cell Polarity Is Lost → Transport Dysfunction

3. Loss of Integrin-ECM Contact → Cell Death (Anoikis)

• The integrin survival signal disappears
• The cell receives a signal to undergo apoptosis (anoikis = "homesickness" in Greek — the cell literally dies because it is not attached to its home)
• This is a protective mechanism: detached cells should not survive (cancer cells evolve to resist anoikis → they can spread and survive in wrong locations = metastasis)

4. Loss of Mechanosensing → Abnormal Remodeling

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Consequences Summary

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TOPIC 20: Necrosis and Apoptosis — The Two Main Forms of Cell Death

The Big Picture

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Types of Necrosis

1. Coagulative Necrosis (Most Common)

• Heart attack: pale, firm myocardium
• Kidney infarct: pale, wedge-shaped area
• Spleen infarct

2. Liquefactive (Colliquative) Necrosis

• In brain infarcts: The brain is very rich in lipids and has few structural proteins → digestive enzymes win → tissue liquefies into a fluid-filled cavity
• In bacterial abscesses: Neutrophils flood the area and release huge amounts of digestive enzymes to destroy bacteria → they also liquefy the surrounding tissue → pus is liquefactive necrosis

• Brain infarcts (cerebral softening = encephalomalacia)
• Bacterial abscesses anywhere
• Amoebic liver abscess

3. Caseous Necrosis

• Caseous necrosis inside a granuloma = pathological signature of TB

4. Fat Necrosis

• Pancreatic enzymes (lipases) are released from injured pancreatic cells
• These enzymes digest the fat cells in and around the pancreas
• Triglycerides are split into glycerol + free fatty acids
• Free fatty acids react with calcium ions → form insoluble calcium soaps (saponification) → visible as chalky white deposits in and around the pancreas
• Classic finding in acute pancreatitis

• Direct physical injury to adipose tissue (e.g., breast trauma)
• Fat cells die → macrophages attempt to digest the fat → form a palpable firm lump that can mimic a tumor on examination

5. Fibrinoid Necrosis

• Malignant hypertension
• Polyarteritis nodosa
• Autoimmune vasculitis
• Transplant rejection

6. Gangrenous Necrosis

• Dry gangrene = coagulative necrosis + desiccation. Tissue dries out, mummifies, turns black. No bacterial infection. Seen in diabetic extremities with poor circulation.
• Wet gangrene = liquefactive necrosis + bacterial superinfection. Swollen, wet, malodorous, rapidly spreading. Much more dangerous.
• Gas gangrene = Clostridium infection in muscle tissue. Bacteria produce gas bubbles within dying tissue (palpable crepitus under the skin). Rapidly fatal.

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TOPIC 21: Apoptosis — Signs and Mechanisms

What Does Apoptosis Look Like? (Signs)

1. Cell shrinkage — the cell condenses (opposite of necrotic swelling)
2. Chromatin condensation — DNA clumps against the nuclear membrane (dark crescent under microscope)
3. Nuclear fragmentation (karyorrhexis) — nucleus breaks into pieces
4. Membrane blebbing — small bubbles form on the membrane surface
5. Formation of apoptotic bodies — the cell breaks into neat, membrane-enclosed packages, each containing organelles and fragments of nucleus
6. Phagocytosis of apoptotic bodies — macrophages and neighboring cells rapidly eat these packages before they can release their contents
7. NO inflammation — this is the defining feature of apoptosis. Because contents are never released, there is no trigger for inflammation.

1. Caspase activation — caspases are proteases (enzymes that cut proteins) that are the executioners of apoptosis
2. Internucleosomal DNA fragmentation — DNA is cut at specific sites → produces fragments of 180-200 base pairs → on a gel, this creates a characteristic "ladder" pattern (used in laboratory confirmation)
3. Phosphatidylserine externalization — normally this phospholipid is on the INNER leaflet of the membrane; during apoptosis it flips to the OUTER surface → acts as an "eat me" flag for macrophages

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Four Mechanisms (Pathways) of Apoptosis

Pathway 1: Receptor-Mediated (Extrinsic) Pathway

• Death receptors: Fas (CD95) on the cell surface; TNFR1 (TNF receptor)
• Death ligands: FasL (on cytotoxic T cells); TNF-α (from macrophages)

1. FasL binds Fas receptor → receptor trimerizes (3 receptors cluster together)
2. The clustered receptors recruit the adapter protein FADD (Fas-Associated Death Domain)
3. FADD recruits and activates procaspase-8 → active caspase-8 forms
4. All this happens in a complex called the DISC (Death-Inducing Signaling Complex)
5. Caspase-8 activates the executioner caspases (3, 6, 7) → these systematically dismantle the cell

• Cytotoxic T cells killing infected cells or tumor cells (via FasL-Fas)
• Immune homeostasis (eliminating excess immune cells after an infection)
• TNF-mediated cell death in inflammation

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Pathway 2: Mitochondrial (Intrinsic) Pathway

• Pro-apoptotic (want the cell to die): BAX, BAK (effectors), BIM, PUMA, NOXA (sensors/activators)
• Anti-apoptotic (want the cell to live): BCL-2, BCL-XL (bodyguards of the mitochondria)

1. Internal damage signal activates BH3-only proteins (BIM, PUMA, etc.)
2. These neutralize BCL-2 and BCL-XL (the bodyguards)
3. Without bodyguards, BAX and BAK oligomerize → form pores in the outer mitochondrial membrane (MOMP — Mitochondrial Outer Membrane Permeabilization)
4. Cytochrome c leaks from the mitochondria into the cytoplasm
5. Cytochrome c + Apaf-1 + procaspase-9 → form the Apoptosome (a molecular machine)
6. Apoptosome activates caspase-9 → which activates executioner caspases 3, 6, 7 → cell death

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Pathway 3: p53-Mediated Pathway

1. DNA double-strand breaks detected by sensor kinases (ATM/ATR)
2. These kinases phosphorylate p53 → p53 stabilizes (normally p53 is continuously degraded)
3. p53 acts as a transcription factor — it "switches on" genes:
   • CDKN1A (p21) → stops cell cycle → gives time for DNA repair
   • If repair fails: PUMA, NOXA → engage the mitochondrial pathway → apoptosis
   • BAX → directly promotes mitochondrial pathway
   • FAS/FASL → can also engage the extrinsic pathway
4. Alternatively, p53 can directly interact with BCL-2 family proteins at the mitochondria (bypassing transcription for faster response)

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Pathway 4: Perforin-Granzyme Pathway

• Perforin: A protein that forms pores in the target cell membrane (works like a molecular drill)
• Granzyme B: A serine protease (enzyme that cuts proteins at specific sites)

1. CTL/NK cell forms a tight immune synapse with the target cell
2. CTL releases granules containing perforin and granzyme B into the synapse
3. Perforin polymerizes → inserts into the target cell membrane → forms a cylindrical pore
4. Granzyme B enters through the pore (or via receptor-mediated endocytosis followed by endosome rupture)
5. Inside the target cell, Granzyme B:
   • Directly cleaves and activates caspase-3 (executioner) → cell dismantles itself
   • Also cleaves BID → tBID → triggers mitochondrial pathway (double-barreled attack)
6. Target cell undergoes rapid, clean apoptosis

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TOPIC 22: Hypoxia, Free Radicals, and Vicious Cycles in Cell Damage

The Step-by-Step Story of Hypoxic Cell Death

Step 1: Oxygen Stops

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Step 2: ATP Depletion — Cascade of Failures

• Normally: pumps 3 Na⁺ out and 2 K⁺ in → maintains low sodium inside the cell
• When it fails: Na⁺ floods in → Cl⁻ follows → water follows osmotically → cell swells (this is why hypoxic cells look ballooned under the microscope)
• ER also swells (ER swelling + ribosome detachment = reduced protein synthesis)

• Normally: pumps Ca²⁺ out of the cell and into the ER
• When it fails: Ca²⁺ floods into the cytoplasm from outside AND from ER stores → cytosolic Ca²⁺ rises dramatically

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Step 3: Emergency Backup Fails Too

• Glucose → lactic acid + 2 ATP (much less efficient than aerobic respiration's 36-38 ATP)
• Lactic acid accumulates → intracellular acidosis (pH drops)
• Low pH INHIBITS glycolytic enzymes → the emergency backup SHUTS ITSELF DOWN
• Now even the meager anaerobic ATP production stops

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Step 4: Ca²⁺ Overload Activates Destructive Enzymes

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Step 5: Mitochondrial Permeability Transition (MPT)

• Mitochondrial membrane potential collapses → ATP synthesis is now impossible even if oxygen returns
• Mitochondria swell → outer membrane ruptures → cytochrome c leaks into cytoplasm → apoptosis pathway activated
• This is the critical "point of no return"

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Step 6: Lysosomal Rupture → Autodigestion

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The Role of Free Radicals in Cell Damage

Where do free radicals come from in hypoxia?

1. Depletion of antioxidants (glutathione, catalase are used up fighting oxidative stress)
2. Reperfusion injury — when oxygen returns to ischemic tissue, the now-damaged mitochondria produce a massive BURST of free radicals

1. Membrane lipids → lipid peroxidation chain reaction → membrane destruction
2. Proteins → oxidation of sulfhydryl groups → enzyme inactivation, protein cross-linking
3. DNA → oxidized bases, strand breaks → mutations or apoptosis signals

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The Vicious Cycle of Cellular Pathology

Hypoxia → No ATP
            ↓
   Ion pump failure → Na⁺ + H₂O in → CELL SWELLS
            ↓
      Ca²⁺ floods in
            ↓
  Phospholipases + Proteases activated
            ↓
    MEMBRANE DAMAGE + STRUCTURAL DAMAGE
            ↓
   MITOCHONDRIAL DAMAGE → Even less ATP
            ↓
         More Ca²⁺ overload
            ↓
   MORE enzyme activation → More damage
            ↑_________________________|
         (Loop continues until death)

• Acidosis → damages enzymes and cell structures
• Free radicals (especially on reperfusion) → amplify membrane and mitochondrial damage
• Lysosome rupture → final autodigestion → irreversible

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TOPIC 23: Mutations — Types, Causes, Hereditary Disease Classification

What is a Mutation?

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Causes of Mutations

Spontaneous (Endogenous) Causes:

• Replication errors: DNA polymerase makes occasional mistakes when copying DNA (about 1 error per billion base pairs — but the genome is 3 billion base pairs, so errors happen)
• Spontaneous chemical reactions:
  • Depurination: A purine base (A or G) falls off the DNA backbone → gap in the sequence
  • Deamination: Cytosine (C) is spontaneously converted to uracil (U) → reads as thymine → C→T transition mutation
• Spontaneous tautomeric shifts: Bases temporarily adopt alternative structures → form wrong base pairs

Induced (Exogenous Mutagens):

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Types of Mutations

By Scale (Size of Change):

• Deletion: Section of chromosome is lost → missing genes
• Duplication: Section is copied twice → extra gene copies
• Inversion: Section is reversed → genes are in wrong orientation
• Translocation: Section of one chromosome is moved to another

• Aneuploidy: Missing or extra whole chromosome (monosomy, trisomy)
• Polyploidy: Complete extra sets of chromosomes (rarely viable in humans)

By Location:

• Germline mutations — in egg or sperm cells → present in ALL cells of the child → can be inherited by offspring
• Somatic mutations — in any body cell after fertilization → only in that cell's descendants → cause cancer, NOT inherited

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Classification of Hereditary Diseases

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TOPIC 24: Chromosomal Diseases — Etiology, Pathogenesis, Classification

What Are Chromosomal Diseases?

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Etiology — How Chromosome Abnormalities Arise

Non-disjunction (Main Cause of Numerical Abnormalities)

• In young mothers, the eggs complete meiosis in days-weeks after fertilization
• A woman is born with all her eggs in a "frozen" state (arrested in meiosis I)
• In older women, eggs have been in this arrested state for 35-45 years → spindle checkpoint proteins have deteriorated → higher non-disjunction rate
• This explains why Down syndrome rate rises sharply with maternal age (1:1500 at 20 → 1:25 at 45)

Structural Abnormalities

• Chromosomal breakage: Radiation, chemicals break chromosomes → rejoined wrongly → inversions, translocations, deletions
• Unequal crossover: During meiosis, chromosomes exchange segments unequally → one gets too much, one gets too little

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Pathogenesis — Why Extra/Missing Chromosomes Cause Disease

• Transcription factors are thrown off balance → entire developmental pathways go wrong
• Structural proteins are in wrong ratios
• Signaling molecules are overabundant → wrong cellular responses
• The effects are complex, pleiotropic (affecting many systems simultaneously) and differ by chromosome

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Classification and Key Examples

Numerical Abnormalities

Structural Abnormalities

• Cri-du-chat syndrome (5p-): deletion of short arm of chromosome 5 → characteristic high-pitched cat-like cry in infancy (laryngeal malformation), intellectual disability, microcephaly
• Williams syndrome (7q11.23 microdeletion): deletion of elastin gene → elfin facial features, cardiovascular malformations (supravalvular aortic stenosis), overly friendly social behavior, surprisingly good verbal ability but poor visuospatial skills

• Robertsonian translocation (14;21): Two chromosomes fuse at their centromeres → carrier has 45 chromosomes but is normal; their offspring has a significantly increased risk of Down syndrome (familial Down syndrome)
• Philadelphia chromosome (t(9;22) in CML): BCR-ABL fusion → constitutively active tyrosine kinase → chronic myeloid leukemia

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TOPIC 25: Multifactorial Diseases; Somatic Genetic Diseases; Non-Traditional Inheritance

Multifactorial Diseases

What they are:

How to recognize them:

• Family clustering — more common in relatives of affected people, but NOT Mendelian ratios (not 25%, 50% etc.)
• Monozygotic (identical) twins: both affected MORE often than dizygotic (fraternal) twins — but NOT 100% concordance (proving environmental contribution)
• Risk INCREASES with number of affected first-degree relatives
• Threshold model: A person accumulates genetic and environmental risk factors. Once total risk crosses a threshold → disease appears. Most people never cross the threshold.

Examples:

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Genetic Diseases of Somatic Cells (Cancer)

• Mutations accumulate over a lifetime in a SINGLE body cell (somatic cell)
• These mutations affect oncogenes, tumor suppressor genes, DNA repair genes
• The mutated cell proliferates, passes mutations to daughters, accumulates more mutations → cancer
• These mutations are NOT present in germline → not inherited by children
• EXCEPTION: Germline mutations in tumor suppressor genes (BRCA1/2, RB1, TP53) PREDISPOSE to cancer — these ARE inherited → hereditary cancer syndromes

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Non-Traditional Inheritance — Four Special Patterns

1. Mitochondrial Inheritance (Maternal Inheritance)

• Mitochondria have their own DNA (mtDNA) — 37 genes, separate from the nuclear genome
• When sperm fertilizes egg → sperm's mitochondria are marked for destruction inside the egg → the embryo inherits ONLY the mother's mitochondria
• Therefore: mitochondrial diseases ONLY pass through mothers

• All children of an affected MOTHER can receive the mutation
• Children of an affected FATHER: NEVER get it from the father's mitochondria (those are destroyed)
• Heteroplasmy: A cell may contain a MIX of normal and mutant mitochondria. Disease severity depends on the ratio.

• MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like Episodes): episodes of stroke-like neurological deficits, seizures, lactic acidosis
• Leber's Hereditary Optic Neuropathy (LHON): Sudden, painless bilateral vision loss in young men (selective for retinal ganglion cells)

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2. Genomic Imprinting

Same deletion, same chromosome region, completely different diseases — because of which parent it came from!

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3. Trinucleotide Repeat Expansion (Dynamic Mutations)

• Most common inherited cause of intellectual disability
• CGG expansions >200 methylate (silence) the FMR1 gene → no FMRP protein → impaired synaptic plasticity
• Males affected more severely (only one X)
• Features: intellectual disability, large ears, prominent jaw, macroorchidism (large testes after puberty), autism spectrum behavior

• CAG repeat codes for glutamine → expanded polyglutamine tract in huntingtin protein
• Mutant huntingtin forms insoluble aggregates in neurons (especially striatum) → toxic → neuronal death
• Mid-life onset (35-50 years typically) → progressive chorea, dementia, psychiatric symptoms → fatal
• Autosomal dominant — one copy is enough to cause disease
• Anticipation: paternal transmission tends to expand the repeat more

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4. Uniparental Disomy (UPD)

• If an imprinted region is on that chromosome → disease (same as if the other parent's contribution were deleted)
• Example: Maternal UPD of chromosome 15 = child has two maternal copies of chr 15 → both imprinted copies in that region → no active paternal gene → Prader-Willi syndrome (even without any deletion)
• Also: UPD can unmask recessive mutations if both copies from one parent carry the same mutation

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TOPIC 26: Single-Gene (Monogenic) Diseases

Four Inheritance Patterns

1. Autosomal Dominant (AD)

• Example: Familial hypercholesterolemia → one LDLR gene → only 50% of normal LDL receptors → LDL not cleared from blood adequately → cardiovascular disease

• Example: Collagen mutations in osteogenesis imperfecta → even one wrong collagen chain in a collagen triple helix ruins the whole helix → extremely fragile bones

• Example: Huntington disease → expanded polyglutamine → forms toxic aggregates → kills neurons

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2. Autosomal Recessive (AR)

• 25% chance child has disease (homozygous mutant)
• 50% chance child is carrier (like parents)
• 25% chance child is completely normal

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3. X-Linked Recessive

• Affected fathers CANNOT pass it to sons (they give Y to sons)
• Affected fathers ALWAYS pass the mutation to daughters (all daughters of affected father are carriers)
• Carrier mothers have 50% chance of affected sons; 50% chance of carrier daughters

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4. X-Linked Dominant

• Rett syndrome (MECP2): Girls develop normally for 12-18 months → then lose purposeful hand use and speech → stereotyped hand-wringing → regression; seizures; autism features. Almost always lethal in males.
• Incontinentia pigmenti (NEMO): Skin, eye, and CNS involvement in females; lethal in males.

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TOPIC 27: Reactivity — Concept, Types, Determining Factors

What is Reactivity?

Simply put: How does the body respond when something acts on it?

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Types of Reactivity

1. Species (Phylogenetic) Reactivity

• All humans develop fever with endogenous pyrogens
• All humans have an HPA axis stress response
• Frogs don't respond to certain pathogens that kill humans
• Rats are naturally resistant to diphtheria toxin

2. Group Reactivity

• Women mount stronger inflammatory and immune responses
• Children have higher fever responses
• Elderly have blunted immune responses

3. Individual Reactivity

• One person might develop an allergy to penicillin; another doesn't
• One smoker develops lung cancer at 50; another smokes all their life without cancer

4. Specific (Immunological) Reactivity

• Antibody production against a specific virus
• T-cell memory for a specific pathogen
• The basis of vaccination

5. Non-specific Reactivity

• Inflammation (same basic process for bacteria, trauma, or chemical)
• Fever
• Phagocytosis
• Acute phase response

Physiological vs. Pathological Reactivity

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Factors That Modify Reactivity

Sex

• Estrogens enhance both innate and adaptive immunity → women mount stronger immune/inflammatory responses → more effective at fighting infections → but also more prone to autoimmune diseases (lupus, Hashimoto's thyroiditis, rheumatoid arthritis — all more common in women)
• Testosterone has mild immunosuppressive effects → men are more vulnerable to infections but less prone to autoimmunity

Age

• Neonates/Infants:
  • Immune system immature → low IgA (secretory immunity), low complement levels, immature T cells
  • CANNOT mount a robust fever response (thermoregulation immature) → fever unreliable indicator in newborns
  • Protected during first 6 months by maternal IgG passed through placenta and breast milk
  • Vulnerable to intracellular pathogens (Listeria), encapsulated bacteria (Haemophilus, Neisseria)
• Elderly:
  • Immunosenescence — the aging of the immune system
  • Thymus involutes → fewer naive T cells → reduced ability to respond to new antigens → reduced vaccine efficacy
  • Remaining T cells have reduced diversity in their receptors
  • Chronic low-grade inflammation ("inflammaging") — elevated baseline inflammatory cytokines → predisposes to atherosclerosis, Alzheimer's, cancer
  • Impaired wound healing, more susceptible to infection

Nutrition

• Protein-energy malnutrition: Severely impairs T-cell immunity (lymphocytes need amino acids to proliferate), phagocyte function, complement synthesis, antibody production
• Specific deficiencies: Vitamin A deficiency → impaired epithelial barrier; Zinc deficiency → impaired T-cell function; Iron deficiency → impaired neutrophil killing
• Obesity: Chronic low-grade inflammation from excess adipose tissue (adipose releases TNF-α, IL-6, leptin) → alters immune responses; impaired neutrophil function; increased infection risk

Nervous System (Psychoneuroimmunology)

• The brain and immune system are in constant bidirectional communication
• Nerve fibers innervate lymph nodes and bone marrow directly
• Neuropeptides (substance P, VIP, neuropeptide Y) modulate immune cell function
• Psychological stress → activates HPA axis → cortisol → immunosuppression
• Pavlovian conditioning can modulate immune responses: pairing a taste stimulus with an immunosuppressant drug → later, the taste alone can suppress the immune response
• Severe depression is associated with reduced NK cell activity and reduced vaccine responsiveness

Endocrine System

Immune System State

• Immunodeficiency (AIDS, DiGeorge syndrome, agammaglobulinemia) → hypoergic
• Allergy/Hypersensitivity → hyperergic to specific antigens
• Autoimmunity → dysergic (immune system targeting self)

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TOPIC 28: Resistance — Concept, Types, Examples; Difference from Reactivity

What is Resistance?

Simply put: How well can the body take a hit without getting sick?

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Types of Resistance

1. Non-specific Passive Resistance

2. Non-specific Active Resistance

3. Specific Resistance

• Antigen-specific antibodies
• Memory T and B cells
• This is the basis of herd immunity and vaccination

4. Innate (Primary, Hereditary) Resistance

• Species resistance: Humans don't get canine distemper; chickens don't get anthrax in their feathers (but die if given anthrax spores by injection)
• Individual genetic resistance: Sickle cell trait (HbAS) → partial resistance to Plasmodium falciparum malaria (the parasite can't thrive in HbS cells)
• CCR5 delta-32 mutation: People homozygous for this mutation lack the CCR5 co-receptor → HIV cannot enter their CD4 cells → natural resistance to HIV infection
• Black rats are naturally resistant to Yersinia pestis (plague bacteria cannot multiply in their macrophages)

5. Acquired Resistance

• Active: After infection or vaccination → immune memory
• Passive: Transfer of maternal antibodies; therapeutic immunoglobulin administration (short-lived)
• Non-immune acquired: Acclimatization (altitude training increases hypoxia resistance); physical training increases cardiovascular resistance

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Resistance vs. Reactivity — Key Differences

You can be HIGHLY REACTIVE but have LOW RESISTANCE. An anaphylactic patient responds explosively to a tiny amount of peanut protein — extremely reactive. But peanuts make them very sick — very low resistance to that allergen.

You can have LOW REACTIVITY but HIGH RESISTANCE. An immunosuppressed (low reactivity) patient might have strong physical barriers, healthy gut microbiome, and good skin integrity — reasonable resistance to surface pathogens even though they can't mount a proper immune response.

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TOPIC 29: Stress — Definition, Etiology, Types; Selye's Triad; GAS Stages

What is Stress?

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Types of Stress

By Outcome:

By Nature of Stressor:

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Selye's Triad — The Three Hallmarks of Stress

1. 🫀 Adrenal Cortex Hypertrophy (Enlargement)

• The adrenal cortex is overworked producing cortisol non-stop
• In response to sustained ACTH stimulation → adrenal cells grow in number and size → the gland physically enlarges
• This is visible even to the naked eye at autopsy in chronically stressed animals

2. 🫃 Thymus and Lymphoid Tissue Involution (Shrinkage)

• Elevated cortisol directly causes apoptosis of lymphocytes → thymus shrinks
• Lymph nodes and spleen also shrink
• Immune competence is progressively suppressed
• This explains why chronically stressed people get more infections and have less effective vaccines

3. 🫘 Gastric and Duodenal Ulcers

• Catecholamines cause vasoconstriction in the stomach wall → mucosal ischemia → weakens protective mucus layer
• Cortisol reduces mucus production and prostaglandin synthesis (prostaglandins normally protect the mucosa)
• Result: acid attacks an unprotected mucosa → ulcers form → can bleed or perforate

Memory trick: "Selye's Triad = Fat adrenals + Shrunken lymph tissue + Bleeding stomach"

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Stages of the General Adaptation Syndrome (GAS)

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Stage 1: Alarm Reaction

• Transient fall in blood pressure
• Brief drop in body temperature
• Transient hypoglycemia
• Brief decrease in defense capacity This is like the split second of "Oh no" before the body starts fighting.

• Hypothalamus activates → CRH released → pituitary releases ACTH → adrenal cortex releases CORTISOL
• Sympathetic nervous system activates → adrenal medulla releases ADRENALINE and NORADRENALINE
• Result: Heart rate and blood pressure rise; blood glucose surges; blood directed to muscles and brain; bronchioles dilate; pupils dilate; digestion suppressed
• Resistance to the stressor rises ABOVE BASELINE — the body is now in high-alert, fighting mode

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Stage 2: Stage of Resistance (Adaptation)

• Resistance to the ORIGINAL stressor is maintained above normal
• Cross-resistance can develop — resistance to OTHER stressors also improves somewhat
• The organism appears healthy and functions well
• But: Selye's triad changes are developing (adrenals enlarged, thymus shrinking, early mucosal changes)
• Energy reserves are being consumed constantly
• If the stressor is removed at this stage → full recovery is possible

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Stage 3: Stage of Exhaustion

• Adrenal cortex depleted → cortisol output drops → loss of anti-inflammatory protection
• All alarm symptoms RETURN but now the body has no capacity to respond to them
• Immune collapse → infections take hold
• Stress ulcers progress → bleed or perforate
• Multi-organ dysfunction
• If the stressor continues → death

Key insight: Exhaustion occurs NOT from a qualitatively different process, but simply because the same processes have used up all available biological reserves.

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TOPIC 30: GAS Pathogenesis; Protective and Damaging Effects of Stress Hormones

The Pathway: How Stress Hormones Get Activated

ANY STRESSOR
        ↓
[Sensory organs/pain receptors/baroreceptors]
        ↓
  LIMBIC SYSTEM
(Amygdala processes threat;
 Hippocampus provides context)
        ↓
  HYPOTHALAMUS
   ↙          ↘
CRH              Sympathetic
                  Activation
  ↓                   ↓
Anterior          Adrenal Medulla
Pituitary
  ↓                   ↓
ACTH          ADRENALINE (80%)
  ↓           NORADRENALINE (20%)
Adrenal
Cortex
  ↓
CORTISOL

1. Fast system (seconds): Sympatho-adrenomedullary axis → catecholamines released → "fight or flight" is on
2. Slower system (minutes to hours): HPA axis → cortisol released → "sustained metabolic mobilization"

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Stress Hormones: Protective Effects (What They're Designed For)

Adrenaline and Noradrenaline (Catecholamines) — Protective Actions

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Cortisol (Glucocorticoids) — Protective Actions

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Stress Hormones: Damaging Effects (When They Stay Too Long)

Catecholamines — Damaging Effects

Cortisol — Damaging Effects (Chronic Excess)

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Summary Comparison Table

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The Core Paradox of the Stress Response

This is why stress causes heart disease, depression, diabetes, immune dysfunction, and accelerated aging — all through the same biological hormones that evolved to protect you.

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