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// =====================================================================
// COVER SLIDE
// =====================================================================
addCoverSlide("Cell Injury, Cell Death\n& Adaptations", "Chapter 2 – Robbins & Kumar Pathologic Basis of Disease");

// =====================================================================
// SECTION 1: Cellular Adaptations
// =====================================================================
addSectionDivider(1, "Cellular Adaptations", "1A3A5A");

addCard(1,
  "What are the four main cellular adaptations to stress? Give one example of each.",
  [
    "1. Hypertrophy – increase in CELL SIZE (e.g., cardiac muscle in hypertension)",
    "2. Hyperplasia – increase in CELL NUMBER (e.g., endometrial hyperplasia with estrogen)",
    "3. Atrophy – decrease in cell size/number (e.g., muscle disuse)",
    "4. Metaplasia – change in cell phenotype (e.g., Barrett esophagus: squamous → columnar)",
    "★ KEY: All are reversible if the stimulus is removed"
  ],
  "Adaptations"
);

addCard(2,
  "What is hypertrophy? What are its physiologic and pathologic examples?",
  [
    "Increase in CELL SIZE (not number), with increased functional capacity",
    "Physiologic: uterus during pregnancy; skeletal muscle with exercise",
    "Pathologic: left ventricular hypertrophy in hypertension",
    "Mechanism: growth factors (IGF-1, TGF-β), mechanical sensors → gene activation → increased protein synthesis",
    "★ Pure hypertrophy occurs in non-dividing cells (cardiac, skeletal muscle)"
  ],
  "Hypertrophy"
);

addCard(3,
  "What is hyperplasia? When is it pathologic vs physiologic?",
  [
    "Increase in CELL NUMBER due to growth factor-driven proliferation",
    "Physiologic: regenerative (liver after hepatectomy); hormonal (breast/uterus at puberty)",
    "Pathologic: endometrial hyperplasia (excess estrogen) → risk of carcinoma",
    "Viral: HPV causes epithelial hyperplasia (warts) → can precede cancer",
    "★ Hyperplasia occurs only in cells capable of division (NOT cardiac/neurons)"
  ],
  "Hyperplasia"
);

addCard(4,
  "List 6 causes of pathologic atrophy.",
  [
    "1. Decreased workload (disuse atrophy) – plaster cast immobilization",
    "2. Loss of innervation (denervation atrophy)",
    "3. Diminished blood supply (senile brain atrophy)",
    "4. Inadequate nutrition (marasmus, cachexia)",
    "5. Loss of endocrine stimulation (post-menopause endometrium/breast)",
    "6. Pressure atrophy (benign tumor compressing adjacent tissue)",
    "Mechanism: ↓ protein synthesis + ↑ ubiquitin-proteasome degradation + autophagy"
  ],
  "Atrophy"
);

addCard(5,
  "What is metaplasia? Give 3 clinical examples and explain its significance.",
  [
    "Reversible change in which one differentiated cell type is replaced by another",
    "1. Barrett esophagus: squamous (esophagus) → columnar (gastric-type) due to GERD",
    "2. Respiratory tract: columnar ciliated → squamous epithelium in smokers",
    "3. Bladder: transitional → squamous (chronic stones/infection)",
    "Mechanism: reprogramming of stem cells by growth factors & cytokines",
    "★ Significance: protective but ↑ risk of malignant transformation (e.g., adenocarcinoma in Barrett)"
  ],
  "Metaplasia"
);

// =====================================================================
// SECTION 2: Causes & Overview of Cell Injury
// =====================================================================
addSectionDivider(2, "Causes of Cell Injury", "1A3A5A");

addCard(6,
  "What are the major causes of cell injury? (List at least 7 categories)",
  [
    "1. Hypoxia/Ischemia – most common; O₂ deprivation",
    "2. Physical agents – trauma, burns, radiation, extreme temps",
    "3. Chemical agents & drugs – CCl₄, acetaminophen overdose",
    "4. Infectious agents – viruses, bacteria, fungi, parasites",
    "5. Immunologic reactions – autoimmunity, hypersensitivity",
    "6. Genetic derangements – inborn errors, enzyme defects",
    "7. Nutritional imbalances – protein deficiency, vitamin deficiency",
    "★ Hypoxia ≠ Ischemia: Ischemia also ↓ metabolic substrates + accumulates wastes"
  ],
  "Causes"
);

addCard(7,
  "How does hypoxia differ from ischemia? Why is ischemia more damaging?",
  [
    "Hypoxia: O₂ deficiency only → cells use anaerobic glycolysis for some ATP",
    "Ischemia: ↓ blood flow → O₂ deprivation + loss of metabolic substrates + accumulation of metabolic wastes (lactate, H⁺)",
    "★ Ischemia is more damaging because anaerobic glycolysis is also impaired",
    "Reperfusion injury adds further damage via ROS generation upon restoration of blood flow"
  ],
  "Hypoxia vs Ischemia"
);

// =====================================================================
// SECTION 3: Reversible Cell Injury
// =====================================================================
addSectionDivider(3, "Reversible Cell Injury", "1A3A5A");

addCard(8,
  "What are the two hallmark morphologic features of reversible cell injury?",
  [
    "1. CELLULAR SWELLING (hydropic change): Most common; first manifestation",
    "   • Caused by failure of ATP-dependent Na⁺/K⁺-ATPase pump",
    "   • Na⁺ accumulates → osmotic water influx → cell & ER enlarge",
    "2. FATTY CHANGE (steatosis): Triglyceride-filled lipid vacuoles",
    "   • Seen in organs of lipid metabolism: liver, heart, kidney",
    "   • Caused by toxic injury disrupting lipid metabolism",
    "★ Both are REVERSIBLE if stimulus is removed"
  ],
  "Reversible Injury"
);

addCard(9,
  "What ultrastructural changes are seen in reversible cell injury?",
  [
    "• Plasma membrane: blebbing, blunting of microvilli",
    "• Mitochondria: swelling, rarefaction (clearing) of matrix",
    "• ER: dilatation, detachment of ribosomes (→ ↓ protein synthesis)",
    "• Nucleus: clumping of nuclear chromatin",
    "• Cytoplasm: myelin figures appear (phospholipid whirls)",
    "★ Gross: organ pallor + mild swelling",
    "★ No nuclear changes = still REVERSIBLE"
  ],
  "Morphology"
);

// =====================================================================
// SECTION 4: Irreversible Injury & Necrosis
// =====================================================================
addSectionDivider(4, "Irreversible Injury & Necrosis", "1A3A5A");

addCard(10,
  "What are the two morphologic hallmarks that indicate IRREVERSIBLE cell injury?",
  [
    "1. SEVERE MITOCHONDRIAL DYSFUNCTION with vacuolization of mitochondria",
    "   → 'Flocculent densities' in mitochondrial matrix",
    "2. PLASMA MEMBRANE DISRUPTION with lysosomal swelling and leakage",
    "   → Lysosomal enzymes digest cell contents (autolysis)",
    "★ Nuclear changes (pyknosis, karyorrhexis, karyolysis) confirm irreversible injury",
    "★ Irreversibility = point of no return, leads to necrosis or apoptosis"
  ],
  "Irreversible Injury"
);

addCard(11,
  "What are the three nuclear changes seen in necrosis?",
  [
    "1. PYKNOSIS – nuclear condensation; basophilic, shrunken nucleus",
    "2. KARYORRHEXIS – fragmentation of the condensed nucleus",
    "3. KARYOLYSIS – dissolution/fading of the nucleus (enzymatic DNase digestion)",
    "★ Mnemonic: PCK → Pack (condense, crumble, clear)",
    "These changes occur over 1–2 days after cell death"
  ],
  "Necrosis – Nuclear Changes"
);

addCard(12,
  "Compare the 6 patterns of tissue necrosis with their key associations.",
  [
    "1. COAGULATIVE – preserved architecture; all organs except brain; ischemia → infarct",
    "2. LIQUEFACTIVE – digested, viscous liquid; brain infarct; bacterial/fungal abscess (pus)",
    "3. CASEOUS – cheese-like, friable; TB granuloma; structureless, amorphous debris",
    "4. FAT NECROSIS – chalky-white Ca²⁺ deposits; acute pancreatitis (saponification)",
    "5. FIBRINOID – bright pink, amorphous; immune-mediated vasculitis",
    "6. GANGRENOUS – clinical term; dry (coagulative) vs wet (+ liquefactive, bacterial)",
    "★ Coagulative = all organs EXCEPT brain"
  ],
  "Patterns of Necrosis"
);

addCard(13,
  "What is coagulative necrosis? Why is the brain an exception?",
  [
    "Architecture of dead tissue is preserved for days → firm texture",
    "Injury denatures structural proteins AND enzymes → ↓ proteolysis",
    "Cells are eosinophilic with ghost outlines; nuclei disappear",
    "Caused by ischemia in all organs except brain",
    "★ Brain exception: high phospholipid content + few structural proteins → undergoes LIQUEFACTIVE necrosis",
    "A localized area of coagulative necrosis = INFARCT"
  ],
  "Coagulative Necrosis"
);

addCard(14,
  "What is caseous necrosis? What disease is it most associated with?",
  [
    "Friable, cheese-like (Latin: caseus) white appearance",
    "Microscopy: structureless granular debris of fragmented lysed cells",
    "Surrounded by a GRANULOMA (epithelioid macrophages + lymphocytes)",
    "★ Most associated with: TUBERCULOSIS",
    "Also: histoplasmosis, coccidioidomycosis",
    "Enclosed granuloma = the diagnostic hallmark"
  ],
  "Caseous Necrosis"
);

addCard(15,
  "What is fat necrosis and what enzyme is responsible?",
  [
    "Focal destruction of fat tissue by release of activated PANCREATIC LIPASES",
    "Occurs in: acute pancreatitis (Chapter 19)",
    "Mechanism: pancreatic enzymes leak → liquefy fat cell membranes → release triglycerides",
    "Lipases split triglycerides → fatty acids combine with Ca²⁺ → chalky-white deposits",
    "This is SAPONIFICATION (soap formation)",
    "Histology: shadowy necrotic fat cells + basophilic Ca²⁺ deposits + inflammation",
    "★ Grossly chalky-white lesions in peritoneum = diagnostic clue for pancreatitis"
  ],
  "Fat Necrosis"
);

// =====================================================================
// SECTION 5: Apoptosis
// =====================================================================
addSectionDivider(5, "Apoptosis", "1A3A5A");

addCard(16,
  "What is apoptosis and how does it differ from necrosis?",
  [
    "Apoptosis: programmed cell death; orderly, energy-dependent elimination of cells",
    "DIFFERENCES vs Necrosis:",
    "• Cell size: shrunken (apoptosis) vs swollen (necrosis)",
    "• Membrane: intact (apoptosis) vs disrupted (necrosis)",
    "• Inflammation: ABSENT (apoptosis) vs PRESENT (necrosis)",
    "• DNA: laddering (180 bp) in apoptosis vs random degradation in necrosis",
    "• Process: controlled, ATP-dependent vs passive, accidental",
    "★ Apoptosis = 'suicide'; Necrosis = 'murder'"
  ],
  "Apoptosis vs Necrosis"
);

addCard(17,
  "What are the morphologic features of apoptosis?",
  [
    "1. Cell shrinkage – dense cytoplasm; tightly packed organelles",
    "2. Chromatin condensation – dense crescent-shaped clumps under nuclear membrane",
    "3. Nuclear fragmentation",
    "4. Cytoplasmic blebs → formation of APOPTOTIC BODIES (membrane-bound fragments)",
    "5. Phagocytosis of apoptotic bodies by adjacent cells or macrophages",
    "★ No leakage → NO inflammation",
    "Histologically: single shrunken eosinophilic cell with dark nucleus fragments"
  ],
  "Morphology of Apoptosis"
);

addCard(18,
  "What are the causes of apoptosis? (Physiologic vs Pathologic)",
  [
    "PHYSIOLOGIC:",
    "• Embryogenesis (organogenesis, removal of webbing)",
    "• Involution of hormone-dependent tissues (post-lactation breast, endometrium)",
    "• Deletion of self-reactive lymphocytes (immune tolerance)",
    "• Normal cell turnover (intestinal epithelium, neutrophil death)",
    "PATHOLOGIC:",
    "• DNA damage (p53 activation → irreparable DNA → apoptosis)",
    "• Viral infections (hepatocyte death → Councilman bodies in viral hepatitis)",
    "• Cytotoxic T-lymphocyte-mediated killing",
    "• Atrophy after duct obstruction (pancreas, parotid)"
  ],
  "Causes of Apoptosis"
);

addCard(19,
  "Describe the two main pathways of apoptosis.",
  [
    "1. INTRINSIC (Mitochondrial) Pathway:",
    "   • Triggered by: DNA damage, oxidative stress, growth factor withdrawal",
    "   • ↑ Bax/Bak (pro-apoptotic) → cytochrome c released from mitochondria",
    "   • Cytochrome c + Apaf-1 → apoptosome → activates caspase-9 → effector caspases",
    "   • BCL-2 inhibits this pathway (anti-apoptotic)",
    "2. EXTRINSIC (Death Receptor) Pathway:",
    "   • FasL binds Fas (CD95) or TNF binds TNFR1",
    "   • FADD adaptor → procaspase-8 → caspase-8 → effector caspases",
    "★ BOTH pathways converge on EXECUTIONER CASPASES (3, 6, 7)"
  ],
  "Apoptosis Pathways"
);

addCard(20,
  "What is the role of BCL-2 in apoptosis?",
  [
    "BCL-2 is an ANTI-APOPTOTIC protein located on mitochondrial membrane",
    "Function: sequesters pro-apoptotic proteins (Bax, Bak) → prevents cytochrome c release",
    "★ BCL-2 overexpression → cells resist apoptosis → promotes cancer survival",
    "Classic example: follicular B-cell lymphoma has t(14;18) → BCL-2 overexpression",
    "BCL-2 family balance (pro vs anti-apoptotic) = 'rheostat' for cell survival",
    "Other anti-apoptotic: BCL-XL, MCL-1",
    "Pro-apoptotic: BAX, BAK, BIM, PUMA, NOXA"
  ],
  "BCL-2 Family"
);

// =====================================================================
// SECTION 6: Mechanisms of Cell Injury
// =====================================================================
addSectionDivider(6, "Mechanisms of Cell Injury", "1A3A5A");

addCard(21,
  "What are the 5 main intracellular mechanisms by which cell injury occurs?",
  [
    "1. ATP DEPLETION – mitochondrial dysfunction; Na⁺/K⁺ pump failure → swelling",
    "2. MITOCHONDRIAL DAMAGE – MPTP opens → ↓ membrane potential → necrosis/apoptosis",
    "3. INTRACELLULAR Ca²⁺ ACCUMULATION – activates enzymes (PLA₂, proteases, endonucleases)",
    "4. REACTIVE OXYGEN SPECIES (ROS) – oxidative stress → lipid peroxidation, DNA damage",
    "5. PLASMA MEMBRANE DAMAGE – direct damage (toxins) or loss of phospholipids",
    "★ These mechanisms are INTERCONNECTED and amplify each other"
  ],
  "Mechanisms"
);

addCard(22,
  "What happens when ATP is depleted in a cell? (Downstream effects)",
  [
    "1. ↓ Na⁺/K⁺-ATPase → Na⁺ influx + K⁺ efflux → cell swelling",
    "2. ↑ Anaerobic glycolysis → lactic acid accumulation → ↓ pH → ↓ enzyme activity",
    "3. ↓ Protein synthesis (ribosomes detach from ER)",
    "4. Lipid deposition (lipoprotein assembly failure)",
    "5. ↑ Cytosolic Ca²⁺ → enzyme activation",
    "6. Mitochondrial permeability transition pore (MPTP) opens at ~5–10% normal ATP → NECROSIS",
    "★ ATP depletion to 5–10% of normal = widespread cellular dysfunction"
  ],
  "ATP Depletion"
);

addCard(23,
  "What are Reactive Oxygen Species (ROS)? How do they cause cell injury?",
  [
    "ROS = partially reduced forms of oxygen: O₂•⁻ (superoxide), H₂O₂, •OH (hydroxyl radical)",
    "Sources: normal metabolism, ischemia-reperfusion, radiation, toxic drugs, inflammation",
    "Mechanisms of injury:",
    "  • Lipid peroxidation – membrane phospholipid destruction",
    "  • Protein oxidation – enzyme inactivation; structural protein damage",
    "  • DNA damage – single/double strand breaks",
    "Antioxidant defenses: SOD (O₂•⁻ → H₂O₂), catalase (H₂O₂ → H₂O), glutathione peroxidase",
    "★ Ischemia-reperfusion: reperfusion floods cell with O₂ → burst of ROS generation"
  ],
  "ROS & Oxidative Stress"
);

addCard(24,
  "How does increased intracellular Ca²⁺ cause cell injury?",
  [
    "Normally: cytosolic Ca²⁺ is very low (~0.1 µmol); pumped into ER and extracellular space",
    "In injury: ischemia, toxins → membrane damage → Ca²⁺ influx from extracellular space + release from ER",
    "Harmful effects of ↑ Ca²⁺:",
    "  • ATPases – accelerates ATP depletion",
    "  • Phospholipases – membrane damage",
    "  • Proteases – cytoskeletal and membrane degradation",
    "  • Endonucleases – DNA and chromatin fragmentation",
    "  • Mitochondrial damage → permeability transition → cytochrome c release",
    "★ Ca²⁺ is a FINAL COMMON PATHWAY in many types of cell death"
  ],
  "Calcium & Cell Injury"
);

addCard(25,
  "What is ischemia-reperfusion injury and why is it important clinically?",
  [
    "Reperfusion of ischemic tissue can paradoxically WORSEN injury",
    "Mechanisms of reperfusion injury:",
    "  1. ROS burst on O₂ reintroduction (from mitochondria, xanthine oxidase, neutrophils)",
    "  2. Intracellular Ca²⁺ overload (restored membrane function, mitochondrial uptake)",
    "  3. Neutrophil infiltration → more ROS and proteases",
    "  4. Complement activation",
    "Clinical importance:",
    "  • Myocardial infarction reperfusion (thrombolysis/PCI)",
    "  • Stroke reperfusion",
    "  • Organ transplantation",
    "★ Explains why rapid reperfusion must be balanced with protective strategies"
  ],
  "Reperfusion Injury"
);

// =====================================================================
// SECTION 7: Cellular Aging & Special Topics
// =====================================================================
addSectionDivider(7, "Special Topics", "1A3A5A");

addCard(26,
  "What is autophagy? How does it relate to cell injury?",
  [
    "Autophagy: 'self-eating' – cell digests its own organelles and proteins via lysosomes",
    "Types: macroautophagy, microautophagy, chaperone-mediated autophagy",
    "Protective role: removes damaged organelles (mitochondria = mitophagy)",
    "Stimulated by: nutrient deprivation, growth factor loss, ER stress",
    "Relevance to injury:",
    "  • Adaptation: helps cells survive stress by recycling components for energy",
    "  • Excessive autophagy → autophagic cell death (type 2 programmed death)",
    "★ Autophagic vacuoles (membrane-bound organelle fragments) = morphologic marker"
  ],
  "Autophagy"
);

addCard(27,
  "What is the 'point of no return' in cell injury?",
  [
    "The threshold beyond which injury becomes IRREVERSIBLE",
    "Key events that mark the point of no return:",
    "  1. Severe mitochondrial dysfunction (vacuolization + flocculent densities)",
    "  2. Profound membrane damage (plasma + lysosomal membranes)",
    "  3. Lysosomal enzyme release → auto-digestion",
    "★ Before this point: cell swelling, fatty change → REVERSIBLE",
    "★ After this point: nuclear changes (pyknosis, karyorrhexis, karyolysis) → NECROSIS",
    "Not always a sharp line – varies by cell type, type of injury, and ATP levels"
  ],
  "Point of No Return"
);

addCard(28,
  "What are the morphologic features used to distinguish apoptosis from necrosis on H&E?",
  [
    "APOPTOSIS:",
    "  • Single shrunken eosinophilic cell or small clusters",
    "  • Dense nuclear chromatin condensation",
    "  • Apoptotic bodies (membrane-bound cellular fragments)",
    "  • No surrounding inflammation",
    "NECROSIS:",
    "  • Groups/zones of cells; cell swelling → ghost outlines",
    "  • Pyknosis → karyorrhexis → karyolysis",
    "  • Cytoplasmic eosinophilia (denatured proteins)",
    "  • INFLAMMATION present",
    "★ Councilman bodies in viral hepatitis = apoptotic hepatocytes"
  ],
  "Histology Comparison"
);

addCard(29,
  "What are the cellular changes of aging and senescence?",
  [
    "Cellular aging = accumulation of sub-lethal injury over time",
    "Key mechanisms:",
    "  1. TELOMERE SHORTENING – replicative senescence; each division ↓ telomere → growth arrest (p53/p21)",
    "  2. Oxidative damage – ROS from normal metabolism accumulates",
    "  3. Defective protein homeostasis – misfolded proteins accumulate",
    "  4. Epigenetic changes – altered gene expression patterns",
    "Features of senescent cells:",
    "  • Enlarged, flat morphology",
    "  • ↑ β-galactosidase activity (senescence marker)",
    "  • SASP: Senescence-Associated Secretory Phenotype → pro-inflammatory",
    "★ Telomerase reactivation = key mechanism in cancer immortalization"
  ],
  "Cellular Aging"
);

addCard(30,
  "What is the role of p53 in cell injury?",
  [
    "p53 = 'Guardian of the Genome'; tumor suppressor protein",
    "Activated by: DNA damage, hypoxia, oncogene activation, ROS",
    "Normal function:",
    "  • Halts cell cycle (G1/S checkpoint via p21) to allow DNA repair",
    "  • If DNA repair fails → activates pro-apoptotic genes (PUMA, NOXA) → apoptosis",
    "  • Activates antioxidant genes",
    "★ Loss/mutation of p53 (most common mutation in cancer) → damaged cells survive and proliferate",
    "★ p53 connects DNA damage → apoptosis (intrinsic pathway)"
  ],
  "p53 & DNA Damage"
);

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