Basic Science Flashcards
what are HLAs? where are these encoded?
Antigens
HLAs: are encoded for by genes on chromosome 6
Which HLA:
Ankylosing spondylitis
Postgonococcal arthritis
Acute anterior uveitis
Reiter’s syndrome (reactive arthritis)
HLA B27
Which HLA:
Narcolepsy
Goodpasture’s
HLA DR2
Which HLA:
Autoimmune hepatitis
Primary biliary cirrhosis
Diabetes mellitus type 1
Dermatitis herpetiformis
Coeliac disease (95% associated with HLA-DQ2)
Primary Sjögren syndrome
HLA DR3
Which HLA:
Rheumatoid arthritis
Diabetes mellitus type 1 (> DR3)
HLA DR4
(rheumatoid arthritis - in particular the DRB1 gene (DRB104:01 and DRB104:04 hence the association with DR4))
which HLA:
Diabetes mellitus type 1
HLA DR3 and DR4 combined
Which HLA:
21-hydroxylase deficiency
HLA-B47
Which HLA:
Hemochromatosis
HLA-A3
Which HLA:
Behcet’s disease
HLA-B5
HLA B51 is a split of B5
What HLA is assoc with rheumatoid? What syndrome is this HLA also assoc with?
Around 70% of patients with rheumatoid arthritis are HLA-DR4. Patients with Felty’s syndrome
(a triad of rheumatoid arthritis, splenomegaly and neutropaenia) are even more strongly
associated with 90% being HLA-DR4
What is CD1?
HLA molecule that presents lipid molecules
What is CD2?
Found on thymocytes, T cells, and some natural killer cells that acts as a ligand for CD58 and CD59 and is involved in signal transduction and cell adhesion
what is CD3?
The signalling component of the T cell receptor (TCR) complex
what is CD4?
Co-receptor for HLA class II; also a receptor used by HIV to enter T cells
What is CD8?
Co-receptor for HLA class I; also found on a subset of myeloid dendritic cells
what are the 4 gel and coombs classification of hypersensitivity reactions? what is the recently added V?
Type I - Anaphylactic
Type II - Cell bound
Type III - Immune complex
Type IV - Delayed hypersensitivity
Type V - Stimulated hypersensitivity
describe type 1 hypersensitivity?
Anaphalaxis
• Antigen reacts with IgE bound to mast cells
• Anaphylaxis, atopy
Describe type 2 hypersensitivity?
Type II - Cell bound
• IgG or IgM binds to antigen on cell surface
• Autoimmune hemolytic anemia, ITP, Goodpasture’s
Describe type 3 hypersensitivity?
Type III - Immune complex
• Free antigen and antibody (IgG, IgA) combine
• Serum sickness, SLE, post-streptococcal glomerulonephritis, extrinsic allergic alveolitis
(especially acute phase)
Describe type 4 hypersensitivity
Type IV - Delayed hypersensitivity
• T cell mediated
• Tuberculosis, Tuberculin skin reaction, grafT versus hosT disease, allergic conTacT
dermaTiTis, scabies, exTrinsic allergic alveoliTis (especially chronic phase)
Describe type 5 hypersensitivity
Type V - Stimulated hypersensitivity
• IgG antibodies stimulate cells they are directed against
• Graves’, myasthenia Gravis
Describe the skin prick test - what is this useful for?
Most commonly used test as easy to perform and inexpensive. Drops of diluted allergen are placed on the skin after which the skin is pierced using a needle. A large number of allergens can be tested in one session. Normally includes a histamine (positive) and sterile water (negative) control. A wheal will typically develop if a patient has an allergy. Can be interpreted after 15 minutes
Useful for food allergies and also pollen and wasp/bee venom
Describe RAST testing?
what is this useful for?
Radioallergosorbent test (RAST)
Determines the amount of IgE that reacts specifically with suspected or known allergens, for example IgE to egg protein. Results are given in grades from 0 (negative) to 6 (strongly positive)
Useful for food allergies inhaled allergens (e.g. pollen) and wasp/bee venom
Blood tests may be used when skin prick tests are not suitable, for example if there is extensive eczema or if the .
Describe skin patch testing - what is this used for?
Useful for contact dermatitis. Around 30-40 allergens are placed on the back. Irritants may also be tested for. The results are read 48 hours later by a dermatologist
IgG
what proportion of serum antibodies?
type of molecule?
what is the role?
75%
Monomer
Enhance phaGocytosis of bacteria and viruses.
IgA
what proportion of serum antibodies?
type of molecule?
what is the role?
15%
Mono+Dimer
Found in secretions, provide localized protection on mucous membranes
IgM
what proportion of serum antibodies?
type of molecule?
what is the role?
10%
Pentamer
first to be secreted, anti-A, B blood antibodies → Blood Transfusion
IgD
what proportion of serum antibodies?
type of molecule?
what is the role?
1%
Monomer
Involved in activation of B cells
IgE
what proportion of serum antibodies?
type of molecule?
what is the role?
0.1%
Monomer
Involved in allergic reactions
How much antibody does an average adult produce everyday?
Each day an average adult produces approximately 3gm of antibodies, about two-thirds of this IgA
IgG
-half life
-how many binding sites
-what 4 things can the Fc portion of IgG do?
• 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).
IgA
-where is this mainly found
-where is this mainly produced
-what does the molecule look like
-what the does Fc portion of IgA do
-what complement pathway does this activate
• 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)
IgM
-when is this produced
-what is the half life
-what kind of molecule is this
-what do the Fc portions of IgM do
-where are momeric forms of IgM found
• 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.
IgD
-what kind of molecule is this
-where is this found
-what may this play a role in
• 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.
IgE:
-where is this found
-what kind of molecule is this
-what is this made in response to
-how may this protect external mucosal surfaces
-what does the Fc portion of IgE do?
• 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.
what kind of disorders are:
• Chronic granulomatous disease
• Chediak-higashi syndrome
• Leukocyte adhesion deficiency
neutrophil disorders
what kind of disorders are:
• IgA deficiency
• Bruton’s congenital agammaglobulinemia
• Common variable immunodeficiency
B-cell disorders
what kind of disorder is DiGeorge syndrome?
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
what kind of disorders are:
• Severe combined immunodeficiency
• Ataxic telangiectasia
• Wiskott-Aldrich syndrome
Combined B- and T-cell disorders
How is ataxic telangiectasia inherited?
-what does this increase the risk of?
-what do patients suffer from?
Ataxic telangiectasia (Autosomal recessive - 10% risk of developing malignancy, lymphoma or
leukaemia, but also non-lymphoid tumours - recurrent chest infections)
How is wiskott-aldrich syndrome inherited?
-what is this thought to be caused by?
-what are the features?
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.
what are the two main types of ANCA?
There are two main types of anti-neutrophil cytoplasmic antibodies (ANCA) - cytoplasmic (cANCA) and perinuclear (pANCA)
what is: • cANCA assoc with?
• pANCA assoc with?
• cANCA - Wegener’s Granulomatosis (Granulomatosis with polyangiitis)
• pANCA - Churg-Strauss syndrome + others
cANCA
-what is the most common target?
-is there a correlation between cANCA levels and disease activity?
-what 2 conditions are assoc?
• 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%
pANCA
-what is the most common target?
-can levels be used to monitor disease activity?
-what 4 diseases in this assoc with?
• 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%
• Inflammatory bowel disease (UC > Crohn’s)
• Connective tissue disorders: RA, SLE, Sjogren’s
• Autoimmune hepatitis
are all ? positive
Other causes of positive ANCA (usually pANCA)
• Inflammatory bowel disease (UC > Crohn’s)
• Connective tissue disorders: RA, SLE, Sjogren’s
• Autoimmune hepatitis
what is C3 deficiency assoc with
what is C5 deficiency assoc with
Whilst C3 deficiency is associated with recurrent bacterial infections, C5 deficiency is more
characteristically associated with disseminated meningococcal infection
what is complement?
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
C1 inhibitor (C1-INH) protein deficiency
-what does this causes?
-what is C1-INH?
-what is the disease mechanism?
• Causes hereditary angiedema
• C1-INH is a multifunctional serine protease inhibitor
• Probable mechanism is uncontrolled release of bradykinin resulting in edema of tissues
what does C1q, C1rs, C2, C4 deficiency (classical pathway components) cause?
• Predisposes to immune complex disease
• E.g. SLE, Henoch-Schonlein Purpura
what does C3 deficiency cause?
• Causes recurrent bacterial infections
what does C5 deficiency cause?
• Predisposes to Leiner disease
• Recurrent diarrhea, wasting and seborrhoeic dermatitis
• Disseminated meningococcal infection.
what does C5-9 deficiency cause?
• Encodes the membrane attack complex (MAC)
• Particularly prone to Neisseria meningitidis infection
how is anion gap worked out? what is a normal anion gap?
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
what are 5 causes of normal anion gap metabolic acidosis?
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
what are 4 causes of raised anion gap?
Raised anion gap - LUKA raises his hands
• Lactate: shock, hypoxia
• Urate: renal failure
• Ketones: DKA, alcohol
• Acid poisoning: salicylates, methanol
what are two types of lactic acidosis?
• Lactic acidosis type A: shock, hypoxia, burns
• Lactic acidosis type B: metformin
what is metabolic alkalosis caused by?
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
what are causes of metabolic alkalosis?
• 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
how does the RAAS contribute to metabolic alkalosis?
• 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
why does hypokalaemia cause metabolic alkalosis?
• In Hypokalemia, K+ shift from cells → ECF. Alkalosis is caused by shift of H+ into cells to
maintain neutrality
what levels of plasma osmolality:
hypertonic
isotonic
hypotonic
hyper - > 290
iso - 290-275
hypo - < 275
describe causes of hyponatraemia with a urinary sodium of >20 and hypovolaemic patient?
Sodium depletion, renal loss (patient often hypovolaemic)
• Diuretics
• Diuretic stage of renal failure
• Addison’s
describe causes of hyponatraemia with a urinary sodium of >20 and euvolaemic patient?
• SIADH (urine osmolality > 500 mmol/kg)
• Hypothyroidism
what are causes of hyponatraemia with a urinary sodium of <20 and patient euvolaemic/hypovolaemic?
Sodium depletion, extra-renal loss
• Diarrhea, vomiting, sweating
• Burns, adenoma of rectum
what are causes of hyponatraemia with a urinary sodium of <20 and patient hypervolaemic and oedematous?
Water excess (patient often hypervolaemic and edematous)
• Secondary hyperaldosteronism: CCF, cirrhosis
• ↓ GFR: renal failure with volume overload
• IV dextrose, psychogenic polydipsia
what are causes of hypernatraemia?
• Dehydration
• Osmotic diuresis e.g. Hyperosmolar non-ketotic diabetic coma
• Diabetes insipidus
• Excess IV saline
what are causes of hyperkalaemia?
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
what is the management of hyperkalaemia?
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
why is hyperkalaemia assoc. with acidosis?
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
what are causes of hypokalaemia with alkalosis?
ALKALOSIS: Vomming from ?alcohol
Konditions - Cushins and Conns
Losing water with Diuretics
Hypokalemia with alkalosis
• Vomiting
• Diuretics
• Cushing’s syndrome
• Conn’s syndrome (primary hyperaldosteronism)
what are the causes of hypokalaemia with acidosis?
ACIDOSIS: Diarrhoea (DOSIS)
RTAcidosis + Acetazolomide
Hypokalemia with acidosis:
• Diarrhea
• Renal tubular acidosis
• Acetazolamide
• Partially treated DKA
what are the features of hypokalaemia on ECG?
• 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
what are causes of hypomagnesaemia?
• Diuretics
• Total Parenteral Nutrition (TPN)
• Diarrhea
• Alcohol
• Hypokalemia, hypocalcemia
what are features of hypomagnesaemia?
• Paraesthesia
• Tetany
• Seizures
• Arrhythmias
• ↓ PTH secretion → hypocalcemia
• ECG features similar to those of Hypokalemia
• Exacerbates digoxin toxicity
what are causes of hypophosphataemia?
• Alcohol excess
• Acute liver failure
• Diabetic ketoacidosis
• Refeeding syndrome (like in anorexia nervosa management)
• Primary hyperparathyroidism
• Osteomalacia
what does hypophosphataemia cause?
• Red blood cell hemolysis
• White blood cell and platelet dysfunction
• Muscle weakness and rhabdomyolysis
• Central nervous system dysfunction
what does vitamin D do to increase calcium levels?
Vitamin D ↑ plasma calcium and plasma phosphate levels by promoting renal tubular absorption
and gut absorption of calcium and increasing renal phosphate reabsorption
what two hormones primarily control calcium?
what others have a role?
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
what are the action of PTH?
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
what does vitamin D do?
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
what are 7 causes of hypocalcaemia?
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
what does osteomalacia cause in terms of calcium and phosphate?
Osteomalacia causes hypocalcemia associated with a low serum phosphate
what does hypocalcaemia do on ECG?
Hypocalcemia causes Prolonged QT in ECG
how does cisplatin affect magnesium?
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
what are the features of hypocalcaemia?
Features
• Tetany: muscle twitching and spasm
• Perioral paraesthesia
• If chronic: depression, cataracts
what is trousseaus sign?
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
what is chvosteks sign?
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
what is the management of hypocalcaemia?
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
what are the most common causes of hypercalcaemia?
The most common causes of hypercalcemia are malignancy (bone metastases, myeloma, PTHrP from squamous cell lung cancer) and primary hyperparathyroidism
how to differentiate MGUS and myeloma?
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
• Sarcoidosis/TB/histoplasmosis
• Vitamin D intoxication
• Acromegaly
• Thyrotoxicosis
• Milk-alkali syndrome
• Drugs: thiazides, Ca++ containing antacids
• Dehydration
• Addison’s disease
• Paget’s disease of the bone and prolonged immobilisation
can all cause:
hypercalcaemia
what is the management of hypercalcaemia?
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
what may hyperuricaemia be secondary to?
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
what may increase synthesis of uric acid? 6
• Lesch-Nyhan disease
• Myeloproliferative disorders
• Diet rich in purines
• Exercise
• Psoriasis
• Cytotoxics
what 5 things may decrease excretion of uric acid?
• Drugs: low-dose aspirin, diuretics, pyrazinamide
• Pre-eclampsia
• Alcohol
• Renal failure
• Lead
what is rheumatoid factor?
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
how can rheumatoid factor be detected?
RF can be detected by:
• Rose-Waaler test: sheep red cell agglutination
• Latex agglutination test (less specific)
what are high levels of rheumatoid factor assoc with?
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)
what does nitric oxide do?
Nitric Oxide: vasodilation+inhibits platelet aggregation
How is nitric acid formed? how long is this half-life?
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
what are the effects of nitric oxide?
• Acts on guanylate cyclase leading to raised intracellular cGMP levels and therefore decreasing Ca++ levels
• Vasodilation, mainly venodilation
• Inhibits platelet aggregation
-What is the underproduction of NO implicated in?
-what does the lack of NO promote?
-what happens to NO in sepsis?
-what are organic nitrates used to treat?
-how does sildenafil affect NO?
• 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
What is ANP?
-what is this secreted by?
-what does ANP work to do?
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
when is ANP secreted and where from? how is this degraded?
• Secreted mainly from myocytes of right atrium and ventricle in response to ↑ blood volume
• Secreted by both the right and left atria (right»_space; left)
• 28 amino acid peptide hormone, which acts via cGMP
• Degraded by endopeptidases
what are the actions of ANP?
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
BNP:
-where is this produced?
-what are causes of raised BNP?
-what are causes of reduced BNP?
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.
what is BNP useful for?
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
what is endothelin?
-what is this secreted initially as?
-how does this lead to calcium release?
-what is this important in the pathogenesis of?
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
what promotes the release of endothelin?
• Angiotensin II
• ADH
• Hypoxia
• Mechanical shearing forces
what inhibits the release of endothelin?
• Nitric oxide • Prostacyclin
what is TNF?
Tumour Necrosis Factor (TNF) is a pro-inflammatory cytokine with multiple roles in the immune system
what is TNF secreted by?
what are its 5 main actions?
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)
what does TNF-alpha bind to? what does TNF alpha activate?
TNF-α binds to p55 and p75 receptors, these receptors can induce apoptosis. It also cause activation of NFkB
what are endothelial effects of TNF?
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.
what are systemic effects of TNF?
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.
name 3 TNF blockers
what are adverse effects of TNF blockers?
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
what are interferons?
-how are these classified?
what do IFN-alpha and IFN-beta bind to?
what does IFN-gamma bind to?
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.
IFN-Alpha:
-what is this produced by?
-what action does this have?
-what diseases is this useful against?
-what are the adverse effects?
• 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
IFN-β
-what is this produced by?
-what action does this have?
-what disease is this important for?
IFN-β
• Produced by fibroBlasts
• Antiviral action
• ↓ the frequency of exacerbations in patients with relapsing-remitting MS
IFN-gamma
-what is this produced by?
-what is the main actio?
-what diseases is this useful in?
• 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
what are leukotrienes?
-what are leukotriene antagonists used for?
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.
what are 4 functions of leukotrienes?
• 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)
how are leukotrienes produced?
• 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
what is interleukin 1?
-what is this secreted by?
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
what are the effects of interleukin 1?
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.
what are the two major subsets of T helper cells?
Th1
Th2
Th1:
-what is his involved in?
-what does this secrete?
Th1
• Involved in the cell mediated response and delayed (type IV) hypersensitivity
• Secrete IFN-gamma, IL-2, IL-3
Th2
-what is this involved in?
-what does this secrete?
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
what causes a raised ALP and raised Ca?
• Paget’s
• Bone metastases
• Hyperparathyroidism
what causes a raised ALP and low calcium?
• Osteomalacia • Renal failure
what is ESR?
-what does this depend on?
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
• Temporal arteritis
• Myeloma
• Other connective tissue disorders e.g. Systemic lupus erythematosus
• Other malignancies
• Infection
• Other factors which raise ESR: increasing age, ♀ sex, anemia
are all causes of
raised ESR
• Polycythemia
• Afibrinogenemia/hypofibrinogenemia
are all causes of
low ESR
• Myelofibrosis
• Leukemoid reactions
• Polycythemia rubra vera
• Infections
• Steroids, Cushing’s syndrome
• Pregnancy, oral contraceptive pill
are all assoc. with
raised Leukocyte alkaline phosphatase:
• Chronic myeloid leukemia
• Pernicious anemia
• Paroxysmal nocturnal hemoglobinuria
• Infectious mononucleosis
are all assoc. with
low leukocyte alkaline phosphatase
what are autosomal recessive conditions all..
Autosomal RECESSIVE conditions are ‘METABOLIC’ - exceptions: inherited ataxias
what are autosomal dominant conditions all…
Autosomal DOMINANT conditions are ‘STRUCTURAL’ - exception: hyperlipidemia type II, hypokalaemic periodic paralysis
what is anticipation?
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
Examples - note dominance of neurological disorders
• Fragile X (CGG)
• Huntington’s (CAG)
• Myotonic dystrophy (CTG)
• Friedreich’s ataxia* (GA A)
• Spinocerebellar ataxia
• Spinobulbar muscular atrophy
• Bulbospinal Neuropathy
• Dentatorubral pallidoluysian atrophy
all demonstrate
anticipation
Describe the DNA found in mitochondria
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
Diseases with mitochondrial inheritence:
-what line of inheritence is this via?
-all children of affected mother or father will inherit disease?
-what is heteroplasmy?
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
what is shown on histology of mitochondrial diseases?
Histology
• Muscle biopsy classically shows ‘red, ragged fibres’ due to ↑ number of mitochondria
• Leber’s optic atrophy
• MELAS syndrome: mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes
• MERRF syndrome: myoclonus epilepsy with ragged-red fibres
• Pearson syndrome: characterized by sideroblastic anemia and exocrine pancreas dysfunction. It
is usually fatal in infancy. The few patients who survive into adulthood often develop symptoms
of Kearns-Sayre syndrome.
• Kearns-Sayre syndrome: onset in patients < 20 years old, external ophthalmoplegia, retinitis
pigmentosa. Ptosis may be seen
• Sensorineural hearing loss
• Neuropathy, ataxia, and retinitis pigmentosa (NARP)
are all…
mitochondrial diseases
what are tumour suppressor genes?
Basics
• Genes which normally control the cell cycle
• Exhibit a recessive effect - both copies must be mutated before cancer occurs
list 4 examples of tumour suppressor genes
Examples • P53
• APC: colorectal cancer
• NF-1: neurofibromatosis
• RB: retinoblastoma
what is myc?
myc is an oncogene which encodes a transcription factor
P53 gene:
-where is this located?
-what cancers is mutated p53 assoc. with?
-what does P53 have a role in?
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
what is li-fraumeni syndrome? what is this caused by?
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.
Down’s syndrome:
what causes down’s syndrome?
how can this be identified at birth?
Down Syndrome: trisomy 21 or G, is a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome.
Downs Syndrome - describe
-facial features
-hands/feet
-neuro signs
-cardio signs
-GI conditions
-fertility issues
• 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
what are the cardiac complications of downs syndrome?
• 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%)
• Subfertility: ♂s are almost always infertile due to impaired spermatogenesis. ♀s are usually subfertile, and have an ↑ incidence of problems with pregnancy and labour
• Learning difficulties
• Short stature
• Repeated respiratory infections (+hearing impairment from glue ear)
• Acute lymphoblastic leukemia
• Hypothyroidism
• Alzheimer’s
• Atlantoaxial instability
are all…
later complications of downs syndrome
what is the risk of downs syndrome at 30/35/40/45`
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
what are the three modes of inheritance of down’s syndrome and what percentage of cases is assoc. with each mode and what is the risk of recurrence?
% 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
what is turner syndrome caused by?
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
Turner syndrome:
- physical appearance
-cardiac issues
-periods?
-neonates?
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)
what is klinefelter syndrome caused by?
Klinefelter Syndrome (Hypogonadotropic hypogonadism) is associated with karyotype 47, XXY
Klinefelter syndrome:
-physical appearance
-reproductive organs
-what does this increase the risk of?
-are gonadotrophin levels raised or reduced?
Features
• Often taller than average
• Lack of secondary sexual characteristics
• Small, firm testes (hypogonadism)
• Infertile
• Gynaecomastia - ↑ incidence of breast cancer
• Elevated gonadotrophin levels
what is the diagnosis of klinefelter syndrome?
Diagnosis is by chromosomal analysis
↓
Karyotyping
LH and FSH in klinefelters vs kallmans?
Klinefelter’s - LH & FSH raised
Kallman’s - LH & FSH low-normal
Kallman syndrome:
-how is this inherited?
-what is this thought to be caused by?
-what may be mentioned in exams?
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.
what are the features of kallman syndrome?
-physical appearance
-reproductive organs
-other clinical features?
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
what is marfan syndrome caused by? how is this inherited?
Marfan Syndrome is an autosomal dominant connective tissue disorder. It is caused by a defect in the fibrillin-1 gene on chromosome 15
what are the physical features of marfans?
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
what are the cardiac complications of marfans syndrome?
• Heart: dilation of the aortic sinuses (seen in 90%) which may lead to aortic regurgitation,
mitral valve prolapse (75%), aortic dissection
what are respiratory complications of marfans?
• Lungs: repeated pneumothoraces
what ophthalmological complications exist of marfans?
• Eyes: upwards lens dislocation (superotemporal ectopia lentis), blue sclera
what is noonan syndrome?
-how is this inherited?
-what causes this?
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.
what are the clinical features of noonan syndrome?
-cardiac
-
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
what is fragile X caused by? how is this inherited?
Fragile X is a trinucleotide repeat disorder, complex X-linked inheritance.
what are the features in fragile X?
-what are the physical characteristics?
-cardiac complications
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
what features may be seen in females with one fragile chromosome and one normal chromosome?
Features in ♀s (who have one fragile chromosome and one normal X chromosome) range from normal to mild
how is fragile X syndrome diagnosed?
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
what is patau syndrome caused by?
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
does increasing maternal age affect the risk of patau syndrome?
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.
what is seen in the head and face with patau syndrome?
• Microcephaly
• Low-set ears
• Cleft palate
• Cutis aplasia (missing portion of the skin/hair)
what eye defects are seen in patau syndrome?
• 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
what brain defect is seen in patau syndrome?
• Holoprosencephaly (failure of the forebrain to divide properly).
what spinal defect is seen with patau syndrome?
• Meningomyelocele (a spinal defect)
what abdominal defect is seen with patau syndrome?
• Omphalocele (abdominal defect)
what is seen in reproductive organs in patau syndrome?
• Abnormal genitalia
what is seen in the hands/feet of patau syndrome patients?
• Abnormal palm pattern
• Overlapping of fingers over thumb.
• Prominent heel
• Deformed feet known as “rocker-bottom feet”
• Polydactyly (extra digits)
what is seen in the urological system in patients with patau syndrome?
• Kidney defects
what is the difference between prada-willi and angelman syndrome?
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
what is prada-willi syndrome caused by?
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
what are the features of prada willi?
-during infancy
-physical appearances
-reproductive organs
-skin complications?
Features
• Hypotonia during infancy
• Dysmorphic features
• Short stature
• Hypogonadism and infertility
• Learning difficulties
• Childhood obesity
• Behavioural problems in adolescence
• Acanthosis nigricans
what is edwards syndrome caused by?
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.
how common is edwards syndrome?
-does incidence change with mothers age?
-what is the survival rate and why?
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.
what are the physical appearances seen with edward’s syndrome?
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
what is seen in babies with edwards syndrome in development?
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
Patau syndrome: what trisomys?
Trisomy 13
Trisomy D
Edward syndrome: what trisomys?
Trisomy 18
Trisomy E
Down’s syndrome: what trisomys?
Trisomy 21
Trisomy G
what vitamin deficiency causes night blindness (nyctalopia)?
A
Retinoids
what vitamin deficiency causes:
Beriberi
• Polyneuropathy, Wernicke-Korsakoff syndrome
• Heart failure
B1
Thiamine
what vitamin deficiency causes:
Pellagra
• Dermatitis
• Diarrhea • Dementia
B3
Niacin (Nicotinic Acid)
what vitamin deficiency causes:
Anemia, irritability, seizures
B6
Pyridoxine
what vitamin deficiency:
Megaloblastic anemia, deficiency during pregnancy - neural tube defects
B9
Folic acid
what vitamin deficiency causes megaloblastic anaemia?
B12
Cyanocobalamin
what vitamin deficiency causes:
Scurvy
• Gingivitis
• Bleeding
C
Ascorbic acid
what vitamin deficiency causes:
Rickets, osteomalacia (good source is cod liver oil)
D
Ergocalciferol, cholecalciferol
what vitamin deficiency causes:
Mild hemolytic anemia in newborn infants, ataxia, peripheral neuropathy
E
Tocopherol, tocotrienol
what vitamin deficiency causes:
Haemorrhagic disease of the newborn, bleeding diathesis
K
Naphthoquinone
what may pellagra occur as a consequence of?
Pellagra may occur as a consequence of isoniazid therapy (isoniazid inhibits the conversion of tryptophan to niacin)
what are the features of pellagra?
Features
• Dermatitis (brown scaly rash on sun- exposed sites - termed Casal’s necklace if around neck)
• Diarrhea
• Dementia, depression
• Death if not treated
where is vitamin B12 absorbed? and how?
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.
what are 5 causes of vitamin B12 deficiency?
• Pernicious anemia
• Post gastrectomy
• Poor diet
• Disorders of terminal ileum (site of absorption): crohn’s, blind-loop etc
• Metformin
what are 4 features of vitamin B12 deficiency?
• Macrocytic anemia
• Sore tongue and mouth
• Neurological symptoms: e.g. Ataxia
• Neuropsychiatric symptoms: e.g. Mood disturbances
what is the management of B12 deficiency?
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
what does vitamin C deficiency cause?
Vitamin C Deficiency (scurvy) leads to defective synthesis of collagen resulting in capillary fragility (bleeding tendency) and poor wound healing
what are the features of vitamin C deficiency?
Features
• Gingivitis, loose teeth
• Poor wound healing
• Bleeding from gums, hematuria, epistaxis
• General malaise
what is vitamin D-resistant rickets caused by? how is this inherited?
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
what are the features of vitamin D-resistant rickets?
Features
• Failure to thrive
• Normal serum calcium, low phosphate, elevated alkaline phosphotase
• X-ray changes: cupped metaphyses with widening of the epiphyses
what is the diagnosis of vitamin D-resistant rickets?
Diagnosis is made by demonstrating ↑ urinary phosphate
what is the management of vitamin D-resistant rickets?
• High-dose vitamin D supplements
• Oral phosphate supplements
what 3 drugs interfere with folate metabolism?
• Trimethoprim • Methotrexate
• Pyrimethamine
what drug can decrease absorption of folate
Drugs which can ↓ absorption • Phenytoin
Where is iron absorbed?
-how much dietary iron is absorbed?
-what structure of iron is better absorbed?
• 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
what increases iron absorption? what decreases iron absorption?
• ↑ by vitamin C, gastric acid
• ↓ by proton pump inhibitors, tetracycline, gastric achlorhydria, tannin (found in tea)
where is iron found in the body?
• Total body iron = 4g
• Hemoglobin = 70%
• Ferritin and hemosiderin = 25%
• Myoglobin = 4%
• Plasma iron = 0.1%
how is iron transported in the body?
Transport
• Carried in plasma as Fe+++ bound to transferrin
how is iron stored in the body?
Storage
• Stored as ferritin in tissues
how is iron excreted from the body?
Excretion
• Lost via intestinal tract following desquamination
what are clinical features of zinc deficiency?
Features
• Perioral dermatitis: red, crusted lesions
• Acrodermatitis
• Alopecia
• Short stature
• Hypogonadism
• Hepatosplenomegaly
• Geophagia (ingesting clay/soil)
• Cognitive impairment
what is the function of endoplasmic reticulum?
Translation and folding of new proteins (rough endoplasmic reticulum), expression of lipids (smooth endoplasmic reticulum)
what is the function of the golgi apparatus?
Sorting and modification of proteins
what is the function of the mitochondria?
Energy production. Contains mitochondrial genome as circular double stranded DNA
what is the function of cell nucleus?
DNA maintenance and RNA transcription
what is the function of lysosome?
Breakdown of large molecules such as proteins and polysaccharides
what is the function of nucleolus?
Ribosome production
what is the function of the ribosome?
Translation of RNA into proteins
what is the function of peroxisome?
Breakdown of metabolic hydrogen peroxide
what is the function of proteasome?
Along with lysosome pathway: degradation of large protein molecules
what are the phases of the cell cycle for mitosis?
M - Mitosis - cell division
G1 - Gap phase 1 - determines length of cell cycle - under influence of p53 S - DNA Synthesis
G2 - Gap phase
what are the four types of membrane receptor?
Ligand-gated ion channel
Tyrosine kinase receptors
Guanylate cyclase receptors
G protein-coupled receptors
Ligand-gated ion channel:
-what responses does this mediate?
-give an example
• Generally mediate fast responses
• E.g. nicotinic acetylcholine, GABA-A & GABA-C, glutamate receptors
Tyrosine kinase receptors:
-what activity does this associate with?
-e.g.?
Tyrosine kinase receptors
• Contain intrinsic enzyme activity
• E.g. Insulin, growth factors, interferon
Guanylate cyclase receptors
-what activity does this associate with?
-give an example
Guanylate cyclase receptors
• Contain intrinsic enzyme activity
• E.g. Atrial natriuretic factor (ANP), nitric oxide receptors
G protein-coupled receptors:
-what do these mediate?
-what are these activated by?
-what do these consist of?
-give examples?
• 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
what does α-1 adrenoceptor cause?
-what agonises this?
• Vasoconstriction
• Relaxation of GI smooth muscle
• Salivary secretion
• Hepatic glycogenolysis
(Agonist → phenylephrine)
what does α-2 adrenoceptor cause?
-what agonises this?
• Mainly presynaptic: inhibition of transmitter release (inc NA, Ach from autonomic nerves)
• Inhibits insulin
• Platelet aggregation
(Agonist → clonidine)
what does β-1 adrenoceptor cause?
-what agonises this?
• Mainly located in the heart
• ↑ heart rate + force
(Agonist → dobutamine)
what does β-2 adrenoceptor cause?
-what agonises this?
• V asodilation
• Bronchodilation
• Relaxation of GI smooth muscle
salbutamol
what does β-3 adrenoceptor cause?
β-3 (Agonist → being developed, may have a role in preventing obesity) • Lipolysis
what pathway does β-1/β-2/β-3 stimulate?
• β-1: stimulate adenylate cyclase
• β-2: stimulate adenylate cyclase
• β-3: stimulate adenylate cyclase
what pathway does α-1 activate?
• α-1:activate phospholipase C → IP3 → DAG
what pathway does α-2 inhibit?
• α-2: inhibit adenylate cyclase
name 4 second messengers and give examples of each?
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
how can you remember molecular biology techniques?
Molecular biology techniques
• Snow (South - NOrth - West)
• Drop (DNA - RNA - Protein)
Describe 3 molecular biology techniques and describe what they detect?
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)
What is PCR? what is the main advantage?
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.
what is necessary to have prior to PCR?
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
Describe what is done in PCR
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
describe reverse transcriptase PCR
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
How many chromosome pairs make up the human genome? how many billion DNA base pairs make up the human genome? How many protein-coding genes exist?
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
Optic canal:
which bone is this in?
which vessels run through it?
what nerve runs through it?
Sphenoid
Ophthalmic A.
Optic nerve (II)
Superior orbital fissure:
which bone is this in?
which vessels run through it?
which nerves run through it?
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)
Inferior orbital fissure:
which bone is this in?
which vessels run through it?
which nerves run through it?
Sphenoid and maxilla
Inferior ophthalmic V.
Infraorbital artery
Infraorbital vein
Zygomatic nerve and infraorbital nerve of maxillary nerve (V2)
Orbital branches of pterygopalatine ganglion
Foramen rotundum:
-what bone is this in?
-what nerve runs through it?
Sphenoid
Maxillary nerve (V2)
Foramen ovale:
which bone is this in?
which vessel runs through it?
which nerve runs through it?
Sphenoid
Accessory meningeal A.
Mandibular nerve (V3)
Jugular foramen:
which bone is this in?
which vessels run through it?
which nerves run through it?
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)
which organs are in direct contact with the right kidney?
Right suprarenal gland
Duodenum
Colon
which organs are separated from the kidney by a layer of peritoneum?
Liver
Distal part of small intestine
which organs are in direct contact with the left kidney?
Left suprarenal gland
Pancreas
Colon
which organs are separated from the left kidney by a layer of peritoneum?
Stomach
Spleen
Distal part of small intestine
Epidermis - what is this? what is this composed of?
Epidermis is the outermost layer of the skin and is composed of a stratified squamous epithelium with an underlying basal lamina
describe the 5 layers of the epidermis
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
Describe the myocardial action potential
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
how much longer does cardiac muscle remain contracted for vs skeletal?
NB cardiac muscle remains contracted 10-15 times longer than skeletal muscle
describe atrial conduction velocity
Spreads along ordinary atrial myocardial fibres at 1 m/sec
describe AV node conduction velocity
0.05 m/sec
describe ventricular conduction velocity
Purkinje fibres are of large diameter and achieve velocities of 2-4 m/sec (this allows a rapid and coordinated contraction of the ventricles)
where is ADH secreted from and what does it do?
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
what does the adrenal medulla do?
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
what is a null hypothesis?
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.
what is a p value?
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.
what does the p-value have to be for the null hypothesis to be rejected?
The null hypothesis is rejected if the p-value is smaller than or equal to the significance level
P-value ≤ significance level
what are 2 types of error that may occur when testing the null hypothesis?
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
what is the power of a study?
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
what are 2 parametric tests?
Parametric tests
• Student’s t-test - paired or unpaired
• Pearson’s product-moment coefficient - correlation
what are 5 non-parametric tests?
• 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
what is paired data vs unpaired data?
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
what are funnel plots used for? how are they drawn?
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.
what does a symmetrical funnel plot indicate?
• A symmetrical, inverted funnel shape indicates that publication bias is unlikely
what does an asymmetrical funnel shape indicate?
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’)
what is central limit theorum?
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
what is a confidence interval?
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)
what is normal distribution?
Normal Distribution is also known as Gaussian distribution or ‘bell-shaped’ distribution. It describes the spread of many biological and clinical measurements
Properties of the normal distribution:
-what percentage of values lie within 1 SD of the mean?
-wht percentage of values lie within 2 SD of the mean?
-what percentage of values lie within 3 SD of the mean?
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
Example: A study is performed to find the normal reference range for IgE levels in adults. Assuming IgE levels follow a normal distribution, what percentage of adults will have an IgE level above 2 standard deviations from the mean?
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%
what is the relationship between mean/median/mode in normal distribution?
Normal distributions: mean = median = mode
what is the relationship between mean/median/mode in positively skewed distributions?
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 ‘
what is the relationship between mean/median/mode in negatively skewed distributions?
• 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 ‘
what is the standard error of the mean?
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
how do you work out standard error of the mean?
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)
does SEM increase or decrease as sample size increases?
Therefore the SEM gets smaller as the sample size (n) ↑
how can a confidence interval for the mean be calculated?
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)
what is relative risk?
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)
what is the CER?
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)
what is the experimental event rate?
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)
what is absolute risk reduction?
Absolute risk reduction = (Control event rate) - (Experimental event rate)
what is relative risk reduction?
Relative risk reduction (RRR) is calculated by dividing the absolute risk reduction by the control event rate
what is the hazard ratio?
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
what is NNT?
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
how is NNT calculated?
NNT = 1 / (CER - EER), or 1 / Absolute Risk Reduction
how do you work out the odds of something?
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
how do you work out odds ratio?
Odds Ratio may be defined as the ratio of the odds of a particular outcome with experimental treatment and that of control
what is a pre-test probability?
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)
what is a post-test probability?
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)
what is pre-test odds?
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)
what is post-test odds?
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)
what is the incidence of disease?
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%.
what is prevalence?
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%.
how can you work out prevalence?
• prevalence = incidence * duration of condition
in chronic disease is the prevalence or the incidence higher?
In chronic diseases the prevalence is much greater than the incidence
in acute disease is the prevalence or the incidence higher?
In acute diseases the prevalence and incidence are similar. For conditions such as the common
cold the incidence may be greater than the prevalence
how can you work out sensitivity?
TP / (TP + FN )
TP - true positive
FN - false negative
Proportion of patients with the condition who have a positive test result
how can you work out specificity?
TN / (TN + FP)
TN: true negative
FP: false positive
Proportion of patients without the condition who have a negative test result
what is positive predictive value?
TP / (TP + FP)
The chance that the patient has the condition if the diagnostic test is positive
what is the negative predictive value?
TN / (TN + FN)
The chance that the patient does not have the condition if the diagnostic test is negative
what is the Likelihood ratio for a positive test result?
sensitivity / (1 - specificity)
How much the odds of the disease increase when a test is positive
what is the Likelihood ratio for a negative test result?
(1 - sensitivity) / specificity
How much the odds of the disease decrease when a test is negative
what are the Wilson and Junger Criteria for screening? 10 points
- The condition should be an important public health problem
- There should be an acceptable treatment for patients with recognised disease
- Facilities for diagnosis and treatment should be available
- There should be a recognised latent or early symptomatic stage
- The natural history of the condition, including its development from latent to declared disease
should be adequately understood - There should be a suitable test or examination
- The test or examination should be acceptable to the population
- There should be agreed policy on whom to treat
- 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 - Case-finding should be a continuous process and not a ‘once and for all’ project
what is correlation?
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)
what is linear regression?
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
what is a randomised control trial?
Participants randomly allocated to intervention or control group (e.g. standard treatment or placebo)
• Practical or ethical problems may limit use
what is a cohort study?
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
what is a case-control study?
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
what is a cross-section survey?
• Provide a ‘snapshot’, sometimes called prevalence studies
• Provide weak evidence of cause and effect
what are the 6 levels of evidence:
Levels of evidence
• Ia -
• Ib -
• IIa -
• IIb -
• III -
• IV -
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
what is the grading of recommendation of a study?
• Grade A
• Grade B
• Grade C
• 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)
what does a trial mean if it is intended to show superiority?
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
what does a trial mean if it is intended to show equivalence?
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
what does a trial mean if it is intended to show non-inferiority?
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
what is intention to treat analysis?
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
what is penetrance in genetic disorders?
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
what is expressivity in genetic disorders?
Expressivity
describes the 'severity' of the phenotype a condition with a high level of expressivity is neurofibromatosis
