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For this to work signalling molecules must not diffuse far. Ligands are taken up rapidly by neighbouring cells, destroyed by extracellular matrix and are immobilised by the extracellular matrix.

Signalling proteins have effects on gene regulatory proteins, metabolic enzymes and cytoskeleton proteins. Response is fast through altered protein function which causes altered cytoplasmic machinery or response it slow due to altered gene transcription which alters protein synthesis.

They are involved in rapid synaptic signalling. Channels are made up of different subunits which are homologous multi-pass transmembrane proteins. Their opening and closing is mediated by a small number of neurotransmitters.

Function directly as enzymes or associated directly with the enzymes they activate. They are usually single pass transmembrane proteins and are heterogenous in strucure. The majority are or are associated with kinases.

7 transmembrane receptors. The trimeric G protein has alpha, beta and gamma subunits and mediates the interaction between the activated receptor and target protein. On activation the alpha subunit separates and it's often the alpha subunit that stimulates the downstream enzyme. GTP is involved.

It is a breast cancer drug that binds to the HER2 receptor blocking access of the ligand and recruits the host's immune system to promote attack and removal of the cancer cells. HER2 is found on the surface of normal mammary cells and is involved in cascading growth signals. It is more numerous in a subset of breast cancers.

The allosteric regulator binds to the allosteric site of the enzyme which is independent of the active site. The regulator has a weak, non-covalent interaction with the active site and it affects the catalytic properties of the active site through affinity or conformational change. e.g.adenosine monophosphate (AMP) activates glycogen phosphorylase.

Phosphate is added to the hydroxyl containing amino acids (serine, threonine and tyrosine) and it is bulky and charged, therefore changes the enzyme by affecting electrostatic interactions. conformational change and sub-cellular distribution.

Adrenaline via adenylate cyclase causes increase in cAMP. cAMP activates protein kinase A which phosphorylates phosphorylase kinase. Phosphorylase kinase activates glycogen phosphorylase through phosphorylation which converts glycogen into glucose-1-phosphate.

Enzymes are secreted as zymogens which are activated by cleavage when and where they are needed. E.g. chymotripsinogen is cleaved to tripsinogen in the duodenum.

Due to incorrect lactase regulation. Lactase converts lactose to galactose and glucose. There is a C/T variant in the regulatory region of the lactase gene and it is C that is associated with developmental down regulation of lactase production. Undigested lactose is broken down by bacteria in the large intestine which causes diarrhoea, flatulence, bloating and nausea.

20S core is made up of 4 stacked rings; alpha, beta, beta, alpha. Beta has the catalytic activity. The 19S part recognises, binds and unfolds the protein and then using ATPases in it's base opens the 20S part so proteins to be degraded can enter.

The control of folding, concentration, cellular localisation and interaction of proteins. Protein synthesis is controlled by transcription and translation and protein quality is controlled by chaperones and degradation. With ageing there is decreased expression, alteration or replacement of the proteasome subunit and amyloid beta containing autophagosomes accumulate.

MAP tau accumulates intraneuronally forming tangles and amyloid beta extraneuronally. Symptoms include dementia and memory loss due to death of cerebral cortex and hippocampal neurones. A mutated form of ubiquitin (UBB+1) is present and means protein substrates can't be disassembled so proteasome activity is inhibited.

Alpha-synuclein accumulates intraneuronally (Lewy bodies). Symptoms include tremor, rigidity, akinesia and postural reflexes caused by death of niagrostriatal neurons. Parkin E3 ubiquitin ligase (E3) is important in UPS and autophagy and is mutated in autosomal recessive juvenile Parkinson's disease.

Inhalation of gastric contents, hypoglycaemia, disinhibition, hypothermia, lactic acidosis and indirectly associated injuries. Increased toxicity of paracetamol and halothane. Increased clearance of phenytoin and phenobarbitone

<50mg/dL increased talkativeness

50-100mg/dL slurred speech, emotional instability and incoordination

100-300mg/dL blurred vision and loss of sensory preception

300-500mg/dL Severe ataxia, convulsions and coma

>500mg/dL hypothermia, respiratory depression and coma

Ethanol metabolism causes acetyl CoA to build up which is converted into ketone bodies and may cause ketoacidosis. Uric acid builds up as it is excreted by the same area of the kidney as lactate. Hypoglycaemia occurs when glycogen stores are depleted.

glutamate to alpha-ketoglutarate

alpha-ketoglutarate to succinate

malate to oxaloacetate

Inhibits gluconeogenesis, causes lactate accumulation, increased fatty acid synthesis and increased formation of triglyceride fat.

Protect the airways, ventilate, check temperature, glucose and acid-base balance, check for associated injuries and check parecetamol/salicylate levels. Haemodialysis in severe cases.

Occurs mostly due to acetaldehyde but bad source of alcohol may also contain methanol. Symptoms include headache, fatigue, thirst and malaise. No good treatments.

Metabolism produces metaldehyde/formaldehyde and methanoic acid. Causes metabolic acidosis, visual disturbances and hypoglycaemia. Treated by raising concentration of ethanol to 100mg/dL so methanol is excreted by the kidney. Haemodialysis may be necessary to remove methanol and treat severe metabolic acidosis.

Causes liver cirrhosis and ultimately failure. Acetaldehyde adducts and lipid peroxidation products activate kupffer cells. Kupffer cells secrete cytokines TGF-beta, ROS and NO which activate stellate cells. Stellate cells secrete extracellular matrix collagen and metalloproteases which ultimately breakdown the extracellular matrix of the liver causing fibrosis and scarring.

Males: 240-320mmol/L <0.35

Females 180-260mmol/L <0.4

Children at 1 day old ~310mmol/L

Children <140mmol/L <1.5

Excessive production: idiopathic gout, malignancy, tumour lysis, alcohol, genetic defects and myeloproliferative disease.

Excessive intake: purine rich diet

Defective excretion: renal failure, drugs, organic acids, low urine volume and genetic defects.

Massive destruction of tumour tissue usually secondary to chemotherapy which is most often seen in patients with leukaemia or lymphoma. Features include urate nephropathy, hyperuricaemia and hypocalcaemia. It can be prevented with allopurinol, fluids and alkalinisation.

A xanthine oxidase inhibitor. It may precipitate an acute gout attack.

A uricosuric drug that increases excretion of uric acid but are contraindicated in renal function.

X-linked recessive disorder that leads to increased purine degradation, hyperuricaemia and increased purine synthesis. Presents between 1st year of life and adulthood. Symptoms include crystalluria, acute renal failure, gout, neurological defects in 2/3. spasticity, self-mutilation, mental retardation, choreoathetosis and growth failure.

A rare autosomal recessive disease where xanthine oxidase deficiency results in preferential excretion of xanthine.

Defective purine metabolism associated with immunodeficiency. Causes neurological defects, gout, renal stones, renal failure, persistent UTIs, immune deficiency and adverse reaction to purine analogue drugs.

Precipitation of crystals of monosodium urate monohydrate in joints, causing acute arthritis and subcutaneously causing tophi. There is associated release of cytokines and lysosomal enzymes which cause inflammation. 3/1000 Ratio of 7:1 males:females.

The most commonly affected joints are the big toe, the ankles and the knees. Pain, tenderness, redness and desquamination (peeling) around the joints. Onset if sudden, often at night and it usually resolves in 1-3weeks. Isolated attack in 5-10% of people. Hyperuricaemia can cause renal parenchymal damage and risk is increased with acid urine or dehydration.

Lifestyle change: weight reduction, low purine diet and alcohol reduction.

Drug treatment if serum urate exceeds 700mmol/L, more than 2 attacks a year, tophi are present, there is renal dysfunction of there is radiological evidence of joint damage. Treatment is to correct dehydration, allopurinol and citrate/bicarbonate.

Fatigue, polyuria, polydipsia, poor wound healing, blurred vision, altered mental state, diabetic ketoacidosis or hyperosmolar non-ketotic acidoses, retinopathy, neuropathy, nephropathy, hypertension, diabetic foot disease, coronary artery disease, peripheral vascular disease, cerebral vascular disease and infections. Retinopathy is due to high sugar levels damaging the blood vessels that supply the back of the eye.

When you eat there is increase GLP-1 which primes beta cells. Insulin is released when blood glucose is high. Glucose enters the beta cells, is converted to glucose-6-phosphate by glucokinase which leads to increased ATP intracellularly and the release of intracellular calcium stores. Calcium causes secretory vesicles containing insulin to fuse with the membrane and endocytose insulin.

Insulin binds to the alpha subunit causes the beta subunits to transphosphorylate each other. The insulin receptor tyrosine kinase is associated with intracellular docking proteins such as insulin receptor substrate-1 (IRS1) which has tyrosine residues and amplifies the signal. It interacts with molecules with an Src homology 2 domain such p85 which regulates PI3K. Leads to stimulation of Akt.

It promotes GLUT4 translocation to the membrane for glucose uptake. Promotes the activation of glycogen synthase, fatty acid synthase, acetyl coAcarboxylase and mTOR. It inhibits hormone sensitive lipase which is needed for lipolysis. Regulates the transcription of specific metabolic enzymes in the hepatocytes to reduce gluconeogenesis and glycogenolysis.

Monogenic disease, with 6 subtypes. One variant is a glucokinase defect so glucose can't be converted to glucose-6-phosphate. G-6-P is crucial in insulin release.

PPARG gene is present in 85% and it normally regulates adipocyte development and function. KCNJ11 occurs in 40% and it is a component of the ATP dependent K+ channel. CAPN10 gene occurs in 10-25% and is a protease that is implicated in insulin secretion. Some people are also genetically determined to put on visceral fat rather than subcutaneous.

They are bioactive proteins secreted by white adipose tissue. They control whole body metabolism by communicating nutrient status. Adiponectin is insulin sensitizing. Resistin, retinol binding protein 1 and MCP-1 are insulin resistance inducing.

Adipose tissue releases FFAs and cytokines, a greater flux of FFA competitively inhibits glycolysis and reduces insulin secretion. Increased FFA metabolism impairs insulin signalling. Increased IRS-1 phosphorylation impairs the IRS/PI3K pathway

It increases demand for insulin so beta cell activity increases and there is more amyloid and insulin production. This causes endoplasmic reticulum stress and death which contributes to beta cell death.

Proinflammatory macrophages of the M1 phenotype are recruited from the blood to the adipose tissue and secrete insulin resistance inducing cytokines such as TNF-alpha and IL-6. These activate inhibitory serine kinases which phosphorylate serine residues of IRS-1 in the liver and adipose tissue, which leads to attenuated insulin signal transduction. TNF-a also suppresses catabolic AMP kinase pathyway in the peripheral tissue which decreases fatty acid oxidation so there is build up toxic metabolites.

Increase in vascular permeability. Advanced glycogen end product receptors are expressed on blood vesssels leading to increased NADH and oxygen free radicals and increased oxidative stress and inflammatory mediators. More glucose enters the sorbitol/aldose reductase pathyway

Used to treat type 2 diabetes. They inhibit the ATP sensitive K+ channels in beta cells of the pancreas and causes membrane depolarisation and influx of calcium which results in insulin release.

Used to treat type 2 diabetes. A bi-guanide that activates hepatic AMP-kinase which is a sensor of intracellular energy status and is normally activated by low ATP levels. Metformin promotes muscle glucose transport, fatty acid synthesis and inhibits VLDL synthesis and hepatic glucose production.

Peroxisome proliferator activated receptors are a steroid nuclear hormone family. 3 isoforms: delta, gamma and alpha.They are ligand activated transcription factors that have a heterodimeric complex with RXR. RXR is constitutively bound to the promotor regions of target genes.

When off it is bound to the corepressor complex which modifies chromatin keeping it off and making sure RNA polymerase can't get in.

When ligand binds to PPAR there is conformational change in the AF2 domain which now binds the coactivator complex. Coactivator recruits transcription machinery and the target gene is turned on.

Activated by fibrates. Hepatocytes. Results in decreased VLDL, increased HDL, increased acetyl Co synthase and decreased fatty acid synthase. Stimulates production of apolipoproteins A1 and A2. Overall effects is alleviation of dyslipidaemia.

Activated by glitazones. Adipose tissue. Improves tissue insulin sensitivity, therefore normalises blood glucose. Increases lipogenesis, decreases lipolysis and decreasses obesity induced inflammation. Anti-atherogenic properties. Associated with increased risk of heart failure, myocardial infarction, bladder cancer and even fractures.

2 activates lipoprotein lipase and 3 inhibits it. The balance between the two determines how fast a particle is degraded. Present in large amounts in VLDL but reduces once particle is degraded by LPL.

Generated by the liver with triglyceride and cholesterol ester packaged into it. Contain one apoB, large amounts of apoC and small amounts of apoE. After LPL apoE increases and apoC decreases.

The domain for LDL receptor binding is on the N terminal between amino acids 130 and 150. 77% of the population have this isoform. There is cysteine on 112 and arginine on 158

15% of the population. Arginine on 112 and 158. Altered alpha helix structure so altered binding activity. Associated with alzheimer's and atherosclerosis.

8% of the population. Cysteine on 112 and 158. A decrease LDL receptor affinity compared to other isoforms. 1.5% of E2/E2 individuals get type 3 hyperlipoproteinaemia.

Patients have elevated cholesterol and triglyceride levels and suffer from atherosclerosis at a relatively early age. ApoE2 has low binding affinity so decelerates the catabolic change of chylomicrons, VLDL and remnant particles. Conditions such as diabetes repress LDL receptor expression and in the absence of fully functional apoE cholesterol levels rise.

Diabetes, high fat diet, obesity, low levels of oestrogen, and hypothyroidism. (Individuals without these conditions with E2/E2 are asymptomatic as the LDL receptor expression is upregulated.)

Genetic disorder characterized by high cholesterol levels, specifically very high levels of LDL in the blood and early cardiovascular disease. Caused by mutation in the LDL receptor gene. 5% of all coronary artery disease occur due to this. Cholesterol levels 11-25mMol. Signs include corneal arcus and tendon xanthoma.

A mosiac protein that binds cholesterol rich LDL particles to be endocytosed and it recognises apoE and apoB100. Defects occur in 1/500. It is a cell surface glycoprotein of 839 amino acids. It contains 2 asparagine linked (N-glycosylation) and 18 serine linked (O-glycosylation) oligosaccharide chains. Dimeric protein with 2 domains folded independently and with different functions.

Presence of a documented LDL receptor mutation or LDL cholesterol levels above the 95th percentile for age and range with; presence of tendon xanthomas, proven coronary artery disease and LDL cholesterol levels above 95th percentile in patient or 1st degree relative under 60.

The signal sequence that encodes 21 amino acids and is cleaved during translocation into the endoplasmic reticulum.

Ligand binding domain. 7 repeats of 40 amino acids each. Each repeat contains 6 cysteine residues that form 3 disulphide bonds. The COOH- terminal end of each repeat contains a negatively charged triplet SDE which is important for ligand binding.

EGF precursor gene homology encodes 400 amino acid sequence that is 33% identical to human epidermal growth factor gene. It is required for the dissociation of lipoproteins from the receptor in the endosome during receptor recycling.

Carbohydrate chain domain encodes 58 amino acids. No significant functional consequence.

Transmembrane domain that encodes 22 hydrophobic amino acids

Cytoplasmic domain encodes 50 amino acids and is important for localisation of the receptor in endocytosis on the cell surface.

Disrupts LDL receptor synthesis in the ER. Mutations occur randomly.

2A is complete block of transport to golgi and 2B is reduced rate of transport. Occurs in the ligand binding domain or the EGF precursor domain.

LDL receptor is transported to the cell surface but can't bind LDL normally. Occurs in the ligand binding domain.

LDL receptor can't be internalised with LDL into the cell. Affects cytoplasmic domain (only 4A) or also membrane spanning region (4B). Only one found the JD mutation where the tyrosine residue in the consensus NPXY sequency is replaced with cysteine.

Block the acid-dependent dissociation of the receptor and ligand in the endosome so the receptor can't be recycled. Mutations occur in the EGF precursor domain.

Genetically inherited: hypertrophic, dilated and arrhythmogenic right ventricular cardiomyopathy.

Secondary to hypertension, valve disease or coronary artery disease.

Defects in the DGC and sarcomere result in cardiomyopathies.

Specialisation of cardiac and skeletal muscle membranes. Large multicomponent complex that had mechanical stabilising and signalling roles associated with pro-survival. Mediates interactions between the cytoskeleton, membrane and extracellular matrix. Disrupted DGC leads to perturbed cell membrane and an increase in Ca which causes apoptosis and necrosis.

Encodes actin

Defect results in nemaline myopathy

Encodes Troponin T

Defect results in nemaline myopathy

Encodes Desmin

Defect results in desmin myopathy

Encodes delta-sarcoglycan

Defect results in limb girdle muscular dystrophy

Encodes lamin A/C

Defect results in emery/dreifuss muscular dystrophy

Amino acid terminal domain encodes the actin binding domain. The central rod domain is 24 spectrin like repeats, has alpha helical coiled structure and actin binding abilities. Cysteine rich domain has several motifs and binds calmodulin. Carboxy-terminal domain has a coiled-coil motif and is important in protein interaction.

65% are gross deletions: deletion cluster 1 spans exons 45-53 and removes part of the rod domain. Deletion cluster 2 spans exons 2-20 and removes some or all of the actin binding sites together with the rod domain. 35% are small deletions and point mutations which are evenly distributed throughout the gene.

Hypercontractile systolic function and diastolic dysfunction. 1/500 young adults but age of onset varies with the causative gene mutation. Autosomal dominant. Can be diagnosed by a transthoracic echocardiography. There is myofibrillar disarray and interstitial fibrosis.

Palpitations, dizziness, syncope, sudden death and the individual may be asymptomatic.

MHY7 gene mutation occurs in 35% of cases. This gene encodes for the beta-myosin heavy chain which is a 1935 amino acid protein. Mutations cluster in 4 regions: actin binding surface, nucleotide binding pocket, hinge region an near the MLC binding site. Defect results in disruption of mechanical and catalytic properties resulting in reduced force generation.

Cardiac dilation and contractile dysfunction. It is caused by both sporadic and genetic disorders. Symptoms include conduction system disease, skeletal myopathy, sensorineural deafness, weakness, fatigue, dyspnea, palpitations and exercise intolerance.

X-linked recessive disorder due to dystrophin mutation. 2/3 born to carriers and 1/3 spontaneous.1/3500 male births. Presents age 3-5. Absence of DGC and reduced dystrophin associated proteins. Cylcles of regeneration, degeneration, fibrosis and adipocyte deposition and eventually degeneration overtakes regeneration.

Elevated CK levels, waddling gait, difficulty climbing stairs and delay in motor milestones. Weakness is progressive and more pronounced in the lower limbs. Cognitive impairment in some. Death is usually secondary to cardiac dysfunction or respiratory complications.

Diagnosed around age 12 and distribution is similar to DMD but less severe. Loss of ambulation varies from adolescence to 50s. Cardiac dysfunction can occur which is characterised by extensive replacement of myocardial fibres by connective tissue in the lateral wall of the left ventricle.

Cardiac investigations are done every 5 years in BMD and every 2 years for first 10 years, then yearly in DMD. Nocturnal hypoventilation and intermittent positive pressure may improve symptoms in DMD. Glucocorticoids improve muscle strength and funtion. Cardiac transplantation may be viable in BMD but not in DMD due to scoliosis and respiratory failure.

Makes up 25% of a persons body weight. In a healthy person 5-10% of bone is replaced every year and 20% of calcium is exchanged. 30% of bone is organic matrix (mostly type 1 collagen). 70% is minerals: calcium, phosphate and magnesium which combine to form hydroxyapatite. ~0.7% bone loss a year is normal in elderly men and post-menopausal women.

Remodelling is a 4 monthly process of resorption, matrix synthesis and then mineralisation. It is important as microcracks occur due to every day stresses of life and bone would be weak if these were allowed to accumulate.

Involved in anabolism (formation) of bone. They mature and move into lacunae to replace osteoclasts and they deposit new bone into the cavity. They produce type 1 collagen, growth factors and regulate osteoclast activity.

Precursors are monocyte cells that are recruited from the blood to the bone surface where they become committed osteoclasts. There mature into resorptive multinuceated activated osteoclasts and secrete hydrogen ions and lytic enzymes to degrade collagen matrix and bone mineral. This generates resorption lacunae (50um deep).

Generalised and significant reduction in bone mass. Occurs in 1/3 women and 1/12 men. A family of disorders in which systemic bone density is sufficiently reduced to place the patient at significant risk of spontaneous fracture.

Rare. Significant increase in bone mass as a result of anabolism exceeding catabolism.

Discrete areas of increased osteoclast activty leads to increased osteoblast activity - pagetic lesions. Resulting bone is denser and weaker because of thickening of cortical bone, bowing and hypertrophy. Affects 3% of over 55s. Increased risk of fractures.

Very treatable so rarely get severe complications. Many are asymptomatic. 30% experience bone pain, skeletal deformity, deafness, neurological symptoms or pathological fractures. 1% get osteosarcoma.

Recent reduction from 3to 2% shows that environmental factors must be important. 15-40% have at least one affected relative. 5q35-linked PDB causes 20% of cases and is caused by over 30 different mutations in the SQSTM1 gene. SQSTM1 encodes a scaffold protein which binds TRAF6 and regulated its ubiquitination and activates the NFkB pathway.

Rare PDB-like disease caused by different mutations in the RANK gene. The RANK receptor doesn't reach the cell surface so intracellular RANK signals activate the RANK-NFkB pathway anyway which leads to increased expression of genes which encode proteins required for osteoclastogenesis and osteoclast activity.

A rare PDB-like disorder caused by a deletion in the osteoprogerin gene (OPG). OPG is a decoy receptor that binds the RANK-ligand preventing activation of RANK. Loss of OPG leads to increased stimulation of RANK-NFkB pathway and increased osteoclast activity.

Biphosphonates bind with high affinity to bone and although they are non-selective tend to bind most to osteoclasts and promote their death. Denosumab is a RANK-ligand targeted antibody (similar to OPG) and is a much more targeted and cleaner treatment.

Normal range is 2.2-2.6mmol/L. 40% is ionised and other 60% is bound to albumin.

Acts on the gut to increase Ca absorption by increased permeability of the brush border, increased synthesis of high affinity ca-binding protein and increased extrusion of ca across the basolateral membrane.

Increased proliferation and differentiation of osteoclast precursors. Also acts on skin and cancer cells.

Acts on parathyroid glands to decrease PTH (negative feedback). Attaches to intracellular receptor protein and then complex is transported to the nucleus where it interacts with DNA to affect synthesis of RNA encoding proteins. This process is regulated by interleukins, interferons and C-MYC.

There are ca sensing receptors on the parathyroid, PTH is secreted when ca is low. 84 aa produced by chief cells. It increases kidney production of calcitriol (vitamin D). Increases recruitment and activation of osteoclasts. Increases tubular reabsorption of ca and decreases resorption of inorganic phosphate.

32aa, secreted by C-cells of the thyroid. Bind to receptors in osteoclasts decreasing resorption of bone. May be important in high turnover states such as PDB.

decreases bone resorption and formation by acting on oestrogen receptors on oestoblasts. Androgens increase bone mass.

90% Hyperparathyroidism or malignancy. Thyrotoxicosis, Addison's disease, excess vitamin D, ectopic PTH and sarcoid. In a steroid suppression test hyperparathyroidism never suppresses, sarcoid always does and malignancy sometimes does.

Vomiting, constipation, abdominal pain, hypertension, arrhythmias, polyuria, polydipsia, tiredness, bone pain, confusion, depression, stupor, coma, psychosis and corneal calcification. Dehydration due to vomiting or renal defects in concentrating urine.

IV saline fluid is given to wash out sodium which is followed by calcium and biphosphonate infusion. Prednisolone and calcitonin can be used in severe cases. Underlying cause should be treated.

1/500-1/1000 mainly over 50s. 3:1 females to males. 75% due to single adenoma and rest >1 adenoma, 4 gland hyperplasia or ectopic PTH. 1% due to parathyroid carcinoma. Bone disease, renal complications but mostly no symptoms. Treatment with surgery to remove adenoma(s) and biphosphonates if Ca>3 or complications.

Increased serum phosphate due to chronic renal failure or phosphate therapy, hypoparathyroidism (post thyroidectomy), Di george syndrome, severe hypomagneamia or idiopathic (vitamin D deficiency, drugs).

Familial disease that causes intellectual impairment, cataracts, calcified basal ganglia and occasional non-specific autoimmune disease.

Short stature, short metacarpals, intellectual impairment and failure of response to PTH.

Irritability, fatigue, cramps, tetany, convulsions, EEG irregularities. Chvosteck's sign: twitching of mouth when tapping on facial nerve. If prolonged cataracts, papilloedema, depression, mental changes, heart failure and chorea.

Acute hypocalcaemia (with tetany) is treated with calcium gluconate. Maintenance is with alpha-calcidol or calcitriol along with calcium. Underlying cause should also be treated.

Occurs particularly in asian women and the elderly due to diet or poor sunlight exposure. Malabsorption occurs after gastric surgery or when there is deficient bile salt production. In renal disease production of calcitriol is impaired. Rarer causes include Fanconi's syndrome, hepatic failure, vitamin D resistant rickets and oncogenic osteomalacia.

Rickets (bone deformity in children) and osteomalacia in adults. Osteomalacia causes bone and muscle pain, tenderness, subclinical fractures, proximal myopathy and waddling gait.

Slight low levels that causes secondary hyperparathyroidism, increased bone turnover, osteoporosis and fracture risk.

Sunlight exposure, oral D2 or D3 supplements, calcium supplements and im cholecalciferol ever 6-12 months. In renal disease patient will need alpha-calcidol or calcitriol.

cAMP is normally at a conc of 10-7 in the cytosol but this can increase 20 fold in seconds. It is synthesised by adenylate cyclase and broken down by AMP phosphodiesterases to 5'AMP. Adenylate cyclase is regulated by G proteins. Gs activates it and Gi inhibits it.

PIP2 is a hydrophobic phospholipid present in small amounts in the inner half of the plasma lipid bilayer. When phospholipase C is activated by a G protein it cleaves PIP2 into diacylglycerol and IP3. IP3 is charged, highly soluble, released into cytosol where is activates intracellular Ca stores from ER.

PI3kinases phosphorylate PIP2 to give PIP3. PIP3 recruits protein kinase B which activates transcription factor NFkB. NFkB inhibits p53 so apoptosis is inhibited. So PIP3 is important in cell survival.

Important in developmental signalling and cell fate. Dysregulation occurs in cancer. Mutations are mainly in APC (sometimes axin) which causes maintenance of Wnt and continued differentiation. Wnt signalling occurs normally in the crypts of the gut causing differentiation of paneth cells into normal cells.

Wnt activates Fz which passes membrane 7 times. Fz and LRP act together as the receptor. Axin and GSK3 are recruited away from beta catalyn (BC) complex so BC can no longer be destroyed. BC builds up in the cytoplasm, passes to nucleus and targets TCP genes important in proliferation. Normally there is no Wnt signalling and beta catalyn is destroyed.

Shrinkage of cell, fragmentation into membrane bound apoptotic bodies, condensation of nuclear chromatin and rapid phagocyotosis by neighbouring cells. Degradation of DNA occurs by endogenous DNAases which cut out the internucleosomal regions into double stranded DNA fragments. DNA fragments are detectable as a ladder pattern in electrophoresis. Organelle and plasma membrane integrity is maintained.