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					                                    CLINICAL SCIENCES
1- A 40-year-old man presents with a purpuric         Assuming a population carrier frequency of 1
rash on his lower limbs. You request                  in 25, what is the chance of her having an
cryoglobulin screening. The report indicates a        affected child?
moderate amount of a mixed cryoglobulin,
having both a monoclonal and a polyclonal               A     1 in 10
component. With what are these typically                B     1 in 50
associated?                                             C     1 in 100
                                                        D     1 in 150
  A     Hepatitis B                                     E     1 in 200
  B     Hepatitis C
  C     Chronic lymphocytic leukaemia                   Your patient would have a 2 in 3 chance of
  D     Chronic myeloid leukaemia                       being a carrier, as she is not affected herself (the
  E     Active SLE                                      history of asthma is coincidental). Her partner
                                                        would have a 1 in 25 chance of being a carrier.
The cryoglobulin associated with hepatitis C            The chance of having an affected child if both
typically contains a monoclonal IgMk with               are carriers is 1 in 4. Therefore the overall
rheumatoid factor activity that binds to polyclonal     chance is 2/3 × 1/25 × 1/4 = 1/150.
IgG, hence the term ‘mixed cryoglobulin’. The           The commonest mistake (which also applies to
cryoglobulin in CLL usually represents the              other autosomal-recessive diseases) is to assume
monoclonal protein produced by the malignant            that her chance of being a carrier is 1 in 2, on
lymphocyte clone. The cryoglobulin in hepatitis B       the premise that there is a 1 in 4 chance of being
and lupus reflects the immune complexes in the          affected, 1 in 4 of not being a carrier and a 1 in
condition and is typically small and polyclonal.        2 chance of being a carrier. As she is not
Cryoglobulins are not associated with CML.              affected, the chance of being a carrier is in fact
                                                        2 in 3 and the chance of not being a carrier is 1
2- In a patient developing anaphylaxis, which of        in 3.
the following is true?
                                                      4- In a parallel group trial, which of the
  A    May be exacerbated by exercise                 following claims for randomisation is the most
  B    Involves leukotriene A4                        appropriate?
  C    Initial symptoms include a sensation of
  coldness                                              A     It guarantees that all variables are well
  D    20% of fatalities are due to respiratory         balanced across the treatment groups prior to
  complications                                         treatment
  E    Less than 10% of patients have a                 B     Any differences in response found
  second episode within 24 hours                        between the treatment groups must be due to
                                                        the treatments rather than chance
Anaphylaxis can be associated with leukotrienes         C     It prevents systematic differences
B4, C4, D4 and E4. The first three are the              between the treatment groups at baseline
mediators that make up the slow-reacting                D     It results in a simplified analysis of the
substance of anaphylaxis (SRSA). Flushing,              trial
warmth and tingling are typical initial symptoms.       E     It ensures that an equal number of
At least 50% of fatalities are due to respiratory       patients receive each treatment
complications, and more than 20% of patients will
have a second episode within 8 hours.                 The purpose of randomisation is to prevent
                                                      systematic differences between treatment groups,
3- A 25-year-old woman is referred to you for         so option C is the correct answer. Although we
treatment of her asthma. She is otherwise well        will often get good balance across the treatment
and there is no significant previous medical          groups, unfortunately randomisation does not
history. During the consultation it transpires        guarantee this, so option A is incorrect. Even if
that her sister died of cystic fibrosis and she is    randomisation is undertaken in a trial, this does
worried about having a child affected with the        not guarantee that differences in response found
same disease. Her chest X-ray is normal.              between the treatment groups must be due to the
treatment. We may still be unlucky and find a            B     Intravenous infusion of isotonic saline
false-positive result, so B is incorrect. We may         C     Oral demeclocycline
hope that randomisation leads to a simplified            D     Oral frusemide
analysis of the trial compared to any other option       E     Restriction of water intake
but it is not the primary objective, so D would not
be the answer of choice. Finally, randomisation        Restriction of water intake is the treatment of
can be used to ensure an equal number of patients      choice for asymptomatic, hyponatraemic patients
receive each treatment; however, in some trials we     with SIADH: if the water intake is less than the
will deliberately wish to have a randomisation         water output, the plasma sodium concentration
ratio such as 3:2, so randomisation does not imply     will increase. If patients are symptomatic, then
equal numbers on each treatment and E is               hypertonic saline may be appropriate, but it should
incorrect.                                             always be given cautiously; frusemide is
                                                       sometimes given at the same time.
5- In an age-/sex-matched, case-control study,         Demeclocycline can also be used, but is
20 children with chronic asthma were                   potentially nephrotoxic. Neither isotonic saline nor
compared with 20 controls from the same                frusemide on its own are appropriate.
general practice. Their birthweights were
compared using a paired t-test. This showed            7- In a randomised controlled trial of
that the controls were 150 g heavier with a            treatments for heart failure in which the
standard error of 100 g. Which is the most             primary end-point is death, which is the most
appropriate conclusion?                                important of the following?

  A     A lower birthweight causes an                    A      To have an independent Data
  increased incidence of asthma                          Monitoring and Ethics Committee to review
  B     Birthweight is not associated with the           the data as it accumulates
  subsequent development of asthma                       B      For the trial statistician to examine the
  C     There is a statistically significant             data whenever a death occurs and stop the
  association (P < 0.05) between low                     trial as soon as the log rank test shows P <
  birthweight and the development of asthma              0.05
  D     There is insufficient evidence to                C      To have a clearly defined set of rules
  conclude whether or not birthweight affects            for a sequential analysis of the data, and only
  the development of asthma                              to stop the trial if it is indicated by this
  E     The study design is inappropriate                analysis
                                                         D      The Trial Steering Committee should
The fairly negative option D is the most                 be kept aware of the results throughout the
appropriate conclusion. From association in an           trial
observational study, we cannot infer cause and           E      To ensure that all patients have a
effect, so option A must be wrong. Statement B is        minimum of 3 months’ follow-up before
stronger than the study justifies. The fact that a       inclusion in the analysis
significant association has not been shown in this
study does not imply that in a larger study an         Option B is a classical mistake to make where the
association might not be found. Option C is            data is tested repeatedly without taking into
incorrect as the ratio of the difference in weights,   account the multiple testing of the data that is
divided by its standard error, is only 1.5, and        implied. Option C gets round this problem, but to
therefore P > 0.05. Finally, the study design would    suggest that the trial would only be stopped on this
be perfectly reasonable for the purpose and            basis is inappropriate as other factors, such as
therefore option E is incorrect                        intolerable adverse effects of treatment, would also
                                                       need to be considered, as would results from other
6- Which of the following is the initial               newly published studies. It is considered good
treatment of choice for the hyponatraemia in           practice for the Trial Steering Committee to be
the majority of patients with the syndrome of          unaware of the results as the trial progresses, and
inappropriate [secretion of] ADH (antidiuretic         therefore D is wrong. Option E sounds plausible
hormone, vasopressin)?                                 but is an unusual restriction and is indeed
                                                       undesirable. Many patients may die within the first
  A      Intravenous infusion of hypertonic            3 months of treatment and therefore this option
  saline                                               would be inappropriate.
                                                           surface dries to form a scab. Platelets and
8- Immunological investigations in a patient               macrophage factors cause local vasodilatation,
with renal disease are important in the                    which produces warmth and increases capillary
diagnostic work-up, which of the following                 permeability, allowing serum and white blood
statements is correct?                                     cells to accumulate and cause swelling.
                                                           After the initial acute inflammation,
  A     Henoch–Schonlein purpura is                        macrophages become active as the main agents
  associated with IgG in the mesangium                     of demolition, removing unwanted fibrin, dead
  B     SLE is typically associated with sparse            cells and bacteria and creating fluid-filled
  deposits of IgG and complement in the                    spaces for granulation tissue. Macrophages also
  glomeruli                                                release factors that stimulate the formation of
  C     C3 nephritic factor is associated with             new capillary buds during this phase, and later
  mesangiocapillary glomerulonephritis type I              they initiate and control fibroblast activity
  D     Minimal-change glomerulonephritis is               during repair. Within the connective tissue,
  associated with hypocomplementaemia                      randomly orientated collagen begins to form
  E     Antiglomerular basement-membrane                   after a few days, reaching a peak of activity
  antibodies are associated with Goodpasture’s             after 5–7 days.
  disease                                                  Epithelial cells at the edge of the wound start to
                                                           proliferate after 24 h and this phase can last for
Minimal-change glomerulonephritis is not                   up to 3 weeks.
associated with complement activation. C3                  Finally, the phase of maturation and
nephritic factor is associated with                        remodelling lasts for up to 12 months, during
mesangiocapillary glomerulonephritis type 2, not           which time the tensile strength of the wound
type 1. SLE nephritis is an immune complex                 increases and the random collagen is replaced
problem; hence deposits of IgG and complement              by a more stable form orientated along lines of
are prolific. Henoch–Schonlein purpura is                  stress.
typically associated with IgA in the mesangium.
Hence immunological examination of both a blood          10- Which of the following features applies to
and renal biopsy will help to define the underlying      acetylcholine-mediated transmission at the
process.                                                 motor endplate?

9- You are asked to see a patient who had a                A      The synaptic fusion complex is made of
chest drain removed 4 days ago. There appears              synaptobrevin, syntaxin and synaptosome-
to be some infection. What are the stages in the           associated protein
cell biology of normal wound healing?                      B      Syntaxin forms a SNAP complex,
                                                           together with NSF, Ca2+ and other proteins
  A     Demolition is the first phase                      C      Tetanus toxin (TeNT) cleaves specific
  B     Maturation and remodelling can                     sites of SNAP-25
  continue for up to a year                                D      Botulinum toxin type B (BoNT/B)
  C     Acute inflammation usually lasts for 6–            cleaves syntaxin
  12 hours                                                 E      Botulinum toxin type A (BoNT/A)
  D     Epithelial cell proliferation is the               cleaves specific sites of synaptobrevin
  hallmark of the demolition phase                         (VAMP)
  E     Collagen deposition is the key process
  during demolition                                      The synaptic fusion complex is made up of
                                                         synaptobrevin, syntaxin and synaptosome-
  The first phase in healing by first intention is the   associated protein (SNAP-25). The fusion
  phase of acute inflammation that lasts up to 3         complex serves to join the membranes of an
  days, if uncomplicated. The initiating factor          acetylcholine vesicle and nerve cell.
  appears to originate from platelets activated by       Synaptobrevin forms a SNAP complex, together
  mature collagen exposed in the wound. Platelets        with NSF, Ca2+ and other proteins. Botulinum
  first aggregate then release a variety of active       toxin type A (BoNT/A) and E (BoNT/E) cleave
  agents including lysosomal enzymes, ATP,               specific sites of SNAP-25, eg BoNT/A recognises
  serotonin and wound cytokines. A fibrin clot           Glu–Ala–Asn–Gln.Botulinum toxin type C
  develops, which completes haemostasis and              (BoNT/C) cleaves syntaxin. BoNT/B, D, F, G and
  provides strength and support to the wound. The        tetanus toxin (TeNT) cleave specific sites of
synaptobrevin (VAMP).                                    gene methylation.
                                                         Both Angelman’s and Prader–Willi syndromes
11- The primary neurochemical disturbance in             occur with equal frequency in both sexes.
idiopathic Parkinson’s disease involves                  Anticipation is a completely different genetic
                                                         mechanism where trinucleotide repeat
  A     Noradrenaline                                    expansions cause increasingly severe
  B     Dopamine                                         phenotypes in successive generations.
  C     Gamma-aminobutyric acid (GABA)                   Variations in X chromosome inactivation are
  D     Substance P                                      thought to partly explain the mild phenotypes
  E     Adrenaline                                       sometimes seen in female carriers of X-linked
                                                         disorders. While modifier genes may well
The pathogenesis of Parkinson’s disease is               explain phenotypic variation between
multifactorial, characterised by a progressive death     individuals with the same syndrome, they do not
of heterogeneous populations of neurones                 explain the differences between the Angelman’s
particularly in the substantia nigra, resulting in a     and Prader–Willi syndromes.
regional loss of the neurotransmitter dopamine. A
60–70% loss of neurones occurs prior to the            13- A 75-year-old man is given a routine health
emergence of symptoms                                  check by his family doctor. He has no specific
                                                       complaints and is not on any regular
12- Angelman’s and Prader–Willi syndromes              medication. Biochemical tests reveal a serum
both involve defects in the same chromosome            alkaline phosphatase activity of 550 U/l (upper
region. What is the best molecular explanation         limit of normal (ULN) 150 U/l); serum
for differences in the phenotypes in these two         creatinine concentration is 132 µmol/l, calcium
conditions?                                            2.42 mmol/l, phosphate 1.21 mmol/l, albumin 41
                                                       g/l. Which of the following is the most likely
  A     It is sex-linked with the Prader–Willi         cause of the high alkaline phosphatase?
  syndrome, occurring mainly in boys
  B     It is due to anticipation, with successive       A      Osteomalacia
  generations becoming more severely affected            B      Osteoporosis
  C     It is related to the degree of X                 C      Paget’s disease of bone
  chromosome inactivation                                D      Primary hyperparathyroidism
  D     It is due to modifying genes on other            E      Renal osteodystrophy
  E     It is due to the differential expression of    Elevated serum alkaline phosphatase activity is
  genes depending on parental origin                   seen most frequently in cholestatic hepatobiliary
                                                       disease and in bone disease in which there is an
  Imprinting is a mechanism that results in            increase in osteoblastic activity. It is therefore not
  differential gene expression according to            a feature of uncomplicated osteoporosis. Serum
  parental origin. It is responsible for a number of   calcium concentration is usually low–normal or
  genetic syndromes, the best known of which are       low in osteomalacia, and is elevated in primary
  the Angelman’s and Prader–Willi syndromes.           hyperparathyroidism. The elevated creatinine
  Angelman’s syndrome causes ataxia and severe         indicates renal impairment, but not to an extent
  learning disability and is caused by absent          likely to cause renal osteodystrophy of a severity
  maternal expression of the 15q11–13                  suggested by an alkaline phosphatase level this
  chromosome region. Conversely, the Prader–           high; furthermore, the serum phosphate is usually
  Willi syndrome (mild/moderate learning               elevated and calcium is low in this condition. A
  disability, hyperphagia and obesity) is caused by    high alkaline phosphatase level is characteristic of
  absent paternal expression of the 15q11–13           Paget’s disease, a common condition in the elderly
  chromosome region. Other syndromes caused            and not always symptomatic.
  by imprinting abnormalities include the
  Beckwith–Wiedermann syndrome                         14- Regarding definitions of true- and false-
  (macroglossia, abdominal wall defects,               positive and -negative rates, which of the
  hypoglycaemia, visceromegaly) and the                following is true?
  Russell–Silver syndrome (small stature). The
  exact mechanism of imprinting is not well              A     The true-positive rate is the same as
  understood but is thought to involve differential      specificity
  B      The false-negative rate is calculated as         the therapeutic use of glyceryl trinitrate, a
  (1 – sensitivity)                                       synthetic compound) and memory. NO has also
  C      A perfect test would have a sensitivity          been implicated in septic shock, adult respiratory
  of 100%                                                 distress syndrome (ARDS) and inflammation.
  D      The false-positive rate is calculated as         Nitrous oxide, also known as ‘laughing gas’, is
  (false-positive/[true-positive + false-positive])       often used in obstetrics and trauma for pain relief.
  E      The true-negative rate is (1 – false-
  negative rate)                                          17- Which of the following antineoplastic agents
                                                          is correctly paired with the site of action at the
The true-positive rate, ie the sensitivity, provides a    cellular level?
measure of how well the test correctly identifies
patients with disease. The true-negative rate, ie the       A     Vinca alkaloids and abnormal
specificity, reflects how well the test correctly           microtubule disassembly
identifies patients without disease. The true-              B     Taxanes and abnormal microtubule
negative rate is calculated as (1 – false-positive          assembly
rate). The false-positive rate is calculated as (false-     C     Irinotecan and topoisomerase
positive/[true-negative + false-positive]). A perfect       inhibition
test should have a sensitivity of 100% and a                D     Inimitab mesylate and competitive
specificity of 100%.                                        inhibition of nucleotide synthesis
                                                            E     Doxorubicin and competitive inhibition
15- In estimating the physiological clearance of            of nucleotide synthesis
10 ml of an intravenous substance which has
been administered at 10 mg/ml, the plasma                 Vinca alkaloids inhibit the assembly of
concentration at equilibration is 15 mg/litre, the        microtubules, while taxanes inhibit the normal
urine concentration is 150 mg/litre and the               cellular disassembly of the microtubule apparatus
subject produces 1440 ml of urine. What is the            during mitosis. Inimitab is a specific tyrosine
clearance of the substance?                               kinase inhibitor. 6-Mercaptopurine (6-MP)-based
                                                          analogues inhibit purine synthesis.
  A      1 ml/min
  B      10 ml/min                                        18- A cross-over trial is being planned to
  C      0.1 ml/min                                       compare the efficacy of two drugs in the
  D      100 ml/min                                       treatment of rheumatoid arthritis. Which of the
  E      Cannot say from the information given            following design considerations should you
Clearance is calculated using the formula (U ×
V)/P where U = urine concentration in mg/ml, V =            A     There should be a run-in period when
urine production in ml/min, P = plasma                      the patient receives a placebo
concentration in mg/ml.The bolus size of the                B     The design should be simplified by
substance is irrelevant to the clearance.                   avoiding randomisation as patients receive
                                                            both treatments
16- Nitric oxide is derived from:                           C     A washout period, where the patient
                                                            receives placebo, should take place between
  A      Cyclic GMP                                         the administration of the two treatments
  B      Endothelium-derived relaxing factor                D     If either drug is thought to be a disease-
  C      GTN                                                modifier, plans to run a cross-over trial
  D      l-Arginine                                         should be abandoned
  E      Nitrous oxide                                      E     Only patients who will guarantee to
                                                            complete both treatments should be recruited
Nitric oxide (NO), which used to be known as
‘endothelium-derived relaxing factor’, is a local         If any treatment in a cross-over trial is a disease-
cellular messenger. It is derived from l-arginine         modifier (in the most extreme case, kills or cures
(an amino acid) by nitric oxide synthase. Its             the patient), then the interpretation of results in
actions increase the levels of intracellular cGMP         any subsequent period becomes impossible.
(cyclic guanosine monophosphate), which has               Option A will quite often be appropriate, but there
effects depending on which cell it is acting upon.        will be situations when a placebo run-in will be
These include modulation of vascular tone (hence          considered unethical. Option B would simply be
bad practice, as only by randomisation of the           measurements into arbitrary categories. As both
treatment order can we be assured that we are           sets of measurements were made on the same
guarding adequately against bias. A wash-out            patients, the measurements are not independent.
period between treatments is often useful in cross-     Although linear regression could be used to model
over trials but, as in option A, the use of a placebo   the relationship between the initial and final
treatment will, in some situations, be unethical.       measurements, to test for a change in the mean
Although we would like to ensure that all patients      albumin levels, the correct test is the paired
who enter trials complete them, the suggestion in       samples t-test.
option E would almost certainly be deemed
unethical                                               21- A 55-year-old woman is diagnosed with
                                                        type 2 diabetes mellitus. Her weight is 76 kg,
19- When planning the radiotherapy dosage for           body mass index 34 kg/m2. After 3 months’ trial
solid tumours, it has to be remembered that the         of dietary modification, she has lost 2 kg in
division of cells is governed by the cell cycle, the    weight, but her Hb A1c, which was 10.2% at
mechanism of which is disrupted by radiation.           diagnosis, is 9.6%. The most appropriate
Which of the following is true concerning the           treatment would now be which of the
cell cycle?                                             following?

  A     All share sequence homologies                     A      Acarbose
  B     G1 is a gap phase under the influence of          B      A sulphonylurea
  the p53 gene                                            C      A thiazolidinedione
  C     S is the mitotic phase                            D      Insulin
  D     G2 is a gap phase when cells contain              E      Metformin
  half as much DNA as non-dividing cells
  E     In normal tissues, cells with significant       Metformin, which acts principally by increasing
  damage to their DNA are arrested at the M             the sensitivity to insulin, is the treatment of choice
  phase                                                 in obese patients with type 2 diabetes, provided
                                                        that the serum creatinine concentration is not
G2 is a gap phase when cells contain twice as           elevated (there is an increased risk of lactic
much DNA as non-dividing cells. M is the mitotic        acidosis with metformin in renal impairment).
phase. G1 is a gap phase under the influence of the     Sulphonylureas are valuable oral hypoglycaemic
p53 gene. G0 is a resting stage with non-dividing       agents, but may cause weight gain.
cells; S represents premitotic DNA synthesis. In        Thiazolidinediones are not yet licensed for
normal tissues, cells with significant damage to        monotherapy in the UK, but may be useful
their DNA are arrested at the G1 phase.                 alternatives to metformin in the future. Acarbose,
                                                        an a-glucosidase inhibitor, is a weak
20- A group of patients have their albumin              hypoglycaemic agent and is used only in
levels measured at hospital admission and again         combination with other agents. This patient may
3 weeks into their hospital stay. Which one of          well come to require insulin, but oral treatment
the following statistical tests is most                 should be tried first.
appropriate to test the hypothesis that the
albumin levels have changed?                            22- Cholesterol is measured in populations
                                                        from Britain, Finland, Japan and the USA, and
  A      Chi-squared test                               the four groups are compared using a one-way
  B      Independent samples t-test                     analysis of variance (anova). Which of the
  C      Linear regression                              following graphical methods could best be used
  D      One-way analysis of variance                   to illustrate the results?
  E      Paired samples t-test
                                                          A     Bar graph showing the mean
Because we require a test that compares two               cholesterol level of each group
groups (albumin level at admission and albumin            B     Box plot showing the median, quartiles
level after 3 weeks); analysis of variance is not         and range for each group
appropriate as it compares more than two groups.          C     Four histograms showing the
The outcome measurement is continuous rather              distribution of cholesterol within each group
than categorical, so the Chi-squared test could not       D     Plot of the mean cholesterol level with a
be used without first dividing the albumin                95% confidence interval for each group
  E    Scatter plot of cholesterol level against          not (in a low-stress job). Both groups (cohorts)
  group                                                   are followed up for an appropriate period and
                                                          the incidence of the outcome of interest (breast
A scatter plot is used to illustrate the relationship     cancer) compared between the two groups. This
between two continuous variables; one of the              is the next best scientific approach to
variables here is not continuous (group) and so a         establishing association when an RCT cannot be
scatter plot is not suitable. Box plots and               undertaken. Unfortunately, the design has two
histograms show the distribution of a continuous          major disadvantages: it would take a
variable. These would be useful for checking the          considerable length of time to complete
assumption that the distribution within each group        (probably in excess of 10 years in this case) and
is approximately normal, but are less useful for          would involve huge numbers of women (as the
illustrating the results of the anova. The one-way        incidence of breast cancer is small).
anova compares the means of the groups, so                In practice, option D – a retrospective case-
displaying the means is the best way to illustrate        control study – is optimal. Women who have
the results. The means should be presented with           suffered the outcome (have just been diagnosed
confidence intervals to give the reader an idea of        as having breast cancer) are identified: these are
whether the differences between the groups were           the ‘cases’. Each case is matched with at least
significant.                                              one woman of the same age and demographic
                                                          characteristics who have not suffered the
23- An oncologist has gained the impression               outcome (have not been diagnosed as having
that many women diagnosed as having breast                breast cancer): these are the ‘controls’. The
cancer also have high levels of work-related              proportions of cases and controls exposed to the
stress. What type of design would be best to test         risk factor (have a high-stress job) are
this possible association?                                compared. This design requires a relatively
                                                          small number of participants and can be
  A    Group comparative, randomised                      completed within a short time – but it does
  controlled trial                                        require retrospective recall of important data by
  B    Cross-over, randomised cross-over trial            the participants. Nevertheless, it is the best
  C    Prospective cohort study                           option for this study.
  D    Retrospective case-control study
  E    Prospective observational study                  24- A middle-aged woman is referred to you by
                                                        her GP with a 6-month history of increasing
  Although the best option is D, some of the other      breathlessness on exertion. Her son is affected
  answers could be considered. In this context, a       with Duchenne’s muscular dystrophy, as was
  randomised controlled trial (RCT) of any              her brother. What would you be concerned
  description (options A and B) would be wholly         about in her?
  inappropriate – and probably unethical, as it
  would involve randomising women to low- or              A     Bronchiectasis
  high-stress jobs and then waiting to see how            B     Cardiomyopathy
  many develop breast cancer. From a strict               C     Emphysema
  scientific viewpoint, this is the best way to           D     Respiratory muscle failure
  establish a causal association – but the ideal is       E     Pericardial effusion
  not always acceptable.
  A prospective observational study (option E) is         Duchenne’s muscular dystrophy (DMD) is an
  also inappropriate. Observational surveys are           X-linked condition that is typically diagnosed in
  used primarily to measure a single characteristic       boys between the ages of 3 and 6 years. The
  of interest in a population. If the objective is to     boys have difficulty walking and develop calf
  look for (causal) associations between two or           pseudohypertrophy. They are typically
  more characteristics (as is the case here), a           wheelchair-bound by early adolescence and are
  slightly different approach is needed.                  unlikely to live beyond 30 years, usually dying
  Option C (a prospective cohort study) is similar        from cardiomyopathy or respiratory failure.
  in most respects to the simple survey offered by        Other complications include contractures,
  option E. An important difference is that the           scoliosis, intellectual impairment and reduced
  study population is divided at the start of the         night vision. The creatine phosphokinase is
  study into those individuals exposed to the risk        grossly elevated and the diagnosis can be made
  factor (in a high-stress job) and those who are         by muscle biopsy. Genetic testing will detect
  around two-thirds of mutations in the dystrophin
  gene.                                                     A     Congenital erythropoietic porphyria
  Because both her son and brother are affected             B     Erythropoietic protoporphyria
  with DMD, this woman is an obligate carrier.              C     Porphyria cutanea tarda
  Female carriers can develop a proximal                    D     Variegate porphyria
  myopathy and there is a 10–20% lifetime risk of           E     None of the above
                                                          The acute porphyrias include acute intermittent
                                                          porphyria and variegate porphyria. These are rare
25- In a cross-over trial comparing two drugs to          genetic errors of haem biosynthesis. Accumulation
treat children suffering from enuresis, the               of porphyrin precursors (porphobilinogen and d-
number of dry nights was recorded in each of              aminolaevulinic acid) cause neuronal and visceral
two 28-day periods of treatment. Which of the             crises. The acute intermittent type is inherited as
following strategies for analysis is the most             an autosomal-dominant, although penetrance is
appropriate?                                              low and around one-third of cases are due to
                                                          mutations. The urinary porphobilinogen level is
  A      Construct a contingency table with the           raised during an acute attack, but only 50% of
  number of dry nights forming the columns,               samples will turn red on standing. Faecal levels of
  and the treatments forming the rows, and                porphyrin are normal in patients with the acute
  apply a Chi-squared test                                intermittent type, unlike the variegate form.
  B      For each child, identify the treatment           Variegate porphyria is also inherited as an
  producing the greater number of dry nights,             autosomal-dominant and is associated with
  and apply an appropriate test of significance           photosensitivity causing blistering.
  to test the null hypothesis that the proportion
  of ‘preferences’ for each treatment is the              27- A 19-year-old woman is referral to you with
  same                                                    a blood pressure of 180/130 mmHg. On
  C      Apply a paired t-test if the differences         examination she has café-au-lait patches and
  in the number of dry nights are                         some axillary freckling. She required surgery
  approximately symmetrical, otherwise apply              for scoliosis as a child. What is the most likely
  a Wilcoxon Signed Rank Sum Test                         underlying diagnosis?
  D      Apply a non-parametric test to
  compare the distribution of the number of                 A     Marfan’s syndrome
  dry nights for the two treatments                         B     Neurofibromatosis type 1
  E      Calculate the correlation coefficient              C     Hypertrophic cardiomyopathy
  between the number of dry nights on each                  D     Tuberous sclerosis
  treatment, and test for a significant                     E     Cushing’s disease
                                                          Neurofibromatosis type 1 (NF1) is an autosomal-
In a cross-over trial it would be sensible to allow       dominant condition diagnosed in an individual
for the possibility of an order effect in the data, but   who has met two or more of the following criteria:
none of the options allows for this. The answers
are therefore not perfect for the question posed but        1     Six or more café-au-lait macules over 5
the best answer is C. If there is no order effect, this     mm in greatest diameter in prepubertal
would be a good method of analysing the data.               individuals and over 15 mm in greatest diameter
Option A ignores the pairing and would therefore            in postpubertal individuals
be a poor method of analysis. Option B is a                 2     Two or more neurofibromas of any type or
reasonable approach but, because it is compressing          one plexiform neurofibroma
the data, would be less efficient than option C.            3     Freckling in the axillary or inguinal
Option D ignores the pairing and should not be              regions
chosen for that reason. Option E would not answer           4     Optic glioma
the relevant question as correlation between the            5     Two or more Lisch nodules (iris
responses to the two treatments is of no interest           hamartomas)
here.                                                       6     A distinctive osseous lesion, such as
                                                            sphenoid dysplasia or thinning of the long-bone
26- Which of the following is an acute                      cortex with or without pseudarthrosis
porphyria?                                                  7     A first-degree relative (parent, sibling, or
  offspring) with NF1 as defined by the above             conjugated hyperbilirubinaemia
  criteria                                                B    Autosomally inherited, severe
                                                          unconjugated hyperbilirubinaemia
  NF1 is due to mutations in the NF1 gene on              C    Autosomal-recessive, mild
  chromosome 17q11, and is one of the most                unconjugated hyperbilirubinaemia
  commonly dominantly inherited conditions.               D    X-linked, severe conjugated
  Hypertension can be caused by renal artery              hyperbilirubinaemia
  stenosis or phaeochromocytomas. Other                   E    X-linked, severe unconjugated
  complications include optic gliomas, vertebral          hyperbilirubinaemia
  dysplasia, pseudarthrosis, intracranial tumours
  and malignant peripheral nerve-sheath tumours.        This is a rare syndrome that can either be
  About half of the people with NF1 have a              autosomal-recessive (type 1) or autosomal-
  learning disability.                                  dominant (type 2). Severe unconjugated
  Tuberous sclerosis is associated with                 hyperbilirubinaemia results from an absence (type
  hypopigmented macules, periungual fibromas,           1) or decrease (type 2) of glucuronyl transferase.
  facial angiofibromas and shagreen patches             As, in effect, it is a prehepatic problem, liver
  (raised connective tissue lesions usually on the      histology is normal. Only those with the type-2
  lower back). Other features include cortical          disease can survive to adulthood. There is no
  tubers in the brain, learning disability, epilepsy    available treatment except liver transplantation
  and renal angiomyolipomas. Hypertrophic
  cardiomyopathy can be a cause of hypertension         30- A study of hospital admissions reports a
  and is associated with skin lentigenes in the very    product moment correlation coefficient
  rare LEOPARD syndrome. Although scoliosis is          between age and length of hospital stay of R =
  a feature of Marfan’s syndrome, this condition        0.76 with a 95% confidence interval of 0.67–
  is not associated with café-au-lait macules or        0.85. How should these results be interpreted?
  hypertension. Cushing’s disease can cause
  increased general skin pigmentation but not             A     Inadequate provision of nursing homes
  café-au-lait macules.                                   prevents the discharge of older patients
                                                          B     Older age was significantly associated
28- Which one of the following is higher at the           with a longer length of stay
apex of the lung than at the base when a person           C     Older patients are sicker and require
is standing?                                              longer stays in hospital
                                                          D     Older patients die more quickly leading
  A      V/Q ratio                                        to shorter hospital stays
  B      Ventilation                                      E     There was no significant relationship
  C      PaCO2                                            between age and length of stay
  D      Compliance
  E      Blood flow                                     A product moment correlation coefficient greater
                                                        than zero indicates a positive association, so older
The alveoli at the apex of the lung are larger than     age is associated with longer stays. As the
those at the base so their compliance is less.          confidence interval excludes the value zero, this
Because of the reduced compliance, less inspired        association is significant. Either A or C may be
gas goes to the apex than to the base. Also,            true, but we do not have enough information to be
because the apex is above the heart level, less         able to reach these conclusions.
blood flows through the apex than through the
base. However, the reduction in air flow is less        31- Which of the following is typically the
than the reduction in blood flow, so that the V/Q       earliest lesion to develop in diabetic
ratio at the top of the lung is greater than it is at   retinopathy?
the bottom. The increased V/Q ratio at the apex
makes PaCO2 lower and PaO2 higher at the apex             A     Blot haemorrhages
than they are at the base.                                B     Dot haemorrhages
                                                          C     Hard exudates
29- Which of the following statements is most             D     Macular oedema
consistent with the Crigler–Najjar syndrome?              E     Soft exudates

  A      Autosomally inherited, severe                  The earliest lesions to be detected in diabetic
retinopathy are usually dot haemorrhages                 E     Weight loss
(capillary microaneurysms) and venous dilatation.
Hard exudates are characteristic of diabetic           Type-1 diabetes is irreversible. Exercise, weight
retinopathy but they, and blot haemorrhages,           loss and decreased production of counter-
usually appear later. These three are the              regulatory hormones can all result in decreased
components of ‘background’ retinopathy. Soft           insulin requirements. The latter can occur with
exudates and macular oedema are later, sight-          Addison’s disease (resulting in a decreased
threatening, preproliferative, changes.                secretion of cortisol) and hypopituitarism
                                                       (decreased secretion of growth hormone and
32- An 8-year-old child is admitted to hospital        cortisol). Autoimmune Addison’s disease occurs
having ingested some of her mother’s iron              more frequently in patients with type-1 diabetes
tablets (ferrous fumarate) 4 hours earlier. Her        than in non-diabetic subjects, as does autoimmune
serum iron concentration is 182 µmol/l. Plain          ovarian failure. However, the evidence of
abdominal X-ray is unremarkable. What would            decreasing ovarian function without an increase in
be the most useful therapeutic measure?                gonadotrophin concentrations makes
                                                       hypopituitarism the most likely cause here. The
  A     Gastric lavage with desferrioxamine            lower limit of detection in many gonadotrophin
  B     Induction of vomiting                          assays includes the lower limit of the normal
  C     Intravenous infusion of                        follicular range, so that frankly low
  desferrioxamine                                      concentrations, such as may occur in
  D     Oral activated charcoal                        hypopituitarism, may not be distinguishable from
  E     Whole bowel irrigation                         low–normal values.

Gastric lavage should only be considered in            34- Which of the following types of studies have
patients with iron poisoning who present within an     the greatest problems with recall bias?
hour of taking the tablets. Inducing vomiting after
this time is ineffective, and, anyway, iron toxicity     A     Case-control studies
often causes vomiting. Activated charcoal poorly         B     Cohort studies
adsorbs inorganic poisons such as iron. Whole            C     Crossover trials
bowel irrigation may be helpful if undissolved           D     Randomised controlled trials
tablets remain in the gut (they are radio-opaque),       E     Systematic reviews
as is more likely to occur when slow-release iron
preparations have been ingested. However, the          A case-control trial studies groups of people with
standard treatment is an intravenous infusion of       an illness and compares them with control subjects
desferrioxamine, which chelates iron and               to try and identify a causal factor, but biases may
facilitates its urinary excretion.                     creep into their interpretation of past events.
                                                       Cohort studies follow subjects through time and,
33- A 38-year-old woman with type-1 diabetes           while potentially time-consuming, they have less
reports at her regular clinic review that she has      recall bias. Double-blinding helps to remove bias
been experiencing frequent episodes of                 from both the patient and researcher. Statisticians
hypoglycaemia during the previous 6 months,            analysing data from randomised controlled trials
despite reducing her overall dose of insulin by        should also be blinded. Systematic reviews can be
almost 50%. Her Hb A1c in the clinic is 5.6%,          confounded by the author’s own prejudice, or bias
having been 6.8 % a year previously. She also          in searching, selecting and interpreting evidence.
says she has lost some weight and that her
periods are becoming scanty and irregular, and         35- Regarding statistical methodology, which of
wonders if she is having an early menopause.           the following statements is most applicable?
Gonadotrophin concentrations are in the
normal early follicular range. What is the most          A     The median and mean do not differ
likely cause of the reduction in her insulin             even when the population distribution is
requirement?                                             skewed
                                                         B     Mean refers to the value that occurs
  A     Addison’s disease                                with the highest frequency
  B     Hypopituitarism                                  C     The value of ‘r’ (coefficient of
  C     Increased exercise                               variation) ranges from -1 to +1
  D     Spontaneous regression of diabetes               D     Incidence is defined as the number of
  cases seen in the population at any given time      sampling?
  E     The probability that a given result
  could have been obtained purely by chance is          A     A sample statistic is a point estimate of
  higher when the p-value is 0.01 rather than           a population parameter
  0.05                                                  B     Sampling error arises when we
                                                        transcribe data incorrectly
Prevalence is defined as the number of cases seen       C     No criteria for sample selection are
in the population at any given time. The value          involved in random sampling
occurring with the highest frequency is the mode.       D     For a set of observations, the standard
The lower the p-value, the lower the possibility        deviation is always less than the standard
that the result is due to chance.                       error of the mean
                                                        E     The inferential process involves
36- A 26-year-old teacher of Ashkenazi Jewish           drawing conclusions about the sample
descent presents with long-standing bone pain.
On examination there is marked                        Sampling error arises when only a portion of the
hepatosplenomegaly. Which genetic disorder            population is studied. Random sampling implies
should be included in the list of differential        that the sample has been selected from a sampling
diagnoses?                                            frame in such a way that every individual has the
                                                      same chance of being selected. In random
  A     Tay–Sachs disease                             sampling, defined criteria for sample selection are
  B     Canavan’s disease                             laid down. The standard error of the mean is the
  C     Niemann–Pick’s disease type A                 standard deviation divided by the square root of
  D     Galactosaemia                                 the sample size, hence it must always be smaller
  E     Gaucher’s disease                             than the standard deviation. Inference is the
                                                      process of drawing conclusions about the
  Gaucher’s disease is a recessively inherited        population using the sample information.
  deficiency of the enzyme glucocerebrosidase,
  which leads to an accumulation of                   38- Which of the following takes place during
  glucosylceramide in lysosomes. It is the most       inspiration?
  common lysosomal storage disease. Clinical
  features include hepatosplenomegaly, anaemia          A     The diaphragm drops by 10 cm during
  and osteopenia. Type 1 disease is the most            normal breathing
  common and is characterised by the lack of            B     A negative pressure of 1–3 mmHg is
  neurological involvement. It can affect both          created
  children and adults and mild forms can first          C     The rib cage recoils
  present in adulthood. It is most prevalent in the     D     Abdominal muscles contract
  Ashkenazi Jewish population and can be treated        E     Accessory muscles relax
  with enzyme replacement therapy. Types 2 and
  3 are associated with neurological involvement.     During normal breathing the diaphragm may drop
  Tay–Sachs, Canavan’s and Niemann–Pick’s             1 cm, creating a pressure drop of 1–3 mmHg and
  disease are all also more common in the             an air intake of 500 ml. During strenuous exercise
  Ashkenazi Jewish population but all result in       the diaphragm may drop 10 cm, producing a
  severe intellectual impairment. Tay–Sachs and       pressure drop of 100 mmHg and an air intake of
  Niemann–Pick’s disease type A (which both           3000 ml. During expiration the rib cage recoils,
  have a macular cherry-red spot that is a useful     the abdominal muscles contract and the accessory
  diagnostic aid) result in death in early            muscles relax.
  childhood, whereas the life expectancy for those
  with Canavan’s disease can be into the teens.       39- In 200 consecutive patients attending a
  Galactosaemia is not more prevalent in the          diabetic out-patients clinic, 27 are found to
  Ashkenazi Jewish population; it usually presents    have diabetic retinopathy. Which of the
  in neonates with hypoglycaemia and acidosis         following statements is correct?
  and is associated with progressive
  hepatosplenomegaly, cataracts and intellectual        A     The incidence of diabetic retinopathy in
  impairment.                                           diabetics in the UK is 13.5%
                                                        B     The incidence of diabetic retinopathy in
37- Which of the following is a characteristic of       this population was 13.5%
  C      The prevalence of diabetic retinopathy         B      The probability of rejecting the null
  in diabetics in the UK is 13.5%                       hypothesis that the treatments have the same
  D      The prevalence of diabetic retinopathy         effect
  in this population was 13.5%                          C      The chance that a clinically significant
  E      This study does not provide any                difference will be observed
  information on the incidence or prevalence of         D      The probability of a type-2 error
  diabetic retinopathy                                  E      The probability of a statistically
                                                        significant treatment effect if the true
The prevalence of a disease is the number of cases      treatment difference is at a prespecified level
present in a population at a point in time. The
incidence of a disease is the number of new cases     It uses a specified size of treatment difference, but
over a period of time. The figure reported in the     A is not correct. Option B would become correct if
question is the prevalence, and the prevalence in     it was extended to say ‘when there is a
this population was 13.5%. This population may        prespecified treatment difference’, but is incorrect
be representative of all diabetics in the UK, in      as it stands. C looks plausible, but the difference
which case we could take 13.5% to be an estimate      being specified in the power calculation might not
of the prevalence in UK diabetics, although it is     correspond to a clinically significant difference
likely that some selection has occurred.              (the difference might be set higher) so C is
                                                      incorrect. Power is often defined as 1 minus the
40- In a patient with chronic hyponatraemia           probability of a type-2 error, so D is wrong.
(sodium concentration 112 mmol/l), which of
the following findings would most suggest a           42- A 38-year-old woman is sent as an
diagnosis of the syndrome of inappropriate            emergency to you with an acute-onset headache
[secretion of] antidiuretic hormone (SIADH)?          and deteriorating conscious level. Her husband
                                                      mentions that her brother has recently had a
  A   Normal cortisol response to ACTH                kidney transplant, although he is not sure why.
  B   Plasma albumin concentration 28 g/l             What condition may be running in the family?
  C   Plasma osmolality 248 mOsmol/kg
  D   Urinary osmolality 350 mOsmol/kg                  A     von Hippel–Lindau disease
  E   Urinary sodium concentration < 20                 B     Hereditary haemorrhagic telangiectasia
  mmol/l                                                C     Polycystic kidney disease
                                                        D     Alport’s syndrome
The most significant finding is that the urine is       E     Tuberous sclerosis
concentrated relative to plasma. This is
inappropriate, in that a low plasma osmolality          Intracranial aneurysms occur in approximately
should suppress ADH secretion and lead to the           10% of individuals with autosomal-dominant
formation of a maximally dilute urine. The low          polycystic kidney disease (ADPKD), and
plasma osmolality reflects the hyponatraemia,           approximately 50% of patients with ADPKD
since sodium is the principal determinant of            have end-stage renal disease by age 60 years. It
extracellular fluid osmolality. A low urine sodium      is a relatively common genetic disorder and
excretion would suggest extrarenal sodium               there are two known ADPKD genes – PKD1,
depletion as a cause of hyponatraemia. Addison’s        accounting for about 85% of cases, and PKD2,
disease, another cause of chronic hyponatraemia,        accounting for about 15% of cases.
is excluded by the cortisol response to ACTH, as it     von Hippel–Lindau disease can cause renal
should be before SIADH is diagnosed. The low            cysts, renal carcinoma and cerebellar
plasma albumin concentration could just reflect         haemangioblastomas, but a history of renal
dilution of the plasma by the excess water, but it      transplant would be unusual. Cerebral
could also suggest chronic liver disease, another       atriovenous malformations can occur in
cause of chronic hyponatraemia                          hereditary haemorrhagic telangiectasia and these
                                                        may result in intracerebral bleeding, but the
41- In the design of a randomised controlled            kidneys are not typically involved. Alport’s
trial, to what does the ‘power of the study’            syndrome causes renal failure and deafness.
refer?                                                  Renal cysts can be found in tuberous sclerosis
                                                        (TS). In addition, there is a high frequency of
  A      The size of treatment difference that          subependymal glial nodules and cortical tubers,
  the trial can be expected to detect                   but these would not explain the history of
  sudden-onset headache.                                 44- In metabolic alkalosis associated with
                                                         prolonged nasogastric aspiration in
43- Whilst treating a diabetic patient who is            postoperative ileus, what is the most important
controlled with insulin you perform fundoscopy           cause of the acid–base disturbance?
and find new vessel disease in the macula lutea.
Which of the following is true of ocular                    A    Hypoventilation
physiology?                                                 B    Increased renal bicarbonate
  A     The macula is rich in rods                          C    Loss of gastric acid
  B     This corresponds with the optic papilla             D    Potassium depletion
  C     The central portion of the macula is                E    Secondary aldosteronism
  known as the fovea centralis
  D     As it corresponds with the blind spot,           Loss of unbuffered gastric acid is the cause of the
  retinopathy will have less functional effect on        metabolic alkalosis seen under these circumstances
  acuity                                                 if there is inadequate replacement of the fluid lost
  E     There is a direct relationship between           with intravenous physiological saline. Increased
  proliferative retinopathy and the frequency            renal bicarbonate reabsorption (needed to allow
  of cataracts                                           adequate renal sodium reabsorption in the
                                                         presence of hypochloraemia), potassium depletion
The macula is rich in cones. The optic papilla is        (gastric secretions contain about 10 mmol/l of
the opening of the optic nerve and corresponds           potassium) and secondary aldosteronism (a result
with the blind spot. The fovea centralis has the         of extracellular fluid loss) all help to maintain the
highest acuity. There is no direct relationship          alkalosis, but they do not cause it. Hypoventilation
between proliferative retinopathy and the                is a compensatory change: on its own,
frequency of cataracts.                                  hypoventilation causes carbon dioxide retention
                                                         and a respiratory acidosis.

45- If the prevalence of Rett syndrome is 1 per 10,000 and a genetic screening test applied in infancy
has a sensitivity of 90% and a specificity of 99.99%, then

  A     The positive predictive value is less than 50% and the negative predictive value is greater
  than 99.99%
  B     The positive predictive value is less than 50% and the negative predictive value is less than
  C     The positive predictive value is greater than 50% and the negative predictive value is greater
  than 99.99%
  D     The positive predictive value is greater than 50% and the negative predictive value is less
  than 99.99%
  E     The positive predictive value and the negative predictive value cannot both be calculated

To see this, tabulate the expected numbers in a population, which, to make the numbers easier, we will take
as 1,000,000:
                       Test positive                 Test negative                 Total
  Rett                 90                            10                            100
  Non-Rett             ~100                          ~999,800                      999,900
  Total                190                           999,810                       1,000,000

We form the column of totals first from the prevalence of Rett syndrome, and then use the sensitivity
applied to the first row and specificity applied to the second row to obtain the tabulated numbers (we
actually expect 99.99+ tests in the non-Rett population). The positive predictive value is therefore 90/190
(< 50%). The negative predictive value is 999,800/999,810 (> 99.99%).

46- A 42-year-old man is put on a proton-pump            acid pump has which of the following features?
inhibitor to suppress symptoms of oesophagitis.
The cell and membrane biology of the gastric                A     Histamine-stimulated acid production
  is independent of the proton pump                      A     Simple indices of circulatory status –
  B      The proton is exchanged with                    such as urine output, blood pressure and
  magnesium ions                                         CVP – correlate well with outcome from
  C      Acetylcholine-stimulated acid                   high-risk surgery
  production is independent of the proton                B     Survivors after major surgery decrease
  pump                                                   their cardiac index and oxygen delivery in the
  D      The proton pump spans the apical                perioperative period below baseline normal
  membrane of the gastric parietal cell                  values
  E      The proton pump spans the basolateral           C     Measurement of mixed venous oxygen
  membrane of the gastric parietal cell                  saturation (SVO2) requires a pulmonary
                                                         venous (PV) catheter to sample pulmonary
The H+–K+-ATPase is embedded in the apical               capillary blood
membrane. The channel is susceptible to agents           D     Cardiac index and oxygen delivery
that bind to cysteine residues (particularly 813 and     correlate poorly with outcome from high-risk
822). The proton pump is the final common                surgery
pathway of histamine and acetylcholine-stimulated        E     Pre- or perioperative beta-blockade can
production, and particularly explains the enhanced       improve survival after major non-cardiac
efficacy of proton-pump inhibitors in comparison         surgery in patients with pre-existing cardiac
to H2 antagonists or acetylcholine antagonists (eg       disease
                                                       Simple indices of circulatory status – such as urine
47- Blood pressure is normally distributed. For        output, blood pressure and CVP – correlate poorly
a sample of 100 Asian women the average blood          with outcome from high-risk surgery. Survivors
pressure is 50, standard deviation = 5, standard       after major surgery increase their cardiac index
error = 1/2. Which one of the following                and oxygen delivery in the perioperative period
statements is correct?                                 above baseline normal values. Measurement of
                                                       mixed venous oxygen saturation (SVO2) requires a
  A     Approximately 95% of Asian women               pulmonary artery (PA) catheter to sample
  have blood pressures in the range (45,55)            pulmonary capillary blood. Cardiac index and
  B     We are approximately 95% confident             oxygen delivery correlate well with outcome from
  that the population average blood pressure           high-risk surgery. Two recent multicentre trials
  for Asian women lies in the interval (49, 51)        have confirmed the advantage of using highly
  C     Blood pressure measurement in Asian            selective pre- or perioperative beta-blockade to
  women is not informative                             improve survival after major non-cardiac surgery
  D     10% of Asian women have blood                  in patients with pre-existing cardiac disease, eg
  pressure below 40 mmHg                               previous heart failure, moderate hypertension and
  E     The mean blood pressure of Asian               myocardial infarction (MI). The regime is started
  women must lie within the range (49, 51)             48–72 h preoperatively and continued for 14–28
                                                       days post-surgery.
Approximately 95% will have blood pressures in
the range (mean ± 2sd) = (50 ± 2(5)) = (50 ± 10) =     49- A 24-year-old woman undergoes resection
(40, 60) so A is incorrect. 2.5% will have blood       of the terminal ileum with fashioning of an
pressures below 40 (D is incorrect). A 95%             ileostomy for Crohn’s disease. Some 2 weeks
confidence interval for average blood pressure is      after surgery, she is making a good recovery,
given by (mean ± 2se) = (50 ± 2 (5)) = (50 ± 1) =      and is eating a high-energy, low-residue diet,
(49, 51), so B is correct. (Although we are 95%        but has a high ileostomy volume, necessitating
confident that the mean lies in this range it may      intravenous fluid replacement. Her serum
not and E is incorrect.)                               calcium concentration is 1.82 mmol/l,
                                                       phosphate 1.28 mmol/l, alkaline phosphatase 82
48- You are called to ICU to see a 65-year-old         U/l (normal < 150), albumin 30 g/l, creatinine
patient who requires controlled mechanical
ventilation after major non-cardiac surgery but        concentration was 2.18 mmol/l, albumin 36 g/l.
is becoming hypoxaemic when the FiO2 is                What is the most likely cause of her
reduced from 0.4 to 0.3. Which of the following        hypocalcaemia?
statements is true?
                                                         A     Formation of insoluble calcium salts in
  the intestine                                           checked in patients with recurrent
  B     Hypoalbuminaemia                                  staphylococcal abscesses
  C     Hypomagnesaemia
  D     Malabsorption of calcium                        Eye involvement is common in pemphigoid.
  E     Malabsorption of vitamin D                      Pemphigoid is associated with subepidermal
                                                        bullae, and in pemphigus they are intraepidermal.
Impaired fat absorption can lead to the formation       Epidermolysis bullosa acquisita is associated with
of insoluble calcium salts in the gut. Fat and          DR-2 and not DR-4. The rash of herpes gestationis
calcium are absorbed in the proximal small              is typically found on the lower abdomen.
intestine, so, too, is vitamin D. Although bile salts
are absorbed distally, and impaired absorption can      52- Degranulation of eosinophils allows which
lead to a secondary decrease in proximal fat            of the following cellular processes?
absorption, this is unlikely to be responsible for
hypocalcaemia developing so quickly. The normal           A     Fusion of the lysosomal membrane with
alkaline phosphatase level also militates against         the plasma membrane
vitamin D deficiency. Hypocalcaemia would                 B     Chemotaxis
normally be expected to stimulate parathyroid             C     Ingestion within a phagosome
hormone secretion and cause the plasma phosphate          D     Intracellular enzymatic degradation
concentration to fall (PTH is phosphaturic).              E     Exocytosis
Patients with ileostomies can lose large amounts
of magnesium through their stomas;                      Basophils, eosinophils and mast cells contain
hypomagnesaemia impairs PTH secretion and can           lysosomes and can release the contents of these
cause hypocalcaemia that is resistant to an             granules by degranulation. This allows them to act
increased provision of calcium.                         against larger infecting organisms such as
                                                        protozoa and helminths, which cannot be engulfed
50- Which of the following tumour-associated            by phagocytosis. Phagocytosis comprises
antigens is linked with the correct cancer?             chemotaxis, ingestion within a phagosome,
                                                        intracellular enzymatic degradation and
  A     CA-125: Testicular teratoma                     exocytosis.
  B     CA 19-9: Pancreatic cancer
  C     Alpha-fetoprotein: Ovarian cancer               53- In a 20-year-old man, recurrent and/or
  D     CEA: Hepatocellular carcinoma                   severe infections with which of the following
  E     HCG: Breast cancer                              organisms would make you suspect
                                                        immunodeficiency associated with
CA-125 is associated with ovarian epithelial            hypogammaglobulinaemia?
cancers. CA 19-9 with pancreatic and some
colorectal cancers. Alpha-fetoprotein is associated       A     Haemophilus influenzae
with hepatocellular carcinoma, hepatoblastoma,            B     Streptococcus pyogenes
testicular teratoma and yolk sac tumours. CEA is          C     Herpes simplex virus
associated with colon carcinoma and some head             D     Candida spp
and neck and lung cancers. HCG is associated              E     Pneumocystis jiroveci
with germ-cell ovarian tumours, choriocarcinoma,
testicular teratoma and seminoma.                       Infections with Haemophilus influenzae and
                                                        Streptococcus pneumoniae occur with this
51- Which of the following statements in                condition, not Streptococcus pyogenes.
relation to skin disease is true?                       Pneumocystis jiroveci (formerly P. carinii), viral
                                                        and candida infections are associated with T-cell
  A     Eye involvement is unusual in benign            deficiencies, including HIV infection.
  mucous membrane pemphigoid
  B     The rash of herpes gestationis most             54- A trial was conducted to look for
  commonly affects the chest                            coagulation abnormalities in patients with
  C     Pemphigus is associated with                    tuberculosis. Serum fibrinogen levels were
  subepidermal bullae                                   taken as a criterion to diagnose coagulation
  D     Epidermolysis bullosa acquisita is              abnormalities. The subjects were divided into
  strongly associated with HLA-DR4                      three groups – those without tuberculosis, those
  E     Nasal swabs should be routinely                 with pulmonary tuberculosis and those with
disseminated fulminant tuberculosis. The mean             What is the most likely diagnosis?
fibrinogen level was calculated for each group
of patients and compared for significant                    A     Osteogenesis imperfecta
difference between the groups. Which of the                 B     Early-onset osteoporosis
following tests would be ideal for this                     C     Ehlers–Danlos syndrome
measurement?                                                D     Malignant bone metastases
                                                            E     Multiple myeloma
  A      Chi-square test
  B      Student’s t test                                   Osteogenesis imperfecta is a dominantly
  C      Regression analysis                                inherited disorder of collagen, and this woman
  D      ANOVA                                              most probably has the type 1 (least severe)
  E      Pearson test                                       form. Type 2 is lethal in utero or shortly after
                                                            birth and type 3 is the severe form where
The appropriateness of a test to examine a                  affected individuals have hundreds of fractures
statistical problem depends upon the scale of               and usually become wheelchair-bound. Clinical
measurement (nominal, ordinal, interval, ratio) and         features include blue sclerae (not always
the type of question being asked. The Chi-square            present, as in this case), early-onset deafness
test is used for nominal data to find out if there is a     and dentinogenesis imperfecta.
significant difference between the proportion of            Ehlers–Danlos syndrome is another
observations falling in each group – for example,           collagenopathy. The classical type is typically
comparing the proportion of children developing             associated with skin laxity and joint
measles between a group receiving a new measles             hypermobility but not with susceptibility to
vaccine and a group not given the vaccine. The              bone fractures.
Student’s t test is used to compare one or two              The other conditions should be considered and
means, whereas ANOVA (analysis of variance) is              excluded. However, none would explain her
used for more than two means, as in this scenario.          previous history of bone fractures, teeth
The Pearson test is used to assess the correlation          discoloration or hearing loss.
(strength of association) between two variables,
whereas regression techniques are used to predict         57- In an audit of hospital episode statistics,
the value of one variable based on the other.             length of hospital stay for acute medical
                                                          admissions is found to be highly positively
55- Only IgE-mediated allergic reactions can be           skewed with a median of 4 days and an
formally tested by skinprick testing. Adverse             interquartile range of 2–10 days. Which of the
reactions to which of the following substances            following statements is correct?
can be tested in this manner?
                                                            A    25% of patients stayed between 2 and
  A      Morphine                                           10 days
  B      Radiocontrast media                                B    50% of patients stayed between 2 and
  C      Scombrotoxins                                      10 days
  D      Colloid plasma expanders                           C    90% of patients stayed between 2 and
  E      Latex                                              10 days
                                                            D    95% of patients stayed between 2 and
Latex can induce allergy through IgE bound to               10 days
mast cells. All the others induce histamine release         E    All patients stayed between 2 and 10
via their direct effects on mast cells, except for          days
scombroid fish poisoning which is related to the
heat-stable toxin in tuna/mackerel/mahi mahi, etc.        The lower quartile has one-quarter of values below
                                                          it, and the upper quartile has one-quarter of values
56- A 27-year-old woman presents with                     above it. The interquartile range, 2–10, is the range
worsening back pain. As a child, she and her              from the lower quartile to the upper quartile, so
sister had several admissions to hospital with            half of all values lie in this range.
bone fractures following minor trauma and she
has recently developed bilateral hearing loss.            58- Which one of the following features in an
Apart from some teeth discoloration and mild              adult patient presenting with porphyrinuria
joint laxity, examination was normal. A                   would most suggest lead poisoning rather than
vertebral X-ray showed partial collapse of L3.            acute intermittent porphyria as a cause?
                                                           ‘moderate’ to ‘mild’ will not be the same as
  A      Abdominal pain                                    moving from ‘mild’ to ‘moderate’). Strictly,
  B      Anaemia                                           both tests also require the data to follow a
  C      Foot drop                                         Normal (Gaussian) distribution – this is unlikely
  D      Hypertension                                      with a short ordinal scale. Options B and E are
  E      Seizures                                          thus the least desirable.
                                                           Options A and D are also effectively the same
Abdominal pain, motor neuropathies and seizures            test. Both take the extreme opposite view to that
can be features of both lead poisoning and acute           adopted above and treat the pain scale as being
intermittent porphyria (although encephalopathy is         wholly categorical (ie ‘nominal’). This, too, has
more common in lead poisoning in children than             some reason to it, and examples can be seen in
in adults). Autonomic neuropathy in acute                  the literature. The Fisher exact test is
intermittent porphyria can cause hypertension but          mathematically very complex and, even with
this is not a feature of lead poisoning. Anaemia           modern computer power, can take a long time to
occurs only in lead poisoning: it is due to                compute. The Chi-square test is an
inhibition of ferrocheletase (the activity of this         approximation to the Fisher exact test, which is
enzyme is normal in AIP) and a decrease in red             based on a very much simpler algebraic formula
cell lifespan. This is also a result of enzyme             that can be computed in a few moments with
inhibition (pyrimidine 5'-nucleotidase) leading to         just a simple calculator. However, the scale is
the accumulation of pyrimidine nucleotides in red          specifically designed to have an ordering to it,
cells, which in turn reduces the stability of the cell     and it is inefficient to ignore this. Options A and
membrane (and is seen on a blood film as                   D are better than B and E, but still not optimal.
basophilic stippling).                                     Option C is a ‘non-parametric’ test, which does
                                                           not assume any underlying distribution for the
59- In a small double-blind study of pain                  data but does take account of the ordering across
following dental surgery, patients are randomly            the scale points. There is a statistical problem in
allocated to receive either an analgesic tablet or         that many observations will be the same (ie
a matching placebo tablet 1 hour                           tied), but as the study is described as small this
preoperatively. All patients were asked to rate            should not be a major concern. There is no ideal
their pain at 4 hours after surgery using the              analysis for this study – but option C makes the
following scale: 0 = nil, 1 = mild, 2 = moderate,          best use of the data and the least dubious
3 = severe. What is the best statistical test for          assumptions about the statistical properties of
analysing the results of this study?                       the pain scale.

  A      Chi-square test
  B      One-way analysis of variance                    60- In Duchenne’s muscular dystrophy, which
  C      Mann–Whitney U-test                             of the following statements applies?
  D      Fisher exact test
  E      Unpaired Student t-test                           A     Serum creatinine kinase is elevated in
                                                           30% of cases
  Although the best answer to this question is C,          B     Exon deletion or duplication in the
  all the other answers have some virtue.                  dystrophin gene occurs in 60% of patients
  Pain is measured here using an ‘ordinal                  C     Prenatal diagnosis involves analysis of
  categorical’ scale. Frequently, such scales are          restriction fragment length polymorphisms
  considered to be continuous (more correctly,             (RFLPs)
  pseudo-continuous) and the literature contains           D     The genetic defect affects mainly
  many instances of this practice. If this                 skeletal muscle
  approximation is made then options B or E are            E     50% of male fetuses are affected
  both appropriate tests – one-way analysis of
  variance is identical mathematically to the            Duchenne’s muscular dystrophy is an X-linked
  unpaired Student t-test when just two groups are       recessive disorder in which affected boys develop
  being compared. However, approximating to a            progressive weakness of the limb-girdle muscles.
  continuous scale is problematic here: there are        Most muscular tissues, including cardiac tissues,
  only four points on the scale; each point is given     are involved. An abnormally high creatinine
  a specific definition; and the distances between       kinase level is found in all these patients. Since
  the points are unlikely to be equal (moving from       60% of patients have an exon deletion or
duplication in the dystrophin gene, this can be          cardiac defects (eg coarctation of the aorta),
tested directly without the need for analysis of         congenital lymphoedema, neck webbing, widely
RFLPs                                                    spaced nipples and cubitus valgus. Noonan’s
                                                         syndrome is an autosomal-dominant condition (so
61- The total cost to the NHS of two treatments          it affects both sexes), and other typical features
for cholecystectomy are to be compared in the            include pulmonary stenosis, neck webbing and
setting of a randomised controlled trial. A total        low-set posteriorly rotated ears.
of 40 patients have received each treatment.
The distribution of the costs is seen to be              63- In a randomised controlled trial of a new
strongly positively skewed. Which of the                 treatment for preventing recurrence of stroke,
following is the preferred method of analysis to         1000 patients are randomised to the new
assess whether average costs differ                      treatment and 1000 to standard therapy. A
significantly?                                           total of 66 patients receiving the new treatment
                                                         suffered recurrent stroke, compared to 110 in
  A     A paired t-test                                  the control arm. What was the relative risk
  B     An independent samples t-test                    reduction?
  C     An independent samples t-test applied
  to the logarithms of the costs                           A      4.4%
  D     A Wilcoxon Signed Ranks Sum Test                   B      6.6%
  E     A Mann–Whitney U-test                              C      11%
                                                           D      40%
It might look at first sight as though either Option       E      60%
C or E would be a good answer (as the
distributions are positively skewed). We have to         The risk of recurrent stroke in the treatment arm
remember, however, that the question relates to          was 6.6% (66/1000). The risk of recurrent stroke
comparing costs, and any transformation of the           in the control arm was 11% (110/1000). The
data or ranking of the data would mean that we           difference in these risks is the absolute risk
were no longer directly comparing costs. Thus,           reduction, 4.4% (11% – 6.6%). The relative risk
although option B is not the optimal way of              reduction is the absolute risk reduction as a
analysing the data, it is the best of the five choices   percentage of the risk in the control group, that is
offered. Options A and D are inappropriate               40% (4.4/11).
because they only apply to paired data.
                                                         64- Which of the following adverse food
62- A 20-year-old woman presents with                    reactions is mediated by IgE-dependent
hypothyroidism. On further questioning it                mechanisms and hence can be ascertained by
transpires she has primary amenorrhoea. She is           skinprick testing?
also of relatively short stature compared to her
sisters. What is the most likely diagnosis?                A      Monosodium glutamate in Chinese food
                                                           B      Scombroid fish poisoning
  A      Turner’s syndrome                                 C      Sulphites on prepacked salads
  B      Down’s syndrome                                   D      Salicylate-induced urticaria
  C      Noonan’s syndrome                                 E      Kiwi fruit
  D      XXX syndrome
  E      Achondroplasia                                  Kiwi fruit is a member of the latex-associated
                                                         foods and adverse reactions to this fruit are
Although Turner’s syndrome (XO) and Down’s               mediated by IgE. All the others are examples of
and Noonan’s syndromes can be associated with            food intolerance, so that detailed history-taking is
short stature and hypothyroidism, Down’s                 essential to making the correct diagnosis.
syndrome and Noonan’s syndrome are not                   Scombroid-fish poisoning causes immediate
associated with menstrual irregularities. Females        diffuse redness, diarrhoea and vomiting following
with an extra X chromosome (XXX syndrome) are            the consumption of fish such as tuna, mackerel
usually tall, whereas individuals with                   and mahi mahi. Monosodium glutamate causes
achondroplasia are usually very short; neither           abdominal bloating and vomiting – the so-called
condition has an increased incidence of                  ‘Chinese restaurant syndrome’. Sulphites on
hypothyroidism or menstrual irregularities. The          prepacked salads causing asthma is called the
other typical features of Turner’s syndrome are          ‘Salad-bar syndrome’.
                                                        test is that lead in the blood is associated with
65- A study is designed to assess the safety of         lower ability scores
recombinant human erythropoietin (rhEPO)                E      The probability that lead in the blood
when used in premature infants of less than 33          affects the ability score is more than 95%
weeks gestation to reduce postnatal
haemoglobin decline. Out of 31 infants given          Option A is incorrectly concluding cause and
the treatment none suffered serious side-effects.     effect from an association in an observational
What should be concluded from this study?             study. Option C is misinterpreting the given P-
                                                      value. The only hypothesis being tested is that lead
  A     rhEPO is safe                                 in the blood and ability scores are not associated,
  B     rhEPO is safe when used in dosages            so D is incorrect. Option E is a way in which
  used in this study                                  significance tests are often classically
  C     Nothing conclusive can be said, a larger      misinterpreted.
  study is needed
  D     rhEPO does not cause serious side-            67- A study is being planned to investigate the
  effects when used in moderate doses                 effect of environmental exposure to pesticides
  E     Premature infants of less than 33 weeks       on the incidence of cancer. Which of the
  gestation can safely be given rhEPO                 following study designs is most appropriate?

Because 0/31 have serious side-effects does not         A     Case-control study
mean that no infants ever will, so the drug has not     B     Case series
been shown to be safe (A, B, D and E are                C     Cohort study
incorrect). If 3% of infants were to have serious       D     Cross-sectional survey
side-effects from taking the drug, then we would        E     Randomised controlled trial
only expect to get 1 in a sample of 30 and it would
not be that surprising to get none. A larger study    A randomised controlled trial is usually considered
needs to be done to try and get a more precise        the ‘gold standard’ study design, however it is not
estimate of the percentage who will suffer serious    suitable here as it would be neither practical nor
side-effects hopefully discounting larger             ethical to randomise subjects to exposure to
percentages.                                          pesticides. A case series would consist of a
                                                      number of patients with cancer who have a past
66- In a cross-sectional study of 600 children,       history of exposure to pesticides. While this may
mental ability scores were calculated from a          be suggestive of a link, it is a very low level of
standardised test. The correlation between lead       evidence. A cross-sectional survey would evaluate
in their blood and their ability score was            the prevalence of cancer rather than the incidence.
reported as r = –0.05, P < 0.05. What does this       A cohort study could answer the study question by
show?                                                 following up an entire population over time,
                                                      measuring exposure to pesticides and observing
  A     Extra patients should be recruited and        for an outcome of cancer. This design is, however,
  randomised to the treatments in such a way          likely to be prohibitively expensive. A case-
  that a balance in mean age is achieved              control study, the past history of pesticide
  B     Higher levels of lead in the blood are        exposure in a group of patients with cancer
  weakly associated with lower ability scores         (cases), would be compared to that of a group of
  C     The association between lead in the           patients without cancer (controls). This would
  blood and ability score is likely to be due to      enable us to answer the study question but avoids
  chance                                              the need for long and expensive follow-up
  D     The null hypothesis for the significance      required for a cohort study.
          Answers Key
1-    b   24-   b       47-   b
2-    a   25-   c       48-   e
3-    d   26-   d       49-   c
4-    c   27-   b       50-   b
5-    d   28-   a       51-   e
6-    e   29-   b       52-   a
7-    a   30-   b       53-   a
8-    e   31-   b       54-   d
9-    b   32-   c       55-   e
10-   a   33-   b       56-   a
11-   b   34-   a       57-   b
12-   e   35-   c       58-   b
13-   c   36-   e       59-   c
14-   b   37-   a       60-   b
15-   b   38-   b       61-   b
16-   d   39-   d       62-   a
17-   c   40-   d       63-   d
18-   d   41-   e       64-   e
19-   b   42-   c       65-   c
20-   e   43-   c       66-   b
21-   e   44-   c       67-   a
22-   d   45-   a
23-   d   46-   d