Physiology

• Cardiovascular System
• The heart as a pump
• Generation of the heartbeat
• Pacemaker tissue
• Cardiac action potential
• Electrical conducting system of the heart
• Cardiac muscle
• Mechanism of contraction
• The cardiac cycle
• Physiological factors governing cardiac output
• Control of cardiac rate
• Control of stroke vole
• Catecholamines
• Response of the heart to stress
• The systemic and pulmonary circulations
• Systemic circulation
• Large conduit arteries
• Resistance vessels
• Capillaries
• Veins
• Pulmonary circulation
• Blood vessels
• Anatomy
• Blood supply
• Endothelium
• Smooth muscle cel layer
• The endothelium
• Vasodilator function
• Vasoconstrictor function
• Regulation of platelet function and haemostats
• Cellular adhesion
• Cell growth
• Cytokines
• Transport and metabolism
• The endocrine function of the heart
• Pathophysiology
• Therapeutic use of BNP
• Respiratory system
• The lungs
• Pulmonary ventilation
• Structure of the lung and thorax
• Thorax
• Lung
• Normal physiology
• Physiological limits to ventilations
• Pathophysiology
• Diffusion of gases
• Measurement of diffusion capacity
• Control mechanisms
• Gastrointestinal system
• The gut
• innervation of the gut
• Small bowel
• Large bowel
• Transit through the gut
• Stomach
• Small bowel
• Large bowel
• Regulation of transit and food processing
• Swallowing (deglutition)
• Stomach
• Cephalic phase
• Gastric phase
• Intestinal phase
• Small bowel
• Large bowel
• The liver
• Clearance function
• Bile
• Bile acid/ salts and the enterohepatic circulation
• Bilirubin
• Synthetic function
• Plasma proteins
• Albumin
• Coagulation factors
• Alpha 1 antitrypsin
• Metabolism
• Carbohydrates
• Amino acids
• The exocrine pancreas
• Anatomy
• Constituents of pancreatic juice
• Control of exocrine function
• Brain and nerves
• The action potential
• Establishing the resting membrane potential
• Initiating the action potential
• Refractory period
• Propagating the action potential
• Synaptic transmission
• Chemical synaptic transmission
• Neurotransmitter release
• Receptor sites
• Postsynaptic potentials
• Function of synapses
• Neuromuscular transmission
• Anatomy
• Release of acetylcholine
• End-plate potential
• Endocrine physiology
• The growth hormone-insulin-like growth factor 1 axis
• The hypothalamic-pituitary-adrenal axis
• Thyroid hormones
• Thyroid hormone structure, synthesis and secretion
• Wolf-Chaikoff effect
• Jod-Basedow effect
• Thyroid hormone action
• The hypothalamic-pituitary-thyroid axis
• The endocrine pancreas
• Insulin
• Insulin synthesis and secretion
• Insulin action
• Insulin metabolism
• Glucagon
• Glucose homeostasis
• The ovary and testis
• Ovary
• Testis
• The breast
• Hormonal regulation of breast
• Lactation
• The posterior pituitary 
• Antidiuretic hormone
• Control of ADH secretion
• Actions of ADH
• Oxycontin
• Renal physiology
• Blood flow and glomerular filtration
• The nephrons dn its blood supply
• Glomerular filtration rate
• Principle of clearance measurement
• Creatinine clearance
• Function of the renal tubules
• Control of glomerular and tubular function
• Autoregulation
• Myogenic resonse
• Tubuloglomerular feedback
• Glomerulotubular balance
• Influences from outside the kidney
• Sodium transport along the nephron
• Proximal tubule
• Thick ascending limb of the loop of Henle
• Distal convoluted tubule
• Collecting dusts
• Factors modulating the renal circulation and sodium excretion
• Circulatory compromise
• Sodium-retaining states
• Potassium transport along the nephrons
• Modulation of renal potassium excretion
• Hyperkalaemia
• Hypokalaemia
• Urinary concentration and dilution
• Urinary concentrating and diluting mechanism
• Renal contribution to acid-base balance
• Reabsorption of filtered bicarbonate
• Excretion of titratable acid
• Excretion of ammonia
• Endocrine function of the kidney
• Vitamin D metabolism and parathyroid hormone
• Vitamin D metabolism
• Parathyroid hormone
• Erythropoietin

Anatomy

• Heart and Major Vessels
• Surface anatomy of the heart
• Apex beat
• Coronary arteries
• Right coronary artery
• Left coronary artery
• Blood supply of the conducting system
• Pericardial cavity
• Relationships of the pericardial cavity
• Aorta
• Lungs
• Lungs and pleural cavities
• Trachea, bronchi and bronchioles
• Alveolar ducts and alveoli
• Liver and Biliary Tree
• Blood supply
• Bile duct
• Pancreatic duct
• Intrahepatic circulation
• Spleen
• Kidneys
• Endocrine glands
• Thyroid gland
• Microanatomy
• Parathyroid glands
• Adrenal gland
• The breast
• Ovary and uterus
• Ovary
• Uterus
• Testis
• Gastrointestinal tract
• Oesophageal sphincters and gastro-oesophageal reflux
• Lower oesophageal sphincter
• External sphincter 
• Gastro-oesophageal reflux
• Peptic ulceration
• Lesser sac of the peritoneum and pseudo-pancreatic cyst
• Structures felt on internal examination
• Rectal examination
• Vaginal examination
• Eye
• Retina
• Optic disc
• Macula lutea
• Retinal vessels
• Lens
• The chambers
• Changes after cataract surgery
• Nervous system
• Blood supply to the brain
• Arterial supply
• Circle of Willis
• Posterior cerebral arteries
• Anterior cerebral artery
• Middle cerebral artery
• Venous system
• Cavernous sinus
• Drainage of the cavernous sinus
• The meninges and haemorrhages
• Extradural haemorrhage
• Subdural haemorrhage
• Subarachnoid haemorrhage
• Cranial nerves
• Oflactory nerve (cranial nerve I)
• Optic nerve (cranial nerve II)
• Optic nerve
• Optic chiasma
• Optic tract
• Lateral geniculate body and visual cortex
• Oculomotor nerve (cranial nerve III)
• Trochlear nerve (cranial nerve IV)
• Trigeminal nerve (cranial nerve V)
• Motor nucleus
• Sensory nuclei
• Trigeminal ganglion 
• Ophthalmic nerve
• Maxillary nerve
• Mandibular nerve
• Abducens nerve (cranial nerve VI)
• Facial nerve (cranial nerve VII)
• Vestibulocochlear nerve (cranial nerve VIII)
• Glossopharyngeal nerve (cranial nerve IX)
• Vagus nerve (cranial nerve X)
• Branches and distribution
• Accessory nerve (cranial nerve XI)
• Cranial root
• Spinal root
• Hypoglossal nerve (cranial nerve XII)
• Pituitary gland
• The spinal cord
• Internal structure of the spinal cord
• Fasciculus gracilis and fasciculus cuneatus
• Lateral corticospinal tract
• Spinothalamic tract
• Ventral corticospinal tract
• Blood supply of the spinal cord
• Segmental innervation
• Upper limb
• Lower limb

Delirium

A sudden change in the mental state or sudden onset of behaviour that is out of character in an older person is most likely to be due to an acute confusional state (delirium). Even if a patient is confused it is paramount to take a history, which may give clues to the cause of the delirium. It also gives you the opportunity to assess the severity of confusion. The patient will benefit from reassurance. Of course, don’t dismiss the possibility that the patient is not confused and her jewellery is indeed missing! A physical review and review of investigations must be done as soon as is possible as delirium is a serious condition with a high morbidity and mortality. Sedation should only be used as a last resort and preferably only once the cause of the delirium has been established.

Vestibulocochlear Nerve (Cranial Nerve VIII)

From the auditory nuclei in the brain stem impulses are transmitted to the inferior colliculus and medial geniculate body of both sides through the trapezoid body and the lateral lemnisci. From there they reach the auditory cortex via the auditory radiations.

Inferior colliculus – lateral lemniscus - medial geniculate body

From the cerebellopontine angle the vestibulocochlear nerve enters the internal acoustic meatus along with the facial nerve (the trigeminal nerve does not pass through the cerebellopontine angle). In the inner ear it innervates the maculae of the utricle and saccule as well as the cristae of the semicircular ducts.

The vestibular ganglion is associated with the vestibular nerve whereas the spiral ganglion is a part of the cochlear nerve which innervates the organ of Corti.

The auditory pathway from the inner ear to the auditory cortex is via the lateral lemniscus, inferior colliculus, medial geniculate body and auditory radiation.

Lyme Disease

The rash is erythema chronicum migrans, which is a feature of early Lyme disease (Stage 1) in 70% of cases. Regional lymphadenopathy may also be a feature. The diagnosis is confirmed by serology. The treatment for early disease is 2-3 weeks of doxycycline or amoxicillin.

Renal Disease and Pregnancy

Pregnancy in patients with significant renal impairment is associated with increased maternal and fetal complications. With this degree of impairment, most will develop hypertension during pregnancy with an associated increase risk of pre-eclampsia (30%), pre-term delivery and potential deterioration in renal function (20%). The maternal renal outlook is often worse in patients with reflux nephropathy and urinary infection should be screened for and treated. Despite this the fetal outcome is usually good with less than 10% fetal loss.

Tryptase

Amongst the array of mediators released by mast cells during anaphylaxis, tryptase has proven to be a reliable marker of mast cell degranulation on account of its stability, relatively long half-life and ease of measurement. Consequently, an elevated tryptase in the correct clinical context is a useful surrogate marker of an anaphylactic/anaphylactoid reaction.

Positively Charged Amino Acid Side Chains

Arginine is positively charged at physiological pH, with a pK value for its side chain of 12.5. The pK is the pH at which 50% of the side chains are protonated. At lower pH the proportion that are protonated rises, as the proton concentration increases. As the pK of the arginine side chain is so much higher than physiological pH, they are almost completely protonated.

Another amino acid that can accept protons at physiological pH, and therefore become positively charged, is histidine. The pK of the histidine side chain is 6.0, and is modified by the local environment. This is much closer to physiological pH, enabling histidine to act as a reversible proton carrier, e.g. in haemoglobin.

Dibasic amino acids with positively charged side chains are cystine, ornithine, arginine and lysine. In cystinuria a defect of the dibasic amino acid transporter in the renal tubule leads to excess quantities of all of these amino acids being present in the urine, when cystine rises to concentrations that are insoluble, leading to the formation of cystine stones.

Subacute combined degeneration of the cord

Subacute combined degeneration of the cord is caused by vitamin B12 deficiency. The early signs usually include loss of vibration sense and position sense. There is usually a symmetrical peripheral neuropathy, which is associated with absence of ankle reflexes. The sensory ataxia leads to a positive Rhomberg's sign. Knee reflexes are often brisk and plantars are extensor due to pyramidal involvement causing upper motor signs.

Vitamin B12 deficiency may also cause optic atrophy and confusion.

Management of Hepatitis

Ribavirin has no effect on hepatitis B replication, but used in combination with interferon is more effective than ribavirin alone in eradicating chronic infection with hepatitis C.

Interferon was until recently first line treatment for chronic hepatitis B infection associated with elevated serum transaminases. However, there is often a flare in ALT (alamine aminotransferase) on starting treatment, which in the presence of end stage liver disease (elevated PT, bilirubin and ascites here) can lead to liver failure so, in these circumstances, it is contra-indicated.

Lamivudine suppresses HBV replication and is safe to use in decompensated end-stage cirrhosis.

Reference

• Yao FY, Terrault NA, Freise C, Maslow L, Bass NM. Lamivudine treatment is beneficial in patients with severly decompensated cirrhosis and actively replicating hepatitis B viral infection awaiting liver transplantation: a comparative study using matched untreated controls. Hepatology 2001; 34: 411-6

Psittacosis

Psittacosis is a systemic illness with primarily pulmonary manifestations. The diagnosis is suggested by exposure to pigeons. The rash (Horder's spots) and splenomegaly are characteristic. Diagnosis can be made by a four-fold increase in the complement-fixing antibodies. Tetracycline for 2 weeks is the treatment of choice.

Immunology and Immnosuppression

• Overview of the immune system
• Immune system components
• Barriers: Skin. Gut and respiratory tract
• Innate/ Natural
• Adaptive/ Acquired
• Innate immunity
• Acute-phase response
• Cytokines: IL. TNF
• Proteins: C3. Serum amyloid P component, CRP, Mannose-binding lectin, Lysozyme, Soluble CD14
• Autoimmune diseases
• Toll-like receptors (TLR)
• Bacterial: Lipopeptides, flagellin, hypomethylated DNA.
• Fungal: Zymozan
• Viral: Single-stranded or double stranded viral RNA)
• Local inflammatory response
• Dilatation & increased permeability of microscopic vessels
• Endothelial activation ￫ Adhesion of white blood cells
• Atraction & activation of phagocytic cells: Neutrophils & mononuclear cells
• Adaptive immunity
• Humoral immunity: Complement system, antibodies
• Cellular immunity: T-Lymphocytes
• Anatomy of the adaptive immune system
• Stem cells of bone marrow ￫ red cells, leucocytes, B cells 
• Thymus ￫ T cells
• Lymph nodes, Spleen, Mucosal-associated lymphoid tissue (MALT)
• B cells
• Antigen ￫ B cells + T helper cells ￫ Immune response ￫ Immunoglobulin production IgM IgG
• T cells
• Receptors + HLA
• Impaired regulation of the immune response: clinical examples
• Clonal disorder
• Multiple myeloma
• Paroxyamal nosturnal haemoglobinuria (PNH): DAF, CD59
• Autoimmunity
• Autoantibodies
• The major histocompatibility complex, antigen presentation and transplantation
• Major histocompatibility complex (MHC)
• Class I & II molecules encoded in HLA region present antigen to T cells
• In mice
• MHC
• Chromosomal region. Encode molecules for foreign tissue rejection
• In human
• Chromosome 6. Human leucocyte antigen (HLA)
• Classes I & II important in 
• Antigen presentation to T cells
• Tissue compatibility for transplantation
• Class III
• Complement proteins. GEnes for tumour necrosis factor (TNF)
• MHC and associated diseases
• Class I
• HLA-B27
• Ankylosing spondylosis, reactive arthitis, psoriatic arthropathy, reiter's syndrome
• HLA-CW6
• Psoriasis
• Class II
• HLA-B8-DR3
• Systemic lpus erythematosus, Addison's disease, Graves' disease, coeliac disease, type 1 diabetes
• HLA-DR4
• Rheumatoid arthritis
• HLA-DR2
• Multiple sclerosis
• Antigen presentation
• B cells recognises soluble antigen
• T cells
• Antigen ￫ Peptides presented by Class I or II on APC
• Class I + peptides from endogenous protein + CD8-positive cytotoxic T cells
• Class II + peptides from exogenous protein + CD4-positive T-helper cells
• Transplantation
• Pathways of immune recognition after transplantation
• Direct pathway: Donor MHC molecules and peptides
• Indirect recognition: MHC on host APC. Exogenous antigen from transplant
• Effector mechanisms of rejection
• Humoral machanisms
• Antibody. Complement activation. Thrombosis. Ischaemia
• Avoided by vitro cross-match
• Cell-mediated mechanisms
• Delayed-type hypersensitivity. CD4. Macrophages. Cytotoxic effects CD8 T cells, natural killer (NK) cells
• Inhibit T cell mediated rejection: Ciclosporin. Tacrolimus
• Chronic rejection
• Obliterative vascular changes
• Immunosuppression
• Xenotransplantation
• Pig kidneys.
• Hyperacute rejection. Complement-dependent. Antibodies to galactose-[1,3]-galactose
• Porcine infectious agents
• T Cells
• T cell receptors
• T cell functions
• T helper cells
• Cytotoxic T cells
• Natural killer T cells
• Regulatory T cells
• Gamm Delta T cells
• Helper cell differentiation
• T-cell development
• Activation of T cells
• Memory cells
• T cell immunodeficiencies: clinical example
• B cells
• Antibody structure and function
• Early development
• T cell dependent and T cell independent responses
• Primary response
• Antibody production and class switching
• Affinity maturation
• Generation of memory cells
• Regulation of B cell activation
• B cell immunodeficiency disorders: clinical examples
• x-linked agammaglobulinaemia 
• Selective IgA deficiency
• Tolerance and autoimmunity
• Mechanisms that maintain tolerance
• Mechanisms of loss of tolerance
• Polyclonal B-cell activation
• Cross-reactivity
• Exposure to previously sequestrated antigens
• Modification of self-antigen
• Autoimmune diseases: clinical examples
• Systemic diseases
• Organ specific diseases
• Complement
• Complement system
• Activation of the complement system
• Functions and regulation of the complement system
• Complement deficiencies: clinical examples
• Inflammation
• Mast cells
• Cell migration
• Adhesion molecules
• Chemokines
• Phagocyte effector functions
• Opsonisation
• Intracellular killing
• Neutrophils
• Macrophages
• Inflammation: clinical examples 
• Increased inflammation
• Familial Mediterranean fever
• Secondary amyloid
• Defective inflammation
• Leucocyte adhesion deficiency
• Chronic granulomatous disease
• Anti-inflammatory therapy
• Non-steroidal anti-inflammatory drugs
• Corticosteroids
• Novel agents
• Immunosuppressive therapy
• Corticosteroids
• Effect on neutrophils
• Effect on lymphocytes and monocytes
• Efects on NF-kB
• Corticosteroid use
• Cytotoxic drugs
• Cytotoxic drug use
• Inhibition of primary response
• Differentiated effect on lymphocytes
• Non-specificity
• Ciclosporin and related compounds
• Therapeutic antibodies or soluble ligands/ receptors
• Agents acting on lymphocytes 
• Anticytokine agents
• Therapeutic antibodies in oncology
• Drug combinations
• The future

Cell Biology

• Ion transport
• Ion channels 
• Ion channels in epithelial cells 
• Epithelial sodium channel (ENaC)
• Liddle's syndrome
• Pseudohypoaldosteronism type 1
• Cystic fibrosis transmembrane conductance regulators
• Cystic fibrosis
• Ion channels in non-epithelial cells
• Cell membrane potential
• Voltage gated sodium channels
• Skeletal muscle cells
• Myotonia
• Paralysis
• Syndrome of hyperkalaemic periodic paralysis
• Cardiac mucle cells
• Long QT syndrome
• Torsades de pointes
• Nerve cells 
• Familial epilepsy
• Class 1 antiarrhythmics
• Quinidine, disopyramide, lidocaine, flecainide
• Antiepileptics 
• Phenytoin and carbamazepine
• Ion carriers
• Carriers that utilise ATP (pumps)
• Na/K ATPase
• Digoxin
• Carriers that utilise secondary active transport mechanisms
• Na/K/2Cl cotransporter
• Loop diuretics (frusemide)
• Bartter's syndrome
• Na/Cl co-transporter
• Thiazide diuretics
• Gitelman's syndrome
• Receptors and intracellular signalling
• Ligand binding. Signal transduction
• Endocrine. Paracrine. Synaptic
• Phosphorylation
• Serine. Threonine.
• Intracellular messengers
• Kinase enzymes
• Protein kinase A (cAMP)
• Protein kinase G (cGMP)
• Protein kinase C (diacylglycerol)
• Membrane-bound receptors and signal transduction
• Receptors on cell surface.
• Ionotropic receptor (With integral ion channel function)
• e.g. nAChR, GABAa, 5HT3
• G protein coupled receptors
• e.g. mAChR, alpha and beta adrenoreceptors, dopamine, 5HT, opiate, peptides
• Gi. Adenylate cyclase
• Gq. Phospholipase C. DAG, IP3
• cAMP. Serine and threonine. Protein kinase A
• Inositol 1,4,5-triphosphate (IP3). Ca
• Diacylglycerol (DAG). Protein kinase C (PKC).
• Cholera
• Receptors with integral enzymatic function
• Receptor tyrosine kinases
• SH2 (src homology 2) domain
• Multiple endocrine neoplasia type 2. RET gene. Chromosome 10
• Proto-oncogenes. Trastuzamab vs HER2. Erlotinib, Geftinib. 
• Receptor guanylate cyclases
• ANP
• Nitric oxide
• Receptors in cytoplasma
• Steroid hormones. Lipophilic substances
• Cell cycle and apoptosis
• Phases: 
• Quiescent phase (G0)
• First gap phase (G1)
• DNA synthesis(S)
• Second gap phase (G2)
• Mitosis (M)
• Mechanisms of regulation
• M-phase kinase
• Catalytic (Cdc2)
• Regulatory (Cyclin)
• Substrate (H1 histone)
• Checkpoint pathways 
• Recognition of DNA damage
• Apoptosis. Block cell cycle. Transcribe response genes. Repair damage
• Appropriate progress made
• Replication before division. Kinetochores paired before metaphase finished
• Proteins involved
• Sensor. Transducer. Effector (Protein kinase ATM. Ataxia telangiectasia)
• Cyclin-dependent kinases (CKDs) 
• Cyclin-dependent kinase inhibitors (CKIs)
• Retinoblastoma gene product phosphorylated by cdm-cyclin D complex
• Apoptosis/ programmed cell death
• Fas receptor (Fas or FasR)
• Fas. Death domain
• Fas ligand (FasL)
• Fas + FasL
• TNF + its receptor (TNF-R1) ￫ Apoptosis
• Downstream from the Fas receptor
• Classical pathway for apoptosis
• Fas + FasL. TNF + TNF-R1. 
• ]Caspase family (cysteine aspartate proteases)
• Pathway involving kinase JNK. 
• c-Jun. Bcl2.
• Cancer and the cell cycle
• Oncogenes. Proto-oncogenes
• Tumour-suppressor genes
• RB gene
• p53
• Haematopoiesis
• Bone marrow structure
• The haematopoietic process
• Bone marrow
• Stem cell
• Progenitor cells
• Maturation
• Peripheral blood
• Role of growth factors
• Stem cell factors (SCF)
• Granulocyte colony-stimulating factor (G-CSF)
• Erythropoietin (EPO)

Codon

Translation is the name of the process of decoding protein sequence from mRNA, the polypeptide amino acid sequence being determined by the base sequence of its mRNA. The RNA bases are ‘read' in a 3-bp or triplet code, each 3-bp unit being referred to as a codon. The ‘decoding' is performed by tRNA, which recognises each codon by virtue of a complementary RNA sequence (the anticodon), which forms a unique part of each tRNA molecule.

ECG changes in hyperkalaemia

The presence of tall, peaked T waves, flattened P waves, prolonged PR interval and wide QRS complexes are pathognomonic of hyperkalaemia. Give IV calcium immediately (10mls, 10% calcium gluconate) and call the renal team.

Cytolytic granules in cytotoxic T cells and NK cells

Cytolytic granules contain membrane perturbing molecules that allow fusion of the killer cell with the target cell. These include perforins and granulysin. Fusion allows the release of granule contents into the target cell, and molecules such as granzymes induce apoptosis.

The membrane attack complex is part of the complement pathway and is not found in cytolytic granules.

Absolute dysphagia

This man has absolute dysphagia and needs to be in hospital. He may have a malignancy, a peptic stricture or a food bolus. Neurological or muscle disorders are less likely. Most would arrange early cautious upper GI endoscopy or failing that a gastrograffin swallow (risk of aspirating barium). If a malignant lesion is likely then further investigations are needed to determine the best treatment strategy. Options include stenting, chemo-radiotherapy, PEG feeding (inserted either endoscopically or surgically) or palliation. Investigations such as CT, PET and endoscopic ultrasound allow staging of malignant disease and a multi-disciplinary approach to treatment is probably best.

Drug-induced hyperkalaemia

Lisinopril
Losartan
Spironolactone
Slow K.


The drugs listed may cause hyperkalaemia, although this is not usually clinically significant when used alone at therapeutic doses. The development of significant drug-induced hyperkalaemia is more likely when more than one of these agents is used in combination, or if the patient has co-existing renal impairment.

DSM-IV criteria for alcohol dependence

The six DSM-IV criteria for alcohol dependence are:
1. inability to cut down
2. repeated efforts to control drinking
3. amnesic periods
4. drinking increasing amounts
5. ongoing drinking despite detrimental consequences
6. withdrawal symptoms.

Risk factors for hepatocellular carcinoma (HCC)

Eighty per cent of cases of hepatocellular carcinoma (HCC) are associated with chronic hepatitis B infection. Most cases of HCC not associated with hepatitis B infection are associated with hepatitis C infection.

Alcoholic cirrhosis and autoimmune chronic active hepatitis also increase the risk of developing HCC.

Several metabolic diseases are also associated with an increased risk for the development of HCC, such as haemochromatosis (iron accumulation), Wilson's disease (copper accumulation), alpha-1-antitrypsin deficiency and glycogen storage diseases.

Alflatoxins are mycotoxins produced by the fungi Aspergillus flavus and Aspergillus parasiticus which contaminate food (e.g. peanuts and corn).

A less common association is with primary biliary cirrhosis which is more typically associated with the subsequent development of cholangiocarcinoma.

Reference

• DeVita VT, Hellman S, Rosenberg SA. Cancer Principles and Practice of Oncology, 5th edn. Philadelphia: Lippincott-Raven.

Paraneoplastic conditions

Paraneoplastic conditions can occur up to several years before the emergence of the underlying tumour. The pathophysiological basis is thought to be autoimmune. A wide variety of clinical syndromes have been described affecting central structures, such as the mesial temporal lobes or spinal cord, or peripheral elements including nerve and muscle.

Causes of swollen optic disc

The optic disc is swollen. If vision were normal, this appearance could be due to papilloedema secondary to raised intracranial pressure (but not due to hypertension in the absence of any retinal haemorrhages or cotton wool spots). However, vision is impaired, making optic disc swelling secondary to an acute optic neuropathy the correct diagnosis.

The commonest cause of acute optic neuropathy in a young woman is multiple sclerosis. It will be important to pursue this possibility in the history:
▪ has this ever happened before?
▪ have you ever had problems with your arms / legs / walking / balance before?
▪ have you ever seen a neurologist about any problems before?

Aside from fundoscopy, key issues to check on examination of the eye are:
▪ visual acuity
▪ presence of a central scotoma
▪ impaired colour appreciation so that, compared with the normal eye, colours look washed out
▪ a relative afferent pupillary defect.
A full neurological examination to look for evidence of deficit elsewhere will be appropriate.

The eventual level of recovery of visual acuity is difficult to predict, hence a guarded prognosis must be given. Deciding whether or not to engage the patient in discussion about multiple sclerosis and/or further tests to pursue this diagnosis requires careful consideration.
Reference

Anthrax (Woolsorters' Disease, Ragpickers' Disease)

Woolsorters were at particularly high risk due to serious inhalational disease. Tanners exposed to infected animals were also susceptible but tended to develop the cutaneous form of the disease.

Atrial Myxoma

Atrial myxomas are the commonest form of cardiac tumour. They far more commonly arise in the left atrium, most frequently attached to the inter-atrial septum. Systemic embolic complications are common and can be devastating. Hence, unless severe co-morbidity precludes anaesthesis, immediate surgical removal is advocated.
Patients may present with dyspnoea, evidence of systemic embolisation or constitutional upset with fever and elevated inflammatory markers.

Septic arthritis

This is likely to be septic arthritis. Obviously, examination of the synovial fluid will help to exclude differentials such as gout and pseudogout. The most likely organisms are beta-haemolytic streptococci (20%) and staphlococci (70%). Antibiotics should be started empirically to cover these if the clinical suspicion is high. Ideally these should be intravenous for 2 weeks and then oral for 4 weeks. Arthroscopy is a risk factor for septic arthritis, but is rare. Fifty percent of cases will have an associated bacteraemia. Early x-rays are almost always normal.

BTS Statement on Malignant Mesothelioma in the United Kingdom

As asbestos is associated with the development of mesothelioma, all patients should be advised that they may be eligible for sate compensation and disability benefits. These claims must be made within 3 years of initial diagnosis.

Reference 

• British Thoracic Society Standards of Care Committee. BTS Statement on Malignant Mesothelioma in the United Kingdom. Thorax 2001; 56: 250–265.

Portal vein

About 75% of the blood supply to the liver comes from the portal vein, which is formed by the union of superior mesenteric and splenic veins.

Inside the liver, blood from the portal vein and from the hepatic artery flows through the tortuous capillaries called sinusoids. The venous outflow to the inferior vena cava from the liver is via the hepatic veins and obstruction to this outflow causes Budd–Chiari syndrome.

The normal portal pressure is about 5-8mm Hg: in portal hypertension it rises above 10–12mm Hg.

Contact dermatitis caused by allergy to eye make-up

Her erythematous, scaly, lichenified eyelids were due to contact dermatitis caused by allergy to the eye make-up she had been using.

Atopic eczema could produce a rash on the eyelids like this, but not in isolation. Look in particular for a history of atopy and involvement of the limb flexures when considering this diagnosis.

Systemic lupus erythematosus characteristically causes a photosensitive rash, which would spare the upper eyelid and not affect it.

Management of acute exacerbation of chronic obstructive pulmonary disease

Oxygen should be given for exacerbation of chronic obstructive pulmonary disease, aiming for oxygen saturation values of 90-92% with corresponding partial pressures of arterial oxygen of 60-65 mmHg. These targets ensure acceptable haemoglobin saturation whilst reducing the liklihood of the hypercapnia that can accompany the use of supplemental oxygen.

Bronchodilators increase the FEV1 and forced vital capacity (FVC) by 15 to 29% over 60 to 120 minutes.

Beta adrenergic agonists are often used as first-line treatment for acute exacerbations of chronic obstructive pulmonary disease, but have not been shown to be superior to anticholinergic agents and the two classes of agent are often used in combination. Side effects are less frequent and milder with ipratropium bromide than with beta agonists.

Metered dose inhalers are cheaper than nebulisers.

Reference

• Stoller JK. Acute exacerbation of chronic obstructive pulmonary disease. N Engl J Med 2002;346(no13):988-994.

Risk factors for hypertrophic cardiomyopathy

Major risk factors for hypertrophic cardiomyopathy are:
▪ Cardiac arrest (ventricular fibrillation)
▪ Spontaneous sustained ventricular tachycardia
▪ Family history of sudden death
▪ Minor risk factors
▪ Unexplained syncope
▪ Left ventricualr wall thickness>30mm
▪ Abnormal blood pressure on exercise(failure to rise from baseline by 25mmHg)
▪ Non sustained Ventricular tachycardia
▪ Left ventricular outflow obstruction
▪ Microvascular obstruction
▪ High risk genetic defect.

Lactulose breath test for detection of small intestine bacterial overgrowth

Bacterial fermentation of an oral dose of the carbohydrate lactulose releases hydrogen. If there is an increase in bacteria in the upper small bowel, or if there is rapid intestinal transit, then an early peak in hydrogen can be detected in expired air.

An oral dose of conjugated bile acid, often glycine-glycocholate, with radiolabelled carbon in the amino portion, can be given as an alternative to lactulose. Bacterial action releases radiolabelled glycine, detected following metabolism as labelled carbon dioxide in the breath.

What functional tests would you use to detect hypolactasia, H pylori infection or malabsorption due to small intestinal disease?

Management of gastrointestinal haemorrhage

In patients with cirrhosis and portal hypertension, gastrointestinal haemorrhage is a major complication and cause of death. Oesophageal varices are present in approximately 50% of patients with cirrhosis. Among patients with varices, the risk of gastrointestinal haemorrhage ranges from 30% to 50% and half of these patients die within 6 weeks after bleeding.

Normal care includes (in addition to resuscitation) airway management, routine antibiotics, early endoscopy along with pharmacotherapy with either vasopressin or octreotide (or related compounds). Glypressin is now the widely used drug. Vasopressin and glypressin reduce portal pressure by splanchnic arteriolar vasoconstriction, whereas somatostatin and octreotide lower portal pressure by decreasing hepatic blood flow.

Temporary tamponade can be achieved with a Sengstaken-Blackmore tube. It should be considered as a salvage procedure. Tamponade is 90% successful at stopping haemorrhage. Unfortunately 50% patients re-bleed within 24 hours of removal of tamponade. Prednisolone has a role, after careful consideration, in patients with alcoholic hepatitis but not in the acute management of variceal haemorrhage.

Drug-induced rash

Purpura in the context of a drug reaction may be an isolated skin reaction, or it may be a manifestation of drug-induced thrombocytopenia or drug-induced vasculitis. Hydralazine is associated with drug-induced lupus-like syndrome that can present with a vasculitic purpuric rash. Systemic features such as fever, malaise and arthralgia may be present, and other organs including the liver, kidney and heart may be affected. Anti-histone antibodies may also be present. The drug should be stopped immediately and systemic corticosteroids may be of benefit. Other drugs associated with a purpuric skin rash include aspirin, sulphonamides, penicillin, thiazides, furosemide and corticosteroids.

British Thoracic Society Guideline on the management of Asthma

In Step Three of asthma treatment, the current British Thoracic Society guideline advises first adding inhaled long-acting beta 2 agonist (LABA) and then assessing the situation.
If there is a good response to LABA, this medication should be continued. If there is benefit from LABA but control is still inadequate, LABA should be continued, and the inhaled corticosteroids should be increased to a high dose. If there is no response to LABA, then that treatment should be stopped and inhaled corticosteroids should be increased to a high dose. Anticholinergics have very little role in the management of stable asthma.

Reference

• See British Thoracic Society, Guideline on the management of Asthma. Thorax, 2003: 58, Supplement I: 1-9.

Causes of rash on face and hands

The V-shaped cut-off at the neck indicates that the rash is photo-induced. Look also for sparing behind the ears, under the chin and nose, and in the upper eyelid fold.

Seborrhoeic dermatitis typically affects the eyebrows and nasolabial folds.

Systemic lupus erythematosus can cause a photosensitive rash, but is not a likely diagnosis in a middle-aged man.

Red cell morphology

Spherocytosis would be associated with auto immune haemolytic anaemia. Schistocytes or red cell fragments would be more in keeping with mechanical red cell destrcution (e.g. thrombotic thrombocytopenia purpura), bite cells occur with oxidative haemolysis (e.g. G6PD deficiency), Burr cells are seen in renal failure and Pappenheimer bodies are seen in thalassasemia.

Emergency endoscopic treatment of oesophageal varices

Since oesophageal varices usually originate in the stomach, tamponade of the varices at the gastrooesophageal junction by inflation of the gastric balloon is usually effective in controlling haemorrhage. Inflation of the oesophageal balloon is rarely required and risks necrosis of the oesophageal wall, necessitating regular reduction of the pressure. Regular aspiration of the appropriate ports prevents build-up of secretions; the gastric aspirate port may be used as a nasogastric tube for delivery of essential oral medication, such as lactulose for the treatment of encephalopathy.
Aspiration pneumonia is a major cause of death and significant morbidity in these patients; the risk is particularly high in confused or encephalopathic patients who should be intubated for airway protection prior to insertion of the tube.

Dermatomes

L2,3 radiates to the anterior thigh.

L5 radiates through the buttock, down the posteriolateral aspect of the thigh, lateral aspect of calf and across the dorsum of the foot to the big toe.

S1 radiates through the inner buttock to the posterior aspect of the thigh, posteriolateral aspect of the calf to the lateral border of the foot.

Intraveous immunoglobulins in clinical practice

Intravenous immunoglobulin (IVIG) replacement is indicated for the prevention of infection in patients with antibody deficiency. This may be primary or secondary, as in some cases of myeloma. Immunological adverse reactions are increased if acute infection is present.

IVIG should be deferred for 24-48 hours and antibiotics commenced. With adequate immunoglobulin replacement serious infections and progression to chronic disease such as bronchiectasis is prevented. However, patients often present late and will benefit even in the presence of suppurative lung disease.

Hepatitis C outbreaks have been associated with IVIG, although modern production methods minimise this risk. Acute renal failure has been associated with IVIG, particularly in older people with pre-existing renal disease, as may occur in myeloma. IVIG should be used with caution in these people but is not contraindicated.

Reference

• Lee ML, Strand V. Intraveous immunoglobulins in clinical practice. New York: Marcl Dekker, 1997.

Maturity Onset Diabetes of the Young (MODY)

Features of Maturity Onset Diabetes of the Young (MODY) include the family history, which is consistent with autosomal dominant inheritance (with 50% chance of transmission to offspring), and the hypersensitivity to sulphonylureas.

The commonest type of MODY (MODY 3) is due to mutation in the HNF1alpha gene, which encodes a transcription factor involved in beta cell development. Other HNFs are implicated in further types of MODY, and in general the hyperglycaemia in these subtypes is progressive, with 30-40% requiring insulin, and risk of microvascular complications which is commensurate with that in type 1 diabetes, matched for glycaemia. Glucokinase mutations reset the set point for glucose homeostasis, and tend to result in mild, non-progressive hyperglycaemia, with low risk of complications.

Drug induced QT prolongation and torsades de pointes

Fig 1: Torsades de Pointes is a rapid ventricular rhythm caused by low potassium, medications (those that block potassium channels), or congenital abnormalities (e.g. Long QT Syndrome) that lengthen the QT interval. The rate is variable 250 and 350 per minute, in brief episodes.

Drugs that may cause torsade de pointes include:

• Disopyramide
• Dofetilide
• Ibutilde
• Procainamide
• Quinidine
• Sotalol
• Bepridil
• Amiodaone
• Arsenic trioxide
• Cisapride
• Erythromycin
• Doperidone
• Droperidol
• Chlorpromazine
• Haloperidol
• Thioridazine
• Pimozide
• Methadone.

Reference

1. Roden D.M. Drug induced prolongation of the QT interval. N Engl J Med 2004; 350:1013-1022.

Source: Fig 1,

Diagnosis of Subarachnoid Haemorrhage (SAH)

Fig 1: Subarachnoid Haemorrhage

CT brain scan is normal in up to 30% of patients with SAH, so that a negative scan cannot be used to exclude the diagnosis if suspected clinically. However, a positive CT brain scan enables the diagnosis to be made non-invasivally.

Fig 2: CT and MRI brain show Subarachnoid Haemorrhage (SAH)

Absence of red blood cells, or the absence of xanthochromia is sensitive for the exclusion of SAH. Where lumbar puncture (LP) is traumatic, the presence of large numbers of red cells may complicate interpretation. In this situation, spectophotometric analysis of the supernatant for red cell pigments may be helpful. 

Bilirubin and oxyhaemoglobin take 12 hours to appear in the cerebrospinal fluid (CSF) following a bleed, and for this reason LP should usually be delayed until more than 12 hours from the onset of symptoms. 

Because of the invasive nature of cerebral angiography, and relatively high complication rate, it is usually reserved for patients whose other investigations are positive.

Fig 3:
a) CT showing subarachnoid haemorrhage,
b) Cerebral angiograms demonstrating 13 aneurysms,
b)3 in the right anterior circulation
c) 5 in the left anterior circulation, and
d) 5 in the posterior circulation.
Arrow heads, aneurysms;
arrow, ruptured aneurysm

Source: Fig 1, Fig 2, Fig 3, 

Effect of coronary artery bypass graft surgery on survival

Fig 1: CABG

Coronary artery bypass grafting has been shown to improve survival in patients with left main stem stenosis (> 60%), triple vessel disease and impaired left ventricular function and triple vessel disease with proximal left anterior descending artery disease, when compared to medical therapy.

Fig 2: Left anterior oblique view showing a calcified lesion in the left coronary trunk that encompasses the origin of the  circumflex artery

Angioplasty is exceedingly high risk and therefore is only contemplated when patients are deemed as non-operative candidates.

Reference

1. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival. Overview of 10-year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994; 344: 563-570

Source: Fig 1, Fig 2, 

Causes of Rheumatoid Arthritis-Associated Anaemia

'Anaemia of RA' is a particular example of anaemia of chronic disorders, and is the commonest type of anaemia in RA. The haemoglobin levels are usually around 10 g/dL, and tend to vary inversely with the erythrocyte sedimentation rate (ESR) and other markers of disease activity.

Reference

• Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 769-772.
• Davis D, Charles PJ, Potter A, Feldmann M, Maini RN, Elliott MJ. Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade. Br J Rheumatol 1997; 36(9): 950-956.
• Wollheim F A. Rheumatoid arthritis - the clinical picture. In: Maddison PS, Isenberg DA, Woo P, Glass DN (eds). Oxford Textbook of Rheumatology vol 2. Oxford Medical Publications, 1993; p 639-661.

Management of Obesity

Up to 20% of the UK population are clinically obese (i.e. BMI>30). This has serious consequences both on mortality and morbidity. Management is based around a negative energy balance as a consequence of long-term low-intensity exercise and diet (500–600 kcal/day defecit).

Crash and fad diets are unlikely to be sustained. All alcohol should be minimised as it contains a significant number of calories though is devoid of nutrition. Drug treatments should only be considered where behaviour modification has failed, and are only likely to work alongside exercise and diet.

Hyperkalaemic distal renal tubular acidosis secondary to tacrolimus

Hyperkalaemia can be a problem post transplant. There are many causes to consider. In this case the notable features are a hyperkalaemia associated with a metabolic acidosis but without evidence of renal failure, lactic acidosis or haemolysis. The patient was notably diabetic. Although enoxaparin can rarely be associated with hyperkalaemia, the presence of risk factors, a metabolic acidosis, and an inappropriately low urine pH is more in keeping with a distal renal tubular acidosis. Tacrolimus has been well described to cause this.

Corticosteroid-Induced Osteoporosis

The pathogenesis of corticosteroid induced osteoporosis is multifactorial:
▪ Corticosteroids reduce osteoblastic activity, and the resulting osteoblast/osteoclast imbalance causes loss of bone.
▪ Corticosteroids reduce intestinal calcium absorption and lower circulating sex steroid levels.
▪ Corticosteroid induced bone loss is fastest in the first 6-12 months of therapy

Reference

Walsh LJ, Wong CA, Pringle M, Tattersfield AE. Use of oral corticosteroids in the community and the prevention of secondary osteoporosis: a cross sectional study. Br Med J 1996;313:344-6

Acquired hypogammaglobulinaemia causes bronchiectasis

Acquired hypogammaglobulinaemia should be excluded, as it requires specific treatment with regular immunoglobulin infusion. In allergic bronchopulmonary aspergillosis, proximal bronchiectasis would be expected.

Cystic Fibrosis Related Diabetes

CF-related diabetes is seen in up to 20% of adult patients with CF. The manifestations of the disease are with weight loss and rapid decline in lung function.

Glucose levels fluctuate for the first few years, but are consistently raised during exacerbations. Diet is not a suitable management for CF-related diabetes. The use of oral hypoglycaemic agents is controversial. The treatment of choice is injectable insulin.

Due to the short life latency of CF patients and that this may be due to the different natural history of the disease, microvascular complications of CF-related diabetes are not common. The condition is not a contraindication for organ transplantation when it is well-controlled.

Reference

• Lanng S. Diabetes mellitus in CF patients. In: Hodson ME, Geddes DM (eds). Cystic Fibrosis, 2nd edn. London: Arnold, 2000:329.

Hospital Infection Control

Acquisition of C. difficile may occur by person-to-person spread in outbreak situations in institutions, such as nursing homes and hospitals and thus a history of antibiotic use is not an essential prerequisite. Mortality in the elderly may be high and isolation is essential. Pneumonia due to M. bovis is TB (though most is due to M. tuberculosis). Vancomycin resistant enterococcal infections are more important than drug-sensitive infections, particularly as enterococcus is generally a pathogen of low virulence. Outbreaks of multidrug resistant Klebsiella can sweep through ITUs very quickly and to devastating effect. MRSA, which is resistant to glycopeptides such as vancomycin, is a potentially untreatable organism and intermediate-resistant isolates have already been recognized in the UK.

Congenital Heart Disease and Pregnancy

Pulmonary hypertension of any cause is associated with a 50% maternal mortality. Other high-risk cardiac conditions are severe mitral, pulmonary or aortic stenosis and Marfan's syndrome with a dilated aortic root. Intracardiac shunts without pulmonary hypertension are relatively safe but require closer follow-up. Operated tetralogy of Fallot without residual pulmonary stenosis is lower risk; coarctation is associated with dissection and is intermediate risk.

Priming of naïve T cells in renal transplant

Priming of naïve T cells is carried out in local lymph nodes by professional antigen presenting cells such as dendritic cells. In the case of a renal transplant this may occur by T cells recognising donor MHC on donor dendritic cells transferred with the graft (direct pathway). It may also occur by the recognition of peptides derived from donor MHC molecules, presented on recipient MHC on recipient antigen presenting cells (indirect pathway).

Macular oedema

Visual impairment more marked for reading than distance is very suggestive of macular disease, and the likely cause of symptoms in this case is diabetic maculopathy, when the central fovea becomes affected by retinal oedema or frank hard exudate. Age-related macular degeneration would be unlikely in a man of this age (48y)

Korsakoff's psychosis

This woman is clearly at high risk of alcohol-related disease as she has a high-risk profession and abnormal blood tests.

The fact that she seems to be confabulating makes Korsakoff's the best diagnosis. She has no evidence of nystagmus or ataxia suggestive of Wernicke's encephalopathy. Subdural haematoma is usually easily diagnosed by CT scan. Alcohol withdrawal usually occurs 48-72 hours after the last alcoholic drink (and we do not have any timings here).

Do not forget to exclude hypoglycaemia, hyponatraemia and hypomagnesaemia as causes of fits in alcoholics.

Uric acid

Uric acid is the degradation product of the purine bases. Orotidine contains a pyrimidine ring and is not degraded by this pathway.

Guanine is metabolized to xanthine, and thence to uric acid.

Adenosine is converted via inosine and hypoxanthine to xanthine, and thence to uric acid.

Dissociative disorders

In dissociative disorders there is a temporary but drastic modification of a person’s character or sense of personal indentity.

Conditions that can present with dissociative symptoms include schizophrenia, TLE, depression, head injury, delirium, dementia, drugs and acute stress disorder.

Other features of TLE can include epigastric discomfort, jamais vu, and intense anxiety or depression.

LSD can cause hallucinations in any modality.

Hyperventilation and disproportionate worrying suggest acute stress disorder.

Features of severe aortic incompetence

Severe aortic incompetence is suggested by the presence of one or more of the following clinical features:
1. Short early diastolic murmur (diastolic pressure in the left ventricle rapidly approaches that in the aorta)
2. Wide pulse-pressure
3. Displaced, hyperdynamic apex beat - implying significant volume overload.

The Austin-Flint murmur may be heard in aortic incompetence (fluttering of the anterior mitral valve leaflet due to turbulance from the regurgitant jet). Whilst a normal heart size on chest radiograph does not preclude a diagnosis of severe aortic incompetence (e.g. acute), it is far more commonly enlarged.

Epinephrine for anaphylaxis

In anaphylaxis, a treatment with intramuscular epinephrine (0.5 ml of 1/1000) is required.

In extremis, epinephrine can be given intravenously, but at reduced dosage: make a 1/10,000 solution (by diluting 1 ml of 1/1000 to 10 ml with 0.9% saline) and give this at 1 ml/min (0.1 mg/min) until a response has been obtained (or a total of 0.5 mg - 5 ml - has been given).

Diagnosis of penicillin allergy

A history of penicillin allergy is relatively common in hospital patients, and is in most not due to type I hypersensitivity reactions.

A diagnosis of penicillin allergy crucially requires a detailed history of the drug reaction, and can be confirmed by a positive skin prick test to the major and minor determinants of penicillin. Skin prick testing is carried out if there is a clinical need for penicillin treatment e.g. treatment of infective endocarditis. A patient is unlikely to develop anaphylaxis with a negative penicillin skin prick test. The detection of penicillin specific IgE in the serum is unreliable.

Further Reading

• Diagnosis and management of penicillin allergy.

Management of infectious diarrhoea

Not all episodes of infectious diarrhoea need treating with antibiotics, and often, resistance to certain antibiotics (e.g. ciprofloxacin) leads to sub-optimal treatment.

Any patient who has been in hospital recently is at risk of C. difficile infection - especially if they may have had antibiotics. This needs to be actively tested for and treated appropriately (metronidazole as first-line treatment, then oral vancomycin). Hence, it is imperative in managing patients with diarrhoea to ensure adequate and suitable stool samples are sent early in the illness. Colonic imaging is usually not indicated in infective colitis (other than a simple X-ray to exclude toxic megacolon) and is only necessary if symptoms persist and stool cultures are negative.

Fig 1: Clostridium Difficile Diarrhoea

Source: Fig 1

Side Effects of Antipsychotics

The side effects of antipsychotics include :

• Extrapyramidal symptoms 
• Stiffness
• Tremor
• Hypersalivation
• Acute dystonia
• Akathisia
• Tardive dyskinesia 
• Anticholinergic symptoms 
• Blurred vision
• Constipation
• Urinary retention
• Dry mouth
• Confusion
• Agitation
• Seizures
• Antihistaminergic symptoms 
• Sedation
• Alpha-blocking effects
• Orthostatic hypotension
• Leucopenia 
• Increased prolactin secretion 
• Amenorrhoea
• Galactorrhoea
• Sexual dysfunction
• Weight gain
• Obstructive jaundice 
• Retinitis pigmentosa (with thioridazine >600 mg/d), 
• Allergic dermatitis / photosensitivity
• Neuroleptic malignant syndrome

Fig 1: Tardive dyskinesia

Akathisia

Acute Dystonia

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Listeria monocytogenes infections

Listeria is spread by ingestion of foodstuffs such as paté and soft cheese, but typically presents with non gastro-intestinal disease, particularly meningitis in immunosuppressed individuals (including pregnant women). Listeria has been occasionally implicated in outbreaks of gastroenteritis, but in most patients this is mild and self-limiting and thus does not come to medical attention.

Clinically useful monoclonal antibodies in treatment

Basiliximab and dacluzimab are antibodies to the IL2 receptor (CD25) expressed on activated T cells. They are used as induction therapy in renal transplantation.

Antibodies to CD3 (OKT3) are used in the treatment of renal transplant rejection.

Rituximab is an antibody to CD20 expressed on B cells and is used in B cell lymphomas.

Antibodies to CD154 (CD40 ligand - a molecule pivotal in T cell costimulation) had great promise in transplantation and autoimmunity. However, trials in humans have stopped after early work showed a high incidence of thrombosis, probably because CD154 is expressed on activated human platelets.

Antibodies to CD8 have not been used clinically.

Interferon-alfa and Ribavirin for Chronic Hepatitis C

Combination therapy with interferon-alfa and ribavirin is generally recommended for those with moderate-sever disease (histological diagnosis of significant scarring and/or significant necrotic inflammation). While NICE guidance suggests that problems with drug interactions, safety, and compliance may arise in existing intravenous drug users, those who have given up the habit should not be excluded from therapy. However, treatment is not generally recommended in those patients who consume large quantities of alcohol, given the increased risk of liver damage.
In cases where a liver biopsy carries a high risk (e.g. haemophilia), treatment can be initiated without histological confirmation.
Both treatment-naïve patients and those who have relapsed following initial response to interferon-alfa should be considered for 6 months of combination therapy.

Phosphate homeostasis

There is now good data that elevated serum phosphate levels are associated with increased cardiovascular risk.

CAPD is not as efficient at clearing phosphate as haemodialysis.

The stimuli to PTH secretion are low serum calcium concentration, low vitamin D levels and elevated phosphate levels.

Vitamin D increases calcium absorption from the gut: it does not lower blood phosphate concentration.

Phosphate binders should be taken just before meals so that they are present in the gut and available to bind phosphate when required.

T Cells

T-helper cells are distinguished by the presence of CD4 on their surface and their ability to recognise peptides presented on MHC class II molecules. Their functions include promoting delayed-type hypersensitivity reactions, characterised by monocyte recruitment, and providing help for B-cell antibody production.

Cytotoxic T cells have CD8 on their surface and recognise peptide presented on MHC class I molecules.

Glasgow/Ranson criteria for severity of acute pancreatitis

The standard method of assessing severity of acute pancreatitis is by using the Glasgow/Ranson criteria. Three or more of the following criteria, based on initial admission score and subsequent repeat tests over 48 hours, constitutes severe disease
▪ 1. Age >55 years
▪ 2. White blood cell count >15 x10 9/l
▪ 3. Glucose>10 mmol/l
▪ 4. Urea>16 mmol/l
▪ 5. PaO2 <60 mmHg
▪ 6. Calcium <2 mmol/l
▪ 7. Albumen <32 g/l
▪ 8. Lactate dehydrogenase >600 units/l
▪ 9. Aspartate/alanine aminotransferase >100 units

A CRP>210mg/L in first 4 days of attack indicates severe disease, and an APACHE score of 9 or more also constitutes a severe attack.

Tests used in Atopic Dermatitis

Total IgE titre does show some correlation with disease activity and it can be a useful screening tool in patients in whom a diagnosis of atopic dermatitis is being considered. Positive radioallergenosorbent (RAST) tests to foods such as nut, wheat and milk are rare in patients with atopic dermatitis, but in Northern European affected adults there are positive RAST tests to:
▪ house dust mite in 50-60%
▪ cat dander in 50%
▪ grass in 75%
▪ birch pollen in 65%.
There is generally a good correlation between skin prick test reactivity and RAST test to these allergens.

Prick tests involve the intradermal injection of allergen with assessment of the immediate urticarial reaction and are believed to reflect type I allergic reactions. In contrast patch tests involve applying antigen to the skin for 48 hours and assessing the subsequent delayed eczematous reaction. This is believed to more closely reflect type IV delayed hypersensitivity reactions and is used clinically to investigate patients with suspected contact allergic dermatitis to environmental antigens such as nickel.

Flexible sigmoidoscopy for pseudomembranous colitis

The diagnosis of pseudomembranous colitis requires direct visualisation of pseudomembranes on bowel mucosa or on microscopic examination of a biopsy sample. 90% of cases can be detected by flexible sigmoidoscopy, although in mild cases pseudomembranes may not be evident macroscopically. The classic sigmoidoscopic appearance of 2 to 10 mm raised yellow nodules are pathognomonic.

An abdominal radiograph may be normal in pseudomembranous colitis, although in severe cases it may show a complicating toxic megacolon. Barium enema and abdominal ultrasound are of no use in confirming or excluding the diagnosis of pseudomembranous colitis, and a positive stool culture for C. difficile toxin would make (rather than exclude) the diagnosis.

Scleritis

Photophobia, visual blurring, keratitic precipitates (best seen with a slit lamp) and irregularity of the pupil are all features of iritis. Severe pain suggests scleritis and is not typical of iritis or the milder condition of episcleritis, where the inflammation usually affects just a sector of the globe of the eye. In scleritis the pain often disturbs sleep, and can literally drive people to bang their head against the wall and ask for the eye to be removed.

Scleritis is often associated with systemic symptoms and a manifestation of vasculitis: check an MSU for blood / protein, full blood count, renal / liver / bone function, inflammatory markers and autoimmune / vasculitic serology (in particular rheumatoid factor and serum ANCA).

Secundum Atrial Septal Defects

Secundum atrial septal defects are often not identified in childhood and can present with non specific symptoms such as lethargy. The first heart sound is often split but equally may be normal. The definitive investigation is transthoracic echocardiography. This will demonstrate first of all the anatomy and secondly using doppler indicate any significant shunting.

Ostium secundum defects are more midseptal and by far more common than primum defects which are more inferiorly displaced towards the AV valve. Primum defects are often associated with anomalies of the mitral and/or tricuspid valve, and as such patients more commonly present in childhood.

It is clear from the clinical picture that this is not a patent ductus arteriosus. Patent foramen ovale (PFO) is a common condition and generally benign. There may be some left to right flow on doppler imaging but this will not be significant. The harsh pansystolic murmur of a ventricular septal defect is usually obvious unless the defect is very large. In this case the patient would be likely to have more pronounced symptoms.

‘Bright white’ signal on T2-weighted MRI in phaeochromocytoma

The image reveals a large left suprarenal mass. The appearances are typical of a phaeochromocytoma which, unlike most other adrenal tumours, demonstrates a distinctive ‘bright white’ signal on T2-weighted MRI.

In Cushing’s disease (corticotroph pituitary adenoma) bilateral adrenal hyperplasia may be seen on adrenal imaging.

Phaeochromocytoma is one component of the M.E.N. type 2 syndrome (medullary thyroid carcinoma, phaeochromocytoma, parathyroid hyperplasia) and not the M.E.N. type 1 syndrome (parathyroid hyperplasia, pancreatic tumours, pituitary tumours).

Risk Factors for Ovarian Cancer

Consistently identified risk factors for ovarian cancer include: ▪ a positive family history ▪ few or no children ▪ older age at first marriage and childbirth. There is a protective effect for childbearing and use of the oral contraceptive pill. There is some evidence that patients with HER-2 over-expression have a worse response to chemotherapy and a worse prognosis, but the reported studies are retrospective only and there is no evidence that the gene is a risk factor for the development of ovarian cancer. Risk factor Relative risk General population 1 Family history 17-50 Nulliparity 4-5 1-2 children 3 Obesity 2 Oral contraceptive 0.5

Chronic Myeloid Leukaemia

It is not unusual nowadays with the advent of routine automated blood counts to pick up a patient with chronic myeloid leukaemia and none of the classical signs of large hepatosplenomegaly. The picture shows an elevated white count with no increase in blast cells and there are myelocytes and metamyelocytes suggestive of chronic phase disease. A bone marrow or peripheral blood cytogenetics should be carried out looking for the Philadelphia chromosome.

Medical Staristics: Sensitivity and specificity

Interpreting the sensitivity and specificity of a test depends on what you are using it for.

The poor specificity of this test means that it would be inappropriate to use it as reason for telling people they have HIV infection; in the at-risk population over 50% diagnosed positive will not have the disease. By contrast, the balance of risk is different in screening blood for HIV, where the risk of missing a positive case far outweighs the risk of discarding some blood units unnecessarily, and similarly in looking for bowel cancer.

The test would also potentially be appropriate in screening for head lice where the disease is not serious but you do not want to miss cases and the treatment is simple and safe.

Predictive value depends as much on prevalence of a condition as the sensitivity. The positive predictive value in young patients means most army recruits with a positive test would be false-positive, with more being false positive than true positive, but since very few are likely to have heart disease a preliminary screening test with a positive predictive value of 48% would be a reasonable test to use.

Ocular manifestiations in rheumatoid arthritis (RA)

Approximately 25 % of patients with rheumatoid arthritis (RA) will have ocular manifestations. keratoconjunctivitis sicca, scleritis, episcleritis, keratitis, peripheral corneal ulceration, and other less common entities such as choroiditis, retinal vasculitis, episcleral nodules, retinal detachments, and macular edema.

Keratoconjunctivitis sicca, or dry eye syndrome, is the most common ocular manifestation of RA and has a reported prevalence of 15 to 25 %. The patient reports a gritty sensation in the eyes .

Scleritis and episcleritis as causes of recurrent red eyes are distinguished on the basis of anatomy and appearance. Symptoms may be similar, but the pain in scleritis is more evident and severe. Tenderness to palpation of the globe can help differentiate the two. After asking the patient to look down with eyelids closed, the physician gently presses the globe. Patients with scleritis have tenderness on palpation, while those with episcleritis do not.. Unlike scleritis, patients with episcleritis do not complain of blurred vision or photophobia. The importance of correctly diagnosing and distinguishing between scleritis and episcleritis is based on the potential ocular and systemic complications associated with scleritis. Studies have shown that patients with RA-associated scleritis have more widespread systemic disease and a higher mortality rate than those episcleritis.

Relationship between ovarian germ cell tumours and serum markers

About 90% of persons with non-dysgerminomatous germ cell tumours produce either alpha-fetoprotein (AFP) or human chorionic gonadotropin (beta-hCG). In contrast, persons with pure dysgerminoma usually produce neither.

These tumour markers are present for some time after surgery. If the presurgical levels are high, 30 days or more may be required before meaningful postsurgical levels can be obtained. The half-lives of AFP and beta-hCG are six days and one day respectively. After treatment, unequal reduction of beta-hCG and AFP may occur, suggesting that the two markers are synthesized by heterogeneous clones of cells within the tumour; thus, both markers should be followed.

Beta-hCG is similar to luteinizing hormone except for its distinctive beta subunit.

Factor V Leiden Gene Mutation

In the absence of a personal thromboembolic history, Warfarin is not indicated - she may develop bleeding on it. However, given the strong family history, one should be concerned that additional thrombophilic problems are present and a full thrombophilia screen should be performed. If the rest of the screen is negative, one should still be cautious because of the family history - there may be thrombophilic tendencies we are yet to discover.

Pregnancy does not need heparin cover in this woman. The presence of Factor V Leiden itself does not prevent the use of the oral contraceptive or HRT, but given the strong family history, the woman should be counselled about the increased risk of thromboembolism versus the potential benefits and her decision documented for future reference.

Patent foramen ovale

Patent foramen ovale occurs in 10% of the population and is found in 40% of patients with a past history of stroke. If these defects are found in patients with a past history of a cerebrovascular accident, a right to left shunt must be looked for by injecting agitated saline and asking the patient to perform a Valsalva manoeuvre. If a significant right to left shunt is demonstrated, then either long-term anticoagulation or percutaneous closure is recommended, as there is a risk of paradoxical embolus. The results of ongoing studies should help determine whether percutaneous closure is superior to anticoagulation alone in this context. When seen as an incidental finding in patients without a history of stroke, no treatment is required.

Reference

• Martin F. Percutaneous transcatheter closure of patent foramen ovale in patients with paradoxical embolism. Circulation 2002; 106: 1034-6.

Pitting oedema of both legs

Cardiac failure and hypoalbuminaemia are common causes of this condition in terminally ill patients. Venous thromboembolism is thought to be present in up to 50% of terminally ill patients and usually presents with insidious painless swelling that may be associated with episodes of breathlessness. Lymphoedema, a protein rich exudate, is indistinguishable from other causes of oedema in the early stages. In time (weeks to months) the protein becomes organised and fibrosed and clinically becomes as 'non-pitting'.

Asthma Attack

Resuscitation is the first priority. Maximum inspired oxygen should be given by facemask: this is best achieved using a reservoir bag at a flow rate of 15 l/min, which can generate an FiO2 of about 85%. Nebulised salbutamol (5-10 mg) driven by oxygen should be given, and many would add ipatropium bromide (Atrovent, 500 microg) to the nebuliser chamber at the same time as the salbutamol. If the woman does not improve, then call for assistance from ICU sooner rather than later.

Although it is always important to consider pneumothorax in any breathless patient, there is no evidence at all to suggest that this woman has bilateral pneumothoraces and she would not be well served by chest decompression.

Subarachnoid Haemorrhage

The investigation of choice in suspected subarachnoid haemorrhage (SAH) is immediate CT scan without contrast, taking very thin cuts through the base of the brain to optimise the chances of seeing small collections of blood. Imaging within 12 hours using modern scanners has a 98-100% sensitivity for SAH.

Lumbar puncture should be performed in suspected SAH if the CT scan is not diagnostic. The CSF specimen should be centrifuged without delay and examined by spectrophotometry for the presence of xanthochromia due to the presence of oxyhaemoglobin and bilirubin. Note, however, that xanthochromia may not be present if the CSF is examined within 12 hours of haemorrhage occurring, so lumbar puncture should be delayed for 24 hours.

Hirsutism

The commonest causes of hirsutism are idiopathic (no cause known), familial / racial, and the polycystic ovarian syndrome (PCOS).

The PCOS usually presents with gradual onset of hirsutism and weight gain on a background of long-standing oligomenorrhoea, typically dating back to puberty.

Virilizing tumours (ovarian or adrenal) are much less common, but should be suspected if there is a sudden onset of symptoms, when examination should look specifically for signs of virilization (male pattern muscle development, clitoromegally).

Serotonin syndrome

Serotonin syndrome is a rapidly progressive condition that is characterised by confusion, agitation, myocolonus, rigidity, tremor, hyperreflexia, hyperthermia, gastrointestinal upset, tachycardia, and hypo or hypertension.
It is due to excessive serotonin caused by a number of mechanisms including increased release of stored serotonin or reuptake inhibition. This is a potentially fatal condition. Treatment includes stopping the offending drug and supportive measures to reduce the risk of rhabdomyolysis.

Goodpasture's syndrome

Goodpasture's syndrome is characterised by diffuse alveolar haemorrhage and glomerulitis. Men are commonly affected with most cases occurring between the ages of 20-30 years. It is more likely to occur in smokers. Exposure to smoke and volatile hydrocarbons is associated with initiation as well as exacerbation of the disease. The anti glomerular basement antibody is present in up to 90% of the patients. Renal histology usually shows a focal segmental necrotizing glomerulitis with crescent formation. The TLCO is increased during active bleeding and can be used to monitor the disease. An increase above 30% of baseline is highly suggestive of an intra-alveolar bleed.

Cell Death

There are two mechanisms for cell death: necrosis, which is a passive response to injury, and apoptosis, a mechanism of programmed cell death for removing excess cells produced during development or for removing cells that are functionally impaired, deficient or abnormal.

Apoptosis can result from multiple stimuli or the removal of survival factors such as hormones or growth factors. p53 is an important initiator following cellular injury.

The process of apoptosis involves a rapid and sustained increase in intracellular calcium that triggers endonuclease activation, leading to cleavage of DNA into fragments of about 180 base pairs. These can be detected as a DNA ‘ladder’ on gel electrophoresis.

Drug-induced Liver injury

Virtually all drugs can cause liver injury. In this case the most recently introduced medication is most likely to be the cause of liver injury, assuming other investigations for chronic liver disease are negative. The prescription drugs to be particularly aware of when assessing a patient with an undiagnosed liver disorder include Augmentin (co-amoxiclav), diclofenac, isoniazid, erythromycin, sodium valproate, amiodarone and phenytoin.

Tuberculosis Meningitis

The combination of space-occupying lesions, high CSF protein, low CSF glucose and CSF lymphocytosis point to this case being tuberculosis meningitis with cerebral tuberculomas. The organism is not seen on microscopy in 20-50% of cases. Cryptococcal meningitis can give a similar picture, although the protein and glucose changes are not usually so marked; cerebral cryptococcomas are uncommon and the organism is normally seen on microscopy in patients as ill as this. Toxoplasmosis, syphilis and lymphoma would not cause such significant changes in the protein, glucose or white cell count.