Haemoglobin is composed of four polypeptide globin chains each with its own iron containing haem molecule. Haem synthesis occurs largely in the mitochondria by a series of biochemical reactions commencing with the condensation of glycine and succinyl coenzyme A under the action of the key rate-limiting enzyme delta-aminolevulinic acid (ALA) synthase. The globin chains are synthesised by ribosomes in the cytosol. Haemoglobin synthesis only occurs in immature red blood cells.
There are three types of haemoglobin in normal adult blood: haemoglobin A, A2 and F:
– Normal adult haemoglobin (HbA) makes up about 96 – 98 % of total adult haemoglobin, and consists of two alpha (α) and two beta (β) globin chains. 
– Haemoglobin A2 (HbA2), a normal variant of adult haemoglobin, makes up about 1.5 – 3.5 % of total adult haemoglobin and consists of two α and two delta (δ) globin chains.
– Foetal haemoglobin is the main Hb in the later two-thirds of foetal life and in the newborn until approximately 12 weeks of age. Foetal haemoglobin has a higher affinity for oxygen than adult haemoglobin. 
Red cells are destroyed by macrophages in the liver and spleen after , 120 days. The haem group is split from the haemoglobin and converted to biliverdin and then bilirubin. The iron is conserved and recycled to plasma via transferrin or stored in macrophages as ferritin and haemosiderin. An increased rate of haemoglobin breakdown results in excess bilirubin and jaundice.

Short vessels called arteriovenous anastomoses (AVAs) link tiny arteries and veins. They have a large lumen diameter. The strong and muscular walls allow AVAs to completely clog the vascular lumen, preventing blood flow from artery to vein (acting like a sphincter). When the AVAs open, they create a low-resistance connection between arteries and veins, allowing blood to flow into the limbs’ superficial venous plexuses. There is no diffusion of solutes or fluid into the interstitium due to their strong muscle walls.

AVAs are densely innervated by adrenergic fibres from the hypothalamic temperature-regulation centre. High sympathetic output occurs at normal core temperatures, inducing vasoconstriction of the AVAs and blood flow through the capillary networks and deep plexuses. When the temperature rises, sympathetic output decreases, producing AVA vasodilation and blood shunting from the artery to the superficial venous plexus. Heat is lost to the environment as hot blood rushes near to the skin’s surface.
AVAs are a specialized anatomical adaptation that can only be found in large quantities in the fingers, palms, soles, lips, and pinna of the ear.

Most vasoconstrictors bind to G-protein coupled receptors. These mediate elevation in intracellular [Ca2+] which leads to vascular smooth muscle contraction. Important vasoconstrictors include noradrenaline, endothelin-1 and angiotensin II.

Increased intracellular Ca2+ is as a result of the release of Ca2+from the sarcoplasmic reticulum and depolarisation and entry of Ca2+via L-type voltage-gated Ca2+channels. Most types of vascular smooth muscle do not generate action potentials – instead, the depolarisation is graded, which allows graded entry of Ca2+.
sequestration by the sarcoplasmic reticulum Ca2+ATPase, removal from the cell by a plasma membrane Ca2+ATPase and Na+/Ca2+exchange decreases intracellular Ca2+, resulting in vasodilation. Relaxation is a result of most endogenous vasodilators when there is an increase in cyclic guanosine monophosphate (cGMP) like nitric oxide) or cyclic adenosine monophosphate (cAMP) like prostacyclin and beta-adrenergic receptor agonists. These activate protein kinases causing substrate level phosphorylation.
Clinically effective vasodilators are L-type Ca2+channel blocker drugs.

The nerves that supply the adductor magnus muscle have an embryologic origin from the anterior divisions of the lumbosacral plexus and include the obturator nerve, posterior division (L2-4), and the tibial portion of the sciatic nerve (L4). It is innervated by the posterior division of the obturator nerve.

Legionella pneumophilais a Gram negative bacterium that is found in natural water supplies and in the soil, transmitted predominantly via inhalation of aerosols generated from contaminated water (direct person-to-person spread of infected patients does not occur). It is the cause of Legionnaires’ disease. Outbreaks of Legionnaires’ disease have been linked to poorly maintained air conditioning systems, whirlpool spas and hot tubs.

The clinical features of the pneumonic form of Legionnaires’ disease include:
Mild flu-like prodrome for 1-3 days
Cough (usually non-productive and occurs in approximately 90%)
Pleuritic chest pain
Haemoptysis
Headache
Nausea, vomiting and diarrhoea
Anorexia
Legionella pneumophilainfections can be successfully treated with macrolide antibiotics, such as erythromycin, or quinolones, such as ciprofloxacin. Tetracyclines, such as doxycycline, can also be used.
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can occur with Legionnaires’ disease and will result in hyponatraemia as is seen in this case.
Legionella pneumophilainfections are resistant to amoxicillin but can be successfully treated with macrolide antibiotics, such as erythromycin, or quinolones, such as ciprofloxacin. Tetracyclines, such as doxycycline, can also be used. The majority of cases of Legionnaires’ disease are caused by Legionella pneumophila, however many other species of Legionella have been identified.
Legionella longbeachae is another less commonly encountered species that has also been implicated in outbreaks. It is predominantly found in soil and potting compost, and has caused outbreaks of Pontiac fever, the non-respiratory and less severe variant of Legionnaires’ disease.

Klumpke palsy, named after Augusta Dejerine-Klumpke, is a neuropathy involving the lower brachial plexus. In contrast, the more common Erb–Duchenne palsy involves the more cephalic portion of the brachial plexus C5 to C6. The brachial plexus is a bundle of individual nerves that exit between the anterior and middle scalene muscles in the anterior lateral and basal portion of the neck. Although the most common anatomical presentation of the brachial plexus is between the anterior and middle scalene, there are variations, with the most common being penetration of the anterior scalene. The main mechanism of injury to the lower brachial plexus is hyper-abduction traction, and depending on the intensity, it will lead to signs and symptoms consistent with a neurological insult.

The most common aetiology resulting in Klumpke palsy is a hyper-abduction trauma to the arm that has enough intensity to traction the lower brachial plexus. Trauma during birth can cause brachial plexus injuries, but again hyper-abduction and traction forces to the upper extremity are usually present.

The history presented by the patient usually depicts a long axis hyper-abduction traction injury with high amplitude and velocity. The typical patient presentation is a decrease of sensation along the medial aspect of the distal upper extremity along the C8 and T1 dermatome. The patient might also present myotome findings that can range from decreasing muscular strength to muscular atrophy and positional deformity. For example, if the neurological damage has led to muscular atrophy and tightening, the patient may present with a claw hand. This deformity presents a finger and wrist flexion. The patient may also describe the severe pain that starts at the neck and travels down the medial portion of the arm. One other sign of a lower brachial plexus injury is Horner syndrome; because of its approximation to the T1 nerve root, it may damage the cephalic sympathetic chain. If this happens, the patient will develop ipsilateral ptosis, anhidrosis, and miosis.

Kaplan-Meier estimate is one of the best options to be used to measure the fraction of subjects living for a certain amount of time after treatment. In clinical trials or community trials, the effect of an intervention is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of a given event, for example death, is called as survival time and the analysis of group data as survival analysis.

The graph plotted between estimated survival probabilities/estimated survival percentages (on Y axis) and time past after entry into the study (on X axis) consists of horizontal and vertical lines.

Bumetanide is primarily used in patients with heart failure who have failed to respond to high doses of furosemide. Bumetanide and furosemide differ primarily in terms of bioavailability and pharmacodynamic potency. In the intestine, furosemide is only partially absorbed, with a bioavailability of 40-50 percent. Bumetanide, on the other hand, is almost completely absorbed in the intestine and has a bioavailability of about 80%. As a result, when it has a better bioavailability than furosemide, it is commonly used in patients with gut oedema.

When taken alone, Bendroflumethiazide is a moderately potent diuretic that is unlikely to control her oedema.

Mannitol is a type of osmotic diuretic used to treat cerebral oedema and high intracranial pressure.

Acetazolamide is a weak diuretic that inhibits carbonic anhydrase. It’s a rare occurrence.

The gastrocnemius is innervated by the anterior rami of S1 and S2 spinal nerves, carried by the tibial nerve into the posterior compartment of the leg.

Bone pain, pathologic fractures, weakness, anaemia, infection, hypercalcemia, spinal cord compression, and renal failure are all signs and symptoms of multiple myeloma (MM). The patient’s condition matched the signs and symptoms of myeloma.

The NICE guidelines for pregnant women with lower UTIs are:
1. Prescribe an antibiotic immediately, taking into account the previous urine culture and susceptibility results or avoiding past antibiotics that may have caused resistance
2. Obtain a midstream urine sample before starting antibiotics and send for urine culture and susceptibility
– Review the choice of antibiotic when the results are available
– change the antibiotic according to susceptibility results if the bacteria are resistant, using a narrow-spectrum antibiotic wherever possible

The first choice of antibiotics for pregnant women aged 12 years and over is:
1. Nitrofurantoin
100 mg modified-release PO BD for 3 days – if eGFR >45 ml/minute

The second-choice (no improvement in lower UTI symptoms on first-choice for at least 48 hours, or when first-choice is not suitable) are:
1. Amoxicillin
500 mg PO TDS for seven days (ONLY if culture results available and susceptible)
2. Cefalexin
500 mg BD for seven days
Alternative second-choices – consult local microbiologist, choose antibiotics based on culture and sensitivity results

The heart sounds are as a result of the various parts of the cardiac cycle.
Heart Sound – Phase of Cardiac Cycle – Mechanical Event:
1st heart sound – Systole starts – there is closure of the atrioventricular (mitral & tricuspid) valves
2nd heart sound – Systole ends – there is closure of the semilunar (aortic and pulmonary) valves
3rd heart sound – Early diastole – this is caused by rapid flow of blood from the atria into the ventricles during the ventricular filling phase
4th heart sound – Late diastole – this is caused by filling of an abnormally stiff ventricle in atrial systole

Nitrates are used in the treatment of angina pectoris and the prevention of myocardial ischaemia. Commonly used examples of nitrates are glyceryl trinitrate and isosorbide dinitrate. Unwanted effects, however, are common and can limit therapy, particularly when angina is severe or when patients are unusually sensitive to the effects of nitrates.
The following are common or very common side effects of nitrates
Arrhythmias
Asthenia
Cerebral ischaemia
Dizziness
Drowsiness
Flushing
Headache
Hypotension
Nausea and vomiting
Diarrhoea, syncope and cyanosis can occur, but these are rare side effects. Dry eyes, bradycardia and metabolic acidosis have not been reported.

Both the medial and lateral pterygoids are innervated by the mandibular division of the trigeminal nerve.

Codeine phosphate is a weak opioid and can be used for the relief of mild to moderate pain where other painkillers such as paracetamol or ibuprofen have proved ineffective.Codeine is metabolised to morphine which is responsible for its therapeutic effects. Codeine 240 mg is approximately equivalent to 30 mg of morphine. The capacity to metabolise codeine can vary considerably between individuals; there is a marked increase in morphine toxicity in people who are ultra rapid metabolisers, and reduced therapeutic effect in poor codeine metabolisers. Codeine is contraindicated in patients of any age who are known to be ultra-rapid metabolisers of codeine (CYP2D6 ultra-rapid metabolisers).Codeine is also contraindicated in children under 12, and in children of any age who undergo the removal of tonsils or adenoids for the treatment of obstructive sleep apnoea due to reports of morphine toxicity.

Cephalosporins of the first generation  include cephalexin, cefradine, and cefadroxil. Urinary tract infections, respiratory tract infections, otitis media, and skin and soft-tissue infections are all treated with them.

Second-generation cephalosporins include cefuroxime, cefaclor, and cefoxitin. These cephalosporins are less vulnerable to beta-lactamase inactivation than the ‘first-generation’ cephalosporins. As a result, they’re effective against germs that are resistant to other antibiotics, and they’re especially effective against Haemophilus influenzae.

Cephalosporins of the third generation include cefotaxime, ceftazidime, and ceftriaxone. They are more effective against Gram-negative bacteria than second generation’ cephalosporins. They are, however, less effective against Gram-positive bacteria such Staphylococcus aureus than second-generation cephalosporins.

Aspirin works by inhibiting cyclo-oxygenase in an irreversible manner, resulting in a decrease in prostaglandin and thromboxane production. As a result, platelet activation and aggregation are reduced.

Hospital Episode Statistics (HES) is a data warehouse containing details of all admissions, outpatient appointments and A and E attendances at NHS hospitals in England.

Each HES record contains a wide range of information about an individual patient admitted to an NHS hospital, including:
– clinical information about diagnoses and operations
– patient information, such as age group, gender and ethnicity
– administrative information, such as dates and methods of admission and discharge
– geographical information such as where patients are treated and the area where they live

Some benefits of HES include:
– monitor trends and patterns in NHS hospital activity
– assess effective delivery of care
– support local service planning
– reveal health trends over time
– determine fair access to health care

Factors that increase glucagon secretion:
↓ Blood glucose
↑ Amino acids
Cholecystokinin
Catecholamines
Acetylcholine

Factors that decrease glucagon secretion:
↑ Blood glucose
Insulin
Somatostatin
Fatty acids, ketoacids

Acute lymphoblastic leukaemia (ALL) is a clonal (malignant) bone marrow disorder in which early lymphoid precursors multiply and replace the marrow’s normal hematopoietic cells. ALL is most common between the ages of 3 and 7, with 75 percent of cases occurring before the age of 6.

Dietary iron may be in the form of haem or non-haem iron. Haem iron is degraded after absorption through the cell surface to release Fe2+. Most non-haem iron is in the form Fe3+, which is reduced at the luminal surface to the more soluble Fe2+, facilitated by hydrochloric acid in gastric secretions (and enhanced by ascorbic acid). Fe2+is taken across the enterocyte apical membrane by the divalent metal transporter (DMT1). In the enterocyte, Fe2+is then either stored in enterocyte epithelial cells as ferritin, or released into portal plasma via the molecule ferroportin at the basolateral membrane.

Flexor digitorum profundus is a fusiform muscle located deep within the anterior (flexor) compartment of the forearm. Along with the flexor pollicis longus and pronator quadratus muscles, it comprises the deep flexor compartment of the forearm.

Flexor digitorum profundus has a dual innervation:

(1) The medial part of the muscle, that inserts to the fourth and fifth digits, is innervated by the ulnar nerve (C8-T1);

(2) The lateral part, that inserts to the second and third digits, is innervated by the median nerve, via anterior interosseous branch (C8-T1).

Clearance is defined as the volume of plasma that is cleared of a substance per unit time. Inulin clearance is the gold standard for measurement of GFR but creatinine clearance is typically used instead. Creatinine is freely filtered and not reabsorbed, but there is a little creatinine tubular secretion. In practice, GFR is usually estimated from the plasma creatinine using a formula e.g. the MDRD equation making an adjustment for age, sex and race.

G-cells are a type of cell found in the stomach’s pyloric antrum, duodenum, and pancreas. The secretion of the peptide hormone gastrin is their major function.

The table below summarizes the many cell types found in the stomach, as well as the substances secreted by each cell type and the function of the secretion:

Cell type/ Substance secreted/ Function of secretion
Parietal cells/ Hydrochloric acid/ Kills microbes and activates pepsinogen
Parietal cells/ Intrinsic factor/Binds to vitamin B12 and facilitates its absorption
Chief cells/ Pepsinogen/ Protein digestion
Chief cells/ Gastric lipase/ Fat digestion
G-cells/ Gastrin/ Stimulates gastric acid secretion
Enterochromaffin-like cells (ECL cells) /Histamine/ Stimulates gastric acid secretion
Mucous-neck cells/ Mucous and bicarbonate/ Protects stomach epithelium from acid
D-cells/ Somatostatin/ Inhibits gastric acid secretion

As the contents of the intestine are isotonic with body fluids and mostly have the same concentration of the major electrolytes, their absorption is active. Water cannot be moved directly, but follows osmotic gradients set up by the transport of ions, primarily mediated by the sodium pump.Na+/K+ ATPase located on the basolateral membrane of the epithelial cells pumps three Na+ ions from the cell in exchange for two K+ ions, against their respective concentration gradients. This leads to a low intracellular concentration of Na+ and a high intracellular concentration of K+. The low intracellular concentration of Na+ ensures a movement of Na+ from the intestinal contents into the cell down its concentration gradient by both membrane channels and transporter protein mechanisms. Na+ is then rapidly pumped again by the basolateral sodium pump. K+ leaves the cell across the basolateral membrane down its concentration gradient linked to an outward movement of Cl- against its concentration gradient (Cl- having entered the cell across the luminal membrane down its concentration gradient).

Grey baby syndrome is a rare but causes significant adverse effect caused by the build-up of chloramphenicol in neonates (particularly preterm babies).

The following are the main characteristics of ‘grey baby syndrome’:

Skin that is ashy grey in colour.
Feeding problems
Vomiting
Cyanosis
Hypotension
Hypothermia
Hypotonia
Collapse of the cardiovascular system
Distension of the abdomen
trouble breathing

Polycythaemia vera (PCV), which is also referred to as polycythaemia rubra vera, is a clonal haematological malignancy in which the bone marrow produces too many red blood cells. It may also result in the overproduction of white blood cells and platelets. It is most commonly seen in the elderly and the mean age at diagnosis is 65-74 years.
Patients can be completely asymptomatic and it is often discovered as an incidental finding on a routine blood count. Approximately 1/3 of patients present with symptoms due to thrombosis, of these 3/4 have arterial thrombosis and 1/4 venous thrombosis. Features include stroke, myocardial infarction, deep vein thrombosis and pulmonary embolism.
The other clinical features of PCV include:
Plethoric appearance
Lethargy and tiredness
Splenomegaly (common)
Pruritis (in 40% – particularly after exposure to hot water)
Headaches, dizziness and sweating (in 30%)
Gouty arthritis (in 20%)
Budd-Chiari syndrome (in 5-10%)
Erythromyalgia (in <5% – burning pain and red/blue discolouration of hands and feet)
Increased incidence of peptic ulcer disease (possibly related to increased histamine release from mast cells)
The diagnosis of PCV requires two major criteria and one minor criterion, or the first major criterion and two minor criteria:
Major criteria:
HB > 18.5 g/dl in men, 16.5 g/dl in women
Elevated red cell mass > 25% above mean normal predicted value
Presence of JAK2 mutation

Minor criteria:
Bone marrow biopsy showing hypercellularity with prominent erythroid, granulocytic and megakaryocytic proliferation
Serum erythropoietin level below normal range
Endogenous erythroid colony formation in vitro
The main aim of treatment is to normalize the full blood count and prevent complications such as thrombosis. Venesection is the treatment of choice but hydroxyurea can also be used to help control thrombocytosis.

Acute mastoiditis is a complication (rare) of acute otitis media (AOM) and the commonest causative organism is Streptococcus pneumoniae.

Generally, acute mastoiditis presents with:
Pyrexia
Recent history of AOM
Mastoid swelling and erythema
Otalgia
Otorrhoea and perforation of tympanic membrane
Post-auricular pain
Protrusion of the ears

Hartmann’s solution (compound sodium lactate) contains: Na+131 mmol/L, K+5 mmol/L, HCO3-29 mmol/L (as lactate), Cl-111 mmol/L, Ca2+2 mmol/L. It can be used instead of isotonic sodium chloride solution during or after surgery, or in the initial management of the injured or wounded; it may reduce the risk of hyperchloraemic acidosis.

Angiotensin II acts to directly increase Na+reabsorption from the proximal tubule (by activating Na+/H+antiporters).