Free preclinical SBA questions for first and second years

B. Raised capillary hydrostatic pressure

Distended neck veins and a tender, congested liver in a man with severe COPD indicate right heart failure secondary to lung disease. The failing right ventricle cannot keep pace with venous return, so systemic venous pressure rises and is transmitted back to the capillaries. Raised capillary hydrostatic pressure makes filtration outstrip reabsorption and lymphatic drainage, and a protein-poor transudate collects in dependent tissues such as the legs, where it pits. Low oncotic pressure and leaky capillaries cause oedema by different routes, in hypoalbuminaemia and inflammation respectively. Takeaway: Heart failure causes oedema mainly by raising venous, and so capillary hydrostatic, pressure.

E. Ergosterol binding that opens membrane pores

Amphotericin B is a polyene. It inserts into the fungal membrane and binds ergosterol, several molecules assembling into a channel through which potassium and other small ions leak out. The membrane loses its barrier function and the cell dies, so the drug is fungicidal. Human membranes contain cholesterol rather than ergosterol, but the selectivity is imperfect, which explains infusion reactions, renal tubular potassium and magnesium loss and impaired urinary concentration. Azoles also target ergosterol, but by preventing its synthesis rather than binding it. Takeaway: amphotericin B binds membrane ergosterol and forms pores that kill the fungus.

A. Robertsonian translocation

A Robertsonian translocation joins the long arms of two acrocentric chromosomes (13, 14, 15, 21 or 22) at or near their centromeres. The short arms carry ribosomal RNA genes repeated on the other acrocentrics, so their loss is harmless, and a balanced carrier is healthy but has 45 chromosomes. If the mother passes on the fused chromosome, commonly 14;21, together with a normal 21, her child has 46 chromosomes but three copies of 21q, giving translocation Down syndrome. Reciprocal translocations and inversions keep the count at 46. Takeaway: A healthy person with 45 chromosomes most likely carries a balanced Robertsonian translocation.

A. Hippocampal CA1 pyramidal neurons

Neurons differ in their sensitivity to global ischaemia. The most vulnerable are the pyramidal neurons of the hippocampal CA1 sector (Sommer sector), together with cerebellar Purkinje cells and pyramidal neurons in neocortical layers 3, 5 and 6. This vulnerability is linked to heavy glutamatergic input: during ischaemia, excess glutamate opens NMDA receptors, calcium floods in and activates destructive enzymes. Bilateral CA1 loss after a cardiac arrest leaves a dense anterograde amnesia while other functions recover. Purkinje cell loss would show as ataxia instead, and mammillary body damage is the lesion of thiamine deficiency. Takeaway: Hippocampal CA1 pyramidal neurons are the most vulnerable to global ischaemia, so cardiac arrest survivors may be left amnesic.

E. Less 7-dehydrocholesterol in the skin

Vitamin D3 is made in the skin when ultraviolet B light converts 7-dehydrocholesterol in the epidermis to previtamin D3, which then isomerises to cholecalciferol. The liver converts it to 25-hydroxyvitamin D, the circulating store that reflects vitamin D status, and the kidney then makes the active 1,25-dihydroxyvitamin D. Ageing skin contains much less 7-dehydrocholesterol, so the same sun exposure produces substantially less vitamin D3 in an older person than in a young adult. Reduced renal 1-alpha-hydroxylase is also an age-related change, but it lowers the active hormone, not the 25-hydroxy form measured here.

Takeaway: Older skin has less 7-dehydrocholesterol, so it makes less vitamin D from sunlight.

C. End arteries without anastomoses

Thrombus from the fibrillating left atrium can embolise to the kidney and block an interlobar or arcuate branch. Renal arterial branches are functional end arteries with no useful anastomoses, so the whole territory beyond the block dies. Because the branches fan out from the hilum, the dead zone is a wedge with its apex at the occluded vessel and its base at the capsule. The solid parenchyma limits seepage of blood into the dead area, so the infarct is pale, as in the heart and spleen. Organs with a dual supply, such as the lung, infarct less readily and bleed into dead tissue. Takeaway: End-arterial organs such as the kidney form pale, wedge-shaped infarcts.

A. Histological grade

Grade is the pathologist's assessment of how closely a tumour resembles its tissue of origin, judged from differentiation, nuclear atypia and mitotic activity. A colonic adenocarcinoma that forms few glands and bears little resemblance to normal epithelium is poorly differentiated, or high grade. Stage is a different measure: it describes the extent of spread, recorded as T for invasion by the primary tumour, N for lymph nodes and M for distant metastases. For most carcinomas, stage predicts outcome better than grade. Takeaway: Grade describes differentiation, while stage describes spread.

B. Oestradiol

As the dominant follicle grows, its granulosa cells secrete rising amounts of oestradiol, which peaks just before the LH surge. Oestradiol acts on the endocervical glands to produce copious, watery, stretchy mucus whose aligned glycoprotein strands help sperm swim through. After ovulation, progesterone from the corpus luteum reverses this, making the mucus thick, sticky and scant, so the fertile mucus disappears within a day or two. LH and FSH act on the ovary rather than the cervix, so any effect they have on mucus is indirect, through the steroids they stimulate.

Takeaway: Pre-ovulatory oestradiol makes cervical mucus clear and stretchy; progesterone thickens it.

E. Chloride influx

Diazepam is a benzodiazepine that binds an allosteric site on the GABA-A receptor, a pentameric ligand-gated chloride channel. It does not open the channel itself but increases the frequency of opening when GABA is bound. The resulting chloride influx hyperpolarises the neurone and moves it away from threshold, which produces anxiolysis, sedation, muscle relaxation and anticonvulsant effects. Takeaway: Benzodiazepines enhance GABA-A chloride influx, which hyperpolarises neurones and reduces their excitability.

C. Costimulatory signalling through CD28

A resting T cell needs two signals. The first is its receptor reading antigenic peptide presented on MHC, and the second is CD28 on the T cell binding CD80 or CD86 on the antigen-presenting cell. Without the second signal the cell becomes anergic. Abatacept is the extracellular domain of CTLA-4 fused to immunoglobulin Fc, and because CTLA-4 binds CD80 and CD86 far more avidly than CD28 does, it outcompetes CD28 and denies that costimulation. Interleukin-2 receptor blockade is the tempting alternative, but it acts after activation rather than at the synapse.

Takeaway: Abatacept is a CTLA-4 fusion protein that outcompetes CD28 for CD80 and CD86, denying T cells their costimulatory second signal.