BHMS 2nd Year Pathology - Chapter 1

from reportlab.lib.pagesizes import A4
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm
from reportlab.lib import colors
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import ListFlowable, ListItem

OUTPUT = "/tmp/workspace/pathology-study-guide/Pathology_Chapter1_StudyGuide.pdf"

doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=2*cm, rightMargin=2*cm,
    topMargin=2.5*cm, bottomMargin=2.5*cm,
    title="BHMS 2nd Year Pathology - Chapter 1 Study Guide",
    author="Orris AI"
)

# ── Colour palette ──────────────────────────────────────────────────────────
NAVY     = colors.HexColor("#1A3557")
TEAL     = colors.HexColor("#0E7C86")
LIME     = colors.HexColor("#4CAF50")
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AMBER_BG = colors.HexColor("#FFF8E1")
RED_BG   = colors.HexColor("#FDECEA")
GREEN_BG = colors.HexColor("#E8F5E9")
GREY_BG  = colors.HexColor("#F5F5F5")
WHITE    = colors.white

# ── Styles ──────────────────────────────────────────────────────────────────
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# ── Helper builders ──────────────────────────────────────────────────────────

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def tip_box(title, items, bg=AMBER_BG, title_bg=AMBER):
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def hr(color=TEAL, thickness=0.8):
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# ── Page number footer ────────────────────────────────────────────────────────

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# ════════════════════════════════════════════════════════════════════════════
# BUILD CONTENT
# ════════════════════════════════════════════════════════════════════════════
story = []

# ── COVER PAGE ───────────────────────────────────────────────────────────────
cover_data = [[
    Paragraph("BHMS 2nd Year", COVER_SUB),
    Paragraph("PATHOLOGY", COVER_TITLE),
    Paragraph("Chapter 1", COVER_SUB),
    Paragraph("Cell Injury, Adaptations &amp; Cell Death", S("CT2", fontSize=16, textColor=WHITE, alignment=TA_CENTER, fontName="Helvetica-Bold", leading=22)),
    sp(10),
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    sp(6),
    Paragraph("Based on Robbins &amp; Kumar Basic Pathology", S("CT4", fontSize=9, textColor=colors.HexColor("#CCE5FF"), alignment=TA_CENTER, fontName="Helvetica", leading=14)),
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story.append(cover_tbl)
story.append(sp(18))

# badge row
badges = [["Etiology", "Pathogenesis", "Cell Injury", "Necrosis", "Apoptosis", "Adaptation", "Aging"]]
badge_tbl = Table(badges, colWidths=[None]*7)
badge_tbl.setStyle(TableStyle([
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story.append(PageBreak())

# ── SECTION 1: Introduction ──────────────────────────────────────────────────
story.append(colored_heading("1.  INTRODUCTION TO PATHOLOGY", NAVY))
story.append(sp(4))
story.append(body("Pathology is the study of <b>causes of disease</b> and the changes in cells, tissues, and organs associated with disease. It forms the scientific foundation of medicine."))
story.append(sp(4))

intro_rows = [
    ["Etiology", "The <i>origin/cause</i> of disease — includes genetic susceptibility and environmental triggers. Why a disease arises."],
    ["Pathogenesis", "The <i>steps</i> in disease development from initial trigger to structural/functional abnormalities. How a disease develops."],
    ["Morphology", "Gross or microscopic appearance of cells/tissues used to diagnose disease."],
    ["Precision Medicine", "Therapies tailored to each individual's specific molecular disease profile."],
]
story.append(make_table(["Term", "Definition"], intro_rows, col_widths=[4*cm, None]))
story.append(sp(8))

# ── SECTION 2: Overview of Cellular Responses ───────────────────────────────
story.append(colored_heading("2.  OVERVIEW OF CELLULAR RESPONSES TO STRESS", TEAL))
story.append(sp(4))
story.append(body("Cells continuously adjust structure and function to maintain <b>homeostasis</b>. When stressed, they respond in three ways:"))
story.append(sp(3))
responses = [
    ["<b>Adaptation</b>", "New steady state achieved; viability preserved (hypertrophy, hyperplasia, atrophy, metaplasia)"],
    ["<b>Reversible Injury</b>", "Structural/functional change that resolves if stimulus is removed"],
    ["<b>Irreversible Injury / Death</b>", "Severe or prolonged stress → necrosis or apoptosis"],
]
story.append(make_table(["Response", "Description"], responses, col_widths=[4.5*cm, None], header_bg=TEAL))
story.append(sp(8))

# ── SECTION 3: Causes of Cell Injury ────────────────────────────────────────
story.append(colored_heading("3.  CAUSES OF CELL INJURY", NAVY))
story.append(sp(4))
causes = [
    ["Hypoxia &amp; Ischemia", "Most common cause; O₂ deficiency; ischemia also reduces nutrients"],
    ["Physical Agents", "Mechanical trauma, extreme temperature, radiation, electric shock"],
    ["Chemical Agents / Drugs", "Hyper/hypotonic solutions, O₂ at high concentration, toxins, poisons"],
    ["Infectious Agents", "Viruses, bacteria, fungi, parasites"],
    ["Immunologic Reactions", "Autoimmune diseases, hypersensitivity reactions (Type I–IV)"],
    ["Genetic Derangements", "Congenital malformations, enzyme defects (e.g., sickle cell disease)"],
    ["Nutritional Imbalances", "Protein-calorie malnutrition, vitamin deficiencies, excess calories"],
]
story.append(make_table(["Cause", "Details"], causes, col_widths=[4.5*cm, None]))
story.append(sp(8))

# ── SECTION 4: Reversible vs Irreversible Injury ────────────────────────────
story.append(colored_heading("4.  CELL INJURY — REVERSIBLE vs. IRREVERSIBLE", TEAL))
story.append(sp(4))
story.append(subsection("4.1  Reversible Cell Injury"))
story.append(body("Early, mild injury — cell recovers if stimulus removed. Features:"))
for b in bullet(["Cellular swelling (most common / earliest finding in almost all cell injury)",
                  "Fatty change (steatosis) — lipid vacuoles in cytoplasm",
                  "Plasma membrane blebs; ER and mitochondria swelling",
                  "Clumping of nuclear chromatin"]):
    story.append(b)
story.append(sp(6))

story.append(subsection("4.2  Necrosis vs. Apoptosis — Comparison"))
story.append(sp(3))
nva = [
    ["Cell size",         "Enlarged (swollen)",                    "Reduced (shrunken)"],
    ["Nucleus",           "Pyknosis → karyorrhexis → karyolysis",  "Fragmented into nucleosome-sized pieces"],
    ["Plasma membrane",   "Disrupted",                             "Intact (altered structure)"],
    ["Cell contents",     "Enzymatic digestion; leaks out",        "Intact, released in apoptotic bodies"],
    ["Inflammation",      "Yes (prominent)",                       "No"],
    ["Nature",            "Always pathologic",                     "Physiologic OR pathologic"],
]
story.append(make_table(["Feature", "NECROSIS", "APOPTOSIS"], nva, col_widths=[4*cm, None, None]))
story.append(sp(8))

# ── SECTION 5: Necrosis ──────────────────────────────────────────────────────
story.append(colored_heading("5.  NECROSIS — PATTERNS", RED))
story.append(sp(4))
story.append(body("Necrosis = cell death with membrane disruption + enzymatic digestion. Always <b>pathologic</b>."))
story.append(sp(4))
nec_patterns = [
    ["<b>Coagulative</b>",   "Architecture preserved (ghost cells); protein denaturation dominates",           "Myocardial infarction, renal infarct"],
    ["<b>Liquefactive</b>",  "Complete digestion → liquid, pus-like",                                         "Brain infarcts, bacterial abscesses"],
    ["<b>Caseous</b>",       "Cheese-like, friable; combo of coagulative + liquefactive",                     "Tuberculosis (TB)"],
    ["<b>Fat Necrosis</b>",  "Chalky white; fatty acids + calcium → soaps (saponification)",                  "Acute pancreatitis"],
    ["<b>Fibrinoid</b>",     "Immune complex deposition in vessel walls; pink amorphous",                     "Vasculitis, malignant hypertension"],
    ["<b>Gangrenous</b>",    "Large area death; dry (arterial) or wet (infected)",                            "Diabetic foot, vascular occlusion"],
]
story.append(make_table(["Type", "Description", "Classic Example"], nec_patterns,
                         col_widths=[3.5*cm, None, 4.5*cm], header_bg=RED))

story.append(sp(6))
story.append(tip_box(
    "CLINICAL TIP",
    ["Cardiac troponin → myocardial necrosis",
     "Transaminases (ALT/AST) → hepatocyte necrosis",
     "Alkaline phosphatase → bile duct necrosis"],
    bg=AMBER_BG, title_bg=AMBER
))
story.append(sp(8))

# ── SECTION 6: Apoptosis ─────────────────────────────────────────────────────
story.append(colored_heading("6.  APOPTOSIS", NAVY))
story.append(sp(4))
story.append(body("<b>Apoptosis</b> = programmed cell death; enzymes degrade own DNA + proteins. Fragments into <b>apoptotic bodies</b> rapidly phagocytosed by macrophages — <u>no inflammation</u>."))
story.append(sp(5))

story.append(subsection("6.1  Causes of Apoptosis"))
apo_causes = [
    ["Embryogenesis", "Loss of growth factor signaling", "Physiologic"],
    ["Tissue turnover", "Loss of survival signals", "Physiologic"],
    ["Hormone involution (endometrium)", "Reduced hormone levels", "Physiologic"],
    ["Immune response decline", "Leukocyte survival signal eliminated", "Physiologic"],
    ["Elimination of self-reactive lymphocytes", "Strong self-antigen recognition", "Physiologic"],
    ["DNA damage", "Activation of pro-apoptotic BH3-only proteins", "Pathologic"],
    ["Misfolded proteins", "ER stress → BH3-only protein activation", "Pathologic"],
    ["Viral infections", "Viral proteins activate caspases; CTL killing", "Pathologic"],
]
story.append(make_table(["Condition", "Mechanism", "Type"], apo_causes,
                         col_widths=[5*cm, None, 2.8*cm]))
story.append(sp(6))

story.append(subsection("6.2  Mechanisms of Apoptosis — Two Pathways"))
path_rows = [
    ["<b>Intrinsic\n(Mitochondrial)</b>",
     "DNA damage, oxidative stress, misfolded proteins",
     "BAX/BAK → cytochrome c release → caspase-9 → effector caspases",
     "Bcl-2 (anti-apoptotic); BH3-only proteins (pro-apoptotic)"],
    ["<b>Extrinsic\n(Death Receptor)</b>",
     "FasL or TNF binding to death receptors",
     "Adaptor proteins → caspase-8 → effector caspases",
     "Used by cytotoxic T lymphocytes (CTLs)"],
]
story.append(make_table(["Pathway", "Triggers", "Mechanism", "Key Regulators"], path_rows,
                         col_widths=[3*cm, 3.5*cm, None, 4*cm], header_bg=TEAL))
story.append(sp(6))

story.append(subsection("6.3  Morphology of Apoptosis"))
for b in bullet(["Cell shrinkage",
                  "Chromatin condensation and margination (crescent-shaped chromatin under nuclear membrane)",
                  "Nuclear fragmentation",
                  "Cytoplasmic blebs → apoptotic bodies",
                  "Rapid phagocytosis by macrophages — NO inflammatory response"]):
    story.append(b)
story.append(sp(8))

# ── SECTION 7: Autophagy ────────────────────────────────────────────────────
story.append(colored_heading("7.  AUTOPHAGY", TEAL))
story.append(sp(4))
for b in bullet([
    "Cellular self-digestion: organelles/proteins sequestered in <b>autophagosomes</b> (double-membrane vesicles)",
    "Protective during <b>nutrient deprivation</b> — provides recycled building blocks",
    "Excessive autophagy can activate apoptosis",
    "Role in: aging, neurodegenerative diseases (Parkinson, Alzheimer), cancer"
]):
    story.append(b)
story.append(sp(8))

# ── SECTION 8: Mechanisms of Cell Injury ────────────────────────────────────
story.append(colored_heading("8.  MECHANISMS OF CELL INJURY", NAVY))
story.append(sp(4))

story.append(subsection("8.1  Mitochondrial Dysfunction"))
for b in bullet([
    "Damaged mitochondria release <b>cytochrome c</b> → triggers intrinsic apoptosis",
    "ATP depletion → failure of Na⁺/K⁺ ATPase → cell swelling → membrane damage → necrosis",
    "Formation of <b>MPTP</b> (mitochondrial permeability transition pore) → loss of membrane potential",
]):
    story.append(b)
story.append(sp(4))

story.append(subsection("8.2  Oxidative Stress &amp; Reactive Oxygen Species (ROS)"))
rос = [
    ["Superoxide (O₂•⁻)",   "Normal metabolism, leukocyte oxidative burst, reperfusion"],
    ["H₂O₂",                 "Dismutation of superoxide"],
    ["Hydroxyl radical (OH•)","Most reactive; generated via Fenton reaction"],
]
story.append(make_table(["ROS Species", "Source"], rос, col_widths=[5*cm, None]))
story.append(sp(3))
story.append(body("<b>ROS Damage:</b>"))
for b in bullet([
    "Lipid peroxidation → membrane damage",
    "Protein oxidation → fragmentation/dysfunction",
    "DNA strand breaks → mutations, apoptosis",
]):
    story.append(b)
story.append(sp(3))
story.append(body("<b>Antioxidant Defenses:</b> Glutathione peroxidase, Catalase, SOD (superoxide dismutase), Vitamins C &amp; E"))
story.append(sp(4))

story.append(subsection("8.3  Membrane Damage — Three Key Sites"))
mem_sites = [
    ["Mitochondrial membrane", "Loss of membrane potential → energy failure + apoptosis"],
    ["Plasma membrane",        "Loss of osmotic balance; influx of fluids/ions; cell lysis"],
    ["Lysosomal membrane",     "Leakage of acid hydrolases → autodigestion → irreversible necrosis"],
]
story.append(make_table(["Site", "Consequence"], mem_sites, col_widths=[5*cm, None]))
story.append(sp(4))

story.append(subsection("8.4  Calcium Homeostasis Disturbance"))
for b in bullet([
    "Normal cytosolic Ca²⁺ very low (~0.1 μmol) vs. extracellular (1.3 mmol)",
    "Ischemia/toxins → excess intracellular Ca²⁺ release from ER + mitochondria",
    "Activates: proteases, phospholipases, endonucleases, ATPases → membrane damage, DNA fragmentation",
]):
    story.append(b)
story.append(sp(4))

story.append(subsection("8.5  Endoplasmic Reticulum (ER) Stress"))
for b in bullet([
    "Misfolded proteins accumulate → activate <b>Unfolded Protein Response (UPR)</b>",
    "UPR: increases chaperones, reduces protein translation (protective)",
    "If overwhelmed → pro-apoptotic signals → apoptosis via mitochondrial pathway",
    "Implicated in: Alzheimer's disease, Type 2 diabetes, neurodegeneration",
]):
    story.append(b)
story.append(sp(4))

story.append(subsection("8.6  DNA Damage"))
for b in bullet([
    "Caused by: radiation, ROS, chemicals",
    "<b>p53</b> accumulates → cell cycle arrest for repair; if irreparable → apoptosis",
    "DNA damage implicated in: aging, cancer, cell death",
]):
    story.append(b)
story.append(sp(4))

story.append(subsection("8.7  Clinicopathologic Examples"))
story.append(sp(3))
cpex = [
    ["Hypoxia/Ischemia",           "Reduced O₂ → ↓ oxidative phosphorylation → ATP depletion → Na⁺/K⁺ pump fails → cell swelling → membrane damage → necrosis"],
    ["Ischemia-Reperfusion Injury","Restoration of blood flow paradoxically worsens injury: massive ROS + neutrophil influx + complement activation. Key in: MI treated with thrombolytics/angioplasty"],
    ["Toxic Cell Injury",          "Direct: HgCl₂ binds membrane proteins → permeability. Metabolic: CCl₄ → CCl₃• in liver → lipid peroxidation → fatty change → necrosis"],
]
story.append(make_table(["Example", "Mechanism"], cpex, col_widths=[4*cm, None]))
story.append(sp(8))
story.append(PageBreak())

# ── SECTION 9: Cellular Adaptations ─────────────────────────────────────────
story.append(colored_heading("9.  CELLULAR ADAPTATIONS TO STRESS", TEAL))
story.append(sp(4))
story.append(body("Adaptations are <b>reversible changes</b> in number, size, phenotype, metabolism, or function of cells in response to environmental stress."))
story.append(sp(5))

story.append(subsection("9.1  Hypertrophy — Increase in Cell SIZE"))
story.append(body("Enlargement of cells → increase in organ size. <i>No new cells formed.</i> Occurs in cells with limited division capacity (cardiac/skeletal muscle)."))
story.append(sp(3))
hyp_rows = [
    ["Physiologic", "Uterus in pregnancy (estrogen); skeletal muscle with exercise"],
    ["Pathologic",  "Cardiac hypertrophy in hypertension or aortic stenosis"],
    ["Mechanism",   "Stretch → growth factors + adrenergic hormones → gene expression → more myofilaments. α-myosin heavy chain → β form (more efficient)"],
    ["Complication","Sustained stress → degenerative changes → ventricular dilation → cardiac failure"],
]
story.append(make_table(["Type", "Details"], hyp_rows, col_widths=[3.5*cm, None], header_bg=TEAL))
story.append(sp(5))

story.append(subsection("9.2  Hyperplasia — Increase in Cell NUMBER"))
story.append(body("Increase in number of cells by proliferation. Occurs in cells capable of division (epithelium, glandular tissue)."))
story.append(sp(3))
hplas_rows = [
    ["Physiologic - Hormonal", "Breast/uterus during puberty and pregnancy"],
    ["Physiologic - Compensatory", "Liver regeneration after partial hepatectomy"],
    ["Pathologic", "Endometrial hyperplasia (excess estrogen); BPH; psoriasis; wound healing"],
    ["Risk",       "Sustained hyperplasia can be a precursor to cancer"],
]
story.append(make_table(["Type", "Example"], hplas_rows, col_widths=[4.5*cm, None], header_bg=TEAL))
story.append(sp(5))

story.append(subsection("9.3  Atrophy — Decrease in Cell SIZE (and sometimes NUMBER)"))
story.append(body("Shrinkage of cell size due to loss of cell substance."))
story.append(sp(3))
story.append(tip_box("CAUSES Mnemonic: DISH-M",
    ["Disuse (immobilization)",
     "Innervation loss (denervation atrophy)",
     "Supply reduction (ischemia)",
     "Hormone withdrawal (endocrine atrophy)",
     "Malnutrition / pressure"],
    bg=GREEN_BG, title_bg=LIME))
story.append(sp(3))
story.append(body("<b>Mechanism:</b> ↓ protein synthesis + ↑ protein degradation via <b>ubiquitin-proteasome pathway</b> and autophagy. May involve apoptosis if severe."))
story.append(sp(5))

story.append(subsection("9.4  Metaplasia — Change in CELL TYPE"))
story.append(body("Reversible replacement of one adult cell type by another better adapted to the stress. Caused by reprogramming of tissue stem cells."))
story.append(sp(3))
meta_rows = [
    ["Columnar → Squamous", "Respiratory epithelium in smokers; Barrett's esophagus (squamous → reverts from columnar)", "Squamous cell carcinoma risk"],
    ["Squamous → Columnar (Intestinal)", "Barrett's esophagus (acid reflux — squamous → intestinal columnar)", "Adenocarcinoma risk"],
    ["Connective tissue → Bone", "Myositis ossificans (trauma)", "Functional impairment"],
]
story.append(make_table(["Change", "Example", "Cancer Risk"], meta_rows,
                         col_widths=[4.5*cm, None, 4*cm], header_bg=TEAL))
story.append(sp(8))

# ── SECTION 10: Intracellular Depositions ───────────────────────────────────
story.append(colored_heading("10.  INTRACELLULAR AND EXTRACELLULAR DEPOSITIONS", NAVY))
story.append(sp(4))

story.append(subsection("10.1  Intracellular Accumulations"))
depo_rows = [
    ["Fatty Change (Steatosis)", "Toxins, malnutrition, diabetes, obesity, alcohol",         "Fatty liver (hepatic steatosis)"],
    ["Cholesterol / Esters",     "Impaired lipid metabolism; atherosclerosis",               "Foam cells in atherosclerotic plaques"],
    ["Proteins",                 "Excess reabsorption or synthesis",                          "Hyaline droplets (nephrotic syndrome); Russell bodies"],
    ["Glycogen",                 "Abnormal glucose/glycogen metabolism",                      "DM; glycogen storage diseases"],
    ["Lipofuscin",               "Oxidative cell injury — 'wear &amp; tear pigment'",         "Brown atrophy in aging; liver, heart"],
    ["Hemosiderin",              "Excess iron; derived from ferritin",                        "Hemochromatosis, hemosiderosis"],
    ["Carbon / Anthracosis",     "Exogenous; inhaled, phagocytosed by macrophages",           "Coal worker's pneumoconiosis"],
    ["Melanin",                  "Excess production",                                         "Freckles, nevi, melanoma"],
    ["Bilirubin",                "Hemolysis, liver disease",                                  "Jaundice"],
]
story.append(make_table(["Substance", "Cause", "Example"], depo_rows,
                         col_widths=[4*cm, None, 5*cm]))
story.append(sp(6))

story.append(subsection("10.2  Extracellular Deposits — Pathologic Calcification"))
calc_rows = [
    ["<b>Dystrophic Calcification</b>",
     "Dead or dying tissue (necrotic areas)",
     "<b>Normal</b>",
     "TB nodules, atherosclerotic plaques, dead parasites, heart valve deposits"],
    ["<b>Metastatic Calcification</b>",
     "Normal tissue",
     "<b>HIGH (hypercalcemia)</b>",
     "Hyperparathyroidism, bone metastases, vitamin D toxicity, sarcoidosis → kidneys, lungs, gastric mucosa, cornea"],
]
story.append(make_table(["Type", "Site of Deposition", "Serum Ca²⁺", "Causes/Sites"], calc_rows,
                         col_widths=[4*cm, 3*cm, 3.5*cm, None], header_bg=RED))
story.append(sp(8))

# ── SECTION 11: Cellular Aging ───────────────────────────────────────────────
story.append(colored_heading("11.  CELLULAR AGING", TEAL))
story.append(sp(4))
story.append(body("Cells can undergo a finite number of divisions (<b>Hayflick limit</b> ≈ 50–70 divisions). Aging is driven by multiple mechanisms:"))
story.append(sp(4))
aging_rows = [
    ["Telomere Shortening",          "Repetitive DNA at chromosome ends shortens with each division → cell cycle arrest (senescence) or apoptosis. Cancer cells bypass this via <b>telomerase</b>."],
    ["Accumulated DNA Damage",       "ROS, chemicals, radiation; DNA repair mechanisms decline with age."],
    ["Defective Protein Homeostasis","Misfolded proteins accumulate; chaperone function and proteasome activity decline."],
    ["Metabolic Alterations",        "Caloric restriction → ↓ ROS + ↓ IGF-1 signaling → extended lifespan."],
    ["Epigenetic Changes",           "Altered methylation and histone modification patterns with age."],
    ["Inflammaging",                 "Low-grade chronic inflammation contributes to aging and age-related diseases."],
]
story.append(make_table(["Mechanism", "Details"], aging_rows, col_widths=[4.5*cm, None], header_bg=TEAL))
story.append(sp(8))

# ── RAPID REVIEW / SUMMARY TABLES ────────────────────────────────────────────
story.append(PageBreak())
story.append(colored_heading("RAPID REVIEW — KEY POINTS AT A GLANCE", RED))
story.append(sp(6))

# Adaptations summary
story.append(subsection("Cellular Adaptations — Quick Comparison"))
adapt_sum = [
    ["Hypertrophy",  "↑ cell size",   "Cells cannot divide (cardiac, skeletal muscle)", "Cardiac hypertrophy, uterus in pregnancy"],
    ["Hyperplasia",  "↑ cell number", "Cells CAN divide (epithelium, glandular)",       "BPH, endometrial hyperplasia, liver regeneration"],
    ["Atrophy",      "↓ cell size",   "Any cell type",                                   "Denervation, disuse, ischemia, starvation"],
    ["Metaplasia",   "Cell type change","Stem cell reprogramming",                        "Smoker's airways, Barrett's esophagus"],
]
story.append(make_table(["Adaptation", "Change", "Occurs in", "Example"], adapt_sum,
                         col_widths=[3*cm, 3*cm, None, 4.5*cm]))
story.append(sp(6))

# Necrosis quick ref
story.append(subsection("Necrosis Patterns — Quick Reference"))
nec_sum = [
    ["Coagulative",  "Solid organ infarcts (heart, kidney)"],
    ["Liquefactive", "Brain infarcts; bacterial/fungal abscesses"],
    ["Caseous",      "TB (granulomatous diseases)"],
    ["Fat",          "Pancreatic necrosis; breast trauma"],
    ["Fibrinoid",    "Immune vasculitis; malignant hypertension"],
    ["Gangrenous",   "Limb/foot ischemia ± infection"],
]
story.append(make_table(["Necrosis Type", "Classic Association"], nec_sum,
                         col_widths=[4.5*cm, None], header_bg=RED))
story.append(sp(6))

# Mechanisms summary
story.append(subsection("Mechanisms of Cell Injury — Quick Reference"))
mech_sum = [
    ["ATP Depletion",       "Na⁺/K⁺ pump fails → cell swelling → necrosis"],
    ["ROS",                 "Lipid peroxidation, DNA breaks, protein damage"],
    ["Ca²⁺ excess",         "Enzyme activation: proteases, phospholipases → membrane/DNA damage"],
    ["Membrane Damage",     "Lysosomal leakage → autodigestion; plasma membrane → osmotic lysis"],
    ["ER Stress (UPR)",     "Misfolded proteins → apoptosis via mitochondrial pathway"],
    ["DNA Damage",          "p53 → arrest → repair or apoptosis"],
]
story.append(make_table(["Mechanism", "Result"], mech_sum, col_widths=[4.5*cm, None]))
story.append(sp(6))

# Calcification summary
story.append(subsection("Calcification — Comparison"))
calc_sum = [
    ["Dystrophic",   "Normal", "Necrotic/dying tissue",  "TB, atherosclerosis"],
    ["Metastatic",   "High",   "Normal viable tissue",   "Hyperparathyroidism, bone mets, Vit D toxicity"],
]
story.append(make_table(["Type", "Serum Ca²⁺", "Site", "Cause"], calc_sum,
                         col_widths=[3.5*cm, 3*cm, None, 5*cm], header_bg=RED))
story.append(sp(8))

# ── MEMORY AIDS / MNEMONICS ───────────────────────────────────────────────────
story.append(colored_heading("MEMORY AIDS &amp; MNEMONICS", AMBER))
story.append(sp(6))

mnemonics = [
    tip_box("Causes of Atrophy\n'DISH-M'",
        ["Disuse", "Innervation loss", "Supply of blood ↓", "Hormone withdrawal", "Malnutrition/Pressure"],
        bg=AMBER_BG, title_bg=AMBER),
    sp(6),
    tip_box("Necrosis Types\n'CLC-FFG'",
        ["Coagulative", "Liquefactive", "Caseous", "Fat necrosis", "Fibrinoid", "Gangrenous"],
        bg=TEAL_BG, title_bg=TEAL),
    sp(6),
    tip_box("Apoptosis Pathways",
        ["Intrinsic = Mitochondrial → cytochrome c → Caspase-9",
         "Extrinsic = Death receptor → Caspase-8",
         "Both converge on Effector Caspases (3, 6, 7)"],
        bg=GREEN_BG, title_bg=LIME),
    sp(6),
    tip_box("ROS Antioxidants\n'GCSVE'",
        ["Glutathione peroxidase", "Catalase", "SOD (superoxide dismutase)", "Vitamin C", "Vitamin E"],
        bg=RED_BG, title_bg=RED),
]
for item in mnemonics:
    story.append(item)

story.append(sp(8))
story.append(hr(NAVY, 1))
story.append(sp(4))
story.append(Paragraph("Source: Robbins &amp; Kumar Basic Pathology (Robbins Pathology), Chapter 1, pp. 16–129  |  Compiled by Orris AI", NOTE))

# ── BUILD PDF ─────────────────────────────────────────────────────────────────
doc.build(story, onFirstPage=add_page_number, onLaterPages=add_page_number)
print(f"PDF successfully created: {OUTPUT}")

"""
Handwriting-style pathology notes PDF
Mimics the style in the uploaded image:
  - Cream/off-white background
  - Green headings: [A] Title :  with underline
  - Navy/dark blue body text with bullet points
  - Kalam handwriting font
  - Generous line spacing
"""

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.units import cm, mm
from reportlab.pdfbase import pdfmetrics
from reportlab.pdfbase.ttfonts import TTFont
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, HRFlowable,
    PageBreak, Table, TableStyle, KeepTogether
)
from reportlab.lib.styles import ParagraphStyle
from reportlab.lib.enums import TA_LEFT, TA_CENTER
import os

# ── Register fonts ────────────────────────────────────────────────────────────
FONT_DIR = "/tmp/workspace/pathology-study-guide/fonts"
pdfmetrics.registerFont(TTFont("Kalam",      f"{FONT_DIR}/Kalam-Regular.ttf"))
pdfmetrics.registerFont(TTFont("Kalam-Bold", f"{FONT_DIR}/Kalam-Bold.ttf"))

# ── Colors ────────────────────────────────────────────────────────────────────
CREAM      = colors.HexColor("#FAFAF5")   # page background (off-white)
GREEN_HDG  = colors.HexColor("#2E7D32")   # heading green (like in photo)
NAVY_BODY  = colors.HexColor("#1A237E")   # dark navy/blue for body text
LIGHT_LINE = colors.HexColor("#C8E6C9")   # soft green underline

# ── Styles ────────────────────────────────────────────────────────────────────
HDG = ParagraphStyle(
    "Heading",
    fontName="Kalam-Bold",
    fontSize=20,
    textColor=GREEN_HDG,
    leading=28,
    spaceBefore=22,
    spaceAfter=2,
)

BODY = ParagraphStyle(
    "Body",
    fontName="Kalam",
    fontSize=14,
    textColor=NAVY_BODY,
    leading=26,
    spaceAfter=6,
    leftIndent=0,
)

BULLET_STYLE = ParagraphStyle(
    "Bullet",
    fontName="Kalam",
    fontSize=14,
    textColor=NAVY_BODY,
    leading=26,
    spaceAfter=10,
    leftIndent=28,
    firstLineIndent=-18,
)

SUB_HDG = ParagraphStyle(
    "SubHdg",
    fontName="Kalam-Bold",
    fontSize=15,
    textColor=NAVY_BODY,
    leading=22,
    spaceBefore=10,
    spaceAfter=4,
    leftIndent=0,
)

NOTE_STYLE = ParagraphStyle(
    "Note",
    fontName="Kalam",
    fontSize=11,
    textColor=colors.HexColor("#555555"),
    leading=16,
    spaceAfter=4,
    leftIndent=14,
)

TABLE_HDR = ParagraphStyle(
    "TableHdr",
    fontName="Kalam-Bold",
    fontSize=13,
    textColor=colors.white,
    leading=18,
    alignment=TA_CENTER,
)

TABLE_CELL = ParagraphStyle(
    "TableCell",
    fontName="Kalam",
    fontSize=12,
    textColor=NAVY_BODY,
    leading=18,
)

# ── Helpers ───────────────────────────────────────────────────────────────────
def heading(label, title):
    """[A] Title :  in green, with underline drawn via HR"""
    text = f"[{label}]  {title} :"
    return [
        Paragraph(f'<font color="#2E7D32">{text}</font>', HDG),
        HRFlowable(width="98%", thickness=1.5, color=GREEN_HDG,
                   spaceBefore=0, spaceAfter=10),
    ]

def bullet(text):
    return Paragraph(f"•   {text}", BULLET_STYLE)

def sub(text):
    return Paragraph(text, SUB_HDG)

def body(text):
    return Paragraph(text, BODY)

def sp(h=8):
    return Spacer(1, h)

def make_table(headers, rows, col_widths=None):
    page_w = A4[0] - 4*cm
    if col_widths is None:
        w = page_w / len(headers)
        col_widths = [w] * len(headers)
    data = [[Paragraph(h, TABLE_HDR) for h in headers]]
    for row in rows:
        data.append([Paragraph(str(c), TABLE_CELL) for c in row])
    t = Table(data, colWidths=col_widths, repeatRows=1)
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,0),  GREEN_HDG),
        ("ROWBACKGROUNDS",(0,1), (-1,-1), [colors.HexColor("#F1F8E9"),
                                            colors.HexColor("#FAFAF5")]),
        ("GRID",          (0,0), (-1,-1), 0.5, colors.HexColor("#A5D6A7")),
        ("TOPPADDING",    (0,0), (-1,-1), 6),
        ("BOTTOMPADDING", (0,0), (-1,-1), 6),
        ("LEFTPADDING",   (0,0), (-1,-1), 8),
        ("RIGHTPADDING",  (0,0), (-1,-1), 8),
        ("VALIGN",        (0,0), (-1,-1), "MIDDLE"),
    ]))
    return t

# ── Page background ───────────────────────────────────────────────────────────
def draw_background(canvas, doc):
    canvas.saveState()
    canvas.setFillColor(CREAM)
    canvas.rect(0, 0, A4[0], A4[1], fill=1, stroke=0)
    # subtle left margin line (like ruled paper)
    canvas.setStrokeColor(colors.HexColor("#E8F5E9"))
    canvas.setLineWidth(0.8)
    canvas.line(1.6*cm, 0, 1.6*cm, A4[1])
    # page number
    canvas.setFont("Kalam", 10)
    canvas.setFillColor(colors.HexColor("#888888"))
    canvas.drawCentredString(A4[0]/2, 1*cm,
        f"Pathology  ·  Chapter 1: Cell Injury & Adaptations  ·  Page {canvas.getPageNumber()}")
    canvas.restoreState()

# ════════════════════════════════════════════════════════════════════════════
# CONTENT
# ════════════════════════════════════════════════════════════════════════════
story = []

# ── TITLE PAGE ────────────────────────────────────────────────────────────────
title_box = Table([[
    Paragraph('<font color="#2E7D32"><b>Pathology Notes</b></font>',
              ParagraphStyle("T1", fontName="Kalam-Bold", fontSize=30,
                             textColor=GREEN_HDG, alignment=TA_CENTER, leading=38)),
    Paragraph('<font color="#1A237E">BHMS 2nd Year</font>',
              ParagraphStyle("T2", fontName="Kalam", fontSize=18,
                             textColor=NAVY_BODY, alignment=TA_CENTER, leading=26)),
    Paragraph('<font color="#1A237E">Chapter 1 : Cell Injury, Adaptations &amp; Cell Death</font>',
              ParagraphStyle("T3", fontName="Kalam-Bold", fontSize=16,
                             textColor=NAVY_BODY, alignment=TA_CENTER, leading=24)),
    Paragraph('<font color="#555555">Based on Robbins &amp; Kumar Basic Pathology</font>',
              ParagraphStyle("T4", fontName="Kalam", fontSize=12,
                             textColor=colors.HexColor("#555555"), alignment=TA_CENTER, leading=18)),
]], colWidths=["100%"])
title_box.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,-1), colors.HexColor("#F1F8E9")),
    ("TOPPADDING",    (0,0), (-1,-1), 18),
    ("BOTTOMPADDING", (0,0), (-1,-1), 18),
    ("LEFTPADDING",   (0,0), (-1,-1), 20),
    ("RIGHTPADDING",  (0,0), (-1,-1), 20),
    ("BOX",           (0,0), (-1,-1), 1.5, GREEN_HDG),
]))
story.append(sp(20))
story.append(title_box)
story.append(PageBreak())

# ═════════════════════════════════════════════════════════
# SECTION 1 - Introduction to Pathology
# ═════════════════════════════════════════════════════════
story += heading("1", "Introduction to Pathology")
story.append(bullet("Pathology = study of <b>causes of disease</b> and changes in cells, tissues & organs."))
story.append(bullet("Provides the <b>scientific foundation</b> for the practice of medicine."))
story.append(sp(4))
story.append(sub("Key Terms :"))
story.append(bullet("<b>Etiology</b>  —  The origin/cause of disease ; includes genetic susceptibility + environmental triggers. Tells us WHY a disease arises."))
story.append(bullet("<b>Pathogenesis</b>  —  Steps in the development of disease from initial trigger to structural/functional abnormalities. Tells us HOW a disease develops."))
story.append(bullet("<b>Morphology</b>  —  Gross or microscopic appearance of cells & tissues used for diagnosis."))
story.append(bullet("<b>Precision Medicine</b>  —  Therapies tailored to each individual's specific molecular disease profile."))
story.append(PageBreak())

# ═════════════════════════════════════════════════════════
# SECTION 2 - Causes of Cell Injury
# ═════════════════════════════════════════════════════════
story += heading("2", "Causes of Cell Injury")
story.append(bullet("<b>Hypoxia & Ischemia</b>  —  Most common cause ; O₂ deficiency + reduced blood supply."))
story.append(bullet("<b>Physical Agents</b>  —  Mechanical trauma, extreme temperature, radiation, electric shock."))
story.append(bullet("<b>Chemical Agents / Drugs</b>  —  Toxins, poisons, hyper/hypotonic solutions, O₂ at high concentration."))
story.append(bullet("<b>Infectious Agents</b>  —  Viruses, bacteria, fungi, parasites."))
story.append(bullet("<b>Immunologic Reactions</b>  —  Autoimmune diseases, hypersensitivity reactions (Type I–IV)."))
story.append(bullet("<b>Genetic Derangements</b>  —  Congenital malformations, enzyme defects (e.g., sickle cell disease)."))
story.append(bullet("<b>Nutritional Imbalances</b>  —  Protein-calorie malnutrition, vitamin deficiencies, excess calories."))
story.append(sp(8))

# ═════════════════════════════════════════════════════════
# SECTION 3 - Reversible Cell Injury
# ═════════════════════════════════════════════════════════
story += heading("3", "Reversible Cell Injury")
story.append(bullet("Cell can <b>recover</b> if stimulus is removed in time."))
story.append(bullet("<b>Cellular Swelling</b>  —  Most common & earliest finding in almost all cell injury. Due to failure of Na⁺/K⁺ ATPase pump."))
story.append(bullet("<b>Fatty Change (Steatosis)</b>  —  Lipid vacuoles appear in cytoplasm (most common in liver)."))
story.append(sp(4))
story.append(sub("Morphology :"))
story.append(bullet("Pale, swollen cytoplasm"))
story.append(bullet("Plasma membrane blebs"))
story.append(bullet("Swelling of ER and mitochondria"))
story.append(bullet("Clumping of nuclear chromatin"))
story.append(PageBreak())

# ═════════════════════════════════════════════════════════
# SECTION A - Necrosis
# ═════════════════════════════════════════════════════════
story += heading("A", "Necrosis")
story.append(bullet("Cell death with <b>disruption of cell membranes</b> + enzymatic digestion of cell contents."))
story.append(bullet("Always <b>PATHOLOGIC</b>  —  never occurs in normal physiology."))
story.append(bullet("<b>Inflammation is prominent</b>  —  cellular contents leak and trigger immune response."))
story.append(sp(4))
story.append(sub("Features :"))
story.append(bullet("Cell size  —  Enlarged (swollen)"))
story.append(bullet("Nucleus  —  Pyknosis (shrinks)  →  Karyorrhexis (fragmentation)  →  Karyolysis (dissolution)"))
story.append(bullet("Plasma membrane  —  Disrupted"))
story.append(bullet("Cell contents  —  Enzymatic digestion ; leaks out into tissue"))
story.append(bullet("Inflammation  —  YES (prominent)"))
story.append(sp(10))

# ═════════════════════════════════════════════════════════
# SECTION B - Types of Necrosis
# ═════════════════════════════════════════════════════════
story += heading("B", "Types of Necrosis")
story.append(sp(4))

story.append(sub("[i]  Coagulative Necrosis :"))
story.append(bullet("Most common type."))
story.append(bullet("Cell architecture is <b>preserved</b> (ghost cells visible under microscope)."))
story.append(bullet("Protein denaturation dominates over enzymatic digestion."))
story.append(bullet("Characteristic of <b>solid organ infarcts</b>  (heart, kidney, spleen)."))
story.append(sp(8))

story.append(sub("[ii]  Liquefactive Necrosis :"))
story.append(bullet("Dead cells are <b>completely digested</b>  —  leaves liquid, pus-like material."))
story.append(bullet("Enzymatic digestion dominates over protein denaturation."))
story.append(bullet("Characteristic of :"))
story.append(Paragraph("        ◦   <b>Brain infarcts</b>  (neurons have little structural proteins)", BULLET_STYLE))
story.append(Paragraph("        ◦   <b>Bacterial/fungal abscesses</b>  (neutrophil enzymes digest tissue)", BULLET_STYLE))
story.append(sp(8))

story.append(sub("[iii]  Caseous Necrosis :"))
story.append(bullet("Term 'Caseous' (cheese-like) is derived from the <b>friable white appearance</b> of the area of Necrosis."))
story.append(bullet("Tissue is <b>Soft & Friable</b>."))
story.append(bullet("<b>Combination</b> of Coagulative & Liquefactive Necrosis."))
story.append(bullet("Characteristic of <b>Granulomatous inflammation</b> due to <b>Tuberculosis</b> or <b>Fungal Infection</b>."))
story.append(sp(8))

story.append(sub("[iv]  Fat Necrosis :"))
story.append(bullet("Necrotic adipose tissue with <b>Chalky-white appearance</b> due to deposition of Calcium."))
story.append(bullet("Characteristic of Trauma of Fat (breast) and <b>Pancreatitis</b>-mediated damage of Peripancreatic Fat."))
story.append(bullet("Fatty acid released by Trauma (e.g., to breast) or Lipase (e.g., Pancreatitis) join Calcium via <b>Saponification</b>."))
story.append(sp(8))

story.append(sub("[v]  Fibrinoid Necrosis :"))
story.append(bullet("<b>Immune complex deposition</b> in vessel walls  —  pink amorphous appearance."))
story.append(bullet("Characteristic of <b>Vasculitis</b> & Malignant Hypertension."))
story.append(bullet("Seen in immune-mediated vascular diseases (e.g., polyarteritis nodosa)."))
story.append(sp(8))

story.append(sub("[vi]  Gangrenous Necrosis :"))
story.append(bullet("Large area of tissue death ; not a specific pattern but a clinical term."))
story.append(bullet("<b>Dry Gangrene</b>  —  coagulative necrosis from arterial occlusion (e.g., diabetic foot)."))
story.append(bullet("<b>Wet Gangrene</b>  —  liquefactive necrosis from secondary bacterial infection."))
story.append(sp(6))

story.append(Note := Paragraph(
    "  Clinical Note :  Necrotic cells release tissue-specific proteins into blood  "
    "—  Cardiac Troponin (myocardial damage),  ALT/AST (liver damage),  "
    "Alkaline Phosphatase (bile duct damage).",
    ParagraphStyle("NoteBox", fontName="Kalam", fontSize=12, textColor=colors.HexColor("#1B5E20"),
                   leading=20, leftIndent=10, rightIndent=10, spaceAfter=6,
                   borderColor=GREEN_HDG, borderWidth=1, borderPadding=8,
                   backColor=colors.HexColor("#E8F5E9"))
))
story.append(PageBreak())

# ═════════════════════════════════════════════════════════
# SECTION C - Apoptosis
# ═════════════════════════════════════════════════════════
story += heading("C", "Apoptosis")
story.append(bullet("<b>Programmed cell death</b>  —  cells activate enzymes that degrade their own DNA & proteins."))
story.append(bullet("Fragments into <b>apoptotic bodies</b> rapidly phagocytosed by macrophages."))
story.append(bullet("<b>No inflammation</b>  —  cellular contents do NOT leak out."))
story.append(sp(4))
story.append(sub("Features :"))
story.append(bullet("Cell size  —  Reduced (shrunken)"))
story.append(bullet("Nucleus  —  Fragmented into <b>nucleosome-sized pieces</b>"))
story.append(bullet("Plasma membrane  —  <b>Intact</b> (but altered structure)"))
story.append(bullet("Cell contents  —  Intact ; released in apoptotic bodies"))
story.append(bullet("Inflammation  —  <b>NO</b>"))
story.append(sp(8))

story.append(sub("Causes of Apoptosis :"))
story.append(sp(3))
story.append(Paragraph("  Physiologic :", ParagraphStyle("P2", fontName="Kalam-Bold", fontSize=13,
                           textColor=GREEN_HDG, leading=20, spaceAfter=4, leftIndent=14)))
story.append(bullet("During <b>embryogenesis</b>  —  organ development & digit formation."))
story.append(bullet("Turnover of proliferative tissues  (intestinal epithelium, lymphocytes)."))
story.append(bullet("Involution of hormone-dependent tissues  (e.g., endometrium)."))
story.append(bullet("Decline of leukocytes at end of immune response."))
story.append(bullet("Elimination of <b>self-reactive lymphocytes</b>  (prevents autoimmunity)."))
story.append(sp(5))
story.append(Paragraph("  Pathologic :", ParagraphStyle("P3", fontName="Kalam-Bold", fontSize=13,
                           textColor=colors.HexColor("#C62828"), leading=20, spaceAfter=4, leftIndent=14)))
story.append(bullet("<b>DNA damage</b>  (radiation, toxins)  —  activation of pro-apoptotic BH3-only proteins."))
story.append(bullet("Accumulation of <b>misfolded proteins</b>  (ER stress)."))
story.append(bullet("Certain <b>viral infections</b>  —  viral proteins activate caspases."))
story.append(bullet("<b>CTL-mediated killing</b>  —  cytotoxic T lymphocytes activate caspases in target cells."))
story.append(PageBreak())

# ═════════════════════════════════════════════════════════
# SECTION D - Mechanisms of Apoptosis
# ═════════════════════════════════════════════════════════
story += heading("D", "Mechanisms of Apoptosis")
story.append(sp(4))

story.append(sub("[i]  Intrinsic (Mitochondrial) Pathway :"))
story.append(bullet("Triggered by : DNA damage, oxidative stress, misfolded proteins."))
story.append(bullet("Pro-apoptotic proteins  <b>BAX / BAK</b>  increase mitochondrial permeability."))
story.append(bullet("<b>Cytochrome c</b>  released from mitochondria  →  activates  <b>Caspase-9</b>  →  Effector caspases  (3, 6, 7)."))
story.append(bullet("Key regulators  :"))
story.append(Paragraph("        ◦   <b>Anti-apoptotic</b>  :  Bcl-2,  Bcl-XL  (keep mitochondria intact)", BULLET_STYLE))
story.append(Paragraph("        ◦   <b>Pro-apoptotic</b>  :  BAX,  BH3-only proteins  (promote cytochrome c release)", BULLET_STYLE))
story.append(sp(8))

story.append(sub("[ii]  Extrinsic (Death Receptor) Pathway :"))
story.append(bullet("Triggered by  :  FasL or TNF binding to <b>death receptors</b>  (Fas, TNFR)."))
story.append(bullet("Adaptor proteins recruited  →  activate  <b>Caspase-8</b>  →  Effector caspases."))
story.append(bullet("Used by  <b>Cytotoxic T Lymphocytes (CTLs)</b>  to kill infected or tumor cells."))
story.append(sp(8))

story.append(sub("Morphology of Apoptosis :"))
story.append(bullet("Cell shrinkage"))
story.append(bullet("Chromatin condensation & margination  (crescent-shaped under nuclear membrane)"))
story.append(bullet("Nuclear fragmentation"))
story.append(bullet("Cytoplasmic blebs  →  Apoptotic bodies"))
story.append(bullet("Rapid phagocytosis by macrophages  —  NO inflammatory response"))
story.append(PageBreak())

# ═════════════════════════════════════════════════════════
# SECTION E - Necrosis vs Apoptosis Comparison
# ═════════════════════════════════════════════════════════
story += heading("E", "Necrosis vs. Apoptosis — Comparison Table")
story.append(sp(6))
nva = [
    ["Feature",           "Necrosis",                           "Apoptosis"],
    ["Cell size",         "Enlarged (swollen)",                  "Reduced (shrunken)"],
    ["Nucleus",           "Pyknosis → karyorrhexis → karyolysis","Nucleosome-sized fragments"],
    ["Plasma membrane",   "Disrupted",                           "Intact (altered structure)"],
    ["Cell contents",     "Leaks out ; enzymatic digestion",     "Intact in apoptotic bodies"],
    ["Inflammation",      "YES (prominent)",                     "NO"],
    ["Nature",            "Always PATHOLOGIC",                   "Physiologic OR Pathologic"],
    ["Phagocytosis",      "By neutrophils/macrophages",          "By macrophages (no inflammation)"],
    ["Energy (ATP)",      "Not required (passive)",              "Required (active process)"],
    ["Caspases",          "Not involved",                        "Central role"],
]
story.append(make_table(nva[0], nva[1:], col_widths=[4.5*cm, None, None]))
story.append(PageBreak())

# ═════════════════════════════════════════════════════════
# SECTION F - Autophagy
# ═════════════════════════════════════════════════════════
story += heading("F", "Autophagy")
story.append(bullet("Cellular self-digestion  :  organelles/proteins sequestered in <b>autophagosomes</b>  (double-membrane vesicles)."))
story.append(bullet("Protective during <b>nutrient deprivation</b>  —  provides recycled building blocks."))
story.append(bullet("Excessive autophagy can activate apoptosis."))
story.append(bullet("Role in  :  Aging,  Parkinson's disease,  Alzheimer's disease,  Cancer."))
story.append(sp(10))

# ═════════════════════════════════════════════════════════
# SECTION G - Mechanisms of Cell Injury
# ═════════════════════════════════════════════════════════
story += heading("G", "Mechanisms of Cell Injury")
story.append(sp(4))

story.append(sub("[i]  Mitochondrial Dysfunction :"))
story.append(bullet("Damaged mitochondria release  <b>cytochrome c</b>  →  triggers intrinsic apoptosis."))
story.append(bullet("ATP depletion  →  failure of  Na⁺/K⁺  ATPase  →  cell swelling  →  membrane damage  →  necrosis."))
story.append(bullet("Formation of  <b>MPTP</b>  (mitochondrial permeability transition pore)  →  loss of membrane potential."))
story.append(sp(8))

story.append(sub("[ii]  Oxidative Stress (ROS) :"))
story.append(bullet("ROS  :  Superoxide (O₂•⁻),  Hydrogen peroxide (H₂O₂),  Hydroxyl radical (OH•)"))
story.append(bullet("Damage caused  :"))
story.append(Paragraph("        ◦   Lipid peroxidation  →  membrane damage", BULLET_STYLE))
story.append(Paragraph("        ◦   Protein oxidation  →  fragmentation/dysfunction", BULLET_STYLE))
story.append(Paragraph("        ◦   DNA strand breaks  →  mutations, apoptosis", BULLET_STYLE))
story.append(bullet("Antioxidant defenses  :  Glutathione peroxidase,  Catalase,  SOD,  Vitamins C & E."))
story.append(sp(8))

story.append(sub("[iii]  Membrane Damage :"))
story.append(bullet("Mitochondrial membrane  —  Loss of membrane potential  →  energy failure."))
story.append(bullet("Plasma membrane  —  Loss of osmotic balance  ;  influx of fluids & ions."))
story.append(bullet("Lysosomal membrane  —  Leakage of acid hydrolases  →  autodigestion  →  irreversible necrosis."))
story.append(sp(8))

story.append(sub("[iv]  Calcium Homeostasis Disturbance :"))
story.append(bullet("Normal cytosolic Ca²⁺  ~0.1 μmol  vs.  extracellular  1.3 mmol."))
story.append(bullet("Ischemia / toxins  →  excess intracellular Ca²⁺."))
story.append(bullet("Activates  :  <b>Proteases,  Phospholipases,  Endonucleases,  ATPases</b>  →  membrane & DNA damage."))
story.append(sp(8))

story.append(sub("[v]  ER Stress :"))
story.append(bullet("Misfolded proteins accumulate  →  activate  <b>Unfolded Protein Response (UPR)</b>."))
story.append(bullet("If overwhelmed  →  pro-apoptotic signals  →  apoptosis via mitochondrial pathway."))
story.append(bullet("Implicated in  :  Alzheimer's disease,  Type 2 diabetes,  neurodegeneration."))
story.append(sp(8))

story.append(sub("[vi]  DNA Damage :"))
story.append(bullet("Caused by  :  Radiation,  ROS,  Chemicals."))
story.append(bullet("<b>p53</b>  accumulates  →  cell cycle arrest for repair  ;  if irreparable  →  apoptosis."))
story.append(PageBreak())

# ═════════════════════════════════════════════════════════
# SECTION H - Cellular Adaptations
# ═════════════════════════════════════════════════════════
story += heading("H", "Cellular Adaptations to Stress")
story.append(bullet("Reversible changes in number, size, phenotype, or function of cells in response to stress."))
story.append(sp(6))

story.append(sub("[i]  Hypertrophy  —  ↑ Cell SIZE (no new cells) :"))
story.append(bullet("Occurs in cells with <b>limited capacity to divide</b>  (cardiac & skeletal muscle)."))
story.append(bullet("<b>Physiologic</b>  :  Uterus in pregnancy ; Skeletal muscle with exercise."))
story.append(bullet("<b>Pathologic</b>  :  Cardiac hypertrophy in hypertension or aortic stenosis."))
story.append(bullet("Mechanism  :  Stretch  →  growth factors + adrenergic hormones  →  more myofilaments."))
story.append(bullet("Sustained stress  →  degenerative changes  →  ventricular dilation  →  cardiac failure."))
story.append(sp(8))

story.append(sub("[ii]  Hyperplasia  —  ↑ Cell NUMBER :"))
story.append(bullet("Occurs in cells <b>capable of division</b>  (epithelium, glandular tissue)."))
story.append(bullet("<b>Physiologic</b>  :  Breast/uterus in puberty & pregnancy ; Liver regeneration."))
story.append(bullet("<b>Pathologic</b>  :  Endometrial hyperplasia (excess estrogen) ; BPH ; Psoriasis."))
story.append(bullet("Sustained pathologic hyperplasia  →  precursor to <b>cancer</b>."))
story.append(sp(8))

story.append(sub("[iii]  Atrophy  —  ↓ Cell SIZE & Function :"))
story.append(Paragraph(
    "  Causes  (Mnemonic  <b>DISH-M</b>)  :  Disuse,  Innervation loss,  Supply of blood ↓,  Hormone withdrawal,  Malnutrition/Pressure.",
    ParagraphStyle("Mne", fontName="Kalam-Bold", fontSize=13, textColor=colors.HexColor("#1B5E20"),
                   leading=20, leftIndent=14, spaceAfter=8,
                   backColor=colors.HexColor("#E8F5E9"), borderPadding=6)
))
story.append(bullet("Mechanism  :  ↓ protein synthesis  +  ↑ protein degradation via <b>ubiquitin-proteasome pathway</b>."))
story.append(sp(8))

story.append(sub("[iv]  Metaplasia  —  Change in CELL TYPE :"))
story.append(bullet("Reversible replacement of one adult cell type by another."))
story.append(bullet("<b>Columnar → Squamous</b>  :  Respiratory epithelium in smokers."))
story.append(bullet("<b>Squamous → Columnar</b>  :  Barrett's esophagus (acid reflux)."))
story.append(bullet("If stimulus persists  →  can predispose to <b>cancer</b>."))
story.append(PageBreak())

# ═════════════════════════════════════════════════════════
# SECTION I - Intracellular Depositions
# ═════════════════════════════════════════════════════════
story += heading("I", "Intracellular Accumulations")
story.append(sp(4))

story.append(sub("[i]  Fatty Change (Steatosis) :"))
story.append(bullet("Abnormal accumulation of <b>triglycerides</b> within parenchymal cells (most common in liver)."))
story.append(bullet("Causes  :  Toxins, Protein malnutrition, Diabetes, Obesity, Alcohol, Anoxia."))
story.append(sp(6))

story.append(sub("[ii]  Pigments :"))
story.append(bullet("<b>Lipofuscin</b>  —  'Wear & tear pigment' ; brownish-yellow ; accumulates in aging cells."))
story.append(bullet("<b>Hemosiderin</b>  —  Excess iron ; golden-yellow granules ; seen in hemochromatosis."))
story.append(bullet("<b>Carbon (Anthracosis)</b>  —  Inhaled ; phagocytosed by alveolar macrophages ; coal worker's pneumoconiosis."))
story.append(bullet("<b>Bilirubin</b>  —  Excess  →  Jaundice."))
story.append(sp(8))

story += heading("J", "Pathologic Calcification")
story.append(sp(4))
calc = [
    ["Feature",         "Dystrophic Calcification",           "Metastatic Calcification"],
    ["Site",            "Dead / necrotic tissue",             "Normal viable tissue"],
    ["Serum Ca²⁺",      "NORMAL",                             "HIGH (hypercalcemia)"],
    ["Examples",        "TB, atherosclerosis, heart valves",  "Hyperparathyroidism, bone metastases, Vit D toxicity"],
]
story.append(make_table(calc[0], calc[1:], col_widths=[4*cm, None, None]))
story.append(PageBreak())

# ═════════════════════════════════════════════════════════
# SECTION K - Cellular Aging
# ═════════════════════════════════════════════════════════
story += heading("K", "Cellular Aging")
story.append(bullet("Cells can undergo finite divisions  →  <b>Hayflick Limit</b>  (≈ 50–70 divisions for most human cells)."))
story.append(sp(5))
story.append(sub("Mechanisms :"))
story.append(bullet("<b>Telomere Shortening</b>  —  Repetitive DNA at chromosome ends shortens with each division  →  senescence or apoptosis. Cancer cells bypass via <b>Telomerase</b>."))
story.append(bullet("<b>Accumulated DNA Damage</b>  —  ROS, chemicals, radiation ; repair mechanisms decline with age."))
story.append(bullet("<b>Defective Protein Homeostasis</b>  —  Misfolded proteins accumulate ; chaperone & proteasome activity decline."))
story.append(bullet("<b>Metabolic Alterations</b>  —  Caloric restriction  →  ↓ ROS + ↓ IGF-1 signaling  →  extended lifespan."))
story.append(bullet("<b>Epigenetic Changes</b>  —  Altered methylation & histone modification patterns with age."))
story.append(bullet("<b>Inflammaging</b>  —  Low-grade chronic inflammation contributes to age-related diseases."))
story.append(sp(14))

# ── Footer note ───────────────────────────────────────────────────────────────
story.append(HRFlowable(width="100%", thickness=1, color=GREEN_HDG, spaceBefore=4, spaceAfter=6))
story.append(Paragraph(
    "Source  :  Robbins & Kumar Basic Pathology (Robbins Pathology),  Chapter 1,  pp. 16–129  |  Notes compiled by Orris AI",
    ParagraphStyle("Src", fontName="Kalam", fontSize=10, textColor=colors.HexColor("#777777"),
                   alignment=TA_CENTER, leading=14)
))

# ════════════════════════════════════════════════════════════════════════════
# BUILD
# ════════════════════════════════════════════════════════════════════════════
OUTPUT = "/tmp/workspace/pathology-study-guide/Pathology_Handwriting_Notes.pdf"
doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=2.2*cm,
    rightMargin=2*cm,
    topMargin=2.2*cm,
    bottomMargin=2*cm,
    title="Pathology Chapter 1 - Handwriting Notes",
    author="Orris AI",
)
doc.build(story, onFirstPage=draw_background, onLaterPages=draw_background)
print(f"PDF created: {OUTPUT}")
import os
print(f"Size: {os.path.getsize(OUTPUT)/1024:.1f} KB")