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PBQs Paper – I: Complete Explanations

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2023 Jan — Problem I

Case: 12-year-old boy, post-injection shock

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Q1a. Mechanism of Shock Involved [Microbiology] — 3 marks

1. Sensitization phase: Prior exposure to the injected antigen (drug/vaccine) causes IgE antibodies to form, which bind to mast cells and basophils via Fc receptors.
2. Re-exposure (this case): The antigen cross-links IgE on mast cells → triggers degranulation → massive release of:
   • Histamine → vasodilation + increased vascular permeability
   • Leukotrienes (LTC4, LTD4) → bronchospasm (wheezes), increased mucus
   • Prostaglandins → vasodilation, pain
   • PAF (platelet-activating factor) → platelet aggregation, bronchoconstriction
3. Result: Massive vasodilation → drop in peripheral resistance → distributive shock (warm skin initially, then cold/clammy), hypotension, tachycardia, bronchospasm, urticaria.

The hallmark is IgE-mediated mast cell degranulation causing systemic vasodilation and bronchospasm.

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Q1b. Appropriate Route + All Routes of Drug Administration [Pharmacology] — 1+2 = 3 marks

• Patient is unconscious → cannot take oral drugs
• Shock state → poor tissue perfusion, so IM/SC absorption unreliable
• IV gives immediate, 100% bioavailable action (epinephrine, IV fluids, corticosteroids)

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Q1c. Etiopathogenesis of Shock [Pathology] — 4 marks

1. Initial/Compensated stage: SNS activation → tachycardia, vasoconstriction, ↑ RR → maintain BP; kidneys conserve water (ADH, RAAS activation)
2. Progressive stage: Compensatory mechanisms fail; tissue hypoxia → anaerobic metabolism → lactic acidosis; widespread cell injury
3. Irreversible stage: Multiple organ failure (MODS) — renal failure (oliguria), ARDS, DIC, liver failure; death inevitable

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2023 Jan — Problem II

Case: 44-year-old woman's child — short stature, flat facies, intellectual disability, hearing defect → Down Syndrome (Trisomy 21)

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Q2a. Chromosomal Defects of Down Syndrome [Anatomy] — 4 marks

1. Non-disjunction (95% of cases):
   • During meiosis I or II, chromosome 21 pair fails to separate properly
   • One gamete gets 2 copies of chr 21; fertilization → 3 copies
   • Maternal age is the key risk factor (age 36 in this case is relevant): At age 35–40, risk ~1/300; at >45, risk ~1/25
   • Mother in this case had her child at 36 — increased risk
2. Robertsonian Translocation (4%):
   • Chr 21 fuses to another acrocentric chromosome (usually chr 14) → 46 chromosomes total but extra chr 21 material
   • Can be inherited (carrier parent) — independent of maternal age
   • Karyotype: 46,XX/XY der(14;21)(q10;q10)
3. Mosaicism (1%):
   • Non-disjunction occurs after fertilization → some cells normal, some trisomic
   • Milder phenotype

• Flat facial profile, epicanthal folds, upslanting palpebral fissures
• Short stature, brachycephaly
• Intellectual disability (cognitive deficiency)
• Hearing defects (common — conductive + sensorineural)
• Congenital heart defects (endocardial cushion defects most common)
• Transverse palmar (simian) crease

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Q2b. Types of Genetic Mutation [Biochemistry] — 3 marks

• Missense mutation: One base changed → different amino acid (e.g., sickle cell disease: GAG→GTG, Glu→Val)
• Nonsense mutation: Codon changed to a STOP codon → truncated, nonfunctional protein (e.g., some β-thalassaemias)
• Silent mutation: Base change but same amino acid coded (degenerate code) — no effect

• Insertions/Deletions: Addition or removal of one or more bases (not in multiples of 3) → reading frame shifted → garbled protein downstream
• Example: Duchenne Muscular Dystrophy (deletion in dystrophin gene)

• Repetitive sequences (e.g., CAG, CGG) expand abnormally
• Examples: Huntington disease (CAG repeats in HTT gene), Fragile X syndrome (CGG repeats)

• Deletions, inversions, translocations, duplications of chromosomal segments
• Example: Cri-du-chat (deletion of chr 5p), Down syndrome translocation

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Q2c. Factors Affecting Growth and Development in a Child [Physiology] — 3 marks

• Determines height potential, growth plate activity, hormone sensitivity
• Chromosomal abnormalities (like trisomy 21) cause short stature by altering cell division and organ development

• Growth Hormone (GH): Primary driver of postnatal linear growth; stimulates IGF-1 from liver
• Thyroid hormones (T3/T4): Essential for CNS maturation and skeletal growth — hypothyroidism causes cretinism
• Insulin: Anabolic; important for fetal growth
• Sex hormones (puberty): Androgen/estrogen drive pubertal growth spurt; estrogens close epiphyseal plates

• Adequate protein (amino acids for IGF-1 synthesis), calories, micronutrients
• Deficiency of zinc, vitamin D, iodine impairs growth
• Malnutrition → failure to thrive, stunting

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2021 Aug — Problem I

Case: Mr. Ram — ruptured appendix → peritonitis; HR 110, T 99°F, BP 90/40, RR 30, urine output 150 mL/day → Septic Shock with Peritonitis

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Q3a. Kirby-Bauer Disk Diffusion Method [Microbiology] — 3 marks

1. Isolate the organism from pus/blood culture of the patient
2. Prepare inoculum: Adjust bacterial suspension to 0.5 McFarland standard (1.5 × 10⁸ CFU/mL)
3. Inoculate plate: Swab the suspension uniformly over a Mueller-Hinton agar plate (standard medium)
4. Apply antibiotic discs: Place paper discs impregnated with specific antibiotics (standard concentrations) on the agar surface — space them ≥24 mm apart
5. Incubate: 37°C for 18–24 hours (aerobic incubation)
6. Read results: Measure the zone of inhibition (clear area around each disc in mm) with a ruler/caliper
7. Interpret using CLSI/EUCAST breakpoints:
   • Sensitive (S): Large zone → organism inhibited → use this antibiotic ✓
   • Intermediate (I): Moderate zone → may work at higher dose
   • Resistant (R): Small/no zone → organism not inhibited → do NOT use

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Q3b. Chemical Mediators and Their Role in Acute Inflammation [Pathology] — 4 marks

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Q3c. IV Normal Saline Distribution Through Body Fluid Compartments + % Extracellular Fluid [Physiology] — 2+1 marks

• Of 1 litre infused:
  • ~750 mL (75%) → Interstitial fluid
  • ~250 mL (25%) → Plasma (intravascular)
  • 0 mL → Intracellular fluid (NaCl cannot freely cross cell membrane)

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2021 Aug — Problem II (partial — beginning visible)

Case: Post-dated pregnancy, obstructed labor, Emergency LSCS (Lower Segment Cesarean Section)

• Anatomy of the uterine lower segment / pelvic anatomy
• Pharmacology of uterotonic agents or anaesthesia
• Physiology of labor / fetal circulation

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Quick Summary Table

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Clinical Case: Post-dated Pregnancy → LSCS → Down Syndrome Baby + BCG Vaccine

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Question 1: Characteristic Features of a Down Syndrome Baby

A. Craniofacial Features

B. Limb and Skeletal Features

• Short stature — generalized growth retardation
• Short, broad hands with stubby fingers
• Clinodactyly of 5th digit — inward curving of little finger
• Transverse palmar crease (Simian crease) — single crease across the palm (normal has two)
• Wide gap between 1st and 2nd toes ("sandal gap")
• Hypotonia — generalized poor muscle tone ("floppy baby"); contributes to feeding difficulties

C. Internal/Systemic Features

• Congenital heart defects (~50%) — most common: endocardial cushion defect (AV septal defect), VSD, ASD
• Gastrointestinal abnormalities — duodenal atresia ("double bubble" on X-ray), Hirschsprung disease, umbilical hernia
• Hearing defects — both conductive (recurrent otitis media) and sensorineural; as seen in this case
• Visual problems — refractive errors, strabismus, cataracts

D. Neurological/Developmental

• Intellectual disability (cognitive deficiency) — IQ typically 25–50; moderate to severe
• Delayed milestones — motor, speech, social development all delayed
• Increased risk of Alzheimer disease in adulthood (chromosome 21 carries APP gene)

E. Immunological (relevant to BCG vaccine)

• Impaired immunity — BCG (live attenuated vaccine) is given to neonates in Nepal for TB protection
• Down syndrome children have relatively intact immune function at birth; BCG is safe and routinely given
• However, they are more susceptible to infections (recurrent respiratory infections, otitis media) due to structural abnormalities and mild immune dysregulation

Maternal Age and Incidence

• Age 35: 1 in 350
• Age 39: 1 in 140
• Age 43: 1 in 50 (The Developing Human: Clinically Oriented Embryology, Table 20.3)

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Question 2: Role of Histone Proteins in Gene Expression

A. Structure of Histones and the Nucleosome

• Histone octamer = 2 copies each of H2A, H2B, H3, H4
• ~147 base pairs of DNA wrapped around the octamer (1.75 superhelical turns)
• Histone H1 (linker histone) sits outside, binds the entry and exit DNA, stabilizing the "beads-on-a-string" structure
• Nucleosomes are connected by linker DNA (20–60 bp spacers)

B. Histones Regulate Gene Expression via Chromatin Accessibility

C. Histone Code — Posttranslational Modifications (PTMs)

D. Epigenetics and Inheritance

E. Clinical Relevance

• HDAC inhibitors (vorinostat, romidepsin) are used in cancer — reactivate silenced tumor suppressor genes
• In Down syndrome itself, trisomy 21 causes epigenetic dysregulation affecting gene expression across multiple chromosomes

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Question 3: Definition of Pharmacogenetics + Clinical Significance

A. Definition

Pharmacogenetics is the study of the genetic basis for variation in drug response — how inherited differences in genes cause individuals to respond differently to the same drug at the same dose.

• Pharmacogenetics = variation in a single gene influencing drug response
• Pharmacogenomics = the sum total of all relevant genetic variation determining drug behavior (multiple genes, genome-wide approach) (Thompson & Thompson: "pharmacogenetics referred to variations in a single gene influencing drug response and pharmacogenomics referred to the sum total of all relevant genetic variation that determine drug behavior")

B. How Genetic Variation Affects Drug Response

• Variants in drug-metabolizing enzymes (especially cytochrome P450s)
• CYP2D6, CYP2C9, CYP2C19, CYP3A4/5 — together metabolize 75–80% of all drugs
• Metabolizer phenotypes:

• Variants in drug targets (receptors, ion channels)
• Variants in immune response genes (HLA alleles)

C. Clinical Significance (Short Note)

• G6PD deficiency → antimalarials (primaquine), sulfonamides cause hemolytic anemia — screen before prescribing
• Malignant hyperthermia → succinylcholine/volatile anaesthetics in RYR1 gene variants → life-threatening
• HLA-B*5701 → abacavir (HIV drug) causes fatal hypersensitivity — test before prescribing (now mandatory)
• HLA-B*1502 → carbamazepine causes Stevens-Johnson syndrome in Southeast Asian populations

• Isoniazid (TB treatment): Slow acetylators (NAT2 deficiency) → drug accumulates → peripheral neuropathy; fast acetylators → drug rapidly inactivated → treatment failure
• Clopidogrel (antiplatelet): CYP2C19 poor metabolizers cannot convert the prodrug to active form → no antiplatelet effect → increased MI/stroke risk

• Oncology: HER2 overexpression → trastuzumab (Herceptin) works; test before use
• KRAS mutation testing → if mutated, anti-EGFR drugs (cetuximab) won't work in colorectal cancer

• Warfarin dosing guided by CYP2C9 (metabolism) and VKORC1 (target gene) genotypes
• Reduces bleeding complications and time to stable anticoagulation

• Pharmacogenomic data helps design drugs targeting specific genetic subtypes
• Reduces trial size by enriching for responders

Summary Diagram

Genetic Variation (SNP, CNV, mutation)
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Affects: Enzymes (CYP450) | Transporters | Receptors | HLA
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→ Altered Pharmacokinetics → Drug toxicity OR treatment failure
→ Altered Pharmacodynamics → Unexpected drug effects
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Clinical Application: Dose adjustment | Drug selection | Avoid ADRs

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Quick Revision Table