(a) Define ischemic heart disease. Enumerate four ischemic syndromes. Discuss the pathogenesis of myocardial infarction. Briefly…

(a) Ischaemic heart disease, myocardial infarction and reperfusion

Ischaemic heart disease is a group of syndromes in which myocardial oxygen supply falls short of demand, in over 90% of cases because of coronary atherosclerotic obstruction.

Four syndromes: angina pectoris (stable, variant or Prinzmetal, and unstable); acute myocardial infarction; chronic ischaemic heart disease with heart failure; and sudden cardiac death.

Pathogenesis of myocardial infarction:

• A vulnerable atheromatous plaque suddenly changes by rupture, fissuring, erosion or intraplaque haemorrhage, often triggered by surges in sympathetic tone, blood pressure or platelet reactivity.
• Exposed subendothelial collagen and tissue factor cause platelet adhesion (via von Willebrand factor), activation and aggregation (thromboxane A2, ADP), and activate the coagulation cascade, forming an occlusive thrombus; local vasospasm adds to the obstruction.
• Within seconds aerobic metabolism stops, contractility is lost and glycogen is depleted. Injury is reversible for about 20–30 minutes; after that, coagulative necrosis spreads from the subendocardium to the epicardium over 3–6 hours and becomes transmural by about 6–12 hours.

Reperfusion modification: early reperfusion (thrombolysis, primary angioplasty) salvages viable myocytes and limits infarct size. The infarct is altered: it is often haemorrhagic, shows contraction-band necrosis from calcium overload, and enzymes such as CK-MB and troponin wash out earlier and peak sooner. Reperfusion injury arises from oxygen free radicals, calcium overload, neutrophil plugging and microvascular damage ("no reflow"). Stunned myocardium and reperfusion arrhythmias may follow.

(b) Methotrexate and furosemide

(i) Methotrexate (dihydrofolate reductase inhibitor):

• Indications: acute lymphoblastic leukaemia, choriocarcinoma, osteosarcoma (high dose with leucovorin rescue), lymphomas and breast cancer; also rheumatoid arthritis, psoriasis, ectopic pregnancy and medical termination of pregnancy.
• Interactions: NSAIDs, salicylates, probenecid and penicillins reduce its renal tubular secretion and raise toxicity; co-trimoxazole (trimethoprim) adds antifolate marrow suppression; leucovorin reverses its effect.
• Side effects: myelosuppression, mucositis, hepatotoxicity and fibrosis, pneumonitis, nephrotoxicity at high dose and teratogenicity.

(ii) Furosemide (loop diuretic, inhibits Na+–K+–2Cl− cotransporter in the thick ascending limb):

• Indications: acute pulmonary oedema, heart failure, nephrotic and cirrhotic oedema, renal failure, hypertension with renal impairment, hypercalcaemia and hyperkalaemia.
• Interactions: aminoglycosides and cisplatin (ototoxicity, nephrotoxicity); NSAIDs blunt diuresis; hypokalaemia potentiates digoxin; reduces lithium clearance.
• Side effects: hypokalaemia, hyponatraemia, hypomagnesaemia, metabolic alkalosis, hypovolaemia, hyperuricaemia, hyperglycaemia and ototoxicity.

(c)(i) CD4 count and viral load in HIV infection

CD4 count: reflects immune status and the risk of opportunistic infection (below 200 cells/µL is severe). Under NACO guidelines (2021) it no longer decides when to start ART, since treatment starts for all as early as possible, but it is used at baseline to find advanced disease, to start cotrimoxazole prophylaxis (CD4 below 200 or WHO stage 3–4, stopped after CD4 stays above 200 for 3 months on ART), and to follow immune recovery on treatment.

Viral load (plasma HIV-1 RNA): reflects replication and predicts progression and transmissibility; it is the preferred test to monitor ART response. NACO does it at 6 months after starting ART and then regularly. Treatment failure means two consecutive values of 1,000 copies/mL or more after adherence counselling. A suppressed load also makes sexual transmission negligible and guides mother-to-child transmission risk. CD4 count falling is a late sign of failure, whereas rising viral load comes first.

(c)(ii) Antigenic structure of Salmonella Typhi and diagnosis

Antigens: somatic O antigen (lipopolysaccharide, heat-stable and alcohol-stable; factors 9 and 12, group D); flagellar H antigen (protein flagellin, phase 1 "d"; heat-labile); and Vi capsular polysaccharide antigen (heat-labile; a virulence factor that can mask O antigen).

Diagnosis: blood culture is the best test in the first week; later bone marrow, stool and urine cultures. Widal test measures O and H agglutinins: rising titre in paired sera over 1–2 weeks, or a single titre above the local baseline (commonly 1:160), supports diagnosis. Anti-O rises early and falls; anti-H rises later and persists, and is raised after vaccination or past infection. Vi antibody is not useful in acute disease but is detected in chronic carriers (gallbladder carriage), so Vi serology, along with stool or bile culture, is used for carrier screening. In Vi-bearing strains, O agglutination appears only after boiling the suspension to remove the Vi antigen.