Upper limb anatomy - 1 File Download – Education ...
Tumour suppressor genesgenes which normally control the cell cycleloss of function results in an increased risk of cancerboth alleles must be mutated before cancer occursExamplesGeneAssociated cancersp53Common to many cancers,?Li-Fraumeni syndromeAPCColorectal cancerBRCA1Breast and ovarian cancerBRCA2Breast and ovarian cancerNF1NeurofibromatosisRbRetinoblastomaWT1Wilm's tumourMultiple tumor suppressor 1 (MTS-1, p16)MelanomaVitamin B1 (thiamine)Water soluble vitamin of the B complex group. One of it's phosphate derivates, thiamine pyrophosphate (TPP), is a coenzyme in these enzymatic reactions:pyruvate dehydrogenase complexpyruvate decarboxylase in ethanol fermentationalpha-ketoglutarate dehydrogenase complexbranched-chain amino acid dehydrogenase complex2-hydroxyphytanoyl-CoA lyasetransketolaseThe clinical consequences of thiamine deficiency are therefore seen first in highly aerobic tissues such as The brain (Wenicke-Korsakoff syndrome) The heart (wet?beriberi).Causes of thiamine deficiency:alcohol excess.?Thiamine supplements are the only routinely recommend supplement in patients with alcoholismmalnutritionConditions associated with thiamine deficiency:Wernicke's encephalopathyNystagmus, ophthalmoplegia and ataxiaIt does not usually involve peripheral neuropathy.Korsakoff's syndromeAmnesiaConfabulationDry beriberi Peripheral polyneuropathy (AlcoholWet beriberi Dilated cardiomyopathyAbetalipoproteinaemia is caused by vitamin E deficiency which can present with peripheral neuropathy and cerebellar ataxia. The absence of ataxia here makes dry beriberi more likely.Vitamin B2 (riboflavin)Riboflavin is a cofactor of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) and is important in energy metabolism.3-4 months of inadequate intake of riboflavin is sufficient to lead to depletion and becoming symptomatic.?Consequences of riboflavin deficiency Angular CheilitisVitamin B3 (niacin)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 tryptophancarcinoid syndrome: increased tryptophan metabolism to serotoninConsequences of niacin deficiencypellagra dermatitis, diarrhoea, dementiaVitamin B6 (pyridoxine)Vitamin B6 is a water soluble vitamin of the B complex group. It is converted to pyridoxal phosphate (PLP) which is a cofactor for many reactions including Transamination, Deamination and Decarboxylation.Causes of vitamin B6 deficiencyisoniazid therapy Usually, prophylactic pyridoxine hydrochloride is prescribed at the same time as Isoniazid to prevent the peripheral neuropathy.?Consequences of vitamin B6 deficiencyperipheral neuropathysideroblastic anemiaVitamin B12 is mainly used in the body for red blood cell development and also maintenance of the nervous system. 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.Causes of vitamin B12 deficiencypernicious anaemia: most common causepost gastrectomyvegan diet?or a poor dietdisorders of terminal ileum (site of absorption): Crohn's, blind-loop etcmetformin (rare)Features of vitamin B12 deficiencymacrocytic anaemiasore tongue and mouthneurological symptomsthe dorsal column is usually affected first (joint position, vibration) prior to distal paraesthesianeuropsychiatric symptoms: e.g. mood disturbancesManagementif no neurological involvement 1 mg of IM hydroxocobalamin 3 times each week for 2 weeks, then once every 3 monthsif 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 cordVitamin C (ascorbic acid)Vitamin C is a water soluble vitamin, It is found in citrus fruits, tomatoes, potatoes, Brussel sprouts, cauliflower, broccoli, cabbage and spinachFunctionsantioxidantcollagen synthesis: acts as a cofactor for enzymes that are required for the hydroxylation proline and lysine in the synthesis of collagenfacilitates iron absorptioncofactor for norepinephrine synthesisVitamin C deficiency (scurvy) Leads to defective synthesis of collagen and connective tissue as?it is a cofactor for enzymes in the production of proline and lysine Capillary Fragility (bleeding tendency) and poor wound healing. It is associated with severe malnutrition as well as drug and alcohol abuse, and those living in poverty with limited access to fruits and vegetables.?Symptoms and signs includeFollicular hyperkeratosis and perifollicular haemorrhageEcchymosis, easy bruisingPoor wound healingGingivitis?with?bleeding and receding gumsSjogren's syndromeArthralgiaOedemaImpaired wound healingGeneralised symptoms such as weakness, malaise, anorexia and depression might convulsionsMenkes Disease is a rare congenital disorder of copper metabolism leading to copper deficiency and osteomalacia is vitamin D deficiency.Vitamin DVitamin D is a fat-soluble vitamin that plays a key role in calcium and phosphate metabolism.In the liver It is converted into the prohormone calcifediol converted into calcitriol (Active vitamin D) in the?kidneys.Sourcesvitamin D2 (ergocalciferol): plantsvitamin D3 (cholecalciferol): dairy products, can be synthesised by the skin from sunlightFunctionsThe effects of vitamin D on osteoblasts are complex and not fully understood. Inhibition of osteoblastic activity would not however be in keeping with a beneficial effect on osteoporosis.increases plasma calcium and plasma phosphateincreases renal tubular reabsorption and?gut absorption of calciumincreases osteoclastic activityincreases renal phosphate reabsorptionConsequences of vitamin D deficiency:rickets: seen in childrenosteomalacia: seen in adultsVitamin D-resistant ricketsX-linked Dominant condition presents in infancy with failure to thrive. It is caused by impaired phosphate reabsorption in the renal tubulesFeaturesfailure to thrivenormal serum calcium, low phosphate, elevated alkaline phosphotasex-ray changes: cupped metaphyses with widening of the epiphysesDiagnosis is made by demonstrating increased urinary phosphateManagementhigh-dose vitamin D supplementsoral phosphate supplementsVitamin KVitamin K is a fat-soluble vitamin which acts as a cofactor in the carboxylation of clotting factors?(II, VII, IX, X), as well as protein C, S and Z.Clinically, it is used to reverse the effects of warfarinisation takes up to 4 hours for there to be a change in the INRVitamin K deficiencyOccurs in conditions affecting fat absorption such ascystic fibrosis, short bowel syndrome, obstructive jaundicedeficiency may also occur after prolonged use of?broad-spectrum antibiotics by eliminating the gut floraVitamin K deficiency bleeding "VKDB" (Haemorrhage Disease of the Newborn) mostly in breastfed babies whose parents have refused prophylaxis.X-linked dominantConditions inherited in a X-linked dominant fashionAlport's syndrome?around 85% of cases 10-15% of cases are inherited in an autosomal recessive fashion rare autosomal dominant variants existing)Rett syndromeVitamin D resistant ricketspseudohypoparathyroidism was previously classified as an X-linked dominant condition but has now been shown to be autosomal dominant.X-linked recessiveOnly males are affected except Turner's syndrome (only having one X chromosome (female with 1y amenorrhea and hemarthrosis (Hemophilia) Turner )X-linked recessive disorders are transmitted by heterozygote females (carriers) No male-to-male transmission. 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.Conditions Androgen insensitivity syndrome?Becker muscular dystrophyColour blindnessDuchenne muscular dystrophyFabry's diseaseG6PD deficiencyHaemophilia A,BHunter's diseaseLesch-Nyhan syndromeIt 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 juvenile gout, is characterized by hyperuricemiaThe typical findings supporting this diagnosis in this patient is the aggressive behaviorself-mutilation child has been hitting himself and biting his fingers? intellectual impairment as well as laboratory finding of hyperuricaemiaNephrogenic diabetes insipidusOcular albinismRetinitis pigmentosaWiskott-Aldrich syndromeChronic granulomatous disease (in > 70%) have varying patterns of inheritance, with the majority being in an X-linked recessive fashionTurner's syndromea chromosomal disorder affecting around 1 in 2,500 females (45,XO or 45,X) caused by either Presence of only one sex chromosome (X) Deletion of the short arm of one of the X chromosomes.? Featuresshort statureshield chest, widely spaced nippleswebbed neckleft-sided cardiac abnormalities bicuspid aortic valve (15%),?coarctation of the aorta (5-10%), Aortic root dilatation.primary amenorrhoeacystic hygroma (often diagnosed prenatally)high-arched palateshort fourth metacarpalmultiple pigmented naevilymphoedema in neonates?(especially feet)gonadotrophin levels will be elevatedhypothyroidism is much more common in Turner'shorseshoe kidney: the most common (10%) renal abnormality in Turner's syndromeA fusion at the lower pole which results in the inferior pole of the kidneys pointing medially. Due to this, the ureters exit the kidneys more anteriorly over the isthmus and there is a higher risk of ureteropelvic junction obstruction and/or secondary urinary tract infection.The majority of women with Turner's have normal intelligenceThere is also an increased incidence of autoimmune disease (especially autoimmune thyroiditis) and Crohn's diseaseDD. congenital adrenal hyperplasia Another cause worth considering in a young hypertensive patient with primary amenorrhoea Kallmann syndrome is characterised by hypogonadotropic hypogonadism and anosmia.Hypothyroidism may be associated with short stature and amenorrhoea but is less likely given the findings of high-arched palate.?Gonadal dysgenesis (46, XX) patients present with primary amenorrhoea but there are no dysmorphic features typical of Turner plete androgen insensitivity (46, XY) patients present with primary amenorrhea but do not have dysmorphic features, or short stature.Noonan syndrome is an autosomal dominant disorder associated with short stature, dysmorphic features and congenital heart disease. Most women with Noonan syndrome develop normal fertility; males may have cryptorchidism.William's syndromeWilliam's syndrome is an inherited neurodevelopmental disorder caused by a microdeletion on chromosome 7FeaturesElfin-like faciesfriendly demeanour characteristic like affect - very friendly and sociallearning difficultiesShort statureTransient neonatal hypercalcaemiaSupravalvular aortic stenosisDiagnosisFluorescence in situ hybridization (FISH) Way to visualize and map the genetic material.Trinucleotide repeat disordersAn abnormal number of repeats (expansions) of a repetitive sequence of three nucleotides. These expansions are unstable enlarge lead to an earlier age of onset in successive generations "Anticipation". In most cases, an increase in the severity of symptoms is also notedAnticipation is earlier onset in successive generations. However, in most cases, an increase in the severity of symptoms is also noted. If both options are presented then B should be chosen, as this represents the more accepted definition of anticipation. What do you think?Examples - note dominance of neurological disordersFragile X (CGG)Huntington's (CAG)myotonic dystrophy (CTG)Friedreich's ataxia (GAA) Friedreich's ataxia is unusual in not demonstrating anticipation.spinocerebellar ataxiaspinobulbar muscular atrophydentatorubral pallidoluysian atrophyWuchereria bancroftiParasitic filarial nematodeAccounts for 90% of cases of filariasisUsually diagnosed by blood smearsUsually transmitted by mosquitosTreatment is with diethylcarbamazineUrinary castsType of castAssociated conditionsRed blood cell casts Dysmorphic red blood cells if found in urine sedimentGlomerulonephritisRenal ischaemia and infarctionWhite blood cell castsAcute pyelonephritisInterstitial nephritisGranular ('muddy-brown') castsAcute tubular necrosisHyaline castsCommon and non-specificMay be seen following exercise or dehydrationEpithelial castsAcute tubular necrosisWaxy castsAdvanced chronic kidney diseaseFatty castsNephrotic syndromeIf a mono-symptomatic haematuria is noted in a middle age patient, in the absence of infection, a bladder tumour should be ruled out.Wilms' tumourOne of the most common childhood malignancies. It typically presents in children < 5 ys median age of 3 Ys.AssociationsBeckwith-Wiedemann syndromeas part of WAGR syndrome with Aniridia, Genitourinary malformations, mental Retardationhemihypertrophyaround one-third of cases are associated with a loss-of-function mutation in the WT1 gene on chromosome 11Featureabdominal mass (most common presenting feature)painless haematuriaflank painother features: anorexia, feverunilateral in 95% of casesmetastases are found in 20% of patients (most commonly lung)Histological features epithelial tubules, areas of necrosis, immature glomerular structures, stroma with spindle cells and small cell blastomatous tissues resembling the metanephric blastemaReferralchildren with an unexplained enlarged abdominal mass in children - possible Wilm's tumour - arrange?paediatric review with 48 hoursManagementnephrectomychemotherapyradiotherapy if advanced diseaseprognosis: good, 80% cure rateTetralogy of FallotThe most common cause of cyanotic congenital heart disease It typically presents at around 1-2 months, although may not be picked up until the baby is 6 months old however, at birth transposition of the great arteries is the more common lesion as patients with TOF generally present at around 1-2 months TOF is a result of anterior malalignment of the aorticopulmonary septum. The four characteristic features are:Ventricular septal defect (VSD)Right ventricular hypertrophyRight ventricular outflow tract obstruction, pulmonary stenosisOverriding aorta.The severity of the right ventricular outflow tract obstruction determines the degree of cyanosis and clinical severityOther featurescyanosiscauses a right-to-left shuntEjection systolic murmur pulmonary stenosis (the VSD doesn't usually cause a murmur)a right-sided aortic arch (25% of patients)chest x-ray shows a 'boot-shaped' heart, ECG shows right ventricular hypertrophyManagementsurgical repair is often undertaken in two partscyanotic episodes may be helped by beta-blockers to reduce infundibular spasmTransposition of the great arteriesTransposition of the great arteries (TGA) is a form of cyanotic congenital heart disease. It is caused by the?failure of the aorticopulmonary septum to spiral during septation. Children of diabetic mothers are at an increased risk of TGA.Basic anatomical changesaorta leaves the right ventriclepulmonary trunk leaves the left ventricleClinical featuresCyanosistachypnoealoud single S2prominent right ventricular impulse"Egg-on-side" appearance on chest x-rayManagementmaintenance of the ductus arteriosus with prostaglandinssurgical correction is the definite treatment.TroponinTroponin is a complex of three proteins involved in skeletal and cardiac muscle contractionSubunits of TroponinTroponin C: binds to calcium ions to activate muscle contraction. Troponin C is released due to both skeletal and cardiac muscle damage resulting in poor specificity as a marker for myocardial necrosis.?Troponin T: binds to tropomyosin, forming a troponin-tropomyosin complex, It is a specific marker for myocardial necrosis.?Troponin I: binds to actin to hold the troponin-tropomyosin complex in place, It is a specific marker for myocardial necrosis.?The sarcoplasmic reticulum regulates the calcium ion concentration in the cytoplasm of striated muscle cells.Upper limb anatomyNerveMotorSensoryTypical mechanism of injury & notesMusculocutaneous nerve (C5-C7)Elbow flexion (supplies?biceps brachii) and supinationLateral part of the forearm Isolated injury rare usually injured as part of brachial plexus injuryAxillary nerve (C5,C6)Shoulder abduction(deltoid muscle)Inferior region of the deltoid muscle Humeral neck fracture/dislocation Results in flattened deltoidRadial nerve (C5-C8)Extension (forearm, wrist, fingers, thumb)Small area between the dorsal aspect of the 1st and 2nd metacarpalsHumeral midshaft fracture Palsy ?wrist dropMedian nerve (C6, C8, T1)LOAF* musclesFeatures depend on the site of the lesion:wrist: paralysis of thenar muscles, opponens polliciselbow: loss of pronation of forearm and weak wrist flexionPalmar aspect of lateral 3? fingers Wrist lesion →?carpal tunnel syndromeUlnar nerve (C8, T1)Intrinsic hand muscles except LOAF*Wrist flexionMedial 1? fingersMedial epicondyle fractureDamage may result in a "Claw Hand"Long thoracic nerve (C5-C7)Serratus anteriorOften during sport following a blow to the ribs. Also possible complication of mastectomyDamage results in a?winged scapulaThe deltoid (C5, C6) and the biceps muscle (C5, C6, C7). The location of the sensory loss points to a C5 lesion. Erb-Duchenne palsy ('waiter's tip')due to damage of the upper trunk of the brachial plexus (C5,C6)may be secondary to shoulder dystocia during birththe arm hangs by the side and is internally rotated, elbow extendedKlumpke injurydue to damage of the lower trunk of the brachial plexus (C8, T1)as above, may be secondary to shoulder dystocia during birth. Also may be caused by a?sudden upward jerk of the handassociated with Horner's syndromeLOAF musclesLateral two lumbricalsOpponens pollisAbductor pollis brevisFlexor pollis brevisUlnar nerveArises from medial cord of brachial plexus (C8, T1)Motor tomedial two lumbricalsaDductor pollicisinterosseihypothenar muscles: abductor digiti minimi, flexor digiti minimiflexor carpi ulnarisSensory Medial 1 1/2 fingers (palmar and dorsal aspects)Paththe ulnar nerve travels through the posteromedial aspect of the upper arm to the flexor compartment of the forearmit then enters the palm of the hand via the?Guyon's canal, superficial to the flexor retinaculum and lateral to the pisiform bone.BranchesBranchSuppliesMuscular branchFlexor carpi ulnarisMedial half of the flexor digitorum profundusPalmar cutaneous branch (Arises near the middle of the forearm)Skin on the medial part of the palmDorsal cutaneous branchDorsal surface of the medial part of the handSuperficial branchCutaneous fibres to the anterior surfaces of the medial one and one-half digitsDeep branchHypothenar musclesAll the interosseous muscles?Third and fourth lumbricals?Adductor pollicisMedial head of the flexor pollicis brevisPatterns of damageDamage at wrist"claw hand" hyperextension of the metacarpophalangeal joints and flexion at the distal and proximal interphalangeal joints of the 4th and 5th digitswasting and paralysis of intrinsic hand muscles (except lateral two lumbricals)wasting and paralysis of hypothenar musclessensory loss to the medial 1 1/2 fingers (palmar and dorsal aspects)Damage at elbowas above (however, ulnar paradox - clawing is more severe in distal lesions)radial deviation of wristTemporal artery biopsySuperficial temporal artery is a terminal branch of the external carotid arteryMain indicationTemporal arteritis Viscosity, ESR and CRP are almost invariably raised in patients with active giant cell arteritis. A normal temporal artery biopsy would make it less likely that he has GCA but is less reassuring than a normal viscosity because GCA can present in the temporal artery with skip lesions.American College of Rheumatology guidelines recommend a temporal artery biopsy ifAge of onset older than 50 yearsNew-onset headache or localized head painTemporal artery tenderness to palpation or reduced pulsationESR > 50 mm/hHistopathologyVessel wall granulomatous arteritis with mononuclear cell infiltrates and giant cell formationProcedurePosition: supine, head 45 degreesUSS doppler to locate the superficial temporal artery or palpateLocal anaestheticArtery within temporoparietal fasciaClamp and ligate the vesselCut 3-5cmLigate the remaining ends with absorbable sutureClose the skinContraindicationGlucocorticoid therapy > 30 daysRisksInjury to facial or auriculotemporal nerve?Ethics If patient diagnosed with cancer and refuse the treatment A CT head and bloods may exclude causes that would impair judgement but would you override his decision even if you noticed evidence of a cerebral metastase? As there is no evidence that this man is suffering from a mental illness referral to a psychiatrist would be inappropriate.Significance testsA null hypothesis (H0) 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.?For example:'there is no difference in the prevalence of colorectal cancer in patients taking low-dose aspirin compared to those who are not'The alternative hypothesis (H1) is the opposite of the null hypothesis, i.e.?There is a difference between the two treatmentsThe?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. It is therefore equal to the chance of making a type I error Two types of errors may occur when testing the null hypothesisType I: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 IINull 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 alphaStudy accepts H0Study rejects H0Reality H0Type 1 error (alpha)Reality H1Type 2 error (beta)Power (1 - beta)The power of a study is?the probability of (correctly) rejecting the null hypothesis when it is false, i.e.?the probability of detecting a statistically significant differencepower =?1 - the probability of a type II errorpower can be increased by increasing the sample sizeThe power of a study may be defined in a number of ways:in general terms, the probability that a statistically significant difference will be detectedprobability of (correctly) rejecting the null hypothesis when it is falsewhich also means the probability of confirming the alternative hypothesis when the alternative hypothesis is truepower = 1 - the probability of a type II error or 1 - βSignificance tests: typesThe type of significance test used depends on whether the data is parametric (something which can be measured, usually normally distributed) or non-parametricParametric testsStudent's t-test - paired or unpaired*Pearson's product-moment coefficient - correlation?We are comparing parametric data from the same patients (they swapped medication halfway through the study) the Student's paired t-test should be used.Non-parametric testsMann-Whitney U test - unpaired dataWilcoxon signed-rank test - compares two sets of observations on a single sampleChi-squared test - used to compare proportions or percentagesSpearman, Kendall rank - correlation*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 groupsSkewed distributionsNormal (Gaussian) distributions: mean = median = modePositively skewed distribution: mean > median > modeNegatively skewed distribution mean < median < modeTo remember the above note how they are in alphabetical order, think positive going forward with '>', whilst negative going backwards '<'Skewed distributionsalphabetical order: mean - median - mode'>' for positive, '<' for negativeVarianceVariance is a measure of the spread of scores away from the mean.Variance = square of standard deviationCell cycleThe cell cycle is regulated by proteins called cyclins (A,B,D,E) control cyclin-dependent kinase (CDK) enzymes (1,2,4,6)PhaseNotesRegulatory proteinsG0'resting' phaseQuiescent cells such as Hepatocytes and more resting cells "?neurons"G1 Gap 1Cells ↑↑ in sizeDetermines length of cell cycleUnder influence of p53 (DNA repair and initiation of apoptosis)Cyclin D / CDK2/ CDK4, Cyclin D / CDK6 and Cyclin E / Regulates transition from G1 to S phase.S SynthesisSynthesis of DNA, RNA and HistoneCentrosome duplicationCyclin A / CDK2 active in S phaseG2 Gap 2Cells continue to ↑↑ in sizeCyclin B / CDK1 regulates transition from G2?to M phaseM MitosisThe?shortest?phase of the cycleCell divisionCell divisionCell division; Mitosis and Miosis.?MitosisMeiosisOccurs in somatic cellsOccurs in gametesResults in 2 diploid daughter cellsResults in 4 haploid daughter cellsDaughter cells are genetically identical to parent cellDaughter cells contain one homologue of each chromosome pair genetically differentsomatic cells have 22 pairs of autosomes and 1 pair of sex chromosomes, i.e. 46XY or 46XXcells with a normal chromosome complement are known as diploid cellsgametes (ova or spermatozoa) have a single copy of each chromosome and are known as haploid cellsMitosisDuring the S phase the cell prepares itself for division by duplicating the chromosomes. Mitosis occurs during the M phase somatic cells divide and replicate (genetically identical diploid daughter cells) tissue to grow and renew itself.?The table below shows the phases of mitosis itself:ProphaseChromatin in the nucleus condensesPrometaphase Breaks down of nuclear membrane microtubules to attach to the chromosomesMetaphase Midline (middle of cell) alignment of Chromosomes Anaphase?????? The paired chromosomes separate at the kinetochores Move to opposite sides of theanaphase 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 cellanaphase B: polar microtubules push against each other, causing the cell to elongate Telophase ??? Chromatids arrive at opposite poles of cell ??? ??? ?????? ?????CytokinesisActin-myosin complex in the centre of the cell contacts 'pinched' into 2 daughter cells Vinca alkaloids and taxanes (Microtubule-targeting agents) (Metaphase arrest)Vinca Alkaliod bind to tubulin stop the polymerisation and assembly of microtubules disrupts spindle formation arresting mitosis.Taxanes ↑↑ polymerisation of tubulin where the microtubule disassemble (also known as the depolymerisation process, metaphase arrest.Examples Vincristine, Vinblastine and VinorelbineTreatment of leukaemias, lymphomas, and advanced-stage breast cancer.?S/E dose-limiting neurotoxicity, manifested mainly as peripheral neuropathy.?Main toxicity is an axonal neuropathy and small sensory fibres disruption of the microtubules within axons and interference with axonal transport.Almost all patients have some degree of neuropathy, the earliest symptoms (paraesthesia in the fingertips and feet)5-fluorouracil, methotrexate and mercaptopurineAntimetabolites Affect the S-phase of the cell cycle. Anthracyclines multiple mechanisms of action but primarily S phase of the cell cycle and work by intercalating DNA.Irinotecan and topotecanTopoisomerase I inhibitors (Topoisomerases are enzymes regulate supercoiling of DNA which is required in mitosis and meiosis.Etoposide and teniposide topoisomerase II inhibitors.Cell organellesOrganelle/macromoleculeMain functionEndoplasmic ReticulumRough endoplasmic reticulumTranslation and folding of new proteinsManufacture of lysosomal enzymesSite of N-linked glycosylationExamples of cells ↑↑RER pancreatic cells, goblet cells, plasma cellsSmooth endoplasmic reticulumSteroid, lipid synthesisExamples of cells ↑↑SER Adrenal cortex, Hepatocytes, Testes,OvariesLysosomeBreakdown of large molecules such as proteins and polysaccharides (proteins tagged with mannose-6- phosphate to ProteasomeAlong with the lysosome degradation of protein molecules that have been tagged with ubiquitin (polypeptides)PeroxisomeCatabolism of very long chain fatty acids and amino acidsResults in the formation of hydrogen peroxideZellweger syndrome a genetic disease which causes peroxisome dysfunction has axial hypotonia and she has abnormal facial features Blood tests elevated long-chain fatty acids level.Golgi apparatusMolecules destined for cell secretion (Modifies, sorts, and packages)Site of O-linked glycosylationGolgi adds mannose-6-phosphate to proteins for trafficking to lysosomesMitochondrionAerobic respiration Contains mitochondrial genome as circular DNANucleus DNA maintenance and RNA transcriptionNucleolus Ribosome productionRibosome Translation of RNA into proteins MicrotubulesMicrotubules 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.necessary for DNA segregation and therefore cell division.?Structurecylindrical structure composed of alternating α and β tubulin subunits which polymerize to form protofilamentsmicrotubules are polarized, having a positive and negative endMolecular transportattachment proteins called dynein and kinesin move up and down the microtubules facilitating the movement of various organelles around the celldynein 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) Transmembrane proteins ion channels are responsible for transport of substances across the cell membrane.?Proteins called SNAREs on the surface of vesicles and their target organelles facilitate docking and fusion.Membrane receptorsThere are four main types of membrane receptor: ligand-gated ion channels, tyrosine kinase receptors, guanylate cyclase receptors and G protein-coupled receptorsLigand-gated ion channel receptorsgenerally mediate fast responsesEx: ?Nicotinic acetylcholine Skeletal muscle contraction is dependent??GABA-A?&?GABA-C,?glutamate receptors.Tyrosine kinase receptorsreceptor 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 ThromobopoietinGuanylate cyclase receptorscontain intrinsic enzyme activitye.g.?atrial natriuretic factor,?brain natriuretic peptideG protein-coupled receptorsgenerally mediate slow transmission and affect metabolic processesactivated by a wide variety of extracellular signals e.g. Peptide hormones, biogenic amines, lipophilic hormones, light7-helix membrane-spanning domainsconsist of 3 main subunits: alpha, beta and gammathe alpha subunit is linked to GDP.Ligand binding causes conformational changes to receptor, GDP is phosphorylated to GTP,and the alpha subunit is activatedG proteins are named according to the alpha subunit (Gs, Gi, Gq)GsGiGqMechanismStimulates adenylate cyclase?→?increases cAMP?→?activates protein kinase AInhibits adenylate cyclase?→?decreases cAMP?→?inhibits protein kinase AActivates phospholipase C?→ Splits PIP2?to?IP3?& DAG?→?(++) protein kinase CExamplesBeta -1receptors (Epinephrine, Nor-epinephrine, Dobutamine)↑↑ HR and cardiac contractility.?Beta-2 receptors (Epinephrine, Salbuterol)H2 receptors(histamine)D1 receptors(dopamine)V2 receptors(vasopressin)Receptors for ACTH, LH, FSH, glucagon, PTH, calcitonin, prostaglandinsM2 Receptor (acetylcholine)↓↓ HR could worsen compensation.Alpha-2 (epinephrine, Norephinephrine)D2 receptors(dopamine)?GABA-B receptorAlpha-1 receptors(epinephrine, norepinephrine)V.C (skin, gut and kidney arterioles).↑↑ total peripheral resistance and mean arterial pressure, as well as facilitate perfusion of the brain, heart and lungs.?H1 receptors(histamine)?V1 receptors(vasopressin)?M1, M3 receptors(acetylcholine)Second messengersmany different typesallow amplification of external stimuluscAMP systemPhosphoinositol systemcGMP systemTyrosine kinase systemLigand:Neurotransmitters(Receptor)Epinephrine (α2, β1, β2)Acetylcholine (M2)Epinephrine (α1)Acetylcholine (M1, M3)--Ligand:HormonesACTH,?ADH,?calcitonin,?FSH,?glucagonhCG,LH, MSH,?PTH,?TSH, GHRH*angiotensin II,?GnRH, GHRH*,?Oxytocin,?TRHANP,?Nitric oxideinsulin,?growth hormone,?IGF, PDGFPrimary effectorAdenylyl cyclasePhospholipase CGuanylate cyclaseReceptor tyrosine kinaseSecondary messengercAMP (cyclic adenosine monophosphate)IP3 (inositol 1,4,5 trisphosphate) and DAG (Diacylglycerol)cGMPProtein phosphatase*the cAMP pathway is the most importantCell surface proteinsThe table below shows the most common cell surface proteins associated with particular cell types:Type of cellCell surface markersHelper T cellCD4, TCR, CD3, CD28Cytotoxic T cellCD8, TCR, CD3, CD28Regulatory T cellCD4, TCR, CD3, ,CD28, CD25MacrophageCD14, CD40, MHC II, B7Natural killer cellCD16, CD56 (unique)B cellCD19, CD20, CD40, MHC II, B7/ Haematopoietic stem cellsCD34The table below lists the major clusters of differentiation (CD) molecules and describes their function.Cluster of differentiationFunctionCD1MHC molecule that presents lipid moleculesCD2Found on thymocytes, T cells some natural killer cells as a ligand for CD58 and CD59 and is involved in signal transduction and cell adhesionCD3The signalling component of all T cell receptor (TCR) complexCD4Found on helper T cells.?Co-receptor for MHC class IIUsed by HIV to enter T cellsCD5Found in the all mantle cell lymphomasCD8Found on cytotoxic T cells.Co-receptor for MHC class IFound on a subset of myeloid dendritic cellsCD14Cell surface marker for macrophagesCD15Expressed on Reed-Sternberg cells (along with CD30) Hodgoken lymphoma CD16Bind to the Fc portion of IgG antibodies, Natural Killer CellCD21Receptor for Epstein-Barr virusCD28Interacts with B7 on antigen presenting cell as costimulation signalCD45Protein tyrosine phosphatase present on all leucocytesCD56Unique marker for Natural killer CellsCD95Acts as the FAS receptor, involved in ApoptosisMHC Major histocompatibility complex bind peptide fragments from pathogens and display them on the cell surface for recognition by the T cellsComplement deficienciesA series of proteins circulate in plasma involved in Inflammatory and immune reactions (Chemotaxis, Cell lysis and Opsonisation)C1 inhibitor (C1-INH) protein deficiencyHereditary AngioedemaC1-INH is a multifunctional serine protease inhibitorprobable mechanism is uncontrolled release of bradykinin resulting in oedema of tissuesC1q, C1rs, C2, C4 deficiency (classical pathway components)predisposes to immune complex disease "Classic Pathway"SLE, Henoch-Schonlein PurpuraC3 deficiency Recurrent bacterial infections capsulated bacteria pneumococcus "Strept. Pneumonia? and ?Haemophilus begins quite soon after birth C5 deficiencyLeiner Disease " erythroderma?desquamativum" Generalised?seborrhoeic?dermatitis,?recurrent?diarrhoea, recurrent skin and internal?infections, and failure to thrive. May be present at birth but more commonly develops within the first few months of life. females > males ↑↑ breast-fed infants.C5 activation have a role in progression of fibrotic liver disease.? C5-9 deficiencyC5a chemotaxis, and C5b first part of the membrane attack complex. Deficiencies of the membrane attack complex prone to?disseminated meningococcal Neisseria?meningitidis?infectionCD59 deficiency Involved in the pathogenesis of paroxysmal nocturnal haemoglobinuria.?Cytokines InterleukinsCytokineMain sourcesFunctionsIL-1MacrophagesAcute inflammation Induces feverIL-2Th1 cellsStimulates growth and differentiation of T cell responseIL-3Activated T helper cellsStimulates differentiation and proliferation of myeloid progenitor cellsIL-4Th2 cellsStimulates proliferation and differentiation of B cellsIL-5Th2 cellsStimulate production of eosinophilsIL-6Macrophages, Th2 cellsStimulates differentiation of B cellsInduces feverIL-8MacrophagesNeutrophil chemotaxisIL-10Th2 cellsInhibits Th1 cytokine productionAlso known as human cytokine synthesis inhibitory factor and is an 'anti-inflammatory' cytokineIL-12Antigen presenting cell, Dendritic cells, macrophages, B cellsActivates NK cells?and?stimulates differentiation of naive T0 cells into Th1 cellsOther cytokinesCytokineMain sourcesFunctionsTumour necrosis factor-αMacrophagesInduces feverNeutrophil chemotaxisInterferon-γTh1 cellsActivates macrophagesIL-1, an acute inflammatory cytokine Key mediator of the immune response secreted mainly by macrophages and monocytes Acts as a Co stimulator of T cell and B cell proliferation.?Other effects include ↑↑ expression of adhesion molecules (Selectin) on the endothelium.Vasodilation and↑↑vascular permeability By (++)release by the endothelium of vasoactive factors such as PAF, Nitric oxide and Prostacyclin It is therefore one of the mediators of shock in sepsis. Along with IL-6 and TNF, it acts on the hypothalamus Pyrexia.Macrophages Responsible for the production of cytokines, including IL-1. Basophils, Neutrophils and Eosinophils all produce proinflammatory cytokines but in lower volumes than macrophages. Immune system cells: adaptive immune responseCell typeFunctions and propertiesHelper T cellsInvolved in the cell-mediated immune responseRecognises antigens presented by MHC class II moleculesExpresses CD4Also expresses CD3, TCR &?CD28Major source of IL-2Mediates acute and chronic organ rejectionCytotoxic T cellsInvolved in the cell-mediated immune responseRecognises antigens presented by MHC class I moleculesInduce apoptosis in virally infected and tumour cellsExpresses CD8Also expresses CD3, TCRMediates acute and chronic organ rejectionB cellsMajor cell of the humoral immune responseActs as an antigen presenting cellMediates hyperacute organ rejectionPlasma cellsDifferentiated from B cellsProduces large amounts of antibody specific to a particular antigenMacrophages and neutrophils may be seen due to local inflammation but are not chiefly responsible for mediating hyperacute organ rejection.T-Helper cells Th1involved in the cell mediated response and delayed (type IV) hypersensitivitysecrete IFN-gamma, IL-2, IL-3Th2involved in mediating humoral (antibody) immunity(++) production of IgE in asthmasecrete IL-4, IL-5, IL-6, IL-10, IL-13Immune system cells: innate immune responseCell typeFunctions and propertiesNeutrophilPrimary phagocytic cell in acute inflammationGranules contain myeloperoxidase and lysozyme?Most common type of white blood cellNucleus Multi-lobedBasophilReleases histamine during allergic responseGranules contain histamine and heparinExpresses IgE receptors on the cell surfaceNucleus Bi-lobed Mast cellPresent in tissues, similar in function to basophils? from different cell linesReleases histamine during allergic responseGranules contain histamine and heparinExpresses IgE receptors on the cell surfaceEosinophilDefends against protozoan and helminthic infectionsNucleus Bi-lobed MonocyteDiffferentiates into MacrophagesNucleus Kidney shapedMacrophageInvolved in phagocytosis of cellular debris and pathogensActs as an antigen presenting cellMajor source of IL-1Natural killer cellInduce apoptosis in virally infected and tumour cells (like T- Cytokines)Dendritic cellActs as an antigen presenting cellLeukotrienesFunctionmediators of inflammation and allergic reactionsCause bronchoconstriction, mucous production↑↑ vascular permeability attract leukocytesLeukotriene D4 identified as the SRS-A (slow reacting substance of anaphylaxis)ProductionSecreted by leukocytesformed from arachidonic acid by action of lipoxygenaseit is thought that NSAID induced bronchospasm in asthmatics 2ry to the express production of leukotrienes due to the ↓↓ of PG synthetaseInterferonInterferons (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-alpha and IFN-beta type 1 receptors IFN-gamma only to type 2 receptors.Interferon-alphaproduced by leucocytesantiviral actionuseful in hepatitis B & C, Kaposi's sarcoma, metastatic renal cell cancer, hairy cell leukaemiaS/E flu-like symptoms and depressionInterferon-betaproduced by fibroblastsantiviral action↓↓↓ exacerbations in patients with relapsing-remitting MSInterferon-gammaPredominately NKC. Also by T helper cellsweaker antiviral action, more of a role in immunomodulation particularly macrophage activationMay be useful in chronic granulomatous disease and osteopetrosis.Immunoglobulin'sAntibodies (immunoglobulins) may be divided into 2 main pairs:Fab region (antigen-binding fragment) Ab region that binds to AntigensFc region (fragment crystallizable region) Ab tail region of an that interacts with cell surface receptors (FC Cell)TypeFrequencyShapeNotesIgG75%Monomer?? Enhance phagocytosis of bacteria and viruses?? Fixes complement and passes to the fetal circulation?? Most abundant isotype in blood serumIgA15%Monomer/ dimer?? Most commonly produced Igs in the body?(but blood serum concentrations < IgG.? The predominant immunoglobulin found in breast milk. Also secretions of digestive, respiratory and urogenital tracts.?? Localized protection on mucous membranes.?? Transported across the interior of the cell via TranscytosisIgM10%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?(They cannot pass to the fetal circulation as crossing causes haemolysis)? Pentamer when secretedIgD1%Monomer?? Role in immune system largely unknown?? Involved in activation of B cellsIgE0.1%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 serumHypersensitivityThe Gell and Coombs classification divides hypersensitivity traditionally divides reactions into 4 types:TypeMechanismExamplesType I AnaphylacticAntigen directly reacts with IgE bound to mast cellsAnaphylaxisAtopy (Asthma, Eczema and?Hayfever)Type II Cell boundIgG or IgM binds to antigen on cell surfaceAutoimmune haemolytic anaemia.Acute haemolytic transfusion reactionsITPPernicious anaemiaGoodpasture's syndromeRheumatic feverPemphigus vulgaris /?Bullous pemphigoidType III Immune complexFree antigen and antibody (IgG, IgA) combineSerum sicknessSystemic lupus erythematosusPost-streptococcal glomerulonephritisExtrinsic allergic alveolitis (Acute Phase)Type IV Delayed hypersensitivityT-cell mediatedTuberculosis?/?tuberculin skin reaction?Graft versus host diseaseAllergic contact dermatitis (normal material but irritates certain patients (Watch, Certain metals nickel…>ScabiesExtrinsic allergic alveolitis (chronic phase)Multiple sclerosisGuillain-Barre syndromeIn recent times a further category has been added:TypeMechanismExamplesType VAntibodies that recognise and bind to the cell surface receptors.? stimulating or blocking ligand bindingGraves' diseaseMyasthenia gravisLatex allergy ?urticarial rash, angioedema and wheezing (after latex contact , balloon)Adrenaline should be given immediately and usual anaphylaxis management.ErythropoiesisRed blood cells (erythrocytes) are produced red bone marrow In adults flat bones (vertebrae, ribs, and sternum) and proximal ends of long bones.In the foetus Erythrocytes are produced mainly in the liver.Erythrocytes consist mainly of Haemoglobin (Hb) heme, containing iron to give the cell its oxygen-binding function, globin protein. Folate and Vit. B12 are required for cell division and DNA synthesis.All types of blood cells are derived from Haematopoietic stem cells differentiate into 2 precursor cells: (lymphoid and myeloid). Erythrocytes originate from myeloid precursor cells.Production of new erythrocytes takes around one week, and lifespan 120 days.Erythropoietin (EPO) regulate Erythropoiesis Produced in the kidneys on detection of decreased oxygen levels in the circulation. This increases uptake of iron, heme biosynthesis, and globin gene transcription. Restored oxygen causes a negative feedback loop to the kidney to return to normal production.Levels of Erythrocytes are represented by the haematocrit, (% of blood volume occupied by erythrocytes. Erythropoiesis can be (↑/↓) changing the haematocrit. Dysfunctional bone marrow may produce ↑↑↑erythrocytes (polycythaemia) or ↓↓↓(anaemia). ↓↓ Components of erythrocytes affect erythropoiesis (iron deficiency or pernicious anaemia "vitamin B12 deficiency")Stages of differentiation in order of development:Cell typeStage of differentiationHaematocytoblastMultipotent stem cell for all types of blood cellsProerythroblastCell has become committed to its developmental pathwayBasophilic erythroblastRibosomes start to accumulate and the nucleus begins to shrinkPolychromatophilic erythroblastNucleus and total cell volume continue to shrinkNormoblastCell nucleus is ejected before developing furtherReticulocyteCells enter the circulationReticulocyte release normal response to anaemia secondary to bleeding.They are polychromatic as they contain a ribosomal RNA mesh like (Reticule)apparent upon staining (Not in mature Erythrocyte)ErythrocyteFully matured cell pale as they contain no nucleusBasophils multiple dark stained granules filling the cytoplasm.?Lymphocytes uniformly small dark stained cells.?Neutrophils segmented nuclei with 2-5 lobes.?Respiratory physiologyChloride shiftCO2 diffuses into RBCsCO2 + H20 by carbonic anhydrase enzyme ?? HCO3- + H+H+ combines with HbHCO3- diffuses out of cell,- Cl- replaces it.Bohr Effect ↑↑ Acidity (↑↑ pCO2) means O2 binds less well to HbHaldane effect ↑↑ pO2 means CO2 binds less well to HbControl of respirationCentral regulatory centresCentral and peripheral chemoreceptorsPulmonary receptorsCentral regulatory centresMedullary respiratory centrePonsApneustic centre (lower pons)Pneumotaxic centre (upper pons)Central and peripheral chemoreceptorscentral: ↑↑ [H+] in ECF stimulates respirationperipheral Carotid + aortic bodies Respond to ↑↑ pCO2 & [H+], lesser extent low pO2Pulmonary receptorsStretch Receptors lung distension ↓↓ of respiratory rate (Hering-Bruer reflex)Irritant Receptor, leading to bronchoconstrictionJuxtacapillary Receptors, (++) by stretching of the microvasculatureHypoxia↓↓ partial pressure of oxygen in the blood V.C of the pulmonary arteries allows blood to be diverted to better aerated areas of the lung ↑↑ efficiency of gaseous exchange.Lung complianceDefined as change in lung volume per unit change in airway pressureCauses of increased complianceAgeEmphysema due to loss alveolar walls and associated elastic tissueCauses of decreased compliancePulmonary oedemaPulmonary fibrosisPneumonectomyKyphosisPulmonary surfactantSurfactant is a mixture of phospholipids, carbohydrates and proteins released by type 2 pneumocytes. The main functioning component is dipalmitoyl phosphatidylcholine (DPPC) which reduces alveolar surface tension.Basicsfirst detectable around 28 weeksas alveoli decrease in size, surfactant concentration is increased, helping prevent the alveoli from collapsingreduces the muscular force needed to expand the lungs (i.e. decreases the work of breathing)lowers the elastic recoil at low lung volumes and thus helps to prevent the alveoli from collapsing at the end of each expirationCollagenCollagen is the main structural protein found in connective tissue and is the most common protein found in the body.Whilst over 20 types of collagen have been identified there are 4-5 which are considered the most important:Collagen typeNotesAssociated conditionsI commonest subtype is I (90% of bodily collagenBone, skin, tendon Osteogenesis imperfectaIIHyaline cartilageVitreous humourIII ThreeReticular fibreGranulation tissue Vascular variant of Ehlers-Danlos syndromeIVLensBasal lamina, Basement membraneAlport syndromeGoodpasture's syndromeVMost interstitial tissuePlacental tissue Classical variant of Ehlers-Danlos syndromeStructureSynthesised by fibroblastsComposed of 3 polypeptide strands that are woven into a helix combination of (Glycine + Proline or Hydroxyproline + Another amino acid)Numerous hydrogen bonds exist within molecule ↑↑ additional strengthThe commonest subtype is I (90% of bodily collagen) Tissues with ↑↑ flexibility ↑↑ type III collagenVitamin C is important in establishing cross-linksCollagen diseasesCommon, acquired defects (typically aging), rarer congenital disorders such as:Osteogenesis imperfecta:8 SubtypesDefect of type I collagen normal quality but ↓↓ quantityType II ↓↓ (quantity and quality)Type III (↓↓ Quality), (normal quantity)Type IV √√ quantity but ↓↓ qualityPatients have bones which fracture easily, loose joint and multiple other defects depending upon which sub type they suffer from.Ehlers Danlos:Multiple sub typesAbnormality of types 1 and 3 collagenPatients have features of hypermobility.Joint dislocations and pelvic organ prolapse. In addition to many other diseases related to connective tissue defects.EpidermisOutermost layer of the skin and is composed of a stratified squamous epithelium with an underlying basal lamina 5 Layers. LayerDescriptionStratum CorneumFlat, dead, scale-like cells filled with keratinContinually shedStratum LucidumClear layer - present in thick skin onlyStratum GranulosumCells form links with neighbours (Junction)Stratum SpinosumSQ. cells begin keratin synthesis?Thickest layer of epidermisStratum GerminativumThe basement membrane(Next to dermis) - single layer of columnar epithelial CellsGives rise to keratinocytes (SQ. cellsin the upper layer)Contains melanocytesEndothelinPotent, 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 Ca++ release. Endothelin pathogenesis of (1ry PHT, Cardiac failure, Hepatorenal syndrome and Raynaud's)Promotes releaseAngiotensin IIADHHypoxiaMechanical shearing forcesInhibits releaseNitric oxideProstacyclinRaised levels in?MIHeart failureARFAsthmaprimary pulmonary hypertensionHLA associationsHLA antigens are encoded for by genes on chromosome 6. HLA A, B and C are class I antigens whilst DP, DQ, DR are class II antigens. Questions are often based around which diseases have strong HLA associations. The most important associations are listed below:HLA-A3haemochromatosisHLA-B51Behcet's diseaseHLA-B27ankylosing spondylitisReiter's syndromeacute anterior uveitisHLA-DQ2/DQ8coeliac diseaseHLA-DR2narcolepsyGoodpasture'sHLA-DR3dermatitis herpetiformis (?rash on both her elbows. The rash is red, is papulovesicular?)Sjogren's syndromeprimary biliary cirrhosisHLA-DR4Type 1 diabetes mellitus associated with HLA-DR3 but is more strongly associated with HLA-DR4.rheumatoid arthritis?- ?70% of patients in particular the?DRB1 gene?(DRB1*04:01 and DRB1*04:04 hence the association with DR4)Patients with Felty's syndrome (a triad of rheumatoid arthritis, splenomegaly and neutropaenia) are even more strongly associated with 90% being HLA-DR4Molecular biology techniquesBasic summary of molecular biology techniquesTechniqueDescriptionSouthern blottingDetects DNANorthern blottingDetects RNAWestern blottingDetects proteinsUses gel electrophoresis to separate native proteins by 3-D structureExamples include the?confirmatory?HIV testSNOW (South -?NOrth -?West)DROP (DNA -?RNA -?Protein)Fluorescence in situ hybridization uses fluorescent DNA or RNA probe to bind to specific gene site of interest for direct visualisation of chromosomal anomalies.Enzyme-linked immunosorbent assay (ELISA)a type of biochemical assay used to detect antigens and antibodiesa colour changing enzyme is attached to the antibody if looking for an antigen and to an antigen if looking for an antibodythe sample therefore changes colour if the antigen or antibody is detectedan example includes the?initial?HIV testPolymerase chain reactionA 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. Uses Prenatal diagnosis.Detection of mutated oncogenes. Diagnosis of infectionsExtensively used in forensics. Prior to the procedure 2 DNA Oligonucleotide primers (Complimentary to specific DNA sequences at either end of the target DNA)Initial Prepsample of DNA is added to test tube with two DNA primersA thermostable DNA polymerase (Taq) is addedThe following cycle mixture is heated to almost boiling point denaturing (uncoiling) of DNAmixture allowed to cool complimentary strands of DNA (Primers) pair up, as there is an excess of the primer sequences they pair with DNA preferentiallyRepeated Cycles with the amount of DNA doubling each timeReverse transcriptase PCRUsed to amplify RNARNA is converted to DNA by reverse transcriptaseGene expression in the form of mRNA (rather than the actually DNA sequence) can therefore be analyzedMuscle contractionSkeletal muscle contractionaction potential reaches the neuromuscular junction, causing a calcium ion influx through voltage-gated calcium channelsthe calcium influx causes the release of acetylcholine into the extracellular spacethe acetylcholine activates nicotinic acetylcholine receptors causing an influx of sodium, triggering an action potentialthe action potential spreads through the T-tubulesthe 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 reticulumthis causes the sarcoplasmic reticulum to release calciumcalcium binds to troponin C (found on actin-containing thin filaments) causing a conformational change, allowing tropomyosin to move, unblocking the binding sitesmyosin binds to the newly released binding site releasing ADP, pulling the Z bands towards each otherATP binds to myosin, releasing actinImage sourced from?WikipediaComponentNotesSarcomereBasic unit of muscles that gives skeletal and cardiac muscles their striated appearance. Segment between two adjacent Z-linesI-bandZone of thin filaments that is not superimposed by thick filamentsA-bandContains the entire length of a single thick filamentH-zoneZone of the thick filaments that is not superimposed by the thin filamentsM-lineMiddle of the sarcomere, cross-linking myosinSarcoplasmic reticulumReleases calcium ion in response to depolarizationActinThin filaments that transmit the forces generated by myosin to the ends of the muscleMyosinThick filamentsBinds to thin filamentTitinConnects the Z-line to the thick filament, altering the structure of tropomyosinTropomyosinCovers the myosin-binding sites on actinTroponin-CBinds with calcium ionsT-tubuleIs an invagination of the sarcoplasmic reticulum?Helps co-ordinate muscular contractionTypes of skeletal muscle fibres (type II fibres are simplified into one category):Type IType IIContraction timeSlowFastColourRed (due to presence of myoglobin)White (due to absence of myoglobin)Main useSustained forceSudden movementMajor fuelTriglyceridesATPMitochondrial densityHighLowMnemonic for type I fibres - 'One Slow, Fat, Red Ox'Muscle relaxantsThere are two main categories of muscle relaxants used in anaesthesia depolarising muscle relaxants suxamethoniumnon-depolarising muscle relaxants Rocuronium, mivacurium, and pancuroniumSuxamethoniumDepolarising neuromuscular blockerInhibits action of acetylcholine at the neuromuscular junctionDegraded by plasma cholinesterase and acetylcholinesteraseFastest onset and shortest duration of action of all muscle relaxantsProduces generalised muscular contraction prior to paralysisAdverse effects include hyperkalaemia, malignant hyperthermia and lack of acetylcholinesteraseAtracuriumNon depolarising neuromuscular blocking drugDuration of action usually 30-45 minutesGeneralised histamine release on administration may produce facial flushing, tachycardia and hypotensionNot excreted by liver or kidney, broken down in tissues by hydrolysisReversed by neostigmineVecuroniumNon depolarising neuromuscular blocking drugDuration of action approximately 30 - 40 minutesDegraded by liver and kidney and effects prolonged in organ dysfunctionEffects may be reversed by neostigmine Anti- cholinesterase Sugammadex is a drug utilised in anaesthesia for reversal of neuromuscular blockade caused by rocuronium and vecuronium Inactivates rocuronium by encapsulating it and form a complex. It does not produce cholinergic effect it can trigger?malignant hyperthermiaPancuroniumNon depolarising neuromuscular blockerOnset of action approximately 2-3 minutesDuration of action up to 2 hoursEffects may be partially reversed with drugs such as neostigmineSleep stagesSleep stageEEGNotesNon-REM stage 1 (N1)Theta wavesLight sleepTransition to this stage be associated with hypnic jerksNon-REM stage 2 (N2)Sleep spindles + K-complexesDeeper sleepRepresents around 50% of total sleepNon-REM stage 3 (N3)Delta wavesDeep sleepParasomnias such as night terrors, nocturnal enuresis, sleepwalkingREMBeta-wavesDreaming occursErectionLoss of muscle tone atonia prevents acting out with dreamsREM sleep disorders REM parasomnias Associated with lucid dreaming and absence of normal atonia during this stage of sleep. Patients acting out their dreams and causing themselves and others physical harm often vivid, intense, and violent movement.N1 → N2 → N3 → REMTheta →?Sleep spindles/K-complexes →?Delta →?BetaThe?Sleep?Doctor's?BrainHypnagogic jerkA type of myoclonus involuntary twitch which occurs when a person is beginning to fall asleep, often causing them to jump and awaken suddenly.occur in non-REM stage 1 (N1) sleep - the lightest sleep stage. Causes Most normal variant, anxiety, caffeine, stress and strenuous activities in the evening,.OncogenesOncogenes are cancer promoting genes that are derived from normal genes (proto-oncogenes). Proto-oncogenes play an important physiological role in cellular growth and differentiation. A 'gain of function' results in an increased risk of cancer. Only one mutated copy of the gene is needed for cancer to occur - a dominant effect. They are implicated in the development of up to 20% of human cancers.?Proto-oncogenes may become oncogenes via the following processes:Mutation (point mutation)Chromosomal translocationIncreased protein expressionExamplesGeneCategoryAssociated cancersABLCytoplasmic tyrosine kinaseChronic myeloid leukaemiac-MYCTranscription factorBurkitt's lymphoma is classically associated with the translocation: t(8;14). Here, the c-MYC gene is translocated next to the gene for IgH. IgH is highly expressed in the body (as it codes for the heavy chain of antibodies), and this leads to an overamplification c-MYC.n-MYCTranscription factorNeuroblastomaBCL-2Apoptosis regulator proteinFollicular lymphomaRETTyrosine kinase receptorMultiple endocrine neoplasia (types II and III)RASG-proteinMany cancers especially?pancreaticerb-B2 (HER2/neu)Tyrosine kinase receptorBreast and ovarian cancerTumour supressory genesTumour suppressor genes restrict or repress cellular proliferation in normal cells. Their inactivation through mutation or germ line incorporation is implicated in renal, colonic, breast, bladder and many other cancers. One of the best known tumour suppressor genes is p53. p53A tumour suppressor gene located on chromosome 17p. Play a crucial role in the cell cycle, preventing entry into the S phase until DNA has been checked and repaired.A key regulator of apoptosis Whilst p53 can trigger cell cycle arrest to allow DNA to be repaired the encoded proteins do not directly repair DNA.It is the most commonly mutated gene in breast, colon and lung cancer Li-Fraumeni syndrome?is a rare autosomal dominant disorder characterised by the early onset of a variety of cancers such as sarcomas and breast cancer. It is caused by mutation in the p53 gene which can present with soft tissue sarcomas, breast carcinoma, glioblastoma, lymphoma and leukaemia. It is a rare autosomal dominant disorder. Other well known genes include BRCA 1 and 2.Obesity: physiologyLeptinLeptin 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)GhrelinWhere 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 mealsthyroxine can increase appetite it does not fit with the clinical picture being describedBreast feedingContraindications of breast feeding:GalactosaemiaViral infections controversial with respect to HIV in the developing world. ↑↑ infant mortality and morbidity associated with bottle feeding some doctors think the benefits outweigh the risk of HIV transmissionSafe Drugs with breastfeeding:Antibiotics:?Penicillins,?Cephalosporins,?TrimethoprimAnticoagulants:?warfarin,?heparinAsthma:?Salbutamol,?TheophyllinesDigoxinEndocrine:?Glucocorticoids (avoid high doses),?Levothyroxine (Too small amount to affect neonatal hypothyroidism screening)Epilepsy:?Sodium valproate,?CarbamazepineHypertension:?Beta-blockers,?Hydralazine, Aldomet (Methyldopa)Psychiatric drugs:?Tricyclic antidepressants,?Antipsychotics (Clozapine should be avoided)Unsafe DrugsAntibiotics:?Ciprofloxacin,?Tetracycline, Chloramphenicol,?SulphonamidesAspirinAmiodaroneCarbimazoleCytotoxic drugsMethotrexateSulfonylureasPsychiatric drugs:?Lithium,?BenzodiazepinesProlactinSource Anterior pituitaryFunction(++) breast development (both initially and further hyperplasia during pregnancy)(++) milk production↓↓ GnRH pulsatility at the hypothalamic level and to a lesser extentBlocks the action of LH on the ovary or testis.RegulationProlactin secretion is under?constant inhibition by dopamineIncreases secretion?Thyrotropin releasing hormonePregnancyOestrogenBreastfeedingSleepStressDrugs Metoclopramide, AntipsychoticsDecreases secretionDopamineDopaminergic agonistsParathyroid glands and disorders of calcium metabolismHyperparathyroidismDisease typeHormone profileClinical featuresCausePrimary hyperparathyroidismPTH (Elevated)Ca2+(Elevated)Phosphate (Low)Urine calcium : creatinine clearance ratio > 0.01May be asymptomatic if mildRecurrent abdominal pain (pancreatitis, renal colic)Changes to emotional or cognitive stateMost cases due to solitary adenoma (80%), multifocal disease occurs in 10-15% and parathyroid carcinoma in 1% or lessSecondary hyperparathyroidismPTH (Elevated)Ca2+?(Low or normal)Phosphate (Elevated)Vitamin D levels (Low)May have few symptomsEventually may develop bone disease, osteitis fibrosa cystica and soft tissue calcificationsParathyroid gland hyperplasia occurs as a result of low calcium, almost always in a setting of chronic renal failureTertiary hyperparathyroidismCa2+(Normal or high)PTH (Elevated)Phosphate levels (Decreased or Normal)Vitamin D (Normal or decreased)Alkaline phosphatase (Elevated)Metastatic calcificationBone pain and / or fractureNephrolithiasisPancreatitisOccurs as a result of ongoing hyperplasia of the parathyroid glands after correction of underlying renal disorder, hyperplasia of all 4 glands is usually the causeDifferential diagnosesIt is important to consider the rare but relatively benign condition of benign familial hypocalciuric hypercalcaemia, caused by an autosomal dominant genetic disorder. Diagnosis is usually made by genetic testing and concordant biochemistry (urine calcium : creatinine clearance ratio <0.01-distinguished from primary hyperparathyroidism).TreatmentPrimary hyperparathyroidismIndications for surgeryElevated serum Calcium > 1mg/dL above normalHypercalciuria > 400mg/dayCreatinine clearance < 30% compared with normalEpisode of life threatening hypercalcaemiaNephrolithiasisAge < 50 yearsNeuromuscular symptomsReduction 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)Secondary hyperparathyroidismUsually managed with medical therapy.Indications for surgery in secondary (renal) hyperparathyroidism:Bone painPersistent pruritusSoft tissue calcificationsTertiary hyperparathyroidismAllow 12 months to elapse following transplant as many cases will resolveThe 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.Nitric oxidePreviously 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 radicalsEffectsacts on guanylate cyclase leading to raised intracellular cGMP levels and therefore decreasing Ca2+ levelsvasodilation, mainly venodilationinhibits platelet aggregationClinical relevanceunderproduction of NO is implicated in hypertrophic pyloric stenosislack of NO is thought to promote atherosclerosisin sepsis increased levels of NO contribute to septic shockorganic 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 dysfunctionsMetabolic alkalosisCaused by a loss of hydrogen ions or a gain of bicarbonate. It is due mainly to problems of the kidney or gastrointestinal tractCausesvomiting / aspiration?(e.g. peptic ulcer leading to pyloric stenos, nasogastric suction)diureticsliquorice,?carbenoxolonehypokalaemiaprimary hyperaldosteronismCushing's syndromeBartter's syndromeMechanism of metabolic alkalosisactivation of renin-angiotensin II-aldosterone (RAA) system is a key factoraldosterone causes reabsorption of Na+?in exchange for H+ in the distal convoluted tubuleECF depletion (vomiting, diuretics) → Na+?and Cl- loss → activation of RAA system → raised aldosterone levelsin hypokalaemia, K+?shift from cells → ECF, alkalosis is caused by shift of H+ into cells to maintain neutralityVit B Thiamine (vitamin B1) deficiency is implicated in the development of Wernicke's encephalopathy and Korsakoff's syndrome (typically seen in alcohol dependence where there is usually concomitant poor nutritional intake). It plays no role in the absorption of iron from the gut.Riboflavin (vitamin B2) is a vitamin which works as a co-factor for a number of enzymes involved in energy release from carbohydrates and fats. Riboflavin supplementation has no impact on iron absorption from the GI tract.Niacin (vitamin B3/nicotinic acid) is important for assisting in DNA replication and repair as well as acting as a co-enzyme for the metabolism of carbohydrates and fats. Deficiency is known as pellagra (a triad of dermatitis, diarrhoea and dementia). Supplementation of niacin does not contribute to iron absorption.Iron metabolismAbsorptionupper small intestine especially the?duodenumabout 10% of dietary iron absorbedFe2+ (ferrous iron) much better absorbed than Fe3+ (ferric iron)absorption is regulated according to body's need↑↑ vitamin C,?gastric acid (↑↑ F+++ F++ in GIT ↑↑ absorption) ↓↓ proton pump inhibitors, Tetracycline, gastric Achlorhydria,?Tannin (found in tea)Distribution in bodyTotal body iron = 4gHaemoglobin = 70%Ferritin and haemosiderin = 25%Myoglobin = 4%Plasma iron = 0.1%Transport Carried in plasma as Fe3+ bound to TransferrinStorage Stored as ferritin in tissuesExcretion Lost via intestinal tract following desquamationCalcium metabolismThe two hormones which primarily control calcium metabolism are:Parathyroid hormoneincreases plasma calcium, decreases plasma phosphateincreases renal tubular reabsorption of calciumincreases osteoclastic activity (an indirect mechanism as osteoclasts don't have PTH receptors)increases renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferoldecreases renal phosphate reabsorption1, 25-dihydroxycholecalciferolincreases plasma calcium and plasma phosphateincreases renal tubular reabsorption and gut absorption of calciumincreases osteoclastic activityincreases renal phosphate reabsorptionOther hormones includecalcitonin: secreted from the parafollicular cells (C-cells) of the thyroid glandthyroxinegrowth hormoneHypercalcaemia: managementThe initial management of hypercalcaemia Rehydration with normal saline, typically 3-4 litres/day. Following rehydration Bisphosphonates may be used. take 2-3 days to work with maximal at 7 daysCalcitonin - quicker effect than bisphosphonatesSteroids SarcoidosisLoop diuretics "Furosemide" are sometimes used Patients who cannot tolerate aggressive fluid rehydration. Used with caution as they may worsen electrolyte derangement and volume depletion.Advice about maintaining good hydration (drinking 3-4 L of fluid per day) no contraindications (such as severe renal impairment or heart failure).Reassure that a low calcium diet is not necessary, as intestinal absorption of calcium is usually reduced.Avoid any drugs or vitamin supplements that could exacerbate the hypercalcaemia.Encourage mobilization where possible to avoid exacerbating the hypercalcaemia.Advise the person to report any symptoms of hypercalcaemia.Hungry bone syndromeUn uncommon entity but can occur after parathyroidectomy for long-standing hyperparathyroidism. The mechanism ↑↑ parathyroid hormone constant stimulus for osteoclast activity hypercalcaemic de-mineralizing the bones (X-ray changes very similar to metastatic lytic lesions if left untreated). Upon removal of the parathyroid adenoma the?hormone levels fall rapidly?(they have a very short half-life). The Osteoclast activity ↓↓ and the bones rapidly begin re-mineralisation - 'hungry bone syndrome'. systemic hypocalcaemia.HypocalcaemiaCausesvitamin D deficiency?(osteomalacia) W| ↓↓ Phosphate Chronic kidney diseaseHypoparathyroidism?(e.g. post thyroid/parathyroid surgery)pseudohypoparathyroidism?(target cells insensitive to PTH)Rhabdomyolysis?(initial stages)magnesium deficiency?(due to end organ PTH resistance)Massive blood transfusionAcute pancreatitisContamination of blood samples with EDTA may also give falsely low calcium levels.FeaturesAs extracellular calcium concentrations are important for muscle and nerve function features of hypocalcaemia as result of neuromuscular excitabilityTetany: muscle twitching, cramping and spasmPerioral paraesthesiaChronic depression, cataractsECG prolonged QT interval, Rare: Atrial fibrillation or torsade de pointesTrousseau's signcarpal spasm if the brachial artery occluded by inflating the blood pressure cuff and maintaining pressure above systolic+ Ve wrist flexion and fingers drawn togetherseen in around 95% of patients with hypocalcaemia and around 1% of normocalcaemic peoplemore sensitive and specific than Chvostek's signChvostek's signtapping over parotid causes facial muscles to twitchseen in around 70% of patients with hypocalcaemia and around 10% of normocalcaemic peopleInvestigationParathyroid hormone is the single most useful test in determining the cause of hypocalcaemiaManagementAcute management of severe hypocalcaemia is with intravenous replacement. Calcium gluconate, 10ml of 10% solution over 10 minutesintravenous calcium chloride is more likely to cause local irritationECG monitoring is recommendedfurther management depends on the underlying causeRicketsdescribes inadequately mineralised bone in developing and growing bones soft and easily deformed bones. It is usually due to vitamin D deficiency. In adults the equivalent condition is termed osteomalaciaPredisposing factorsDietary deficiency of calcium, for example in developing countries↑↑ breast feeding (especially where the mother is vitamin D deficient)unsupplemented cow's milk formulaLack of sunlightFeaturesDelayed Growth.in toddlers - genu varum (bow legs), in older children - genu valgum (knock knees)Widening of the wrist joints W small hand due to an excess of non-mineralized Osteoid at the growth plate.'Rickety Rosary' - swelling at the costochondral junctionkyphoscoliosisCraniotabes - soft skull bones in early lifeHarrison's sulcus↓↓ serum Ca - symptoms may results from hypocalcaemia↑↑ ALPManagementOral vitamin D.DD. Schmid type metaphyseal chondrodysplasia is a very rare AD disease that can present like rickets Bowed legs, Short stature and Widening of the growth plate.?HypokalaemiaPotassium and hydrogen can be thought of as competitors. Hyperkalaemia tends to be associated with acidosis because as potassium levels rise fewer hydrogen ions can enter the cellsHypokalaemia with AcidosisDiarrhoeaRenal tubular acidosisAcetazolamide (↓↓↓ Carbonic Anhydrase enzyme ↓↓ HCO3)Partially treated diabetic ketoacidosisHypokalaemia with AlkalosisVomitingThiazide?and loop diureticsCushing's syndromeConn's syndrome (primary hyperaldosteronism)Magnesium deficiency? hypokalaemia. (normalizing the potassium level may be difficult until the magnesium deficiency has been corrected)Hypokalaemia and hypertensionHypokalaemia with hypertension (Endocinological causes)Cushing's syndromeConn's syndrome (1ry Hyperaldosteronism)Renal Artery Stenosis.Liddle's syndrome (Autosomal Dominant, Abnormal ↑↑ Na channels in the Kidney Reabsorbition of Na HTN and ↓↓ K)11-beta hydroxylase (--) DD. (21-hydroxylase (- -) 90% of congenital adrenal hyperplasia cases, is not associated with hypertension)Carbenoxolone (anti-ulcer drug) and liquorice excess can potentially cause hypokalaemia associated with hypertensionCushing's and Conn's would be associated with a high aldosterone and a low renin, renal artery stenosis would be associated with a high renin and aldosterone, Liddle's is associated with a low renin and aldosterone.Hypokalaemia without hypertensionDiureticsGI loss (e.g.?Diarrhoea, vomiting)Renal tubular acidosis?(Type 1 and 2) Type 4 renal tubular acidosis is associated with hyperkalaemiaBartter's syndrome Autosomal recessive, ↓↓↓ chloride absorption at the Na+?K+?2Cl- cotransporter in the ascending loop of Henle Gitelman syndrome ↓↓↓ Thiazide-sensitive Na+?Cl- transporter in the distal convoluted tubule hypokalaemia and normotension.HyperkalaemiaPlasma potassium levels are regulated by a number of factorsAldosteroneAcid-base balance H+ and K+ compete for exchange with Na+ across cell membranes and in the distal tubuleInsulin levels ECG changes tall-tented T waves, small P waves, widened QRS leading to a sinusoidal pattern and AsystoleCauses of hyperkalaemia:Acute kidney injuryDrugs Potassium sparing diuretics,?ACE inhibitors,?Angiotensin 2 receptor blockers,?spironolactone,?CiclosporinUnfractionated and low molecular weight Heparin (--) Aldosterone secretion.Beta-blockers interfere with potassium transport into cells and can potentially cause hyperkalaemia in renal failure , beta-agonists (Salbutamol) emergency treatmentMetabolic acidosisAddison's diseaseRhabdomyolysisMassive blood transfusionFoods that are high in potassium:Salt substitutes (Contain potassium rather than sodium)Bananas, Oranges, kiwi fruit, Avocado, Spinach, TomatoesPseudohyperkalaemiaa rise in serum K+ due to excessive leakage of potassium from cells, during or after blood is taken. It is a laboratory artefact and does not represent the true serum potassium concentration. The majority of potassium is intracellular and thus leakage from cells can significantly impact serum levels. In this case the potassium is released as the large numbers of platelets aggregate and degranulate.Causes Haemolysis during venepuncture (excessive vacuum of blood drawing or too fine a needle gauge)Delay in the processing of the blood specimenAbnormally ↑↑↑ (platelets, leukocytes, or erythrocytes (such as myeloproliferative disorders))Familial causesMeasuring an arterial blood gas give a quick and accurate measure of true serum potassium. For a lab sample (using lithium heparin tube) requesting a slow spin (on the lab centrifuge) and walking the sample to the lab should ensure an accurate result.HyponatraemiaCaused by water excess or sodium depletion. Causes of pseudohyponatraemia include?hyperlipidaemia?(increase in serum volume) or a taking blood from a drip arm. Urinary sodium and osmolarity levels aid making a diagnosisUrinary sodium > 20 mmol/lSodium depletion, renal loss (patient often hypovolaemic)diuretics:?thiazides, loop diureticsAddison's diseaseDiuretic stage of renal failure.Patient often EuvolaemicSIADH?(urine osmolality > 500 mmol/kg) ?paired osmolalities exclude SIADH and diabetes insipidushypothyroidismUrinary sodium < 20 mmol/lExtra-renal loss of Na Diarrhoea,?vomiting, sweatingburns,?adenoma of rectumWater excess (patient often Hypervolaemic and Oedematous)secondary hyperaldosteronism:?heart failure,?liver cirrhosisNephrotic syndromeIV dextrosepsychogenic polydipsiaManagement of hyponatremia is primarily based around 2 parameters:Acute hyponatremiaDevelops over a period of less than 48 hours excessive fluid intake, either parenteral or oral. Common examples include post-operative parenteral fluids and athletes.Symptoms are usually severe When hyponatraemia develops over a short duration brain cannot adapt is cerebral oedemaChronic hyponatremiaIf the duration is unknown or it is present for more than 48 hours.Symptoms are usually less severe than acute.Mild hyponatremiaModerate hyponatremiaSevere hyponatremiaSerum Na+130-134 mmol/l120-129 mmol/lLess than 120 mmol/lSymptomsNon-specific symptoms (headache, lethargy, nausea, vomiting, dizziness, confusion, and muscle crampsSame as mildSeizures, coma, and respiratory arrestManagementFluid restriction (less than 800 mL/day)Loop diureticsHypertonic saline (3%) in first 3-4 hours to increase Na+ >120 mmol/lRest is the same as mildBolus of hypertonic saline until symptom resolutionWith or without conivaptanFluids intake should be less than urine output in the following patients:Oedematous states like heart failure and cirrhosisSIADHRenal failurePsychogenic polydipsiaHypovolaemic hyponatraemiaHypovolaemic hyponatraemiarehydration with sodium chloride 0.9% or a balanced crystalloid (Hartmann's)avoid rapid correction of sodium in order to reduce the risk of osmotic complications such as central pontine myelinolysisEuvolaemic hyponatraemiacheck urine and serum osmolality. Does the patient meet the criteria for SIADH?treat the underlying cause where possible in SIADHfluid restriction (500-750mls/day)monitor fluid balance and perform daily weightsconsider demeclocycline or tolvaptan (under specialist supervision). Both inhibit the action of antidiuretic hormone.Hypervolaemic hyponatraemiafluid and salt restrictionconsider diureticstreat the underlying cause (e.g. cardiac failure)Vasopressin/ADH receptor antagonists (conivaptan)Act on V1(vasoconstriction) and V2 receptors (selective water dieresis W sparing the electrolytes.) They should be avoided in patients who have hypovolemic hyponatremia.They can stimulate the?thirst?receptors leading to the desire to drink free water. They can be?hepatotoxic?in patients with underlying liver disease.?Decompressive craniotomy would help alleviate ↑↑ ICP due to cerebral oedema is not an appropriate first line treatmentComplications:Osmotic demyelination syndrome (central pontine myelinolysis)?can occur due to over-correction of severe hyponatremia. To avoid this, Na+ levels are only raised by 4 to 6 mmol/l in a 24-hour period. Symptoms usually occur after 2 days and are usually irreversible. Dysarthria, dysphagia, paraparesis or quadriparesis, seizures, confusion, and coma. Patients are awake but are unable to move or verbally communicate, also called?'Locked-in syndrome’SIADH: causesHyponatraemia secondary to the dilutional effects of excessive water retention Causes of SIADHCategoryExamplesMalignancysmall cell lung cancer, pancreas, prostateNeurologicalstrokeSubarachnoid haemorrhageSubdural haemorrhagemeningitis/encephalitis/abscessInfectionsTuberculosisPneumoniaDrugsSulfonylureas (Reported with glimepiride and glipizide)SSRIs, TCACarbamazepineVincristineCyclophosphamideOther causesPositive end-expiratory pressure (PEEP)PorphyriasManagementCorrection must be done slowly to avoid precipitating central pontine myelinolysisFluid restriction is the 1st Line Giving oral or IV salt would not treat his hyponatraemia as it is caused by the dilutionary affect of increased ADH.Demeclocycline ↓↓ the responsiveness of the collecting tubule cells to ADHADH (vasopressin) receptor antagonists (Vasopressin Antagonist) have been developed.Lithium can cause diabetes insipidus but this is associated with a ↑↑ Na. Only tends to ↑↑ Antidiuretic hormone levels following a severe overdosageHypophosphataemiaCausesalcohol excessacute liver failurediabetic ketoacidosisrefeeding syndromeprimary hyperparathyroidismosteomalaciaConsequencesred blood cell haemolysiswhite blood cell and platelet dysfunctionmuscle weakness and rhabdomyolysiscentral nervous system dysfunctionHyperuricaemiaMay be seen secondary to either increased cell turnover or reduced renal excretion of uric acid may be asymptomatic patients who have not attacks of goutMay be associated with hyperlipidaemia and hypertension.(IF routine or insurance purposes if hyperuricaemia check for lipid &Bl. Pressure) It may also be seen in conjunction with the Metabolic SyndromeIncreased synthesisLesch-Nyhan diseaseMyeloproliferative disordersDiet rich in purinesExercisePsoriasisCytotoxicsDecreased excretionDrugs Low-dose aspirin, Diuretics, PyrazinamidePre-eclampsiaAlcoholRenal failureLeadGastrointestinal hormoneSourceStimulusActionsGastrinG cells in antrum of the stomachDistension of stomach, vagus nerves (mediated by gastrin-releasing peptide), luminal peptides/amino acidsInhibited by: low antral pH, somatostatinIncrease HCL,?pepsinogen?and IF secretion,?increases gastric motility,?stimulates parietal cell maturationCCKI cells in upper small intestinePartially digested proteins and triglyceridesIncreases secretion of enzyme-rich fluid from pancreas?Contraction of gallbladder?and relaxation of sphincter of Oddi.↓↓ gastric emptying (relaxation of the stomach) trophic effect on pancreatic acinar cells, induces satiety (vagal stimulation).SecretinS cells in upper small intestineAcidic chyme, fatty acidsIncreases secretion of bicarbonate-rich fluid from pancreas and hepatic duct cells,?decreases gastric acid secretion, trophic effect on pancreatic acinar cellsVIPSmall intestine, pancreasNeuralStimulates secretion by pancreas and intestines,?inhibits acid secretionSomatostatinD cells in the pancreas & stomachFat, bile salts and glucose in the intestinal lumenDecreases acid?and?pepsinsecretion, decreases gastrin secretion,?decreases pancreatic enzyme secretion, decreases insulin and glucagon secretioninhibits trophic effects of gastrin, stimulates gastric mucous productionK and L cells secrete gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) respectively. These are incretins which rise in a response to glucose and modulate the metabolism. Certain medications are known as incretin mimetics such as the GLP-1 agonists which enhance the effects.ECL cells (also known as enterochromaffin like cells) are found in the stomach and secrete histamine which increases acid secretion to help with digestion.?Gastrinoma secretes excessive gastrin which causes increased HCL production, resulting in peptic ulcers. Gastrin is usually produced by the G cells in the antrum of the stomach. increase HCL production and gastrointestinal motility.?pancreatic insufficiency likely secondary to chronic pancreatitis, given the weight loss and steatorrhoea as well as the history of alcohol misuse. Secretin increases the secretion of bicarbonate-rich fluid from pancreas and hepatic duct cells and it can be used as a test for pancreatic function (secretin stimulation test). Somatostatinoma is a somatostatin-producing tumour arising from the D cells in the pancreas and stomach. Somatostatin is produced by D cells in the pancreas & stomach. The newly-diagnosed diabetes is likely due to the excessive secretion of somatostatin, as somatostatin inhibits the release of insulin and glucagon.Growth hormoneAnabolic hormone secreted by the Somatotroph cells of the Anterior lobe of the pituitary gland. Growth hormone is also responsible for changes in protein, lipid, and carbohydrate metabolismNotesFurther detailSourceAnterior pituitary:?Somatotrophs 50% of the cells of the anterior pituitary glandFunctionPostnatal growth and development↑↑↑ ( lipolysis and gluconeogenesis)Binds to transmembrane receptor for growth factor .Binding of GH to the receptor leads to receptor dimerizationActs directly on tissues (++ division and multiplication?Chondrocytes, Osteoblasts)Acts indirectly via insulin-like growth factor 1 (IGF-1) (primarily secreted by the liver)Regulation↑↑↑ secretion?byGrowth Hormone Releasing Hormone (GHRH) " released in pulses by the hypothalamus"Fasting.Exercise.Sleep (particularly delta sleep)↓↓↓ secretion by GlucoseSomatostatin (itself increased by somatomedins, circulating insulin-like growth factors " IGF-1 and IGF-2"Conditions associated with GH disorders↑↑ GH: Acromegaly↓↓ GH: resulting in short statureIn autosomal dominant diseases:Both homozygotes and heterozygotes manifest disease (there is no carrier state)Both males and females affectedOnly affected individuals can pass on disease, except:Spontaneous mutation new mutation in one of gametes (80% of individuals with achondroplasia have unaffected parents)disease is passed on to 50% of childrennormally appears in every generation (although see below)Non-penetrance lack of clinical signs and symptoms (normal phenotype) despite abnormal gene.(40% otosclerosis)risk remains same for each successive pregnancyAD ConditiondAR ConditionAchondroplasia fibroblast growth factor receptor 3Acute intermittent porphyriaAdult polycystic diseaseAntithrombin III deficiencyEhlers-Danlos syndromeFamilial adenomatous polyposisHereditary non-polyposis colorectal carcinomaHereditary haemorrhagic telangiectasiaHereditary spherocytosisHuntington's diseaseHyperlipidaemia type IIHypokalaemic periodic paralysisMalignant hyperthermiaMarfan's syndromesMyotonic dystrophyNeurofibromatosisNoonan syndromeOsteogenesis imperfectaPeutz-Jeghers syndrome ?noncancerous hamartomatous polyps GIT intestines) & ↑↑ developing cancer.RetinoblastomaRomano-Ward syndrome (Congenetal long QT, No deafness) Tuberous sclerosisVon Hippel-Lindau syndrome ?visceral cysts and?benign tumors?, Chromosome 3Von Willebrand's disease Type 3? (most severe form) is AR trait. Around 80% of patients have Type 1 diseaseAlbinismAtaxic telangiectasiaCongenital adrenal hyperplasiaCystic fibrosisCystinuriaFamilial Mediterranean FeverFanconi anaemiaFriedreich's ataxiaGilbert's syndrome debate (AD)Glycogen storage diseaseHaemochromatosisHomocystinuriaLipid storage disease: Tay-Sach's, Gaucher, Niemann-PickMucopolysaccharidoses: Hurler'sPhenylketonuria (PKU)Sickle cell anaemiaThalassaemiasWilson's diseaseAutosomal recessive 'metabolic' Except: Hunter's and G6PD X-linked recessivehyperlipidaemia type II?and?hypokalaemic periodic paralysis? ADAutosomal dominant 'structural', Except:Ataxia telangiectasia and Friedreich's ataxia ARGenetic Terms Penetrance and expressivityNot all patients with the same gene mutation (i.e. genotype) exhibit the same degree of observable characteristics (i.e. phenotype). This phenomenon is described using two terms - penetrance and expressivity.?Penetrance describes the proportion of a population of individuals who carry a disease-causing allele who express the related disease phenotype.?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 genesEnvironmental factorsAllelic variationPenetrancedescribes 'how likely' it is that a condition will develop (examples of conditions with incomplete penetrance include retinoblastoma and Huntington's diseasein contrast, achondroplasia shows 100%, or complete, penetrance?If the genotype is present but the phenotype is not observed, the trait shows incomplete penetrance. This is one explanation why monogenic disorders, such as osteogenesis imperfecta, do not always have predictable patterns of inheritance in the population.Expressivitydescribes the 'severity' of the phenotype examines the statistical variability among a population of genotypesa condition with a high level of expressivity is neurofibromatosisAneuploidyis the presence of an abnormal number of chromosomes in the cell, for example, an extra chromosome in Down syndrome (trisomy 21).Anticipation refers to the increasing severity of an inherited disorder in subsequent generations, such as demonstrated in Huntington's disease.X-inactivation also known as lyonization, is the process by which one of the copies of the X-chromosome is inactivated in female mammals.Inherited metabolic disordersGlycogen storage diseaseDisorderDeficient enzymeNotesVon Gierke's disease (type I)Glucose-6-phosphataseHepatic glycogen accumulation. Key features ?hypoglycaemia,?lactic acidosis, hepatomegalyPompe's disease (type II)Lysosomal alpha-1,4-glucosidaseCardiac, hepatic and muscle glycogen accumulation. Key features include?cardiomegalyCori disease (type III)Alpha-1,6-glucosidase (debranching enzyme)Hepatic, cardiac glycogen accumulation. Key features include?muscle hypotoniaMcArdle's disease (type V)Glycogen phosphorylase (myophosphorylase)Skeletal muscle glycogen accumulation. Key features include?myalgia,?myoglobinuria with exerciseLysosomal storage diseaseDisorderDefectNotesGaucher's diseaseBeta-glucocerebrosidaseMost common lipid storage disorder Autosomal recessive accumulation of glucocerebrosidase in the brain, liver and spleen. Key features Massive ?hepatosplenomegaly,?aseptic necrosis of the femurTay-Sachs diseaseHexosaminidase AAccumulation of GM2?ganglioside within lysosomes. Key features ?developmental delay (motor affection,…)cherry red spot on the macula Visual problem liver and spleen normal size(cf.?Niemann-Pick)Niemann-Pick diseaseSphingomyelinaseKey features ?hepatosplenomegaly, cherry red spot on the maculaFabry diseaseAlpha-galactosidase-AAccumulation of ceramide trihexoside in the lysosomes. 2nd commonest after Gaucher's diseaseKey features ?angiokeratomas,?peripheral neuropathy of extemeties, renal failureKrabbe's diseaseGalactocerebrosidaseKey features ?peripheral neuropathy,?optic atrophy,?globoid cellsMetachromatic leukodystrophyArylsulfatase ADemyelination of the central and peripheral nervous systemMucopolysaccharidosesDisorderDefectNotesHurler syndrome (type I)Alpha-1-iduronidaseAccumulation of glycosaminoglycans (heparan and dermatan sulfate). Key features include gargoylism, hepatosplenomegaly,?corneal cloudingHunter syndrome (type II)Iduronate sulfataseAccumulation of glycosaminoglycans (heparan and dermatan sulfate). Key features include coarse facial features, behavioural problems/learning difficulties short stature, no corneal cloudingAlkaptonuria Autosomal recessive disorder of phenylalanine and tyrosine metabolism caused by ↓↓↓enzyme homogentisic dioxygenase (HGD) ↑↑toxic homogentisic acid polymerises and forms a pigment The kidneys filter the homogentisic acid (hence black urine) but eventually it accumulates in cartilage and other connective tissue (ochronosis). Alkaptonuria is generally a benign and often asymptomatic condition. Possible features include:Ear brown/bluish pigment of the ear cartilageEye Pigmented scleraHeart Cardiac valve involvement and coronary calcificationJoints Arthropathy, intervertebral disc calcification may result in back painKidneyUrine turns black if left exposed to the airRenal stonesTreatmenthigh-dose vitamin Cdietary restriction of phenylalanine and tyrosineHomocystinuriarare autosomal recessive disease caused by a?deficiency of cystathionine beta synthase.( Down's syndrome have an excess of cystathionine beta synthase)This results in severe elevations in plasma and urine homocysteine concentrations.Featuresoften patients have fine, fair hairmusculoskeletal: may be similar to Marfan's - arachnodactyly etcneurological patients may have?learning difficulties, seizuresocular: downwards (inferonasal) dislocation of lensincreased risk of arterial and venous thromboembolismalso malar flush, livedo reticularisCystinuria not homocystinuria is associated with recurrent renal stonesDiagnosis is made by the cyanide-nitroprusside test, which is also positive in cystinuria.Treatment is?vitamin B6 (pyridoxine)?supplements.Cystic fibrosisAutosomal recessive defect in the cystic fibrosis transmembrane conductance regulator gene (CFTR) (codes a cAMP-regulated chloride channel)Causing increased viscosity of secretions (lungs and pancreas)80% of CF cases are due to delta F508 on the long arm of chromosome 7. 1 per 2500 births, and the carrier rate is 1 in 25Organisms which may colonise CF patientsStaphylococcus aureusPseudomonas aeruginosaBurkholderia cepacia* previously known as?Pseudomonas cepaciaAspergillusPresenting featuresneonatal period (around 20%):?meconium ileus, less commonly prolonged jaundicerecurrent chest infections?(40%)malabsorption (30%): steatorrhoea, failure to thriveother features (10%): liver diseaseWhilst many patients are picked up during newborn screening programmes or early childhood, around 5% of patients are diagnosed after the age of 18 years.Other features of cystic fibrosisshort staturediabetes mellitusdelayed pubertyrectal prolapse?(due to bulky stools)nasal polypsmale infertility, female subfertilityManagement of cystic fibrosis (CF) involves a multidisciplinary approachregular (at least twice daily) chest physiotherapy and postural drainage. Parents are usually taught to do this. Deep breathing exercises are also usefulhigh calorie diet, including high fat intake*patients with CF minimise contact with each other?to prevent cross infection with?Burkholderia cepacia?complex and?Pseudomonas aeruginosavitamin supplementationpancreatic enzyme supplements taken with each mealsheart and lung transplantLumacaftor/Ivacaftor (Orkambi)For patients who are?homozygous for the delta F508 mutationlumacaftor ↑↑ number of CFTR proteins that are transported to the cell surfaceivacaftor is a potentiator of CFTR already at the cell surface ↑↑probability that the defective channel will be open and allow chloride ions to pass through the channel poreGalactosaemiaAutosomal recessive condition caused by the absence of galactose-1-phosphate uridyl transferase intracellular accumulation of galactose-1-phosphateFeaturesjaundicefailure to thrivehepatomegalycataractshypoglycaemia after exposure to galactoseFanconi syndromeDiagnosisurine reducing substancesManagement is with a galactose free dietPhenylketonuriaAutosomal Recessive disorder of phenylalanine metabolism (- -) in phenylalanine hydroxylase (enzyme converts Phenylalanine Tyrosine).In a small cases (- -) Tetrahydrobiopterin-deficient Cofactor (secondary to defective dihydrobiopterin reductase). The gene for phenylalanine hydroxylase is located on chromosome 12. The incidence of PKU is around 1 in 10,000 live births.↑↑↑ Phenylalanine learning difficulties and seizures. FeaturesPresents by 6 months developmental delayChild classically has fair hair and blue eyesLearning difficultiesSeizures typically infantile spasmsEczema'Musty' odour to urine and sweat secondary to phenylacetate, a phenylketoneDiagnosisGuthrie test the 'heel-prick' test done at 5-9 days of life Looks for other biochemical disorders such as hypothyroidismHyperphenylalaninaemiaPhenylpyruvic acid in urineManagementpoor evidence to strict diet prevents learning disabilitiesdietary restrictions are however important during pregnancy as genetically normal fetuses may be affected by high maternal phenylalanine levelsPrader-Willi syndromeAn 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 gene deleted from father (Paternal)Angelman syndrome gene deleted from mother (Maternal)Prader-Willi syndrome 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)Paternal uniparental disomy of chromosome 15FeaturesHypotonia during infancyDysmorphic featuresShort statureHypogonadism and infertilityLearning difficultiesChildhood obesityBehavioural problems in adolescenceFragile X syndromeFragile X syndrome is a trinucleotide repeat disorder.Features in maleslearning difficultieslarge low set ears, long thin face, high arched palatemacroorchidismhypotoniaautism is more commonmitral valve prolapseFeatures in females (who have one fragile chromosome and one normal X chromosome) range from normal to mildDiagnosiscan be made antenatally by chorionic villus sampling or amniocentesisanalysis of the number of CGG repeats using restriction endonuclease digestion and Southern blot analysisFabry's disease X-linked recessive inherited ↓↓ alpha-galactosidase A enzyme abnormal deposits of a fatty substance (globotriaosylceramide) in blood vessel walls. narrowing of blood vessels, symptoms and signs which include:Limb painRaynaud's diseaseSensory neuropathy burning pain/paraesthesia in childhoodCardiac arrhythmias, Cardiomyopathy, early cardiovascular disease.Cerebrovascular: TIAs/strokesNephrotic syndrome proteinuriaDermatological manifestation AnhidrosisAngiokeratomas, cornea verticillataLens opacitiesManagement: Enzyme replacement therapy with agalsidase alfaDD CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is an inherited condition which presents with a history of migraines and multiple strokes. It is not associated with angiokeratomas or corneal whirls. MELAS or mitochondrial encephalopathy with lactic acidosis and stroke symptoms is weakened by the absence of lactic acidosis in the stem. There is no evidence of connective tissue disease in the stem to suggest primary CNS angiitisAchondroplasiaautosomal dominant?disorder associated with short stature. It is caused by a mutation in the (FGFR-3) gene. This results in abnormal cartilage giving rise to:short limbs (rhizomelia) with shortened fingers (brachydactyly)large head with frontal bossing and narrow foramen magnummidface hypoplasia with a flattened nasal bridge'trident' handslumbar lordosisIn 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.?TreatmentThere is no specific therapy. However, some individuals benefit from limb lengthening procedures. These usually involve application of Ilizarov frames and targeted bone fractures. A clearly defined need and end point is the cornerstone of achieving success with such procedures.Noonan syndromeAD condition associated with a normal karyotype 'male Turner's'.caused by a defect in a gene on chromosome 12Features similar to Turner's syndrome webbed neckwidely-spaced nipplesshort staturepectus carinatum and excavatum) characteristic clinical signs may also be seen:cardiac: pulmonary valve stenosisptosistriangular-shaped facelow-set earscoagulation problems: factor XI deficiencyDiGeorge syndromeA primary immunodeficiency disorder caused by?T-cell deficiency and dysfunction microdeletion syndrome (deletion of a section of chromosome 22).?Autosomal dominant velocardiofacial syndrome and 22q11.2 deletion syndrome.Features can be remembered with the mnemonic CATCH22:C ?Cardiac abnormalities Tetralogy of Fallot and truncus arteriosus.A Abnormal facies small jaw and mouth, low set ears and long faceT Thymic aplasia T-lymphocyte deficiency/dysfunction recurrent infection.C ?Cleft palate Aspiration Pneumonia. H ?Hypocalcaemia/ hypoparathyroidism seizure.22 Caused by chromosome 22 deletionDown's syndrome (Trisomy 21)Epidemiology and geneticsRisk increasing maternal ageAge (years)Risk201 in 1,500301 in 800 (900)351 in 270 (300)401 in 100451 in 50 or greaterCytogeneticsMode% of casesRisk of recurrenceNondisjunction94% Commonest1 in 100 if under mother < 35 yearsRobertsonian translocation(usually onto 14)5% (1 in 20)high risk of recurrence if either parent is a carrier of the translocation.10-15% if mother is translocation carrier2.5% if father is translocation carrierMosaicism presence of two genetically different populations of cells in the body1%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 higherClinical featuresface:?upslanting palpebral fissures,?epicanthic folds,?Brushfield spots in iris, protruding tongue,?small low-set ears, round/flat faceflat occiputHand single palmar crease,?pronounced 'sandal gap' between big and first toeHypotoniaHirschsprung's diseaseDuodenal atresiaCardiac complicationsEndocardial cushion defect?(most common, 40%, also known as atrioventricular septal canal defects)VSD?(c. 30%)Secundum atrial septal defect?(c. 10%)Tetralogy of Fallot?(c. 5%)Isolated patent ductus arteriosus?(c. 5%)Later complicationsAtlantoaxial instabilityAlzheimer's diseaselearning difficultiesShort statureHypothyroidismRepeated respiratory infections?(+hearing impairment from glue ear)SubfertilityMales are almost always infertile ↓↓spermatogenesis. Females are usually subfertile rather than infertility and have an increased incidence of problems with pregnancy and labourAcute lymphoblastic leukaemiaTriple screen blood test from the mother or Amniocentesis?Genetic imprinting is unlikely to be involved in Down's syndrome. It is due to the differential expression of genes depending on parental origin and occurs in reciprocally inherited disorders, such as Prader-Willi syndrome and Angelman syndrome.Ebstein's anomalyA congenital heart defect low insertion of the tricuspid valve large atrium and small ventricle. 'atrialisation' of the right ventricle".AssociationsTricuspid incompetence (pan-systolic murmur, giant V waves in JVP)Wolff-Parkinson White syndromeEbstein's anomaly may be caused by exposure to lithium in-uteroFamilial hypercholesterolaemiaAutosomal dominant? affect around?1 in 500?people. Mutations in the gene encodes LDL-receptor protein.↑↑↑ levels of LDL-cholesterol if untreated, may cause early cardiovascular disease (CVD). The presence of tendon xanthomata and cholesterol levels meet the diagnostic criteria for familial hypercholesterolaemia.(Heterozygos) Homozygous familial hypercholesterolaemia is exceedingly rare - most patients die in their teenage years from a myocardial infarction.Case findingSuspect FH as a possible diagnosis in adults with:Total cholesterol level > 7.5 mmol/l and/orPersonal or family history of premature coronary heart disease (< 60 years) in an index individual or first-degree relative)Children of affected parents:if One parent is affected by familial hypercholesterolaemia, testing in children by age 10if Both parents are affected by familial hypercholesterolaemia, testing in children by age 5Clinical diagnosis is now based on the?Simon Broome criteria:Adults total cholesterol (TC) > 7.5 mmol/l and LDL-C > 4.9 mmol/l Children TC > 6.7 mmol/l and LDL-C > 4.0 mmol/l+Definite FH Tendon xanthoma in patients or 1st or 2nd degree relatives or DNA-based evidence of FHPossible FH Family history of MI ( < 50 years in 2nd degree relative, < 60 in 1st degree ) or a family history of ↑↑ cholesterol levelsManagementUse of CVD risk estimation using standard tables is not appropriate in FH as they do not accurately reflect the risk of CVDReferral to a specialist lipid clinic is usually required↑↑ dose statins?are usually used first-lineinhibit HMG-CoA reductase ↓↓ the mevalonate pathway reduced cholesterol levels.?First-degree relatives 50% chance of having the disorder offered screening. Statins should be discontinued in women 3 months before conception due to the risk of congenital defects↑↑ LDL despite ↑↑ dose Atorvastatin TTT with Evolocumab prevents PCSK9-mediated LDL receptor degradationUsed under certain conditions only dosage is 140mg every 2 weeks and LDL cholesterol is persistently > 3.5 mmol/l.Evolocumab binds selectively to PCSK9 prevents circulating PCSK9 from binding to the low-density lipoprotein receptor (LDLR) on the liver cell surface preventing PCSK9-mediated LDLR degradation. Increasing liver LDLR levels ↓↓ in serum LDL-cholesterol. ↓↓ LDL cholesterol > 50% in 85% of patients who are treated.Other AgentsFibratesManagement of hyperlipidaemia, particularly raised triglycerides.Fibrates work through?activating PPAR alpha receptors? ↑↑ lipoprotein lipase (LPL) activity ↓↓ triglyceride levels ↑↑(HDL) synthesis.Adverse effects:GIT side-effects are common↑↑ risk of?thromboembolismNiacin or nicotinic acid (vitamin B3) inhibits hepatic diacylglycerol acyltransferase-2 which is required for triglyceride synthesisBile acid sequestrants are a class of drugs which work by binding to bile salts reducing reabsorption of bile acids.?Apolipoprotein E is a protein involved in the metabolism of fats it specifically removes chylomicron remnants.Ezetimibe ↓↓ intestinal absorption of cholesterol.secondary causesCauses of predominantly hypertriglyceridaemiaD.M (types 1 and 2)ObesityAlcoholChronic renal failureDrugsThiazides, Non-selective beta-blockers, Unopposed oestrogenliver diseaseCauses of predominantly hypercholesterolaemiaNephrotic syndromeCholestasisHypothyroidismCardiovascular risk assessment Identify people > 40 years ↑↑ risk of IHD defined as a 10-year risk of?10%?or greater.?QRISK2?CVD risk assessment tool for patients aged <= 84 years. Patients >= 85 years are at high risk of CVD due to their age. QRISK2 should not be used in the following situations as there are more specific guidelines for these patient groups:Type 1 diabeticspatients with ↓↓ glomerular filtration rate (eGFR) < 60 ml/min and/or Albuminuriapatients with a history of Familial hyperlipidaemiaQRISK2 may underestimate CVD risk in this groups:people treated for HIVpeople with serious mental health problemspeople taking medicines cause dyslipidaemia such as antipsychotics, corticosteroids or immunosuppressant drugspeople with autoimmune disorders/systemic inflammatory disorders SLEMeasuring lipid levelsWhen measuring lipids both the total cholesterol and HDL should be checking to provide the most accurate risk of CVD. A full lipid profile should also be checked (i.e. including triglycerides) before starting a statin. The samples does not need to be fasting.In the vast majority of patient the cholesterol measurements will be fed into the QRISK2 tool. If however the patient's cholesterol is very high we should consider familial hyperlipidaemia. NICE recommend the following that we should consider the possibility of familial hypercholesterolaemia and investigate further if the total cholesterol concentration is > 7.5 mmol/l and there is a family history of premature coronary heart disease. They also recommend referring people with a total cholesterol > 9.0 mmol/l or a non-HDL cholesterol (i.e. LDL) of > 7.5 mmol/l even in the absence of a first-degree family history of premature coronary heart disease.Interpreting the QRISK2 resultProbably the headline changes in the 2014 guidelines was the new, lower cut-off of 10-year CVD risk cut-off of 10%.?'formal' assessment of CVD risk using age, gender and smoking historylipid profile to further inform the QRISK2 scoreNICE now recommend we offer a statin to people with a QRISK2 10-year risk of >= 10%Lifestyle factors are of course important and NICE recommend that we give patients the option of having their CVD risk reassessed after a period of time before starting a statin.Atorvastatin 20mg should be offered first-line.Special situationsType 1 diabetes mellitusNICE recommend that we 'consider statin treatment for the primary prevention of CVD in all adults with type 1 diabetes'atorvastatin 20 mg should be offered if type 1 diabetics who are:older than 40 years, orhave had diabetes for more than 10 years orhave established nephropathy orhave other CVD risk factorsChronic kidney disease (CKD)atorvastatin 20mg should be offered to patients with CKDincrease the dose if a greater than 40% reduction in non-HDL cholesterol is not achieved and the eGFR > 30 ml/min. If the eGFR is < 30 ml/min a renal specialist should be consulted before increasing the doseSecondary preventionAll patients with CVD should be taking a statin in the absence of any contraindication.Atorvastatin 80mg should be offered first-line.Follow-up of people started on statinsThus, an isolated hypertriglyceridaemia in the presence of significant cardiovascular risk factors, in a patient not currently on a statin, should be managed with the introduction of a statin.While fibrates are well known to be effective against hypertriglyceridaemias, his risk factor burden is enough that a statin (which is also functional on triglyceride levels, not just LDLs) is the first choiceNICE recommend we follow-up patients at 3 monthsrepeat a full lipid profileif the non-HDL cholesterol has not fallen by at least 40% concordance and lifestyle changes should be discussed with the patientNICE recommend we consider increasing the dose of atorvastatin up to 80mgLifestyle modificationsThese are in many ways predictable but NICE make a number of specific points:Cardioprotective diettotal fat intake should be <= 30% of total energy intakesaturated fats should be <= 7% of total energy intakeintake of dietary cholesterol should be < 300 mg/daysaturated fats should be replaced by monounsaturated and polyunsaturated fats where possiblereplace saturated and monounsaturated fat intake with olive oil, rapeseed oil or spreads based on these oilschoose wholegrain varieties of starchy foodreduce their intake of sugar and food products containing refined sugars including fructoseeat at least 5 portions of fruit and vegetables per dayeat at least 2 portions of fish per week, including a portion of oily fisheat at least 4 to 5 portions of unsalted nuts, seeds and legumes per weekPhysical activityeach week aim for at least 150 minutes of moderate intensity aerobic activity or 75 minutes of vigorous intensity aerobic activity or a mix of moderate and vigorous aerobic activitydo musclestrengthening activities on 2 or more days a week that work all major muscle groups (legs, hips, back, abdomen, chest, shoulders and arms) in line with national guidance for the general populationWeight managementno specific advice is given, overweight patients should be managed in keeping with relevant NICE guidanceAlcohol intakeagain no specific advice, other than the general recommendation that males drink no more than 3-4 units/day and females no more than 2-3 units/daySmoking cessationsmokers should be encouraged to quitMitochondrial diseasesWhilst 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 RNAMitochondrial inheritance has the following characteristics:inheritance is only via the maternal line as the sperm contributes no cytoplasm to the zygotenone of the children of an affected male will inherit the disease As the sperm contributes no cytoplasm to the zygoteall of the children of an affected female will inherit the diseasegenerally, encode rare neurological diseasespoor genotype:phenotype correlation - within a tissue or cell there can be different mitochondrial populations - this is known as heteroplasmyA proximal myopathy may also be evident, and elevation of serum lactate and pyruvate is frequently seen, as is the case with many mitochondrial conditions.?Histologymuscle biopsy PCR and DNA analysis classically shows 'red, ragged fibres' due to increased number of mitochondriaExamples include:Leber's optic atrophy Rapid onset visual ↓↓ loss , peripapillary telangiectasia (On fundoscopy)It affects males more than females for unknown reasonsMELAS syndromemitochondrial encephalomyopathy lactic acidosis and stroke-like episodescharacterised by short stature, recurrent migraines, vomiting, muscle weakness, seizures and then development of multiple strokes at an early age (normally before 40 for diagnosis to be considered) along with progressive dementia.MERRF syndromemyoclonus epilepsy with ragged-red fibrescognitive impairment developing after a period of normal development, seizures, myoclonic jerks, Wolff-Parkinson-White syndrome and worsening vision (consistent with optic atrophy).Kearns-Sayre syndromeonset in patients < 20 years old, characterised by ptosis, external ophthalmoplegia in the first or second decades of life, retinitis pigmentosa and cardiac conduction defects (atrioventricular nodal block, often requiring cardiac pacing).?external ophthalmoplegia, retinitis pigmentosa. Ptosis may be seenMaternally inherited diabetes and deafness (MIDD)Diabetessensorineural hearing lossend stage renal failure.Sensorineural hearing lossAcute phase proteinsAcute phase proteinsCRP*procalcitoninferritinfibrinogenalpha-1 antitrypsincaeruloplasminserum amyloid Aserum amyloid P component**haptoglobincomplementDuring the acute phase response the liver decreases the production of other proteins (sometimes referred to as negative acute phase proteins). Examples include:AlbuminTransthyretin (formerly known as prealbumin)transferrinretinol binding proteincortisol binding protein*Levels of CRP are commonly measured in acutely unwell patients. CRP is a protein synthesised in the liver and binds to phosphocholine in bacterial cells and on those cells undergoing apoptosis. In binding to these cells it is then able to activate the complement system. CRP levels are known to rise in patients following surgery. However, levels of greater than 150 at 48 hours post operatively are suggestive of evolving complications.plays a more significant role in other mammals such as miceAlkaline phosphataseCauses of raised alkaline phosphatase (ALP)liver: cholestasis, hepatitis, fatty liver, neoplasiaPaget'sosteomalaciabone metastaseshyperparathyroidismrenal failurephysiological: Pregnancy significantly elevated in pregnancy. This would also explain the borderline anaemiagrowing childrenhealing fracturesThe table below splits the causes according to the calcium levelRaised ALP and raised calciumRaised ALP and low calciumBone metastasesHyperparathyroidismOsteomalaciaRenal failureAcute tubular necrosisis the?most common cause?of acute kidney injury (AKI) seen in clinical practice. Necrosis of renal tubular epithelial cells severely affects the functioning of the kidney. In the early stages ATN is reversible if the cause if removed.There are two main causes of ATNischaemiashocksepsisnephrotoxinsaminoglycosidesmyoglobin secondary to?rhabdomyolysisradiocontrast agentsleadFeaturesfeatures of AKI: raised urea, creatinine, potassiummuddy brown casts in the urineHistopathological featurestubular epithelium necrosis: loss of nuclei and detachment of tubular cells from the basement membranedilatation of the tubules may occurnecrotic cells obstruct the tubule lumenPhases of ATNoliguric phasepolyuric phaserecovery phase?Hypovolaemia reduces glomerular perfusion and filtration rates, which over time causes renal cell hypoxia and necrosis of the renal tubular epithelium. This is the mechanism of renal injury in this case, but acute tubular necrosis (ATN) can arise from other means e.g. sepsis or nephrotoxic agents.Diabetic nephropathycommonest cause of end-stage renal disease (ESRD) in the western world33% of type 1 diabetes mellitus diabetic nephropathy by the age of 40 yearsapproximately 5-10% of patients with type 1 diabetes mellitus develop (ESRD)The pathophysiology is poorly understood, however:changes to the haemodynamics of the glomerulus is thought to be key, increased glomerular capillary pressurenon-enzymatic glycosylation?of the basement membrane and hyaline arteriosclerosisis thought to play a key role histological changes include: Basement membrane thickening,Capillary obliteration, Mesangial widening. Nodulular hyaline areas develop in the glomuli -?Kimmelstiel-Wilson nodulesRisk factors for developing diabetic nephropathyModifiableNon-modifiableHypertensionHyperlipidaemiaSmokingPoor glycaemic controlRaised dietary proteinMale sexDuration of diabetesGenetic predisposition (ACE gene polymorphisms)DDApple-green birefringence under polarised light Amyloidosis.Enlarged and hypercellular glomeruli Acute post-streptococcal glomerulonephritis.Crescent moon shaped glomeruli Rapidly progressive (crescentic) glomerulonephritis.Wire looping of capillaries in the glomeruli Diffuse proliferative gAdrenal medullaThe 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 ganglionAlpha-thalassaemiaAlpha-thalassaemia is due to a deficiency of alpha chains in haemoglobin2 separate alpha-globulin genes are located on each chromosome 16Clinical severity depends on the number of alpha globulin alleles affected:If 1 or 2 alpha alleles are affected hypochromic and microcytic, but normal Hb level. If are 3 alpha alleles are affected hypochromic microcytic anaemia + splenomegaly. (Hb H disease)If all 4 alpha alleles are affected (i.e. homozygote) Death in utero (hydrops fetalis, Bart's hydrops)Anaesthetic agentsThe table below summarises some of the more commonly used IV induction agentsAgentSpecific featuresPropofolGABA receptor agonistRapid onset of anaesthesiaPain on IV injectionRapidly metabolised with little accumulation of metabolitesProven anti emetic propertiesModerate myocardial depressionWidely used especially for maintaining sedation on ITU, total IV anaesthesia and for daycase surgerySodium thiopentoneExtremely rapid onset of action making it the agent of choice for rapid sequence of inductionMarked myocardial depression may occurMetabolites build up quicklyUnsuitable for maintenance infusionLittle analgesic effectsKetamineNMDA receptor antagonistMay be used for induction of anaesthesiaHas moderate to strong analgesic properties can be used in neuropathic pain poorly responsive to titrated opioids and oral adjuvant analgesics (e.g. antidepressant and/or anticonvulsant) particularly when there is abnormal pain sensitivity (e.g. allodynia, hyperalgesia or hyperpathia).?Produces little myocardial depression making it a suitable agent for anaesthesia in those who are haemodynamically unstableMay induce state of dissociative anaesthesia resulting in nightmaresEtomidateHas favorable cardiac safety profile with very little haemodynamic instabilityNo analgesic propertiesUnsuitable for maintaining sedation as prolonged (and even brief) use may result in adrenal suppressionPost operative vomiting is commonOther AnalgescsGabapentin acts by modulation of the voltage-gated calcium channel.?Pregabalin is a GABA analogue.?Benzodiazepines are GABA agonists.?Local anaesthetics (e.g. lidocaine) are sodium channel blockers.Local anaesthetic agentsLidocaineAn amideLocal anaesthetic and a less commonly used antiarrhythmic (affects Na channels?in the axon)Hepatic metabolism, protein bound, renally excretedToxicity: due to IV or excess administration. Increased risk if liver dysfunction or low protein states. Note acidosis causes lidocaine to detach from protein binding.?Local anesthetic toxicity can be treated with IV 20% lipid emulsion creates a lipid phase that extracts the hydrophobic molecules of LA from the aqueous plasma phase and hence reduces serum LA concentration.Drug interactions: Beta blockers, ciprofloxacin, phenytoinFeatures of toxicity: Initial CNS over activity then depression as lidocaine initially blocks inhibitory pathways then blocks both inhibitory and activating pathways. Cardiac arrhythmias.Increased doses may be used when combined with adrenaline to limit systemic absorption.CocainePure cocaine is a salt, usually cocaine hydrochloride. It is supplied for local anaesthetic purposes as a paste.It is supplied for clinical use in concentrations of 4 and 10%. It may be applied topically to the nasal mucosa. It has a rapid onset of action and has the additional advantage of causing marked vasoconstriction.It is lipophillic and will readily cross the blood brain barrier. Its systemic effects also include cardiac arrhythmias and tachycardia.Apart from its limited use in ENT surgery it is otherwise used rarely in mainstream surgical practice.BupivacaineBupivacaine binds to the intracellular portion of sodium channels and blocks sodium influx into nerve cells, which prevents depolarization.It has a much longer duration of action than lignocaine and this is of use in that it may be used for topical wound infiltration at the conclusion of surgical procedures with long duration analgesic effect.Cardiotoxic and is therefore contra indicated in regional blockage in case the tourniquet fails.Levobupivicaine (Chirocaine) is less cardiotoxic and causes less vasodilation.PrilocaineSimilar mechanism of action to other local anaesthetic agents. However, it is far less cardiotoxic and is therefore the agent of choice for intravenous regional anaesthesia e.g. Biers Block.All local anaesthetic agents dissociate in tissues and this contributes to their therapeutic effect. The dissociation constant shifts in tissues that are acidic e.g. where an abscess is present, and this reduces the efficacy.Doses of local anaestheticsAgentDose plainDose with adrenalineLignocaine3mg/Kg7mg/KgBupivacaine2mg/Kg2mg/KgPrilocaine6mg/Kg9mg/KgThese are a guide only as actual doses depend on site of administration, tissue vascularity and co-morbidities.Maximum total local anaesthetic dosesLignocaine 1% plain - 3mg/ Kg - 200mg (20ml)Lignocaine 1% with 1 in 200,000 adrenaline - 7mg/Kg - 500mg (50ml)Bupivicaine 0.5% - 2mg/kg- 150mg (30ml)Maximum doses are based on ideal body weightEffects of adrenalineAdrenaline may be added to local anaesthetic drugs. It prolongs the duration of action at the site of injection and permits usage of higher doses (see above). It is contra indicated in patients taking MAOI's or tricyclic antidepressants. The toxicity of bupivacaine is related to protein binding and addition of adrenaline to this drug does not permit increases in the total dose of bupivacaine, in contrast to the situation with lignocaine.Antibiotics: mechanism of actionInhibit cell wall formation (beta-lactams)penicillins:?binds transpeptidase blocking cross-linking of peptidoglycan cell wallscephalosporinscarbapenems and monobactamscarbapenems and monobactamsInhibit protein synthesis:?these antibiotics are bateriostaticDrugMechanism of actionAdverse effectsAminoglycosidesBinds to 30S subunit misreading of mRNANephrotoxicityOtotoxicityTetracyclinesDoxycyclineBinds to 30S subunit block binding of aminoacyl-tRNADiscolouration of teethPhotosensitivityChloramphenicolBinds to 50S subunit↓↓ peptidyl transferaseAplastic anaemiaClindamycinBinds to 50S subunit↓↓translocation (movement of tRNA from acceptor site to peptidyl site)C. difficile diarrhoeaMacrolidesBinds to 50S subunit↓↓ translocation (movement of tRNA from acceptor site to peptidyl site)Nausea (especially erythromycin) P450 ↓↓, ↑↑QT intervalfusidic acidInhibit DNA synthesisquinolones (e.g. ciprofloxacin)metronidazolesulphonamidestrimethoprimInhibit RNA synthesisrifampicinAntidiuretic hormoneStaphylococcibacteria which are often found normal commensal organisms but may also cause invasive disease. Some basic facts include:Gram-positive coccifacultative anaerobesproduce catalaseThe two main types of Staphylococci Staphylococcus aureus Staphylococcus epidermidis? Coagulase-positive? Causes skin infections (cellulitis), abscesses, osteomyelitis, toxic shock syndrome? Coagulase-negative? Cause of central line infections and infective endocarditisAcute epiglottitisis rare but serious infection caused by?Haemophilus influenzae?type B. Prompt recognition and treatment is essential as airway obstruction may develop. Epiglottitis was generally considered a disease of childhood but in the UK it is now more common in adults due to the immunisation programme. The incidence of epiglottitis has decreased since the introduction of the?Hib vaccine. Patients from travelling communities may not always receive a full course of immunisation.?Featuresrapid onsethigh temperature, generally unwellstridordrooling of salivaInvestigationschest x-raya lateral view in acute epiglottis will show swelling of the epiglottis - the 'thumb sign'in contrast, a posterior-anterior view in croup will show subglottic narrowing, commonly called the 'steeple sign'CampylobacterThe commonest bacterial cause of infectious intestinal disease caused by the Gram-negative bacillus?Campylobacter jejuni. (faecal-oral route) .Incubation period of 1-6 days.FeaturesUsually mild, with Prodrome headache and general tirednessExcept immunocompromised on methotrexate and a severe infection (fever, bloody diarrhoea and prolonged history). She should therefore be given an antibiotic. The BNF advise clarithromycin first-line.prodrome: headache malaisediarrhoea: often bloodyabdominal pain: may mimic appendicitisManagementUsually self-limiting the BNF advises treatment if severe or the patient is immunocompromised. Clinical Knowledge summaries also recommend antibiotics if severe symptoms (high fever, bloody diarrhoea, or more than eight stools per day) or symptoms have last more than one weekthe first-line antibiotic is?clarithromycinciprofloxacin is an alternative although the BNF states that?'Strains with decreased sensitivity to ciprofloxacin isolated frequently'ComplicationsGuillain-Barre syndrome may follow?Campylobacter jejuni?infectionsReiter's syndromesepticaemia, endocarditis, arthritisDD. Non- bloody Diarrhea (Campylobacter, Diverticulitis, E. coli, Cholera, Giardiasis) MeaslesMeasles is now rarely seen in the developed world following the adoption of immunisation programmes. Outbreaks are occasionally seen, particularly when vaccinations rates drop, for example after the MMR controversy of the early 2000s.OverviewRNA paramyxovirusspread by dropletsinfective from prodrome until 4 days after rash startsincubation period = 10-14 daysFeaturesprodrome: irritable, conjunctivitis, feverKoplik spots (before rash): white spots ('grain of salt') on buccal mucosarash: starts behind ears then to whole body, discrete maculopapular rash becoming blotchy & confluent InvestigationsIgM antibodies can be detected within a few days of rash onsetManagementmainly supportiveadmission may be considered in immunosuppressed or pregnant patientsnotifiable disease → inform public healthComplicationsOtitis media: the most common complicationPneumonia: the most common cause of deathEncephalitis: typically occurs 1-2 weeks following the onset of the illness)Sub acute Sclerosing SanencephalitisVery rare may present 5-10 years following the illness.Febrile convulsionsKeratoconjunctivitis corneal ulcerationDiarrhea↑↑ Incidence of appendicitisMyocarditisManagement of contactsif a child not immunized against measles comes into contact with measles then MMR should be offered (vaccine-induced measles antibody develops more rapidly than that following natural infection)this should be given within 72 hoursChickenpoxcaused by primary infection with varicella zoster virus. Shingles is a reactivation of the dormant virus in dorsal root ganglionHighly infectiousspread via the respiratory routecan be caught from someone with shinglesinfectivity = 4 days before rash, until 5 days after the rash first appeared*incubation period = 10-21 daysClinical features (tend to be more severe in older children/adults)fever initiallyitchy, rash starting on head/trunk before spreading. Initially macular then papular then vesicularsystemic upset is usually mildManagement is supportivekeep cool, trim nailscalamine lotionschool exclusion: NICE Clinical Knowledge Summaries state the following:?Advise that the most infectious period is 1–2 days before the rash appears, but infectivity continues?until all the lesions are dry and have crusted over (usually about 5 days after the onset of the rash).immunocompromised patients and newborns with peripartum exposure should receive varicella zoster immunoglobulin (VZIG). If chickenpox develops then IV aciclovir should be consideredA common complication is secondary bacterial infection of the lesionsNSAIDs may increase this riskwhilst this commonly may manifest as a single infected lesion/small area of cellulitis, in a small number of patients?invasive group A streptococcal soft tissue infections may occur resulting in necrotizing fasciitisPneumonia the most common and serious complication of chickenpox infection in adults. Auscultation of the chest is often unremarkable. Varicella zoster immunoglobulin is used for the prevention of varicella in at-risk groups (e.g. Immunocompromised, pregnant women), rather than for treatmentRare complications includeencephalitis (cerebellar involvement may be seen)disseminated haemorrhagic chickenpoxarthritis, nephritis and pancreatitis may very rarely be seen.Herpes simplex virus2 strains of the herpes simplex virus (HSV) in humans: HSV-1 and HSV-2. Whilst it was previously thought HSV-1 accounted for oral lesions (cold sores) and HSV-2 for genital herpes it is now known there is considerable overlapFeaturesprimary infection: may present with a severe gingivostomatitiscold sorespainful genital ulcerationPap smear. Multinucleated giant cells representing infection by the herpes simplex virus. Note the 3 M's; Multinucleation, Margination of the chromatin, Molding of the nucleiManagementgingivostomatitis: oral aciclovir, chlorhexidine mouthwashcold sores: topical aciclovir although the evidence base for this is modestgenital herpes: oral aciclovir. even if the presentation is delayed for up to 5 days Some patients with frequent exacerbations may benefit from longer term aciclovirPregnancyelective caesarean section at term is advised if a primary attack of herpes occurs during pregnancy at greater than 28 weeks gestationwomen with recurrent herpes who are pregnant should be treated with suppressive therapy and be advised that the risk of transmission to their baby is lowHIV: the virusHIV is a RNA retrovirus of the lentivirus genus (lentiviruses are characterized by a long incubation period)two variants - HIV-1 and HIV-2HIV-2 is more common in west Africa, has a lower transmission rate and is thought to be less pathogenic with a slower progression to AIDSBasics structurespherical in shape with two copies of single-stranded RNA enclosed by a capsid of the viral protein p24a matrix composed of viral protein p17 surrounds the capsidenvelope proteins: gp120 and gp41pol gene encodes for viral enzymes reverse transcriptase, integrase and HIV protease Cell entryHIV can infect CD4 T cells, macrophages and dendritic cellsgp120 binds to CD4 and CXCR4 on T cells and CD4 and CCR5 on macrophagesmutations in CCR5 can give immunity to HIVimmunological changes are seen in progressive HIV:reduction in CD4 countincrease B2-microglobulindecreased IL-2 productionpolyclonal B-cell activationdecrease NK cell functionreduced delayed hypersensitivity responsesReplicationafter entering a cell the enzyme reverse transcriptase creates dsDNA from the RNA for integration into the host cell's genome Viral Meningitis Viral meningitis does not require any treatment and is usually a self-limiting infection Most cases of are caused by Enterovirus.This should be DD from viral encephalitis different presentation and treatment. Same organism can cause both presentations (HSV)Enteroviruses are positive-sense single stranded RNA viruses (Coxsackievirus, echovirus and rhinovirus).Can cause a range of different diseases in adults and children Hand, Foot and Mouth disease, herpangina and pericarditis.Exotoxins and endotoxinsEndotoxins only released following lysis of the cell. Exotoxins Gram +Ve bacteria with the notable exceptions of?Vibrio cholerae?and some strains of?E. coli It is possible to classify exotoxins by their primary effects:pyrogenic toxinsenterotoxinsneurotoxinstissue invasive toxinsmiscellaneous toxinsPyrogenic toxins↑↑ release of endogenous cytokines fever, rash.Superantigens bridge the Major Histocompatibility Complex MHC class II protein on Antigen-Presenting cells + T cell receptor of T cells Massive cytokine releaseOrganismToxinNotesStaphy. AureusToxic shock syndrome (TSST-1 superantigen) toxin↑↑ fever, Hypotension, Exfoliative rashStrept. PyogenesStreptococcal pyrogenic exotoxin A & C Scarlet feverEnterotoxinsAct on the GIT causing one of two patterns of illness:Diarrhoeal illnessVomiting illness ('food poisoning')OrganismToxinNotesVibrio choleraeCholera toxin (++) adenylate cyclase (via Gs) ↑↑ cAMP ↑↑ Cl? secretion and ↓↓ Na+ absorptionShigella dysenteriaeShiga toxin (- -) 60S ribosome → Epithelial cell deathE.coli1.?Heat labile toxin2.?Heat stabile toxin(++) Adenylate cyclase (via Gs) ↑↑ cAMP → Watery diarrhea(++) guanylate cyclase ↑↑ cGMP → Watery diarrhoeaStaph. Aureus Staph. EnterotoxinVomiting and diarrhoeal illness lasting < 24 hoursBacillus cereus CereulidePotent cytotoxin destroys mitochondria. vomiting illness which may present within 4 hours of ingestionNeurotoxinsNeurotoxins act on the nerves (tetanus) or the neuromuscular junction (botulism) causing anismToxinNotesClostridium tetaniTetano-spasminBlocks the release of the inhibitory neurotransmitters GABA and glycine continuous motor neuron activity → continuous muscle contraction → lockjaw and respiratory paralysisClostridium botulinumBotulinum toxinBlocks acetylcholine (ACh) release flaccid paralysisTissue invasive toxinsOrganismToxinNotesClostridium perfringens α-toxin, a lecithinase Gas gangrene (myonecrosis) and haemolysisStaph. AureusExfoliatin Staphylococcal scalded skin syndromeMiscellaneous toxinsOrganismToxinNotesCorynebacterium diphtheriaDiphtheria toxinADP ribosylates elogation factor (EF-2) inhibition. Causing a 'diphtheric membrane' on tonsils caused by necrotic mucosal cells. Systemic distribution necrosis of Myocardial, Neural and Renal tissuePseudomonas AeruginosaExotoxin A inhibits EF-2 by the same mechanism as aboveBacillus AnthracisOedema factor (EF)Forms a calmodulin-dependent adenylate cyclase ↑↑ cAMP,↓↓ function of neutrophils/macrophages → ↓↓ phagocytosisBordetella PertussisPertussis Exotoxin(- -) Gi? increases in cAMP levels, ↓↓ function of neutrophils/macrophages → ↓↓ phagocytosisEndotoxins are lipopolysaccharides that are released from Gram-negative bacteria such as?Neisseria meningitidis.Escherichia coliA facultative Anaerobic, Lactose-fermenting, Gram Negative rod (normal gut commensal)? variety of diseases in humans including:Diarrheal illnessesUTIsNeonatal meningitisSerotypesE. coli?may be classified according to the antigens which may trigger an immune response:AntigenOriginNotesOLipopolysaccharide layerKCapsuleNeonatal meningitis secondary to?E. coli?is usually caused by a serotype that contains the capsular antigen K-1HFlagellinE. coli?O157:H7 (Flagellin) Severe, Haemorrhagic, watery diarrhoea. It has a high mortality rate and can be complicated by haemolytic uraemic syndrome. It is often spread by contaminated ground beef.Haemolytic Uraemic Syndrome. E.coli O157: H7 strain.Bloody diarrhea + acute renal failure (high urea) + Haemolytic Anaemia (as confirmed by the presence of schistocytes). DD. Salmonella, shigella and campylobacter can cause bloody diarrhoea but do not commonly cause haemolytic anaemia.Cholera is not a cause of bloody diarrheaCholangitisCombination of bacterial infection and biliary obstructionMost common organisms Escherichia coli? Klebsiella species,?Enterococcus species, Streptococcus?species?Clinical featuresCharcot's triad Fever (90% cases) + Right upper quadrant pain + JaundiceReynolds pentad: Above plus confusion and hypotensionInvestigationsUSS 1st lineCT scanERCP: may be 1st line if high clinical suspicion and suitable for treatmentTreatmentERCP -usually after 72 hours of antibioticsPercutaneous transhepatic cholangiogram and biliary drainMycobacterium marinumis one of many mycobacteria that can cause disease in humans. Fish tank granuloma typically presents in patients who have had an exposure to, or frequently work with fish. It has an incubation period of 3-4 weeks and lesions can be painful or painless. A cut or break in the skin can be enough for the organism to enter the blood stream and track up the lymphatic system (sporotrichoid spread). RickettsiaeGram-negative obligate intracellular parasites variety of diseases that are typically characterised by fever, headache and rash.Single or multiple Eschars (Dark black crust?)Except Q fever cause by?Coxiella burnetti? pneumonia but no rash. The Weil-Felix reaction is positive except in Q fever. Rickettsial diseases are all treated with tetracyclines.DiseaseCauseVectorNotesRocky Mountain (Spotted fever) Rickettsia ricketsii TickHeadache and fever are commonRash starts on the peripheries (wrist, ankles) centrally. It is initially maculopapular before becoming vasculiticEndemic to east coast of USQ fever Coxiella burnetti No vectorNo rash but causes pneumoniaEndemic typhus Rickettsia typhi FleaRash starts centrally then spreads to the peripheriesEpidemic typhus Rickettsia prowazekii Human body louseEhrlichliosis Ehrlichia TickHelminths Nematodes (roundworms)WormNotesTreatmentStrongyloides StercoralisLarvae are present in soil and gain access to the body by penetrating the skinFeatures include diarrhoea, abdominal pain, papulovesicular lesions where the skin has been penetrated by infective larvae e.g. soles of feet and buttocks, larva currens: pruritic, linear, urticarial rash, if the larvae migrate to the lungs a pneumonitis similar to Loeffler's syndrome may be triggeredIvermectin and - bendazoles Enterobius vermicularis(pinworm)Threadworm infestation is asymptomatic 90% of cases, possible features include perianal itching, particularly at night; girls may have vulval symptomsDiagnosis may be made by the applying sticky plastic tape to the perianal area and sending it to the laboratory for microscopy to see the eggs-bendazolesAncylostoma duodenale,?Necator americanus(hookworms)Larvae penetrate skin of feet; gastrointestinal infection → AnaemiaThin-shelled ova-bendazolesLoa loaTransmission by deer fly and mango flyCauses red itchy swellings below the skin called 'Calabar swellings', may be observed when crossing conjunctivaeDiethylcarbamazineTrichinella spiralisTypically develops after eating raw porkFeatures include fever, periorbital oedema and myositis (larvae encyst in muscle)-bendazolesOnchocerca volvulusSpread by female black flies Causes 'river blindness'. Features include blindness, hyperpigmented skin and possible allergic reaction to microfilariaIvermectinrIVERblindness Wuchereria bancroftiTransmission by female mosquitoCauses blockage of lymphatics → elephantiasisDiethylcarbamazineToxocara canis?(dog roundworm)Transmitted through ingestion of infective eggs.Features include visceral larva migrans and retinal granulomas?VISCious dogs → blindnessDiethylcarbamazineAscarislumbricoides(giant roundworm)Eggs are visible in faecesMay cause intestinal obstruction and occasional migrate to lung (Loffler's syndrome)-bendazolesCestodes (tapeworms)WormNotesTreatmentEchinococcus granulosusTransmission through ingestion of eggs in dog faeces. Definite host is dog, which ingests hydatid cysts from sheep, who act as an intermediate host. Often seen in farmers.Features include liver cysts and anaphylaxis if cyst ruptures (e.g. during surgical removal)bendazolesTaenia soliumOften transmitted after eating undercooked pork. Cysticercosis Painless nodules on the neck, face and arms Skin biopsy of nodule reveals white cystic NeurocysticercosisSeizers Sructure mass lesions in the brain 'swiss cheese appearance' T. Solium eggs.CT head numerous small focal calcification throughout both cerebral hemispheres with no enhancementNoodle-like material in his stoolDD Amoebic encephalitis normal on CT "early stages" then some patchy low-level enhancement. bendazolesTrematodes (flukes)WormNotesTreatmentSchistosoma haematobiumHosted by snails, which release cercariae that penetrate skin.Causes 'swimmer's itch' - frequency, haematuria. Risk factor for squamous cell bladder cancerPraziquantelParagonimus westermaniCaused by undercooked crabmeat, results in secondary bacterial infection of lungsPraziquantelClonorchis sinensisCaused by undercooked fishFeatures include biliary tract inflammation. Known risk factor for cholangiocarcinomaPraziquantelFasciola hepatica?(liver fluke) May cause biliary obstructionTriclabendazoleDisseminated intravascular coagulationSimultaneous coagulation and haemorrhage caused by the initial formation of thrombi which consume clotting factors (factors 5,8) and platelets, ultimately leading to bleeding.Causes includeInfectionMalignancyTrauma e.g. major surgery, burns, shock, dissecting aortic aneurysmLiver diseaseObstetric complicationsKey pointsClinically bleeding is usually a dominant feature, bruising, ischaemia and organ failureBlood tests: prolonged clotting times, thrombocytopenia, decreased fibrinogen, increased fibrinogen degradation productsThe excess fibrin strands cause mechanical damage to the red blood cells elevated D-dimer levels, and microangiopathic pathology (schistocytes) on peripheral smears are suggestive findingsTreat the underlying cause and supportive managementDDA bite cell is an abnormally shaped red blood cell with one or more semicircular portions removed from the cell margin. These “bites” result from the removal of denatured haemoglobin by macrophages in the spleen. Glucose-6-phosphate dehydrogenase deficiency (G6PD), in which uncontrolled oxidative stress causes haemoglobin to denature and form Heinz bodies, is a common disorder that leads to the formation of bite cells.The Heinz Bodies are seen as antigenic and are quickly phagocytosed. Because the Heinz Bodies are derivatives of haemoglobin, they are located inside the cell, and thus phagocytosis takes a significant “bite” out of the cell.Dacrocytes (teardrop cells) are usually characteristic of myelofibrosis and seen with marrow disorders or marrow infiltrations, really because of improper production of blood cells from the bone marrow. In post-splenectomy patients, the number of dacrocytes drastically increases, since the spleen cannot remove the improperly formed cells.Red cells varying in shape from elongated to oval, and rich in haemoglobin, are called elliptocytes. They can be seen in hereditary disorders, such as hereditary elliptocytosis, or in acquired disorders, such as iron deficiency anaemia, infectious anaemias, thalassaemia, and in newborn babies.Post operative fluid managementIntravenous fluids mmolNaKClBicarbonateLactatePlasma137-1474-5.595-10522-25-0.9% Saline153-153--Dextrose / saline30.6-30.6--Hartmans1304110-28Post operative fluid management↑↑ Saline hyperchloraemic acidosisThe use of electrolyte balanced solutions (Ringers lactate/ Hartmans) favoured over normal saline. In addition to this, solutions of 5% dextrose and dextrose/saline combinations are now generally not recommended for surgical patients. The guidance includes:Fluids given should be documented clearly and easily availableAssess the patient's fluid status when they leave theatre.Haemodynamically stable and euvolaemic restart oral fluid intake as soon as possibleReview patients whose urinary sodium is < 20Oedematous, hypovolaemia if present should be treated first then (-Ve balance of Na and water) monitored using urine Na levels.Solutions such as Dextran 70 used in caution in patients with sepsis ↑↑↑ risk of developing acute renal injury.Causes of ↓↓ Conscious level Post operatively Hyponatraemic encephalopathy.Pediatrics + ↑↑ hypotonic intravenous fluids such as 0.45% sodium chlorideCentral pontine myelinolysis. Consequence of rapidly correctly hyponatraemia.Excessive use of patient controlled analgesia↓↓conscious level and respiratory depression especially if opiates such as morphine were prescribedHyperosmolar hyperglycaemic Complication of diabetes mellitus and can result in reduced conscious level.Post-splenectomy sepsisSplenic atrophy splenic artery embolization and splenectomy for trauma. Diagnosis of hyposplenism is difficult Peripheral markers Howell-Jolly bodies these are neither 100% sensitive or specific.The most sensitive test is a radionucleotide labelled red cell scan.?↑↑ risk of post-splenectomy sepsisParticularly with encapsulated organisms Normally, organisms are opsonised by the spleen After SpleenectomyOrganism r undetected at an immunological level due to loss of the spleen. individuals are recommended to be vaccinated and have antibiotic prophylaxis.?Key recommendationsAll those with hyposplenism or may become so (such as prior to an elective splenectomy) should receive pneumococcal, Haemophilus type b and meningococcal type C vaccines. These should be administered 2 weeks prior to splenectomy or two weeks following splenectomy. The vaccine schedule for meningococcal disease essentially consists of a dose of Men C and Hib at 2 weeks and then a dose of the MenACWY vaccine one month later. Those aged under 2 may require a booster at 2 years. A dose of pneumococcal polyvalent polysaccharide vaccine (PPV) is given at two weeks. A conjugated vaccine (PCV) is offered to young children. The PCV is more immunogenic but covers fewer serotypes. Boosting PPV is either guided by serological measurements (where available) or by routine boosting doses at 5 yearly intervals.Annual influenza vaccination is recommended in all casesAntibiotic prophylaxis is offered to all. The risk of post-splenectomy sepsis is greatest immediately following splenectomy and in those aged less than 16 years or greater than 50 years. Individuals with a poor response to pneumococcal vaccination are another high-risk group. High-risk individuals should be counselled to take penicillin or macrolide prophylaxis. Those at low risk may choose to discontinue therapy. All patients should be advised about taking antibiotics early in the case of intercurrent infections.Asplenic individuals travelling to malaria endemic areas are at high risk and should have both pharmacological and mechanical protection.DosingPenicillin V 500mg BD or amoxicillin 250mg BDRenal anatomyEach kidney is about 11cm long, 5cm wide and 3cm thick in a deep gutter alongside the projecting vertebral bodies, on the anterior surface of psoas major. In most cases the left kidney lies approximately 1.5cm higher than the right. The upper pole of both kidneys approximates with the 11th rib (beware pneumothorax during nephrectomy). On the left hilum is located at the L1 vertebral level and the right kidney at level L1-2 The lower border of the kidneys is usually alongside L3.?RelationsRight KidneyLeft KidneyPosteriorQuadratus lumborum, diaphragm psoas major, transversus abdominisQuadratus lumborum, diaphragm psoas major, transversus abdominisAnteriorHepatic flexure of colonStomach, Pancreatic tailSuperiorLiver, Adrenal glandSpleen, Adrenal glandIf we consider relations according to whether they are in direct contact or whether there is peritoneum in-between:Right kidneyDirect contactLayer of peritoneum in-betweenRight suprarenal glandDuodenumColonLiverDistal part of small intestineLeft kidneyDirect contactLayer of peritoneum in-betweenLeft suprarenal glandPancreasColonStomachSpleenDistal part of small intestineFascial coveringEach kidney and suprarenal gland is enclosed within a common layer of investing fascia, derived from the transversalis fascia. It is divided into anterior and posterior layers (Gerotas fascia).Renal structureKidneys are surrounded by an outer cortex and an inner medulla (contains between 6 and 10 pyramidal structures). The papilla marks the innermost apex of these. They terminate renal pelvis, into the ureter.Lying in a hollow within the kidney is the renal sinus. This contains:Branches of the renal arteryTributaries of the renal veinMajor and minor calyces'sFatStructures at the renal hilum (V A U)The renal vein lies most anteriorly, then renal artery (it is an end artery) and the ureter lies most posterior.Renal physiologyAfferent arteriole to nephron opens onto the glomerular capillary blood to an efferent arteriole (supplying peritubular capillaries and medullary vasa recta)the kidney receives up to 25% of resting cardiac outputControl of blood flowthe kidney is able to autoregulate its blood flow between systolic pressures of 80-180mmHg so there is little variation in renal blood flowthis is achieved by myogenic control of arteriolar tone (both sympathetic input and hormonal signals (renin) are responsiblerenal Cortical blood flow > Medullary blood flow (tubular cells more prone to ischaemia)Glomerular structure and functionblood inside the glomerulus has considerable hydrostatic pressurethe basement membrane has pores allow free diffusion of smaller solutes.larger negatively charged molecules such as Albumin are unable to crossThe glomerular filtration rate (GFR) = concentration of a solute in the urine, times the volume of urine produced per minute / divided by the plasma GFR = (urine concentration (mmol/l) x urine volume (ml/min)) / plasma concentration (mmol/l)concentration (assuming that the solute is freely diffused e.g. inulin)in clinical practice creatinine is used because it is subjected to very little proximal tubular secretionalthough subject to variability, the typical GFR is 125ml per minuteGlomerular Filtration Rate = Total volume of plasma per unit time leaving the capillaries entering the Bowman's capsuleRenal clearance = volume plasma from which a substance is removed per minute by the kidneysSubstances used to measure GFR have the following features:InertFree filtration from the plasma at the glomerulus (not protein bound)Not absorbed or secreted at the tubulesPlasma concentration constant during urine collection (Ex: inulin, creatinine).the clearance of a substance is dependent onits diffusivity across the basement membrane Tubular secretion and / or reabsorptionGlucose which is freely filtered across the basement membrane is usually reabsorbed from tubules giving a clearance of zeroTubular functionReabsorption and secretion of substances occurs in the tubulesIn the proximal tubule substrates (glucose, amino acids and?phosphate)? co-transported with sodium across the semi permeable membrane2/3 of filtered water reabsorbed in the proximal tubulesThis will lead to ↑↑ urea concentration in the distal tubule allowing for its ↑↑ diffusionSubstances to be secreted into the tubules are taken up from the Peritubular blood by tubular cellsSolutes such as para-aminohippuric acid are cleared with a single passage through the kidneys and this is why it is used to measure renal plasma flow. Ions such as Ca++ and P+ will have a tubular reabsorption that is influenced by plasma PTH levelsK+ may be both secreted and reabsorbed and is co-exchanged with sodiumLoop of HenleApproximately 60 litres of water containing 9000mmol sodium/Day enters the descending limb of the loop of Henle in 24 hoursLoops from the juxtamedullary nephrons run deep into the medullaThe osmolarity of fluid changes and is greatest at the tip of the papillaThe thin ascending limb is impermeable to water, but ↑↑ permeable to Na and Cl ions at the beginning of the thick ascending limb the fluid is hypo osmotic compared with adjacent interstitial fluid reabsorption of Na+ and Cl- ions occurs by both facilitated and passive diffusion pathways.The loops of Henle are co-located with vasa recta similar solute compositions to the surrounding extracellular fluid preventing the diffusion and subsequent removal of this hypertonic fluidThe energy dependent reabsorption of Na+ and Cl- in the thick ascending limb helps to maintain this osmotic gradientRenin-angiotensin-aldosterone systemAdrenal cortex (mnemonic?GFR - ACD)Zona?Glomerulosa(outer) Mineralocorticoids, mainly?AldosteroneZona?Fasciculate (middle) Glucocorticoids, mainly?CortisolZona?Reticularis (inner) Androgens, mainly?Dehydroepiandrosterone (DHEA)Reninan enzyme that is?released by the renal juxtaglomerular cells in response to?reduced renal perfusionhydrolyses Angiotensinogen angiotensin IStimulating renin secretionhypotension causing reduced renal perfusionhyponatraemiasympathetic nerve stimulationcatecholaminesErect postureReducing renin secretion Drugs beta-blockers, NSAIDsAngiotensin IIAngiotensin-converting enzyme (ACE) in the lungs (angiotensin I → angiotensin II)Actions:V.C ↑↑ blood pressure and?V.C of efferent arteriole of the glomerulus?→ ↑↑ filtration fraction (FF) to preserve GFR. (FF = GFR / renal plasma flow)(++) thirst?(via the hypothalamus)(++) Aldosterone?and?ADH?release↑↑ proximal tubule Na+/H+?activityAldosteroneReleased by the Zona Glomerulosa in response to ↑↑?AngiotensinII, K+ and ACTH levelsCauses retention of Na+?in exchange for K+/H+?in distal tubulePotassium sparing diureticsDivided intoEpithelial sodium channel blockers (Amiloride and Triamterene)Amiloride is a weak diuretic ?blocks the epithelial sodium channel in the distal convoluted tubule.Usually given with thiazides or loop diuretics as an alternative to potassium supplementation.Aldosterone antagonists (Spironolactone and Eplerenone).Spironolactone is an aldosterone antagonist acts act in the distal convoluted tubule.Indicationsascites: patients with cirrhosis develop a 2ry hyperaldosteronism. Relatively large doses such as 100 or 200mg are often usedHeart failureNephrotic syndromeConn's syndromeLiddle’s syndrome A rare Autosomal Dominant due to a gain of function mutation inability to degrade the epithelial sodium channels in the distal convoluted tubule (DCT) resulting in increased activity.?Patients may experience(hypertension, hypokalaemia and metabolic alkalosis)Amiloride counters this by selectively blocking the epithelial sodium transport channels in the DCT and collecting duct.Antidiuretic hormone Synthesized in the supraoptic nuclei of the hypothalamus, released by the posterior pituitary pituitary Promotes water reabsorption in the collecting ducts of the kidneys by the insertion of aquaporin-2 channels Conserves body waterIncreased by?extracellular fluid osmolality increasevolume decreasepressure decreaseangiotensin IIDecreased byextracellular fluid osmolality decreasevolume increase↓↓ temperature.Diabetes insipidus (DI)Either a deficiency of antidiuretic hormone, ADH, (cranial DI) or an insensitivity to antidiuretic hormone (nephrogenic DI).Cranial DI treated by desmopressin, an analog of ADHRenal stonesType of stonesFeaturesPercentage Calcium oxalateHypercalciuria is a major risk factor (various causes) (↑↑PTH)Hyperoxaluria may also increase riskHypocitraturia citrate forms complexes with calcium making it more soluble.Hyperuricosuria cause uric acid stones to which calcium oxalate bindsOthers antifreeze ingestion, Vit. C abuse and malabsorption (e.g. Crohn disease) Radio-opaque/ dense (white) (< than calcium phosphate stones).85%CystineAR of transmembrane cystine transport ↓↓ absorption of cystine from intestine and renal tubuleMultiple stones may form (staghorn calculi.)Relatively radiodense because they contain sulphur1%Uric acida product of purine metabolism Diseases with extensive tissue breakdown (Malignancy)?May precipitate when urinary pH low (Acid), ↓↓ urine volume, arid climates.More common in children with inborn errors of metabolismRadiolucent (Not appear x-ray)5-10%Calcium phosphateIn renal tubular acidosis (↑↑ urinary Ph) ↑↑ supersaturation of urine with Ca++ and P+types 1 and 3 ↑↑stone formation, (↑↑ P loss Hypophosphatemia) (types 2 and 4 do not)Radio-opaque stones (composition similar to bone)10%StruviteStones formed from?Mg++, Ammonium and P+As result of?urease producing bacteria? Proteus mirabilis (recurrent infection) hydrolyze urea to ammonia and alkalize the urine crystals can precipitateSlightly radio-opaque2-20%Effect of urinary pH on stone formationUrine pH will show individual variation (pH 5-7). Post prandially pH (↓↓) as purine metabolism will produce uric acid Then the urine becomes more alkaline (alkaline tide). When the stone is not available for analysis the pH of urine may help to determine which stone was present.Stone typeUrine acidityMean urine pHCalcium phosphateNormal- alkaline>5.5Calcium oxalateVariable6Uric acidAcid5.5StruvateAlkaline>7.2CystineNormal6.5Cardiovascular physiologyLeft ventricular ejection fraction = (stroke volume / end diastolic LV volume ) * 100%Stroke volume = end diastolic LV volume - end systolic LV volumeCardiac output = stroke volume (ESV) x heart ratePulse pressure = Systolic Pressure - Diastolic PressureFactors which increase pulse pressure↓↓ diastolic pressure ↓↓ compliant aorta (this tends to occur with advancing age)↑↑ Systolic pressure ↑↑ stroke volumeSystemic vascular resistance = mean arterial pressure / cardiac outputCardiac action potentialPhaseDescriptionMechanism0Rapid depolarisationRapid sodium influxThese channels automatically deactivate after a few ms1Early repolarisationEfflux of potassium2PlateauSlow influx of calcium3Final repolarisationEfflux of potassium4Restoration of ionic concentrationsResting potential is restored by Na+/K+?ATPaseSlow entry of Na+?into the cell ↓↓ the potential difference until the threshold potential is reached, triggering a new action potentialConduction velocityCardiac muscle remains contracted 10-15 times longer than skeletal muscle.SiteSpeedAtrial and ventricular muscles 0.5m/secAV node conduction0.05 m/secBundle of His and rt & lt brs?2m/sec.?Purkinje fibres?large diameter and velocities of 2-4 m/sec, the?fastest conduction in the heart rapid and coordinated contraction of the ventriclesLow blood pressure Regulation Variety of physiological responses. RAAS activation↑↑ aldosterone ↑↑ epithelial Na channels (ENAC) ↑↑ Na reabsorption.Bradykinin (potent vasodilator) broken down by angiotensin-converting enzyme (ACE).?↑↑ Anti-diuretic hormone ↑↑ insertion of AQP-2 channels in the collecting duct ↑↑ water reabsorption.AtherosclerosisA number of changes can be seen:initial endothelial dysfunction is triggered by a number of factors such as smoking, hypertension and hyperglycaemiathis results in a number of changes to the endothelium including pro-inflammatory, pro-oxidant, proliferative and reduced nitric oxide bioavailabilityfatty infiltration of the subendothelial space by low-density lipoprotein (LDL) particlesmonocytes 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 plications of atherosclerosis (coronary arteries)Once a plaque has formed a number of complications can develop: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 anginaThe plaque may rupture, potentially causing a complete occlusion of the coronary artery. This may result in a myocardial infarctionAtrial natriuretic peptidesecreted mainly from myocytes of right atrium and ventricle in response to increased blood volumesecreted by both the right and left atria (right >> left)28 amino acid peptide hormone, which acts via cGMPdegraded by endopeptidasesActionsnatriuretic, i.e. promotes excretion of sodiumlowers BPantagonises actions of angiotensin II, aldosteroneCongenital heart disease: typesAcyanotic - most common causesVentricular septal defects (VSD) The commonest accounts for 30%However, in adult patients ASDs are the more common new diagnosis as they generally presents later.Atrial septal defect?(ASD)Patent ductus arteriosus (PDA)Coarctation of the aortaAortic valve stenosisCyanotic - most common causesTetralogy of FallotFallot's is overall more common than TGA. TGA at birth is the more common?lesion , Fallot's around 1-2 monthsTransposition of the great arteries?(TGA)Tricuspid atresiaThe presence of cyanosis in pulmonary valve stenosis depends very much on the severity and any other coexistent defectsPatent ductus arteriosusa form of congenital heart defectgenerally classed as 'acyanotic'. However, uncorrected can eventually result in late cyanosis in the lower extremities, termed differential cynaosis.connection between the pulmonary trunk and descending aortausually the?ductus arteriosus closes with the first breaths due to increased pulmonary flow which enhances prostaglandins clearancemore common in premature babies, born at high altitude or maternal rubella infection in the first trimesterFeaturesleft subclavicular thrillcontinuous 'machinery' murmurlarge volume, bounding, collapsing pulsewide pulse pressureheaving apex beatManagementindomethacin or ibupofengiven to the neonateinhibits prostaglandin synthesiscloses the connection in the majority of casesif associated with another congenital heart defect amenable to surgery then?prostaglandin E1 is useful to keep the duct open?until after surgical repairCongenital infectionsCytomegalovirus commonest congenital infection. Maternal infection is usually asymptomaticRubella (↓↓↓)ToxoplasmosisCytomegalovirusCharacteristic featuresSensorineural deafnessCongenital cataractsGlaucomaCongenital heart disease (PDA)Cerebral calcification75% of patientsHydrocephalusChorioretinitisGrowth retardationPurpuric skin lesionsOther FeaturesGrowth retardationCerebral palsyMicrophthalmia'Salt and pepper' Retinopathy " Chorioretinitis"HepatosplenomegalyPurpuric skin lesionsCerebral palsyHepatosplenomegalyAnaemiaCerebral palsy.Encephalitis/seizuresSensorineural deafnessPneumonitisHepatosplenomegalyJaundiceAnaemiaCerebral perfusion pressureThe net pressure gradient causing blood flow to the brain is tightly autoregulated to maximise cerebral perfusion. A sharp rise in CPP ↑↑ ICP↓↓↓ CPP cerebral ischaemia. CPP= Mean arterial pressure (MAP) - Intra cranial pressure (ICP)Following Trauma, the CPP has to be carefully controlled and the may require invasive monitoring of the ICP and MAP.The Cushing reflex physiological nervous system response to ↑↑ ICP hypertension(↑↑ Mean pressure) and bradycardia.?A sympathetic reflex therefore hypertension counter parasympathetic reflex by stimulation of the baroreceptors resulting in bradycardia.Spinal cordLocated in a canal within the vertebral column that affords it structural support.Rostrally it continues to the medulla oblongata of the brain and caudally it tapers at a level corresponding to the L1-2 interspace (in the adult), a central structure, the filum terminale anchors the cord to the first coccygeal vertebra.The spinal cord is characterised by cervico-lumbar enlargements and these, broadly speaking, are the sites which correspond to the brachial and lumbar plexuses respectively.There are some key points to note when considering the surgical anatomy of the spinal cord:* During foetal growth the spinal cord becomes shorter than the spinal canal, hence the adult site of cord termination at the?L1-2 level.* Due to growth of the vertebral column the spine segmental levels may not always correspond to bony landmarks as they do in the cervical spine.* The spinal cord is incompletely divided into two symmetrical halves by a?dorsal median sulcus?and?ventral median fissure. Grey matter surrounds a central canal that is continuous rostrally with the ventricular system of the CNS.The spinothalamic tract is responsible for carrying sensory fibres for pain and temperature. It decussates at the same level the nerve root enters the spinal cord, and hence temperature loss is contralateral. The dorsal column medial lemniscus carries sensory fibres for fine touch and vibration (and unconscious proprioception). It decussates at the medulla and hence the fine touch and vibration loss is ipsilateral. The corticospinal tract is a descending tract which has already decussated (at the medulla). It is responsible for inhibiting movement of muscles. Loss of its function causes an upper motor neuron lesion on the ipsilateral side (if affected in the spinal cord)* The grey matter is sub divided cytoarchitecturally into?Rexeds laminae.The?Rexed laminae?comprise a system of ten layers of?grey matter?(I–X), identified in the early 1950s by?Bror Rexed?to label portions of the?grey columns?of the?spinal cord.[1][2]Similar to?Brodmann areas, they are defined by their cellular structure rather than by their location, but the location still remains reasonably consistenLaminaeEditPosterior grey column: I–VILamina I:?marginal nucleus of spinal cord?or posteromarginal nucleus[3]Lamina II:?substantia gelatinosa of Rolando[3]Laminae III and IV:?nucleus proprius[3]Lamina V: Neck of the dorsal horn. Neurons within lamina V are mainly involved in processing sensory afferent stimuli from cutaneous, muscle and joint mechanical nociceptors as well as visceral nociceptors. This layer is home to wide dynamic range tract neurons, interneurons and propriospinal neurons. Viscerosomatic pain signal convergence often occurs in this lamina due to the presence of wide dynamic range tract neurons resulting in pain referral.[4]Lamina VI: Base of the dorsal horn. No nociceptive input occurs here, instead this lamina receives input from large-diameter fibres innervating muscles and joints and from muscle spindles which are sensitive to innocuous joint movement and muscle stretch to feed forward this information to the cerebellum where it can modulate muscle tone accordingly.?[5]Lateral grey column: VII and XLamina VII: intermediomedial nucleus,?intermediolateral nucleus,?posterior thoracic nucleus?in the thoracic and upper lumbar region[6]Lamina X: an area of grey matter surrounding the?central canal.[6][3]Anterior grey column: VIII–IXLamina VIII: motor?interneurons; Commissural nucleus[6]Lamina IX: hypaxial (body wall muscles), lateral (in limb regions) and medial (back muscles)?motor neurons, also?phrenic?and?spinal accessory?nuclei at cervical levels, and?Onuf's nucleus?in the sacral region0197485* Afferent fibres entering through the dorsal roots usually terminate near their point of entry but may travel for varying distances in?Lissauers tract. In this way they may establish synaptic connections over several levels* At the tip of the dorsal horn are afferents associated with nociceptive stimuli. The ventral horn contains neurones that innervate skeletal muscle.The key point to remember when revising CNS anatomy is to keep a clinical perspective in mind. So it is worth classifying the ways in which the spinal cord may become injured. These include:Trauma?either direct or as a result of disc protrusionNeoplasia?either by direct invasion (rare) or as a result of pathological vertebral fractureInflammatory diseases?such as Rheumatoid disease, or OA (formation of osteophytes compressing nerve roots etc.Vascular?either as a result of stroke (rare in cord) or as complication of aortic dissectionInfection?historically diseases such as TB, epidural abscesses.The anatomy of the cord will, to an extent dictate the clinical presentation. Some points/ conditions to remember:Brown- Sequard syndrome-Hemisection of the cord producing ipsilateral loss of proprioception and upper motor neurone signs, plus contralateral loss of pain and temperature sensation. The explanation of this is that the fibres decussate at different levels.Lesions below L1 will tend to present with lower motor neurone signsForamina of the skullForamenBoneVesselsNervesOptic canalSphenoidOphthalmic arteryOptic nerve (II)Superior orbital fissureSphenoidSuperior ophthalmic veinInferior ophthalmic veinOculomotor nerve (III)Trochlear nerve (IV)lacrimal, frontal and nasociliary branches of ophthalmic nerve (V1)Abducent nerve (VI)Inferior orbital fissureSphenoid and maxillaInferior ophthalmic veinsInfraorbital arteryInfraorbital veinZygomatic nerve and infraorbital nerve of maxillary nerve (V2)Orbital branches of pterygopalatine ganglionForamen rotundumSphenoid-Maxillary nerve (V2)Foramen ovaleSphenoidAccessory meningeal arteryMandibular nerve (V3)Jugular foramenOccipital and temporalPosterior meningeal arteryAscending pharyngeal arteryInferior petrosal sinusSigmoid sinusInternal jugular veinGlossopharyngeal nerve (IX)Vagus nerve (X)Accessory nerve (XI)Cranial NervesNerveFunctionsLesionsPathway/foramenI (Olfactory)SmellCribriform plateII (Optic)SightOptic canalIII (Oculomotor)Eye movement (Inf O, MR, SR, IR) 3 rectusPupil constrictionAccomodationEyelid openingPtosis Out and Down ' gazedilated, fixed pupilSuperior Orbital Fissure (SOF)IV (Trochlear) Eye movement (SO) Out and Upward gaze "Diplopia"SOFV (Trigeminal)Facial sensationMasticationTrigeminal neuralgiaLoss of corneal reflex (afferent)Loss of facial sensationParalysis of mastication musclesDeviation of jaw to weak sideV1: SOFV2: Foramen Rotundum?V3: Foramen OvaleVI (Abducens)Eye movement (LR)Palsy results in defective abduction → horizontal diplopiaCN6 arises from the pons which sits on the clivus SOFVII (Facial)Facial movementTaste (anterior 2/3rds of tongue)LacrimationSalivationflaccid paralysis of upper + lower faceloss of corneal reflex (efferent)loss of tastehyperacusisInternal auditory meatusVIII (Vestibulocochlear)Hearing, balanceHearing lossVertigo, nystagmusInternal auditory meatusIX (Glossopharyngeal)Taste (posterior 1/3rd of tongue)SalivationSwallowing?Mediates input from carotid body &sinusLesions may result in;hypersensitive carotid sinus reflexloss of gag reflex (afferent)Jugular foramenX (Vagus)PhonationSwallowingInnervates visceraUvula deviates away from site of lesionloss of gag reflex (efferent)Jugular foramenXI (Accessory)Head and shoulder movement↓↓ turning head to contralateral sideJugular foramenXII (Hypoglossal)Tongue movementTongue deviates towards side of lesionHypoglossal canalDermatomesNerve rootLandmarkMnemonicsC2Posterior half of the skull (cap)C3High turtleneck shirtC4Low-collar shirtC5Ventral axial line of upper limbC6Thumb + index fingerMake a 6 with your left hand by touching the tip of the thumb & index finger together - C6C7Middle finger + palm of handC8Ring + little fingerT4NipplesT4 at the Teat PoreT5Inframammary foldT6Xiphoid processT10UmbilicusBellybuT-TENL1Inguinal ligamentL for ligament, 1 for 1nguinalL4Knee capsDown on aLL fours - L4L5Big toe, dorsum of foot (except lateral aspect)L5 = Largest of the 5 toesS1Lateral foot, small toeS1 = the smallest oneS2, S3GenitaliaBrachial plexus OriginAnterior rami of C5 to T1Sections of the plexusRoots, trunks, divisions, cords, branchesMnemonic:Real Teenagers Drink Cold BeerRootsLocated in the posterior trianglePass between scalenus anterior and mediusTrunksLocated posterior to middle third of clavicleUpper and middle trunks related superiorly to the subclavian arteryLower trunk passes over 1st rib posterior to the subclavian arteryDivisionsApex of axillaCordsRelated to axillary artery?C8 radiculopathy evidenced by reduced sensation in the C8 dermatome (the medial side of the hand over the little finger) and weakness of the C8 myotome (flexion of the distal interphalangeal and metacarpophalangeal joints).?Elbow extension is weak as it has roots from both C7 and C8 and so cannot be used alone to decide between the two levels clinically.?C6 or C7 roots and these are unaffected as evidenced by normal elbow flexion and thumb sensation (C6) and normal sensation over the middle finger (C7).The C8 nerve root exits the spine below the C7 vertebra, being the only cervical nerve root which exits below a vertebra. The rest of the cervical nerve roots derive their name from the vertebra below them. The most common acute pathology causing a radiculopathy is a disc herniation and therefore this is the correct answer.Radial nerveContinuation of posterior cord of the brachial plexus (root values C5 to T1) Pathway In the axilla: lies posterior to the axillary artery on subscapularis, latissimus dorsi and teres major.Enters the arm between the brachial artery and the long head of triceps (medial to humerus).Spirals around the posterior surface of the humerus in the groove for the radial nerve.At the distal third of the lateral border of the humerus it then pierces the intermuscular septum and descends in front of the lateral epicondyle.At the lateral epicondyle it lies deeply between brachialis and brachioradialis where it then divides into a superficial and deep terminal branch.Deep branch crosses the supinator to become the posterior interosseous nerve.Regions innervatedMotor (main nerve)TricepsAnconeusBrachioradialisExtensor carpi radialisMotor (posterior interosseous branch)SupinatorExtensor carpi ulnarisExtensor digitorumExtensor indicisExtensor digiti minimiExtensor pollicis longus and brevisAbductor pollicis longusSensoryThe area of skin supplying the proximalphalanges on the dorsal aspect of the hand is supplied by the radial nerve (this does not apply to the little finger and part of the ring finger)Muscular innervation and effect of denervationAnatomical locationMuscle affectedEffect of paralysisShoulderLong head of tricepsMinor effects on shoulder stability in abductionArmTricepsLoss of elbow extensionForearmSupinatorBrachioradialisExtensor carpi radialis longus and brevisWeakening of supination of prone hand and elbow flexion in mid prone positionPatterns of damagewrist dropsensory loss to small area between the dorsal aspect of the 1st and 2nd metacarpalsAxillary damageAs aboveparalysis of tricepsPopliteal fossaBoundaries of the popliteal fossaLaterallyAbove Biceps femoris (toward UL) Below Lateral head of gastrocnemius and Plantaris MediallyAbove Semimembranosus and SemitendinosusBelow Medial head of gastrocnemius Floor (bone, joint, muscle)Popliteal surface of the femur, posterior ligament of knee joint and popliteus muscleRoof (Fascia)Superficial and deep fasciaContentsPopliteal artery and veinSmall saphenous veinCommon peroneal nerveTibial nervePosterior cutaneous nerve of the thighGenicular branch of the obturator nerveLymph nodesRuptured Popliteal Cyst Sudden onset of pain, associated first with symptoms behind the knee, and calf swelling (weeks after the original incident).Significant osteoarthritis of the knee predisposes to the condition.Physiotherapy and Analgesia the mainstay of therapy for the condition. DD. Pseudogout and septic arthritis is primarily associated with anterior knee pain and swelling.A ruptured calf muscle is more likely to present with pain in the body of the calf itself, rather than pain behind the knee.Brain tumoursMRI contrast is the investigation of choice as its the most sensitive. Single or even multiple well-demarcated lesions are seen with adjacent oedematous changes. Non-enhancing lesions following the introduction of contrast enhancement are far less likely to be metastatic in origin. Contrast-enhanced MRI also has the advantage of detecting leptomeningeal involvement. Bigger metastatic foci appear as ring enhanced lesions with a central non-enhancing area due to underlying necrotic tissue.Whilst a CT scan with contrast enhancement increases diagnostic accuracy, it is not as sensitive as an MRI scan with contrast.Magnetic resonance angiography (MRA) is used to visualise blood vessels and would not be of much benefit in this situation.?Magnetic resonance venography is used to determine the absence of blood flow within the sinuses, which would occur in the presence of venous sinus thrombosis.The majority of adult tumours are supratentorial, where as the majority of childhood tumours are infratentorial.Type of tumourFeaturesMetastasesCommonest form of brain tumours. They are often multiple and not treatable with surgical mon Sources:lung (most common)breastbowelskin (namely melanoma)kidneyGliolastoma multiforme? Commonest 1ry tumour in adultsand Poor prognosis (~ 1yr).Imaging Solid tumours with central necrosis and a rim that enhances with contrast.Disruption of the blood-brain barrier and therefore are associated with vasogenic oedemaHistology:?Pleomorphic tumour cells border necrotic areasTreatment Surgical with postoperative chemotherapy and/or radiotherapy.↑↑↑ invade normal brain and resection nearly incomplete. Even if incompletely resected conditions such as rising ICP can be addressed with tumour debulking and survival and quality of life prolonged.?Dexamethasone is used to treat the oedema.Meningioma2nd most common primary brain tumour in adultsTypically benign, extrinsic tumours extra-axial lesions (not from brain parenchyma) Arise from the?dura mater with symptoms by compression rather than invasion.Site Falx Cerebri, Superior Sagittal Sinus, convexity or skull base.Histology:?Spindle cells in concentric whorls and calcified psammoma bodiesCT (will show?contrast enhancement) and MRI Treatment: observation, radiotherapy or surgical resection(Curative).Vestibular schwannoma? 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??The most common primary brain tumour in children? Histology:?Rosenthal fibres?(corkscrew eosinophilic bundle)MedulloblastomaAggressive paediatric tumour within the (Temporal and Frontal lobe) infratentorial compartment. may reach considerable size before becoming symptomatic. Tumours in the speech and visual areas will typically produce early symptoms It spreads through the CSF system.. Histology:?Small, blue cells. Rosette pattern of cells with many mitotic figuresTreatment is surgical resection and chemotherapyEpendymoma? Commonly seen in the?4th ventricle? May cause?hydrocephalus? Histology:?perivascular pseudorosettesOligodendroma? Benign,?slow-growing tumour common in the frontal lobes? Histology:?Calcifications with 'fried-egg' appearanceHaemangioblastoma??Vascular tumour of the cerebellum? Associated with?von Hippel-Lindau syndrome? Histology:?foam cells and high vascularityPituitary adenoma? 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? 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.Clinical trial: phasesClinical trials are commonly classified into 4 phases;PhaseGoalNotesIDetermines pharmacokinetics and pharmacodynamics and side-effects prior to larger studiesConducted on healthy volunteersIIAssess efficacy + dosageInvolves small number of patients affected by particular diseaseMay be subdivided intoIIa - assesses optimal dosingIIb - assesses efficacyIIIAssess effectivenessTypically involves 100-1000's of people, often as part of a randomised controlled trial, comparing new treatment with established treatmentsIVPostmarketing surveillanceMonitors for long-term effectiveness and side-effectsStudy designStudy typeKey featuresRandomised controlled trialParticipants randomly allocated to intervention or control group (e.g. standard treatment or placebo)Practical or ethical problems may limit useCohort studyRisk factor to who will get the disease Observational and prospective selected according to their exposure to a particular agent (medicine, toxin) andFollowed-up to see how many develop a disease or other outcome.The usual outcome measure is the relative risk. (number of events /total)Ex: include Framingham Heart Study. Case-control study From the disease to investigate Risk factor Observational and retrospective.?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.The usual outcome measure is the odds ratio ( Diseased/non diseased of the same groupInexpensive, produce quick resultsUseful for studying rare conditionsProne to confoundingCross-sectional surveyProvide a 'snapshot', sometimes called?prevalence studiesProvide weak evidence of cause and effectStudy design evidence and recommendationsLevels of evidenceIa from meta-analysis of randomised controlled trialsIb from at least one randomised controlled trialIIa from at least one well designed controlled trial which is not randomisedIIb from at least one well designed experimental trialIII from case, correlation and comparative studiesIV from a panel of expertsGrading of recommendationGrade A - based on evidence from at least one randomised controlled trial (Ia or Ib)Grade B - based on evidence from non-randomised controlled trials (iIIa, IIb or III)Grade C - based on evidence from a panel of experts (IV)Study design: new drugsWhen a new drug is launched One option is a placebo controlled trial.Whilst this provide robust evidence may be unethical if established treatments are available and it does not provide a comparison with standard treatments.If a drug is to be compared to an existing treatment a statistician decide whether the trial is intended to show superiority, equivalence or non-inferiority:superiority: The natural aim of a trial one problem is the large sample size needed to show a significant benefit over an existing treatmentequivalence: 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 effectnon-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 Once a drug has been shown to be non-inferior large studies may be performed to show superiorityIt should be remembered that drug companies may not necessarily want to show superiority over an existing product. If it can be demonstrated that their product is equivalent or even non-inferior then they may compete on price or convenience.Incidence and prevalence2 terms are used to describe the frequency of a condition in a population.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%.The?prevalence?is the total number of cases per population at a particular point in time (Cross sectional Study)Ex: 2,500 adults asked about weigh If 500 of the adults were obese the prevalence of obesity would be 0.2 or 20%.The most important factor when determining how many resources/ how much help will be required for patients iv certain areaRelationshipprevalence = incidence * duration of conditionChronic diseases the prevalence is much > incidenceAcute diseases the prevalence and incidence are similar. For conditions such as the common cold the incidence may be greater than the prevalenceScreening test statisticsPatients and doctors need to know if a disease or condition is present or absent. Tests can be used to help us decide. Tests generally guide us by indicating how likely it is that the patient has the condition.?In order to interpret test results we need to have a working knowledge of the statistics used to describe them.Contingency tables (also known as 2 * 2 tables, see below) are used to illustrate and calculate test statistics such as sensitivity. It would be unusual for a medical exam not to feature a question based around screening test statistics. Commit the following table to memory and spend time practising using it as you will be expected to make calculations using it in your exam.TP = true positive; FP = false positive; TN = true negative; FN = false negativeDisease presentDisease absentTest positiveTPFPTest negativeFNTNThe table below lists the main statistical terms used in relation to screening tests:MeasureFormulaPlain englishSensitivityTP / (TP + FN )Proportion of patients with the condition who have a positive test resultSpecificityTN / (TN + FP)Proportion of patients without the condition who have a negative test resultPositive predictive valueTP / (TP + FP)The chance that the patient has the condition if the diagnostic test is positiveNegative predictive valueTN / (TN + FN)The chance that the patient does not have the condition if the diagnostic test is negativeLikelihood ratio for a positive test resultsensitivity / (1 - specificity)How much the odds of the disease increase when a test is positiveLikelihood ratio for a negative test result(1 - sensitivity) / specificityHow much the odds of the disease decrease when a test is negativePositive and negative predictive values are prevalence dependent. Likelihood ratios are not prevalence dependent.PrecisionThe precision quantifies a tests ability to produce the same measurements with repeated tests.Screening: Wilson and Junger criteria1. The condition should be an important public health problem?2. There should be an acceptable treatment for patients with recognised disease3. Facilities for diagnosis and treatment should be available4. There should be a recognised latent or early symptomatic stage5. The natural history of the condition, including its development from latent to declared disease should be adequately understood6. There should be a suitable test or examination7. The test or examination should be acceptable to the population8. There should be agreed policy on whom to treat9. The cost of case-finding (including diagnosis and subsequent treatment of patients) should be economically balanced in relation to the possible expenditure as a whole10. Case-finding should be a continuous process and not a 'once and for all' projectIntention to treat analysis is a method of analysis for randomized controlled trials all patients randomly assigned to one of the treatments are analysed together, regardless of whether or not they completed or received that treatmentIntention to treat analysis is done to avoid the effects of crossover and drop-out, which may affect the randomization to the treatment groupsStudy BiasBias describes?the situation in a trial where one outcome is systematically favoured. It should be noted that there is considerable variation in the definitions and classification of bias. The table below lists some of the more common types of bias.TypeDescriptionSelection biasError in assigning individuals to groups leading to differences which may influence the outcome. Subtypes include?sampling bias?where the?subjects are not representative of the population. This may be due to?volunteer bias. An example of volunteer bias would be a study looking at the prevalence of?Chlamydia?in the student population. Students who are at risk of?Chlamydia?may be more, or less, likely to participate in the study. A similar concept is?non-responder bias. If a survey on dietary habits was sent out in the post to random households it is likely that the people who didn't respond would have poorer diets than those who did.Other examples include?loss to follow up biasprevalence/incidence bias (Neyman bias): when a study is investigating a condition that is characterised by early fatalities or silent cases. It results from missed cases being omitted from calculationsadmission bias (Berkson's bias): cases and controls in a hospital case control study are systematically different from one another because the combination of exposure to risk and occurrence of disease increases the likelihood of being admitted to the hospitalhealthy worker effectRecall biasDifference in the accuracy of the recollections retrieved by study participants, possibly due to whether they have disorder or not. E.g. a patient with lung cancer may search their memories more thoroughly for a history of asbestos exposure than someone in the control group. A particular problem in?case-control studies.Publication biasFailure to publish results from valid studies, often as they showed a negative or uninteresting result. Important in meta-analyses where studies showing negative results may be excluded.Work-up bias (verification bias)In studies which compare new diagnostic tests with gold standard tests, work-up bias can be an issue. Sometimes clinicians may be reluctant to order the gold standard test unless the new test is positive, as the gold standard test may be invasive (e.g. tissue biopsy). This approach can seriously distort the results of a study, and alter values such as specificity and sensitivity. Sometimes work-up bias cannot be avoided, in these cases it must be adjusted for by the researchers.Expectation bias (Pygmalion effect)Only a problem in non-blinded trials.?Observers may subconsciously measure or report data in a way that favours the expected study outcome.Hawthorne effectDescribes a group changing it's behaviour due to the knowledge that it is being studiedLate-look biasGathering information at an inappropriate time?e.g. studying a fatal disease many years later when some of the patients may have died alreadyProcedure biasOccurs when subjects in different groups receive different treatmentLead-time biasOccurs when two tests for a disease are compared, the new test diagnoses the disease earlier, but there is no effect on the outcome of the diseaseDetection bias: Outcomes are sought after more in one group than in anotherObserver bias: There is observer subjectivity about the outcomePublication bias: Studies that report negative findings are less likely to be publishedRecall bias: Patients are more likely to recall exposures that they believe are related to the outcomeResponse bias: Those who respond to a questionnaire / volunteer for a trial are not representative of the populationNormal distributionis also known as the Gaussian distribution or 'bell-shaped' distribution. It describes the spread of many biological and clinical measurements with is a continuous probability distribution (Not discrete probability distribution)Properties of the Normal distributionsymmetrical i.e. Mean = mode = median68.3% of values lie within 1 SD of the mean95.4% of values lie within 2 SD of the mean99.7% of values lie within 3 SD of the meanthis is often reversed, so that within 1.96 SD of the mean lie 95% of the sample valuesthe 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 rangeStandard deviationthe standard deviation (SD) is a measure of how much dispersion exists from the meanSD = square root (variance)Numbers needed to treat and absolute risk reductionNumbers needed to treat (NNT) is a measure that indicates how many patients would require an intervention to reduce the expected number of outcomes by oneIt is calculated by 1/(Absolute risk reduction) and is rounded to the next highest whole numberExperimental event rate (EER) = (Number who had particular outcome with the intervention) / (Total number who had the intervention)Control event rate (CER) = (Number who had particular outcome with the control/ (Total number who had the control)Absolute risk reduction = CER-EER or EER-CER?The absolute risk reduction (ARR) may be calculated by finding the absolute difference between the control event rate (CER) and the experimental event rate (EER). You will often find both versions of the above listed in different sources. In some ways in doesn't matter which you use as you will end up with the same answer but from a technical point of view:if the outcome of the study is undesirable then ARR = CER - EERif the outcome of the study is desirable then ARR* = EER - CER*this may be more accurately termed absolute benefit increase, rather than absolute risk reductionOdds and odds ratioOdds are a ratio of the number of people who incur a particular outcome to the number of people who do not incur the outcome. The odds ratio may be defined as the ratio of the odds of a particular outcome with experimental treatment and that of control.?Odds vs. probabilityIn contrast, probability is the fraction of times you'd expect to see an event in many trials. When expressed as a single number probability is always between 0 and 1. So, if we take the example of rolling a dice:the probability of rolling a six is 1/6 or 0.166666the odds of rolling a six is 1/5 or 0.2Odds ratios are the usual reported measure in case-control studies. It approximates to relative risk if the outcome of interest is rare.For example, if we look at a trial comparing the use of paracetamol for dysmenorrhoea compared to placebo we may get the following resultsTotal number of patientsAchieved = 50% pain reliefParacetamol6040Placebo9030The odds of achieving significant pain relief with paracetamol = 40 / 20 = 2The odds of achieving significant pain relief with placebo = 30 / 60 = 0.5Therefore the odds ratio = 2 / 0.5 = 4Confidence interval and standard error of the meanCI a range of values within which the true effect of intervention is likely to lieThe likelihood of the true effect lying within the confidence interval is determined by the confidence level. For example a confidence interval at the 95% confidence level means that the confidence interval should contain the true effect of intervention 95% of the time.How is the confidence interval calculated?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?SEM = standard deviation SD / Square root √ Sample Size (n)?SEM gets smaller as the sample size (n) increasesA 95% confidence interval: (Mean +/- 2 SE).lower limit = mean - (1.96 * SEM)upper limit = mean + (1.96 * SEM)For 90% this would 1.645if a small sample size is used (n < 100) use a 'Student's T critical value' look-up table to replace 1.96 with a different valueHazard ratioThe 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 timeRelative riskThe usual outcome measure Cohort study 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). The term relative risk ratio is sometimes used instead of relative risk.EER = rate at which events occur in the experimental groupCER = rate at which events occur in the control groupFor example, if we look at a trial comparing the use of paracetamol for dysmenorrhoea compared to placebo we may get the following resultsTotal number of patientsExperienced significant pain reliefParacetamol10060Placebo8020Experimental event rate, EER = 60 / 100 = 0.6Control event rate, CER = 20 / 80 = 0.25Therefore the relative risk ratio = EER / CER = 0.6 / 0.25 = 2.4If the risk ratio is > 1 then the rate of an event (in this case experiencing significant pain relief) is increased compared to controls. It is therefore appropriate to calculate the relative risk increase if necessary (see below).If the risk ratio is < 1 then the rate of an event is decreased compared to controls. The relative risk reduction should therefore be calculated (see below).Relative risk reduction (RRR)?or?relative risk increase (RRI)?is calculated by dividing the absolute risk change by the control event rate RRI = (EER - CER) / CER = (0.6 - 0.25) / 0.25 = 1.4 = 140%Funnel plotA 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.InterpretationA symmetrical, inverted funnel shape indicates that publication bias is unlikelyConversely, 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')Fitness to flyCardiovascular diseaseunstable angina, uncontrolled hypertension, uncontrolled cardiac arrhythmia, decompensated heart failure, severe symptomatic valvular disease: should not flyuncomplicated myocardial infarction: may fly after 7-10 dayscomplicated myocardial infarction: after 4-6 weekscoronary artery bypass graft: after 10-14 dayspercutaneous coronary intervention: after 5 daysstroke: patients are advised to wait 10 days following an event, although if stable may be carried within 3 days of the eventRespiratory diseasepneumonia: should be 'clinically improved with no residual infection'pneumothorax: absolute contraindication, the CAA suggest patients may travel 2 weeks after successful drainage if there is no residual air. The British Thoracic Society used to recommend not travelling by air for a period of 6 weeks but this has now been changed to?1 week post check x-rayPregnancymost airlines do not allow travel after?36 weeks for a single pregnancy?and after?32 weeks for a multiple pregnancymost airlines require a certificate after 28 weeks confirming that the pregnancy is progressing normallySurgerytravel should be avoided for 10 days following abdominal surgerylaparoscopic surgery: after 24 hourscolonoscopy: after 24 hoursfollowing the application of a plaster cast, the majority of airlines restrict flying for 24 hours on flights of less than 2 hours or?48 hours for longer flightsHaematological disorderspatients with a haemoglobin of greater than 8 g/dl may travel without problems (assuming there is no coexisting condition such as cardiovascular or respiratory disease)Folate metabolismDrugs which interfere with metabolismtrimethoprimmethotrexatepyrimethamineDrugs which can reduce absorptionphenytoinEthics 3 Main frameworks for (Patients who lack (or are suspected of lacking) capacity refuse mon law Patients in?emergency scenariosMental Capacity Act (MCA) Patients who require treatment for?physical disorders?that affect brain function. Remember this may be delirium secondary to sepsis or a primary brain disorder such as dementiaMental Health Act (MHA)Patients who require treatment for?mental disorders. For patients already admitted to hospital, a section 5(2) is used if there is not the time for a more formal section 2 or 3. A typical scenario would be a patient who has a mental health disorder attempting to discharge themselves, when it is thought this may result in harm?Mental Capacity Act?It applies to adults over the age of 16 and sets out who can take decisions if a patient becomes incapacitated (e.g. following a stroke). Mental capacity includes the ability to make decisions affecting daily life, healthcare and financial issues 5 key principlesA person must be assumed to have capacity unless it is established that he lacks capacityA person is not to be treated as unable to make a decision unless all practicable steps to help him to do so have been taken without successA person is not to be treated as unable to make a decision merely because he makes an unwise decisionAn act done, or decision made, under this Act for or on behalf of a person who lacks capacity must be done, or made, in his best interestsBefore the act is done, or the decision is made, regard must be had to whether the purpose for which it is needed can be as effectively achieved in a way that is less restrictive of the person's rights and freedom of actionPre- and post- test odds and probabilityPre-test probability = PrevalenceThe proportion of people with the target disorder in the population at risk at a specific time (point prevalence) or time interval (period prevalence)For example, the prevalence of rheumatoid arthritis in the UK is 1%Post-test probabilityThe proportion of patients with that particular test result who have the target disorderPost-test probability = post test odds / (1 + post-test odds)Pre-test oddsThe 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 oddsThe odds that the patient has the target disorder after the test is carried outPost-test odds = pre-test odds x likelihood ratiolikelihood ratio for a positive test result = sensitivity / (1 - specificity) ................
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