Basic science Flashcards
eGFR equation
GFR = ( urine concentration (mmol/l) x urine volume (ml/min) ) / plasma concentration (mmol/l)
MA of RCTs level of evidence
Ia
RCT level of evidence
1b
Control trial, not randomised level of evidence
2a
2b level of evidence
evidence from at least one well designed experimental trial
3 level of evidence
evidence from case, correlation and comparative studies
4 level of evidence
evidence from a panel of experts
what regulates cell cycle
proteins called cyclins which in turn control cyclin-dependent kinase (CDK) enzymes.
phases of cell cycle
G0,G1,S,G2,M
G0
‘resting’ phase
quiescent cells such as hepatocytes and more permanently resting cells such as neurons
G1
Gap 1, cells increase in size
determines length of cell cycle
under influence of p53
regulatory proteins G1
Cyclin D / CDK4, Cyclin D / CDK6 and Cyclin E / CDK2: regulates transition from G1 to S phase
S
Synthesis of DNA, RNA and histone
centrosome duplication
regulatory proteins S
Cyclin A / CDK2: active in S phase
G2
Gap 2, cells continue to increase in size
regulatory preoteins G2
Cyclin B / CDK1: regulates transition from G2 to M phase
M
Mitosis - cell division
the shortest phase of the cell cycle
negative predictive value equation
TN / (TN + FN)
sensitivity equation
TP / (TP + FN )
specificity equation
TN / (TN + FP)
PPV equation
TP / (TP + FP)
likelihood ratio for a positive result
sensitivity / (1 - specificity)
How much the odds of the disease increase when a test is positive
likelihood ratio negative test
(1 - sensitivity) / specificity
How much the odds of the disease decrease when a test is negative
most common congenital infection in the UK
CMV
Sensorineural deafness Congenital cataracts Congenital heart disease (e.g. patent ductus arteriosus) Glaucoma congenital infection
rubella
Cerebral calcification
Chorioretinitis
Hydrocephalus
congenital infection
toxoplasmosis
Growth retardation
Purpuric skin lesions
congenital infection
CMV
audit definition
a quality improvement process that seeks to improve patient care and outcomes through systematic review of care against explicit criteria and the implementation of change
what phase of mitosis does vincristine act on?
metaphase
These drugs bind to tubulin stopping the polymerisation and assembly of microtubules. This, in turn, disrupts spindle formation arresting mitosis at metaphase.
what happens in prophase
Chromatin in the nucleus condenses
prometaphase
Nuclear membrane breaks down allowing the microtubules to attach to the chromosomes
metaphase
Chromosomes aligned at middle of cell
anaphase
The paired chromosomes separate at the kinetochores and move to opposite sides of the cell
telophase
Chromatids arrive at opposite poles of cell
cytokinesis
Actin-myosin complex in the centre of the cell contacts resulting in it being ‘pinched’ into two daughter cells
parametric tests
Student’s t-test - paired or unpaired*
Pearson’s product-moment coefficient - correlation
non-parametric tests
Mann-Whitney U test
compares ordinal, interval, or ratio scales of unpaired data
Wilcoxon signed-rank test
compares two sets of observations on a single sample, e.g. a ‘before’ and ‘after’ test on the same population following an intervention
chi-squared test
used to compare proportions or percentages e.g. compares the percentage of patients who improved following two different interventions
Spearman, Kendall rank - correlation
what are compliment
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 deficiency
C1 inhibitor (C1-INH) protein deficiency causes hereditary angioedema C1-INH is a multifunctional serine protease inhibitor probable mechanism is uncontrolled release of bradykinin resulting in oedema of tissues
classical pathway compliment and deficiency
C1q, C1rs, C2, C4 deficiency (classical pathway components)
predisposes to immune complex disease
e.g. SLE, Henoch-Schonlein Purpura
c3 deficiency
predisposes to bacterial infections
C5 deficiency
predisposes to Leiner disease
recurrent diarrhoea, wasting and seborrhoeic dermatitis
C5-9 deficiency
encodes the membrane attack complex (MAC)
particularly prone to Neisseria meningitidis infection
IL-1 source and functions
Macrophages Acute inflammation
Induces fever
IL-2 source and functions
Th1 cells Stimulates growth and differentiation of T cell response
IL-3 source and functions
Activated T helper cells Stimulates differentiation and proliferation of myeloid progenitor cells
IL-4 source and functions
Th2 cells Stimulates proliferation and differentiation of B cells
IL-5 source and functions
Th2 cells Stimulate production of eosinophils
IL-6 source and functions
Macrophages, Th2 cells Stimulates differentiation of B cells
Induces fever
IL-8 source and functions
Macrophages Neutrophil chemotaxis
IL-10 source and functions
Th2 cells
Inhibits Th1 cytokine production
Also known as human cytokine synthesis inhibitory factor and is an ‘anti-inflammatory’ cytokine
IL-12 source and functions
Dendritic cells, macrophages, B cells
Activates NK cells and stimulates differentiation of naive T cells into Th1 cells
TNF alpha source and functions
Macrophages Induces fever
Neutrophil chemotaxis
interferon Y source and functions
Th1 cells Activates macrophages
type 1 error
the null hypothesis is rejected when it is true - i.e. Showing a difference between two groups when it doesn’t exist, a false positive. This is determined against a preset significance level (termed alpha). As the significance level is determined in advance the chance of making a type I error is not affected by sample size. It is however increased if the number of end-points are increased. For example if a study has 20 end-points it is likely one of these will be reached, just by chance.
type 2 error
the null hypothesis is accepted when it is false - i.e. Failing to spot a difference when one really exists, a false negative. The probability of making a type II error is termed beta. It is determined by both sample size and alpha
define the power of a study
the probability of (correctly) rejecting the null hypothesis when it is false, i.e. the probability of detecting a statistically significant difference
power = 1 - the probability of a type II error
power can be increased by increasing the sample size
what is atrial nartiuretic peptide?
secreted mainly from myocytes of right atrium and ventricle in response to increased 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
effects of ANP
natriuretic, i.e. promotes excretion of sodium
lowers BP
antagonises actions of angiotensin II, aldosterone
artherosclerosis stages
initial endothelial dysfunction is triggered by a number of factors such as smoking, hypertension and hyperglycaemia
this results in a number of changes to the endothelium including pro-inflammatory, pro-oxidant, proliferative and reduced nitric oxide bioavailability
fatty infiltration of the subendothelial space by low-density lipoprotein (LDL) particles
monocytes migrate from the blood and differentiate into macrophages. These macrophages then phagocytose oxidized LDL, slowly turning into large ‘foam cells’. As these macrophages die the result can further propagate the inflammatory process.
smooth muscle proliferation and migration from the tunica media into the intima results in formation of a fibrous capsule covering the fatty plaque.
artherosclerosis complications
the plaque forms a physical blockage in the lumen of the coronary artery. This may cause reduced blood flow and hence oxygen to the myocardium, particularly at times of increased demand, resulting clinically in angina
the plaque may rupture, potentially causing a complete occlusion of the coronary artery. This may result in a myocardial infarction
what is p53
p53 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?
rare autosomal dominant disorder characterised by the early onset of a variety of cancers such as sarcoma, breast cancer and leukaemias. It is caused by mutation in the p53 gene.
vitamin D function
increases plasma calcium and plasma phosphate
increases renal tubular reabsorption and gut absorption of calcium
increases osteoclastic activity
increases renal phosphate reabsorption
vitamin d deficiency causes
rickets: seen in children
osteomalacia: seen in adults
cerebral metastasis features
Metastatic brain cancer is the most common form of brain tumours. They are often multiple and not treatable with surgical intervention.
Tumours that most commonly spread to the brain include: lung (most common) breast bowel skin (namely melanoma) kidney
glioblastoma features
Glioblastoma is the most common primary tumour in adults and is associated with a poor prognosis (~ 1yr).
- On imaging they are solid tumours with central necrosis and a rim that enhances with contrast. Disruption of the blood-brain barrier and therefore are associated with vasogenic oedema.
- Histology: Pleomorphic tumour cells border necrotic areas
- Treatment is surgical with postoperative chemotherapy and/or radiotherapy. Dexamethasone is used to treat the oedema.
meningioma features
The second most common primary brain tumour in adults
- Meningiomas are typically benign, extrinsic tumours of the central nervous system. They arise from the dura mater of the meninges and cause symptoms by compression rather than invasion.
- They typically are located at the falx cerebri, superior sagittal sinus, convexity or skull base.
- Histology: Spindle cells in concentric whorls and calcified psammoma bodies
- Investigation is with CT (will show contrast enhancement) and MRI, and treatment will involve either observation, radiotherapy or surgical resection.
schwannoma features
A vestibular schwannoma (previously termed acoustic neuroma) is a benign tumour arising from the eighth cranial nerve (vestibulocochlear nerve). Often seen in the cerebellopontine angle. It presents with hearing loss, facial nerve palsy (due to compression of the nearby facial nerve) and tinnitus.
- Neurofibromatosis type 2 is associated with bilateral vestibular schwannomas.
- Histology: Antoni A or B patterns are seen. Verocay bodies (acellular areas surrounded by nuclear palisades)
- Treatment may involve observation, radiotherapy or surgery.
pilocytic astrocytoma features
The most common primary brain tumour in children
• Histology: Rosenthal fibres (corkscrew eosinophilic bundle)
medulloblastoma features
A medulloblastoma is an aggressive paediatric brain tumour that arises within the infratentorial compartment. It spreads through the CSF system. Treatment is surgical resection and chemotherapy.
• Histology: Small, blue cells. Rosette pattern of cells with many mitotic figures
ependymoma features
- Commonly seen in the 4th ventricle
- May cause hydrocephalus
- Histology: perivascular pseudorosettes
oligodendroma features
Benign, slow-growing tumour common in the frontal lobes
• Histology: Calcifications with ‘fried-egg’ appearance
haemangioblastoma features
- Vascular tumour of the cerebellum
- Associated with von Hippel-Lindau syndrome
- Histology: foam cells and high vascularity
pituitary adenoma features
Pituitary adenomas are benign tumours of the pituitary gland. They are either secretory (producing a hormone in excess) or non-secretory. They may be divided into microadenomas (smaller than 1cm) or macroadenoma (larger than 1cm).
- Patients will present with the consequences of hormone excess (e.g. Cushing’s due to ACTH, or acromegaly due to GH) or depletion. Compression of the optic chiasm will cause a bitemporal hemianopia due to the crossing nasal fibers.
- Investigation requires a pituitary blood profile and MRI. Treatment can either be hormonal or surgical (e.g. transphenoidal resection).
craniopharyngioma features
Most common paediatric supratentorial tumour
- A craniopharyngioma is a solid/cystic tumour of the sellar region that is derived from the remnants of Rathke’s pouch. It is common in children, but can present in adults also. It may present with hormonal disturbance, symptoms of hydrocephalus or bitemporal hemianopia.
- Histology: Derived from remnants of Rathke pouch
- Investigation requires pituitary blood profile and MRI. Treatment is typically surgical with or without postoperative radiotherapy.
vitamin c functions
antioxidant
collagen synthesis: acts as a cofactor for enzymes that are required for the hydroxylation proline and lysine in the synthesis of collagen
facilitates iron absorption
cofactor for norepinephrine synthesis
vitamin c deficiency features
gingivitis, loose teeth
poor wound healing
bleeding from gums, haematuria, epistaxis
general malaise
what is fragile X?
trinucleotide repeat disorder
fragile X features
Features in males learning difficulties large low set ears, long thin face, high arched palate macroorchidism hypotonia autism is more common mitral valve prolapse
Features in females (who have one fragile chromosome and one normal X chromosome) range from normal to mild
equation for standard error mean
SEM = SD / square root (n)
where SD = standard deviation and n = sample size
therefore the SEM gets smaller as the sample size (n) increases
95% confidence interval equation
lower limit = mean - (1.96 * SEM)
upper limit = mean + (1.96 * SEM)
collagen structure
Composed of 3 polypeptide strands that are woven into a helix, usually a combination of glycine with either proline or hydroxyproline plus another amino acid
Numerous hydrogen bonds exist within molecule to provide additional strength
Many subtypes but commonest subtype is I (90% of bodily collagen), tissues with increased levels of flexibility have increased levels of type III collagen
Vitamin C is important in establishing cross-links
Synthesised by fibroblasts
where is type 1 collagen found and what are the associated conditions?
Bone, skin, tendon Osteogenesis imperfecta
where is type 2 collagen found ?
Hyaline cartilage, vitreous humour
where is type 3 collagen found and what are the associated conditions?
Reticular fibre, granulation tissue Vascular variant of Ehlers-Danlos syndrome
where is type 4 collagen found and what are the associated conditions?
Basal lamina, lens, basement membrane Alport syndrome, Goodpasture’s syndrome
where is type 5 collagen found and what are the associated conditions?
Most interstitial tissue, placental tissue Classical variant of Ehlers-Danlos syndrome
dry beriberi
B1 (thiamine deficiency)
peripheral neuropathy
wet beriberi
B1 (thiamine deficiency)
dilated cardiomyopathy
causes of thiamine deficiency
alcohol excess. Thiamine supplements are the only routinely recommend supplement in patients with alcoholism
malnutrition
LVEF equation
Left ventricular ejection fraction = (stroke volume / end diastolic LV volume ) * 100%
stroke volume equation
Stroke volume = end diastolic LV volume - end systolic LV volume
factors which increase pulse pressure
a less compliant aorta (this tends to occur with advancing age)
increased stroke volume
systemic vascular resistance calculation
Systemic vascular resistance = mean arterial pressure / cardiac output
vitamin k dependent clotting factors
II, VII, IX, X
how are oncogenes different from tumor supressor genes?
Tumor suppressor genes - loss of function results in an increased risk of cancer
Oncogenes - gain of function results in an increased risk of cancer
CML associated gene
ABL
Cytoplasmic tyrosine kinase
Burkitt’s lymphoma associated gene
c-MYC Transcription factor
neuroblastoma associated gene
n-MYC Transcription factor
follicular lymphoma associated gene
BCL-2 Apoptosis regulator protein
MEN 2+3 gene
RET Tyrosine kinase receptor
RAS gene conditions
G-protein Many cancers especially pancreatic
erb-B2 associated cancer
erb-B2 (HER2/neu) Tyrosine kinase receptor Breast and ovarian cancer
ADH secreted from?
Synthesized in the supraoptic nuclei of the hypothalamus, released by the posterior pituitary
ADH function
Conserves body water Promotes water reabsorption in the collecting ducts of the kidneys by the insertion of aquaporin-2 channels
ADH regulation
Increases secretion extracellular fluid osmolality increase volume decrease pressure decrease angiotensin II
Decreases secretion
extracellular fluid osmolality decrease
volume increase
temperature decrease
Diabetes insipidus (DI) is a condition characterised by either a deficiency of antidiuretic hormone, ADH, (cranial DI) or an insensitivity to antidiuretic hormone (nephrogenic DI)
Cranial DI can be treated by desmopressin, an analog of ADH
Di George syndrome cause
T-cell deficiency and dysfunction. It is an example of a microdeletion syndrome (deletion of a section of chromosome 22).
Di George syndrome features
C - Cardiac abnormalities A - Abnormal facies T - Thymic aplasia C - Cleft palate H - Hypocalcaemia/ hypoparathyroidism (parathyroid gland hypoplasia) 22 - Caused by chromosome 22 deletion
what infection are patients with t-cell dysfunction at risk of
recurrent viral and fungal infections
e.g. cryptococcus
homocystinuria features
often patients have fine, fair hair
musculoskeletal: may be similar to Marfan’s - arachnodactyly etc
neurological patients may have learning difficulties, seizures
ocular: downwards (inferonasal) dislocation of lens
increased risk of arterial and venous thromboembolism
also malar flush, livedo reticularis
homocystinuria diagnosis
cyanide-nitroprusside test, which is also positive in cystinuria.
homocystinuria cause
rare autosomal recessive disease caused by a deficiency of cystathionine beta synthase. This results in severe elevations in plasma and urine homocysteine concentrations.
homocystinuria treatment
vitamin B6 (pyridoxine)
southern blotting detects
DNA
SNOW DROP
northern blotting detects
RNA
SNOW DROP
Western blotting detects
proteins
Uses gel electrophoresis to separate native proteins by 3-D structure
Examples include the confirmatory HIV test
SNOW DROP
what is ELISA?
a type of biochemical assay used to detect antigens and antibodies
a colour changing enzyme is attached to the antibody if looking for an antigen and to an antigen if looking for an antibody
the sample therefore changes colour if the antigen or antibody is detected
an example includes the initial HIV test
4 main types of membrane receptor
- ligand gated ion channels
- tyrosine kinase receptors
- guanylate cyclase receptors
- GPCRS
ligand-gated ion channel receptors
generally mediate fast responses
e.g. nicotinic acetylcholine, GABA-A & GABA-C, glutamate receptors
tyrosine kinase receptors
receptor tyrosine kinase: insulin, insulin-like growth factor (IGF), epidermal growth factor (EGF)
non-receptor tyrosine kinase: PIGG(L)ET: Prolactin, Immunomodulators (cytokines IL-2, Il-6, IFN), GH, G-CSF, Erythropoietin and Thromobopoietin
guanylate cyclase receptors
contain intrinsic enzyme activity
e.g. atrial natriuretic factor, brain natriuretic peptide
GPCRS
generally mediate slow transmission and affect metabolic processes
activated by a wide variety of extracellular signals e.g. Peptide hormones, biogenic amines (e.g. adrenaline), lipophilic hormones, light
7-helix membrane-spanning domains
consist of 3 main subunits: alpha, beta and gamma
the alpha subunit is linked to GDP.Ligand binding causes conformational changes to receptor, GDP is phosphorylated to GTP,and the alpha subunit is activated
G proteins are named according to the alpha subunit (Gs, Gi, Gq)
what does Gs do?
Stimulates adenylate cyclase → increases cAMP → activates protein kinase A
Beta-1 receptors (epinephrine, norepinephrine, dobutamine)
• Beta-2 receptors (epinephrine, salbuterol)
• H2 receptors (histamine)
• D1 receptors (dopamine)
• V2 receptors (vasopressin)
• Receptors for ACTH, LH, FSH, glucagon, PTH, calcitonin, prostaglandins
what does Gi do?
Inhibits adenylate cyclase → decreases cAMP → inhibits protein kinase A
M2 receptors (acetylcholine)
• Alpha-2 receptors (epinephrine, norephinephrine)
• D2 receptors (dopamine)
• GABA-B receptor
what does Gq do?
Activates phospholipase C → splits PIP2 to IP3 & DAG → activates protein kinase C
Alpha-1 receptors (epinephrine, norepinephrine)
• H1 receptors (histamine)
• V1 receptors (vasopressin)
• M1, M3 receptors (acetylcholine)
Type 1 hypersensitivity reaction
Antigen reacts with IgE bound to mast cells • Anaphylaxis
• Atopy (e.g. asthma, eczema and hayfever)
Type 2 hypersensitivity reaction
IgG or IgM binds to antigen on cell surface • Autoimmune haemolytic anaemia
• ITP
• Goodpasture’s syndrome
• Pernicious anaemia
• Acute haemolytic transfusion reactions
• Rheumatic fever
• Pemphigus vulgaris / bullous pemphigoid
type 3 hypersensitivity
Type III - Immune complex Free antigen and antibody (IgG, IgA) combine • Serum sickness
• Systemic lupus erythematosus
• Post-streptococcal glomerulonephritis
• Extrinsic allergic alveolitis (especially acute phase)
Type 4 hypersensitivity reaction
T-cell mediated • Tuberculosis / tuberculin skin reaction
• Graft versus host disease
• Allergic contact dermatitis
• Scabies
• Extrinsic allergic alveolitis (especially chronic phase)
• Multiple sclerosis
• Guillain-Barre syndrome
Type 5 hypersensitivity reaction
Antibodies that recognise and bind to the cell surface receptors.
This either stimulating them or blocking ligand binding • Graves’ disease
• Myasthenia gravis
Ulnar nerve motor to…
medial two lumbricals aDductor pollicis interossei hypothenar muscles: abductor digiti minimi, flexor digiti minimi flexor carpi ulnaris
Down’s syndrome features
face: upslanting palpebral fissures, epicanthic folds, Brushfield spots in iris, protruding tongue, small low-set ears, round/flat face
flat occiput
single palmar crease, pronounced ‘sandal gap’ between big and first toe
hypotonia
congenital heart defects (40-50%, see below)
duodenal atresia
Hirschsprung’s disease
Down’s syndrome cardiac defects
multiple cardiac problems may be present
endocardial cushion defect (most common, 40%, also known as atrioventricular septal canal defects)
ventricular septal defect (c. 30%)
secundum atrial septal defect (c. 10%)
tetralogy of Fallot (c. 5%)
isolated patent ductus arteriosus (c. 5%)
later complications of Down’s
subfertility: males are almost always infertile due to impaired spermatogenesis. Females are usually subfertile, and have an increased incidence of problems with pregnancy and labour learning difficulties short stature repeated respiratory infections (+hearing impairment from glue ear) acute lymphoblastic leukaemia hypothyroidism Alzheimer's disease atlantoaxial instability
Most common lipid storage disorder resulting in accumulation of glucocerebrosidase in the brain, liver and spleen. Key features include hepatosplenomegaly, aseptic necrosis of the femur
Gaucher’s disease
cherry red spots on macula, normal liver
Tay-Sachs disease Hexosaminidase A Accumulation of GM2 ganglioside within lysosomes. Key features include developmental delay, cherry red spot on the macula, liver and spleen normal size (cf. Niemann-Pick)
cherry red spots on macula, enlarged liver
Niemann-Pick disease Sphingomyelinase Key features include hepatosplenomegaly, cherry red spot on the macula
NNT
1 / (control event rate - experimental event rate)
OR
1 / Absolute Risk Reduction
Turners syndrome features
short stature
shield chest, widely spaced nipples
webbed neck
bicuspid aortic valve (15%), coarctation of the aorta (5-10%)
primary amenorrhoea
cystic hygroma (often diagnosed prenatally)
high-arched palate
short fourth metacarpal
multiple pigmented naevi
lymphoedema in neonates (especially feet)
gonadotrophin levels will be elevated
hypothyroidism is much more common in Turner’s
horseshoe kidney: the most common renal abnormality in Turner’s syndrome
There is also an increased incidence of autoimmune disease (especially autoimmune thyroiditis) and Crohn’s disease
turners syndrome pathophysiology
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.
down’s syndrome genetics
94% Nondisjunction
5% Robertsonian translocation
1% mosaicism
Raised PAPP-A and abnormal nuchal translucency
Down’s syndrome
trinucleotide repeat disorders
Fragile X (CGG) Huntington's (CAG) myotonic dystrophy (CTG) Friedreich's ataxia* (GAA) spinocerebellar ataxia spinobulbar muscular atrophy dentatorubral pallidoluysian atrophy
*Friedreich’s ataxia is unusual in not demonstrating anticipation
PTH actions
Increase calcium levels and decrease phosphate levels
Increases bone resorption
Immediate action on osteoblasts to increase ca2+ in extracellular fluid
Osteoblasts produce a protein signaling molecule that activate osteoclasts which cause bone resorption
Increases renal tubular reabsorption of calcium
Increases synthesis of 1,25(OH)2D (active form of vitamin D) in the kidney which increases bowel absorption of Ca2+
Decreases renal phosphate reabsorption
1,25 dihydroxycholecalciferol effects
Increases plasma calcium and plasma phosphate
Increases renal tubular reabsorption and gut absorption of calcium
Increases osteoclastic activity
Increases renal phosphate reabsorption in the proximal tubule
Calcitonin effects
Secreted by C cells of thyroid
Inhibits osteoclast activity
Inhibits renal tubular absorption of calcium
Which drug for TB can cause burning in the feet?
Isoniazid therapy can cause a vitamin B6 deficiency causing peripheral neuropathy
Vitamin B6 deficincy consequences
peripheral neuropathy
sideroblastic anaemia
Noonan’s syndrome
‘male Turner’s’, Noonan 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
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
role of T helper cells
Involved in the cell-mediated immune response
Recognises antigens presented by MHC class II molecules
Expresses CD4
Also expresses CD3, TCR & CD28
Major source of IL-2
Mediates acute and chronic organ rejection
role of cytotoxic T cells
Involved in the cell-mediated immune response
Recognises antigens presented by MHC class I molecules
Induce apoptosis in virally infected and tumour cells
Expresses CD8
Also expresses CD3, TCR
Mediates acute and chronic organ rejection
role of B cells
Major cell of the humoral immune response
Acts as an antigen presenting cell
Mediates hyperacute organ rejection
role of plasma cells
Differentiated from B cells
Produces large amounts of antibody specific to a particular antigen
Wilson and Junger screening criteria
- 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
Blood tests in DIC
prolonged clotting times, thrombocytopenia, decreased fibrinogen, increased fibrinogen degradation products
Causes of DIC
Infection Malignancy Trauma e.g. major surgery, burns, shock, dissecting aortic aneurysm Liver disease Obstetric complications
Haemophillia inheritance
In X-linked recessive inheritance only males are affected. An exception to this seen in examinations are patients with Turner’s syndrome, who are affected due to only having one X chromosome. X-linked recessive disorders are transmitted by heterozygote females (carriers) and male-to-male transmission is not seen. Affected males can only have unaffected sons and carrier daughters.
Each male child of a heterozygous female carrier has a 50% chance of being affected whilst each female child of a heterozygous female carrier has a 50% chance of being a carrier.
The possibility of an affected father having children with a heterozygous female carrier is generally speaking extremely rare. However, in certain Afro-Caribbean communities G6PD deficiency is relatively common and homozygous females with clinical manifestations of the enzyme defect are seen.
Cardiac cycle stages
0 Rapid depolarisation 1 Early repolarisation
2 Plateau
3 Final repolarisation
4 Restoration of ionic concentrations
what causes phase 0 of cardiac cycle?
Rapid sodium influx
These channels automatically deactivate after a few ms
what causes phase 1 of cardiac cycle?
Efflux of potassium
what causes phase 2 of cardiac cycle?
Slow influx of calcium
what causes phase 3 of cardiac cycle?
Efflux of potassium
what causes phase 4 of cardiac cycle?
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
define penetrance
Penetrance describes the proportion of a population of individuals who carry a disease-causing allele who express the related disease phenotype.
define expressivity
Expressivity describes the extent to which a genotype shows its phenotypic expression in an individual.
These phenomena are thought to be due to a number of factors, including:
Modifier genes
Environmental factors
Allelic variation
PKU features
usually presents by 6 months e.g. with developmental delay
child classically has fair hair and blue eyes
learning difficulties
seizures, typically infantile spasms
eczema
‘musty’ odour to urine and sweat*
PKU pathophysiology
autosomal recessive condition caused by a disorder of phenylalanine metabolism. This is usually due to defect in phenylalanine hydroxylase, an enzyme which converts phenylalanine to tyrosine. In a small number of cases the underlying defect is a deficiency of the tetrahydrobiopterin-deficient cofactor, e.g. secondary to defective dihydrobiopterin reductase. High levels of phenylalanine lead to problems such as learning difficulties and seizures. The gene for phenylalanine hydroxylase is located on chromosome 12. The incidence of PKU is around 1 in 10,000 live births.
PKU diagnosis
Guthrie test: the ‘heel-prick’ test done at 5-9 days of life - also looks for other biochemical disorders such as hypothyroidism
hyperphenylalaninaemia
phenylpyruvic acid in urine
PKU management
poor evidence base to suggest strict diet prevents learning disabilities
dietary restrictions are however important during pregnancy as genetically normal fetuses may be affected by high maternal phenylalanine levels
Bohr effect
increasing acidity (or pCO2) means O2 binds less well to Hb
Haldane effect
increase pO2 means CO2 binds less well to Hb
main functioning component of surfactant
dipalmitoyl phosphatidylcholine (DPPC) which reduces alveolar surface tension.
surfactant released by…
type 2 pneumocytes
Relative risk reduction
(EER - CER) / CER
Relative risk ratio
EER / CER
corneal reflexes nerves
Ophthalmic nerve (V1) Facial nerve (VII)
Jaw jerk reflex
Mandibular nerve (V3) Mandibular nerve (V3)
Gag reflex nerves
Glossopharyngeal nerve (IX) Vagal nerve (X)
carotid sinus nerve
Glossopharyngeal nerve (IX) Vagal nerve (X)
pupillary light reflex nerve
Optic nerve (II) Oculomotor nerve (III)
lacrimation reflex nerves
Ophthalmic nerve (V1) Facial nerve (VII)
define p value
is the probability of obtaining a result by chance at least as extreme as the one that was actually observed, assuming that the null hypothesis is true
Alkaptonuria
Alkaptonuria (ochronosis) is a rare autosomal recessive disorder of phenylalanine and tyrosine metabolism caused by a lack of the enzyme homogentisic dioxygenase (HGD) which results in a build-up of toxic homogentisic acid. The kidneys filter the homogentisic acid (hence black urine) but eventually it accumulates in cartilage and other tissues.
Alkaptonuria is generally a benign and often asymptomatic condition. Possible features include:
pigmented sclera
urine turns black if left exposed to the air
intervertebral disc calcification may result in back pain
renal stones
Treatment
high-dose vitamin C
dietary restriction of phenylalanine and tyrosine
nitric oxide effects
acts on guanylate cyclase leading to raised intracellular cGMP levels and therefore decreasing Ca2+ levels
vasodilation, mainly venodilation
inhibits platelet aggregation
clinical relevance NO
underproduction of NO is implicated in hypertrophic pyloric stenosis
lack of NO is thought to promote atherosclerosis
in sepsis increased 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
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
IgG
75% Monomer • Enhance phagocytosis of bacteria and viruses
• Fixes complement and passes to the fetal circulation
• Most abundant isotype in blood serum
GAMDE
IgA
15% Monomer/ dimer • IgA is the predominant immunoglobulin found in breast milk. It is also found in the secretions of digestive, respiratory and urogenital tracts and systems
• Provides localized protection on mucous membranes
• Most commonly produced immunoglobulin in the body (but blood serum concentrations lower than IgG
.)
• Transported across the interior of the cell via transcytosis
IgM
10% Pentamer • First immunoglobulins to be secreted in response to an infection
• Fixes complement but does not pass to the fetal circulation
• Anti-A, B blood antibodies (note how they cannot pass to the fetal circulation, which could of course result in haemolysis)
Pentamer when secreted
IgD
1% Monomer • Role in immune system largely unknown
• Involved in activation of B cells
IgE
0.1% Monomer • Mediates type 1 hypersensitivity reactions
• Binds to Fc receptors found on the surface of mast cells and basophils
• Provides immunity to parasites such as helminths
• Least abundant isotype in blood serum
types of T cells
Th1 and Th2
Th1 cells do what
involved in the cell-mediated response and delayed (type IV) hypersensitivity
secrete IFN-gamma, IL-2, IL-3
Th2 cells do what
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
Endothelin
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
Promotes release angiotensin II ADH hypoxia mechanical shearing forces
Inhibits release
nitric oxide
prostacyclin
Raised levels in MI heart failure ARF asthma primary pulmonary hypertension
funnel plot use
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.
Interpretation
a symmetrical, inverted funnel shape indicates that publication bias is unlikely
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’)
Immunological changes in HIV
reduction in CD4 count increase B2-microglobulin decreased IL-2 production polyclonal B-cell activation decrease NK cell function reduced delayed hypersensitivity responses
5 epidermal layers
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
Come (corneum) Let's (lucidum) Get (granulosum) Sun (spinosum) Burnt (basale)
Skeletal muscle contraction
action potential reaches the neuromuscular junction, causing a calcium ion influx through voltage-gated calcium channels
the calcium influx causes the release of acetylcholine into the extracellular space
the acetylcholine activates nicotinic acetylcholine receptors causing an influx of sodium, triggering an action potential
the action potential spreads through the T-tubules
the depolarization activates L-type voltage-dependent calcium channels (dihydropyridine receptors) in the T-tubule membrane, which are close to calcium-release channels (ryanodine receptors) in the adjacent sarcoplasmic reticulum
this causes the sarcoplasmic reticulum to release calcium
calcium binds to troponin C (found on actin-containing thin filaments) causing a conformational change, allowing tropomyosin to move, unblocking the binding sites
myosin binds to the newly released binding site releasing ADP, pulling the Z bands towards each other
ATP binds to myosin, releasing actin
Fabry’s disease
Overview
X-linked recessive
deficiency of alpha-galactosidase A
Features burning pain/paraesthesia in childhood angiokeratomas lens opacities proteinuria early cardiovascular disease
Leptin
Leptin is thought to play a key role in the regulation of body weight. It is produced by adipose tissue and acts on satiety centres in the hypothalamus and decreases appetite. More adipose tissue (e.g. in obesity) results in high leptin levels.
Leptin stimulates the release of melanocyte-stimulating hormone (MSH) and corticotrophin-releasing hormone (CRH). Low levels of leptin stimulates the release of neuropeptide Y (NPY)
Ghrelin
Where as leptin induces satiety, ghrelin stimulates hunger. It is produced mainly by the P/D1 cells lining the fundus of the stomach and epsilon cells of the pancreas. Ghrelin levels increase before meals and decrease after meals
odds ratio
ad/bc
causes of metabolic alkalosis
vomiting / aspiration (e.g. peptic ulcer leading to pyloric stenos, nasogastric suction) diuretics liquorice, carbenoxolone hypokalaemia primary hyperaldosteronism Cushing's syndrome Bartter's syndrome
mechanism of 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 in hypokalaemia, K+ shift from cells → ECF, alkalosis is caused by shift of H+ into cells to maintain neutrality
superiority trial
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
equivalence trial
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
non-inferiority trial
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
drugs contraindicated in breast feeding
antibiotics: ciprofloxacin, tetracycline, chloramphenicol, sulphonamides psychiatric drugs: lithium, benzodiazepines aspirin carbimazole methotrexate sulfonylureas cytotoxic drugs amiodarone
skewed distribution
alphabetical order: mean - median - mode
‘>’ for positive, ‘
function of microtubules
Microtubules are components of the cytoskeleton of the cytoplasm. They help guide movement during intracellular transport and also help bind internal organelles. Microtubules are found in all cells except red blood cells.
microtubules structure
cylindrical structure composed of alternating α and β tubulin subunits which polymerize to form protofilaments
microtubules are polarized, having a positive and negative end
molecular transport microtubules
attachment proteins called dynein and kinesin move up and down the microtubules facilitating the movement of various organelles around the cell
dynein moves in a retrograde fashion, down the the microtubule towards the centre of the cell (+ve → -ve)
kinesin moves in an anterograde fashion, up the microtubule away from the centre, towards the periphery (-ve → +ve)
EEG theta waves
Non-REM stage 1 (N1) Theta waves Light sleep
Transition to this stage be associated with hypnic jerks
N2 sleep stage on EEG
Non-REM stage 2 (N2) Sleep spindles + K-complexes Deeper sleep
Represents around 50% of total sleep
delta waves on EEG
Non-REM stage 3 (N3) Delta waves Deep sleep
Parasomnias such as night terrors, nocturnal enuresis, sleepwalking
REM sleep on EEG
REM Beta-waves Dreaming occurs
Loss of muscle tone, erections
stages of sleep with EEG findings
N1 → N2 → N3 → REM
Theta → Sleep spindles/K-complexes → Delta → Beta
The Sleep Doctor’s Brain
what is interferon alpha
produced by leucocytes
antiviral action
useful in hepatitis B & C, Kaposi’s sarcoma, metastatic renal cell cancer, hairy cell leukaemia
adverse effects include flu-like symptoms and depression
what is interferon beta
produced by fibroblasts
antiviral action
reduces the frequency of exacerbations in patients with relapsing-remitting MS
what is interferon gamma
predominately natural killer cells. Also by T helper cells
weaker antiviral action, more of a role in immunomodulation particularly macrophage activation
may be useful in chronic granulomatous disease and osteopetrosis
interferon binding sites
FN-alpha and IFN-beta bind to type 1 receptors whilst IFN-gamma binds only to type 2 receptors.
what is cerebral perfusion pressure
net pressure gradient causing blood flow to the brain. The CPP is tightly autoregulated to maximise cerebral perfusion. A sharp rise in CPP may result in a rising ICP, a fall in CPP may result in cerebral ischaemia. It may be calculated by the following equation:
CPP= Mean arterial pressure - Intra cranial pressure
Following trauma, the CPP has to be carefully controlled and the may require invasive monitoring of the ICP and MAP.
standard deviation
square root variance
achondroplasia genetics
Achondroplasia is an autosomal dominant disorder associated with short stature. It is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR-3) gene.
In most cases (approximately 70%) it occurs as a sporadic mutation. The main risk factor is advancing parental age at the time of conception. Once present it is typically inherited in an autosomal dominant fashion.
achndroplasia features
short limbs (rhizomelia) with shortened fingers (brachydactyly)
large head with frontal bossing and narrow foramen magnum
midface hypoplasia with a flattened nasal bridge
‘trident’ hands
lumbar lordosis
what is williams syndrome
inherited neurodevelopmental disorder caused by a microdeletion on chromosome 7
features williams syndrome
elfin-like facies characteristic like affect - very friendly and social learning difficulties short stature transient neonatal hypercalcaemia supravalvular aortic stenosis
diagnosis of williams syndrome
Diagnosis is made by FISH studies
posterior to right kidney
Quadratus lumborum, diaphragm, psoas major, transversus abdominis
posterior to left kidney
Quadratus lumborum, diaphragm, psoas major, transversus abdominis
anterior to right kidney
Hepatic flexure of colon
anterior to left kidney
Stomach, Pancreatic tail
superior to right kidney
Liver, adrenal gland
superior to left kidney
Spleen, adrenal gland
structure of renal hilum
The renal vein lies most anteriorly, then renal artery (it is an end artery) and the ureter lies most posterior.
contents popliteal fossa
Popliteal artery and vein Small saphenous vein Common peroneal nerve Tibial nerve Posterior cutaneous nerve of the thigh Genicular branch of the obturator nerve Lymph nodes
histopathology acute tubular necrosis
tubular epithelium necrosis: loss of nuclei and detachment of tubular cells from the basement membrane
dilatation of the tubules may occur
necrotic cells obstruct the tubule lumen
phases of anaphase
anaphase A: cohesins that bind sister chromatids together are cleaved, followed by shortening of the kinetochore microtubules which pulls the daughter chromosomes to opposite ends of the cell
anaphase B: polar microtubules push against each other, causing the cell to elongate
what does troponin C bind to
calcium ions
what does troponin T bind to
tropomyosin
what does troponin I bind to
actin to hold toponin-tropomyosin complex in place
what is myosin
the thick component of muscle fibres. Actin slides along myosin to generate muscle contraction.
3 places that control respiration
central regulatory centres
central and peripheral chemoreceptors
pulmonary receptors
central regulatory centres
medullary respiratory centre apneustic centre (lower pons) pneumotaxic centre (upper pons)
central and peripheral chemoreceptors
central: raised [H+] in ECF stimulates respiration
peripheral: carotid + aortic bodies, respond to raised pCO2 & [H+], lesser extent low pO2
pulmonary receptors
stretch receptors, lung distension causes slowing of respiratory rate (Hering-Bruer reflex)
irritant receptor, leading to bronchoconstriction
juxtacapillary receptors, stimulated by stretching of the microvasculature
most common renal stone
alcium oxalate Hypercalciuria is a major risk factor (various causes)
Hyperoxaluria may also increase risk
Hypocitraturia increases risk because citrate forms complexes with calcium making it more soluble
Stones are radio-opaque (though less than calcium phosphate stones)
Hyperuricosuria may cause uric acid stones to which calcium oxalate binds 85%
cystine stones
Inherited recessive disorder of transmembrane cystine transport leading to decreased absorption of cystine from intestine and renal tubule
Multiple stones may form
Relatively radiodense because they contain sulphur 1%
uric acid stones
Uric acid is a product of purine metabolism
May precipitate when urinary pH low
May be caused by diseases with extensive tissue breakdown e.g. malignancy
More common in children with inborn errors of metabolism
Radiolucent 5-10%
calcium phosphate stones
May occur in renal tubular acidosis, high urinary pH increases supersaturation of urine with calcium and phosphate
Renal tubular acidosis types 1 and 3 increase risk of stone formation (types 2 and 4 do not)
Radio-opaque stones (composition similar to bone) 10%
struvite stones
Stones formed from magnesium, ammonium and phosphate
Occur as a result of urease producing bacteria (and are thus associated with chronic infections)
Under the alkaline conditions produced, the crystals can precipitate
Slightly radio-opaque 2-20%
prolactin function
Stimulates breast development (both initially and further hyperplasia during pregnancy)
Stimulates milk production
It decreases GnRH pulsatility at the hypothalamic level and to a lesser extent, blocks the action of LH on the ovary or testis.
prolactin regulation
Prolactin secretion is under constant inhibition by dopamine
Increases secretion thyrotropin releasing hormone pregnancy oestrogen breastfeeding sleep stress drugs e.g. metoclopramide, antipsychotics
Decreases secretion
dopamine
dopaminergic agonists
riboflavin deficiency
Riboflavin is a cofactor of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) and is important in energy metabolism.
Consequences of riboflavin deficiency:
angular cheilitis
iron absorption
upper small intestine especially the duodenum
about 10% of dietary iron absorbed
Fe2+ (ferrous iron) much better absorbed than Fe3+ (ferric iron)
absorption is regulated according to body’s need
increased by vitamin C, gastric acid
decreased by proton pump inhibitors, tetracycline, gastric achlorhydria, tannin (found in tea)
iron distribution
total body iron = 4g haemoglobin = 70% ferritin and haemosiderin = 25% myoglobin = 4% plasma iron = 0.1%
what is fabry disease?
Overview
X-linked recessive
deficiency of alpha-galactosidase A
Features burning pain/paraesthesia in childhood angiokeratomas lens opacities proteinuria early cardiovascular disease
primary hyperparathyroidism
PTH (Elevated)
Ca2+ (Elevated)
Phosphate (Low)
Urine calcium : creatinine clearance ratio > 0.01
May be asymptomatic if mild
Recurrent abdominal pain (pancreatitis, renal colic)
Changes to emotional or cognitive state
Most cases due to solitary adenoma (80%), multifocal disease occurs in 10-15% and parathyroid carcinoma in 1% or less
secondary hyperparathyroidism
PTH (Elevated)
Ca2+ (Low or normal)
Phosphate (Elevated)
Vitamin D levels (Low)
May have few symptoms
Eventually may develop bone disease, osteitis fibrosa cystica and soft tissue calcifications
Parathyroid gland hyperplasia occurs as a result of low calcium, almost always in a setting of chronic renal failure
tertiary hyperparathyroidism
Ca2+ (Normal or high) PTH (Elevated) Phosphate levels (Decreased or Normal) Vitamin D (Normal or decreased) Alkaline phosphatase (Elevated) Metastatic calcification Bone pain and / or fracture Nephrolithiasis Pancreatitis Occurs as a result of ongoing hyperplasia of the parathyroid glands after correction of underlying renal disorder, hyperplasia of all 4 glands is usually the cause
indications for surgery in primary hyperparathyroidism
Elevated serum Calcium > 1mg/dL above normal
Hypercalciuria > 400mg/day
Creatinine clearance < 30% compared with normal
Episode of life threatening hypercalcaemia
Nephrolithiasis
Age < 50 years
Neuromuscular symptoms
Reduction in bone mineral density of the femoral neck, lumbar spine, or distal radius of more than 2.5 standard deviations below peak bone mass (T score lower than -2.5)
indications for surgery in secondary hyperparathyroidism
Bone pain
Persistent pruritus
Soft tissue calcifications
treatment for tertiary hyperparathyroidism
The presence of an autonomously functioning parathyroid gland may require surgery. If the culprit gland can be identified then it should be excised. Otherwise total parathyroidectomy and re-implantation of part of the gland may be required.
growth hormone source
Anterior pituitary: Somatotrophs comprise 50% of the cells of the anterior pituitary gland
growth hormone function
Postnatal growth and development
Numerous actions on protein, carbohydrate and fat metabolism (including increasing lipolysis and gluconeogenesis) Mechanism of action
acts on a transmembrane receptor for growth factor
binding of GH to the receptor leads to receptor dimerization
acts directly on tissues and also indirectly via insulin-like growth factor 1 (IGF-1), primarily secreted by the liver
growth hormone regulation
Increases secretion growth hormone releasing hormone (GHRH): released in pulses by the hypothalamus fasting exercise sleep (particularly delta sleep)
Decreases secretion
glucose
somatostatin (itself increased by somatomedins, circulating insulin-like growth factors, IGF-1 and IGF-2)
Conditions associated with GH disorders
excess GH: acromegaly
GH deficiency: resulting in short stature
antibody regions
Fab region: antigen-binding fragment - the region that binds to antigens
Fc region: fragment crystallizable region - the tail region of an antibody that interacts with cell surface receptors
leukotriene function
mediators of inflammation and allergic reactions
cause bronchoconstriction, mucous production
increase vascular permeability, attract leukocytes
leukotriene D4 has been identified as the SRS-A (slow reacting substance of anaphylaxis)
leukotriene production
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
renin effects
secreted by juxtaglomerular cells and hydrolyses angiotensinogen to produce angiotensin I
stimulating renin release
hypotension causing reduced renal perfusion hyponatraemia sympathetic nerve stimulation catecholamines erect posture
factors reducing renin secretion
drugs: beta-blockers, NSAIDs
what is lesch Nyhan syndrome?
known as juvenile gout, is characterized by hyperuricemia. It is a genetic condition with an X-linked pattern of inheritance. It is caused by a defect in the purine salvage pathway due to the absence of the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) enzyme which catalyzes the conversion of hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine monophosphate (GMP). The consequence is an accumulation of uric acid. The typical findings supporting this diagnosis in this patient is the aggressive behavior, self-mutilation, intellectual impairment as well as laboratory finding of hyperuricemia.
what is nyacin?
Niacin is a water soluble vitamin of the B complex group. It is a precursor to NAD+ and NADP+ and hence plays an essential metabolic role in cells.
Biosynthesis
Hartnup’s disease: hereditary disorder which reduces absorption of tryptophan
carcinoid syndrome: increased tryptophan metabolism to serotonin
Consequences of niacin deficiency:
pellagra: dermatitis, diarrhoea, dementia
what is prader-willi syndrome?
rader-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
Prader-Willi syndrome is associated with the absence of the active Prader-Willi gene on the long arm of chromosome 15. This may be due to:
microdeletion of paternal 15q11-13 (70% of cases)
maternal uniparental disomy of chromosome 15
Features hypotonia during infancy dysmorphic features short stature hypogonadism and infertility learning difficulties childhood obesity behavioural problems in adolescence
prader willi v angelman
Deletion of chromosome 15
Prader-Willi - paternal
Angelman syndrome - maternal
phases of cardiac 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
pre-test probability
The proportion of people with the target disorder in the population at risk at a specific time (point prevalence) or time interval (period prevalence)
post-test probability
The proportion of patients with that particular test result who have the target disorder
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)
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)
organisation of adrenal cortex
zona glomerulosa (on outside): mineralocorticoids, mainly aldosterone zona fasciculata (middle): glucocorticoids, mainly cortisol zona reticularis (on inside): androgens, mainly dehydroepiandrosterone (DHEA)
renin
an enzyme that is released by the renal juxtaglomerular cells in response to reduced renal perfusion
other factors that stimulate renin secretion include hyponatraemia, sympathetic nerve stimulation
hydrolyses angiotensinogen to form angiotensin I
angiotensin 2
angiotensin-converting enzyme (ACE) in the lungs converts angiotensin I → angiotensin II
angiotensin II has a wide variety of actions:
causes vasoconstriction of vascular smooth muscle leading to raised blood pressure and vasoconstriction of efferent arteriole of the glomerulus → increased filtration fraction (FF) to preserve GFR. Remember that FF = GFR / renal plasma flow
stimulates thirst (via the hypothalamus)
stimulates aldosterone and ADH release
increases proximal tubule Na+/H+ activity
aldosterone
released by the zona glomerulosa in response to raised angiotensin II, potassium, and ACTH levels
causes retention of Na+ in exchange for K+/H+ in distal tubule
phas 1 trial
Determines pharmacokinetics and pharmacodynamics and side-effects prior to larger studies Conducted on healthy volunteers
phase 2 trials
Assess efficacy + dosage Involves small number of patients affected by particular disease
May be subdivided into
IIa - assesses optimal dosing
IIb - assesses efficacy
phase 3 trials
Assess effectiveness Typically involves 100-1000’s of people, often as part of a randomised controlled trial, comparing new treatment with established treatments
phase 4 trials
Postmarketing surveillance Monitors for long-term effectiveness and side-effects
