Basic Science Flashcards

Question

IgG what proportion of serum antibodies? type of molecule? what is the role?

Answer 1

75% Monomer Enhance phaGocytosis of bacteria and viruses.

Answer 2

15% Mono+Dimer Found in secretions, provide localized protection on mucous membranes

Answer 3

10% Pentamer first to be secreted, anti-A, B blood antibodies → Blood Transfusion

Answer 4

1% Monomer Involved in activation of B cells

Answer 5

0.1% Monomer Involved in allergic reactions

Answer 6

Each day an average adult produces approximately 3gm of antibodies, about two-thirds of this IgA

Answer 7

• IgG makes up approximately 75% of the serum antibodies. • IgG has a half-life of 7-23 days depending on the subclass. • IgG is a monomer and has 2 epitope-binding sites • The Fc portion of IgG can activate the classical complement pathway. • The Fc portion of IgG can bind to macrophage and neutrophils for enhanced phaGocytosis. • The Fc portion of IgG can bind to NK cells for antibody-dependent cytotoxicity (ADCC). • The Fc portion of IgG enables it to cross the placenta. (IgG is the only class of antibody that can cross the placenta and enter the fetal circulation).

Answer 8

• IgA makes up approximately 15% of the serum antibodies, it has a half-life of ≈ 5 days. • IgA is found mainly in body secretions (saliva, mucous, tears, colostrum and milk) as secretory IgA (sIgA) where it protects internal body surfaces exposed to the environment by blocking the attachment of bacteria and viruses to mucous membranes. • Secretory IgA is the most immunoglobulin produced. • IgA is made primarily in the mucosal-associated lymphoid tissues (MALT). • IgA appears as a dimer of 2 "Y"-shaped molecules and has 4 epitope-binding sites and a secretory component to protect it from digestive enzymes in the secretions • The Fc portion of secretory IgA binds to components of mucous and contributes to the ability of mucous to trap microbes. • IgA can activate the alternative complement pathway. (IgA ≈ Alternate)

Answer 9

• IgM makes up approximately 10% of the serum antibodies and is the first antibody produced during an immune response. • IgM has a half-life of about 5 days. • IgM is a pentamer and has 10 epitope-binding sites • The Fc portions of IgM are able to activate the classical complement pathway (most efficient) • Monomeric forms of IgM are found on the surface of B-lymphocytes as B-cell receptors or sIg.

Answer 10

• IgD makes up approximately 1% of the serum antibodies. • IgD is a monomer and has 2 epitope-binding sites. • IgD is found on the surface of B-lymphocytes (along with monomeric IgM) as a B-cell receptor or sIg where it may control of B-lymphocyte activation and suppression. • IgD may play a role in eliminating B-lymphocytes generating self-reactive autoantibodies.

Answer 11

• IgE makes up about 0.002% of the serum antibodies with a half-life of 2 days. • Most IgE is tightly bound to basophils and mast cells via its Fc region. • IgE is a monomer and has 2 epitope-binding sites. • IgE is made in response to parasitic worms (helminths) and arthropods. It is also often made in response to allergens. • IgE may protect external mucosal surfaces by promoting inflammation, enabling IgG, complement proteins, and leucocytes to enter the tissues. • The Fc portion of IgE can bind to mast cells and basophils where it mediates many allergic reactions. Cross linking of cell-bound IgE by antigen triggers the release of vasodilators for an inflammatory response. • The Fc portion of IgE made against parasitic worms and arthropods can bind to eosinophils enabling opsonization. This is a major defense against parasitic worms and arthropods.

Answer 12

neutrophil disorders

Answer 13

B-cell disorders

Answer 14

T-cell disorders • DiGeorge syndrome is an example of a microdeletion syndrome. Patients are consequently at ↑ risk of viral and fungal infections. C - Cardiac abnormalities A - Abnormal facies T - Thymic aplasia C - Cleft palate H - Hypocalcaemia/ hypoparathyroidism 22 - Caused by chromosome 22 deletion

Answer 15

Combined B- and T-cell disorders

Answer 16

Ataxic telangiectasia (Autosomal recessive - 10% risk of developing malignancy, lymphoma or leukaemia, but also non-lymphoid tumours - recurrent chest infections)

Answer 17

Wiskott-Aldrich syndrome inherited in an X-linked recessive fashion and is thought to be caused by mutation in the WASP gene. Features include recurrent bacterial infections (e.g. chest), eczema and thrombocytopenia with low IgG.

Answer 18

There are two main types of anti-neutrophil cytoplasmic antibodies (ANCA) - cytoplasmic (cANCA) and perinuclear (pANCA)

Answer 19

• cANCA - Wegener's Granulomatosis (Granulomatosis with polyangiitis) • pANCA - Churg-Strauss syndrome + others

Answer 20

• Most common target serine proteinase 3 (PR3) • Some correlation between cANCA levels and disease activity • Wegener's granulomatosis, positive in > 90% • Microscopic polyangiitis, positive in 40%

Answer 21

• Most common target is myeloperoxidase (MPO) • Cannot use level of pANCA to monitor disease activity • Associated with immune crescentic glomerulonephritis (positive in c. 80% of patients) • Microscopic polyangiitis, positive in 50-75% • Churg-Strauss syndrome, positive in 60% • Wegener's granulomatosis, positive in 25%

Answer 22

Other causes of positive ANCA (usually pANCA) • Inflammatory bowel disease (UC > Crohn's) • Connective tissue disorders: RA, SLE, Sjogren's • Autoimmune hepatitis

Answer 23

Whilst C3 deficiency is associated with recurrent bacterial infections, C5 deficiency is more characteristically associated with disseminated meningococcal infection

Answer 24

Complement is a series of proteins that circulate in plasma and are involved in the inflammatory and immune reaction of the body. Complement proteins are involved in chemotaxis, cell lysis and opsonisation

Answer 25

• Causes hereditary angiedema • C1-INH is a multifunctional serine protease inhibitor • Probable mechanism is uncontrolled release of bradykinin resulting in edema of tissues

Answer 26

• Predisposes to immune complex disease • E.g. SLE, Henoch-Schonlein Purpura

Answer 27

• Causes recurrent bacterial infections

Answer 28

• Predisposes to Leiner disease • Recurrent diarrhea, wasting and seborrhoeic dermatitis • Disseminated meningococcal infection.

Answer 29

• Encodes the membrane attack complex (MAC) • Particularly prone to Neisseria meningitidis infection

Answer 30

Metabolic Acidosis is commonly classified according to the anion gap. This can be calculated by: (Na+ + K+) - (Cl- + HCO-3). If a question supplies the chloride level then this is often a clue that the anion gap should be calculated. The normal range = 10-18 mmol/L

Answer 31

Normal anion gap (hyperchloraemic metabolic acidosis) NORMAL: Nausea(GI loss) O- AcetazOlamide R- RTA M - aMMonium chloride A - Addisons' • Gastrointestinal bicarbonate loss: diarrhea, ureterosigmoidostomy, fistula • Renal tubular acidosis • Drugs: e.g. Acetazolamide • Ammonium chloride injection • Addison's disease

Answer 32

Raised anion gap - LUKA raises his hands • Lactate: shock, hypoxia • Urate: renal failure • Ketones: DKA, alcohol • Acid poisoning: salicylates, methanol

Answer 33

• Lactic acidosis type A: shock, hypoxia, burns • Lactic acidosis type B: metformin

Answer 34

Metabolic Alkalosis may be caused by a loss of hydrogen ions or a gain of bicarbonate. It is due mainly to problems of the kidney or gastrointestinal tract

Answer 35

• Vomiting / aspiration (e.g. Peptic ulcer leading to pyloric stenosis, nasogastric suction) • Diuretics • Liquorice, carbenoxolone • Hypokalemia • Primary hyperaldosteronism • Congenital adrenal hyperplasia • Cushing's syndrome • Bartter's syndrome

Answer 36

• Activation of renin-angiotensin II-aldosterone (RAA) system is a key factor • Aldosterone causes reabsorption of Na+ in exchange for H+ in the distal convoluted tubule • ECF depletion (vomiting, diuretics) → Na+ and Cl- loss → activation of RAA system → raised aldosterone levels

Answer 37

• In Hypokalemia, K+ shift from cells → ECF. Alkalosis is caused by shift of H+ into cells to maintain neutrality

Answer 38

hyper - > 290 iso - 290-275 hypo - < 275

Answer 39

Sodium depletion, renal loss (patient often hypovolaemic) • Diuretics • Diuretic stage of renal failure • Addison's

Answer 40

• SIADH (urine osmolality > 500 mmol/kg) • Hypothyroidism

Answer 41

Sodium depletion, extra-renal loss • Diarrhea, vomiting, sweating • Burns, adenoma of rectum

Answer 42

Water excess (patient often hypervolaemic and edematous) • Secondary hyperaldosteronism: CCF, cirrhosis • ↓ GFR: renal failure with volume overload • IV dextrose, psychogenic polydipsia

Answer 43

• Dehydration • Osmotic diuresis e.g. Hyperosmolar non-ketotic diabetic coma • Diabetes insipidus • Excess IV saline

Answer 44

Causes of Hyperkalemia: • Acute renal failure • Drugs*: potassium sparing diuretics, ACE inhibitors, Cyclosporin • Metabolic acidosis • Addison's • Rhabdomyolysis • Massive blood transfusion *β-blockers interfere with potassium transport into cells and can potentially cause Hyperkalemia in renal failure patients

Answer 45

Stabilisation of the cardiac membrane • intravenous calcium gluconate Short-term shift in potassium from extracellular to intracellular fluid compartment • combined insulin/dextrose infusion • nebulised salbutamol Removal of potassium from the body • calcium resonium (orally or enema) • loop diuretics • dialysis

Answer 46

Potassium and hydrogen can be thought of as competitors. Hyperkalemia tends to be associated with acidosis because as potassium levels rise fewer hydrogen ions can enter the cells

Answer 47

Hypokalemia with alkalosis • Vomiting • Diuretics • Cushing's syndrome • Conn's syndrome (primary hyperaldosteronism)

Answer 48

Hypokalemia with acidosis: • Diarrhea • Renal tubular acidosis • Acetazolamide • Partially treated DKA

Answer 49

• U waves • Small or absent T waves (occasionally inversion) • Prolong PR interval • ST depression • Long QT n Hypokalemia, U have no Pot and no T, but a long PR and a long QT

Answer 50

• Diuretics • Total Parenteral Nutrition (TPN) • Diarrhea • Alcohol • Hypokalemia, hypocalcemia

Answer 51

• Paraesthesia • Tetany • Seizures • Arrhythmias • ↓ PTH secretion → hypocalcemia • ECG features similar to those of Hypokalemia • Exacerbates digoxin toxicity

Answer 52

• Alcohol excess • Acute liver failure • Diabetic ketoacidosis • Refeeding syndrome (like in anorexia nervosa management) • Primary hyperparathyroidism • Osteomalacia

Answer 53

• Red blood cell hemolysis • White blood cell and platelet dysfunction • Muscle weakness and rhabdomyolysis • Central nervous system dysfunction

Answer 54

Vitamin D ↑ plasma calcium and plasma phosphate levels by promoting renal tubular absorption and gut absorption of calcium and increasing renal phosphate reabsorption

Answer 55

The two hormones which primarily control calcium metabolism are: • parathyroid hormone (PTH) • vitamin D • Calcitonin: secreted from the C cells of the thyroid gland • Thyroxine • Growth hormone

Answer 56

Actions of parathyroid hormone (↑ plasma Ca from bones and kidneys and activation of Vit-D) • ↑ plasma calcium, ↓ plasma phosphate • ↑ renal tubular reabsorption of calcium • ↑ osteoclastic activity • ↑ renal conversion of 25-hydroxy vitamin D to 1,25 dihydroxy vitamin D • ↓ renal phosphate reabsorption

Answer 57

Actions of vitamin D (↑ plasma Ca from bones and kidneys and GIT) • ↑ plasma calcium and ↑ plasma phosphate • ↑ renal tubular reabsorption and gut absorption of calcium • ↑ osteoclastic activity • ↑ renal phosphate reabsorption

Answer 58

Causes • Vitamin D deficiency (osteomalacia) • Chronic renal failure • Hypoparathyroidism (e.g. Post thyroid/parathyroid surgery) • Pseudohypoparathyroidism (target cells insensitive to PTH) • Rhabdomyolysis (initial stages) • Magnesium deficiency (due to end organ PTH resistance) Acute pancreatitis may also cause hypocalcemia. Contamination of blood samples with EDTA may also give falsely low calcium levels

Answer 59

Osteomalacia causes hypocalcemia associated with a low serum phosphate

Answer 60

Hypocalcemia causes Prolonged QT in ECG

Answer 61

Cisplatin, often used in the management of non-small cell lung cancer, is a well known cause of magnesium deficiency. Without first correcting magnesium levels it is difficult to reverse hypocalcemia

Answer 62

Features • Tetany: muscle twitching and spasm • Perioral paraesthesia • If chronic: depression, cataracts

Answer 63

Trousseau's sign • Carpal spasm if the brachial artery occluded by inflating the blood pressure cuff and maintaining pressure above systolic • Wrist flexion and fingers drawn together • Seen in around 95% of patients with hypocalcemia and around 1% of normocalcaemic people

Answer 64

Chvostek's sign • Tapping over parotid causes facial muscles to twitch • Seen in around 70% of patients with hypocalcemia and around 10% of normocalcaemic people

Answer 65

Management • Acute management of severe hypocalcemia is with intravenous replacement. The preferred method is with intravenous calcium gluconate, 10ml of 10% solution over 10 minutes • Intravenous calcium chloride is more likely to cause local irritation • ECG monitoring is recommended • Further management depends on the underlying cause

Answer 66

The most common causes of hypercalcemia are malignancy (bone metastases, myeloma, PTHrP from squamous cell lung cancer) and primary hyperparathyroidism

Answer 67

One of the key differentiating features between monoclonal gammopathy of uncertain significance (MGUS) and myeloma is the absence of complications such as immune paresis, hypercalcemia and bone pain

Answer 68

hypercalcaemia

Answer 69

Management The initial management of hypercalcemia is rehydration with normal saline, typically 3-4 litres/day. Following rehydration bisphosphonates may be used. They typically take 2-3 days to work with maximal effect being seen at 7 days Other options include: • Calcitonin - quicker effect than bisphosphonates • Steroids in sarcoidosis

Answer 70

Hyperuricemia ↑ levels of uric acid may be seen secondary to either ↑ cell turnover or ↓ renal excretion of uric acid. Hyperuricemia may be found in asymptomatic patients who have not experienced attacks of gout Hyperuricemia may be associated with both hyperlipidemia and hypertension. It may also be seen in conjunction with the metabolic syndrome

Answer 71

• Lesch-Nyhan disease • Myeloproliferative disorders • Diet rich in purines • Exercise • Psoriasis • Cytotoxics

Answer 72

• Drugs: low-dose aspirin, diuretics, pyrazinamide • Pre-eclampsia • Alcohol • Renal failure • Lead

Answer 73

Rheumatoid factor is an IgM antibody against IgG Rheumatoid Factor (RF) is a circulatinjg antibody (usually IgM) which reacts with antigenic sites on the Fc portion of the patients own IgG

Answer 74

RF can be detected by: • Rose-Waaler test: sheep red cell agglutination • Latex agglutination test (less specific)

Answer 75

RF is positive in 70-80% of patients with rheumatoid arthritis; high titre levels are associated with severe progressive disease (prognosis but NOT a marker of disease activity)

Answer 76

Nitric Oxide: vasodilation+inhibits platelet aggregation

Answer 77

Nitric Oxide previously known as endothelium derived relaxation factor, nitric oxide (NO) has emerged as a molecule which is integral to many physiological and pathological processes. It is formed from L-arginine and oxygen by nitric oxide synthetase (NOS). An inducible form of NOS has been shown to be present in macrophages. Nitric oxide has a very short half-life (seconds), being inactivated by oxygen free radicals

Answer 78

• Acts on guanylate cyclase leading to raised intracellular cGMP levels and therefore decreasing Ca++ levels • Vasodilation, mainly venodilation • Inhibits platelet aggregation

Answer 79

• Underproduction of NO is implicated in hypertrophic pyloric stenosis • Lack of NO is thought to promote atherosclerosis • In sepsis ↑ levels of NO contribute to septic shock • Organic nitrates (metabolism produces NO) is widely used to treat cardiovascular disease (e.g. Angina, heart failure) • Sildenafil is thought to potentiate the action of NO on penile smooth muscle and is used in the treatment of erectile dysfunctions

Answer 80

Atrial Natriuretic Peptide (ANP) is a powerful vasodilator, and a protein (polypeptide) hormone secreted by heart muscle cells. It is involved in the homeostatic control of body water, sodium, potassium and fat (adipose tissue). ANP acts to ↓ the water, sodium and adipose loads on the circulatory system, thereby reducing blood pressure

Answer 81

• Secreted mainly from myocytes of right atrium and ventricle in response to ↑ blood volume • Secreted by both the right and left atria (right >> left) • 28 amino acid peptide hormone, which acts via cGMP • Degraded by endopeptidases

Answer 82

Actions • Natriuretic, i.e. Promotes excretion of sodium • Lowers BP • Antagonises actions of angiotensin II, aldosterone BNP - actions: • Vasodilator • Diuretic and natriuretic • Suppresses both sympathetic tone and the renin-angiotensin-aldosterone system

Answer 83

B-type Natriuretic Peptide (BNP) hormone produced mainly by the left ventricular myocardium in response to strain Whilst heart failure is the most obvious cause of raised BNP levels any cause of left ventricular dysfunction such as myocardial ischemia or valvular disease may raise levels. Raised levels may also be seen due to ↓ excretion in patients with chronic kidney disease. Factors which ↓ BNP levels include: treatment with ACE inhibitors, angiotensin-2 receptor blockers and diuretics.

Answer 84

Diagnosing patients with acute dyspnea • A low concentration of BNP(< 100pg/ml) makes a diagnosis of heart failure unlikely, but raised levels should prompt further investigation to confirm the diagnosis • NICE currently recommends BNP as a helpful test to rule out a diagnosis of heart failure Prognosis in patients with chronic heart failure • Initial evidence suggests BNP is an extremely useful marker of prognosis Guiding treatment in patients with chronic heart failure • Effective treatment lowers BNP levels Screening for cardiac dysfunction • Not currently recommended for population screening

Answer 85

Endothelin is a potent, long-acting vasoconstrictor and bronchoconstrictor. It is secreted initially as a prohormone by the vascular endothelium and later converted to ET-1 by the action of endothelin converting enzyme. It acts via interaction with a G-protein linked to phospholipase C leading to calcium release. Endothelin is thought to be important in the pathogenesis of many diseases including primary pulmonary hypertension (endothelin antagonists are now used), cardiac failure, hepatorenal syndrome and Raynaud's

Answer 86

• Angiotensin II • ADH • Hypoxia • Mechanical shearing forces

Answer 87

• Nitric oxide • Prostacyclin

Answer 88

Tumour Necrosis Factor (TNF) is a pro-inflammatory cytokine with multiple roles in the immune system

Answer 89

TNF is secreted mainly by macrophages and has a number of effects on the immune system, acting mainly in a paracrine fashion: • Activates macrophages and neutrophils • Acts as costimulator for T cell activation • Key mediator of bodies response to gram NEGATIVE septicemia • Similar properties to IL-1 • Anti-tumour effect (e.g. Phospholipase activation)

Answer 90

TNF-α binds to p55 and p75 receptors, these receptors can induce apoptosis. It also cause activation of NFkB

Answer 91

Endothelial effects include ↑ expression of selectins and ↑ production of platelet activating factor, IL-1 and prostaglandins. TNF promotes the proliferation of fibroblasts and their production of protease and collagenase. It is thought fragments of receptors act as binding points in serum.

Answer 92

Systemic effects include pyrexia, ↑ acute phase proteins and disordered metabolism leading to cachexia. TNF is important in the pathogenesis of rheumatoid arthritis - TNF blockers (e.g. infliximab, etanercept) are now licensed for treatment of severe rheumatoid.

Answer 93

TNF blockers • Infliximab: monoclonal antibody, IV administration • Etanercept: fusion protein that reversibly binds soluble TNF receptors, subcutaneous administration • Adalimumab: monoclonal antibody, subcutaneous administration • Adverse effects of TNF blockers include reactivation of latent tuberculosis and demyelination

Answer 94

Interferons (IFN) are cytokines released by the body in response to viral infections and neoplasia. They are classified according to cellular origin and the type of receptor they bind to. IFN-α and IFN-β bind to type-1 receptors, whilst IFN-gamma binds only to type-2 receptors.

Answer 95

• Produced by Leucocytes • Antiviral action • Useful in hepatitis B & C, kaposi's sarcoma, metastatic renal cell cancer, hairy cell leukemia • Adverse effects include fLu-Like symptoms and depression

Answer 96

IFN-β • Produced by fibroBlasts • Antiviral action • ↓ the frequency of exacerbations in patients with relapsing-remitting MS

Answer 97

• Produced by T lymphocytes & NK cells • weaker antiviral action (inhibit viral duplication), more of a role in immunomodulation particularly macrophage activation • May be useful in chronic granulomatous disease and osteopetrosis

Answer 98

Leukotrienes are fatty molecules of the immune system that contribute to inflammation in asthma and bronchitis. Leukotriene antagonists are used to treat asthma and bronchitis.

Answer 99

• Mediators of inflammation and allergic reactions • Cause bronchoconstriction, mucous production • ↑ vascular permeability, attract leukocytes • Leukotriene D4 has been identified as the SRS-A (slow reacting substance of anaphylaxis)

Answer 100

• secreted by leukocytes • formed from arachidonic acid by action of lipoxygenase • it is thought that the NSAID induced bronchospasm in asthmatics is secondary to the express production of leukotrienes due to the inhibition of prostaglandin synthetase

Answer 101

Interleukin 1 (IL-1) is a key mediator of the immune response. It is secreted mainly by macrophages and monocytes and acts as a costimulator of T cell and B cell proliferation

Answer 102

Acts as a costimulator of T cell and B cell proliferation Other effects include increasing the expression of adhesion molecules on the endothelium. By stimulating the release by the endothelium of vasoactive factors such as PAF, nitric oxide and prostacyclin it also causes vasodilation and ↑ vascular permeability. It is therefore one of the mediators of shock in sepsis. Along with IL-6 and TNF, it acts on the hypothalamus causing pyrexia.

Answer 103

Th1 • Involved in the cell mediated response and delayed (type IV) hypersensitivity • Secrete IFN-gamma, IL-2, IL-3

Answer 104

Th2 • Involved in mediating humoral (antibody) immunity • e.g. Stimulating production of IgE in asthma • Secrete IL-4, IL-5, IL-6, IL-10, IL-13

Answer 105

• Paget's • Bone metastases • Hyperparathyroidism

Answer 106

• Osteomalacia • Renal failure

Answer 107

ESR is a non-specific marker of inflammation and depends on both the size, shape and number of red blood cells and the concentration of plasma proteins such as fibrinogen, α2-globulins and gamma globulins

Answer 108

raised ESR

Answer 109

raised Leukocyte alkaline phosphatase:

Answer 110

low leukocyte alkaline phosphatase

Answer 111

Autosomal RECESSIVE conditions are 'METABOLIC' - exceptions: inherited ataxias

Answer 112

Autosomal DOMINANT conditions are 'STRUCTURAL' - exception: hyperlipidemia type II, hypokalaemic periodic paralysis

Answer 113

Trinucleotide Repeat Disorders are genetic conditions caused by an abnormal number of repeats (expansions) of a repetitive sequence of three nucleotides. These expansions are unstable and may enlarge which may lead to an earlier age of onset in successive generations - a phenomenon known as anticipation*. In most cases, an ↑ in the severity of symptoms is also noted

Answer 114

anticipation

Answer 115

Mitochondrial Diseases: Whilst most DNA is found in the cell nucleus, a small amount of double-stranded DNA is present in the mitochondria. It encodes protein components of the respiratory chain and some special types of RNA

Answer 116

Mitochondrial inheritance have the following characteristics: • Inheritance is only via the maternal line as the sperm contributes no cytoplasm to the zygote • All children of affected ♂s will not inherit the disease • All children of affected ♀s will inherit it • Generally encode rare neurological diseases • Poor genotype:phenotype correlation • Heteroplasmy: within a tissue or cell there can be different mitochondrial populations

Answer 117

Histology • Muscle biopsy classically shows 'red, ragged fibres' due to ↑ number of mitochondria

Answer 118

mitochondrial diseases

Answer 119

Basics • Genes which normally control the cell cycle • Exhibit a recessive effect - both copies must be mutated before cancer occurs

Answer 120

Examples • P53 • APC: colorectal cancer • NF-1: neurofibromatosis • RB: retinoblastoma

Answer 121

myc is an oncogene which encodes a transcription factor

Answer 122

P53 Gene is a tumour suppressor gene located on chromosome 17p. It is the most commonly mutated gene in breast, colon and lung cancer P53 is thought to play a crucial role in the cell cycle, preventing entry into the S phase until DNA has been checked and repaired. It may also be a key regulator of apoptosis

Answer 123

Li-Fraumeni Syndrome is a rare autosomal dominant disorder characterized by the early onset of a variety of cancers such as sarcomas and breast cancer. It is caused by mutation in the p53 gene.

Answer 124

Down Syndrome: trisomy 21 or G, is a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome.

Answer 125

• Face: upslanting palpebral fissures, epicanthic folds, Brushfield spots in iris, protruding tongue, small ears, round/flat face • Flat occiput • Single palmar crease, pronounced 'sandal gap' between big and first toe • Hypotonia • Congenital heart defects • Duodenal atresia • Hirschsprung's disease • ♀: subfertility • ♂: infertility

Answer 126

• Multiple cardiac problems may be present • Endocardial cushion defect (40%, also known as atrioventricular septal canal defects) • V entricular septal defect (30%) • Secundum atrial septal defect (10%) • Tetralogy of fallot (5%) • Isolated patent ductus arteriosus (5%)

Answer 127

later complications of downs syndrome

Answer 128

Risk 20 1 in 1,500 30 1 in 800 35 1 in 270 40 1 in 100 45 1 in 50 or greater One way of remembering this is by starting at 1/1500 at 30 years and then dividing by 3 (i.e. 3 times more common) for every extra 5 years of age

Answer 129

% of cases Risk of recurrence Mode: Nondisjunction % of cases: 94% Risk of recurrence: 1 in 100 if under mother < 35 years Mode: Robertsonian translocation(usually onto 14) % of cases: 5%, Risk of recurrence: 10-15% if mother is translocation carrier, 2.5% if father is translocation carrier Mode:Mosaicism* % of cases: 1% The chance of a further child with Down's syndrome is approximately 1 in 100 if the mother is less than 35 years old. If the trisomy 21 is a result of a translocation the risk is much higher

Answer 130

Turner Syndrome is a chromosomal disorder affecting around 1 in 2,500 ♀s. It is caused by either the presence of only one sex chromosome (X) or a deletion of the short arm of one of the X chromosomes. Turner's syndrome is denoted as 45, XO or 45 X

Answer 131

Features • Short stature • Shield chest, widely spaced nipples • Webbed neck • Bicuspid aortic valve (15%), coarctation of the aorta (5-10%) • Primary amenorrhoea • High-arched palate • Short fourth metacarpal • Multiple pigmented naevi • Lymphedema in neonates (especially feet)

Answer 132

Klinefelter Syndrome (Hypogonadotropic hypogonadism) is associated with karyotype 47, XXY

Answer 133

Features • Often taller than average • Lack of secondary sexual characteristics • Small, firm testes (hypogonadism) • Infertile • Gynaecomastia - ↑ incidence of breast cancer • Elevated gonadotrophin levels

Answer 134

Diagnosis is by chromosomal analysis ↓ Karyotyping

Answer 135

Klinefelter's - LH & FSH raised Kallman's - LH & FSH low-normal

Answer 136

Kallman Syndrome is a recognised cause of delayed puberty secondary to hypogonadotrophic hypogonadism. It is usually inherited as an X-linked recessive trait. Kallman's syndrome is thought to be caused by failure of GnRH-secreting neurons to migrate to the hypothalamus. The clue given in many questions is lack of smell (anosmia) in a boy with delayed puberty.

Answer 137

Features • 'Delayed puberty' • Hypogonadism, cryptorchidism (including undescended tests) • Anosmia • Sex hormone levels are low • LH, FSH levels are inappropriately low/normal • Patients are typically of normal or above average height • Cleft lip/palate and visual/hearing defects are also seen in some patients

Answer 138

Marfan Syndrome is an autosomal dominant connective tissue disorder. It is caused by a defect in the fibrillin-1 gene on chromosome 15

Answer 139

Features • Tall stature with arm span > height ratio > 1.05 • High-arched palate • Arachnodactyly (spider fingers; fingers are abnormally long, in some cases all or few fingers can be bent backwards of 180 degrees) • Pectus excavatum • Pes planus • Scoliosis of > 20 degrees

Answer 140

• Heart: dilation of the aortic sinuses (seen in 90%) which may lead to aortic regurgitation, mitral valve prolapse (75%), aortic dissection

Answer 141

• Lungs: repeated pneumothoraces

Answer 142

• Eyes: upwards lens dislocation (superotemporal ectopia lentis), blue sclera

Answer 143

Noonan Syndrome: Often thought of as the '♂ Turner's', Noonan's syndrome is an autosomal dominant condition associated with a normal karyotype. It is thought to be caused by a defect in a gene on chromosome 12.

Answer 144

As well as features similar to Turner's syndrome (webbed neck, widely-spaced nipples, short stature, pectus carinatum and excavatum), a number of characteristic clinical signs may also be seen: • Cardiac: pulmonary valve stenosis • Ptosis • Triangular-shaped face • Low-set ears • Coagulation problems: factor XI deficiency

Answer 145

Fragile X is a trinucleotide repeat disorder, complex X-linked inheritance.

Answer 146

Features in ♂s • Learning difficulties • Large low set ears, Long thin face, High arched palate • Macroorchidism (Large testes) • Hypotonia • Autism is more common • Mitral valve prolapse

Answer 147

Features in ♀s (who have one fragile chromosome and one normal X chromosome) range from normal to mild

Answer 148

Diagnosis • Can be made antenatally by chorionic villus sampling or amniocentesis • Analysis of the number of CGG repeats using restriction endonuclease digestion and southern blot analysis

Answer 149

Patau Syndrome, also known as trisomy 13 and trisomy D, is a chromosomal abnormality, a syndrome in which a patient has an additional chromosome 13 due to a non-disjunction of chromosomes during meiosis. Some are caused by Robertsonian translocations

Answer 150

the risk of this syndrome in the offspring ↑ with maternal age at pregnancy, with about 31 years being the average. Patau syndrome affects approximately 1 in 25,000 live births.

Answer 151

• Microcephaly • Low-set ears • Cleft palate • Cutis aplasia (missing portion of the skin/hair)

Answer 152

• Structural eye defects, including microphthalmia, peters anomaly, cataract, iris and/or fundus (coloboma), retinal dysplasia or retinal detachment, sensory nystagmus, cortical visual loss, and optic nerve hypoplasia

Answer 153

• Holoprosencephaly (failure of the forebrain to divide properly).

Answer 154

• Meningomyelocele (a spinal defect)

Answer 155

• Omphalocele (abdominal defect)

Answer 156

• Abnormal genitalia

Answer 157

• Abnormal palm pattern • Overlapping of fingers over thumb. • Prominent heel • Deformed feet known as "rocker-bottom feet" • Polydactyly (extra digits)

Answer 158

• Kidney defects

Answer 159

Prader-Willi Syndrome is an example of genetic imprinting where the phenotype depends on whether the deletion occurs on a gene inherited from the mother or father: • Prader-Willi syndrome if gene deleted from father • Angelman syndrome if gene deleted from mother

Answer 160

Prader-Willi syndrome is associated with the absence of the active Prader-Willi gene on the long arm of chromosome 15 (same as Marfan’s chromosome). This may be due to: • Microdeletion of paternal 15q11-13 (70% of cases) • Maternal uniparental disomy of chromosome 15

Answer 161

Features • Hypotonia during infancy • Dysmorphic features • Short stature • Hypogonadism and infertility • Learning difficulties • Childhood obesity • Behavioural problems in adolescence • Acanthosis nigricans

Answer 162

Edwards Syndrome Trisomy 18 (also known as Trisomy E or Edwards Syndrome) is a genetic disorder caused by the presence of all or part of an extra 18th chromosome. It is the second most common autosomal trisomy, after Down’s Syndrome, that carries to term.

Answer 163

The incidence of the syndrome is estimated as 1 in 3,000 live births. Incidence ↑ as the mother's age ↑. The syndrome has a very low rate of survival, resulting from heart abnormalities, kidney malformations, and other internal organ disorders.

Answer 164

Infants born with Edward’s syndrome may have some or all of the following characteristics: • Intestines protruding outside the body (omphalocele) • Arthrogryposis (a muscle disorder that causes multiple joint contractures at birth) • Microcephaly accompanied by a prominent occiput • Low-set, malformed ears • Abnormally small jaw (micrognathia) • Cleft lip/cleft palate • Upturned nose • Narrow eyelid folds (palpebral fissures) • Widely-spaced eyes (ocular hypertelorism) • Ptosis • A short sternum • Clenched hands • Underdeveloped thumbs and or nails • Absent radius • Webbing of the second and third toes • Clubfoot or rocker bottom feet, • Undescended testicles

Answer 165

Infants born with Edward’s syndrome may have some or all of the following characteristics: • Kidney malformations • Structural heart defects at birth • Esophageal atresia • Mental retardation • Developmental delays • Growth deficiency • Feeding difficulties • Breathing difficulties

Answer 166

Trisomy 13 Trisomy D

Answer 167

Trisomy 18 Trisomy E

Answer 168

Trisomy 21 Trisomy G

Answer 169

A Retinoids

Answer 170

B1 Thiamine

Answer 171

B3 Niacin (Nicotinic Acid)

Answer 172

B6 Pyridoxine

Answer 173

B9 Folic acid

Answer 174

B12 Cyanocobalamin

Answer 175

C Ascorbic acid

Answer 176

D Ergocalciferol, cholecalciferol

Answer 177

E Tocopherol, tocotrienol

Answer 178

K Naphthoquinone

Answer 179

Pellagra may occur as a consequence of isoniazid therapy (isoniazid inhibits the conversion of tryptophan to niacin)

Answer 180

Features • Dermatitis (brown scaly rash on sun- exposed sites - termed Casal's necklace if around neck) • Diarrhea • Dementia, depression • Death if not treated

Answer 181

Vitamin B12 is actively absorbed in the Terminal Ileum It is absorbed after binding to intrinsic factor (secreted from parietal cells in the stomach) and is actively absorbed in the terminal ileum. A small amount of vitamin B12 is passively absorbed without being bound to intrinsic factor.

Answer 182

• Pernicious anemia • Post gastrectomy • Poor diet • Disorders of terminal ileum (site of absorption): crohn's, blind-loop etc • Metformin

Answer 183

• Macrocytic anemia • Sore tongue and mouth • Neurological symptoms: e.g. Ataxia • Neuropsychiatric symptoms: e.g. Mood disturbances

Answer 184

Management • If no neurological involvement 1 mg of IM hydroxocobalamin 3 times each week for 2 weeks, then once every 3 months • If a patient is also deficient in folic acid then it is important to treat the B12 deficiency first to avoid precipitating subacute combined degeneration of the cord

Answer 185

Vitamin C Deficiency (scurvy) leads to defective synthesis of collagen resulting in capillary fragility (bleeding tendency) and poor wound healing

Answer 186

Features • Gingivitis, loose teeth • Poor wound healing • Bleeding from gums, hematuria, epistaxis • General malaise

Answer 187

Vitamin D-Resistant Rickets is an X-linked dominant (along with Rett and Alport syndrome) condition which usually presents in infancy with failure to thrive. It is caused by impaired phosphate reabsorption in the renal tubules

Answer 188

Features • Failure to thrive • Normal serum calcium, low phosphate, elevated alkaline phosphotase • X-ray changes: cupped metaphyses with widening of the epiphyses

Answer 189

Diagnosis is made by demonstrating ↑ urinary phosphate

Answer 190

• High-dose vitamin D supplements • Oral phosphate supplements

Answer 191

• Trimethoprim • Methotrexate • Pyrimethamine

Answer 192

Drugs which can ↓ absorption • Phenytoin

Answer 193

• Upper small intestine • About 10% of dietary iron absorbed • Fe++ (ferrous iron) much better absorbed than Fe+++ (ferric iron) • Absorption is regulated according to bodies need

Answer 194

• ↑ by vitamin C, gastric acid • ↓ by proton pump inhibitors, tetracycline, gastric achlorhydria, tannin (found in tea)

Answer 195

• Total body iron = 4g • Hemoglobin = 70% • Ferritin and hemosiderin = 25% • Myoglobin = 4% • Plasma iron = 0.1%

Answer 196

Transport • Carried in plasma as Fe+++ bound to transferrin

Answer 197

Storage • Stored as ferritin in tissues

Answer 198

Excretion • Lost via intestinal tract following desquamination

Answer 199

Features • Perioral dermatitis: red, crusted lesions • Acrodermatitis • Alopecia • Short stature • Hypogonadism • Hepatosplenomegaly • Geophagia (ingesting clay/soil) • Cognitive impairment

Answer 200

Translation and folding of new proteins (rough endoplasmic reticulum), expression of lipids (smooth endoplasmic reticulum)

Answer 201

Sorting and modification of proteins

Answer 202

Energy production. Contains mitochondrial genome as circular double stranded DNA

Answer 203

DNA maintenance and RNA transcription

Answer 204

Breakdown of large molecules such as proteins and polysaccharides

Answer 205

Ribosome production

Answer 206

Translation of RNA into proteins

Answer 207

Breakdown of metabolic hydrogen peroxide

Answer 208

Along with lysosome pathway: degradation of large protein molecules

Answer 209

M - Mitosis - cell division G1 - Gap phase 1 - determines length of cell cycle - under influence of p53 S - DNA Synthesis G2 - Gap phase

Answer 210

Ligand-gated ion channel Tyrosine kinase receptors Guanylate cyclase receptors G protein-coupled receptors

Answer 211

• Generally mediate fast responses • E.g. nicotinic acetylcholine, GABA-A & GABA-C, glutamate receptors

Answer 212

Tyrosine kinase receptors • Contain intrinsic enzyme activity • E.g. Insulin, growth factors, interferon

Answer 213

Guanylate cyclase receptors • Contain intrinsic enzyme activity • E.g. Atrial natriuretic factor (ANP), nitric oxide receptors

Answer 214

• Generally mediate slow transmission and affect metabolic processes • Activated by a wide variety of extracellular signals e.g. Peptide hormones, biogenic amines, lipophilic hormones and light. • Consist of 3 main subunits: α, β and gamma • Ligand binding → conformational changes to receptor, this induces exchange of GDP for GTP • E.g. Muscarinic acetylcholine, adrenergic receptors, GABA-B

Answer 215

• Vasoconstriction • Relaxation of GI smooth muscle • Salivary secretion • Hepatic glycogenolysis (Agonist → phenylephrine)

Answer 216

• Mainly presynaptic: inhibition of transmitter release (inc NA, Ach from autonomic nerves) • Inhibits insulin • Platelet aggregation (Agonist → clonidine)

Answer 217

• Mainly located in the heart • ↑ heart rate + force (Agonist → dobutamine)

Answer 218

• V asodilation • Bronchodilation • Relaxation of GI smooth muscle salbutamol

Answer 219

β-3 (Agonist → being developed, may have a role in preventing obesity) • Lipolysis

Answer 220

• β-1: stimulate adenylate cyclase • β-2: stimulate adenylate cyclase • β-3: stimulate adenylate cyclase

Answer 221

• α-1:activate phospholipase C → IP3 → DAG

Answer 222

• α-2: inhibit adenylate cyclase

Answer 223

Cyclic AMP • E.g. Adrenaline, noradrenaline, glucagon, LH, FSH, TSH, calcitonin, parathyroid hormone Protein kinase activity • E.g. Insulin, growth hormone and factor, prolactin, oxytocin, erythropoietin. Calcium and/or phosphoinositides • E.g. ADH, GnRH, TRH Cyclic GMP • E.g. ANP, nitric oxide

Answer 224

Molecular biology techniques • Snow (South - NOrth - West) • Drop (DNA - RNA - Protein)

Answer 225

Southern blotting Detects DNA Northern blotting Detects RNA Western blotting Detects proteins (Uses gel electrophoresis to separate native proteins by 3-D structure. Examples include the confirmatory HIV test)

Answer 226

Polymerase Chain Reaction (PCR) is a molecular genetic investigation technique. The main advantage of PCR is its sensitivity: only one strand of sample DNA is needed to detect a particular DNA sequence.

Answer 227

Prior to the procedure it is necessary to have two DNA oligonucleotide primers. These are complimentary to specific DNA sequences at either end of the target DNA

Answer 228

Initial prep • Sample of DNA is added to test tube along with two DNA primers • A thermostable DNA polymerase (Taq) is added The following cycle then takes place • Mixture is heated to almost boiling point causing denaturing (uncoiling) of DNA • Mixture is the allowed to cool: complimentary strands of DNA pair up, as there is an excess of the primer sequences they pair with DNA preferentially

Answer 229

Reverse transcriptase PCR • Used to amplify RNA • RNA is converted to DNA by reverse transcriptase • Gene expression in the form of mRNA (rather than the actually DNA sequence) can therefore be analyzed

Answer 230

The human genome is stored on 23 chromosome pairs. The haploid human genome has a total of 3 billion DNA base pairs, making up estimated 20,000-25,000 protein-coding genes

Answer 231

Sphenoid Ophthalmic A. Optic nerve (II)

Answer 232

Sphenoid Superior ophthalmic V. Inferior ophthalmic V. Oculomotor nerve (III) Trochlear nerve (IV) lacrimal, frontal and nasociliary branches of ophthalmic nerve (V1) Abducent nerve (VI)

Answer 233

Sphenoid and maxilla Inferior ophthalmic V. Infraorbital artery Infraorbital vein Zygomatic nerve and infraorbital nerve of maxillary nerve (V2) Orbital branches of pterygopalatine ganglion

Answer 234

Sphenoid Maxillary nerve (V2)

Answer 235

Sphenoid Accessory meningeal A. Mandibular nerve (V3)

Answer 236

Occipital and temporal Posterior meningeal A. Ascending pharyngeal A. Inferior petrosal sinus Sigmoid sinus Internal jugular V. Glossopharyngeal nerve (IX) Vagus nerve (X) Accessory nerve (XI)

Answer 237

Right suprarenal gland Duodenum Colon

Answer 238

Liver Distal part of small intestine

Answer 239

Left suprarenal gland Pancreas Colon

Answer 240

Stomach Spleen Distal part of small intestine

Answer 241

Epidermis is the outermost layer of the skin and is composed of a stratified squamous epithelium with an underlying basal lamina

Answer 242

Stratum corneum Flat, dead, scale-like cells filled with keratin, Continually shed Stratum lucidum Clear layer - present in thick skin only Stratum granulosum Cells form links with neighbours Stratum spinosum Squamous cells begin keratin synthesis, Thickest layer of epidermis Stratum germinativum The basement membrane - single layer of columnar epithelial cells, Gives rise to keratinocytes, Contains melanocytes

Answer 243

0 - Rapid depolarisation Rapid sodium influx These channels automatically deactivate after a few ms 1- Early repolarisation Efflux of potassium 2- Plateau Slow influx of calcium 3 - Final repolarisation Efflux of potassium 4 - Restoration of ionic concentrations Resting potential is restored by Na+/K+ ATPase There is slow entry of Na+ into the cell decreasing the potential difference until the threshold potential is reached, triggering a new action potential

Answer 244

NB cardiac muscle remains contracted 10-15 times longer than skeletal muscle

Answer 245

Spreads along ordinary atrial myocardial fibres at 1 m/sec

Answer 246

0.05 m/sec

Answer 247

Purkinje fibres are of large diameter and achieve velocities of 2-4 m/sec (this allows a rapid and coordinated contraction of the ventricles)

Answer 248

Antidiuretic hormone (ADH) is secreted from the posterior pituitary gland. It promotes water reabsorption in the collecting ducts of the kidneys by the insertion of aquaporin-2 channels

Answer 249

The adrenal medulla secretes virtually all the adrenaline in the body as well as secreting small amounts of noradrenaline. It essentially represents an enlarged and specialised sympathetic ganglion

Answer 250

A null hypothesis states that two treatments are equally effective (and is hence negatively phrased); A significance test uses the sample data to assess how likely the null hypothesis is to be correct.

Answer 251

The p value is the probability of obtaining a result at least as extreme as the one that was actually observed, assuming that the null hypothesis is true.

Answer 252

The null hypothesis is rejected if the p-value is smaller than or equal to the significance level P-value ≤ significance level

Answer 253

Two types of errors may occur when testing the null hypothesis • Type I: the null hypothesis is rejected when it is true - i.e. Showing a difference between two groups when it doesn't exist (= significance level) • Type II: the null hypothesis is accepted when it is false - i.e. Failing to spot a difference when one really exists

Answer 254

The power of a study is the probability of (correctly) rejecting the null hypothesis when it is false • power = 1 - the probability of a type II error • power can be ↑ by increasing the sample size

Answer 255

Parametric tests • Student's t-test - paired or unpaired • Pearson's product-moment coefficient - correlation

Answer 256

• Mann-Whitney - unpaired data • Wilcoxon matched-pairs - compares two sets of observations on a single sample • Chi-squared test - used to compare proportions or percentages • Spearman, Kendall rank – correlation • McNemar's test is used on nominal data to determine whether the row and column marginal frequencies are equal

Answer 257

Paired data refers to data obtained from a single group of patients, e.g. Measurement before and after an intervention. Unpaired data comes from two different groups of patients, e.g. Comparing response to different interventions in two groups

Answer 258

Funnel Plot is primarily used to demonstrate the existence of publication bias in meta-analyses. Funnel plots are usually drawn with treatment effects on the horizontal axis and study size on the vertical axis.

Answer 259

• A symmetrical, inverted funnel shape indicates that publication bias is unlikely

Answer 260

Conversely, an asymmetrical funnel indicates a relationship between treatment effect and study size. This indicates either publication bias or a systematic difference between smaller and larger studies ('small study effects')

Answer 261

Central Limit Theorem (CLT): the random sampling distribution of mean would always tend to be normal irrespective of the population distribution for which the sample were drown. The mean of the random sampling distribution of means is equal to the mean of the original population

Answer 262

Confidence Interval (CI): describes the range of value around a mean, an odds ratio, a pvalue or a standard deviation within which the true value lies. 95% CI → 5% chance the true mean value for variable lies outside the range CI = mean ± 2xSE (Standard Error)

Answer 263

Normal Distribution is also known as Gaussian distribution or 'bell-shaped' distribution. It describes the spread of many biological and clinical measurements

Answer 264

Properties of the Normal Distribution • Symmetrical i.e. Mean = Median = Mode • 68.3% of values lie within 1 SD of the mean • 95.4% of values lie within 2 SD of the mean • 99.7% of values lie within 3 SD of the mean • This is often reversed, so that within 1.96 SD of the mean lie 95% of the sample values • The range of the mean - (1.96 *SD) to the mean + (1.96 * SD) is called the 95% confidence interval, i.e. if a repeat sample of 100 observations are taken from the same group 95 of them would be expected to lie in that range

Answer 265

For normally distributed data 95.4% of values lie within 2 standard deviations of the mean, leaving 4.6% outside this range. Therefore 2.3% of values will be higher and 2.3% will be lower than 2 standard deviations from the mean. This figure is sometimes approximated to 2.5%

Answer 266

Normal distributions: mean = median = mode

Answer 267

Positively skewed distribution: mean > median > mode • To remember the above note how they are in alphabetical order, think positive going forward with '>', whilst negative going backwards '

Answer 268

• Negatively skewed distribution mean < median < mode • To remember the above note how they are in alphabetical order, think positive going forward with '>', whilst negative going backwards '

Answer 269

The Standard Error of the Mean (SEM) is a measure of the spread expected for the mean of the observations - i.e. how 'accurate' the calculated sample mean is from the true population mean

Answer 270

Key point • SEM = S / square root (n) • Where S = standard deviation and n = sample size Standard error of the mean = standard deviation / square root (number of patients)

Answer 271

Therefore the SEM gets smaller as the sample size (n) ↑

Answer 272

A confidence interval for the mean can be calculated in a similar way to that for a single observation i.e. the 95% confidence interval = mean - (1.96 *SEM) to the mean + (1.96 * SEM)

Answer 273

Relative Risk (RR) is the ratio of risk in the experimental group (experimental event rate, EER) to risk in the control group (control event rate, CER)

Answer 274

CER = rate at which events occur in the control group Control event rate = (Number who had particular outcome with the control) / (Total number who had the control)

Answer 275

EER = rate at which events occur in the experimental group Experimental event rate = (Number who had particular outcome with the intervention) / (Total number who had the intervention)

Answer 276

Absolute risk reduction = (Control event rate) - (Experimental event rate)

Answer 277

Relative risk reduction (RRR) is calculated by dividing the absolute risk reduction by the control event rate

Answer 278

The Hazard Ratio (HR) is similar to relative risk but is used when risk is not constant to time. It is typically used when analysing survival over time

Answer 279

Numbers needed to treat (NNT) is a measure that indicates how many patients would require an intervention to ↓ the expected number of outcomes by 1. It is rounded to the next highest whole number

Answer 280

NNT = 1 / (CER - EER), or 1 / Absolute Risk Reduction

Answer 281

Odds - remember a ratio of the number of people who incur a particular outcome to the number of people who do not incur the outcome, NOT TO THE TOTAL NUMBER OF PEOPLE

Answer 282

Odds Ratio may be defined as the ratio of the odds of a particular outcome with experimental treatment and that of control

Answer 283

Pre-test probability = Prelivence of a condition The proportion of people with the target disorder in the population at risk at a specific time (point prevalence) or time interval (period prevalence) Where the likelihood ratio for a positive test result = sensitivity / (1 - specificity)

Answer 284

The proportion of patients with that particular test result who have the target disorder Post-test probability = post test odds / (1 + post-test odds) Where the likelihood ratio for a positive test result = sensitivity / (1 - specificity)

Answer 285

Pre-test odds The odds that the patient has the target disorder before the test is carried out Pre-test odds = pre-test probability / (1 - pre-test probability) Where the likelihood ratio for a positive test result = sensitivity / (1 - specificity)

Answer 286

Post-test odds The odds that the patient has the target disorder after the test is carried out Post-test odds = pre-test odds x likelihood ratio Where the likelihood ratio for a positive test result = sensitivity / (1 - specificity)

Answer 287

The incidence is the number of new cases per population in a given time period. For example, if condition X has caused 40 new cases over the past 12 months per 1,000 of the population the annual incidence is 0.04 or 4%.

Answer 288

The prevalence is the total number of cases per population at a particular point in time. For example, imagine a questionnaire is sent to 2,500 adults asking them how much they weigh. If from this sample population of 500 of the adults were obese then the prevalence of obesity would be 0.2 or 20%.

Answer 289

• prevalence = incidence * duration of condition

Answer 290

In chronic diseases the prevalence is much greater than the incidence

Answer 291

In acute diseases the prevalence and incidence are similar. For conditions such as the common cold the incidence may be greater than the prevalence

Answer 292

TP / (TP + FN ) TP - true positive FN - false negative Proportion of patients with the condition who have a positive test result

Answer 293

TN / (TN + FP) TN: true negative FP: false positive Proportion of patients without the condition who have a negative test result

Answer 294

TP / (TP + FP) The chance that the patient has the condition if the diagnostic test is positive

Answer 295

TN / (TN + FN) The chance that the patient does not have the condition if the diagnostic test is negative

Answer 296

sensitivity / (1 - specificity) How much the odds of the disease increase when a test is positive

Answer 297

(1 - sensitivity) / specificity How much the odds of the disease decrease when a test is negative

Answer 298

1. The condition should be an important public health problem 2. There should be an acceptable treatment for patients with recognised disease 3. Facilities for diagnosis and treatment should be available 4. There should be a recognised latent or early symptomatic stage 5. The natural history of the condition, including its development from latent to declared disease should be adequately understood 6. There should be a suitable test or examination 7. The test or examination should be acceptable to the population 8. There should be agreed policy on whom to treat 9. The cost of case-finding (including diagnosis and subsequent treatment of patients) should be economically balanced in relation to the possible expenditure as a whole 10. Case-finding should be a continuous process and not a 'once and for all' project

Answer 299

Correlation The correlation coefficient (sometimes referred to as Pearson's product-moment coefficient) indicates how closely the points lie to a line drawn through the plotted data. It is denoted by the value R which may lie anywhere between -1 and 1. For example R = 1 - strong positive correlation (e.g. Systolic blood pressure always ↑ with age) R = 0 - no correlation (e.g. There is no correlation between systolic blood pressure and age) R = - 1 - strong negative correlation (e.g. Systolic blood pressure always ↓ with age)

Answer 300

In contrast to the correlation coefficient, linear regression may be used to predict how much one variable changes when a second variable is changed. A regression equation may be formed, y = a + bx, where y = the variable being calculated a = the intercept value, when x = 0 b = the slope of the line or regression coefficient. Simply put, how much y changes for a given change in x x = the second variable

Answer 301

Participants randomly allocated to intervention or control group (e.g. standard treatment or placebo) • Practical or ethical problems may limit use

Answer 302

Two (or more) are selected according to their exposure to a particular agent (e.g. medicine, toxin) and followed up to see how many develop a disease or other outcome • The usual outcome measure is the relative risk. • Examples include Framingham Heart Study Randomized treatment prevents systemic diference between treatment groups

Answer 303

Patients with a particular condition (cases) are identified and matched with controls. Data is then collected on past exposure to a possible causal agent for the condition • Inexpensive, produce quick results • Useful for studying rare conditions • Prone to confounding

Answer 304

• Provide a 'snapshot', sometimes called prevalence studies • Provide weak evidence of cause and effect

Answer 305

Levels of evidence • Ia - evidence from meta-analysis of randomised controlled trials • Ib - evidence from at least one randomised controlled trial • IIa - evidence from at least one well designed controlled trial which is not randomised • IIb - evidence from at least one well designed experimental trial • III - evidence from case, correlation and comparative studies • IV - evidence from a panel of experts

Answer 306

• Grade A - based on evidence from at least one randomised controlled trial (i.e. Ia or Ib) • Grade B - based on evidence from non-randomised controlled trials (i.e. IIa, IIb or III) • Grade C - based on evidence from a panel of experts (i.e. IV)

Answer 307

Superiority: whilst this may seem the natural aim of a trial one problem is the large sample size needed to show a significant benefit over an existing treatment

Answer 308

Equivalence: an equivalence margin is defined (-delta to +delta) on a specified outcome. If the confidence interval of the difference between the two drugs lies within the equivalence margin then the drugs may be assumed to have a similar effect

Answer 309

Non-inferiority: similar to equivalence trials but only the lower confidence interval needs to lie within the equivalence margin (i.e. -delta). Small sample sizes are needed for these trials. Once a drug has been shown to be non-inferior large studies may be performed to show superiority

Answer 310

Intention to treat analysis is a method of analysis for randomized controlled trials in which all patients randomly assigned to one of the treatments are analysed together, regardless of whether or not they completed or received that treatment. Intention to treat analysis is done to avoid the effects of crossover and drop-out, which may affect the randomization to the treatment groups

Answer 311

Penetrance describes 'how likely' it is that a condition will develop examples of conditions with incomplete penetrance include retinoblastoma and Huntington's disease in contrast, achondroplasia shows 100%, or complete, penetrance

Answer 312

Expressivity describes the 'severity' of the phenotype a condition with a high level of expressivity is neurofibromatosis