Bones: (a) Osteoblasts: make:type I collogen released as osteoid, PGE2, osteocalvin & osteonectin;and have receptors for: PTH, vitamin D, PGE2, glucocorosteroids. (b) Osteoclasts: multi-nucleated, resorb bone, sit in Howships lacunae;PTH, Vit D, prostaglandins => increased activity; calcitonin => reduced activity. (c) Compact (or cortical) bone: 80% of skeletal mass, has Harversian system (or osteon). Osteocytes lie in lacunae between the lamellae. (d) Spongy (cancellous or trabecular) bone: very metabolically active. (e) BMP: Bone morphogenic protein. (f) Wolff's law: change in static relation of bone => change in internal structure, external form and physiological function.(g) BMU: bone multicellular units=> coupling of bone breakdown and formation.

(a) Bone growth: (i) Intramembranous = vascular fibrous CT under stress converted directly to bone, (ii) Endochondrial= cartilage model, (iii) Osteoneal. (b) Bone mass (BMC, BMD): measured by dual energy X-ray densitometer. (c) Bone mass factors: genetic, age, sex, hormones, exercise, diet, steroid drugs, early menopause, osteoperosis => reduced bone strength. (d) Bone growth factors: Loading, raw materials, Ca-regulating hormones (calcitonin,PTH, vit D), Systemic hormones (glucocortio-steroids, prostaglandins, growth hormones). (e) Fracture repair: Haemotoma (granulation tissue) =>form osteoblasts/chondroblasts => callus (woven bone) => mineralisation=> increased vascularity => remodelling. (f) Bone pathologies: Marrow(anaemia, leukaemia), achondroplasia, rickets, renal ostedystrophy (metabolic disease), osteoporosis, osteomyelitis (infection).

Cartilage: (a) Hyaline = type 2 collogen+ CAG's. eg. articular cartilage, (b) Fibro- = like dense CT, coarser collogen, less GAG's, eg. tendon insertion, intervertebral disks, (c) Elastic = has pericondrium, elastic matrix, very flexible,eg.external ear, epiglottis.

Joints: (a) Synovial: synovial cavity +fluid, articular cartilage, articular capsule, eg. limb joints.Articular cartilage has 'basket weave' arches of collogen fibres to resist shear, and hydrated glycoprotein gel. (b) Cartilaginous:continuous cartilage bridge, eg. intervertebral disks, sternum, pubic symphis, (c) Fibrous: fibrous tissue bridge, eg. face and skull bones.

Joint pathology: Rhumatoid arthritis, Osteoartritis,Gout.
 

Neuromuscular transmission:
(a) Normal intracellular Ca is 10^-7M. (b) Synaptic transmission: one direction only, depends on amount of ACh, easily blocked, acts across cell boundares, Ca dependant. (c)Action potential (AP): either direction, all-or-none action, resistant to most blockers, within one cell or process, not Ca dependant.

AP propagates along fibre -> AP enters transverse tubule => Ca released from sarcoplasmic reticulum (SR) => cross-linking of contractile proteins => tension => Ca reuptake => relaxation.

AP action on muscle: (a) At Motor Nerve Terminal (MNT): Axional AP => Ca entry => ACh vesicles emptying => ACh release =>(b) In synaptic cleft: Diffusion of ACh => ACh binds to ACh receptor => Channels open => Depolarisation at end plate (P_Na+K)=> (c) In muscle cell: Muscle AP (P_Na -P_K).To limit stimulation time: (a) in synaptic cleft: ACh is hydrolysised (by cholinesterase) => choline uptaken by MNT => (b) In MNT: choline and AcCoA are synthesed into more ACh (by choline acetyl-transferase) forming new ACh vesicles.

Diseases affecting motor AP: Myasthenia graves=> muscle weakness & drooping eyelids; Botulism (very toxic poison); Motor neuron disease=>secondary muscle wasting.

Parathyrodism (PTH) actions: (a) bone: increased Ca and phosphate release (needs vit D as cofactor),(b) kidney: increased Ca resorption, reduced phosphate, (c) GIT: increased Ca and phosphate absorption. PTH diseases: (a) Hypoparathyrodism: Autoimmune atrophy or surgical removal => reduced Ca => neuromuscular excitability=> spasms. (b) Hyperparathyrodism: Tumor => reduced muscle excitability => muscle weakness, anorexia, bone pain, renal calculi.

Two skeletal muscle types: (a) Fast (phasic): white, few mitochondria, few capillaries, glycolosis, fatigues quickly; (b)Slow (twitch): red, many mitochondria, many capillaries, less glycogen, oxidative phosphorylation energy mainly, slow contraction over long time.
 

Pain:
Pain types: (a) Superficial: well localised, little delay, short duration, via (i) 'A' nerve  fibres = short myelinated axons, sharp pain, (ii) 'C' nerve fibres = very small unmyelinated axons, dull throbing pain. (b) Deep: poor localisation, muscles, skeleton, CT, via C nerve fibres. (c) Visceral: often referred, hard to localise, via 'C' nerve fibres, eg. shoulder pain from liver, angina from ischaemia, or stretching of hollow organ. (d) Dental: pulp has myelinated and unmyelinated axons. (e) Itch.

(a) Pain results in: increased skeletal muscletone, reduced BP (vagal inhibition), sweating, nausea, vomiting, pallor, pupil dilation, urination and defecation.(b) Pain increased by: neurotransmitters (ACh, serotonin), kinins (bradykinin from protein breakdown),metabolites (ATP, lactic acid, K+), venoms (eg. formic acid in nettles,enzymes in venom), irritants. Other factors: activities (threats, seeing blood), analgesia (NSAID's, reduced PGE), congenital absence of pain, inflammation, (c) Descending 5-HT axons:  interneuron inhibits pain entering spinal cord, uses ankephaline (d) Pain pathway:(i) Reticular formation (pain, autonomic effects, cortical arrousal), (ii) Parietal cortex, (iii) Frontal cortex (stress).
 

NSAIDs in Gout: (a) Gout: over-production or under-excretion of urate (from purine breakdown) => Naurate crystals deposit in joints, soft tissue, and urinary tract => activates kinin, complement, plamin systems => neutrophils and phagocytes accumulate.(b) Predisposing factors: upper social class, family historyin 30%, regular alcohol, diet, starvation. (c) Aims: Reduce pain, stiffness and long-term deformity. Increase mobility. Effect is increased by sustained treatment. (d) Management: (i) Identify predisposingfactors;(ii) Advise on general measures ie. reduce purine foods (kidney, herings, shellfish), alcohol, weight, hypertension (but not with diuretics);(iii) Specific action needed if more than 2 symptomatic episodes with >600 umol/l.
Specific action: (a) Acute: reduce inflammation and pain using maximun NSAID dose for 2 days (eg. Ibuprofen) an analgesic, but nausea, dizziness, dyspepsia, and diarrhoea. (b) Chronic:(i) inhibit leucocyte migration into joint (Colchinine, which binds to a microtubular protein => 'drunken walk' of cells); (ii) inhibit uric acid synthesis (Allopurinol inhibits xanthine oxidase, but accumulates if renal insufficiency, don't use if on anti-cancer drugs or warfarin); (iii) increase uric acid excretion (Uricosurice).

Steroid drugs: (a) Glucocortoids(eg. cortisol, prednisolone, hydrocortisone) => increase glucose and protein catabolism. Adrenal corticoids are controlled by ACTH frompituitary. (b) Cortisol: made from cholesterol via. prenesolone.90% bound in plasma by: (i) CBG (cortisol binding globulin) has high affinity but low capacity, and (ii) albumin - has low affinity, high capacity.(c) Mechanism: Cortisol binds with glucocorticoid receptor in cytoplasm forming steroid-receptor complex -> transported to nucleus -> steroid-responsive element (GRE) on DNA -> stimulate/inhibit mRNA transcription. But response time 6 to 24 hours after injection, so needs bronchodilator too for asthma attack. Half life 90 minutes. (d) Effects: (i) increased glucose and protein catabolism, reduced peripheral glucose use; (ii) 'permits' lipolytic hormone action=> 'lemon on sticks'; (iii) anti-inflammatory: reduced vasodilation,reduced phagocyte actiivity, reduced healing; (iv) anti-immune:reduced clonal expansion of T and B cells, reduced IL-1, reduced phospholipase-1,reduced histamine. (e) Side-effects: (i) Na and water retension=> hypertension; (ii) increased bone breakdown => kidney stones;(iii) increased gastric acid; (iv) reduced growth hormone; (v) reduced immunity. (vi) If on long-term steroids, no endogenous response=> recovery on withdrawal is unpredicatable. (f) Mineralocorticoids (eg. Aldosterone controlled by renin-angiotensin system.) => Na+ and water resorbtion.

Glucose control:  to keep blood glucose at 5mmol/l when fasting. (a) Glucose lowered by: increased uptake by cells (via glucose carrier protein); glycolosis in cytoplasm -> pyruvate +ATP -> citric acid cycle in mitochondria -> fully oxidised; synthesis of glycogen, AA and fatty acid. (b) Glucose increasedby: Beta-oxidation of fatty acid => spares glucose; glycogen -> glucosein liver; muscle glycogen -> glucose phosphate -> lactate -> glucose (by Cori cycle in liver); AA (esp. alanine) and glycerol -> glucose. (c) Insulin: from Beta cells of Islets of Langerhands in Pancrease => reduced blood glucose as: increased glucose and AA uptake (except in brain), increased carbohydrate metabolism, reduced lipid breakdown, increased fatty acidand glycerol synthesis and uptake by adipose. (d) Somatostatin: (from Islet Delta cells) inhibits insulin. (e) Glucagon: from Alpha cells, released when glucose low or AA's high (as AA's stimulate insulin, but if low carbohydrate diet, then hypoglycaemia). (f) Catecholamines: (Adrenaline/Noradrenaline) released from adrenal medulla by symp. nerve action. (g) Glucocorticoids: NOT increased during fasting, but assists glucagon's action. Increases appeptide.

Diabetis: (a) Type I = insulin dependant; (b) Type II = non-insulin dependant; (c) High blood glucose => exceeds renal threshold (Tmax = 11mmol/l) => osmotic diuresis=> polyuria => reduced AA uptake and protein synthesis => reduced growth/weight=> increased lipid metabolism => ketoacidosis => respiratory compensation. Brain especially needs glucose. (d) Treatment: restrict diet carbohydrate, reduce weight if obese, insulin injection if necessary; (e) Secondary diabetis = as excess diabetogenic hormone (cortisol, growth hormone, or glucagon).

Protein: (a) 9 essential AA's (amino acids); (b) Amination (add NH4+ to keto-acid => AA); (c) Transamination: (AA-1 -> Keto-acid-1 while Keto-acid-2 -> AA-2); (d) Deanimination: (AA -> glucose and ketones for energy); (e) Synthesis of pyrimidinesand purines (for nucleic acids), creatinine (for muscle energy store),and messenger molecules; (f) nitrogen balance: N losses: Urea (90% of total), uric acid, creatinine, hair/nails/desquamation.

Lipids: (a) Chylomicrons: (large fat particles from meal). (b) VLDL released by liver when blood fat is low. (c) IDL returned from tissues and converted to LDL by liver. (d) HDL are mostly protein, remove cholesterol from tissues returning it to liver.(e) Apo-B-100 on LDL is recognised by receptor pits. (f) Lipid hypothesis: high HDL and low LDL => reduced arthersclerosis => reduced CHD and strokes.

Metabolic rate: (a) Direct (heat) or Indirect (oxygen usage) calorimetry. (b) "Specific dynamic action of food or protein" => increased metabolism after a meal; (c) Thermonuclear range is 20 to 27 deg. C. (d) Basal metabolic reate (BMR) is per body surface  area for comparison; is higher in males, young, increased symp nerve and thyroid hormone. (e) Energy stores: Triglycerides-> fatty acids (FA) + glycerol; Glycogen -> glucose; Protein -> AA -> glucose; FA's are Beta-oxidised -> ATP; glucose via glycolysis and oxidation ->ATP. (f) Energy used for: mechanical work, transport, synthesis,signalling, detoxification, and heat.

Temperature control: Thermoreceptors (core and peripheral) -> thermoregulatory centre (in hypothalamus) compares with set-point -> nerve signals to change heat production and loss. In cold: increase: muscle tone, shivering, catacholamines, brown fat oxidation in infants, peripheral vasoconstriction, piloerection. In heat: increase sweating, vasodilate periphery, reduce catacholamines. Pyrexis (fever) due to toxins (from bacteria or immune cells) => increase hypothalamus set-point => shivering.

Diet: (a) Male: 3000 kcal = 12.6 MJoules,46g protein, + essential FA's; (b) Female: 2200 kcal (increased if pregnant or lactating), 36g protein. (c) Only 30% of energy should be from fat (ie. 15% by weight) to reduce arthersclerosis risk. (d) Vitamins: only small stores of B1, B2, B6, C, D, K, folate, biotin, and niacin.(e) Hunger and Satiety centres in hypothalamus. Higher CNS may affect these in bulomia and anorxia. (f) BMI = weight/(heightx height). If BMI<20 => under-nourished. If >28 obese.(g) Undernutrition (eg. poverty, fasting before surgery, malabsorption) => hypoglycaemia, muscle wasting reduced infection resistance, reduced plasma proteins (oedema and ascites), increased fat metabolism (possible ketoacidosis); (h) Dietary supplements helpful esp. vitamins. Enteral (tube into GIT) or parenteral (IV into eg. SVC to reduce hyper-osmolity and clotting). (i) Weight loss diet: 1000 kcal. (j) If hepaticor renal failure, limit protein. (k) In Coeliac disease give gluton-free diet.

Swallowing reflex: Pressure on pharyngeal wall=> peristalic wave in oesaphagus, glottis closes and epiglottis and larnyx moves up (to protect trachea), oesophageal spincters open. Swallowing centre is in medulla oblongata.

Stomach: (a) Resovoir, mixing (by approx 3 self-generated waves per minute). (b) Parasymp, distension, and gastrin => reduced contraction force (NOT rate). (c) Symp, fat/acidin duodenum, and cholecytokinin secretion => increased contraction force.

Vomiting: (a) Oesophageal sphincters relax, glottis closes, stomach relaxes, muscles of abdomen, diaphragm, and duodenumcontract. (b)  H+ loss => alkanosis and dehydration.

Small intestine: (a) Segmentation => mixing; (b) Localised peristalsis; (c) Migratory motility complex (MMC) is powerful wave from stomach sweeping small intestine's contents intolarge intestine via ileo-caecal valve.

Large intestine: (a) Mass movement: sustained contraction of circular muscle = 'gastro-colic reflex' => initiates defeacation.(b) Distended rectum => sensory to spinal cord => parasymp from sacral cord=> contract sigmoid colon more and relax internal anal sphincter. But Distended rectum also gives concious awareness => somatic nerves contract external sphincters => urge returns later.

Diarrhoea: (a) Is due to:(i) increased bowel motility as inflammation (eg. enterovirus),(ii) osmotic retension of fluid in intestine as poor absorption of nutrient molecules,(iii) excess secretion by mucosa (eg.cholera toxin). (b) Results in: loss of water, K+ and HCO3- => dehydration, hypokalaemia, and acidosis. (d) Treatment: oral rehydration = boiled and cooled water + Na (salt) + sucrose (as water absorbed with Na and glucose via cotransporter). Give IV fluids if extreme.
 

Digestion: enzymes degrade food into simpler molecules

Saliva: (a) Sublingual, submandibular, parotid and buccal glands; (b) Buffers, mucus lubricates eating and speech, amalyse starts digestion, lysozyme attack bacteria; (c) Medulla oblongata controls silivary reflex via parasympcranal nerves (VII, IX).

Gastric (stomach) secretions: (a) Parietal cells, use H+ATPase and carbonic anhydrase to release HCl acid into stomach and bicarbonate into stomach venous blood.(b) Has cephalic (CNS sees food), gastric (gastrin indicates food is in stomach), and intestinal (food enters duodenum) phases. (c) Acid secretion increased by ACh (from parasymp), gastrin, histamine (H2 receptors).(d) Intrinsic factor released to bind vit B12. (e) Pepsinogen released by chief cells, activated to pepsin by acid. (f) Mucus contains bicarbonate.

Pancreatic secretions: Controlled by: Secretin, CCk, and parasymp nerves. Acini secretions -> Pancreatic ducts - > common bile duct -> 2nd part duodenum. Contain: (a) Bicarbonate to neutralise stomach acid, (b) Protease precursors (eg.trypsionogen) to further breakdown proteins. (c) Amalyse to breakdown carbohydrate. (d) Lipases & cholesterol easterases.

Liver: Lobule= functional unit. (See a figure of sinusoids layout in notes). Liver functions: (a) Fed state: High insulin: Glucose -> Glycogen; Glucose ->AA's -> Proteins; Glucose -> Fatty acids -> Adipose tissue. (b) Fasting state: High glucagon (needs permissive glucocorticoid level) and Adrenaline: Glycogen, AA, and Glycerol -> Glucose -> Blood; Fatty acids -> Beta-oxidation-> Ketone bodies + energy. (c) Conjugates bilirubin making it soluble for excretion as bile pigment: (i) Bile = Bilesalts + Bile pigments + Bicarbonate + Cholesterol + Lecithrin. Bile is secreted from liver -> Hepatic duct -> Stored & concentrated in gall-bladder -> Cystic bile duct -> Common bile duct -> 2nd part duodenum. (ii) Bile salts: emulsify fats into tiny droplets (miscelles). Made from cholesterol, reabsorbed by small intestine. (iii) Bile pigments: mostly bilirubin, which is waste from haemoglobin breakdown: Hb porphyin -> insoluble bilirubin-> associated with Albumin in blood -> conjugated with glucuronic acid in liver (soluble) -> excreted in bile -> converted to Urobilogen by gut bacteria. (d) Detoxifies drugs, toxins, hormones, and alcohol. Most things absorbed from GIT go through liver first so high first-pass metabolism (loss) of some drugs. (e) AA metabolism releases ammonia (toxic). Liver converts it to urea for excretion. (f) Makes Plasma proteins (controls coloid osmotic pressure - if low -> oedemia); Clotting factors (vit K dependant globulins, if low -> bleeding problems); Activates vitamin D (needed for Ca uptake from GIT) and vit D further activated in kidneys. (g) Kupffer cells phagocytose old red blood cells & bacteria. (h) Stores glycogen, iron, copper and vitamins.

Jaundice: Yellow/green eyes and skin: (a) Pre-hepatic: due to excess blood breakdown, eg. B12 deficiency = macrocytic anaemia = big cells rupture faster => INCREASES unconjugated bilirubin. (b) Hepatic: due to liver damage, (eg.Hep A) liver cannot conjugate bilirubin. (c) Post-hepatic or Obstructive: Bile duct obstructed, eg. gall stone or tumor, INCREASES conjugated bilirubin, colicy pain.

Intestine: can only absorb monosaccrides (fructose, glucose, NOT sucrose) and AA's. Enzymes in brush border breakdown oglio-sacchrides (sucrose, lactose) & peptides. Absorption from GIT is transfer of digestion products from GIT lumen into blood. (a) Big surface area: Mucosal folds, villi, microvilli. (b) Secondard active transport of glucose & glactose with Na+, via Na+ co-transporter: Na+ pumped into space between cells (paracellular space) by ATPase pump. More Na+ diffuses in from lumen via co-transporter, which also brings glucose in. Glucose diffuses into capillaries. (c) Facilitated diffusion of fructose. Need carrier to diffuse through cell membrane. Not active so needs concentration gradient. (d) Secondary active transport of AA's similar to (b) above. (e) Some endocytosis of whole proteins in babies (to absorb Ig's from mother's milk) (f) Fatty acid droplets diffuse through membrane -> converted to triglycerides in endothelial cell and return to blood via lymphatic system, as droplets (cylomicrons) too large for blood capillaries. (g) Water absorbed by osmosis, secondary to NaCl absorption, so needs higher Na concentration inside cells than lumen. Na pumped into space between cells, then into capillaries. Hence Oral rehydration = Sterile water + Salt + Glucose (as better absorption than if just given water). (h) Fat soluble vitamins (A,D,E,K) absorbed with fat. (i) Most water soluble vitamins diffuse in. But: B12 needs intrinsic factor, made in stomach and absorbed in terminal ileum. Ca needs Ca binding protein + vit D.Iron as ferrous iron (Fe2+) binds to transferrin -> enters endothelial cell via receptor.
 

Immune system: Response depends on: infectious agent, body's experience and genetics (NOTE: ‘Bugs’ here means microbes, toxins, and foreign bodies). There are two type of immunity:

1. Natural or Innate immunity: (a) Character: (i) Rapid, (ii) non-specific, (iii) Not increased by repeated exposure. (b) Components: (i) Natural barriers (skin, muscosial epithelium); (ii) Phagocytic cells (neutrophils, macrophages); (iii) Natural killer cells; (iv) Complement (via alternate pathway); (v) Cytokines; (vi) Prostaglandins.

2. Acquired or Specific immunity: (a) Character: (i) Specific to each antigen, (ii) is increased by repeated exposure (memory) eg. booster vaccinations; (iii) Regulates itself (if not regulated => hypersensitivity, autoimmune);(iv) Knows self (host) from non-self (foreign) cells. (b) Components: (i)Humoral: Activated T-helpers (Th2) activate B-lymphocytes, which multiply, become Plasma cells and produce antibodies (AB’s) againstantigen (Humoral response) AB's only attack bugs in body fluids (eg. blood), NOT inside cells. (ii) Cellular: This is a defense against bugs that hide inside cells (eg. virues and some bacteria). Antigen Presenting Cells (APC's eg. Macrophages) have special MHCII (Major Histo-Compatibility class 2) molecules on their surface. APC's eat bugs, and put the bug antigens beside their MHC class II molecules. CD4 T-helper (Th1) lymphocytes recognise the MHC II and if the antigenis not known, trigger CD8 T-cytotoxic (Tc) lymphocyte proliferation. All nucleated cells have MHC I molecules on their surfaces. Tc cells kill self cells which have the foreign antigens expressed beside their MHC I molecules, so killing the viruses inside (Cellular response). Takes 7 to 10 days for first response, but only 2 days if reinfected by same virus later.

AB dependant cell-mediated cytotoxicity (ADCC): cytotoxic cells which kill cells covered with IgG antibody.

Immunisation: deliberate cellular immunity; (a) Active: give antigen (disabled bug or toxin) -> causes AB and cellular response. Is active defense. (b) Passive: give AB or serum from immunised person which already contains AB's against bug. Fast immunity. eg. Rh- mothers, Hep A vaccination.
 

Antibody (AB): (a) AllAB's are immunoglobulins (Ig's). (b) Epitope is part of antigen recognised by AB. (c) Ig's have: (i) Fab region that binds to antigen, very variable to match antigen, and (ii) Fc region that is constant, recognised by immune cells, phagocytes & first part of complement system. (d) Opsonisation = AB binds to antigen, then phagocytes attack. (e) There are five classes of Ig: Secreted: (i) IgG = small, easily penetrates tissues, is 75% of Ig pool, stays high long after infection. IgG1 and IgG3 activate complement & clear protein. IgG2 and IgG4 react with carbohydrate antigens, but are poor oponsions. (ii) IgM = big, poorly penetrates tissues, 10% of Ig pool, is main "early" antibody, appearing quickly after infection. (iii) IgA = mucosal Ig = "mucosal antiseptic paint"; attacks antigen in mucous; if deficient -> decreased GIT protection; has "secretory piece" to prevent digestion in GIT. (f) Not secreted, but are cell-surface receptors: (iv) IgD = in membrane of B-lymphocytes to recognise the specific antigen. (v)IgE = made by plasma cells, but used as antigen receptor on mast cells and basophils, which degranulate if meet that antigen -> increases vascular permeability, linked with food allergies & asthma. (f) Antibody response phases: (i) Primary: Lag (no AB detectable), Log (rapid increase of AB), Plateau, Decline. (ii) Secondary: Quick & lasts longer, higher AB level, mainly IgG.

Hypersensitivity: (a)Type I = Immediate allergic reaction, uses IgE, eg. pollen, drugs, bee sting, peanuts. First contact: B-cells make IgE against specific antigen and insert into mast cell membrane. Second contact: Antigen binds to mast cell IgE-> degranulates releasing histamine, proteases and prostaglandins. Local effect: eg. Bronchospasm in lungs, oedema. Systemic: Anaphalectic shock to bee stings. (b) Type II = Antibodies to antigens on cells of specific tissues/cells, localised, organ specific auto-immune disease,uses IgG & IgM, eg. Good pastures syndrome. (c) Type III = Antibodies to widely distribute antigens in serum, non-organ specific autoimmunity, uses IgG & IgM, antigens in serum + AB -> insoluble immune complexes -> deposit in joints, kidneys, brain, misrovessels, eg. SLE diseases.(d) Type IV = cell mediated, delayed response. 3 subtypes: (i) Contact hypersensitivity = epidermal ezematic reaction at contactsite, eg. nickel & chromate in cheap jewellry. Develops in a week; (ii)Tuberculin sensitivity = Heath test for TB immunity. (iii)Granulatomatus hypersensitivity (very important!), bugs hide in macrophages and cannot be destroyed -> epitheloid granuloma forms, eg. in lungs fibrous walls enclose macrophages infected withTB or asbestos, develops in 4 weeks.

Tolerance: (a) Immune system should not attack self. (b) Tolerance is learned or acquired. (c) Two main ways: (i) Clonal deletion= self-reactive immature lymphocytes deleted by apoptosis (eg. inThymas); (ii) Functional inactivation or anergy = mature lymphocytes recognise their specific antien, but response inhibited (eg. by lack of cytokines). (d) But also: (iii) Clonal abortion = immature B-cells in bone marrow inhibited. (iv) Clonal exhaustion = repeated stimulation by self-antigens through T-independant pathway (so no memory cells formed) => exhausts reactive cells. (v) Clonal ignorance = Low conc. of antigen => no activation. (e) If T-cells are tolerant => no B-cell response as B-cells need T-cell help=> no AB formed. Immature lymphocytes more easily made tolerant than mature ones.

Auto-immune disease: is due to breakdown of tolerance mechanisms. In autoimmune diseases and graft rejection, antigen is always present so response keeps going. (a) Organ specific: against antigen on specific organ (Type II hypersensitivity).eg.(i) Hashimotos & Cushings diseases (Thyroid); (ii) Addisons disease (Adrenals); (iii) Pernicious anaemia (Stomach); (iv) IDDM diabetes (Pancreas). (b) Non-organ specific: against widespead antigen (Type III hypersentivity). eg. (i) Scleroderma (skin); (ii) Systemic Lupus Erythematous or SLE (Kidneys); (iii) Rhumatoid arthritis (Joints); (iv) Dermatoyosites (Muscle).

Cytokines: Soluble molecules made mainly by T-lymphocytes to instruct specific cells to alter proliferation, secretion, migration, etc. Give fast amplification of signal. Short half-life. Most have local action (ie. autocrine, paracrine).Overproduction => autoimmune diseases, septic shock, adult respiratory distress syndrome. Th1 cells make pro-inflammatory cytokines (IL-1) & interferon (IFN) => increases MHC expression and T-cytotoxic activity (Cellular immunity). Th2 cells make anti-inflammatory cytokines and help B-cells (Humoral immunity). So if viruses invade, increases Th1 and decreases Th2 to increase cellular response.

Complement: Many complex pro-enzymes in serum which activate each other in a cascade, so highly amplified response => opsonising and destruction of bugs. (a) Classical pathway is activated by antigen/AB complex. (b) Alternative pathway by endotoxin from bacteria cell walls.

Peptic Ulcers: (a)Two types: (i) Type 1 = high in stomach, or lower oesaphagus (no acid); (ii) Type 2 = distal stomach & duodenum (much acid). (b) Character: chronic, pain 2 hours after food, relieved by food or alkali. (c) Due to: increased acid, pepsin, H.pylori, NSAID's, loss of mucus integrity and protection. (d) Defences: Mucous, bicarbonate, prostaglandins. (e) Parietal cells make acid, which is secreted by H-ATPase pumps. Histamine, ACh, gastrin => increase acid. Prostaglandins (PGE2, PGI2) =>decrease Acid. (f) Aims: decrease pain, heal ulcer, prevent recurrance and complications. (g) Theraphy: (i) Anti-acids (eg.Aluminium hydroxide) => decrease Acid. But Al => constipation, Mg => diahorrea. Poorly absorbed, systemic alkinosis. (ii) H2 (histamine) receptor antagonists (eg. Cinethidine) => decrease acid and pepsin. Well absorbed, BUT some dizziness, mental confusion. (iii) Proton-pump inhibitor (eg. Benzimidazole) => decreases acid. Binds irreversibly to proton pump, BUT expensive. (iv) Anti-muscarinics (eg. Atropine, Pirenzepine) => decreases acid and pepsin, and slows emptying. Inhibit muscarinic receptor (M2), BUT dry mouth, blurred vision, tachycardia. (v)Cyto-protectant (eg. Misoprostal) is a prostaglandin analogue that increases mucosal blood flow, decreases acid, prevents damage from long-term NSAID's such as Aspirin.(vi) In the past surgically devide vagal nerve branch.