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REASONING QUESTION ANSWERS - COMPLETE SET

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SECTION 1: NERVE MUSCLE PHYSIOLOGY

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• Summation at intermediate frequency
• Incomplete tetanus - partial relaxation between contractions
• Complete tetanus (smooth, sustained maximal contraction) at higher frequencies

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• Continuous activation of troponin-tropomyosin complex
• Sustained, unregulated contraction (contracture)
• ATP depletion and eventual muscle damage
• Clinically seen in malignant hyperthermia (uncontrolled SR Ca2+ release)

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1. Stores oxygen within the muscle cell, serving as a local O2 reserve during brief interruptions in blood flow
2. Facilitates O2 diffusion from capillary to mitochondria (acts as an O2 carrier within the cell)
3. Has higher O2 affinity than hemoglobin, so it picks up O2 readily from blood

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• Each nerve impulse releases enough ACh to activate thousands of receptors simultaneously
• This guarantees that every motor nerve action potential reliably triggers a muscle action potential (high safety factor at the NMJ, ~3-4x)
• It compensates for ACh degradation by acetylcholinesterase and ensures sufficient EPP to exceed threshold
• Concentrated in the junctional folds to maximize exposure to released ACh

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• Type I (MHC-I / slow MHC): Low ATPase activity → slow cross-bridge cycling → slow contraction but fatigue-resistant (relies on oxidative metabolism). Found in postural muscles.
• Type IIa (fast oxidative): Intermediate ATPase → fast and moderately fatigue-resistant
• Type IIx/IIb (fast glycolytic): Very high ATPase → fastest contractions but fatigue quickly

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• Sustained ATP supply during prolonged activity
• Efficient use of oxygen delivered by myoglobin and blood
• Reduced dependence on anaerobic glycolysis (which produces lactic acid and is less efficient)

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• Myosin defect: Impaired cross-bridge formation → reduced force, weakness
• Actin defect: Disrupted thin filament → poor myosin binding
• Troponin/tropomyosin defect: Ca2+ regulation fails → either constitutive contraction or inability to contract
• Titin defect: Loss of passive elasticity and structural support → sarcomere instability

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1. Store neurotransmitters (e.g., ACh at NMJ) in a concentrated, protected form, preventing degradation
2. Are docked at active zones on the presynaptic membrane
3. On arrival of an action potential, Ca2+ influx triggers exocytosis - vesicles fuse with the presynaptic membrane, releasing NT into the synaptic cleft (quantal release - each vesicle releases a fixed quantum of NT)
4. Membrane is recycled by endocytosis after exocytosis (clathrin-mediated or kiss-and-run)

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• Myelinated fibers: Saltatory conduction (impulse jumps from node to node) → fast conduction (up to 120 m/s), less energy use
• Unmyelinated fibers: Continuous conduction along entire membrane → slow (0.5-2 m/s), more energy
• Myelin also electrically insulates the axon, reducing ion leakage
• Loss of myelin (demyelination, e.g., multiple sclerosis) → slowed or blocked conduction → sensory/motor deficits

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• Terminates the postsynaptic receptor activation
• Prevents continuous muscle stimulation
• Allows the muscle to relax between stimuli
• Choline is taken back up by the presynaptic terminal (choline transporter) for ACh re-synthesis

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SECTION 2: ENDOCRINE SYSTEM

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• TSH secretion falls (secondary hypothyroidism)
• Thyroid gland receives no TSH stimulation
• T3/T4 production drops (tertiary hypothyroidism)
• Result: hypothyroid state - fatigue, weight gain, cold intolerance, myxedema
• This is hypothalamic (tertiary) hypothyroidism

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• Greater glucose uptake by cells
• Enhanced glycogenesis, lipogenesis, protein synthesis
• Risk of hypoglycemia as blood glucose falls readily
• This is the opposite of insulin resistance
• Clinically, this state resembles the effect of giving exogenous insulin

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• Hypotension (cortisol needed for vascular tone)
• Hypoglycemia (loss of gluconeogenesis)
• Weakness and fatigue
• Hyponatremia and hyperkalemia (also lose aldosterone in primary adrenal failure)
• Hyperpigmentation (loss of cortisol → high ACTH and MSH)
• Inability to handle stress → Addisonian crisis (life-threatening)

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• Insufficient iodine → decreased T3/T4 synthesis
• Low T3/T4 → loss of negative feedback → TSH rises
• Persistent TSH stimulation → goiter (thyroid gland enlargement)
• Clinical manifestations of hypothyroidism
• In pregnancy: cretinism (irreversible mental retardation, short stature in offspring)

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• GH excess → Acromegaly
• Enlargement of hands, feet, jaw (prognathism), skull
• Soft tissue thickening, organomegaly
• Glucose intolerance/diabetes (GH is anti-insulin)
• Carpal tunnel syndrome, arthritis
• Hypertension, cardiac complications

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• Without glucagon, hypoglycemia occurs especially during fasting
• The counter-regulatory response to hypoglycemia is impaired
• Normally other counter-regulatory hormones (epinephrine, cortisol) partially compensate, but severe hypoglycemia risk remains, especially in diabetics on insulin

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• Overactivation (excess cortisol): Cushing's syndrome - truncal obesity, hyperglycemia, hypertension, immunosuppression, muscle wasting, osteoporosis
• Underactivation (insufficient cortisol): Addison's disease - hypotension, hypoglycemia, fatigue, hyperpigmentation
• Chronic HPA overactivation (chronic stress) → immune suppression, cardiovascular disease, mood disorders

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• Hypercalcemia (bone resorption increases, renal Ca2+ reabsorption increases)
• Hypophosphatemia (phosphaturia increases)
• Increased calcitriol (1,25-OH Vitamin D) → increased gut Ca2+ absorption
• Clinical: kidney stones, bone pain, weakness, constipation, polyuria (stones, bones, groans, psychic moans)
• Excess PTH = hyperparathyroidism

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• Brain is exclusively dependent on glucose
• Hypoglycemia → brain dysfunction (seizures, coma, death)
• Hyperglycemia → osmotic damage, glycation of proteins, vascular damage

• High glucose → insulin secretion → glucose uptake → glucose falls → insulin secretion stops
• Low glucose → glucagon secretion → glycogenolysis → glucose rises → glucagon stops

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• Cortisol peaks around 6-8 AM (just before waking) to prepare the body for activity - mobilizes energy, increases alertness
• Troughs at midnight
• CRH pulses from hypothalamus → ACTH pulses → cortisol pulses following this cycle
• This pattern optimizes metabolic readiness for daytime activity
• Disruption (shift work, jet lag) leads to metabolic dysregulation

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• Produces releasing and inhibiting hormones (TRH, CRH, GnRH, GHRH, somatostatin, dopamine) controlling all anterior pituitary hormones
• Produces ADH and oxytocin (stored/released from posterior pituitary)
• Receives inputs from higher brain centers (stress, emotion, light) and peripheral feedback (hormones, temperature, osmolarity)
• Regulates body temperature, appetite, thirst, sleep, circadian rhythms

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• Increases basal metabolic rate (BMR) by uncoupling oxidative phosphorylation (increases thermogenesis)
• Upregulates Na/K-ATPase → increased O2 consumption
• Stimulates protein synthesis and breakdown
• Increases heart rate, cardiac output (positive chronotropic and inotropic effects)
• Hyperthyroidism: BMR elevated 60-100% above normal; hypothyroidism: 30-50% below normal

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• Neurons: Ca2+ triggers neurotransmitter vesicle exocytosis; Ca2+ maintains nerve membrane stability (hypocalcemia → decreased threshold → tetany, seizures)
• Muscle: Ca2+ binds troponin C to initiate contraction; SR releases and reuptakes Ca2+ to control contraction-relaxation cycle
• General: Ca2+ is a second messenger for many signaling pathways; maintains cell membrane potential
• Hypocalcemia → neuromuscular hyperexcitability (Chvostek's sign, Trousseau's sign, tetany)

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• The hypothalamic "set point" changes (maturation of kisspeptin neurons in the arcuate nucleus)
• The brain becomes less sensitive to gonadal steroid negative feedback
• GnRH pulses increase in frequency and amplitude
• This drives FSH and LH surges → gonadal activation → sex hormone production → secondary sexual characteristics

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• Central DI: ADH production/release is deficient
• Nephrogenic DI: Kidneys don't respond to ADH (V2 receptor mutation or AQP2 defect)

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• Increased BMR (increased O2 consumption, heat production)
• Weight loss despite increased appetite
• Glucose intolerance (increased glycogenolysis)
• Protein catabolism → muscle wasting
• Increased cholesterol turnover (lowers cholesterol)

• Increased heart rate (tachycardia, palpitations) - T3 increases cardiac beta-receptor sensitivity and SA node firing
• Increased cardiac output
• Widened pulse pressure
• Atrial fibrillation (in severe cases)
• High-output cardiac failure (chronic)

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• Mediates most of GH's growth effects (GH→liver→IGF-1→target tissues)
• Stimulates chondrocyte proliferation at epiphyseal plates → linear growth in children
• Promotes protein synthesis, muscle growth, organ development
• Has insulin-like effects: increases glucose uptake
• Acts via tyrosine kinase receptors (IGF-1R)
• GH deficiency in childhood → low IGF-1 → dwarfism; GH excess → high IGF-1 → gigantism/acromegaly

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1. Wolff-Chaikoff effect: High iodine acutely inhibits thyroid hormone synthesis and release (autoregulation)
2. Reduces vascularity of the thyroid gland (makes it firmer and less vascular) - critical to reduce surgical bleeding risk in the highly vascular thyroid
3. Decreases thyroid hormone release, helping control hyperthyroid state pre-operatively

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• Reduced T3/T4 → reduced BMR → less heat production
• Body temperature tends to be lower
• Patient feels cold (cold intolerance)
• To compensate and feel comfortable, they prefer warm/hot environments

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• High estrogen and progesterone (from placenta) competitively inhibit prolactin's action at the mammary gland receptors
• Estrogen structurally inhibits the effect of prolactin on alveolar cells
• After delivery, estrogen and progesterone levels drop sharply (loss of placenta)
• Prolactin can now act unopposed → lactation begins within 2-3 days postpartum

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• Acts on beta-1 receptors directly → direct chronotropic effect (tachycardia)
• This direct positive chronotropic effect overrides and masks the baroreceptor-mediated reflex bradycardia
• The net result is tachycardia (direct effect dominates)
• Compare with norepinephrine: predominantly alpha effect → vasoconstriction → BP rises → reflex bradycardia (no direct beta-1 override)

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• Aldosterone causes initial Na+ and water retention → increased blood volume → increased BP
• Elevated BP increases renal perfusion pressure → pressure natriuresis/diuresis - the kidney excretes excess Na+ and water to normalize volume
• Also, reduced proximal tubule Na+ reabsorption (due to elevated BP)
• Net result: Despite continued aldosterone action, Na+ balance is restored, but hypertension and hypokalemia persist

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• It compresses the optic chiasm - specifically the crossing fibers from the nasal retina
• This causes bitemporal hemianopia (loss of peripheral/temporal visual fields in both eyes)
• Perimetry (visual field testing) detects this characteristic pattern and monitors tumor progression

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• Purple striae: Cortisol excess → protein catabolism → skin thinning → underlying blood vessels visible; also impairs collagen synthesis → skin fragility → stretch marks appear purple/red
• Truncal obesity: Cortisol stimulates fat deposition preferentially in face, neck, abdomen (centripetal distribution); possibly due to differential receptor sensitivity in visceral vs. peripheral fat
• Red cheeks (plethora): Thin skin + increased vascularity; also polycythemia (cortisol stimulates erythropoiesis)
• Moon face: Redistribution of fat to face (fat pad deposition); fluid retention

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• Visceral/central fat: Has more glucocorticoid receptors → promotes fat deposition and lipolysis inhibition centrally
• Peripheral/limb fat: Cortisol promotes lipolysis here → peripheral fat is mobilized and redistributed centrally
• Result: Fat accumulates at face (moon face), neck (buffalo hump), abdomen, while limbs remain thin
• This paradox (central obesity + peripheral wasting) is pathognomonic of Cushing's

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• Polyuria: Hyperglycemia exceeds renal glucose threshold (~180 mg/dL) → glucose appears in urine (glucosuria) → osmotic diuresis (glucose draws water with it) → large urine volumes
• Polydipsia: Loss of water through polyuria → dehydration → increased plasma osmolarity → stimulates thirst center in hypothalamus
• Polyphagia: In Type 1 DM, cells cannot take up glucose (no insulin) → cellular starvation despite high blood glucose → hunger signals persist; also elevated glucagon promotes catabolic state

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• High prolactin inhibits GnRH pulsatility (acts on hypothalamic kisspeptin/GnRH neurons)
• Without GnRH pulses, FSH and LH are not secreted
• No FSH/LH → no follicular development → no ovulation → no estrogen/progesterone cycle → amenorrhea (lactational amenorrhea)
• This is a natural, temporary contraceptive mechanism

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• TSH receptor antibodies (TSI) stimulate retroorbital fibroblasts which express TSH receptors
• Fibroblasts produce glycosaminoglycans (hyaluronic acid) → water retention → retroorbital edema
• Lymphocytic infiltration and inflammation of extraocular muscles
• Increased retroorbital fat and connective tissue volume
• All this pushes the eyeball forward
• Note: This is not caused by high T3/T4 directly - it's the autoimmune process, which is why treating thyroid hormone levels doesn't always resolve proptosis

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• Myxedema: Decreased thyroid hormone → reduced degradation of glycosaminoglycans (hyaluronic acid, chondroitin sulfate) in connective tissue → accumulate in skin → attract water → non-pitting edema (mucin accumulates, not fluid from pressure)
• Carotenemia (yellow skin): Thyroid hormone needed for conversion of beta-carotene to Vitamin A in the liver. In hypothyroidism, this conversion is reduced → carotene accumulates in blood and skin → yellow-orange tint (especially palms, soles); differs from jaundice (sclerae not yellow in carotenemia)

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1. It is required for normal GH secretion (hypothyroid children have reduced GH pulses)
2. T3 is needed for GH receptor expression and IGF-1 production in target tissues
3. T3 directly stimulates chondrocyte maturation and ossification at growth plates
4. Thyroid hormone is critical for brain maturation (critical period: fetal life to age 3)
5. Without T3/T4, bone age lags, linear growth stops → short stature (cretinism if severe in infancy)

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• Reduced mitochondrial activity → impaired ATP production
• Accumulation of glycosaminoglycans in muscle tissue
• Impaired muscle metabolism → proximal myopathy
• Also, hyponatremia (in severe cases) contributes

• Excess T3 → increased protein catabolism → muscle wasting (thyrotoxic myopathy)
• Negative nitrogen balance
• Hypokalemia (increased Na/K-ATPase activity)
• Mitochondrial uncoupling reduces net ATP availability for contraction

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• Upregulates hepatic LDL receptors → increased uptake and clearance of LDL cholesterol
• Increases bile acid synthesis from cholesterol (via CYP7A1 enzyme upregulation)
• Increases cholesterol turnover and excretion
• In hypothyroidism, cholesterol rises (reduced LDL clearance); in hyperthyroidism, it falls
• Thyroid analogs (like eprotirome) that selectively activate hepatic thyroid receptors (without cardiac effects) have been investigated as cholesterol-lowering drugs

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• Low T3/T4 → increased TRH → elevated prolactin (TRH also stimulates prolactin) → inhibits GnRH → anovulation, amenorrhea
• Irregular menstrual cycles, menorrhagia
• Impaired endometrial development

• Excess T3/T4 → altered GnRH pulsatility, elevated SHBG → altered free estrogen levels
• Oligomenorrhea, anovulation
• Increased early pregnancy loss

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• Increased glycogenolysis in liver → hepatic glucose output increases
• Increased gluconeogenesis
• Increased glucose absorption from gut (T3 upregulates intestinal glucose transporters)
• Increases insulin resistance (counterregulatory to insulin)
• Decreases insulin half-life (increases insulin degradation)
• Net result: blood glucose rises, insulin response is inadequate → glucose intolerance or frank DM

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• Thiocyanates and isothiocyanates: Compete with iodide for uptake by thyroid (block NIS - sodium-iodide symporter)
• Progoitrin: Converted to goitrin in the gut → inhibits thyroid peroxidase (TPO) → blocks T3/T4 synthesis
• In an already hypothyroid patient, consuming goitrogens would further suppress already low thyroid hormone production, worsening the condition

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• Mental defect: Thyroid hormone is essential for brain maturation, myelination of neurons, neuronal migration, and synapse formation. Critical period is fetal life to age 3. Permanent, irreversible damage to CNS if T3/T4 absent.
• Short stature: Thyroid hormone needed for GH secretion and action, bone growth plate maturation, and chondrocyte differentiation. Without it, epiphyseal ossification is delayed and growth is severely stunted.
• Also: coarse features, enlarged tongue, umbilical hernia, constipation, hoarse cry

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• Normally, infant suckling stimulates nipple mechanoreceptors → afferent signals → hypothalamus → oxytocin release from posterior pituitary → myoepithelial cell contraction → milk ejection
• After repeated suckling-oxytocin associations, higher brain centers (auditory cortex) establish conditioned pathways
• The cry of the baby (a conditioned stimulus) activates neural pathways that trigger hypothalamic oxytocin release without physical nipple stimulation
• This is the neuroendocrine basis of "let-down" reflex triggered by the baby's cry

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• Early sex hormone (estrogen/testosterone) secretion causes early growth spurt (patient is tall for age initially)
• However, sex hormones also cause premature closure of epiphyseal growth plates
• Once plates close, no further linear growth is possible
• Since this happens years before normal puberty, the total duration of growth is shortened
• Net result: Child is initially tall but stops growing early → final adult height is shorter than expected (dwarf relative to peers)

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• Glucose cannot enter cells (no GLUT4 translocation without insulin) → cellular starvation
• Body interprets this as a starvation state → activates lipolysis (fat breakdown) and proteolysis (muscle protein breakdown)
• Gluconeogenesis runs continuously
• Despite eating more (polyphagia), calories cannot be stored as fat or glycogen without insulin
• Energy is lost in urine as glucose (glucosuria)
• Net result: weight loss despite increased food intake

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1. PTH acts on proximal tubule of kidney → stimulates 1-alpha hydroxylase
2. This enzyme converts 25-OH-Vitamin D to 1,25-(OH)2-Vitamin D (calcitriol)
3. Calcitriol acts on small intestinal epithelium → upregulates calbindin D and calcium channels (TRPV6)
4. This increases active transcellular calcium absorption in the duodenum and jejunum

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• Decreased bone mineral density (BMD) with aging: osteoclast activity outpaces osteoblast activity
• In women post-menopause: loss of estrogen → increased RANK-L expression → osteoclast activation → accelerated bone resorption
• Decreased calcium absorption from gut (reduced vitamin D activation, reduced renal 1α-hydroxylase)
• Secondary hyperparathyroidism of aging (low Ca2+ → high PTH → bone resorption)
• Reduced physical activity → less mechanical loading (less osteoblast stimulation)
• Result: osteoporosis → trabecular thinning → fractures at hip, vertebrae, wrist

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• Calcium ions normally stabilize voltage-gated Na+ channels by binding near the channel's external face and raising the activation threshold
• Low Ca2+ → channels are less stabilized → threshold for Na+ channel opening is lowered
• Even small depolarizations can trigger action potentials
• Spontaneous, repetitive firing of motor and sensory nerves occurs
• Clinical features: muscle cramps, carpopedal spasm, Chvostek's sign (facial tap → facial twitch), Trousseau's sign (BP cuff → carpopedal spasm)

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• Glucocorticoids (e.g., prednisolone) exert potent anti-inflammatory and immunosuppressive effects
• Inhibit NF-kB → reduced cytokine production (IL-1, IL-2, TNF-α, IFN-γ)
• Suppress T-cell proliferation and activation
• Reduce lymphocyte trafficking and adhesion molecule expression
• Inhibit macrophage and dendritic cell function (reduce antigen presentation)
• Net result: blunted immune response against the foreign transplanted tissue, preventing rejection

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1. Inhibit osteoblast activity and promote osteoblast apoptosis → reduced bone formation
2. Increase RANK-L/OPG ratio → enhanced osteoclast activity → increased bone resorption
3. Decrease intestinal calcium absorption (antagonize Vitamin D effects)
4. Increase renal calcium excretion
5. Low Ca2+ → secondary hyperparathyroidism → further bone resorption
6. Decrease sex hormone production (inhibit GnRH/LH/FSH) → loss of estrogen/testosterone effect on bone

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• Cortisol (and other adrenal androgens) normally stimulate erythropoiesis (red blood cell production)
• Cortisol stimulates EPO production and the response of bone marrow to EPO
• Adrenal androgens (DHEA) contribute to erythropoiesis stimulation
• In adrenal insufficiency: loss of these stimuli → normochromic, normocytic anemia
• Also, associated chronic inflammation and poor nutrition contribute
• Aldosterone deficiency → hyponatremia → hemodilution (artifactual anemia component)

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1. Increase gluconeogenesis in liver (upregulate PEPCK, G6Pase - key gluconeogenic enzymes)
2. Increase proteolysis in peripheral tissues (muscle) → provide amino acid substrates for gluconeogenesis
3. Increase lipolysis → glycerol used for gluconeogenesis; FFA cause insulin resistance
4. Decrease glucose uptake in peripheral tissues (inhibit GLUT4 translocation in muscle/fat = insulin resistance)
5. Net result: Blood glucose rises - "steroid-induced diabetes"

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• Low cortisol → loss of negative feedback on anterior pituitary → ACTH rises markedly
• ACTH is derived from pro-opiomelanocortin (POMC), the same precursor as MSH (Melanocyte-Stimulating Hormone)
• High ACTH + high MSH → melanocyte stimulation → increased melanin production
• Pigmentation in sun-exposed areas, skin creases, buccal mucosa, pressure points, scars
• Not seen in secondary adrenal insufficiency (where ACTH is low)

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• Low dose (1-3 mcg/kg/min): DA1 receptors → renal and mesenteric vasodilation → increases renal perfusion (preserves kidney function in shock)
• Moderate dose (3-10 mcg/kg/min): Beta-1 receptors → positive inotropic effect → increases cardiac output (key in cardiogenic shock)
• High dose (>10 mcg/kg/min): Alpha-1 receptors → vasoconstriction → raises BP (like norepinephrine)

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• Phase 1 (initial rise): Epinephrine acts on alpha-1 receptors (predominant at high doses) → vasoconstriction → increased BP; also beta-1 → increased heart rate/contractility
• Phase 2 (fall below baseline): As plasma epinephrine concentration drops, the beta-2 effect predominates (beta-2 has higher affinity) → vasodilation in skeletal muscle and other vascular beds → BP falls transiently below normal
• Then BP returns to normal as epinephrine is cleared

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• Reduced thyroid hormone → accumulation of glycosaminoglycans (hyaluronic acid, chondroitin sulfate) in the dermis and subcutaneous tissues
• These hygroscopic molecules attract and retain water in the interstitial spaces
• However, the water is bound to mucopolysaccharides, not freely mobile
• Pressing the skin does not displace the fluid (unlike pitting edema) because it is gel-like
• Hence the term "non-pitting" or "brawny" edema → myxedema

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• Aldosterone initially causes Na+ and water retention (tendency toward edema)
• However, the aldosterone escape phenomenon occurs:
  • Increased blood volume → increased atrial stretch → ANP (atrial natriuretic peptide) release
  • Increased renal perfusion pressure → pressure natriuresis
  • These mechanisms cause the kidney to excrete the excess Na+ and water
• So despite persistent hyperaldosteronism, Na+ balance is restored and edema does not develop
• However, hypertension and hypokalemia do persist

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• ADH binds V2 → Gs protein → adenylyl cyclase → cAMP → PKA activation → phosphorylation of aquaporin-2 (AQP2)
• Phosphorylated AQP2 inserts into the apical membrane → water reabsorption
• V2 receptor mutation → ADH cannot signal → AQP2 not inserted → water cannot be reabsorbed
• Result: Nephrogenic diabetes insipidus - massive dilute urine output despite adequate (often elevated) ADH levels
• Treatment: thiazide diuretics (paradoxically reduce urine volume by causing mild volume depletion) and low-sodium diet

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SECTION 3: REPRODUCTIVE SYSTEM

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• Disruption of FSH/LH pulsatility → impaired folliculogenesis → anovulation
• Without ovulation: no corpus luteum → no progesterone → irregular or absent cycles
• Causes: PCOS (high LH:FSH, androgen excess), thyroid disorders, hyperprolactinemia, hypothalamic amenorrhea
• Impact on fertility: Reduced or absent ovulation → difficulty conceiving; also altered endometrium affects implantation

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• Possible causes: Varicocele (most common), cryptorchidism, hormonal disorders (low FSH/LH/testosterone), genetic (Klinefelter's syndrome, Y chromosome microdeletions), heat exposure, infections (mumps orchitis), chemotherapy, drugs (anabolic steroids)
• Effect on fertility: Reduces probability of fertilization; severely oligospermic men may need assisted reproduction (IUI, IVF, ICSI)

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• Blocked or damaged tubes → egg cannot meet sperm → reduced natural fertility
• Increased risk of ectopic pregnancy (fertilized egg implants in scarred tube)
• Chronic endometritis may impair implantation
• Requires fertility evaluation; may need IVF to bypass damaged tubes

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• In utero testosterone from testes drives male sexual differentiation (normal process)
• Excess exogenous testosterone: complex effects on HPG axis programming
• In adults: Exogenous testosterone suppresses HPG axis → reduced FSH/LH → impaired spermatogenesis → infertility (paradox: testosterone = low sperm count)
• May also affect secondary sex characteristics and behavior

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• Missing a pill → hormone levels fall transiently
• < 24 hours late: Take immediately, low risk
• > 24-48 hours: Risk of FSH/LH rebound → possible follicle development → ovulation risk increases
• Withdrawal bleeding (breakthrough bleeding) may occur
• Backup contraception recommended

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• Removes cholesterol from sperm plasma membrane → increased membrane fluidity
• Hyperpolarization followed by membrane potential changes
• Enables the acrosome reaction (when sperm meets zona pellucida)
• Increases sperm motility (hyperactivation)
• Without capacitation: sperm cannot penetrate zona pellucida or fuse with egg
• Capacitation factors in female tract: bicarbonate, albumin, progesterone

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• As the dominant follicle matures → estrogen rises progressively
• When estrogen reaches a threshold (~200 pg/mL for >36 hours), it switches from negative to positive feedback on the hypothalamus/pituitary
• This triggers a massive GnRH pulse → LH surge (10-12x baseline, FSH also surges)
• LH surge triggers: final oocyte maturation (completion of meiosis I), follicle rupture, ovulation (~36 hours after LH peak), and luteinization of granulosa cells → corpus luteum formation

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1. Gas exchange: O2 and CO2 diffusion (fetal Hb has higher O2 affinity)
2. Nutrition: Glucose, amino acids, fatty acids, vitamins transported to fetus
3. Waste removal: Fetal CO2, urea excreted to maternal blood
4. Hormone production: hCG (maintains corpus luteum for first trimester), progesterone (prevents uterine contractions), estrogen, HPL
5. Immune protection: IgG transfer (passive immunity)
6. Barrier: Partially separates maternal and fetal blood

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• hCG (human chorionic gonadotropin): Peaks at 8-12 weeks (exactly when nausea peaks); structural similarity to TSH → causes mild hyperthyroidism → nausea; directly stimulates chemoreceptor trigger zone
• Estrogen: Rising estrogen levels → known to sensitize the vomiting center
• Relaxation of lower esophageal sphincter (progesterone) → acid reflux
• Olfactory hypersensitivity (evolutionary protection from harmful foods during organogenesis)
• Morning is worse because cortisol is lower, blood glucose lower after overnight fast

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• Negative feedback prevents hormone excess: e.g., estrogen/progesterone inhibit GnRH/FSH/LH (prevents continuous stimulation)
• Positive feedback drives ovulation: mid-cycle estrogen surge → LH surge (timed, critical event)
• Without feedback: Either continuous stimulation (polycystic ovaries, ovarian hyperstimulation) or complete shutdown
• Precise cyclical hormone changes are needed for: follicle development, ovulation, corpus luteum function, endometrial preparation, and either pregnancy or menstruation

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1. Primary: Suppress GnRH pulsatility → low FSH/LH → no follicular development, no ovulation
2. Cervical mucus: Progestin thickens cervical mucus → impermeable to sperm
3. Endometrium: Progestin makes endometrium thin and atrophic → unfavorable for implantation (backup)
4. Tubal motility: Altered → impaired sperm and egg transport

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• The testes are located in the scrotum specifically to maintain this lower temperature
• Heat-sensitive enzymes in spermatogonia and spermatocytes denature at core body temperature
• Working in hot environments → scrotal temperature rises → impairs spermatogenesis → oligospermia or azoospermia
• Also applies to: tight underwear, laptops on lap, frequent hot baths
• This is the same mechanism behind cryptorchidism-related infertility (undescended testes at core body temperature)

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• After oral absorption, androgens are carried via portal circulation directly to the liver
• Liver rapidly oxidizes and inactivates testosterone (17-beta dehydrogenase, CYP enzymes)
• Very little reaches systemic circulation in active form
• Therefore, oral testosterone is not used clinically (exception: 17-alpha methylated androgens like methyltestosterone resist first-pass but are hepatotoxic)
• Instead, androgens are given IM (testosterone cypionate/enanthate), transdermally (gel, patch), or buccally to bypass first-pass metabolism

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• Before menstruation, the endometrium releases tissue plasminogen activator (t-PA) and plasmin
• These fibrinolytic enzymes digest fibrin clots as blood collects in the uterine cavity
• This prevents blood from clotting in the uterus, facilitating smooth expulsion
• Clots in menstrual blood indicate abnormally heavy flow (>80 mL) that overwhelms fibrinolytic capacity → sign of menorrhagia

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• Progesterone (from corpus luteum) causes ductal and lobular dilation, increased glandular tissue
• Estrogen stimulates ductal proliferation
• Both hormones cause water and Na+ retention (progesterone has weak aldosterone-like effect; estrogen causes fluid retention)
• Increased blood flow to breast tissue
• Net result: breast engorgement, edema, and tenderness (mastodynia)
• These symptoms resolve with menstruation as progesterone and estrogen fall

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• The follicular phase typically takes ~14 days for the dominant follicle to mature and produce enough estrogen
• When estrogen threshold (~200 pg/mL) is sustained for ~36 hours, the switch to positive feedback occurs
• This triggers the LH surge (~day 13)
• Ovulation follows approximately 36-40 hours after the LH surge peak → typically day 14
• In a 28-day cycle, the luteal phase (always ~14 days, fixed) then follows
• The follicular phase is variable; in longer cycles (e.g., 35 days), ovulation is ~day 21

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• Progesterone maintains uterine quiescence (prevents contractions), maintains endometrium, and supports early embryo
• hCG from the trophoblast rescues the corpus luteum from weeks 3-10
• The placenta takes over progesterone production only from weeks 8-10 (luteal-placental shift)
• Before week 8-10: If the ovaries are removed, progesterone falls → uterine contractions, endometrial breakdown → abortion
• After week 10: Ovariectomy does not terminate pregnancy (placenta is self-sufficient)

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SECTION 4: CENTRAL NERVOUS SYSTEM

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• Normal function: Selectively controls what enters the brain (protects from pathogens, toxins, immune cells)
• If compromised: Cerebral edema (vasogenic type) - protein-rich fluid enters brain → increased ICP
• Pathogens can enter → encephalitis, meningitis
• Immune cells enter → neuroinflammation
• Drugs normally excluded can now access the brain (therapeutic opportunity but also toxicity risk)
• Seen in: stroke, traumatic brain injury, infections, multiple sclerosis

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• Obstructive/non-communicating: Block within ventricular system (aqueductal stenosis most common) → ventricles dilate proximal to block
• Communicating: Block at arachnoid villi (post-meningitis, subarachnoid hemorrhage)
• Increased ICP → headache, vomiting, papilledema, altered consciousness
• In infants: bulging fontanelle, macrocephaly

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• Cannot generate fever: No set-point adjustment in response to pyrogens
• Cannot sweat: Heat dissipation impaired
• Cannot shiver: Heat generation mechanism absent
• Poikilothermia: Body temperature fluctuates with the environment (like reptiles)
• Clinical: hyperthermia (loss of cooling) or hypothermia (loss of heat conservation) depending on the environment
• Also called central hyperthermia when hypothalamic damage causes temperature dysregulation

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• Complete optic nerve cut (unilateral): Monocular blindness (ipsilateral eye) + loss of direct pupillary light reflex in that eye (consensual reflex preserved via opposite optic tract)
• Partial damage: scotoma, reduced visual acuity in affected eye
• Optic chiasm damage: bitemporal hemianopia
• Optic tract damage: contralateral homonymous hemianopia

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• Complete transaction: Loss of all motor and sensory function below the injury
  • Cervical: Quadriplegia + respiratory failure (if above C4)
  • Thoracic: Paraplegia
• Hemisection (Brown-Sequard): Ipsilateral motor loss + ipsilateral fine touch/vibration loss + contralateral pain/temperature loss
• Acute: Spinal shock (flaccid paralysis, areflexia)
• Chronic: Upper motor neuron signs (spasticity, hyperreflexia, Babinski's sign)

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• Neurons cannot store glycogen (unlike liver/muscle)
• Neurons cannot use fatty acids as fuel (impermeable to long-chain fatty acids; BBB also excludes them)
• Brain uses ~20% of the body's total glucose and O2 despite being only 2% of body weight
• ATP is needed continuously for: Na/K-ATPase (maintaining RMP), neurotransmitter synthesis, axonal transport, synaptic vesicle cycling
• No anaerobic capacity: Even seconds of hypoxia causes neuronal dysfunction; 4-5 minutes of ischemia → irreversible neuronal death

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• Autoimmune T-cells (CD4+ and CD8+) attack myelin basic protein and other myelin antigens
• This is a case of molecular mimicry - immune response to a viral antigen cross-reacts with myelin
• Oligodendrocytes (which form CNS myelin) are destroyed
• Loss of myelin → impaired saltatory conduction → slowed or blocked nerve conduction
• Results in plaques (demyelinated patches) throughout CNS → variable symptoms (vision loss, weakness, numbness, coordination problems)
• CNS has limited remyelination capacity (unlike PNS)

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• Brain is highly metabolically active → produces large amounts of reactive oxygen species (ROS)
• Relatively poor antioxidant defenses compared to peripheral tissues (lower catalase, glutathione)
• High lipid content (myelin) → lipid peroxidation easily damages membranes
• Neurons are post-mitotic - cannot be replaced once lost
• Blood-brain barrier, while protective, also limits antioxidant delivery from the blood
• Microglial activation (brain's immune cells) releases pro-inflammatory cytokines and ROS
• Net: any oxidative/inflammatory insult causes disproportionate, often irreversible neuronal damage

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• Increased ICP: Headache (stretching of pain-sensitive meninges/vessels) + papilledema → blurred vision. Causes: tumor, hemorrhage, hydrocephalus
• Meningitis: Meningeal irritation → severe headache + photophobia
• Posterior fossa tumor/lesion: Cerebellar/brainstem compression → headache + vision changes
• Cavernous sinus thrombosis: Affects CN III, IV, VI → blurred/double vision + headache
• Migraine: Cortical spreading depression + trigeminovascular activation → unilateral headache + visual aura

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• Loss of UMN control → lower motor neurons are released from inhibitory control
• Spasticity: Increased muscle tone (loss of descending inhibition on stretch reflex)
• Hyperreflexia: Exaggerated deep tendon reflexes
• Muscle spasms: Spontaneous activation of spinal reflex arcs
• Paralysis: Loss of voluntary motor command from brain (no corticospinal input)
• Babinski's sign positive

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• Frontal lobe: Personality change, executive dysfunction, motor deficits (precentral gyrus), Broca's aphasia
• Parietal lobe: Sensory deficits, spatial neglect, Gerstmann syndrome
• Temporal lobe: Memory loss (hippocampus), Wernicke's aphasia, hearing deficits
• Occipital lobe: Visual deficits
• Cerebellum: Ataxia, dysmetria, intention tremor
• Brainstem: Cranial nerve palsies, respiratory/cardiac centers affected (life-threatening)
• General: Raised ICP → headache, vomiting, herniation

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• Hippocampus (medial temporal lobe): Critical for forming new memories (declarative/explicit); damage → anterograde amnesia (Alzheimer's disease primarily affects here early)
• Entorhinal cortex: Gateway to hippocampus; early Alzheimer's target
• Basal forebrain (nucleus basalis of Meynert): Cholinergic neurons projecting to cortex; lost in Alzheimer's
• Prefrontal cortex: Working memory, executive function; affected in frontal dementias
• Thalamus (mediodorsal nucleus): Relay for memory; damaged in Korsakoff's syndrome
• Mechanisms: Amyloid plaques and neurofibrillary tangles (Alzheimer's), Lewy bodies, vascular ischemia

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• Basal ganglia normally regulate the initiation, scaling, and smoothness of voluntary movement
• In Parkinson's: Loss of dopaminergic neurons in substantia nigra pars compacta
• Dopamine normally inhibits the indirect pathway (which inhibits movement) and facilitates the direct pathway (which promotes movement)
• Loss of dopamine → overactivity of subthalamic nucleus → excessive inhibition of thalamus → reduced cortical motor activation
• Resting tremor: Abnormal oscillatory activity in basal ganglia-thalamo-cortical circuits
• Rigidity: Increased muscle tone due to loss of normal basal ganglia inhibitory tone

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1. Endogenous opioid release: Acupuncture needles stimulate A-delta and C fibers → release of endorphins, enkephalins, and dynorphins from the PAG (periaqueductal gray) and other CNS centers
2. Gate control theory: Stimulation of A-beta fibers (touch/pressure) activates inhibitory interneurons in the dorsal horn → close the "gate" to pain signals from C fibers
3. Descending inhibitory pathways: Activation of PAG → descending serotonergic and noradrenergic pathways → inhibit dorsal horn pain transmission
4. Diffuse Noxious Inhibitory Control (DNIC): One painful stimulus inhibits pain elsewhere

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• Pain signals travel via small C fibers and A-delta fibers (unmyelinated/thin myelinated)
• Touch/rubbing signals travel via large A-beta fibers (large myelinated, fast)
• In the dorsal horn (substantia gelatinosa): A-beta fiber stimulation activates inhibitory interneurons (enkephalinergic)
• These interneurons inhibit the T-cell (transmission cell) that relays pain signals to the brain
• This is the "gate" - touch stimulation "closes the gate" to pain
• Basis for: rubbing a bumped area, TENS therapy, massage

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1. Reverberating (re-entrant) circuits: The signal re-enters the circuit repeatedly via collateral branches → self-sustaining neuronal firing even after initial stimulus ceases
2. Slow PSPs: Some neurotransmitters produce long-lasting EPSPs (via metabotropic receptors/second messengers)
3. Summation of EPSPs: Accumulated depolarization exceeds threshold even without new input
4. Persistent Na+ channels: Some neurons have intrinsic pacemaker activity after suprathreshold stimulation

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• Prefrontal lobotomy disconnects the prefrontal cortex from the limbic system
• Patients after lobotomy still perceive pain (sensory-discriminative component via thalamus/somatosensory cortex is intact) but they report it doesn't bother them (affective-motivational component is lost)
• The suffering and emotional response to chronic pain is abolished
• This historical procedure is now replaced by less destructive methods (deep brain stimulation, cingulotomy)

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• In thalamic lesions (especially after thalamic stroke), the inhibitory controls normally regulating pain signals are damaged
• The thalamic syndrome (Dejerine-Roussy syndrome) results: spontaneous severe pain, hyperalgesia (exaggerated pain response), allodynia (pain from non-painful stimuli)
• Mechanism: Loss of thalamic inhibitory neurons → excessive, unmodulated relay of pain signals to cortex
• The affective component is amplified because thalamo-limbic connections are disrupted

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1. Extreme stress/fear activates the hypothalamus-PAG (periaqueductal gray) axis
2. PAG releases endogenous opioids (endorphins) → activate mu-opioid receptors in dorsal horn → inhibit pain transmission
3. Norepinephrine (from locus coeruleus) and serotonin (from raphe nuclei) are released via descending pathways → further inhibit pain
4. Prefrontal cortex redirects attention to survival → pain suppressed cognitively
5. High circulating adrenaline also has mild analgesic effects

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1. Receptor density: Fingertips and thumbs have very high density of Meissner's corpuscles (touch) - ~2,500/cm²; back has far fewer
2. Cortical representation (somatotopy): The somatosensory cortex allocates more neurons to the hands (especially thumbs) than the back (homunculus - hands are disproportionately large)
3. Smaller receptive fields: Hand receptors have smaller receptive fields → two stimuli at close distance are perceived as separate
4. Normal two-point discrimination: fingertip ~2mm; back ~40-70mm

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1. Does not go silent - neighboring cortical areas expand into it (cortical reorganization/plasticity)
2. Input from adjacent body parts now activates the "limb zone" → sensations referred to the absent limb
3. C-fiber nerve endings at the amputation stump continue to generate impulses (neuroma formation)
4. The brain's body schema (stored representation of the body) still contains the limb
5. Reverberating circuits and thalamic pain mechanisms contribute to phantom pain

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• Initially high resistance to passive stretch (due to spastic muscles)
• Suddenly resistance melts away (like a clasp knife closing)
• Mechanism: The initial stretch activates muscle spindles → high spinal reflex tone (UMN lesion releases this)
• As stretch continues, Golgi tendon organs (GTOs) are activated → they inhibit the motor neuron via Ib afferents (autogenic inhibition/inverse stretch reflex) → sudden release
• Sign of UMN lesion

• Rhythmic involuntary muscle contractions in response to sustained stretch
• In UMN lesion: hyperactive stretch reflex + loss of descending inhibition
• Sustained dorsiflexion of foot → stretch of calf → reflex contraction → releases stretch → stretch again → repeating cycle
• The hyperactive Ia-motor neuron loop oscillates at 5-8 Hz

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• Loss of all voluntary motor commands from brain (corticospinal tract)
• Loss of vestibulospinal tract (postural control)
• Loss of reticulospinal tract (antigravity tone regulation)
• Spinal reflexes intact (below lesion) but: No integration of vestibular, visual, proprioceptive inputs that normally maintain balance
• Postural adjustments require supraspinal integration (cerebellum, basal ganglia, vestibular nuclei, motor cortex)
• Cannot make anticipatory or reactive postural corrections → falls when unsupported

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• In Parkinson's/basal ganglia lesions: Loss of dopamine → overactivity of indirect pathway → excessive inhibition of thalamus → reduced thalamo-cortical output to motor cortex and reticulospinal system
• Reticulospinal facilitation of spinal gamma and alpha motor neurons is altered
• Both agonist and antagonist muscles show increased tone simultaneously ("lead pipe" rigidity)
• Unlike spasticity (UMN), rigidity is uniform throughout range of motion and present at rest
• Cogwheel rigidity = rigidity + resting tremor superimposed

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• Cerebellum dampens oscillations in the stretch reflex by predicting movement and sending corrective signals (feed-forward control)
• Cerebellar lesion → loss of damping → the leg swings back and forth several times (pendular) before stopping
• The stretch reflex itself is intact (LMN and spinal arc intact)
• Cerebellum normally detects when the reflex contraction has "overshot" and applies braking → absent in cerebellar lesions

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• Cerebellum provides real-time correction of voluntary movements (compares intended vs. actual movement via comparator function)
• In cerebellar lesion: No corrective signals → the moving limb overshoots or undershoots the target
• Intention tremor: Tremor that increases as finger approaches the nose (worst at the endpoint) - because cerebellar corrections are absent
• Also: slow, irregular movements (dysdiadochokinesia if testing rapid alternating movements)
• Cerebellar lesions affect the ipsilateral side (cerebellum controls same-side body)

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• Dopamine itself cannot cross the blood-brain barrier (BBB)
• L-dopa (levodopa) - the amino acid precursor of dopamine - crosses the BBB via large neutral amino acid transporters
• Once inside the brain, aromatic amino acid decarboxylase (DOPA decarboxylase) converts L-dopa to dopamine
• Dopamine is then released in the striatum → restores dopaminergic signaling → reduces symptoms (bradykinesia, rigidity, tremor)
• Given with carbidopa (peripheral DOPA decarboxylase inhibitor) to prevent peripheral conversion and reduce side effects

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• Loss of dopamine in substantia nigra → altered balance in basal ganglia circuitry
• Overactivity of subthalamic nucleus (STN) and internal globus pallidus (GPi)
• Abnormal, rhythmic oscillatory activity is generated in the basal ganglia-thalamo-cortical loop (4-6 Hz)
• This oscillatory activity is transmitted via thalamus to motor cortex → rhythmic motor output → resting tremor
• Tremor is present at rest (unlike cerebellar intention tremor) and suppresses with voluntary movement (because voluntary movement disrupts the oscillation)
• "Pill-rolling" tremor is characteristic

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• The cerebellum receives and sends information ipsilaterally through a double-crossing arrangement:
  1. Descending motor pathways (corticospinal) cross once in the medullary pyramids (from left cortex to right spinal cord)
  2. Cerebellar output also crosses once (via superior cerebellar peduncle → crosses to contralateral thalamus)
  3. Cerebellar input (spinocerebellar tracts) carries ipsilateral information
• The net effect of these two crossings: cerebellar hemisphere controls the same (ipsilateral) side of the body
• Right cerebellar lesion → right-sided symptoms (right-sided ataxia, dysmetria, dysdiadochokinesia)

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• In normal adults, descending UMN (corticospinal tract) inhibits the primitive flexor withdrawal reflex
• In UMN lesion: Loss of corticospinal inhibition → primitive reflex is released
• The extensor plantar reflex emerges: big toe dorsiflexion + fanning of other toes (Babinski's sign)
• This is normal in infants (immature corticospinal tracts until ~18 months)
• Positive Babinski = definitive sign of corticospinal (UMN) damage

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• Gamma motor neurons innervate the intrafusal fibers of the muscle spindle (not the main extrafusal muscle fibers)
• Gamma stimulation → intrafusal fiber contraction → stretches the nuclear bag/chain regions → activates the Ia sensory endings (annulospiral endings)
• Ia afferents → dorsal horn → synapse on alpha motor neurons → alpha motor neuron activation → extrafusal fiber contraction
• This is the gamma loop (gamma → spindle → Ia → alpha → muscle)
• Gamma stimulation effectively sensitizes the spindle, causing it to drive the stretch reflex even without external muscle lengthening

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1. Vigorous voluntary effort in distant muscles → descending facilitory signals from motor cortex and reticular formation travel to spinal cord
2. These descending signals increase the excitability of alpha motor neurons throughout the cord (generalized facilitation)
3. Spinal interneurons and gamma motor neurons are also facilitated (increased spindle sensitivity)
4. When the tendon is tapped, the same Ia input now encounters a more excitable motor neuron pool → larger, brisker reflex response
5. Also distracts patient from voluntarily suppressing the reflex

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• Sudden dorsiflexion of the foot → stretches the gastrocnemius → activates spindle Ia afferents → reflex contraction (plantarflexion) → this reduces stretch → spindle fires less → but then the foot is dorsiflexed again by the examiner → cycle repeats
• In UMN lesion, the reflexes are so hyperactive that this self-sustaining oscillation continues → sustained clonus
• Normal people: The corticospinal tract suppresses this hyperactive response
• Sustained clonus (>5 beats) = definitive sign of UMN lesion

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• Loss of corticospinal inhibitory fibers to the spinal cord
• Loss of descending inhibition on both alpha and gamma motor neurons
• Gamma motor neurons become hyperactive → muscle spindles are continuously facilitated → increased sensitivity to stretch
• Any tendon tap → massive Ia afferent discharge → large alpha motor neuron activation → exaggerated DTR
• Also, Renshaw cell inhibition is reduced (loss of corticospinal input to inhibitory interneurons)
• Net: stretch reflex arc is hyperactive → clonus, spasticity, exaggerated DTRs, Babinski's sign

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• EEG pattern resembles wakefulness - desynchronized, low voltage, high frequency waves (like an alert brain)
• Yet the person is deeply asleep (very difficult to awaken in terms of arousal threshold)
• Muscle atonia: Postural muscles are completely relaxed/paralyzed (via active inhibition from the brainstem/pontine areas)
• Vivid dreaming occurs
• Autonomic instability: Irregular heart rate, blood pressure, breathing - unusual for sleep
• Contrasted with NREM sleep where EEG is synchronized (slow waves) and body can move

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SECTION 5: SPECIAL SENSES

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• The lens normally accommodates (changes shape to focus on near objects) via contraction of the ciliary muscle → zonule fibers relax → lens thickens (increases curvature/refractive power)
• A rigid lens cannot increase its curvature → inability to focus on near objects (presbyopia)
• This is normal aging: lens proteins (crystallins) cross-link and harden progressively after age 40
• Distance vision remains relatively normal; near vision requires reading glasses (converging lenses)

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• Bright light → retinal photoreceptors (rods and melanopsin-containing ipRGCs) activated → optic nerve → pretectal nuclei (midbrain)
• Pretectal nucleus activates the Edinger-Westphal nucleus (parasympathetic preganglionic)
• Preganglionic fibers travel with CN III → synapse in the ciliary ganglion
• Postganglionic fibers → sphincter pupillae (circular muscle of iris) → pupil constriction (miosis)
• Bilateral (both pupils constrict even if only one eye is illuminated - consensual reflex)
• Purpose: Reduce the amount of light entering the eye to prevent photoreceptor overload

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• Three types of cones in the retina, each maximally sensitive to different wavelengths:
  • S-cones (Blue): ~420 nm
  • M-cones (Green): ~530 nm
  • L-cones (Red): ~560 nm
• Different colors stimulate these three cones in different ratios → brain interprets the combination as a specific color
• Opponent process theory (Hering): At higher levels (ganglion cells, LGN, cortex), color signals are processed as opposites: red-green, blue-yellow, and black-white channels
• Color processing ultimately in the V4 area of the visual cortex

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• Normal cornea is spherically curved, providing ~70% of the eye's refractive power
• Irregular astigmatism: Corneal surface has different radii of curvature in different meridians
• Light rays in different planes focus at different points → blurred, distorted vision at all distances
• Regular astigmatism: Two principal meridians perpendicular to each other (correctable with cylindrical lenses)
• Keratoconus: Progressive corneal thinning and cone-shaped protrusion → irregular astigmatism → contact lenses or corneal transplant needed

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• Perforation → reduced vibration of tympanic membrane → less efficient sound transmission to ossicles → conductive hearing loss
• Severity depends on size and location of perforation
• Small central perforations: mild loss; large or marginal: significant loss
• Air-bone gap on audiometry (bone conduction preserved, air conduction reduced)
• Small perforations may heal spontaneously; large ones need tympanoplasty
• Risk of middle ear infection (otitis media) as barrier is lost

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1. Interaural Time Difference (ITD): Sound reaches one ear before the other (microseconds) → binaural neurons in the medial superior olive (MSO) detect the time delay → horizontal localization
2. Interaural Level Difference (ILD): The head creates a "sound shadow" for the far ear → louder in nearer ear → processed in lateral superior olive (LSO)
3. Head-Related Transfer Function (HRTF): Pinna shape modifies the spectrum of sounds differently for front/back/elevation → processed in dorsal cochlear nucleus and inferior colliculus
4. Vertical localization: Mainly by pinna spectral cues

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• Damage to the base (high-frequency region): high-frequency hearing loss (most common type - noise-induced, presbycusis)
• Damage to apex (low-frequency): low-frequency loss (rare)
• Hair cell damage → sensorineural hearing loss (bone conduction also reduced, unlike conductive loss)
• No air-bone gap on audiometry
• Associated with tinnitus (ringing - spontaneous activity in partially damaged auditory pathway)
• Loss of outer hair cells → reduced amplification (OHCs provide cochlear amplifier via electromotility of prestin)

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1. Mechanical damage: Excessive basilar membrane vibration → stereocilia of hair cells bend beyond elastic limit → stereocilia breakage
2. Metabolic exhaustion: Prolonged intense stimulation depletes hair cell ATP → Na/K-ATPase failure → ionic homeostasis lost
3. Excitotoxicity: Excessive glutamate release from hair cells → overactivation of AMPA receptors on auditory nerve dendrites → Ca2+ influx → dendrite swelling → nerve damage
4. Reactive oxygen species (ROS): Generated by intense acoustic stimulation → oxidative damage to hair cells
5. Hair cells are not regenerated in mammals → permanent loss

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• Anosmia (total loss of smell) or hyposmia (reduced)
• Olfactory receptor neurons (ORNs) in the olfactory epithelium project directly to the olfactory bulb (CN I)
• ORNs can regenerate (uniquely among neurons) - supported by basal stem cells
• Recovery possible if damage is mild
• Causes: trauma (cribriform plate fracture → shear olfactory fibers), viral upper respiratory infections (COVID-19 notably causes anosmia - damages olfactory epithelium/sustentacular cells), chemical exposure, neurodegenerative diseases (early Parkinson's, Alzheimer's)

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1. Receptor level: Prolonged odorant exposure → receptor desensitization (G-protein uncoupling, cAMP-gated channel adaptation) → ORN firing decreases
2. Olfactory bulb: Granule cell interneurons mediate lateral inhibition → inhibit mitral cells (the output neurons)
3. Centrifugal signals: Cortical feedback to olfactory bulb modulates sensitivity (top-down suppression)
4. Cognitive adaptation: Cortical habituation - the brain learns to filter out constant, non-threatening olfactory signals

• This is why you quickly stop noticing your own perfume but notice others'

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• Other senses: sensory signals → thalamus → cortex (relay via thalamus)
• Olfaction: olfactory bulb → piriform cortex (primary olfactory cortex) → amygdala and hippocampus DIRECTLY (no thalamic relay)
• Amygdala: Emotional processing center - olfactory input here directly triggers emotional memories and fear/pleasure responses
• Hippocampus: Memory formation - smells powerfully evoke autobiographical memories (Proustian memory phenomenon)
• This direct limbic access explains why smells can instantly trigger intense emotions and vivid memories

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• Salty: Na+ ions enter taste cells directly through amiloride-sensitive Na+ channels → depolarization
• Sour (acid): H+ ions block K+ channels → depolarization; also enter directly
• Sweet: Sweeteners bind GPCRs (T1R2/T1R3 heterodimer) → Gα-gustducin → PLC → IP3 → Ca2+ release → depolarization
• Bitter: Bind T2R family GPCRs → similar downstream pathway (Ca2+ release via PLCβ2/IP3)
• Umami: Glutamate binds T1R1/T1R3 → similar GPCR cascade

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• Carries taste sensation from the anterior 2/3 of the tongue
• Also carries parasympathetic fibers to sublingual and submandibular glands
• Damage: Loss of taste from anterior 2/3 of tongue (primarily sweet, salty, sour) - unilateral if one side damaged
• Also reduced salivation on that side
• Taste from posterior 1/3 (CN IX - glossopharyngeal) and epiglottis (CN X) is preserved
• Common complication of middle ear surgery (it passes through the middle ear)

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• Damage → cortical ageusia (inability to recognize/identify tastes consciously)
• Elementary taste sensations may be partially preserved (via brainstem reflexes)
• Patient may be unable to identify or describe what they are tasting
• Also affects food preferences, appetite regulation (orbitofrontal cortex integration of taste + reward)
• Often associated with damage to surrounding language/sensory areas

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• Damage → vertigo (illusion of spinning/movement), nausea, vomiting (nausea is mediated via vestibulo-vagal reflex)
• Imbalance and ataxia (cannot maintain equilibrium without vestibular input)
• Nystagmus (eyes drift toward damaged side, corrective saccade away)
• Romberg's test positive (eyes closed worsens balance - remove visual compensation)
• Unilateral damage: Brain compensates over weeks via central adaptation (plasticity of vestibular nuclei)
• Bilateral damage: Permanent balance impairment, oscillopsia (blurred vision when moving)

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• Motion sickness occurs when there is mismatch between vestibular, visual, and proprioceptive inputs
• Example in a car: Eyes (looking at the interior) say "not moving"; Vestibular apparatus says "accelerating/turning"
• The cerebellum/brainstem detects this sensory mismatch
• The brain interprets this conflict as possible poisoning (evolutionary hypothesis: visual-vestibular mismatch in nature may mean toxin ingestion causing hallucinatory input) → vomiting response activated (chemoreceptor trigger zone + vomiting center stimulated via histamine and ACh pathways)
• Treatment: antihistamines (meclizine), anticholinergics (scopolamine)

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• Otolith organs (utricle and saccule) detect linear acceleration and the effect of gravity (tilt)
• Calcium carbonate otoconia (otoliths) rest on the gelatinous membrane over hair cells
• Gravity/acceleration displaces the otolith membrane → bends hair cell stereocilia → signals head position and linear acceleration
• Damage: Loss of ability to detect head tilt and linear acceleration
• BPPV (benign paroxysmal positional vertigo): Dislodged otoconia from utricle into semicircular canals → position-dependent vertigo
• Without otolith input: Poor vertical orientation, cannot distinguish up/down in dark

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• Physiological nystagmus (optokinetic/vestibular): Normal response to sustained movement of the visual field or caloric stimulation of the vestibular system; helps stabilize the visual image (vestibulo-ocular reflex)
• Pathological nystagmus:
  • Vestibular: Unilateral vestibular damage → imbalance in tonic activity between left and right vestibular nuclei → eyes drift toward lesion, fast phase away (Ewald's law)
  • Cerebellar: Loss of gaze-holding mechanism → gaze-evoked nystagmus (horizontal, changes direction with gaze)
  • CNS: Brainstem, MLF lesions → internuclear ophthalmoplegia

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• The vestibular nerve (CN VIII, vestibular division) carries signals from semicircular canals and otolith organs to vestibular nuclei and cerebellum
• Acute damage: Severe vertigo, nausea, vomiting, nystagmus (fast phase away from lesion)
• Falling toward the side of the lesion
• Romberg's test positive - falls toward affected side with eyes closed
• Chronic: Central compensation occurs (vestibular nuclei plasticity)
• Complete bilateral loss: Permanent ataxia, oscillopsia, inability to walk in the dark

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• It is where the optic nerve exits the eye and the central retinal artery/vein enter
• This area has no photoreceptors (no rods or cones) - cannot transduce light
• Therefore, any image falling on this area cannot be detected → physiological blind spot
• In normal vision, the brain "fills in" the blind spot using information from surrounding retina and the other eye → we are not aware of it
• Tested by Mariotte's blind spot experiment

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1. Highest cone density (~150,000 cones/mm² in the foveal center, no rods)
2. 1:1 convergence: Each foveal cone has its own ganglion cell (private line) - maximal spatial resolution; peripheral retina: many rods/cones share one ganglion cell
3. Absence of overlying blood vessels and ganglion cells (foveola is pit-shaped, inner retinal layers are displaced) → light hits cones directly without scattering
4. Only L and M cones (highest resolution) - no S-cones in foveal center
5. Largest cortical representation in the visual cortex (cortical magnification factor)

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• In DM, persistent hyperglycemia leads to increased glucose in the lens
• Lens lacks insulin-dependent glucose transporters → glucose enters freely
• Aldose reductase converts excess glucose to sorbitol (via polyol pathway)
• Sorbitol cannot exit the lens cells (membrane impermeable to it) → osmotic accumulation → lens cell swelling
• Advanced glycation end-products (AGEs) accumulate → cross-link crystallin proteins → lens opacification
• Also: oxidative stress (reduced glutathione in DM) damages lens proteins
• Net: diabetic cataract (nuclear and cortical)

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1. Neural retina (contains photoreceptors, ganglion cells) - inner layer
2. Retinal pigment epithelium (RPE) - outer layer, firmly attached to choroid

• The neural retina separates from the RPE
• Photoreceptors (rods and cones) are normally nourished by diffusion from choroidal blood vessels through the RPE
• When detached, this nutrient supply is severed → ischemia and metabolic deprivation of photoreceptors
• RPE normally phagocytoses shed outer segment discs (visual cycle) → without this, outer segments accumulate and degenerate
• The longer the detachment, the greater the permanent photoreceptor loss → urgent surgical reattachment needed

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• Water (n=1.333) and corneal tissue (n=1.376) have almost the same refractive index
• Therefore, the air-cornea interface effectively disappears → the cornea provides almost no refraction
• The remaining refractive power (lens) is insufficient to focus images on the retina
• Result: Blurred vision (extreme hyperopia)
• Solution: Wearing a diving mask restores the air-cornea interface

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• Blocks muscarinic receptors on the sphincter pupillae → mydriasis (pupil dilation)
• Blocks muscarinic receptors on the ciliary muscle → cycloplegia (paralysis of accommodation)
• Without ciliary muscle contraction, the lens cannot round up (increase curvature) to focus on near objects
• Result: Blurred near vision (inability to accommodate)
• Used clinically for fundoscopy (dilates pupil for better view) and in children to measure true refractive error (cycloplegic refraction)

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• The lens is normally elastic; at rest (distant vision) it is flattened by taut zonule fibers; for near vision, ciliary muscle contracts → zonule relaxes → lens rounds up (accommodates)
• With age: Lens proteins (alpha, beta, gamma crystallins) cross-link and become insoluble → lens becomes progressively stiffer (sclerosis of the nucleus)
• Ciliary muscle may also weaken slightly
• Net: Amplitude of accommodation decreases progressively from ~14 D in a young child to <2 D by age 55
• Reading glasses (converging lenses) needed for near work by age 40-45

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• UV rays (<380 nm): Absorbed by the cornea (far UV) and lens (near UV: 300-380 nm). These short wavelengths would be focused in front of the retina and damage photopigments if they reached the retina. The lens efficiently filters UV. Note: aphakic patients (no lens, e.g., after cataract surgery) can see some near-UV.
• Infrared (>700 nm): Photoreceptor pigments (rhodopsin, iodopsins) do not absorb infrared efficiently. IR photons lack enough energy to isomerize the 11-cis retinal chromophore (requires precise energy match). IR is absorbed and converted to heat by the ocular media.

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• Rods contain only rhodopsin (a single pigment type) - maximally sensitive at ~500 nm → cannot discriminate wavelength → only provide black-and-white (achromatic) information
• Cones contain three different opsins (S, M, L-cones) with different spectral sensitivities → different colors stimulate different cone combinations
• The brain compares the ratio of activation across the three cone types to determine color (trichromatic theory)
• Cones are concentrated in the fovea (high acuity, color vision in bright light - photopic vision)
• Color blindness: Usually deficiency or mutation of M-cones (deuteranopia) or L-cones (protanopia) - the most common forms (X-linked recessive)

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• Rods (used for low-light/night vision) contain rhodopsin, which is bleached by light (photoisomerization of 11-cis retinal to all-trans retinal)
• Dark adaptation takes 30-40 minutes (rhodopsin regeneration via visual cycle)
• Red light (>620 nm) is at the far end of the visible spectrum - rods have minimal absorption of red wavelengths (rhodopsin absorption peak ~500 nm)
• Red goggles in bright light allow cones to function (cone pigments absorb red) but spare rhodopsin from bleaching
• So when entering darkness (dark room/cockpit), rods are already pre-adapted → immediate night vision capability
• Aircraft pilots: Critical for rapid dark adaptation when switching from bright cockpit to night sky

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• Also inhibits PDE6 (phosphodiesterase type 6 in retinal photoreceptors) - less potent but cross-reactivity occurs
• PDE6 is the enzyme that breaks down cGMP in cones during phototransduction
• cGMP normally closes cGMP-gated channels; it is the key second messenger in the phototransduction cascade
• Sildenafil inhibits PDE6 → cGMP accumulates in cones → altered phototransduction
• Blue cones appear most affected (their PDE6 may have greater sildenafil sensitivity)
• Result: Transient blue-green color disturbance, bluish tinge to vision (cyanopsia), increased light sensitivity
• Resolves as drug is cleared

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CONCISE REASONING ANSWERS — EXAM FORMAT

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SECTION 1: NERVE MUSCLE PHYSIOLOGY

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• Voltage-gated Na⁺ channels are already inactivated at -30 mV
• Membrane is in depolarization block → cannot generate action potential
• Result: Muscle contraction fails completely

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• No ACh release (botulinum) or no receptor activation (curare)
• No end-plate potential → no muscle action potential
• Result: Complete flaccid paralysis

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• Individual twitches fuse → Summation → Tetanus
• Complete tetanus = maximum sustained force
• Prolonged stimulation → muscle fatigue (ATP depletion, lactic acid)

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• Actin-myosin overlap is lost → no cross-bridges form
• Based on the length-tension relationship
• Result: Force generation falls to zero

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• Ca²⁺ binds troponin C continuously → sustained unregulated contraction (contracture)
• ATP depleted → muscle damage
• Seen clinically in malignant hyperthermia

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• Stores O₂ within the cell as a local reserve
• Facilitates O₂ diffusion from capillary to mitochondria
• Higher O₂ affinity than hemoglobin → picks up O₂ readily
• Critical for sustained aerobic metabolism in Type I (slow-twitch) fibers

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• Ensures high safety factor (~3-4x) at NMJ
• Every nerve impulse reliably triggers a muscle action potential
• Compensates for rapid ACh degradation by AChE
• Located in junctional folds to maximize ACh exposure

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• Different MHC isoforms = different ATPase activity rates
• Type I (slow MHC): Low ATPase → slow, fatigue-resistant (posture)
• Type II (fast MHC): High ATPase → fast, powerful (explosive movement)
• Allows muscles to be specialized for speed, endurance, or power

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• Mitochondria = site of aerobic ATP production
• Contraction is energy-intensive (myosin cycling, SR Ca²⁺ pumping, Na/K-ATPase)
• Abundant in Type I fibers → sustained oxidative ATP supply
• Reduces dependence on anaerobic glycolysis

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• Myosin defect → impaired cross-bridge formation → reduced force
• Troponin defect → Ca²⁺ regulation failure
• Symptoms: Muscle weakness, fatigue, atrophy, abnormal tone
• Example: Nemaline myopathy, hypertrophic cardiomyopathy

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• Store neurotransmitter (e.g., ACh) in concentrated, protected form
• On action potential arrival → Ca²⁺ influx → exocytosis into synaptic cleft (quantal release)
• Each vesicle releases ~5,000-10,000 ACh molecules
• Membrane recycled by endocytosis after release

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• Both produce myelin → saltatory conduction

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• Saltatory conduction (node to node) → fast conduction (up to 120 m/s)
• Less energy used, less ion leakage
• Demyelination (e.g., MS) → slowed/blocked conduction → neurological deficits

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• Rapidly hydrolyzes ACh (acetate + choline) within milliseconds
• Terminates receptor activation → muscle relaxation
• Choline recycled back into presynaptic terminal
• AChE inhibitors (neostigmine, organophosphates) → cholinergic crisis

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SECTION 2: ENDOCRINE SYSTEM

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• No TRH → No TSH → No T3/T4
• Tertiary (hypothalamic) hypothyroidism
• Symptoms: fatigue, weight gain, cold intolerance, myxedema

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• Enhanced insulin sensitivity → increased glucose uptake
• Risk of hypoglycemia
• Opposite of insulin resistance

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• Addison's disease
• Key features: hypotension, hypoglycemia, hyponatremia, hyperkalemia, hyperpigmentation (high ACTH/MSH)
• Life-threatening in stress → Addisonian crisis

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• Low T3/T4 → low negative feedback → TSH rises → goiter (thyroid enlargement)
• Clinical: hypothyroidism
• In pregnancy: Cretinism in offspring (irreversible)

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• Epiphyseal plates closed → no height increase
• Acromegaly: enlarged hands, feet, jaw, organomegaly
• Glucose intolerance/diabetes (GH is anti-insulin)

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• Hypoglycemia, especially during fasting
• Impaired counter-regulatory response
• Other hormones (epinephrine, cortisol) partially compensate

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• Overactivation: Cushing's syndrome (truncal obesity, hyperglycemia, hypertension, immunosuppression)
• Underactivation: Addison's disease (hypotension, hypoglycemia, fatigue)

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• Hypercalcemia + Hypophosphatemia
• Bone resorption ↑, renal Ca²⁺ reabsorption ↑, calcitriol synthesis ↑ → gut absorption ↑
• Classic: "Stones, bones, groans, psychic moans"

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• Brain exclusively depends on glucose → must maintain narrow range (70-100 mg/dL)
• Hypoglycemia → seizures/coma; hyperglycemia → vascular damage
• Dual hormonal control (insulin + glucagon) provides precise rapid regulation

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• Controlled by the suprachiasmatic nucleus (SCN)
• Peaks at 6-8 AM (prepares body for activity)
• Troughs at midnight
• Disruption (shift work, jet lag) → metabolic dysregulation

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• Master integrator of nervous and endocrine systems
• Produces all releasing/inhibiting hormones controlling anterior pituitary
• Produces ADH and oxytocin (posterior pituitary)
• Integrates stress, emotion, light, and peripheral hormone feedback

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• T3 increases BMR by uncoupling oxidative phosphorylation → thermogenesis
• Upregulates Na/K-ATPase → increased O₂ consumption
• Hyperthyroidism: BMR +60-100%; Hypothyroidism: BMR -30-50%

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• Neurons: Ca²⁺ triggers NT exocytosis; stabilizes membrane (hypocalcemia → tetany, seizures)
• Muscle: Ca²⁺ binds troponin C to initiate contraction
• Hypocalcemia → Chvostek's and Trousseau's signs

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• Before puberty: hypothalamus hypersensitive to negative feedback of low sex steroids
• At puberty: kisspeptin neurons mature → set point changes → less sensitive to negative feedback
• GnRH pulses increase → FSH/LH surge → gonadal activation

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• Central DI: ADH deficiency; Nephrogenic DI: V2 receptor/AQP2 mutation
• No ADH effect → AQP2 not inserted into collecting duct → water not reabsorbed
• Result: Massive polyuria (up to 20 L/day) + polydipsia + high plasma osmolarity

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• Metabolic: Weight loss, increased BMR, heat production, glucose intolerance, muscle wasting
• Cardiovascular: Tachycardia, increased cardiac output, widened pulse pressure, atrial fibrillation, high-output cardiac failure

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• Both: Na⁺ retention, K⁺ loss (hypokalemia), metabolic alkalosis, hypertension
• Aldosterone only: Pure mineralocorticoid effect, no hyperglycemia
• Cortisol excess extra: Hyperglycemia, immunosuppression, muscle wasting, osteoporosis

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• Produced by liver in response to GH
• Mediates most growth effects of GH
• Stimulates chondrocyte proliferation at epiphyseal plates → linear growth
• Low IGF-1 → dwarfism; High → gigantism/acromegaly

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• Wolff-Chaikoff effect: High iodine inhibits thyroid hormone synthesis and release
• Reduces vascularity and firmness of gland → reduces surgical bleeding risk
• Controls hyperthyroid state pre-operatively

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• Low T3/T4 → reduced BMR → reduced heat production
• Body temperature lower → cold intolerance
• Patient seeks warm environment for comfort

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• High estrogen and progesterone (from placenta) block prolactin's action on mammary glands
• After delivery: placenta expelled → estrogen/progesterone drop sharply
• Prolactin acts unopposed → lactation begins within 2-3 days

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• Epinephrine's direct beta-1 effect → tachycardia overrides baroreceptor reflex bradycardia
• Compare: Norepinephrine (predominantly alpha) → vasoconstriction → reflex bradycardia does occur

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• This is the Aldosterone Escape Phenomenon
• Initial Na⁺ retention → ↑blood volume → ↑BP → pressure natriuresis/diuresis
• ANP release also contributes
• Hypertension and hypokalemia persist despite sodium escape

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• GH-secreting pituitary adenoma expands and compresses the optic chiasm
• Crosses fibers from nasal retina are damaged → Bitemporal hemianopia
• Perimetry detects this characteristic visual field defect

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• Purple striae: Cortisol → skin thinning + impaired collagen → stretch marks visible
• Truncal obesity: Visceral fat has more GC receptors → fat deposited centrally
• Red cheeks: Thin skin + polycythemia (cortisol stimulates erythropoiesis)
• Moon face: Redistribution of fat to face

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• Visceral fat: More glucocorticoid receptors → fat deposition
• Peripheral fat: Cortisol promotes lipolysis → fat mobilized and redistributed centrally
• Result: Central obesity + peripheral wasting (pathognomonic)

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• Polyuria: Hyperglycemia → glucosuria → osmotic diuresis
• Polydipsia: Water loss → dehydration → high plasma osmolarity → thirst centre stimulated
• Polyphagia: No insulin → cells cannot uptake glucose → cellular starvation despite high blood glucose

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• Suckling → prolactin rises → inhibits GnRH pulsatility (via kisspeptin neurons)
• No GnRH → No FSH/LH → No follicle development → No ovulation → Amenorrhea
• This is lactational amenorrhea (natural contraception)

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• TSH receptor antibodies stimulate retroorbital fibroblasts (not caused directly by T3/T4)
• Fibroblasts produce glycosaminoglycans → water retention + inflammation → retroorbital edema
• Increased retroorbital volume → eyeball pushed forward (proptosis)

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• Myxedema: Low T3/T4 → glycosaminoglycans accumulate in skin → attract water → non-pitting edema
• Carotenemia: Thyroid hormone needed to convert beta-carotene → Vitamin A; conversion reduced → carotene accumulates → yellow-orange skin (sclera not yellow — differs from jaundice)

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• T3 required for normal GH secretion and GH receptor expression
• T3 directly stimulates chondrocyte maturation at epiphyseal plates
• Critical for brain maturation in early life
• Result: Short stature; cretinism if severe in infancy

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• Hypothyroid: Reduced mitochondrial ATP, glycosaminoglycan accumulation → proximal myopathy
• Hyperthyroid: Excess T3 → protein catabolism, muscle wasting (thyrotoxic myopathy), hypokalemia

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• T3 upregulates hepatic LDL receptors → increased LDL clearance
• Increases bile acid synthesis from cholesterol (via CYP7A1)
• Hypothyroidism → high cholesterol; hyperthyroidism → low cholesterol

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• Hypothyroid: High TRH → elevated prolactin → inhibits GnRH → anovulation, amenorrhea
• Hyperthyroid: Alters GnRH pulsatility, elevated SHBG → oligomenorrhea, anovulation, increased miscarriage

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• T3 → increases glycogenolysis, gluconeogenesis, intestinal glucose absorption
• Insulin resistance increased; insulin degradation accelerated
• Net: Blood glucose rises → glucose intolerance/diabetes

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• Cabbage contains goitrogens (thiocyanates, goitrin)
• Block NIS (sodium-iodide symporter) → inhibit iodide uptake
• Inhibit thyroid peroxidase (TPO) → block T3/T4 synthesis
• Worsens already low thyroid hormone production

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• Mental defect: T3 essential for brain myelination, neuronal migration, synapse formation (critical period: fetal to age 3) → irreversible if deficient
• Short stature: T3 needed for GH secretion, growth plate maturation, chondrocyte differentiation

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• Conditioned neuroendocrine reflex
• Repeated suckling-oxytocin associations → auditory cortex forms conditioned pathway
• Baby's cry → hypothalamus releases oxytocin → myoepithelial cell contraction → milk ejection

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• Early sex hormones cause initial growth spurt (tall for age initially)
• BUT sex hormones → premature epiphyseal plate closure
• Once plates close → no further growth → shorter final adult height

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• No insulin → cells cannot uptake glucose (no GLUT4 translocation)
• Body in "starvation" state → lipolysis + proteolysis activated
• Calories lost as glucosuria; cannot be stored as fat/glycogen without insulin

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• PTH → kidney → stimulates 1α-hydroxylase → converts 25-OH Vit D to 1,25-(OH)₂ Vit D (calcitriol)
• Calcitriol → intestine → upregulates calbindin D and TRPV6 → increased active Ca²⁺ absorption
• PTH acts indirectly via calcitriol

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• Decreased BMD with aging; post-menopausal: estrogen loss → RANK-L upregulation → osteoclast activation
• Reduced Ca²⁺ absorption → secondary hyperparathyroidism → bone resorption
• Result: Osteoporosis → hip, vertebral, wrist fractures

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• Hypocalcemia → voltage-gated Na⁺ channels are less stabilized → threshold lowered
• Spontaneous action potentials even without stimulus
• Clinical: muscle cramps, Chvostek's sign, Trousseau's sign

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• Inhibit NF-kB → reduce IL-2, TNF-α, IFN-γ
• Suppress T-lymphocyte proliferation and activation (cellular immunity mediates rejection)
• Reduce antigen presentation by macrophages/DCs
• Net: Blunted immune response against transplanted tissue

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• Inhibit osteoblasts → reduced bone formation
• Increase RANK-L → osteoclast activation → bone resorption
• Decreased intestinal Ca²⁺ absorption + increased renal Ca²⁺ excretion → secondary hyperparathyroidism
• Also suppress sex hormones → loss of bone protection

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• Cortisol and adrenal androgens stimulate erythropoiesis
• Their loss → normochromic normocytic anemia
• Aldosterone deficiency → hyponatremia → hemodilution component

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• Increase gluconeogenesis (upregulate PEPCK, G6Pase)
• Increase proteolysis → amino acid substrates for gluconeogenesis
• Inhibit GLUT4 translocation → peripheral insulin resistance
• Net: Steroid-induced diabetes

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• Low cortisol → loss of negative feedback → ACTH rises markedly
• ACTH derived from POMC — same precursor as MSH
• High ACTH + MSH → melanocyte stimulation → excess melanin → hyperpigmentation
• Not seen in secondary adrenal insufficiency (ACTH is low there)

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• Low dose (1-3 mcg/kg/min): DA1 → renal vasodilation → protects kidneys
• Moderate dose (3-10): Beta-1 → positive inotrope → increases cardiac output
• High dose (>10): Alpha-1 → vasoconstriction → raises BP
• Versatility makes it useful in cardiogenic and septic shock

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• Phase 1 (rise): Alpha-1 → vasoconstriction + Beta-1 → increased HR/contractility
• Phase 2 (fall): As concentration drops, Beta-2 effect predominates → vasodilation in skeletal muscle → BP falls transiently

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• Low T3/T4 → glycosaminoglycans (hyaluronic acid) accumulate in dermis
• These hygroscopic molecules bind water in gel-like form
• Water is not freely mobile → pressing does not displace it → non-pitting (myxedema)

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• Aldosterone Escape: Initial Na⁺ retention → ↑blood volume → ↑BP → pressure natriuresis + ANP release
• Na⁺ balance is restored → no edema
• But hypertension and hypokalemia persist

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• V2 receptor: ADH → Gs → cAMP → PKA → phosphorylates AQP2 → inserts into collecting duct apical membrane
• Mutation → signaling fails → AQP2 not inserted → water not reabsorbed
• Result: Nephrogenic DI — massive dilute urine despite high ADH levels

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SECTION 3: REPRODUCTIVE SYSTEM

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• Disrupted FSH/LH → impaired folliculogenesis → anovulation
• No corpus luteum → no progesterone → irregular/absent cycles
• Causes: PCOS, hyperprolactinemia, hypothyroidism, hypothalamic amenorrhea

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• Causes: Varicocele (most common), cryptorchidism, Klinefelter's, heat exposure, anabolic steroids
• Impact: Reduced fertilization probability → may need IUI/IVF/ICSI

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• PID → scarring and adhesions of fallopian tubes
• Blocked tubes → egg cannot meet sperm → reduced fertility
• Increased risk of ectopic pregnancy

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• Removes cholesterol from sperm membrane → increased membrane fluidity
• Enables the acrosome reaction (penetration of zona pellucida)
• Hyperactivation of sperm motility
• Without capacitation: sperm cannot fertilize the egg

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• Rising estrogen from dominant follicle → at threshold → switches to positive feedback
• Triggers massive GnRH pulse → LH surge (10-12x baseline)
• LH surge → final oocyte maturation, follicle rupture, ovulation (~36 hours later), corpus luteum formation

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• Gas exchange (O₂/CO₂), nutrition (glucose, amino acids), waste removal
• Hormone production: hCG (maintains CL first trimester), progesterone, estrogen, HPL
• Passive immunity: IgG transfer to fetus

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• hCG peaks at 8-12 weeks → stimulates CTZ; structural similarity to TSH → mild hyperthyroid state
• Rising estrogen sensitizes vomiting center
• Progesterone → lower esophageal sphincter relaxation → acid reflux

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1. Primary: Suppress GnRH → low FSH/LH → no ovulation (most important)
2. Progestin → thick cervical mucus → impermeable to sperm
3. Atrophic endometrium → unfavorable for implantation

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• Spermatogenesis requires temperature 2-3°C below core body temperature (34°C)
• Heat-sensitive enzymes in spermatogonia denature at core body temperature
• High environmental heat → scrotal temperature rises → impairs spermatogenesis → oligospermia/azoospermia

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• Orally absorbed androgens → portal circulation → extensive first-pass metabolism in liver
• Liver rapidly inactivates testosterone
• Given IM, transdermally, or buccally to bypass first-pass effect
• Exception: 17α-methylated androgens resist first-pass but are hepatotoxic

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• Endometrium releases tissue plasminogen activator (t-PA) and plasmin before menstruation
• These fibrinolytic enzymes digest fibrin clots in the uterine cavity
• Clots in menstrual blood = heavy flow exceeds fibrinolytic capacity → sign of menorrhagia

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• Progesterone (luteal phase) → ductal/lobular dilation, glandular tissue increase
• Estrogen → ductal proliferation
• Both cause Na⁺ and water retention → breast engorgement and tenderness (mastodynia)
• Resolves after menstruation when progesterone and estrogen fall

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• Follicular phase: ~14 days for dominant follicle to produce enough estrogen
• Estrogen threshold sustained → positive feedback → LH surge (day 13)
• Ovulation ~36 hours after LH peak → day 14
• Luteal phase is always fixed at ~14 days

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• Before week 8-10: Corpus luteum (in ovary) is the sole source of progesterone
• Progesterone maintains uterine quiescence and endometrium
• Removal of ovaries → progesterone falls → uterine contractions → abortion
• After week 10: Placenta takes over progesterone → ovariectomy no longer terminates pregnancy

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SECTION 4: CENTRAL NERVOUS SYSTEM

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• Vasogenic cerebral edema → increased ICP
• Pathogens and immune cells enter → encephalitis/meningitis, neuroinflammation
• Seen in: stroke, TBI, MS, infections

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• Hydrocephalus — CSF accumulates → ventricles dilate
• Increased ICP → headache, vomiting, papilledema, altered consciousness
• Infants: bulging fontanelle, macrocephaly

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• Cannot sweat, shiver, or adjust set point for fever
• Poikilothermia (body temperature follows environment)
• Central hyperthermia or hypothermia depending on environment

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• Complete unilateral cut → Monocular blindness + loss of direct pupillary light reflex (consensual reflex preserved)
• Optic chiasm → Bitemporal hemianopia
• Optic tract → Contralateral homonymous hemianopia

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• Complete: Loss of all motor and sensory function below injury level
• Cervical above C4: Quadriplegia + respiratory failure
• Acute: Spinal shock (flaccid paralysis, areflexia)
• Chronic: UMN signs (spasticity, hyperreflexia, Babinski)

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• Cannot store glycogen; cannot use fatty acids for fuel
• Use 20% of body's O₂ and glucose (only 2% of body weight)
• ATP needed for Na/K-ATPase, NT synthesis, axonal transport
• 4-5 minutes ischemia → irreversible neuronal death

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• Autoimmune T-cells attack myelin basic protein (molecular mimicry)
• Oligodendrocytes destroyed → demyelination → impaired saltatory conduction → nerve conduction slowed/blocked
• CNS has limited remyelination capacity

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• Increased ICP (tumor, hemorrhage, hydrocephalus) → meningeal stretch + papilledema
• Meningitis → meningeal irritation
• Posterior fossa lesion → brainstem/cerebellar compression
• Migraine → cortical spreading depression + trigeminovascular activation

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• UMN pathways interrupted → LMN released from inhibitory control
• Spasticity, hyperreflexia, muscle spasms = released spinal reflex arcs
• Paralysis = no voluntary motor commands from cortex

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• Frontal: Personality, motor (precentral gyrus), Broca's aphasia
• Temporal: Memory, Wernicke's aphasia
• Cerebellar: Ataxia, dysmetria, intention tremor
• General: Raised ICP → headache, herniation (life-threatening)

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• Hippocampus → new memory formation; early Alzheimer's target
• Nucleus basalis of Meynert → cholinergic neurons; lost in Alzheimer's
• Prefrontal cortex → working memory, executive function
• Mechanisms: amyloid plaques + neurofibrillary tangles (Alzheimer's)

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• Basal ganglia dysfunction (Parkinson's disease)
• Loss of dopaminergic neurons in substantia nigra pars compacta
• Dopamine loss → overactivity of indirect pathway → excessive thalamic inhibition → reduced motor cortex output
• Resting tremor = abnormal 4-6 Hz oscillations in basal ganglia-thalamo-cortical loop

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• Release of endogenous opioids (endorphins, enkephalins) from PAG
• Gate control theory — stimulates A-beta fibers → inhibitory interneurons → closes pain gate
• Activates descending inhibitory pathways (PAG → serotonin/noradrenaline → dorsal horn inhibition)

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• Gate Control Theory (Melzack & Wall, 1965)
• Rubbing activates large A-beta fibers → inhibitory interneurons in dorsal horn activated
• Interneurons inhibit pain transmission (T-cell) from C/A-delta fibers → pain signal gated out
• Basis of TENS therapy and massage

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• Reverberating (re-entrant) circuits — signal re-enters circuit via collaterals → self-sustaining
• Slow EPSPs via metabotropic receptors persist after stimulus ends
• Summation of EPSPs maintains depolarization above threshold

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• Prefrontal cortex handles affective/emotional component of pain (suffering)
• Lobotomy disconnects PFC from limbic system
• Patient still perceives pain (sensory-discriminative intact) but pain no longer bothers them (affective component lost)

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• Thalamic syndrome (Dejerine-Roussy)
• Loss of thalamic inhibitory neurons → pain signals relayed without modulation
• Hyperalgesia, allodynia, spontaneous burning pain

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• Extreme stress → hypothalamus activates PAG → endorphin release → mu-opioid receptor activation
• Descending inhibitory pathways (serotonin + noradrenaline) block dorsal horn transmission
• Attention redirected to survival by prefrontal cortex

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• Higher receptor density (Meissner's corpuscles ~2,500/cm² on fingertips vs. few on back)
• Smaller receptive fields on fingertips
• Larger cortical representation in somatosensory cortex (homunculus — hands are disproportionately large)

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• Somatosensory cortex does not go silent after amputation
• Adjacent cortical areas expand into the "limb zone" (cortical reorganization)
• Stimulation of adjacent body parts → sensation referred to absent limb
• Stump neuromas generate spontaneous impulses
• Brain's body schema retains the limb representation

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• Clasp knife: UMN lesion → hyperactive stretch reflex; continued stretch activates GTOs → Ib inhibition (autogenic inhibition) → sudden release of resistance
• Clonus: UMN lesion → hyperactive Ia-motor neuron loop; sustained dorsiflexion → self-sustaining oscillation at 5-8 Hz because descending inhibition is absent

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• Loss of voluntary motor (corticospinal), vestibulospinal, and reticulospinal tracts
• Cannot integrate vestibular, visual, proprioceptive inputs for balance (requires supraspinal processing)
• No anticipatory or reactive postural corrections possible

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• Loss of dopamine → overactivity of indirect pathway → excessive GPi inhibition of thalamus
• Reticulospinal tone to spinal motor neurons is altered
• Both agonist and antagonist muscles show increased tone simultaneously → "lead pipe rigidity"
• Unlike spasticity — uniform throughout range of motion, present at rest

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• Cerebellum normally damps oscillations in the stretch reflex (feed-forward control)
• Cerebellar lesion → loss of damping → leg swings back and forth (pendular, multiple swings)
• Stretch reflex arc itself is intact

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• Cerebellum = comparator (intended vs. actual movement); provides real-time correction
• Cerebellar lesion → no correction → dysmetria (overshoot/undershoot)
• Intention tremor — worsens as finger approaches target
• Ipsilateral — cerebellar lesions affect the same side

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• Dopamine cannot cross BBB
• L-dopa crosses BBB via large neutral amino acid transporter
• Converted to dopamine in brain by DOPA decarboxylase
• Given with carbidopa (peripheral DOPA decarboxylase inhibitor) to prevent peripheral conversion and side effects

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• Loss of dopamine → abnormal 4-6 Hz oscillations in basal ganglia-thalamo-cortical circuit
• Transmitted via thalamus → motor cortex → rhythmic motor output = resting tremor
• Present at rest; suppresses with voluntary movement (distinguishes from cerebellar tremor)

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• Double-crossing arrangement:
  1. Corticospinal tract crosses once (pyramidal decussation)
  2. Cerebellar output crosses once (superior cerebellar peduncle)
• Two crossings cancel out → net ipsilateral control
• Right cerebellar lesion → right-sided ataxia, dysmetria

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• Normally: corticospinal tract inhibits the extensor plantar reflex (primitive reflex)
• UMN lesion → inhibition is lost → primitive reflex released
• Result: Big toe dorsiflexion + fanning of toes (Babinski's sign)
• Normal in infants until ~18 months (immature corticospinal tracts)

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• Gamma → intrafusal fiber contraction → stretches nuclear bag → activates Ia afferents
• Ia afferents → dorsal horn → alpha motor neurons → extrafusal muscle contraction
• This is the gamma loop → sensitizes spindle → drives stretch reflex without external stretch

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• Isometric contraction of distant muscles → descending facilitory signals from motor cortex and reticular formation
• Increase excitability of alpha motor neurons throughout cord
• Same Ia input → larger, brisker reflex response
• Also prevents voluntary suppression of the reflex

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• UMN lesion → loss of descending inhibition → hyperactive stretch reflex
• Sustained dorsiflexion → reflex plantarflexion → stretch again → self-sustaining oscillation
• Sustained clonus (>5 beats) = definitive UMN sign

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• UMN lesion → gamma motor neurons hyperactive → spindles hypersensitive
• Any tap → massive Ia discharge → exaggerated alpha motor neuron response
• Also: Renshaw cell inhibition reduced (less corticospinal input to inhibitory interneurons)

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• EEG resembles wakefulness (desynchronized, low voltage, high frequency)
• Yet the person is deeply asleep (high arousal threshold)
• Complete muscle atonia (postural muscles paralyzed by brainstem inhibition)
• Vivid dreaming + autonomic instability (irregular HR, BP, breathing)
• Waking brain in a sleeping body = paradox

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SECTION 5: SPECIAL SENSES

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• Cannot increase curvature during accommodation
• Inability to focus on near objects → Presbyopia
• Normal aging: lens proteins cross-link and harden after age 40
• Corrected with converging (reading) glasses

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• Light → retina → optic nerve → pretectal nuclei → Edinger-Westphal nucleus (CN III parasympathetic)
• → Ciliary ganglion → sphincter pupillae → miosis (pupil constriction)
• Bilateral reflex (both pupils constrict even if one eye stimulated)

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• Trichromatic theory: Three cone types (S-blue ~420nm, M-green ~530nm, L-red ~560nm)
• Different colors stimulate cones in different ratios → brain interprets combination as specific color
• Higher level: Opponent process theory (red-green, blue-yellow channels)
• Color processing in V4 cortex

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• Irregular astigmatism → different meridians have different radii → light focuses at different points
• Blurred distorted vision at all distances
• Keratoconus: progressive corneal thinning → irregular astigmatism

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• Reduced tympanic membrane vibration → impaired ossicular chain movement
• Conductive hearing loss (air-bone gap on audiometry)
• Risk of middle ear infection (loss of protective barrier)

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• Interaural Time Difference (ITD): Different arrival time → processed in medial superior olive (MSO) → horizontal localization
• Interaural Level Difference (ILD): Head shadow effect → processed in lateral superior olive (LSO)
• Pinna spectral cues → vertical localization

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• Sensorineural hearing loss (bone conduction also reduced; no air-bone gap)
• Base damaged → high-frequency loss (most common — noise-induced, presbycusis)
• Associated tinnitus
• Outer hair cell damage → loss of cochlear amplifier (prestin-based electromotility)

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• Stereocilia breakage (excessive basilar membrane vibration)
• Excitotoxicity — excess glutamate → AMPA receptor overactivation → Ca²⁺ influx → nerve dendrite damage
• ROS generation → oxidative damage
• Hair cells are not regenerated in mammals → permanent loss

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• Anosmia (total) or hyposmia (partial)
• ORNs can regenerate (unique among neurons) via basal stem cells
• COVID-19: damages sustentacular cells and olfactory epithelium → anosmia

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• Receptor desensitization — prolonged odorant → G-protein uncoupling → ORN firing decreases
• Granule cell lateral inhibition in olfactory bulb → inhibits mitral cells (output neurons)
• Cortical habituation — brain filters out constant, non-threatening olfactory input

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• Olfactory system has unique direct connection to limbic system (no thalamic relay)
• Olfactory bulb → piriform cortex → amygdala and hippocampus DIRECTLY
• Amygdala = emotional processing; Hippocampus = memory
• Explains Proustian memory phenomenon and instant emotional recall from smells

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• Salty: Na⁺ enters via amiloride-sensitive Na⁺ channels
• Sour: H⁺ blocks K⁺ channels → depolarization
• Sweet/Bitter/Umami: GPCR → gustducin → PLC → IP3 → Ca²⁺ release
• Travels via: CN VII (anterior 2/3), CN IX (posterior 1/3), CN X (epiglottis) → NTS → thalamus → gustatory cortex

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• Loss of taste from anterior 2/3 of tongue (sweet, salty, sour primarily)
• Also reduced salivation (submandibular, sublingual glands)
• Posterior 1/3 taste (CN IX) preserved
• Common complication of middle ear surgery

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• Vertigo, nausea, vomiting (vestibulo-vagal reflex)
• Imbalance and ataxia
• Nystagmus (fast phase away from damaged side)
• Romberg's positive (eyes closed worsens balance)

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• Sensory conflict theory: Mismatch between vestibular, visual, and proprioceptive inputs
• Cerebellum/brainstem detects conflict → activates vomiting center (via histamine and ACh pathways)
• Treatment: Antihistamines (meclizine), Anticholinergics (scopolamine)

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• Optic disk = where optic nerve exits + central retinal artery/vein enter
• No photoreceptors (rods or cones) → cannot transduce light → physiological blind spot
• Brain "fills in" the gap using surrounding retinal information

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• Highest cone density (~150,000 cones/mm²)
• 1:1 cone-to-ganglion cell ratio (private line) → maximum spatial resolution
• No overlying blood vessels or ganglion cells (foveola is a pit) → light hits cones directly
• Largest cortical magnification factor in visual cortex

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• Hyperglycemia → excess lens glucose → aldose reductase converts glucose to sorbitol (polyol pathway)
• Sorbitol cannot exit lens → osmotic accumulation → lens cell swelling
• AGEs cross-link crystallin proteins → lens opacification
• Oxidative stress → reduced glutathione → further damage

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• Photoreceptors are nourished by diffusion from choroidal blood vessels through RPE
• Detachment separates neural retina from RPE → ischemia and metabolic deprivation
• RPE cannot phagocytose outer segment discs → outer segment degeneration
• Urgent surgical reattachment needed to prevent permanent loss

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• Cornea provides 70% of refractive power due to large refractive index difference between air (n=1.0) and cornea (n=1.376)
• Underwater: Water (n=1.333) ≈ Cornea (n=1.376) → air-cornea interface effectively disappears
• Cornea provides no refraction → lens alone insufficient → blurred vision (extreme hyperopia)
• Solution: Diving mask restores air-cornea interface

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• Homatropine = anticholinergic (antimuscarinic)
• Blocks ciliary muscle → cycloplegia (paralysis of accommodation)
• Lens cannot round up → cannot focus on near objects → blurred near vision
• Also causes mydriasis (useful for fundoscopy)

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• Lens crystallins cross-link → lens becomes stiff (nuclear sclerosis)
• Cannot round up during accommodation
• Amplitude of accommodation decreases from ~14D (child) to <2D (age 55)
• Corrected with converging (reading) glasses

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• UV: Absorbed by cornea (far UV) and lens (near UV) before reaching retina
• Infrared: Photopigments (rhodopsin, iodopsins) do not absorb IR; IR photons lack enough energy to isomerize 11-cis retinal
• IR converted to heat by ocular media

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• Rods: Single pigment (rhodopsin) → cannot discriminate wavelength → achromatic (black and white)
• Cones: Three different opsins (S, M, L) → ratio of cone activation determines color perception
• Concentrated in fovea (photopic/bright light vision)
• Color blindness = deficiency/mutation of M-cones (deuteranopia) or L-cones (protanopia)

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• Rods contain rhodopsin (peak absorption ~500 nm — green range)
• Rhodopsin is minimally bleached by red light (>620 nm)
• Red goggles allow cones to function in bright light but preserve rhodopsin (rods already dark-adapted)
• When entering darkness → immediate night vision (no 30-40 min dark adaptation needed)

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• Sildenafil is PDE5 inhibitor but also cross-inhibits PDE6 (in retinal cones)
• PDE6 breaks down cGMP in the phototransduction cascade
• PDE6 inhibition → cGMP accumulates in cones → altered phototransduction
• Blue cones most affected → cyanopsia (bluish tinge), increased light sensitivity
• Transient — resolves as drug is cleared

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Exam Tip: The bold/highlighted phrases are the key examiner-scoring points. Include at least 3-4 bolded concepts per answer in your exam response for full marks.

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• Cover banner with dark background — Title, subtitle, and all 5 topics listed
• 5 colour-coded sections with orange section banners:
  • Section 1 — Nerve Muscle Physiology (17 Q&As)
  • Section 2 — Endocrine System (48 Q&As)
  • Section 3 — Reproductive System (14 Q&As)
  • Section 4 — Central Nervous System (27 Q&As)
  • Section 5 — Special Senses (22 Q&As)
• Every examiner key-phrase is bolded in the answers
• Compact bullet format — 3-4 points per question, no wasted space
• Footer reminder: "Bold text = examiner key-scoring phrases — include at least 3-4 bold concepts per exam answer for full marks"