Hereditary non-polyposis syndrome (HNPCC) is the most common type of inherited colorectal cancer. It often presents in younger and younger generations down a family. FAP presents with 100’s-1000’s of polyps and is less common. Li-Fraumeni syndrome and Fanconi syndrome are rare. For Peutz-Jeghers syndrome, the thing you will look for in the question stem is discoloured spots on the lips, this is classic.

Gastrin is released from G cells in the antrum of the stomach after a meal. It stimulates parietal cells to release HCl. Gastrin is stimulated by a number of things: antrum distention, vagal stimulation, peptides (especially amino acids) in the stomach, hypercalcemia. Gastrin release is inhibited by acid, SST, GIP, VIP, secretin, glucagon, and calcitonin.

Proton pump inhibitors can reduce gastric acid secretion by up to 99%. Acid production resumes following the normal renewal of gastric parietal cells.

Carbon monoxide (CO) poisoning, considered as the great imitator of other diseases, as the patients present with a myriad of symptoms. The carbon monoxide diffuses rapidly across the pulmonary capillary membrane binding to the haem molecule with a very high affinity (240 times that of oxygen) forming carboxy-haemoglobin (COHb). Non-smokers have a baseline COHb of ,3% while smokers have a baseline COHb of 10-15%.

Use of Hyperbaric oxygen therapy (HBOT) for treatment of mild to moderate CO poisoning is not routine.
The selection criteria for HBOT in cases of CO poisoning include:
• COHb levels > 20-25%
• COHb levels > 20% in pregnant patient
• Loss of consciousness
• Severe metabolic acidosis (pH <7.1)
• Evidence of end-organ ischemia (e.g., ECG changes, chest pain, or altered mental status)
Principle of HBOT:
Exposing patients to 100 percent oxygen under supra-atmospheric conditions results in a decrease in the half-life (t1/2) of COHb, from , 90 min in atmospheric air to , 30 minutes. The amount of oxygen dissolved in the blood also rises from , 0.3 to 6 mL/dL, increasing the delivery of non-haemoglobin-bound oxygen to the tissues.

Insulin/dextrose infusion will increase the activity of the sodium-potassium pump in the cells, which will in turn decrease serum potassium levels.

Absolute contraindications for fibrinolytic use in STEMI

Prior intracranial haemorrhage (ICH)
Known structural cerebral vascular lesion
Known malignant intracranial neoplasm
Ischemic stroke within 3 months
Suspected aortic dissection
Active bleeding or bleeding diathesis (excluding menses)
Significant closed head trauma or facial trauma within 3 months
Intracranial or intraspinal surgery within 2 months
Severe uncontrolled hypertension (unresponsive to emergency therapy)
For streptokinase, prior treatment within the previous 6 months

Osteomalacia is a condition due to defective mineralization of osteoid. Occurs as a result of Vitamin D deficiency secondary to poor dietary intake and sun exposure, malabsorption e.g., inflammatory bowel disease and gastrointestinal bypass surgery. Radiological findings include reduced bone mineral density (a non specific finding), inability to radiologically distinguish vertebral body trabeculae (the film appears poor quality), looser pseudo fractures, fissures, or narrow radiolucent lines (these are the characteristic findings). Osteolytic or punched out lesions may be seen with multiple myeloma and bony metastases. Areas of sclerosis may be observed with conditions like osteosclerosis and Paget disease. A Brodie abscess is a subacute osteomyelitis, which may persist for years before progressing to a chronic, frank osteomyelitis.

Granulomatosis with polyangiitis (GPA, previously known as Wegener’s granulomatosis) is a systemic vasculitis that affects both small and medium-sized vessels. Patients typically initially suffer from a limited form that may consist of constitutional symptoms and localized manifestations such as chronic sinusitis, rhinitis, otitis media, ocular conditions. In later stages, more serious manifestations may arise, including pulmonary complications and glomerulonephritis, although the skin, eyes, and heart may also be involved but these lesions are less common.
Diagnosis is based on laboratory testing (positive for PR3-ANCA/c-ANCA), imaging, and biopsy of affected organs, which demonstrate necrotizing granulomatous inflammation. GPA is treated with immunosuppressive drugs, typically consisting of glucocorticoids combined with methotrexate, cyclophosphamide, or rituximab. Relapses are common and the following systems are affected: Lower respiratory tract (95% of cases), renal involvement (80% of cases), skin lesions (45% of cases), ocular involvement (45% of cases) and cardiac involvement (33% of cases).

Secretin is a peptide hormone produced in the S cells of the duodenum, which are located in the intestinal glands. In humans, the secretin peptide is encoded by the SCT gene.
Secretin helps regulate the pH of the duodenum by
1) inhibiting the secretion of gastric acid from the parietal cells of the stomach and
(2) stimulating the production of bicarbonate from the ductal cells of the pancreas.
G cells in the antrum of the stomach release gastrin
I cells in upper small intestine release CCK
D cells in the pancreas & stomach secrete somatostatin
K cells secrete gastric inhibitory peptide, an incretin, which also promotes triglyceride storage.

Malingering is not considered a mental illness. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), malingering receives a V code as one of the other conditions that may be a focus of clinical attention. The DSM-5 describes malingering as the intentional production of false or grossly exaggerated physical or psychological problems. Motivation for malingering is usually external (e.g., avoiding military duty or work, obtaining financial compensation, evading criminal prosecution, or obtaining drugs).

Malingering should be strongly suspected if any combination of the following factors is noted to be present: (1) medicolegal context of presentation; (2) marked discrepancy between the person’s claimed stress or disability and the objective findings; (3) lack of cooperation during the diagnostic evaluation and in complying with the prescribed treatment regimen; and (4) the presence in the patient of antisocial personality disorder (ASPD).

This patient is be pretending to be sick in order to get morphine.

Loss of vision after consumption of antifreeze is a characteristic presentation of methanol poisoning.

Pathophysiology of methanol toxicity:
When ingested, methanol is absorbed rapidly via the gastrointestinal tract in less than 10 minutes. Methanol is not protein-bound and is absorbed directly into the total body water compartment.
Metabolism occurs mainly in the liver through serial oxidation via alcohol dehydrogenase and aldehyde dehydrogenase but begins with alcohol dehydrogenase present in the gastric mucosa.
Alcohol dehydrogenase oxidizes methanol to formaldehyde, and aldehyde dehydrogenase subsequently oxidizes formaldehyde to formic acid.
Formic acid is the primary toxic metabolite that accounts for the associated anion gap metabolic acidosis and end-organ damage.

Clinical presentation:
Patients who present within the first 12 to 24 hours following ingestion may appear normal, and this is described as the latent period.
Nausea, vomiting, and abdominal pain subsequently ensue, followed by CNS depression and hyperventilation due to metabolic acidosis.
Ocular symptoms associated with retinal toxicity are often evident in the form of blurry vision, decreased visual acuity, photophobia, and “halo vision.”

Treatment:
Treatment options for methanol toxicity include supportive care, fomepizole (Antizole, 4-Methylpyrazole or 4MP), ethanol, dialysis, and folate.

Hyperacute rejection appears in the first minutes following transplantation and occurs only in vascularized grafts. This very fast rejection is characterized by vessel thrombosis leading to graft necrosis. Hyperacute rejection is caused by the presence of antidonor antibodies existing in the recipient before transplantation. These antibodies induce both complement activation and stimulation of endothelial cells to secrete Von Willebrand procoagulant factor, resulting in platelet adhesion and aggregation. The result of these series of reactions is the generation of intravascular thrombosis leading to lesion formation and ultimately to graft loss. Today, this type of rejection is avoided in most cases by checking for ABO compatibility and by excluding the presence of antidonor human leukocyte antigen (HLA) antibodies by cross-match techniques between donor graft cells and recipient sera. This type of rejection is also observed in models of xenotransplantation of vascularized organs between phylogenetically distant species when no immunosuppressive treatment is given to the recipients.

Charles Bonnet syndrome (CBS) involves visual hallucinations due to eye disease, usually associated with a sharp decline in vision. The phenomenon is seen in patients with moderate or severe visual impairment. It can occur spontaneously as the vision declines or it may be precipitated, in predisposed individuals, by concurrent illness such as infections elsewhere in the body.

It is not clear why CBS develops or why some individuals appear to be predisposed to it. It is particularly noted in patients with advanced macular degeneration. It has been suggested that reduced or absent stimulation of the visual system leads to increased excitability of the visual cortex (deafferentation hypothesis). This release phenomenon is compared to phantom limb symptoms after amputation.

CBS is much more common in older patients because conditions causing marked visual loss are more common in older people. However, it can occur at any age and has been described in children.
The prevalence is hard to assess due to considerable under-reporting, perhaps because patients frequently fear that it is a sign of mental illness or dementia. However, it is thought to occur in:
About 10-15% of patients with moderate visual loss.
Possibly up to 50% of people with severe visual loss.
Presentation:
The nature of the hallucination depends on the part of the brain that is activated. The hallucinations may be black and white or in colour. They may involve grids/brickwork/lattice patterns but are typically much more complex:

The hallucinations are always outside the body.
The hallucinations are purely visual – other senses are not involved.
The hallucinations have no personal meaning to the patient.
Hallucinations may last seconds, minutes or hours.
CBS tends to occur in a ‘state of quiet restfulness’. This may be after a meal or when listening to the radio (but not when dozing off).
Symptoms also have a tendency to occur in dim lighting conditions.
Patients may report high levels of distress, with some patients reporting anger, anxiety and even fear associated with the hallucinations.

CHA₂DS₂-VASc score is used for atrial fibrillation stroke risk calculation.
Congestive heart failure – 1 point
Hypertension – 1 point
Age ≥75 years – 2 points
Diabetes mellitus – 1 point
Stroke/Transient Ischemic Attack/Thromboembolic event – 2 points
Vascular disease (prior MI, PAD, or aortic plaque) – 1 point
Age 65 to 74 years – 1 point
Sex category (i.e., female sex) – 1 point
Score of 2 or more is considered as high risk and anticoagulation is indicated. This patient’s score is 4, so he needs life-long warfarin to prevent a stroke.

The most probable diagnosis for this patient is delirium tremens due to alcohol withdrawal, which should be treated as a medical emergency. 
Delirium tremens is a hyperadrenergic state and is often associated with tachycardia, hyperthermia, hypertension, tachypnoea, tremor, and mydriasis.
Treatment:
– The most common and validated treatment for alcohol withdrawal is benzodiazepine: first-line treatment includes oral lorazepam.
– If the symptoms persist, or the medication is refused, parenteral lorazepam, haloperidol or olanzapine should be given.
– Central-acting, alpha-2 agonists such as clonidine and dexmedetomidine should not be used alone for the treatment of alcohol withdrawal.
– It is also recommended to avoid using alcohol, antipsychotics, anticonvulsants, beta-adrenergic receptor blockers, and baclofen for the treatment of alcohol withdrawal as there are not enough studies to support the safety of these.

Burkitt lymphoma is a germinal centre B-cell-derived cancer that was instrumental in the identification of MYC as an important human oncogene more than three decades ago. Recently, new genomics technologies have uncovered several additional oncogenic mechanisms that cooperate with MYC to create this highly aggressive cancer.

Bradycardia and miosis should be anticipated following the administration of anticholinesterases.

Anticholinesterase agents include the following medications:
– Pyridostigmine, neostigmine, and edrophonium which play a significant role in the diagnosis and the management of myasthenia gravis.
– Rivastigmine, galantamine and donepezil are cholinesterase inhibitors found to be significantly useful in the management of Alzheimer’s disease.

Mechanism of action and pharmacological effects:
Inhibition of cholinesterase increases the level and the duration of action of acetylcholine within the synaptic cleft.

Thus, cholinergic effects such as a reduction in heart rate (bradycardia), miosis (pupillary constriction), increased secretions, increased gastrointestinal motility and reduction in BP may occur with anticholinesterases.

Toxins such as organophosphates and carbamates also are primarily anticholinergic and cause the following typical SLUDGE symptoms:
– Salivation
– Lacrimation
– Urination
– Diaphoresis
– Gastrointestinal upset
– Emesis

PCR is a simple, yet elegant, enzymatic assay, which allows for the amplification of a specific DNA fragment from a complex pool of DNA. PCR can be performed using source DNA from a variety of tissues and organisms, including peripheral blood, skin, hair, saliva, and microbes. Only trace amounts of DNA are needed for PCR to generate enough copies to be analysed using conventional laboratory methods. For this reason, PCR is a sensitive assay. Each PCR assay requires the presence of template DNA, primers, nucleotides, and DNA polymerase. The DNA polymerase is the key enzyme that links individual nucleotides together to form the PCR product. The above mentioned components are mixed in a test tube or 96-well plate and then placed in a machine that allows repeated cycles of DNA amplification to occur in three basic steps. The machine is essentially a thermal cycler. It has a thermal block with holes, into which the test tubes or plates holding the PCR reaction mixture are inserted. The machine raises and lowers the temperature of the block in discrete, precise and pre-programmed steps. The reaction solution is first heated above the melting point of the two complementary DNA strands of the target DNA, which allows the strands to separate, a process called denaturation. The temperature is then lowered to allow the specific primers to bind to the target DNA segments, a process known as hybridization or annealing. Annealing between primers and the target DNA occurs only if they are complementary in sequence (e.g. A binding to G). The temperature is raised again, at which time the DNA polymerase is able to extend the primers by adding nucleotides to the developing DNA strand. With each repetition of these three steps, the number of copied DNA molecules doubles.

In general, the aim is to keep the homocysteine (Hcy) concentration as close to normal as possible. In patients who are fully-responsive to pyridoxine, standard doses can lead to tHcy levels below 50 μmol/L (and sometimes within the normal range). Some patients who are partially-responsive to pyridoxine may be able to achieve a tHcy level below 50 μmol/L if they are also on a low-Met diet; for others it is not a realistic goal.

Mechanism of action of low molecular weight heparin (LMWH):
It inhibits coagulation by activating antithrombin III. Antithrombin III binds to and inhibits factor Xa. In doing so it prevents activation of the final common path; Xa inactivation means that prothrombin is not activated to thrombin, thereby not converting fibrinogen into fibrin for the formation of a clot.

LMHW is a small fragment of a larger mucopolysaccharide, heparin. Heparin works similarly, by binding antithrombin III and activating it. Heparin also has a binding site for thrombin, so thrombin can interact with antithrombin III and heparin, thus inhibiting coagulation.
Heparin has a faster onset of anticoagulant action as it will inhibit not only Xa but also thrombin, while LMWH acts only on Xa inhibition.

Compared to heparin, LMWHs have a longer half-life, so dosing is more predictable and can be less frequent, most commonly once per day.

Dosage and uses:
LMWH is administered via subcutaneous injection. This has long-term implications on the choice of anticoagulant for prophylaxis, for example, in orthopaedic patients recovering from joint replacement surgery, or in the treatment of DVT/PE.

Adverse effects:
The main risk of LMWH will be bleeding. The specific antidote for heparin-induced bleeding is protamine sulphate.
Less commonly it can cause:
Heparin-induced thrombocytopenia (HIT)
Osteoporosis and spontaneous fractures
Hypoaldosteronism
Hypersensitivity reactions

Type I interferons (IFNs) form a network of homologous cytokines that bind to a shared, heterodimeric cell surface receptor and engage signalling pathways that activate innate and adaptive immune responses.

Severe acute respiratory syndrome (SARS) is a viral respiratory illness caused by a coronavirus called SARS-associated coronavirus (SARS-CoV). SARS was first reported in Asia in February 2003.
In general, SARS begins with a high fever (temperature greater than 38.0°C). Other symptoms may include headache, an overall feeling of discomfort, and body aches. Some people also have mild respiratory symptoms at the outset. About 10 to 20 percent of patients have diarrhoea. After 2 to 7 days, SARS patients may develop a dry cough. Most patients develop pneumonia. 

Philadelphia translocation, t(9;22), is a marker of poor prognosis in acute lymphoblastic leukaemia (ALL).

ALL is the malignancy of lymphoid progenitor cells affecting B or T cell lineage. This results in the arrest of lymphoid cell maturation and proliferation of immature blast cells (lymphoblasts), leading to bone marrow and tissue infiltration.

ALL is the most common type of childhood cancers. Its peak incidence is between two to three years of age.

Acute B lymphoblastic leukaemia (B-ALL) is the most common type of ALL, involving overproduction of B-cell lymphoblasts. It is manifested by low initial WCC and is associated with a good prognosis.

Poor prognostic factors for ALL include:
1. Pre-B cell or T-cell ALL (T-ALL)
2. Philadelphia translocation, t(9;22)
3. Age <2 years or >10 years
4. Male sex
5. CNS involvement
6. High initial WBC (e.g. >100 x 10^9/L)
7. non-Caucasian

The C8 nerve forms part of the radial and ulnar nerves via the brachial plexus, and therefore has motor and sensory function in the upper limb. It originates from the spinal column from below the cervical vertebra 7 (C7).
The C8 nerve receives sensory afferents from the C8 dermatome. This consists of all the skin on the little finger, and continuing up slightly past the wrist on the palmar and dorsal aspects of the hand and forearm.
The other options available correspond to the C6 or C7 roots and these are unaffected as evidenced by normal elbow flexion and thumb sensation (C6) and normal sensation over the middle finger (C7). Elbow extension is weak as it has roots from both C7 and C8 and so cannot be used alone to decide between the two levels clinically.
The C8 nerve contributes to the motor innervation of many of the muscles in the trunk and upper limb. Its primary function is the flexion of the fingers, and this is used as the clinical test for C8 integrity, in conjunction with the finger jerk reflex.

Trunk:
– Pectoralis major – Medial and lateral pectoral nerves (C5, C6, C7, C8, T1)
– Pectoralis minor – Medial pectoral nerve (C5, C6, C7,C8, T1)
– Latissimus dorsi – Thoracodorsal nerve (C6, C7, C8)
Upper arm:
– Triceps brachii – Radial nerve (C6, C7,C8)
Forearm
– Flexor carpi ulnaris – Ulnar nerve (C7, C8, T1)
– Palmaris longus – Median nerve (C7,C8)
– Flexor digitorum superficialis – Median nerve (C8, T1)
– Flexor digitorum profundus – Median and Ulnar nerves (C8, T1)
– Flexor pollicis longus – Median nerve (C7,C8)
– Pronator quadratus – Median nerve (C7,C8)
– Extensor carpi radialis brevis – Deep branch of the radial nerve (C7,C8)
– Extensor digitorum – Posterior interosseous nerve (C7,C8)
– Extensor digiti minimi – Posterior interosseous nerve (C7,C8)
– Extensor carpi ulnaris – Posterior interosseous nerve (C7,C8)
– Anconeus – Radial nerve (C6, C7,C8)
– Abductor pollicis longus – Posterior interosseous nerve (C7,C8)
– Extensor pollicis brevis – Posterior interosseous nerve (C7,C8)
– Extensor pollicis longus – Posterior interosseous nerve (C7,C8)
– Extensor indicis – Posterior interosseous nerve (C7,C8)
Hand
– Palmaris brevis – Superficial branch of ulnar nerve (C8, T1)
– Dorsal interossei – Deep branch of ulnar nerve (C8, T1)
– Palmar interossei – Deep branch of ulnar nerve (C8, T1)
– Adductor pollicis – Deep branch of ulnar nerve (C8, T1)
– Lumbricals – Deep branch of ulnar, Digital branches of median nerve
– Opponens pollicis – Recurrent branch of median nerve (C8, T1)
– Abductor pollicis brevis – Recurrent branch of median nerve (C8, T1)
– Flexor pollicis brevis – Recurrent branch of median nerve (C8, T1)
– Opponens digiti minimi – Deep branch of ulnar nerve (C8, T1)
– Abductor digiti minimi – Deep branch of ulnar nerve (C8, T1)
– Flexor digiti minimi brevis – Deep branch of ulnar nerve (C8, T1)

Temazepam is a medication that is often prescribed for the treatment of short-term insomnia. It belongs to the benzodiazepine family of drugs and is classed as intermediate-acting, meaning that it can take between six and twenty-four hours for the drug to take effect.

Although it is known that shorter-acting benzodiazepines are more harmful and more likely to cause addiction, temazepam is, nevertheless, a highly addictive drug. It should not be taken for longer than four weeks.

-Adverse effects associated with the use of benzodiazepine hypnotics (to which the elderly are most vulnerable) include confusion, over sedation, increased risks of falls and consequent fractures

-Withdrawal from a benzodiazepine hypnotic must be agreed between the clinician and the patient – patients should never be forced or threatened. The risks of continued benzodiazepine use should be explained. An agreed schedule for reduction of and gradual withdrawal from the benzodiazepine hypnotic should also be agreed. This will involve substitution of the hypnotic with a long-acting benzodiazepine (e.g. diazepam) and a subsequent gradual reduction in dose of the substituted benzodiazepine -the substituted benzodiazepine can then be withdrawn in steps of about one-eighth to one-tenth every fortnight
Example: withdrawal schedule for patient on temazepam 20mg nocte
week 1 – temazepam 10mg, diazepam 5mg
week 2 – stop temazepam, diazepam 10mg
week 4 – diazepam 9mg
week 6 – diazepam 8mg
continue reducing dose of diazepam by 1mg every fortnight – tapering of dose may be slower if necessary

European guidelines for the treatment of syndrome of inappropriate antidiuresis include the following recommendations for the management of moderate or profound hyponatremia:
– Restrict fluid intake as first-line treatment.
– Second-line treatments include increasing solute intake with 0.25–0.50 g/kg per day or a combination of low-dose loop diuretics and oral sodium chloride.
– Use of lithium, demeclocycline, or vasopressin receptor antagonists is not recommended.
Recommendations on the treatment of SIADH from an American Expert Panel included the following:
– If chronic, limit the rate of correction.
– Fluid restriction should generally be first-line therapy.
– Consider pharmacologic therapies if serum Na + is not corrected after 24-48 hr of fluid restriction or if the patient has a low urinary electrolyte free water excretion.
– Patients being treated with vaptans should not be on a fluid restriction initially.
– Water, 5% dextrose or desmopressin can be used to slow the rate of correction if the water diuresis is profound.

The phrenic nerve provides the primary motor supply to the diaphragm, the major respiratory muscle.
Phrenic nerve paralysis is a rare cause of exertional dyspnoea that should be included in the differential diagnosis. Fluoroscopy is considered the most reliable way to document diaphragmatic paralysis. During fluoroscopy a patient is asked to sniff and there is a paradoxical rise of the paralysed hemidiaphragm. This is to confirm that the cause is due to paralysis rather than unilateral weakness.

In such a clinical scenario, NICE guidelines support initiating treatment with bisphosphonates without waiting for a DEXA scan.

Osteoporosis is defined as low bone mineral density caused by altered bone microstructure ultimately predisposing patients to low-impact, fragility fractures.

Management:
Vitamin D and calcium supplementation should be offered to all women unless the clinician is confident they have adequate calcium intake and are vitamin D replete
Alendronate is the first-line treatment. Around 25% of patients cannot tolerate alendronate, usually due to upper gastrointestinal problems. These patients should be offered risedronate or etidronate.
Strontium ranelate and raloxifene are recommended if patients cannot tolerate bisphosphonates.
Other medications that are useful in the treatment of osteoporosis are denosumab, teriparatide, raloxifene, etc.

V/Q scanning carries a slightly increased risk of childhood cancer compared with CTPA – 1/280,000 versus less than 1/1,000,000 – but carries a lower risk of maternal breast cancer. The rest of the options are true.

The ECG findings are suggestive of anterior myocardial infarction and the most likely artery affected is the left anterior descending artery. Occlusion of the right coronary artery will be shown by ST elevation in lead II, III, aVF and occlusion of the circumflex artery will show changes in leads I, aVL, V5 and V6. To have ST elevation, there should be complete occlusion of the artery.