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General Nosology - Complete Study Guide

Based on Robbins & Kumar Basic Pathology, Robbins Cotran & Kumar Pathologic Basis of Disease, and standard pathophysiology curricula. Written in plain, simple language.

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1. Pathological Process, Pathological Reaction, Pathological Condition vs. Disease. Typical Pathological Processes

• Pathological reaction - the smallest, quickest abnormal response. It is short-lived and resolves on its own. Example: brief redness and swelling after a bee sting, or a brief rise in heart rate when frightened. It disappears once the stimulus is gone and leaves no lasting damage.
• Pathological process - a set of typical changes in cells and tissues that occurs in many different diseases and situations. It has its own mechanism, stages, and pattern - but it is NOT a disease by itself. Examples: inflammation, fever, edema, hypoxia, cell injury, thrombosis. The same process (e.g., inflammation) occurs whether you have pneumonia, appendicitis, or a sprained ankle.
• Pathological condition - a stable, persistent structural or functional deviation. It does not actively progress but it does not fully heal either. Example: a scar after a heart attack, a missing limb, post-operative adhesions. The organism is in a new "steady state."
• Disease - a complex, evolving process with a specific etiology, definite pathogenesis, specific clinical signs and symptoms, defined stages, and specific outcomes. A disease involves the whole organism and disrupts its adaptation to the environment. Example: type 2 diabetes, tuberculosis, hypertension.

• Inflammation
• Fever
• Hypoxia (oxygen deficiency)
• Thrombosis and embolism
• Edema
• Dystrophy (cellular degeneration)
• Atrophy
• Hypertrophy / hyperplasia
• Cell injury and necrosis
• Tumor growth

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2. Etiology - Causes and Conditions in Disease

• Exogenous (external - infections, trauma, toxins)
• Endogenous (internal - genetic defects, metabolic disorders)

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3. Pathogenesis - Main Mechanisms of Pathogenic Factors

1. Direct physical damage - mechanical agents tear membranes, electricity burns tissue, radiation breaks DNA strands.
2. Hypoxia and energy failure - most agents ultimately disrupt oxygen delivery. Without O2, the cell's ATP factories (mitochondria) fail. Without ATP: Na/K pumps stop → cell swells; Ca2+ pumps fail → calcium floods in; everything breaks down.
3. Oxidative stress (Free Radical damage) - many agents generate reactive oxygen species (ROS - superoxide, H2O2, hydroxyl radical). ROS attack lipid membranes (lipid peroxidation), proteins, and DNA.
4. Calcium overload - intracellular Ca2+ normally is very low (~0.1 µmol). Injury raises it dramatically, activating destructive proteases, phospholipases, and endonucleases.
5. Membrane damage - phospholipase activation, oxidative stress, or mechanical stretching disrupts the plasma membrane, letting toxins in and vital molecules out.
6. DNA damage - radiation, chemicals, and ROS damage the genetic code, leading to mutations, impaired protein synthesis, or triggering cell death (apoptosis).
7. Protein misfolding - stress causes proteins to fold incorrectly → ER stress → activation of damaging pathways.
8. Inflammatory mediators - cytokines (TNF, IL-1, etc.) amplify damage beyond the initial site.

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

• Physical (ischemia, hyperthermia)
• Chemical (acidosis, hypoxia products, excess Ca2+)
• Biological (activated proteases, cytokines)
• Neurogenic (altered nerve signaling)
• Immune (antibodies that attack self-tissue)

• Example in shock: Low blood pressure → less blood to heart → weaker heart output → even lower blood pressure → worsening shock. The disease accelerates itself.
• Example in cell injury with hypoxia: ATP depletion → pump failure → cell swelling → more membrane damage → more ATP loss.

• Etiological therapy = removes the cause (antibiotics for infection)
• Pathogenetic therapy = breaks the disease chain (fluids in shock, antihypertensives in hypertension)
• Symptomatic therapy = relieves symptoms only (painkillers)

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5. Outcomes of Disease. Mechanisms of Recovery. Protective-Adaptive Reactions. Compensation

1. Full recovery - complete restoration of structure and function
2. Recovery with defect - function restored, but some structural damage remains (e.g., scar)
3. Transition to chronic - disease persists long-term
4. Disability - permanent functional impairment
5. Death - complete failure of vital functions

• Urgent (emergency) mechanisms: Activated immediately. Examples: increased heart rate and breathing, pain reflex withdrawal, fever, blood clotting, inflammation.
• Relative stabilization mechanisms: Activated over hours-days. Examples: cardiovascular compensation in blood loss (increased cardiac output, vasoconstriction), activation of kidney compensation.
• Long-term (sustained) mechanisms: Activated over weeks-months. Examples: hypertrophy of the remaining kidney after one is removed, callus formation on bone fractures, immune memory.

• Hypertrophy - surviving cells grow bigger (e.g., one kidney hypertrophies after the other is removed)
• Hyperplasia - cells multiply (e.g., liver regeneration)
• Functional redistribution - other organ systems take over (e.g., lungs compensate for acidosis by increasing breathing rate)

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6. Pathogenic Action of Mechanical Factors. Crush Syndrome

• Direct cell membrane disruption (tearing)
• Compression → ischemia → hypoxia
• Shear forces destroying cell architecture
• Bleeding and hematoma formation

1. During compression: Muscles are ischemic (no blood flow). Cells are energy-starved but alive.
2. After release (reperfusion): Blood flow suddenly returns. This triggers:
   • Massive myocyte death → release of myoglobin, potassium, phosphate, and creatine kinase into blood
   • "Reperfusion injury" - returning blood brings oxygen that generates a sudden burst of ROS
3. Myoglobinemia: Myoglobin (from dead muscle) floods the blood.
4. Acute kidney injury: Myoglobin is filtered by glomeruli but is toxic to tubular cells - it precipitates in acidic urine, blocks tubules, and causes acute tubular necrosis → renal failure.
5. Hyperkalemia: Released potassium from dead cells can cause fatal heart arrhythmias.
6. Hypovolemic shock: Fluid shifts into damaged tissue (third spacing) → reduced blood volume → shock.
7. DIC (disseminated intravascular coagulation) can develop due to tissue factor release from necrotic muscle.

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7. Shock - Definition, Types, General Pathogenesis

1. Decreased effective circulating volume (either real loss or maldistribution)
2. Decreased cardiac output → hypotension
3. Compensatory phase: Baroreceptors detect low pressure → adrenaline and noradrenaline released → tachycardia, vasoconstriction, oliguria. (This phase can maintain BP for a while)
4. Progressive phase: Compensation fails. Hypoxia worsens in tissues. Cells shift to anaerobic metabolism → lactic acidosis. Acidosis further weakens the heart and vessels.
5. Irreversible phase: Multi-organ failure (kidney, lung, liver, heart), disseminated intravascular coagulation. Death is inevitable even with treatment.

• Cardiogenic shock: Myocardial contractility failure
• Hypovolemic: Low preload (not enough blood returning to heart)
• Septic shock: Cytokine storm → massive vasodilation, endothelial damage, coagulopathy

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8. Pathogenic Action of Low Temperature. Hypothermia

• Vasoconstriction of skin vessels (to preserve core temperature) → skin appears pale, numb
• Shivering - muscle heat generation (emergency mechanism)
• Increased heart rate initially, then slowing
• Local cold injury: frostbite - ice crystals form in cells → direct membrane damage; on thawing, reperfusion injury occurs

1. Mild (32-35°C): Shivering, tachycardia, vasoconstriction, confusion. Body is still fighting to maintain temperature.
2. Moderate (28-32°C): Shivering stops (muscle ATP depleted). Heart rate slows (bradycardia). Drowsiness. Dangerous arrhythmias begin.
3. Severe (<28°C): Loss of consciousness, ventricular fibrillation risk, no reflexes, apparent "death."

• Ice crystal formation → membrane puncture
• Slowing of enzymatic reactions → metabolic failure
• Vascular damage → edema on rewarming
• Paradoxical cold-induced vasodilation ("paradoxical undressing" - seen before death)

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

1. High temperature denatures enzymes
2. Cell membranes lose fluidity and function
3. Endothelial damage → DIC
4. Liver, kidney, and brain damage from direct heat injury + hypoxia

1. Burn shock (0-3 days): Massive fluid loss through burned skin + fluid shift into tissues (third spacing) → hypovolemic shock. Also: high potassium from dead cells.
2. Acute burn toxemia (days 3-10): Absorption of burn toxins (denatured proteins, bacteria) → fever, tachycardia, organ stress.
3. Septicemia (days 10-30+): Burned skin is no barrier to infection. Bacteria enter bloodstream → sepsis.
4. Exhaustion/recovery: Prolonged catabolic state, muscle wasting, wound healing.

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10. Low Barometric Pressure & Low O₂ Partial Pressure. Altitude Sickness

• Increased breathing rate (hyperventilation) - raises O2 in lungs
• Increased heart rate and cardiac output
• Kidneys retain bicarbonate (to compensate for respiratory alkalosis from hyperventilation)
• Increased red blood cell production (EPO from kidney → more RBCs → more O2 carrying capacity)
• Cells shift: more mitochondria, more 2,3-DPG (helps hemoglobin release O2 to tissues)

• Hyperventilation causes respiratory alkalosis
• Cerebral vasoconstriction → headache, confusion
• Pulmonary hypertension → fluid leaks into lungs
• Brain and lung edema

• Acute Mountain Sickness (AMS): Headache, nausea, fatigue, poor sleep. Onset 6-12 hrs after ascent.
• High-Altitude Pulmonary Edema (HAPE): Fluid in lungs → breathlessness, pink frothy sputum. Life-threatening.
• High-Altitude Cerebral Edema (HACE): Brain edema → confusion, ataxia, coma. Life-threatening.

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11. High Barometric Pressure. Caisson Disease

1. Nitrogen bubbles form in joints, muscles, spinal cord, brain, lungs
2. Bubbles obstruct small vessels → ischemia
3. Bubbles activate complement and coagulation
4. Mechanical tissue damage from bubble expansion

• Joint pain ("bends") - the classic symptom
• Neurological signs (spinal cord bubbles) - paralysis
• Chokes: chest pain, cough (lung bubbles)
• Long term: avascular necrosis of bone (femoral head)

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12. Pathogenic Effects of Electricity

1. Type of current: AC (alternating current) is more dangerous than DC at same voltage - causes tetanic muscle spasm (including respiratory muscles)
2. Voltage and amperage: Higher = more damage. Household current can be fatal.
3. Duration of contact: Longer = more energy transferred
4. Path through body: Heart-to-heart path (hand-to-hand) is most dangerous (arrhythmias); current through brain also fatal
5. Body resistance: Dry skin has high resistance (protection); wet skin has low resistance (much more dangerous)
6. Frequency: 50-60 Hz (household) is most dangerous to the heart

• Entry and exit burns (electrothermal burns) - often worse than they look; deep tissue destruction
• Muscle coagulation necrosis along current path
• Vascular thrombosis

• Cardiac arrest (ventricular fibrillation) - most common cause of death
• Respiratory arrest - tetanic spasm of respiratory muscles
• Neurological effects - loss of consciousness, seizures, brain damage
• Rhabdomyolysis - massive muscle destruction → acute kidney injury (same as crush syndrome)
• Secondary injury - falls due to muscle spasm

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13. Pathogenic Action of Sound, Noise, and Ultrasound

• Sound is mechanical vibration. Excessive sound causes noise-induced hearing loss (NIHL).
• Mechanism: high energy sound waves create mechanical overload on the hair cells (stereocilia) of the organ of Corti in the cochlea → metabolic exhaustion, mechanical damage → hair cell death (these cells do NOT regenerate in humans)
• Acute: very loud noise (gunshot, explosion) causes immediate hair cell destruction - barotrauma
• Chronic: long-term moderate noise causes gradual loss - begins with high frequency hearing loss (4000 Hz dip on audiogram)
• Beyond the ear: chronic noise activates the stress response - elevated cortisol and adrenaline → cardiovascular effects (hypertension)

• Diagnostic ultrasound (medical) is safe - low intensity
• High-intensity ultrasound (industrial, therapeutic): cavitation (formation and implosion of microscopic bubbles in fluid) causes local tissue destruction
• Also: local heating of tissue
• Therapeutic use: lithotripsy (breaking kidney stones), physiotherapy

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14. Ionizing Radiation. Radiation Sickness. Chronic Radiation Sickness

1. Direct effect: Radiation directly breaks chemical bonds, especially in DNA (single-strand and double-strand breaks)
2. Indirect effect (more important): Radiation ionizes water molecules → generates reactive oxygen species (ROS, free radicals) → these attack DNA, proteins, and lipids

• Bone marrow (hematopoietic cells)
• Intestinal epithelium
• Gonads (sperm and egg precursors)
• Skin epithelium
• Embryo/fetus

1. Formation stage: Gradual accumulation of damage. Non-specific symptoms: fatigue, headache, sleep disturbances, decreased appetite. Changes in the nervous system dominate at first.
2. Established stage: Bone marrow suppression becomes visible. Anemia, leukopenia, thrombocytopenia → infections, hemorrhages. Immune deficiency. Degenerative changes in nervous system.
3. Recovery stage: If exposure stops and dose was sublethal - gradual recovery; though some damage (genetic mutations, increased cancer risk) is permanent.

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15. Acute Radiation Sickness - Forms and Changes

1. Primary reaction (hours): Nausea, vomiting, headache, fever, weakness. Caused by products of cell breakdown and CNS effects of radiation.
2. Latent (apparent recovery) phase (days to weeks): Patient feels better. But behind the scenes, bone marrow is being destroyed. Duration inversely proportional to dose.
3. Manifest illness phase: Bone marrow failure becomes clinically apparent:
   • Leukopenia (low white cells) → severe infections, sepsis
   • Thrombocytopenia (low platelets) → bleeding, hemorrhage
   • Anemia (low red cells) → fatigue, shortness of breath
   • GI damage: mouth ulcers, diarrhea, malabsorption
   • Hair loss (alopecia)
4. Recovery (if survived): Gradual reconstitution of bone marrow (stem cells that survived begin multiplying). Takes weeks to months.

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16. Cell Injury - Definition and Classification

• Reversible injury: Cell is damaged but can recover if the stimulus is removed. The cell is stressed but alive. Signs: swelling, fatty change, mitochondrial swelling.
• Irreversible injury: The "point of no return" is passed - the cell will die. Signs: severe membrane damage, massive calcium influx, complete ATP depletion.

• Acute (sudden, e.g., ischemia)
• Chronic (gradual, e.g., repeated toxin exposure)

• Hypoxic/ischemic
• Toxic (chemical, drugs)
• Infectious
• Immunological
• Genetic
• Nutritional
• Physical (trauma, radiation, heat, electricity)

• Injury → adaptation (hypertrophy, atrophy, etc.)
• Injury → reversible damage → recovery
• Injury → irreversible damage → necrosis or apoptosis

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17. Typical Manifestations of Cell Injury. Metabolic Changes

• Cell swelling (the earliest sign): Na/K pump fails without ATP → sodium accumulates inside → water follows → cell balloons up
• Fatty change: In liver and heart - lipid droplets accumulate (fat metabolism disrupted)
• Loss of microvilli (brush border of intestinal cells)
• Membrane blebbing (plasma membrane bulges outward)
• Mitochondrial swelling
• Dilation of the endoplasmic reticulum
• Clumping of chromatin in nucleus

1. ATP depletion: The central problem. Without oxygen: mitochondria switch to anaerobic glycolysis → much less ATP produced.
2. Lactic acid accumulation: Anaerobic metabolism makes lactic acid → intracellular acidosis (pH drops) → enzymes work poorly.
3. Na/K pump failure: Na+ and water enter cell → cell swelling. K+ leaks out.
4. Ca2+ influx: Intracellular Ca2+ rises dramatically → activates:
   • Phospholipases → destroy membranes
   • Proteases → destroy cytoskeletal proteins
   • Endonucleases → destroy DNA
   • ATPases → further deplete ATP
5. Increased membrane permeability: Cell contents (LDH, troponin, creatine kinase) leak out - this is why we measure these enzymes in blood to detect cell damage!
6. Ribosome detachment from ER: Protein synthesis stops.

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18. Disturbance of the Barrier Function of the Plasma Membrane

A. Mechanical Stretching

B. Membrane Phospholipases

• Elevated intracellular Ca2+ (from ischemia, toxins)
• Acidosis

C. Lipid Peroxidation (Free Radical Attack)

1. OH• attacks a fatty acid → fatty acid becomes a lipid radical
2. The lipid radical attacks a neighboring fatty acid → chain reaction
3. Result: membrane fatty acids are oxidized → lipid hydroperoxides form → membrane loses fluidity, becomes rigid, then breaks apart

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19. Matrix (Structural) Functions of the Plasma Membrane - Causes, Pathogenesis, and Consequences of Impairment

• Anchors the cytoskeleton (via integrins and spectrin)
• Maintains cell shape
• Mediates cell-cell and cell-matrix adhesion
• Contains receptors and ion channels

• Cytoskeletal disruption by proteases (activated by Ca2+)
• Mutations in structural proteins (e.g., spectrin mutations in hereditary spherocytosis)
• Autoantibodies against membrane proteins
• Physical damage

• Loss of cytoskeletal anchorage → membrane blebs form (balloon-like bulges)
• Bleb formation → eventual separation of membrane fragments
• Loss of cell polarity (in epithelial cells) → loss of tight junctions → barrier function fails in organs

• Red blood cells: abnormal shape → premature destruction by spleen → hemolytic anemia
• Epithelial cells: loss of tight junctions → leaky gut or leaky lung (edema)
• Muscle cells: membrane fragility → muscular dystrophy (e.g., dystrophin mutations in Duchenne)
• Endothelial cells: loss of shape → vascular leakage → edema and inflammation

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20. Main Forms of Cell Death - Necrosis and Apoptosis

Necrosis

• Cell swelling then rupture
• Eosinophilia (pink staining - due to protein denaturation)
• Nuclear changes: pyknosis (shrinkage) → karyorrhexis (fragmentation) → karyolysis (dissolution)
• Leakage of cell contents → inflammation

• Ischemic: from oxygen cut-off
• Toxic: from chemical/drug damage
• Traumatic: from mechanical injury
• Infectious: bacterial toxins, viruses

Apoptosis

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21. Signs of Apoptosis and Its Mechanisms

• Cell shrinkage (opposite of necrosis)
• Chromatin condensation - dense, crescentic clumps at nuclear periphery
• Nuclear fragmentation - nucleus breaks into pieces
• Membrane blebbing - surface bubbles form
• Apoptotic bodies - cell breaks into membrane-enclosed fragments containing organelles and nuclear material
• Phagocytosis of fragments by neighboring cells or macrophages - NO inflammation
• DNA ladder on gel electrophoresis (characteristic 180-bp fragments from endonuclease activity)

1. Mitochondrial (Intrinsic) Pathway

• BH3-only sensor proteins activate BAX and BAK
• BAX/BAK punch holes in mitochondrial outer membrane
• Cytochrome c leaks into the cytoplasm
• Cytochrome c + Apaf-1 + procaspase-9 form the "apoptosome"
• Apoptosome activates caspase-9 → activates executioner caspases (3, 6, 7)
• BCL-2 and BCL-XL proteins inhibit this pathway (survival signals)

2. Receptor-Mediated (Extrinsic/Death Receptor) Pathway

• Ligand binds receptor → receptor trimerizes → recruits adaptor protein FADD
• FADD activates procaspase-8 → active caspase-8 → executioner caspases
• Used to eliminate self-reactive lymphocytes and virus-infected cells

3. p53-Mediated Pathway

• DNA damage → p53 protein accumulates
• p53 is "guardian of the genome" - it can either stop the cell cycle (to allow repair) or trigger apoptosis if damage is irreparable
• p53 activates BAX and Apaf-1 transcription → feeds into the mitochondrial pathway

4. Perforin-Granzyme Pathway (Cytotoxic T lymphocyte pathway)

• Cytotoxic T cells (CTLs) recognize infected or malignant cells
• CTLs release perforin (punches pores in target cell membrane) and granzymes (proteases that enter through pores)
• Granzyme B directly activates executioner caspases inside the target cell
• Also activates BID (a BH3-only protein) → triggers mitochondrial pathway
• This is how the immune system kills virus-infected cells

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

1. O2 drops → mitochondria cannot make ATP via oxidative phosphorylation
2. Switch to anaerobic glycolysis → lactic acid accumulates → pH drops
3. ATP depletion effects:
   • Na/K-ATPase fails → Na+ and water enter → cell swells
   • Ca2+-ATPase fails → Ca2+ floods cytoplasm
   • Ribosome detachment → protein synthesis stops
4. High Ca2+ activates phospholipases → membrane damage
5. High Ca2+ activates proteases → cytoskeleton damage
6. Lysosomes rupture → acid hydrolases digest the cell from within

• During ischemia: xanthine oxidase is activated; NADPH oxidase primed
• When blood returns (reperfusion): sudden O2 arrival creates burst of ROS
• ROS attack membranes (lipid peroxidation chain reaction)
• ROS oxidize proteins → enzymes denature
• ROS cause DNA strand breaks

• Superoxide dismutase (converts O2•− → H2O2)
• Catalase and glutathione peroxidase (convert H2O2 → H2O)
• Vitamins C and E

Hypoxia → ATP↓ → Na pump fails → Cell swells
                                         ↓
                               Membrane damage
                                         ↓
                        More Ca2+ enters (membrane leaky)
                                         ↓
                    Phospholipases + proteases activated
                                         ↓
                         Even more membrane damage
                                         ↓
                          Cell cannot recover → necrosis
                                         ↑
                         ATP depleted further ←┘

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23. Mutations - Causes, Types, Role in Hereditary Disease. Classification of Hereditary Diseases

• Spontaneous: Errors in DNA replication, spontaneous base deamination
• Induced (mutagenic agents):
  • Physical: ionizing radiation (X-rays, gamma rays, UV light)
  • Chemical: alkylating agents, benzene, aflatoxin, cigarette smoke
  • Biological: some viruses (integrating viral DNA near oncogenes)

• Gene (point) mutations: Change in a single base pair - substitution, insertion, or deletion
  • Missense: Changed codon → different amino acid (e.g., sickle cell - glutamate → valine)
  • Nonsense: Changed codon → stop codon → truncated protein
  • Frameshift: Insert or delete base(s) → shifts reading frame → completely different protein
• Chromosomal mutations: Deletions, duplications, inversions, translocations of large segments
• Genomic mutations: Changes in chromosome number (aneuploidy, polyploidy)

• Germline (hereditary): In germ cells - passed to offspring
• Somatic: In body cells - not inherited; can cause cancer

1. Monogenic (single-gene) diseases - mutation in one gene (e.g., cystic fibrosis, Huntington's)
2. Chromosomal diseases - changes in chromosome number or structure (e.g., Down syndrome)
3. Multifactorial diseases - multiple gene variants + environmental factors (e.g., diabetes, hypertension)
4. Mitochondrial diseases - mutations in mitochondrial DNA
5. Epigenetic/imprinting disorders - abnormal gene expression without DNA change

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24. Chromosomal Diseases - Etiology, Pathogenesis, Classification

• Meiosis: Non-disjunction (chromosomes fail to separate) → gamete has wrong number → offspring has trisomy or monosomy
• Mitosis after fertilization: Post-zygotic non-disjunction → mosaic patterns
• Structural rearrangements: Deletions, translocations, inversions, duplications during DNA repair or replication

• Too many or too few copies of genes disrupt the dosage of gene products
• Even one extra chromosome (trisomy) means ~50% more copies of all genes on that chromosome - this disrupts development
• Most trisomies and monosomies are lethal in utero (spontaneous abortion)
• Only certain chromosomes are "survivable" in trisomy (13, 18, 21, sex chromosomes)

• Trisomy 21 (Down syndrome): Intellectual disability, characteristic facial features, heart defects, increased risk of leukemia and Alzheimer's
• Trisomy 18 (Edwards syndrome): Severe intellectual disability, heart/kidney defects, usually fatal by age 1
• Trisomy 13 (Patau syndrome): Brain malformations, usually fatal early
• Turner syndrome (45,X): Female, short stature, gonadal dysgenesis, infertility, no Barr body
• Klinefelter syndrome (47,XXY): Male, tall, testicular atrophy, infertility, gynecomastia

• Deletions (e.g., 5p- = Cri du chat syndrome)
• Translocations (e.g., Philadelphia chromosome t(9;22) in CML - though this is a somatic mutation)
• Inversions
• Ring chromosomes

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

Multifactorial Diseases

• Caused by interaction of multiple gene variants (polymorphisms) + environmental triggers
• Neither genetics nor environment alone causes disease - both are needed
• Examples: type 2 diabetes, hypertension, coronary artery disease, schizophrenia, asthma, most common birth defects (neural tube defects, cleft lip)
• Risk increases with number of affected relatives (polygenic threshold model)
• Often show: familial clustering, concordance in twins (identical > fraternal but not 100%)

Genetic Diseases of Somatic Cells (Acquired genetic changes)

• Mutations occurring in non-germline cells after birth
• The key example is cancer - mutations in proto-oncogenes, tumor suppressor genes, DNA repair genes
• Not inherited by children
• Each cancer cell lineage has its own unique set of somatic mutations

Hereditary Diseases with Non-Traditional Inheritance:

• Mitochondrial DNA is inherited only from the mother (all mitochondria come from the egg)
• Diseases: MELAS, MERRF, Leber's hereditary optic neuropathy
• Pattern: all children of affected mother are affected; no paternal transmission

• Some genes are expressed only from the maternal chromosome, others only from the paternal one - depends on which parent contributed the gene
• Loss of the maternal copy of 15q11-13 → Angelman syndrome (happy puppet syndrome)
• Loss of the paternal copy of 15q11-13 → Prader-Willi syndrome (hyperphagia, obesity, mild intellectual disability)

• Certain genes contain short repeated sequences (e.g., CAG) that can expand over generations
• More repeats = more severe disease (anticipation)
• Examples: Huntington's disease (CAG in HTT gene), Fragile X syndrome (CGG in FMR1), Myotonic dystrophy

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

Autosomal Dominant (AD)

• One mutant allele is enough to cause disease
• Affected person has 50% chance of passing it to each child
• Mechanism: usually loss of function of a structural/signaling protein OR dominant negative effect (mutant protein interferes with normal protein)
• Examples:
  • Huntington's disease (toxic gain-of-function of expanded huntingtin)
  • Marfan syndrome (FBN1 gene - fibrillin-1 defect - weak connective tissue: tall, aortic dilation, lens dislocation)
  • Familial hypercholesterolemia (LDL receptor defect - early atherosclerosis)
  • Neurofibromatosis (NF1 gene)

Autosomal Recessive (AR)

• Need two mutant alleles (one from each parent) to show disease
• Carriers (one allele) are usually healthy
• Examples:
  • Cystic fibrosis (CFTR gene - Cl- channel defect → thick mucus in lungs and GI)
  • Sickle cell disease (HBB gene - beta globin point mutation → abnormal hemoglobin S → sickling under low O2)
  • Phenylketonuria (PKU) (PAH gene - phenylalanine hydroxylase defect → phenylalanine accumulates → brain damage if untreated)
  • Tay-Sachs (HEXA gene - hexosaminidase A defect → GM2 ganglioside accumulates in neurons)

X-Linked Recessive

• Gene on the X chromosome. Males (XY) have only one copy - one mutation is enough to cause disease. Females are usually carriers.
• Examples:
  • Hemophilia A (Factor VIII deficiency - bleeding disorder)
  • Duchenne muscular dystrophy (dystrophin deficiency - progressive muscle weakness)
  • G6PD deficiency (hemolytic anemia triggered by oxidative stress)
  • Color blindness

X-Linked Dominant (rare)

• One copy is enough; affected males often more severely affected

Pathogenetic mechanisms:

• Enzyme deficiency → substrate accumulates (storage diseases) or product is absent
• Defective structural proteins → weakness of vessel walls, connective tissue, muscle
• Receptor/transporter defects → substance accumulates in blood or is missing from cells
• Transcription factor defects → abnormal development

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27. Reactivity - Definition, Types, Dependence on Regulatory Systems

1. Species (biological) reactivity: Responses common to all members of a species (e.g., all humans develop fever in response to infection)
2. Group reactivity: Responses common to a group (by age, sex, race, constitution):
   • Children: more reactive to infections; fever tends to be higher; less immune memory
   • Elderly: reduced reactivity (less fever, less inflammation, more susceptible to infections)
   • Males vs. females: different hormonal influences (estrogens generally enhance immune reactivity)
3. Individual reactivity: Unique response pattern of a specific person (based on genetics, experience, condition)
4. Specific reactivity: The immune response - specifically directed against a particular antigen (antibody formation, T-cell activation)
5. Nonspecific reactivity: General defense responses not directed at one antigen (fever, inflammation, acute phase proteins)
6. Physiological reactivity: Normal, within the healthy range
7. Pathological reactivity: Exaggerated, diminished, or qualitatively altered - the basis of hypersensitivity, allergy, or immunodeficiency

• Nervous system: Higher activity → lower reactivity (less explosive responses). Inhibits excessive immune activation. Vagus nerve has anti-inflammatory effects.
• Endocrine system: Glucocorticoids (cortisol) → suppress inflammation, reduce immune reactivity. Sex hormones → estrogen enhances immunity; testosterone is slightly immunosuppressive. Thyroid hormones → increase general reactivity.
• Immune system: Its own state determines specific reactivity. Immunodeficiency → low reactivity. Autoimmune states → excessive reactivity.

• Age: Children and elderly have altered reactivity
• Sex: Hormonal differences
• Nutrition: Protein deficiency → reduced reactivity
• Sleep and fatigue: Reduce reactivity
• Prior disease: Alter subsequent responses

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28. Resistance - Definition, Types, Difference from Reactivity

1. Nonspecific resistance: Defense against any harmful agent, not requiring prior contact. Examples:
   • Skin and mucous membranes as physical barriers
   • Stomach acid (kills bacteria)
   • Lysozyme in tears and saliva
   • Phagocytes (macrophages, neutrophils)
   • Complement system
   • Natural killer cells
2. Specific resistance (immunity): Defense against a specific pathogen, requiring prior exposure (or vaccination). Examples:
   • Antibodies (immunoglobulins)
   • Memory T and B cells
   • Vaccination-induced immunity
3. Active resistance: The organism's own mechanisms
4. Passive resistance: Transferred from outside - e.g., maternal antibodies to newborn, immune serum
5. Absolute resistance: Complete inability to be affected (e.g., humans are absolutely resistant to canine distemper virus)
6. Relative resistance: Depends on dose and conditions (most human resistance is relative)

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

• Physical stressors: trauma, cold, heat, infection, pain, surgery, hemorrhage
• Psychological stressors: fear, anger, anxiety, grief, conflict
• Biological stressors: infection, toxins, heavy physical exercise
• Any stimulus that threatens homeostasis

1. Eustress ("good stress"): Moderate, short-lived, enhances performance and adaptation. Example: exercise, excitement, challenge.
2. Distress ("harmful stress"): Excessive or prolonged, damages the organism. Example: chronic work overload, chronic pain.
3. Acute stress: Brief, intense (fight-or-flight response)
4. Chronic stress: Persistent, leads to pathological changes over time

1. Adrenal cortex hypertrophy (enlarged adrenal glands from chronic stimulation)
2. Thymus and lymph node atrophy (immune suppression by glucocorticoids)
3. Gastric and duodenal ulcers (excess cortisol + sympathetic stimulation → reduced mucus, increased acid)

1. Alarm reaction stage:
   • Immediate response to stressor
   • "Fight or flight" - adrenaline and noradrenaline released from adrenal medulla
   • Signs: increased heart rate, blood pressure, respiratory rate, blood glucose; dilated pupils, blood shifted to muscles
   • Brief resistance falls before rising (shock phase), then countershock follows
   • CRH → ACTH → cortisol axis activates
2. Stage of resistance (adaptation):
   • The organism is fully mobilized and coping with the stressor
   • Cortisol levels remain high - anti-inflammatory, anti-immune, protein-catabolizing, gluconeogenic
   • The organism appears to function normally but is burning resources
   • Adaptation to this specific stressor, but possibly reduced resistance to other stressors
3. Stage of exhaustion:
   • Resources are depleted. Adrenal glands can no longer maintain cortisol production. Adaptive mechanisms fail.
   • Return of alarm reaction symptoms, but now they cannot be compensated
   • Immune suppression → infections
   • Metabolic exhaustion: muscle wasting, organ failure
   • Disease of adaptation (ulcers, hypertension, immunodeficiency, diabetes) develops
   • Death if stressor continues

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

1. Stressor perceived by cortex or sensory pathways
2. → Hypothalamus releases CRH (corticotropin-releasing hormone)
3. → Anterior pituitary releases ACTH (adrenocorticotropic hormone)
4. → Adrenal cortex releases cortisol (glucocorticoid)
5. Simultaneously: hypothalamus activates sympathetic nervous system
6. → Adrenal medulla releases adrenaline (epinephrine) and noradrenaline (norepinephrine)

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Quick Reference Summary Table

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