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GROUP A

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Question 1

(a) Definition of GFR & Calculation of Net Filtration Pressure [1+2 marks]

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NFP = (P_GC + π_BC) − (P_BC + π_GC) NFP = (55 + 0) − (15 + 30) NFP = 55 − 45 = +10 mmHg

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(b) Factors Affecting GFR [2 marks]

• ↑ Glomerular capillary hydrostatic pressure (e.g., ↑ systemic BP) → ↑ GFR
• ↑ Bowman's capsule pressure (e.g., urinary obstruction/ureteric stone) → ↓ GFR
• ↑ Plasma oncotic pressure (e.g., dehydration, hypoproteinemia) → ↓/↑ GFR

• Mesangial cell contraction (via angiotensin II, endothelin) → ↓ filtration surface area → ↓ GFR
• Glomerulonephritis → reduced surface area → ↓ GFR

• Afferent arteriolar dilation → ↑ P_GC → ↑ GFR
• Afferent arteriolar constriction (e.g., sympathetic activation, NSAIDs) → ↓ P_GC → ↓ GFR

• Efferent arteriolar constriction (e.g., angiotensin II) → ↑ P_GC → ↑ GFR (mild); but also ↑ oncotic pressure → net effect: maintains GFR at moderate vasoconstriction

• Myogenic mechanism: ↑ BP → afferent arteriole stretches and constricts → maintains GFR
• Tubuloglomerular feedback (TGF): ↑ NaCl at macula densa → adenosine → afferent arteriolar constriction → ↓ GFR

• Angiotensin II → constricts efferent > afferent → maintains GFR in low-flow states
• ANP (atrial natriuretic peptide) → dilates afferent, constricts efferent → ↑ GFR
• Prostaglandins → dilate afferent → protect GFR (important in low-flow states)
• Norepinephrine/Epinephrine → afferent constriction → ↓ GFR

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Question 2

(a) Reabsorption of Glucose in the Proximal Convoluted Tubule [2 marks]

1. On the luminal (apical) membrane: Glucose is co-transported with Na⁺ via SGLT2 (sodium-glucose linked transporter 2) in the early PCT and SGLT1 in the late PCT
   • SGLT2: low-affinity, high-capacity (reabsorbs ~90% of filtered glucose); 1 Na⁺ : 1 glucose
   • SGLT1: high-affinity, low-capacity; 2 Na⁺ : 1 glucose
2. Na⁺ gradient driving SGLT is maintained by Na⁺/K⁺-ATPase on the basolateral membrane (active transport — primary active)
3. On the basolateral membrane: Glucose exits the cell into peritubular capillaries via GLUT2 (early PCT) and GLUT1 (late PCT) by facilitated diffusion

• Renal threshold for glucose: ~180 mg/dL plasma glucose — above this, glucose appears in urine (glucosuria)
• Transport maximum (Tm_G): ~375 mg/min (average); maximum rate at which the tubule can reabsorb glucose
• Above Tm: excess glucose remains in tubular fluid → osmotic diuresis

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(b) Reabsorption of Na⁺ in Different Parts of the Nephron [3 marks]

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Question 3

(a) Draw and Label a Typical Nephron [2 marks]

                        CORTEX
    ┌─────────────────────────────────────────┐
    │                                         │
    │   Bowman's Capsule                      │
    │       ┌──┐                              │
    │    ───┤  ├───  Glomerulus               │
    │       └──┘                              │
    │         │                               │
    │   Proximal Convoluted Tubule (PCT)       │
    │   ┌──────────────┐                      │
    │   └──────────────┘                      │
    │         │                               │
    │   Distal Convoluted Tubule (DCT)         │
    │   ┌──────────────┐                      │
    │   └──────────────┘                      │
    │         │          │                    │
    │       Connecting tubule                 │
    │         │                               │
    └─────────┼──────────────────────────────┘
              │          MEDULLA
    ┌─────────┼──────────────────────────────┐
    │         ↓                              │
    │   Loop of Henle                        │
    │      │                                 │
    │   Descending limb (thin)               │
    │      │                                 │
    │   Thin ascending limb                  │
    │      │                                 │
    │   Thick ascending limb (TAL)           │
    │      │                                 │
    │   Collecting Duct                      │
    │      │                                 │
    │      ↓                                 │
    │   Renal Pelvis → Ureter               │
    └────────────────────────────────────────┘

    Blood supply:
    Afferent arteriole → Glomerulus → Efferent arteriole
    → Peritubular capillaries / Vasa recta

1. Renal corpuscle (Glomerulus + Bowman's capsule)
2. Proximal convoluted tubule (PCT)
3. Descending limb of loop of Henle
4. Thin ascending limb of loop of Henle
5. Thick ascending limb of loop of Henle
6. Macula densa (at junction of TAL and DCT)
7. Distal convoluted tubule (DCT)
8. Connecting tubule
9. Collecting duct
10. Afferent arteriole, Efferent arteriole
11. Peritubular capillaries / Vasa recta

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(b) Difference Between Cortical and Juxtamedullary Nephron; Why Maximum Reabsorption Occurs in PCT [2+1 marks]

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1. Large surface area: Brush border microvilli on luminal surface amplify absorptive surface area ~20-fold
2. High metabolic activity: PCT cells are rich in mitochondria → abundant ATP for active transport (Na⁺/K⁺-ATPase)
3. Numerous transport proteins: Highest density of carriers (SGLT2, NHE3, Na-phosphate, Na-amino acid cotransporters)
4. Freely permeable to water: AQP1 channels allow water to follow solute reabsorption iso-osmotically
5. Bulk reabsorption: Na⁺, Cl⁻, K⁺, HCO₃⁻, glucose, amino acids, water — all reabsorbed together
6. Favorable peritubular forces: Low oncotic pressure and high hydrostatic pressure in peritubular capillaries favor fluid reabsorption into capillaries
7. No regulatory constraints: Reabsorption is obligatory and not subject to hormonal regulation (unlike DCT/collecting duct), ensuring maximum baseline reabsorption

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Question 4

(a) Hypothalamic Releasing and Inhibitory Hormones [2 marks]

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(b) Clinical Features of Hypersecretion of Growth Hormone [2 marks]

• Coarsening of facial features
• Prognathism (protrusion of jaw), malocclusion of teeth
• Macroglossia (enlarged tongue)
• Prominent supraorbital ridges
• Enlarged nose, lips, ears
• Frontal bossing

• Acral enlargement — large spade-like hands, broad feet
• Patient notices increasing ring/glove/shoe size
• Carpal tunnel syndrome (nerve compression)

• Excessive sweating (hyperhidrosis) — common early symptom
• Skin thickening, skin tags, oily skin
• Deepening of voice

• In children (Gigantism): excessive linear growth (height >7 feet)
• In adults: no increase in height but bone thickening

• Insulin resistance → diabetes mellitus (secondary)
• Hypertension
• Hypercalciuria, renal stones

• Cardiomegaly, cardiomyopathy → heart failure
• Hypertension

• Headache (from pituitary tumour)
• Bitemporal hemianopia (compression of optic chiasma)
• Hypopituitarism (compression of normal pituitary)

• Hepatomegaly, splenomegaly, renomegaly
• Goitre

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Question 5

(a) Menstruation & Uterine Endometrial Changes During Monthly Female Reproductive Cycle [1+2 marks]

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• Withdrawal of progesterone and estrogen → vasoconstriction of spiral arteries → ischemia → necrosis of functionalis layer
• Shedding of endometrial functionalis, blood, mucus, and cellular debris
• Endometrium reduced to thin basalis layer (~1 mm)

• Rising estrogen from developing follicles stimulates endometrial regeneration
• Rapid proliferation of epithelial cells, stromal cells, and glands
• Endometrium thickens from ~1 mm → ~3–5 mm
• Glands are straight, narrow, tubular
• Spiral arteries elongate
• Peak: just before ovulation (day 13–14) — endometrium well-vascularized

• Progesterone (from corpus luteum) acts on estrogen-primed endometrium
• Glands become tortuous, coiled, and secretory — filled with glycogen-rich fluid (nourishment for potential blastocyst)
• Endometrium thickens further to 5–7 mm
• Stromal cells enlarge (predecidual change)
• Spiral arteries become highly coiled and tortuous
• If no fertilization: corpus luteum degenerates → progesterone/estrogen fall → spiral artery vasoconstriction → menstruation begins (Day 28/Day 1)

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(b) Effects of Estrogen and Progesterone on Breast [2 marks]

1. Stimulates growth and development of ductal system (lactiferous ducts) of the breast
2. Promotes stromal development and fat deposition → breast enlargement at puberty
3. Causes nipple development and pigmentation of areola
4. Increases blood supply to breasts
5. Stimulates prolactin receptors in breast tissue

1. Stimulates development of lobules and alveoli (secretory acini) — the milk-producing units
2. Causes breast swelling and fullness in the luteal phase (water retention, ductal dilation)
3. Induces premenstrual breast tenderness (mastalgia)
4. Necessary for full lobulo-alveolar development (in conjunction with estrogen, prolactin, insulin, cortisol)
5. Prepares breast for lactation during pregnancy

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GROUP B

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Question 6 — Clinical Case: 45-year-old with Polyuria, Polydipsia, Polyphagia

(a) Diagnosis [1 mark]

• Polyuria (osmotic diuresis due to glucosuria)
• Polydipsia (dehydration from osmotic diuresis → thirst)
• Polyphagia (cellular starvation despite hyperglycemia due to insulin deficiency/resistance)

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(b) Laboratory Investigations to Confirm the Diagnosis [4 marks]

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(c) Complications of Diabetes Mellitus [2.5 marks]

1. Diabetic Ketoacidosis (DKA) — Type 1 DM; hyperglycemia + ketoacidosis + dehydration
2. Hyperosmolar Hyperglycaemic State (HHS/HONK) — Type 2 DM; extreme hyperglycemia (>600 mg/dL), no ketosis, altered sensorium
3. Hypoglycemia — from excess insulin/OHA treatment

• Diabetic foot (neuropathy + PVD + infection)
• Increased susceptibility to infections (TB, candidiasis, UTI, skin infections)
• Cataracts and glaucoma
• Hepatic steatosis (NAFLD)

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Question 7 — Thyroid Gland

(a) Hormones Secreted from the Thyroid Gland [2.5 marks]

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(b) Steps of Synthesis of Thyroid Hormones [2.5 marks]

• Dietary iodide (I⁻) is actively transported from blood into follicular cells against a concentration gradient via Na⁺/I⁻ symporter (NIS) on the basolateral membrane
• Driven by Na⁺/K⁺-ATPase; concentration is 20–40× plasma levels (stimulated by TSH)

• I⁻ is transported to the apical membrane via pendrin (Cl⁻/I⁻ exchanger)
• At the apical membrane, thyroid peroxidase (TPO) oxidizes I⁻ → I° (active iodine/I₂), using H₂O₂ (generated by DUOX2 enzyme)

• TPO iodinates tyrosine residues on thyroglobulin (Tg) in the follicular lumen
• Monoiodotyrosine (MIT) → one iodine added
• Diiodotyrosine (DIT) → two iodines added

• TPO catalyzes coupling of iodotyrosine residues:
  • DIT + DIT → T₄ (thyroxine) — remains bound to Tg
  • MIT + DIT → T₃ (triiodothyronine) — remains bound to Tg
• Tg-hormone complex is stored in colloid as colloid/thyroglobulin

• TSH stimulates follicular cells to endocytose colloid droplets (pinocytosis)
• Lysosomes fuse with endosomes → lysosomal proteases cleave Tg → release free T₃, T₄, MIT, DIT

• Free T₃ and T₄ are released into the bloodstream
• MIT and DIT are deiodinated by iodotyrosine deiodinase → iodine recycled

• 99% of T₃/T₄ bound to carrier proteins: Thyroxine-binding globulin (TBG) (major), transthyretin, albumin

• Only free (unbound) hormone is biologically active

TSH stimulates every step of synthesis and secretion. Propylthiouracil (PTU) and carbimazole block TPO (organification and coupling). Perchlorate blocks NIS.

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(c) Thyroid Function Tests [2.5 marks]

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(d) Myxedema [2.5 marks]

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Question 7 (OR) — Adrenal Gland

(a) Hormones from the Adrenal Gland [2.5 marks]

• Epinephrine (Adrenaline) — ~80%
• Norepinephrine (Noradrenaline) — ~20%
• Small amounts of Dopamine

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(b) Functions of Cortisol [2.5 marks]

1. Carbohydrate: Stimulates gluconeogenesis; inhibits peripheral glucose uptake → raises blood glucose (anti-insulin); stimulates glycogen synthesis in liver
2. Protein: Stimulates protein catabolism in muscle, skin, bone → provides amino acids for gluconeogenesis; inhibits protein synthesis
3. Fat: Stimulates lipolysis (free fatty acid mobilization); causes redistribution of fat (central obesity — trunk, face, neck)

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(c) Features of Cushing Syndrome [2.5 marks]

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(d) Features of Addison's Disease [2.5 marks]

• Precipitated by infection, surgery, trauma, or sudden steroid withdrawal
• Severe hypotension, shock, vomiting, abdominal pain, confusion, coma
• Medical emergency: IV hydrocortisone + IV saline + glucose

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GROUP B

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Question 8

(a) Mechanism of Inspiration and Expiration [2 marks]

1. Neural signal: Inspiratory neurons in the dorsal respiratory group (DRG) of the medulla fire → send impulses via phrenic nerve (C3, C4, C5) to diaphragm and via intercostal nerves (T1–T11) to external intercostal muscles
2. Muscle contraction:
   • Diaphragm contracts → flattens and descends (~1.5 cm quiet; up to 10 cm deep breathing) → increases vertical diameter of thorax
   • External intercostal muscles contract → ribs move upward and outward ("bucket handle" movement) → increases anteroposterior and transverse diameters
3. Thoracic volume increases → intrapleural pressure falls (from –5 to –8 cmH₂O)
4. Lungs expand (elastic recoil opposes this) → intrapulmonary (alveolar) pressure falls below atmospheric (~–1 to –3 cmH₂O)
5. Air flows in down the pressure gradient (atmosphere → alveoli) until pressures equalize

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1. Inspiratory neurons stop firing → diaphragm and external intercostals relax
2. Elastic recoil of lungs and chest wall → thoracic volume decreases
3. Intrapleural pressure rises back to –5 cmH₂O; alveolar pressure rises to +1 to +3 cmH₂O (above atmosphere)
4. Air flows out down the pressure gradient (alveoli → atmosphere)
5. No muscle contraction required — entirely passive

• Internal intercostal muscles contract → depress ribs → reduce thoracic volume
• Abdominal muscles (rectus abdominis, external oblique) contract → push diaphragm upward
• Alveolar pressure rises higher → faster airflow out

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(b) Effect of Lesion on Respiration [3 marks]

• The phrenic nerve supplies the diaphragm, which contributes ~70% of quiet tidal volume
• Unilateral lesion: Paralysis of ipsilateral hemidiaphragm → paradoxical movement (rises on inspiration due to negative intrathoracic pressure from contralateral side) → reduced but not absent breathing (compensated by intercostals)
• Bilateral lesion: Complete diaphragmatic paralysis → severe respiratory insufficiency → respiratory failure; patient dependent on accessory muscles only
• Reason: Diaphragm is the primary muscle of inspiration; its paralysis drastically reduces tidal volume

• Vagus carries afferent fibers from pulmonary stretch receptors (Hering-Breuer reflex)
• Bilateral vagotomy: Eliminates the Hering-Breuer inflation reflex → inspiratory neurons not switched off at end of inspiration → breaths become deeper and slower (prolonged inspiration, increased tidal volume)
• Also disrupts irritant receptors and J-receptors → impaired cough reflex, impaired response to pulmonary congestion
• Reason: Vagus carries inhibitory feedback from lung stretch receptors that normally terminate inspiration; without it, inspiration is prolonged

• Disconnects all supraspinal respiratory control from spinal motor neurons
• Breathing ceases completely → apnea and death
• Reason: The essential respiratory rhythm generators (DRG and VRG — pre-Bötzinger complex) are located in the medulla. Severing below medulla removes all descending respiratory drive to phrenic and intercostal motor neurons. The spinal cord alone cannot generate rhythmic breathing.

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Question 9

(a) Oxyhemoglobin Dissociation Curve — Draw, Label & Significance of Flat and Steep Parts [1.5+1 marks]

100|──────────────╗
   |             ╗ ╚═╗  ← FLAT PART (60–100 mmHg)
 % |            ╝    ╚╗
Hb |           ╝      ╚╗
Sat|          ╝         ╚╗
   |        ╝             ╚╗
 50|       ╝                ╚╗ ← STEEP PART (10–60 mmHg)
   |      ╝                   ╚╗
   |    ╝                       ╚╗
   |  ╝                           ╚
  0|──────────────────────────────────
   0    20    40    60    80   100
         PO₂ (mmHg)

Key Points:
• P₅₀ = 26.6 mmHg (PO₂ at which Hb is 50% saturated)
• Arterial blood: PO₂ ~100 mmHg → SaO₂ ~98%
• Venous blood: PO₂ ~40 mmHg → SvO₂ ~75%
• Oxygen loading: lungs (flat part)
• Oxygen unloading: tissues (steep part)

• Corresponds to oxygen loading in the lungs
• Even if PO₂ falls from 100 → 60 mmHg (e.g., high altitude, mild lung disease), saturation only falls from 98% → 90% → Hb remains well-saturated → acts as a safety buffer
• Ensures adequate O₂ loading despite moderate drops in alveolar PO₂

• Corresponds to oxygen unloading in the tissues
• A small drop in tissue PO₂ (from 40 → 20 mmHg) causes a large release of O₂ from Hb
• Facilitates efficient O₂ delivery to metabolically active tissues
• During exercise (↑ CO₂, ↓ pH, ↑ temperature, ↑ 2,3-DPG) → Bohr effect shifts curve rightward → even more O₂ unloaded

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(b) Definition and Classification of Hypoxia [2.5 marks]

• PaO₂ is reduced → low arterial O₂ saturation
• Reasons:
  • Low atmospheric PO₂ (high altitude)
  • Hypoventilation (opiate overdose, respiratory muscle paralysis, COPD)
  • Ventilation-perfusion (V/Q) mismatch (pneumonia, pulmonary embolism, asthma)
  • Diffusion impairment (pulmonary fibrosis, ARDS)
  • Right-to-left cardiac shunt (congenital heart disease)

• Normal PaO₂ but reduced O₂ carrying capacity of blood
• Reasons:
  • Anaemia (low Hb — iron deficiency, aplastic anaemia)
  • Carbon monoxide poisoning (CO displaces O₂ from Hb; forms carboxyhaemoglobin)
  • Methaemoglobinaemia (Fe²⁺ oxidized to Fe³⁺ — cannot carry O₂)
  • Haemoglobinopathies (sickle cell, thalassaemia)

• Normal PaO₂ and Hb, but inadequate blood flow to tissues
• Reasons:
  • Heart failure (↓ cardiac output)
  • Shock (hypovolaemic, septic, cardiogenic)
  • Local ischaemia (atherosclerosis, arterial obstruction, venous stasis)

• Normal PaO₂, Hb, and blood flow, but cells cannot utilize O₂
• Reasons:
  • Cyanide poisoning (inhibits cytochrome c oxidase — complex IV of electron transport chain)
  • Carbon monoxide (also histotoxic at cellular level)
  • Severe sepsis (mitochondrial dysfunction)

Additional: Some texts include Demand hypoxia — when O₂ consumption exceeds even normal supply (e.g., extreme exercise, hyperthyroidism).

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Question 10

(a) Differences Between Action Potential of SA Node and Ventricular Muscle [2.5 marks]

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(b) Genesis of Pacemaker Potential and Its Significance [2.5 marks]

• After repolarization, membrane potential is negative → HCN (Hyperpolarization-activated Cyclic Nucleotide-gated) channels open
• Allow slow inward current of Na⁺ (and some K⁺) → progressive depolarization
• Called "funny" because activated by hyperpolarization (opposite to normal channels)
• Modulated by cAMP: Sympathetic stimulation ↑ cAMP → ↑ If → faster depolarization (↑ HR); Parasympathetic ↓ cAMP → ↓ If → slower HR

• K⁺ channels (IKr, IKs) that repolarized the cell gradually close → ↓ outward K⁺ current → net inward current increases → depolarization proceeds

• As membrane reaches ~–50 mV, T-type (transient) Ca²⁺ channels open → inward Ca²⁺ current → accelerates the final phase of depolarization toward threshold
• At threshold (~–40 mV): L-type Ca²⁺ channels open → rapid upstroke of action potential

1. Automaticity: Gives the SA node its intrinsic ability to generate spontaneous rhythmic impulses without external stimulation — the basis of the heartbeat
2. Dominant pacemaker: SA node depolarizes fastest (60–100/min) → overdrive suppresses subsidiary pacemakers (AV node 40–60/min, Purkinje 20–40/min)
3. Rate regulation: Sympathetic (↑ slope of Phase 4 → ↑ HR) and parasympathetic (↓ slope, more negative trough → ↓ HR) directly modulate pacemaker potential — basis of autonomic HR control
4. Clinical relevance: Sick sinus syndrome = failure of SA node pacemaker potential → bradycardia/asystole

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Question 11

(a) Definition of Cardiac Cycle & Its Events [1+1.5 marks]

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(b) Calculation of Cardiac Cycle Time & Properties of Isometric Contraction Period [1+1.5 marks]

Cardiac cycle time = 60 seconds ÷ Heart Rate = 60 ÷ 75 = 0.8 seconds (800 ms)

• Atrial systole: 0.1 s
• Ventricular systole: 0.3 s (IVC + ejection)
• Ventricular diastole: 0.5 s (IVR + filling)

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1. Duration: ~0.05 seconds (50 ms)
2. All four cardiac valves are closed simultaneously — mitral and tricuspid (just closed), aortic and pulmonary (not yet opened)
3. Volume is constant (isovolumetric): Since no blood enters or leaves the ventricle, ventricular volume remains equal to EDV throughout this phase
4. Pressure rises steeply: Ventricular pressure rises rapidly from ~0–8 mmHg (left ventricle) to ~80 mmHg to exceed aortic diastolic pressure
5. Muscle fiber length does not change but tension increases — isometric contraction in mechanical terms
6. Highest rate of pressure rise (dP/dt max): This phase has the maximum rate of pressure development — an index of myocardial contractility
7. Energy expenditure: High ATP consumption despite no external work done (no ejection)
8. S1 heart sound marks the beginning of this phase (AV valve closure)
9. Correlates with the QRS complex on ECG (ventricular depolarization initiates it)

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Question 12

(a) Definition of EDV & Factors Affecting EDV [1+1.5 marks]

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1. ↑ Venous return — most important determinant:
   • Increased blood volume (hypervolaemia, fluid overload, excess sodium retention)
   • Exercise (muscle pump, venoconstriction)
   • Lying down (gravity eliminated — more venous return)
   • Increased sympathetic venous tone (venoconstriction → ↑ venous return)
2. Prolonged diastole (↓ Heart rate): More time for filling → ↑ EDV
3. Increased compliance of ventricle: Ventricle fills to greater volume at lower pressure
4. Atrial contraction (atrial kick): Contributes ~30% of final EDV

1. ↓ Venous return:
   • Haemorrhage, dehydration (↓ blood volume)
   • Standing up (venous pooling in legs)
   • Positive pressure ventilation (impedes venous return)
2. ↑ Heart rate (tachycardia): Less diastolic filling time → ↓ EDV
3. Reduced ventricular compliance (ventricular hypertrophy, cardiac tamponade, constrictive pericarditis)
4. Atrial fibrillation: Loss of atrial kick → ↓ final ventricular filling

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(b) Draw and Label a Normal ECG & What Different Waves Represent [1+1.5 marks]

         R
         |
    0.5  |  ↑ ~1mV
mV   |   |
     |   |
  ──P╮   |        T╮
     ╰─Q─┴─S──────╰──────
     |   |  ST    |
     ↑   ↑  seg   ↑
     P  QRS       T

Time intervals:
• PR interval: 0.12–0.20 s
• QRS duration: 0.06–0.10 s  
• QT interval: 0.35–0.44 s
• RR interval: 0.8 s (at 75 bpm)

Amplitude:
• P wave: <0.25 mV, <0.11 s
• R wave: varies by lead (up to ~2.5 mV in V5)
• T wave: ~0.3 mV

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Question 13 — Clinical Case: Road Traffic Accident with 3L Blood Loss

(a) Explanation of Clinical Features [2.5 marks]

• Massive blood loss → ↓ circulating blood volume → ↓ venous return → ↓ EDV (preload) → ↓ stroke volume (Frank-Starling) → ↓ cardiac output
• ↓ CO → ↓ mean arterial pressure (MAP = CO × TPR)
• Despite compensatory ↑ TPR, the volume loss is too great → BP falls
• Result: Systolic BP <90 mmHg (hypotension)

• ↓ BP → detected by baroreceptors (carotid sinus and aortic arch)
• Baroreceptor afferents → medullary cardiovascular centre → ↓ parasympathetic (vagal) tone + ↑ sympathetic outflow
• ↑ Sympathetic stimulation → ↑ SA node firing rate via β₁ receptors → tachycardia
• Also: ↓ venous return activates cardiopulmonary (low-pressure) receptors → further sympathetic activation
• Tachycardia compensates by maintaining CO = HR × SV

• ↓ CO → sympathetic adrenergic activation → α₁ receptor mediated cutaneous vasoconstriction
• Blood is redirected away from skin (non-vital) to vital organs (brain, heart, kidneys) — selective vasoconstriction
• Reduced cutaneous blood flow → skin appears pale and cold
• Sympathetic cholinergic activation of sweat glands → sweating → skin feels clammy
• Reason: Survival priority — vital organ perfusion over skin

• ↓ CO → ↓ cerebral perfusion → cerebral hypoxia
• Cerebral hypoxia causes neurological symptoms — initially restlessness, anxiety, agitation, confusion (followed by lethargy and coma in later stages)
• Adrenal medulla releases epinephrine (catecholamine surge) → CNS stimulation, anxiety, restlessness
• Increased sympathetic arousal also contributes

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(b) Compensatory Responses Activated [2.5 marks]

1. Baroreceptor reflex (most rapid):
   • ↓ BP → ↓ stretch of carotid/aortic baroreceptors → ↓ inhibitory afferents to vasomotor centre
   • → ↑ sympathetic outflow + ↓ parasympathetic
   • → Tachycardia, ↑ myocardial contractility, arteriolar vasoconstriction, venoconstriction
2. Chemoreceptor activation:
   • ↓ perfusion → ↓ O₂, ↑ CO₂ → peripheral chemoreceptors (carotid/aortic bodies) stimulated
   • → ↑ sympathetic activity → ↑ vasoconstriction
3. CNS ischaemic response (last resort, severe shock):
   • Direct ischaemia of vasomotor centre → massive sympathetic discharge → extreme vasoconstriction (MAP can rise to 250 mmHg transiently)

1. Adrenal medulla activation:
   • Sympathetic stimulation → ↑ Epinephrine + Norepinephrine release → tachycardia, vasoconstriction, ↑ cardiac contractility, bronchodilation
2. Renin-Angiotensin-Aldosterone System (RAAS):
   • ↓ renal perfusion + ↑ sympathetic stimulation of juxtaglomerular cells → ↑ Renin secretion
   • Renin → Angiotensinogen → Angiotensin I → (ACE) → Angiotensin II
   • Angiotensin II: vasoconstriction, ↑ aldosterone, ↑ ADH, ↑ thirst
   • Aldosterone → ↑ Na⁺ and water reabsorption in collecting duct → ↑ blood volume
3. ADH (Vasopressin) release:
   • ↓ blood volume sensed by cardiopulmonary receptors + ↑ plasma osmolality → posterior pituitary releases ADH
   • ADH → ↑ water reabsorption in collecting duct; also vasoconstriction (V1 receptors)
4. Transcapillary refill:
   • ↑ vasoconstriction → ↓ capillary hydrostatic pressure → net osmotic reabsorption of interstitial fluid into capillaries → auto-hemodilution (restores volume, dilutes Hb)

1. ↑ Erythropoietin (EPO) secretion from kidneys → stimulates bone marrow → ↑ RBC production (over days–weeks)
2. Thirst (via angiotensin II, ADH, hypothalamic osmoreceptors) → ↑ oral fluid intake
3. Protein synthesis → restoration of plasma proteins (albumin, globulins) over days

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Question 14

Definition of Blood Pressure & Its Determinants [2.5 marks]

MAP = Cardiac Output (CO) × Total Peripheral Resistance (TPR) Pulse Pressure = Systolic BP − Diastolic BP

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Classification of Blood Pressure & Normal Values [2.5 marks]

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Mechanisms for Regulation of Blood Pressure [2.5 marks]

1. Baroreceptor Reflex (most important rapid regulator):
   • Stretch receptors in carotid sinus (CN IX) and aortic arch (CN X)
   • ↑ BP → ↑ baroreceptor firing → NTS in medulla → ↓ sympathetic, ↑ parasympathetic → ↓ HR, ↓ contractility, vasodilation → BP falls back to normal
   • ↓ BP → opposite → tachycardia, vasoconstriction → BP restored
2. Chemoreceptor Reflex:
   • Peripheral (carotid/aortic bodies): respond to ↓ PO₂, ↑ PCO₂, ↓ pH → ↑ sympathetic → vasoconstriction
3. CNS Ischaemic Response:
   • Severe ↓ BP → cerebral ischaemia → massive sympathetic discharge (last resort)
4. Venoarteriolar reflex, Cushing reflex (↑ ICP → ↑ BP)

1. Renin-Angiotensin-Aldosterone System (RAAS) (see below)
2. ADH (Vasopressin): ↑ water reabsorption + vasoconstriction (V1 receptors)
3. Adrenal catecholamines: Epinephrine/Norepinephrine from medulla
4. Natriuretic Peptides (ANP/BNP): Released with ↑ atrial stretch → vasodilation + natriuresis → ↓ BP

1. Pressure natriuresis and diuresis (most powerful long-term mechanism):
   • ↑ BP → ↑ renal perfusion → ↑ Na⁺ and water excretion → ↓ blood volume → ↓ BP
   • Steady state BP is the set point at which renal fluid output = intake
2. RAAS (chronic volume control via aldosterone)
3. ADH (chronic water retention)

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Renin-Angiotensin-Aldosterone System (RAAS) Mechanism [2.5 marks]

1. ↓ Renal perfusion pressure (sensed by juxtaglomerular cells — intrarenal baroreceptors)
2. ↑ Sympathetic stimulation of JG cells (β₁ receptors)
3. ↓ NaCl delivery to macula densa (tubuloglomerular feedback)
4. Hyponatraemia, hypovolaemia

STIMULUS (↓ BP / ↓ blood volume / ↑ sympathetic)
            ↓
Juxtaglomerular (JG) cells of afferent arteriole
            ↓
     Secrete RENIN (protease enzyme)
            ↓
  Angiotensinogen (α-2 globulin from liver)
            ↓ [Renin cleaves]
     Angiotensin I (10 amino acids — inactive)
            ↓ [ACE — Angiotensin Converting Enzyme]
              (lungs — mainly; also kidney, endothelium)
     Angiotensin II (8 amino acids — ACTIVE)
            ↓
   ┌─────────────────────────────────────┐
   │                                     │
   ▼                                     ▼
Adrenal cortex               Vascular smooth muscle
(Zona Glomerulosa)           AT1 receptors
   ↓                                     ↓
Aldosterone                      Vasoconstriction
   ↓                             ↑ TPR → ↑ BP
Collecting duct:
↑ ENaC expression
↑ Na⁺/K⁺-ATPase
→ Na⁺ + H₂O retention
→ K⁺ + H⁺ excretion
→ ↑ Blood volume → ↑ BP

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Question 14 (OR) — Regulation of Respiration

Neural Centers for Regulation of Respiration [3 marks]

• Location: Nucleus tractus solitarius (NTS), dorsomedial medulla
• Function: Primarily inspiratory neurons; generates basic respiratory rhythm; receives afferents from peripheral chemoreceptors (via CN IX, X) and lung stretch receptors; drives phrenic nerve (inspiration)

• Location: Nucleus ambiguus + nucleus retroambiguus, ventrolateral medulla
• Sub-regions:
  • Pre-Bötzinger complex (rostral VRG): Respiratory rhythm generator — the pacemaker of breathing; generates rhythmic bursts even in isolation
  • Bötzinger complex: Expiratory neurons; inhibit inspiratory neurons
  • Caudal VRG: Active expiratory neurons → drive internal intercostals and abdominals (forced expiration only)
  • Rostral VRG: Inspiratory neurons for accessory muscles and upper airway

• Location: Nucleus parabrachialis and Kölliker-Fuse nucleus, upper pons
• Function: Limits inspiration — sends inhibitory signals to DRG → switches off inspiration → determines respiratory rate and tidal volume; without it, breathing is deeper and slower (apneusis prevented)

• Location: Lower pons
• Function: Stimulates and prolongs inspiration (apneusis = prolonged inspiratory gasp if unchecked); normally inhibited by the pneumotaxic centre and vagal stretch receptor feedback
• Lesion (with vagotomy): Apneustic breathing — prolonged gasping inspirations

• Hypothalamus: Modifies breathing with emotional state, temperature (fever → ↑ RR)
• Cerebral cortex: Voluntary control of breathing (speech, holding breath, forced hyperventilation)
• Limbic system: Emotional influences (anxiety → hyperventilation)

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Inspiratory RAMP Signal [2 marks]

• At the start of each breath, inspiratory neuron firing begins weakly
• Over ~2 seconds (quiet breathing), the firing rate progressively increases
• This produces a smoothly increasing diaphragm contraction → steady lung inflation (rather than a jerky, sudden gasp)
• At the end of inspiration, the signal is abruptly switched off ("off-switch") → passive expiration begins

1. Pneumotaxic center (upper pons) — primary switch-off; limits inspiratory time
2. Pulmonary stretch receptor feedback (via vagus — Hering-Breuer reflex) — secondary switch-off when lungs sufficiently inflated

1. Produces smooth, controlled lung inflation — prevents sudden large pressure changes
2. Allows precise control of tidal volume — the ramp continues until the off-switch fires
3. Respiratory rate is controlled by: (a) how fast the ramp rises, and (b) when the off-switch fires
4. ↑ Pneumotaxic stimulation → off-switch fires earlier → shorter inspiration → ↑ RR, ↓ tidal volume
5. ↓ Pneumotaxic → longer ramp → deeper slower breathing

---

Chemoreceptors for Regulation of Respiration [3 marks]

---

Hering-Breuer Inflation Reflex [2 marks]

• Slowly adapting pulmonary stretch receptors (SARs) — located in the smooth muscle of airways (trachea, bronchi, bronchioles)

1. Lung inflation → stretch of airways → SARs activated → discharge increases progressively with inflation
2. Afferent signals travel via myelinated fibres in the vagus nerve (CN X) to the medulla
3. Signals reach the NTS (DRG) → activate the inspiratory off-switch (pneumotaxic centre also involved)
4. Inhibit inspiratory neurons → inspiration terminates
5. Expiration begins passively

• Lung deflation activates SARs (low firing) → removes inhibition from inspiratory neurons → next inspiration triggered (Hering-Breuer deflation reflex)

1. Sets tidal volume — prevents excessive tidal volume and over-inflation of lungs
2. Sets respiratory rate — by switching off inspiration earlier → shorter inspiratory time → more breaths per minute
3. Prevents pneumothorax (barotrauma) by limiting inspiratory pressure
4. Important in newborns and during anaesthesia (tidal volumes >800 mL in adults trigger this reflex; it is more important in infants where it is active at normal tidal volumes)
5. Vagotomy eliminates this reflex → slow, deep breathing (apneustic pattern with apneustic centre intact)

---

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GROUP A

Sheikh Hasina Medical University, Khulna

1st Professional MBBS — Physiology Paper 1, May 2023

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Question 1

(a) Resting Membrane Potential — Definition & Genesis [1+1.5 marks]

• Neuron: –70 mV
• Skeletal muscle: –90 mV
• Cardiac muscle: –85 to –90 mV
• Smooth muscle: –50 to –60 mV

---

1. K⁺ leak channels (K⁺ dominates RMP):
   • At rest, membrane is 50–100× more permeable to K⁺ than Na⁺ (leak K⁺ channels are open)
   • K⁺ diffuses outward down its concentration gradient → positive charges leave → inside becomes negative
   • This creates an electrical gradient opposing further K⁺ efflux
   • Equilibrium point for K⁺ (Nernst potential) ≈ –94 mV
2. Na⁺ leak (small inward current):
   • Small Na⁺ permeability → Na⁺ leaks inward → slightly depolarizes (makes RMP less negative than K⁺ equilibrium)
   • Nernst potential for Na⁺ ≈ +61 mV
3. Large intracellular anions (A⁻):
   • Large negatively charged proteins and organic phosphates cannot cross the membrane → trapped inside → contribute to intracellular negativity (Gibbs-Donnan equilibrium)
4. Na⁺-K⁺-ATPase pump (electrogenic contribution):
   • Pumps 3 Na⁺ out for every 2 K⁺ in → net export of positive charge → directly contributes approximately –3 to –4 mV to RMP (electrogenic)
   • More importantly, maintains the concentration gradients of Na⁺ and K⁺ that drive the leak currents
   • Without the pump, gradients would dissipate → RMP would collapse

---

(b) Draw and Label Action Potential of a Neuron; Spike Potential [1.5+1 marks]

        +35|          ╭──╮  ← OVERSHOOT (Peak)
           |         /    \
           |        /      \
     mV    |       /        \
           |      /          \
        0  |─────╯            ╲────────────────
           |  ↑                \
           | Threshold          \  REPOLARIZATION
           | (~-55mV)            \      (Phase 3)
      -55  |...........           \
           |                       ╲
      -70  |════════════════════════╲══╮═══════  ← RMP
           |     RMP                   ╲     ↑
      -80  |                            ╰──╯
           |                           AFTER-HYPERPOLARIZATION
           |                           (Undershoot)
           |_____________________________________________
           0    0.5    1.0    1.5    2.0  (milliseconds)

PHASES:
0 = Upstroke/Depolarization (Na⁺ channels open) → 0 to +35mV
1 = Early repolarization (K⁺ efflux begins)
2 = Plateau (absent in neuron; present in cardiac)
3 = Repolarization (K⁺ efflux, Na⁺ channels inactivate)
4 = After-hyperpolarization (K⁺ channels slow to close)

Labels on diagram:
1. Resting membrane potential (–70 mV)
2. Threshold potential (–55 mV)
3. Depolarization (upstroke) — Phase 0
4. Overshoot/Peak (+35 mV)
5. Repolarization — Phase 3
6. After-hyperpolarization (undershoot, –80 mV)
7. Absolute refractory period (during depolarization + early repolarization)
8. Relative refractory period (during after-hyperpolarization)

---

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Question 2

(a) Definition of Action Potential & Differences Between Receptor Potential and Action Potential [1+1.5 marks]

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(b) Draw and Label Cell Membrane Structure; Functions of Membrane Proteins [1.5+1 marks]

EXTRACELLULAR FLUID
         │
    ─────┼────────────────────────────────────────
  ╔══════╧══════╗   Glycoprotein   Glycolipid
  ║  Peripheral ║       │              │
  ║   protein   ║   ╭──┴──╮        ╭──┴──╮
  ╚═════════════╝   │  TM │        │     │
                    │     │        │     │
    ──────────────  │     │  ──────│     │──────
   ░░░░░░░░░░░░░░░  │     │ ░░░░░░░│     │░░░░░
   ░░Phospholipid░  │     │ ░░░░░░░│     │░░░░░ ← Lipid
   ░░ Bilayer    ░  │     │ ░░░░░░░│     │░░░░░   bilayer
   ░░░░░░░░░░░░░░░  │     │ ░░░░░░░│     │░░░░░
    ──────────────  ╰──┬──╯ ──────╰──┬──╯──────
                       │             │
    ════════════════╗  │   Integral  │
    Peripheral      ║  │   (Trans-   │
    protein (inner) ╚══╝   membrane) │
                              protein│
INTRACELLULAR FLUID
         │
    ─────┼────────────────────────────────────────

Key labels:
1. Phospholipid bilayer (hydrophilic heads outside, hydrophobic tails inside)
2. Integral/transmembrane proteins (span full bilayer)
3. Peripheral proteins (attached to surface, not spanning)
4. Glycoproteins (carbohydrate chains on outer surface)
5. Glycolipids (lipid + carbohydrate)
6. Cholesterol (between phospholipids — controls fluidity)
7. Hydrophilic head (phosphate group)
8. Hydrophobic tail (fatty acid chains)

---

1. Transport proteins (channels and carriers):
   • Ion channels (Na⁺, K⁺, Ca²⁺, Cl⁻) — passive transport
   • Carrier proteins (GLUT transporters) — facilitated diffusion
   • Pumps (Na⁺/K⁺-ATPase) — active transport
2. Receptor proteins:
   • Bind hormones, neurotransmitters, growth factors
   • Examples: insulin receptor (tyrosine kinase), β-adrenergic receptor (GPCR), nicotinic ACh receptor (ligand-gated ion channel)
3. Enzymatic proteins:
   • Catalyze reactions at membrane surface
   • Examples: adenylyl cyclase (produces cAMP), ACE (angiotensin converting enzyme), Na⁺/K⁺-ATPase
4. Structural/Anchoring proteins:
   • Link membrane to cytoskeleton (spectrin, ankyrin in RBCs)
   • Maintain cell shape and membrane integrity
5. Cell adhesion molecules (CAMs):
   • Attach cells to each other or extracellular matrix
   • Examples: integrins, cadherins, selectins
6. Identification/Antigen proteins:
   • Cell surface markers — self-recognition, immune identification
   • ABO blood group antigens, MHC (HLA) molecules
7. Signal transduction proteins (G-proteins):
   • Transmit signals from receptor to intracellular effectors
   • Examples: Gs, Gi, Gq proteins coupling receptors to adenylyl cyclase or phospholipase C

---

Question 3

(a) Landsteiner's Law & Why ABO is Called Classic Blood Group [1.5+1 marks]

1. "If an agglutinogen (antigen) is present on the red blood cells, the corresponding agglutinin (antibody) is absent in the plasma."
2. "If an agglutinogen is absent from the red blood cells, the corresponding agglutinin is always present in the plasma."

---

1. First blood group discovered — Karl Landsteiner described it in 1901 (Nobel Prize 1930) — the original/classic system
2. Universal clinical importance — most significant for blood transfusion compatibility; mismatched transfusion is potentially fatal
3. Naturally occurring antibodies (isohemagglutinins) — Anti-A and Anti-B antibodies are present without prior sensitization (exposure to foreign blood) — unlike other blood group antibodies that require sensitization; these arise from exposure to environmental antigens (food, bacteria) with similar structures
4. Landsteiner's law applies strictly — the reciprocal antigen-antibody relationship is absolute in ABO
5. Template for all other blood group systems — established the fundamental principles (antigens, antibodies, compatibility testing) used for all subsequent blood group discoveries (Rh, Kell, Duffy, Kidd, etc.)
6. Genetic determination — ABO antigens are controlled by a single gene locus on chromosome 9 with three alleles (I^A, I^B, i) — a model for co-dominant inheritance
7. Tissue expression — ABO antigens are expressed not just on RBCs but also on platelets, vascular endothelium, epithelial cells, and secretions — making them important beyond just transfusion medicine

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(b) Effects of Mismatched Blood Transfusion & Reason for Kidney Shutdown [1.5+1 marks]

1. Agglutination — donor RBCs clump due to recipient's antibodies binding donor antigens → clumps block capillaries
2. Intravascular haemolysis — complement activation (classical pathway) → membrane attack complex (MAC) → lysis of donor RBCs → release of haemoglobin, haem, and RBC debris into plasma
3. Haemoglobinaemia — free Hb in plasma → haemoglobinuria (red/brown urine)

---

1. Haemoglobin precipitation in renal tubules:
   • Free plasma Hb filtered at glomerulus → in acidic tubular fluid → precipitates as acid haematin crystals → physically blocks renal tubules (tubular obstruction) → back-pressure → ↓ GFR
2. Renal vasoconstriction:
   • Complement-mediated (C3a, C5a) and antigen-antibody complexes → reflex renal arteriolar vasoconstriction → ischaemia of renal cortex → acute tubular necrosis (ATN)
   • ↓ renal blood flow → ↓ GFR → oliguria/anuria
3. Haemoglobin toxicity:
   • Free Hb is directly nephrotoxic to proximal tubular cells → oxidative injury → tubular cell necrosis
   • Free Hb scavenges nitric oxide → renal vasoconstriction
4. DIC:
   • Microthrombi in glomerular capillaries → ↓ filtration surface → ↓ GFR
   • Bilateral renal cortical necrosis in severe DIC
5. Shock-induced renal ischaemia:
   • Systemic hypotension → ↓ renal perfusion pressure → prerenal component → compounding tubular injury

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Question 4

(a) Stimulus for Secretion and Functions of Cholecystokinin (CCK) [1+1.5 marks]

1. Fatty acids and monoglycerides in the duodenum — most potent stimulus (products of fat digestion)
2. Proteins and amino acids (especially phenylalanine, tryptophan, methionine) in duodenum
3. Gastric acid entering duodenum (minor stimulus)
4. Distension of the duodenum (minor)
5. Vagal stimulation (cholinergic — minor)

---

1. Gallbladder contraction — contracts gallbladder smooth muscle → expels bile into duodenum (most important action; CCK = "gallbladder-contracting hormone")
2. Relaxation of sphincter of Oddi — allows bile and pancreatic juice to flow into duodenum
3. Pancreatic enzyme secretion — stimulates acinar cells → secretion of digestive enzymes (lipase, amylase, proteases) — acts synergistically with secretin
4. Inhibition of gastric emptying — contracts pyloric sphincter + inhibits antral motility → slows delivery of chyme into duodenum (allows time for digestion)
5. Augments secretin action — potentiates secretin's stimulation of pancreatic HCO₃⁻ secretion
6. Trophic effect on pancreas — promotes growth and maintenance of pancreatic acinar cells
7. Satiety signal — acts on hypothalamus (via vagal afferents and circulation) → suppresses appetite → reduces food intake
8. Stimulates intestinal motility — increases segmentation in small intestine

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(b) Factors Regulating Gastric Emptying & Law of the Gut [1.5+1 marks]

1. Large volume of gastric content (distension) → ↑ gastric peristalsis
2. Liquid meals empty faster than solid
3. Isotonic solutions empty faster than hyper/hypotonic
4. Carbohydrates empty fastest; then proteins; fats slowest
5. Gastrin (minor) — increases antral peristalsis
6. Motilin — increases gastric motor activity (interdigestive)
7. Erect posture (gravity aids)

1. Fat in duodenum — most powerful inhibitor; via CCK + neural reflex
2. Acid (↓ pH) in duodenum — triggers secretin release → inhibits gastric motility
3. Hyperosmolar solutions in duodenum — osmoreceptors trigger inhibitory reflex
4. Distension of duodenum — stretch receptors → enterogastric reflex (via vagus and intrinsic plexus)
5. Pain, fear, anxiety — sympathetic activation → inhibits gastric motility
6. CCK, Secretin, GIP (Gastric Inhibitory Peptide / GIP) — hormonal inhibition
7. Fatty acids, amino acids in duodenum → enterogastrones
8. Drugs: Anticholinergics, opioids (delay emptying)

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"Local distension of the gut causes contraction above (oral/proximal to) and relaxation below (aboral/distal to) the point of stimulation, resulting in propulsion of contents along the gut."

1. Bolus of food distends the gut wall
2. Sensory (afferent) neurons of Meissner's (submucosal) plexus detect distension
3. Ascending (oral) limb: Interneurons activate excitatory motor neurons → release ACh and substance P → circular muscle contracts → propulsion
4. Descending (aboral) limb: Interneurons activate inhibitory motor neurons → release NO, VIP, ATP → circular muscle relaxes → receptive relaxation
5. Longitudinal muscle contraction above and relaxation below further aids propulsion

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Question 5

(a) Steps and Factors Necessary for Erythropoiesis [1.5+1 marks]

Pluripotent Haematopoietic Stem Cell (PHSC)
        ↓
Common Myeloid Progenitor (CMP)
        ↓
BFU-E (Burst Forming Unit — Erythroid)
        ↓
CFU-E (Colony Forming Unit — Erythroid)
        ↓
PROERYTHROBLAST (Pronormoblast)
    — Largest cell; large nucleus; basophilic cytoplasm; no Hb yet
        ↓
BASOPHILIC ERYTHROBLAST (Early normoblast)
    — Active ribosome synthesis; cytoplasm deeply basophilic; begins Hb synthesis
        ↓
POLYCHROMATOPHILIC ERYTHROBLAST (Intermediate normoblast)
    — ↑ Hb; cytoplasm mixed pink-blue (polychromatic); nucleus shrinking
        ↓
ORTHOCHROMATIC ERYTHROBLAST (Late normoblast)
    — Cytoplasm nearly pink (Hb-rich); nucleus pyknotic (dark, condensed)
        ↓ (nuclear extrusion)
RETICULOCYTE
    — Anucleate; contains residual ribosomal RNA (basophilic stippling on supravital stain)
    — Released into blood; matures in 1–2 days in circulation
        ↓
MATURE ERYTHROCYTE (RBC)
    — Biconcave disc, 7.2 µm; no nucleus/organelles; full Hb content (~34g/dL)

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(b) Neural Regulation of Defecation Reflex [2.5 marks]

• Rectum normally empty; internal anal sphincter (IAS) tonically contracted (sympathetic, L1–L2 via hypogastric nerve)
• External anal sphincter (EAS) tonically contracted (voluntary, pudendal nerve, S2–S4)

• Mass movement (peristalsis) propels faeces into rectum → rectal distension → stretch receptors activated

1. Rectal distension → myenteric plexus activated → short reflex
2. Peristaltic waves spread down sigmoid colon and rectum
3. Rectosphincteric reflex (RAIR): Rectal distension → IAS relaxes transiently (via NO/VIP from myenteric plexus) — allows sampling

1. Afferent signals travel via pelvic nerves (S2–S4) to the sacral defecation center (S2–S4)
2. Parasympathetic outflow (pelvic nerve, S2–S4):
   • Strengthens peristaltic waves in sigmoid colon and rectum
   • Further relaxation of IAS
3. Sympathetic inhibition withdrawn (hypogastric nerve, L1–L2) → IAS relaxes further

• Voluntary contraction of EAS (pudendal nerve activation) → overrides reflex
• Rectum accommodates (receptive relaxation) → urge subsides temporarily

• Cerebral cortex (frontal lobe): Voluntary inhibition/facilitation via corticospinal tracts
• Pontine defecation center: Coordinates defecation (analogous to pontine micturition center)
• In spinal cord injury above S2: Defecation reflex intact but voluntary control lost → reflex (automatic) defecation

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Question 6 — Clinical Case: Pallor, Weakness, Fatigue, Respiratory Distress; Hb 7 g/dL; MCV, MCH, MCHC decreased

(a) Probable Reason for the Report [2.5 marks]

• Hb = 7 g/dL (severely low; normal: male 13.5–17.5, female 12–15.5 g/dL) → anaemia
• MCV decreased → microcytic RBCs (small)
• MCH decreased → hypochromic RBCs (low Hb per cell)
• MCHC decreased → low Hb concentration in each RBC

1. Iron is essential for haem synthesis (Fe²⁺ + protoporphyrin IX → haem; 4 haem + 4 globin → Hb)
2. In iron deficiency: insufficient haem → ↓ Hb synthesis per cell
3. Erythroid precursors undergo extra divisions (because cytoplasmic Hb threshold for division is not reached) → smaller cells (microcytosis)
4. Each cell contains less Hb than normal → hypochromia (pale centre >1/3 of RBC diameter on smear)
5. ↓ Hb per cell (MCH) and ↓ Hb concentration per unit volume of cells (MCHC)

1. Chronic blood loss — most common cause (menorrhagia in females, peptic ulcer, GI malignancy, hookworm infestation)
2. Inadequate dietary intake — poor diet, vegetarian/vegan diet, poverty
3. Malabsorption — coeliac disease, post-gastrectomy (↓ acid → ↓ Fe³⁺ → Fe²⁺ conversion), Crohn's disease
4. Increased demand — pregnancy, lactation, growth spurts in children/adolescents

• Pallor: ↓ Hb → ↓ oxyhaemoglobin (pink colour) in skin, conjunctiva, mucous membranes
• Weakness and fatigue: ↓ O₂ delivery to muscles → anaerobic metabolism → lactic acid → fatigue; also direct iron deficiency in mitochondrial enzymes
• Respiratory distress: ↓ O₂-carrying capacity → tissue hypoxia → compensatory ↑ respiratory rate (hyperventilation) to maximize O₂ uptake

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(b) Significance of MCV, MCH, and MCHC [2.5 marks]

• Definition: Average volume of a single RBC
• Calculation: MCV = Haematocrit (%) × 10 / RBC count (millions/µL) — unit: femtolitres (fL)
• Normal: 80–100 fL

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• Definition: Average weight/mass of Hb in a single RBC
• Calculation: MCH = Hb (g/dL) × 10 / RBC count (millions/µL) — unit: picograms (pg)
• Normal: 27–32 pg

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• Definition: Average concentration of Hb per unit volume of RBCs (Hb density within cells)
• Calculation: MCHC = Hb (g/dL) × 100 / Haematocrit (%) — unit: g/dL or %
• Normal: 32–36 g/dL

• MCHC is the most reliable of the three indices (least affected by cell size)
• Most sensitive indicator of IDA — MCHC falls last as iron stores deplete
• Hereditary spherocytosis is the classic cause of elevated MCHC (spherocytes have less membrane surface relative to volume → concentrated Hb)
• Used with MCV and MCH to complete the morphological classification of anaemia
• Quality control marker: An MCHC >38 g/dL usually indicates a laboratory error or haemolysis

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Question 7 — Cell Membrane Transport

Classify Cell Membrane Transport with Examples [2.5 marks]

CELL MEMBRANE TRANSPORT
         │
    ─────┴─────────────────────────
    │                             │
PASSIVE TRANSPORT            ACTIVE TRANSPORT
(No energy required;         (Energy required;
 down concentration          against concentration
 gradient)                   gradient)
    │                             │
    ├─ Simple Diffusion       ─── Primary Active Transport
    │   e.g. O₂, CO₂,             e.g. Na⁺/K⁺-ATPase,
    │   lipid-soluble drugs,       Ca²⁺-ATPase (SERCA),
    │   ethanol, urea              H⁺/K⁺-ATPase (stomach)
    │
    ├─ Facilitated Diffusion  ─── Secondary Active Transport
    │   (carrier or channel)       │
    │   e.g. GLUT1 (glucose),      ├─ Co-transport (Symport)
    │   AQP (water-aquaporin),     │   e.g. SGLT1/2 (Na⁺-glucose),
    │   ion channels               │   NKCC2 (Na⁺-K⁺-2Cl⁻)
    │                              │
    └─ Osmosis                     └─ Counter-transport (Antiport)
        (water movement                e.g. Na⁺/H⁺ exchanger (NHE3),
         via AQP or lipid)             Na⁺/Ca²⁺ exchanger (NCX)

VESICULAR TRANSPORT
    │
    ├─ Endocytosis (into cell)
    │   ├─ Phagocytosis (large particles; e.g. bacteria by macrophages)
    │   ├─ Pinocytosis (fluid; "cell drinking")
    │   └─ Receptor-mediated endocytosis (e.g. LDL receptor, transferrin)
    │
    └─ Exocytosis (out of cell)
        e.g. neurotransmitter release, insulin secretion, mucus secretion

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Properties of Primary Active Transport [2.5 marks]

1. Energy source: Directly uses ATP hydrolysis (ATP → ADP + Pᵢ + energy) — hence "primary"
2. Direction: Always moves ions against their electrochemical gradient (uphill transport)
3. Carrier protein: Requires a specific ATPase pump protein (e.g., Na⁺/K⁺-ATPase, Ca²⁺-ATPase, H⁺/K⁺-ATPase)
4. Specificity: Highly specific — each pump transports only specific ion(s)
5. Saturable: Has a maximum transport rate (Tmax) when all pump molecules are occupied
6. Inhibitable: Blocked by specific inhibitors:
   • Na⁺/K⁺-ATPase: Ouabain, digoxin (cardiac glycosides)
   • H⁺/K⁺-ATPase: Proton pump inhibitors (omeprazole)
   • Ca²⁺-ATPase: Thapsigargin
7. Electrogenic: Na⁺/K⁺-ATPase transports 3 Na⁺ out and 2 K⁺ in → net export of one positive charge → contributes to negative RMP
8. Temperature-dependent: Rate decreases at low temperatures (enzyme activity ↓)
9. Regulated: Activity modulated by:
   • Intracellular Na⁺ concentration (↑ intracellular Na⁺ → ↑ pump activity)
   • Aldosterone (↑ Na⁺/K⁺-ATPase synthesis in collecting duct)
   • Thyroid hormones (↑ pump number → ↑ BMR)
10. Ubiquitous: Na⁺/K⁺-ATPase present in virtually every cell; accounts for 20–40% of resting cellular energy expenditure

• Na⁺/K⁺-ATPase: 3 Na⁺ out, 2 K⁺ in (most important)
• Ca²⁺-ATPase (SERCA): Ca²⁺ into SR/ER; Ca²⁺ out of cell (plasma membrane Ca²⁺-ATPase, PMCA)
• H⁺/K⁺-ATPase: H⁺ out of parietal cell → gastric acid secretion
• H⁺-ATPase: H⁺ secretion in renal collecting duct (type A intercalated cells)

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Significance of Na⁺-K⁺ Pump [2.5 marks]

• Maintains the concentration gradients (high intracellular K⁺, high extracellular Na⁺) that generate the resting membrane potential (–70 mV)
• Direct electrogenic contribution (3 Na⁺ out, 2 K⁺ in) ≈ –3 to –4 mV
• Without it: gradients dissipate → RMP collapses → cells depolarize → loss of excitability

• Prevents osmotic swelling (see below)

• The Na⁺ gradient created by the pump drives co-transporters and exchangers (SGLT, NHE3, NKCC2, etc.) — Na⁺ entry coupled to glucose, amino acid, Ca²⁺ transport
• All secondary active transport is indirectly powered by the Na⁺/K⁺-ATPase

• Na⁺/K⁺-ATPase on basolateral membrane of renal tubular cells → creates low intracellular Na⁺ → drives Na⁺ entry from tubular lumen → responsible for >99% of Na⁺ reabsorption → blood pressure and volume regulation

• Drives glucose and amino acid absorption from gut (via SGLT1 and Na⁺-amino acid cotransporters)

• Digoxin inhibits the pump → ↑ intracellular Na⁺ → ↓ Na⁺/Ca²⁺ exchange → ↑ intracellular Ca²⁺ → ↑ cardiac contractility (positive inotropy) — basis of digitalis therapy

• Accounts for ~20–40% of basal metabolic rate heat production — important in thermogenesis
• Thyroid hormones upregulate pump → ↑ BMR

• Restores ion gradients after action potentials — essential for repeated firing of neurons and muscle contraction

• Na⁺/H⁺ exchanger (driven by Na⁺ gradient) mediates H⁺ secretion in kidney → HCO₃⁻ reabsorption → acid-base regulation

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How Na⁺-K⁺ Pump Maintains Cell Volume [2.5 marks]

1. Cells contain large amounts of impermeant intracellular solutes (proteins, organic phosphates, large anions) that cannot leave the cell
2. These create an intracellular osmotic pressure that would continuously attract water into the cell → cell swelling → lysis
3. Additionally, Na⁺ continuously leaks inward (down gradient) → ↑ intracellular osmolarity → osmotic water entry

1. Na⁺ pumping (3 Na⁺ out per cycle):
   • Continuously extrudes the Na⁺ that leaks in
   • Na⁺ is kept extracellular → Na⁺ acts as an "excluded osmole" — it is osmotically active outside but effectively excluded from inside
   • This counteracts the osmotic effect of intracellular impermeant anions
2. Net solute extrusion:
   • 3 Na⁺ pumped out vs. 2 K⁺ pumped in = net loss of 1 osmole per cycle from cell
   • Intracellular osmolarity is maintained equal to extracellular (isotonic)
   • Water has no net osmotic driving force → cell volume is stable
3. Electrogenic effect:
   • Net export of positive charge → inside negative → K⁺ (positive) is held inside by electrical gradient
   • This reduces effective intracellular K⁺ osmolarity (K⁺ is electrostatically "captured" — not free to exert full osmotic effect)

• Ouabain (pump inhibitor): Cells swell progressively → cellular oedema → cell death
• Metabolic poisoning (↓ ATP): Same result — pump fails → cell swells
• Cold (4°C): Pump slows → slow swelling; warming restores volume

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Question 7 (OR) — Coagulation

Definition of Clot & Fate of Clot [2.5 marks]

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• Platelets within the clot contain thrombosthenin (actomyosin-like contractile protein)
• Platelets contract → pull fibrin strands together → clot shrinks and becomes denser/firmer
• Serum (plasma minus fibrinogen/clotting factors) is squeezed out
• Brings wound edges closer together → strengthens the seal

• Fibroblasts and endothelial cells from surrounding tissue invade the clot
• Fibroblasts deposit collagen → clot replaced by fibrous tissue (scar)
• In larger vessels: organized clot may partially or fully occlude the lumen (thrombus)

• Plasminogen (inactive) bound within the clot is activated to plasmin by:
  • t-PA (tissue plasminogen activator — from endothelial cells) — most important
  • u-PA (urokinase-type plasminogen activator)
  • Streptokinase (bacterial), staphylokinase
• Plasmin cleaves fibrin → Fibrin Degradation Products (FDPs) including D-dimers
• Clot gradually dissolves → vascular patency restored
• Therapeutic use: t-PA, streptokinase, alteplase used in MI, stroke, PE to lyse clots

• In larger vessel thrombi: channels may form through the organized clot → partial restoration of blood flow

• If clot is not properly anchored or is too large → breaks off → embolus → travels to lung (PE), brain (stroke), or other organs

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Basic Steps of Coagulation [2.5 marks]

1. Vascular injury → subendothelial Tissue Factor (TF/Factor III) exposed
2. TF binds circulating Factor VII → forms TF-VIIa complex
3. TF-VIIa complex activates Factor X → Xa (and also Factor IX → IXa)

1. Exposed collagen activates Factor XII → XIIa (contact activation; also prekallikrein, HMWK)
2. XIIa activates Factor XI → XIa
3. XIa activates Factor IX → IXa
4. IXa + Factor VIIIa (co-factor) + Ca²⁺ + phospholipid (on platelet surface) = "Tenase complex" → activates Factor X → Xa

• Cleaves Fibrinogen (Factor I) → Fibrin monomers
• Fibrin monomers polymerize → loose fibrin polymer (soluble)
• Thrombin activates Factor XIII → XIIIa (transglutaminase)
• Factor XIIIa cross-links fibrin → stable, insoluble fibrin polymer (clot)

1. Thrombin also activates Factors V, VIII, XI (positive feedback amplification) and platelets

EXTRINSIC           INTRINSIC
Injury → TF        XII → XIIa
TF + VII → VIIa    XI  → XIa
          ↓         IX → IXa
         X ← ─────────── IXa + VIIIa (Tenase)
         ↓
        Xa + Va (Prothrombinase)
         ↓
   Prothrombin → THROMBIN
         ↓
   Fibrinogen → Fibrin monomer → [XIIIa] → Cross-linked FIBRIN CLOT

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Why Coagulation is Called a Positive Feedback Mechanism [2.5 marks]

• Thrombin (the key product) activates its own upstream co-factors:
  • Thrombin activates Factor V → Factor Va (accelerates prothrombinase complex → more thrombin)
  • Thrombin activates Factor VIII → Factor VIIIa (accelerates tenase complex → more Factor Xa → more thrombin)
  • Thrombin activates Factor XI → XIa → more Factor IXa → more Xa → more thrombin
• Result: A small initial trigger → exponential amplification → massive thrombin burst

• Thrombin activates platelets → activated platelets release ADP, TXA₂ → recruit and activate more platelets → more phospholipid surface for coagulation → more thrombin generation

• Factor XIIa activates more Factor XII → self-perpetuating contact activation

• Each step activates the next and feeds back to amplify earlier steps
• A tiny amount of initial Factor Xa or thrombin triggers increasingly large amounts of downstream product

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Why Blood Does Not Clot Inside the Cardiovascular System [2.5 marks]

• Intact endothelium is perfectly smooth → platelets do not adhere (no subendothelial collagen or TF exposed)
• No contact activation of Factor XII
• Physical smoothness prevents turbulence-induced activation

• Endothelial cells constitutively synthesize prostacyclin (PGI₂) via cyclooxygenase
• PGI₂ → ↑ cAMP in platelets → potent platelet aggregation inhibitor and vasodilator
• Counteracts thromboxane A₂

• Endothelial NOS (eNOS) constitutively produces NO
• NO → ↑ cGMP in platelets → inhibits platelet activation and aggregation
• Also causes vasodilation

• Endothelial cells express thrombomodulin on their surface
• Thrombomodulin binds thrombin → thrombin-thrombomodulin complex activates Protein C
• Activated Protein C + Protein S (cofactor) → degrades Factor Va and Factor VIIIa → ↓ thrombin generation
• Converts thrombin from pro-coagulant to anticoagulant

• Plasma serine protease inhibitor (serpin)
• Continuously inactivates thrombin, Factors IXa, Xa, XIa, XIIa
• Action is enormously enhanced (1000×) by heparan sulphate on endothelial surface (endogenous heparin-like molecules)
• Basis of therapeutic heparin action

• Released by endothelium
• Inhibits TF-VIIa complex and Factor Xa → blocks extrinsic pathway initiation

• Endothelium releases t-PA → converts plasminogen → plasmin → dissolves any microthrombi that form

• Continuous flowing blood dilutes and washes away any activated clotting factors before they can accumulate to critical concentrations
• Carries activated factors to liver for degradation
• Prevents local concentration required for clot initiation

• Liver removes activated clotting factors, thrombin-antithrombin complexes from circulation

• Normal endothelium carries negative surface charge → repels negatively charged platelets → prevents adhesion

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