human physiology



membranes - `link cells, partition, control events, anchor to ecm, phosopholipids, polar head non polar tails. membrane proteins - carbs and glycoproteins act as receptors for communication, also connect cells: desmosomes: protein projections to link, elastic tissue e.g skin, protein rich. tight junctions: physically touch to block passage of movement, drives movement through cells, not exclusively permeable water and ions. gap junctions: channel between cells, limits what can pass through, link cells up e.g heart and muscle. 

protein anchorage - integrins, cells interact with matrix, alpha and beta subunits, motifs identify components in matrix. RER - proteins synthesised on ribosomes enter lumen and are distrubtd to other organelle or secreted from cell. SER - contains enzymes for fatty acid and steroid synthesis, contains calcium - secondary messanger. mitochondria - free radicals produced (aging). 

cytoskeleton: microfilaments - usually actin. microtubules usually tubulin, involved in centromeres. intermediate filaments - form directional highways for molecules. diffusion: net flux proportional to conc gradient, surface area and membrane permeability. facilitated diff: solute binds to transporter protein, conformational change, solute is released on other side. binding sites have chemical specificity, affinity and saturation. no energy required, goes along conc gradient. 

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cells 2

primary active transport: e.g Ca ATPase, Na-K ATPase etc uses atp to make conformational change. against conc. secondary: no ATP uses electrochemical gradient, natural energy diff

calcium regulation in organelle, intracellular fluid and extra. primary active T into organelle and extracellular fluid. diffusion back into cell. secondary active T coupled with Na from inside to outside cell. epithelial transport - Na diffuses from lumen to epithelial cell and is actively transported out into blood. 

regulation of activity in cells: transcription of DNA - activation or inhibition by transcription factors. Splicing RNA - activity of splicosome. mRNA degradation - activity of RNAase. protein degradation: activity or proteosome. Allosteric and covalent modulation - signla ligands, protein kinases and phosphatases. 

cholesterol in membrane helps pinching to form vesciles. 

allosteric modulation - modulator molecules binds to regulatotory site which induces conformational change in functional site so ligand can bind. covalent - chemical reaction causes conformational change e.g add phosophate group - phosphorylation or using protein kinases. 

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cellular communication

intercellular chemical messangers - hormone secretion, nerve impulses to neuron or effector cell, nerve impusle releases hormone into blood to target cell, pacrine - from one cell to another and autcrine - from one cell to same cell. lipid soluable - bound to proteins or found free, receptor is inside cell, mainly in nucleus. act as transcription factors. 

lipid insoluble - e.g Ca ligand binding receptor opens ion channels. can be enzyme linked e.g tyrosine kinase receptor autophosphorylation or growth factors. JAK kinase recruits other proteins - partnership. G protein linked receptors e,g acetylcholine, G protein has alpha, beta and gamma subunits, alpha part activates other proteins. cAMP and GPCR are secondary messengers which promote phosphorylation and amplify response massively. cellular responses induced by cAMP - active transport, ion channels open, ER protein synthesis and Ca transport, dna synthesis, lipid and glycogen breakdown or synthesis and microtubule secretion. 

calcuim/ calmodulin- dependant protein kinase system - Ca can make Ca ion channels open (store operated calcium entry) - secondary messenger, calcuim binds to calmodulin which activatees or inhibits many proteins including calmodulin dependant protein kinases. 

transforming growth factor B - homodimeric polypeptides that regualte cell growth, differentiation, transdifferentiation and matrix contraction, uses cell surface serine/threonine kinase receptiors

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cells and homeostasis

TGFB exists in latent and active forms. when latent - wrapped in latent binding proteins, released by degradation of pro-segments by protesases e.g plasmins and cathepsins. due to pro-segments binding to mannose 6-phosphate receptors. TGFbeta is a well established pro-fibriotic protein - fibriotic diseases - diabetic retinpathy and fibrosarcoma. 

homeostatic control systems - negative feedback - push variable in direction opposite to original change e.g temp, minimises change from the set point. positive feedback - initial disturbance sets off train events e.g uterus contraction. homeo - reduces changes in internal enviro and minimises fluctuations form the norm.

heat loss and gain - radiation - electromagnetic waves, medium and gradient dependant. conduction - physical interaction, convection - movement aiding change in heat. evaportation - convert liquid to gas burns calories. 

control of heat production = muscle contraction, shivering, non shivering thermogenesis in kids and animals uses brown fat adipose tissue. control heat loss - blood flow to skin, blood vessles contrlled by vasoconstrcor sympathetic nerves, basal muscle contraction and voluntary movement minimised, behaviour important. sweat - active secretion controlled by sympathetic nerves to glands, evaportation causes cooling effect. insensible water loss - diffusion through skin and respitory lining

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homeostasis + nervous system

increase heat loss - vasodilation of skin, sweating, behavrious. decrease heat production- decrease muscle tone, voluntary action, food appetite and secretion of adrenaline. decrease heat loss - vasoconstrictin, reduction of surface area and behaviour. increase heat production - increase muslce otne, shiver, inrease food appetite and increase adrenaline. 

acts with endocrine system, enables fast response. diseases - neurodefenerative: demyelinating, modd disorders, viral and bacterial infections, control of important physiological functions e.g appetite and blood pressure. CNS and peripheral NS. CNS - brain and spinal cor. in adult CNS - ependymal cells, oligodendrocytes, myelinated axons, microglia. 

neuron structure. cell body - nucleus, RER and mitochondria. Dendrites - outgrowths from cell body, recieve input from other neurons. Axon = nerve fibre extending from axon hillock, may be myelinated, contains microtubules. axon terminal - synapse, release of neurotransmitter. nodes of ranvier.

afferent (sensory neurons) - transmit information to CNS, have sensory receptors at peripheral end. Efferent (motor) neurons - transmit information from CNS to effector organ or neurones. Interneurons - transmit from neuron to neuron, are found exclusively in CNS, can be inhibitory or excitatory, 99% of all neurons, can be specialised e.g retina.

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brain and spinal cord - input refions of sensory nerves, output of motor, many interneurons. grey matter - internueons, cell bodies and dendrites or efferent, synapses and glia. white matter - axons, myelin sheaths, descending and ascending fibre tracts or pathways.

neuroglial cells - glial cells - metabolic support, remove neurotransmitter from extracellular space, blood brain barrier, some act as stem cells. BBB - selctive transport of molecules, majro obsticle for drugs, microglia and some immune cells can negotiate way to pass.

choroid plexus system - brain and spine is surrounded by fluid filled ventricles, fluid - cerebrospinal fluid, provides physcial support and nourishment, produced by special population of ependymal cells, can detect lymphocytes or bacteria to indicate disease, or high levels of protein can be detected e.g transferrin - indicates leaky choroid plexus. 

PNS - interface between CNS and enviro. neuronal and sensory cells, 12 pairs of cranial nerves and 31 pairs of spinal nerves. somatic and autonomic nervous systme. spinal nerves - 8 cervical, 12 thoracic, 5 lumbar and 5 sacral. somatic - sensorty and motor neurons innervating skeletal muscle. autonomic - sympathetic nervous system and parasympathetic. autonmic - includes enteric nervous system (network of neurons surrounding GIT).

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autonomic nervous system - motor control of heart, smooth muscle and glands. para and sympathetic nervous system. symp - fight or flight, para- promotes routine activities and digestion and restoring homeostasis. e.g symp - dilates pupil, para - constricts. symp - increase rate of force of heart contraction, para - decreases. symp - relaxation of broncial smooth muscle, para - contraction. bladder symp = relax, para - contract.

spinal ganglia - pre and post ganglionic neurons. sympathetic nervous systme - pre ganglionic symp neurons - leave thoracic and lumbar regions of spine, synapse at ganglia close to spinal cord, are cholinergic - acetylcholine release which innervates the adrenal medulla causing release of adrenaline. post ganaglionic symp neurons  are noradrenergic - neurotransmitter released is noradrenaline. 

parasympathetic nervous system - pre ganglionic para neurons - leave brainstem and sacral region, synapse at ganglia close to effector organ, are cholinergic - acetylcholine released. post ganglionic para neurons are cholinergic - acetylcholine is released at the neuron effector organ synapse.

dendritic arborization is the signalling unit which is vital for neuronal function. 

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neruomuscular junction - one alpha moto nueron originated from the CNS with cell body in grey matter or brain stem will synpase with several muscle fibers. they are fast and myelinated and acetycho is used. sacrolemma. acetycholine esterase degrades used. when action potential enters pre synaptic terminal ca2 enters gates making acetylcho released. denervation causes muscle atrophy. during embryonic develop superluous contacts are made bt/wn axons and developing muscle fibres to ensure survival of neurons and enforce proper contacts. re-innervating axons contact muscle preciscely at the previous site.  myotatic reflex - knee jerk - sensory neurons form divergant pathway from extensor muscle, intermediate neuron in grey matter, moto form convergent pathway to flexor muscle. excitatory synpase to brain. EPSPs depolarise as a result of increased Na and Ca. IPSP hyperpolarize as a result of increased Cl or K. synaptic intergrations - summation of EPSPS and IPSPs.  neurotransmittors - needs to be synthesised in neuron, be in presynaptic terminal, mimics action of endogenously released transmitter, have specific mechanism for removing from celft.biogenic amines - noradrenaline, adrenaline, dopamine, histamines. amino acids - glutamate, GABA mainly in brain.  ACh - somatic efferent system (neuromuscular), all pre-ganglionic of automnomic and all post ganglionic of the parasymp nervous system

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ACh - acetyl coA and choline in the pre synaptic terminal. CoA is important and recycled in cleft back into pre-synpatic terminal. can be nicotinic ionotropic receptors - ligand gated ion channels, e.g neuromuscular junction, relys on influx of ions, short lived. muscarinic metabotropic receptors - G protein coupled, e.g smooth muscle and cardiac muscle - conformation changes activate ion channels or act as secondary messengers and can be long lived. 

noradrenaline - post ganglionic sympathertic neurons. catecholamine synthesied from tyrosine - DOPA - sopamine - noradrenaline which shows evolution - increased specialisation. deficiency of dopmaine = parkinsons. action of NA is terminated by reuptake.noradrenergic synapse - amphetamine works by blocking NA uptake/removal from cleft. stimulates cells for much longer. increased rate and force of contraction in heart. B-blokers act of B-adrenergic receptors and reduce force of contraction. 

synaptic terminals not fixed, cocaine increases numberss through regulation of MEF2 gene. changing the balance of protein synthesis can cause autism or fragile X syndrome. Cholinergic - neurons secreting ACh, cholinoreceptor - ACh receptor. muscarinic antagonist - muscarinic blocker - anti-muscarinic drug. mimetic - mimiking or promoting action of. lytic - inhibiting or terminating action of..

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nicotinic - e.g NMJ  are short lived ionotropic receptors - ligand gated ion channels. Muscarinic receptors (metabotropic) are G-protein coupled, found at synapse of post-ganglionic parasymp nerve terminals. e.g parasympathetic synapse at smooth muscle or cardiac muscle. e.g atrial cells - parasymp, ACh binds, release of alpha-GTP from G protein due to phosphorylation of GTP to GDP, activation of K channels causes eflux of K causing hyperpolarisation, decerase in heart rate.

G-alpha has Gi (ion channels), Gs(increase cAMP), Gg (increase DAG) and G12,13 (activates RHO) subunits. BetaGamma subunit does ion channels and phosphorylation - receptor kinases. GPCR signalling integrates cells responses to other signalling pathways which is why muscarinic responses are longer lived.

ACh synapse pre-synaptic inhibitor drugs - presynaptic toxins e.g botulinum inhibit exocytosis. hemicholinum inhibits ACh production. tetanus toxin prevents fusion of vesicles to membrane which works on inhibitory neurons so causes increased muscle contractions. 

synaptic and post synaptic inhibitor drugs - depolarising blocking agnts. anticholinesterases. e.g nerve gas inhibits acetylcholinesterase causing uncontrolled muscle spasms. tetrodoxin in overies of fish bind to sodium channels and prevent action potential. 

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muscarinic receptors

5 receptor types - 4+5 (gi + Gq) not well known in CNS. M1 (Gi,s,q)- neuronal mainly CNS, some glands, mainly inhibition of K channels. M2 (Gi)- cardiac, signal via cAMP and activation of K channels. M3 (Gq) - glandualar and smooth muscle - vasoconstriction of lungs but vasodilation of blood vessels, signal via IP/Ca. 

drugs stimulating muscarinic receptors are termed parasympathomimetics as effects resemble stimulation of parasymp system. drugs inhibitng muscarinic receptors are called parasympatholytics are inhibit parasymp nervous system. effects of parasympathetic nervous system are mediated by ACh acting at muscarinic receptors at target organ. 

muscarinic agonists: Bethanechol and Pilocarpine drugs only act on muscarinic receptors so are used to treat bladder hypotonia and gluacoma. in cardiovascular: decreases cardiac output by vasodilation to decrease blood pressure. causes contraction of smooth muscle so more peristaltic activity, bladder contraction and constriction of bronchioles. Eye - pupil constriction - constriction of cilary muscle - decreased introcular pressure - gluacoma. glands - increased secretion. brain - tremor, hypothermia, increased locomotion, increased cognition.

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the brain

cerebrum, diencephalon, cerebellum, midbrain, pons and medulla oblongata. intricate ventricular system filled with cerebrospinal fluid. forebrain )cerebral cortex) becomes largest part of CNS and obscures other brain bits. 

medulla oblongata ( next to spine start)- major relay centre, junction of fibres to spine. control of involuntary functions - vital reflex centre: breathing and blood pressure. nonvital reflex centre: swallowing coughing and vomiting. 

cerebellum (at back) - coordination of movement and balance. integration of info from eye, muscles, joints, ears, skin etc. 

Diencephalon (middle) - thalamus: relay station and sense of awareness. Hypothalamus: major homostasis regulation of AMS and endocrine system, controls hormone secretion by pituitary gland, neural centres controlling hunger, thirst, sexual behaviour, form limbic system and circadian rhythms. limbic system - interconnecting group of structures controls emotions, olfaction and hippocampus - memory. 

cerebrum - cerebral cortex and sub-cortical nuclei (basal ganglia) - bulk of brain controls language, intellect, sensory anaylsis and motor coordination. 2 hemispheres, each controls contra-lateral side of body connected via corpus callosum.

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humans have largest and most convoluted cerebral cortex except for dolphins. frontal lobe, parietal lobe, occipital lobe and temporal lobe. evidence for localised functions - accidens and strokes, studies in animal models, PET scans and MRI recording electrical activity and blood flow. 

somatosensory cortex - analyses imput from mechanoreceptors, thermoreceptors, pain receptors and skin, muscles and internal organs. located in parietal lobe. recieves info from opposite side of body. somatotopic organisation in cortex (sensory homunculus). rodent whisker 'barrels' each whisker is represented in a topographical fasion in the cerebral cortex. there is plasticity within the neurons which is why blind people have better other senses. 

motor cortex is responsible for voluntary movement in frontal lobe. mapped motor cortex - motor homunculous. cortical areas involved in language, 90% of left hemisphere dedicated. Broca's area - articulation, wenicke's area - interpretation of language. 

2 neurons in c.cortex - projection and interneurons. projection - pyramid shape, excitatroy and use glutamate. interneurons - inhibitory and use GABA. glutamate - synthesised during KReb's cycle, mainly ionotropic (NMDA receptors used in memory) and some are metabotropic. Glial cells (astrocytes) take up toxic glutamate from synpase. 

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GABA and glycine - amino acid transmitters. both IPSP by openning Cl- causing hyperpolarisation. Benzodiazipines are sedatives and enhance cl conductance. 

parkinsons - dopamine deficiency in substantia nigral neuron in brain stem - supply L-dopa. depression - supple serotonin (5HT) to increase levels of other neurotransmitters (NE and dopamine. 

caffiene - inhibts GABA release and increases glutamate activity. Alcohol does opposite. 

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the ear

somatic senses - touch, temp, pain. Special - taste, smell, sight, vestibular stystem - gravity and acceleration. sensory - afferent nerve ending/receptor cell responds to stimuli - graded potential makes receptor potential - action potentials activated in afferent nerves. 

highly specialised neuroepithelial cells in ears acta s trnaducers convert external signals to electrical impulses. sound waves to mechanical energy in middle ear to electrical impuses in inner ear. sensory epithelia in the cochlea of innner ear - organ of corti - steriocillia.

external ear - auricle and tempanic membrane. middle - ossicles, malleus, inucs, stapes - transmits sound vibrations from tympanic membrane to oval window and inner ear. Inner ear - osseous labryrinth: vestibule and cochlea. osseous lab - perilymph. membranous lab- endolymph : semicircular dicts, utricle and saccule and cochlear duct. sensory epithelium: ampullae, macula and auditory system organ of corti. 

cochlea - organ of hearing, coiled. vestibular and tympanic cavities. stapes induces vibration in membrane of oval window - vibrations in cochlea fluid and pressure difference - vibrations in basilar membrane where sensory epithelium rest. cochlear duct - contains organ of corti. organ of corti - tectorial membrane and basilar membrane. 1 row inner hair cells 3 rows outer. supporting cells connected to basilar membrane - transmit mechanical vibrations to hair cells contain microtubules, actin and intermediate filaments. 

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hair cells - steriocillia - mechanosensors, modified giant microvilli, bundle of actin filaments with tip-links. cuticular plate - actin netword attached to sterocillia. nerve endings - receptor potential, release glutamate at afferent nerve terminal action potential in cochlear nerves. tip link - 2 helically intertwined protofilaments. 

mechanical vibration of basilar membrane - transmitted to hair cells via supporting cells - outer hair cells make shearing forces between stereocillia and tectorial membrane - stereocillia defelection. excitation - defelection towards longest one - K influx - depolarisation - receptor pot - release of glutamate. endolymph has high K so electrical gradient across membrane as hair cells have low K. 

afferent neuronal synapses - convey info from steriocillia to brain. efferent - modulate membrance pot of hair cell from brain to change ampfliciation of signals. alternate openning and closing of ion channels creates graded receptor potential. impulses along auditory nerve to brain. 

perilymph in vestibular cavity Na high, K low. opposite in cochlear duct endolymph. K recycling - K efflux through KCNQ4 channel at base of outer hair cells - through gap junctions in supporting cells - return to stria vascularis - secreted into endolymph. 

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deafness genes in ionic homeostasis of cholear duct. mutations in: KCNQ4 of OHC and KCNQ1 of stria vasularis. connexins in gap junction of supporting cells: 26,30,31,32. basilar membrane mechanical properties - stiffness gradient along length ensures diff sound freq. narrow + thick at base = high freq. Apex- wide and thin. 

inner hair cells - transformers, mechanical to electrical to brain. outer hair cells - amplifiers, have electromotility - membrane based motor in lateral plasma membrane, prestin changes the shape in response to depolarising current. actin filaments in stereocillia are cross-linked, F actin, polar, right handed double helical polymers. Myosin VI VII and XV important for hearing, diff tails, cell migration, endocytosis and transport, membrane-actin interactions. stereocillia have lateral links. tip links consist of cadherin23 and protocadherin15. fimbrin and espin crosslinks in body. 

causes: noise, infection, age, hereditary. damaged hair cells degenerate and are replaced by supporting cells. actin and crosslinkers espin filaments undergo treadmilling, assemble at tip, diassemble at base.

espin mutation in jerker mouse - short thing stereocillia, hair cell degeneration, deafness and vestibular dsyfunction. actin motor myosin XVa mutation in shaker 2 - transports whirlin to tip, short stereocillia, deafness. 

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stereocillium tip complex protein whirlin mutation in whirler - transported to tip by myosin XVa - short and disorganised stereocilia, deafness and vestibular dsyfunction. shaker-waltzer behaviour - vestibular abnormalities - hyperactive, circling and head tossing n jerker mouse. 

myosin - transport proteins within hair cell and connect actin bundle to membrane. myosin VI localises to base maybe anchorage. Myosin VIIa and Ic localise along shaft. myosin XVa located at barbed + end of tip. 

usher syndrome - myosin VIIa molecular motor in shaker-1 model, binds to harmonin and SANS 2 other USH proteins. essential for differentiation and organisation. also important in vision, expressed in sensory hair cells, retinal pigmented epithelia and photoreceptor cells. mutations - usher 1B syndrome and retinitus pigmentosa - role in phagocytosis photoreceptor discs needed for organelle transport and ospin clearance from connecting cilium - causing abnormal accumulation of opsin and impaired phagocytosis. - death of photoreceptors blindness. 

CDH23 and PCDH15 cell-cell adhesion proteins - waltzer and ames waltzer. atypical cadherins - transmembrane proteins and bind to actin filaments via harmonin. waltzer - non syndromic deafness. adhesion is Ca dependant. control morphogenesis and function in stereocillia. vital for mechanotransduction. components of extracellular filaments tip links and lateral links.

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tip link - myosin VXa tether - channel - PCDH15 - CDH23 - harmonin - myosin 1C

waltzer - defects in organisation. ames waltzer - outer hair cells disorganisation. 

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eye 1

cornea - pupil-iris. Light passes through effectively as transport. 3 layer cornea - epithelial, stroma (rigid) and endothelial cells which control ionic and osmotic pressure - very important! myotic sight - short sited - make cornea flatter. Aqueus humour is liquid between lens and cornea, drained through canal of schlem, increased liquid - increased pressure - glaucoma

the lens - capable of accomodation, no direct blood supply, all nutrients from bathing meduim, no nerves, exquisite cellular organisation, changes shape due to cilary muscles and suspensory ligaments. lens has elongating cells at corners - one cell differentiates into fibre cell and one stays as daughter cell, nucleus in middle, germinative cells at corners, collagen capsule layer of epithelial cells - no cell division there, cortical fires - no nuclei, all cells work together with lots of gap junctions for communication and transport.

calcuim signalling - G protein coupled receptors, Ach (muscarinic - glaucoma, ATP- dry eye, Histaminergic - allergy). Tyrosine-kinase receptors ( Epidermal growth factors and PDGF - growth, differentiation and cataract). Both activate PLCgamma, which activates InsP3 which opens Ca channels. causes release of calcium and get more into cell. Ca is transported out of cell by Ca/ATPase to keep equilibrium. Ach induced Ca mobilisation major in central anterior region not equator, varies in species

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eye lecture 1

Get excitatory 50% concentration and test with antagonist to see if it works, if so work out inhibitory 50% mark to measure affinity for particular figure.

cataract - opacity of lens, cortical, nuclear and posterior capsular cataracts.Nuclear cataract Ca levels are normal, Cortical Ca levels very high. high levels make calcium dependant proteins work more. Stop Na/K atpase so high levels of Na in cell which stops NA/Ca channel so Ca is trapped in cell.

UV, malnutrition, disease, stress and genetics. UV - photooxidation. Poor diet - diarhoea - osmotic issues in eye. Myotonic dystrophy/downs syndrome more likely to have it. oxidative stress - radicals, hydrogen peroxide - lens has to deal with everyday, catalysed by external stimuli eg UV. Lens has good defenses - non enzymatic antioxidants e.g Vit C + E and caratempods. Then enzymatic protection eg catalase.

cataracts - no cure, only surgery, freeze lens and it pops out. treatment for PCO - laser to remove light scattering tisse forming hole in back of lens. most cataract surgery patients develop posterior capsule opacification. management of PCR - intraocular lens. square edge forms barrier to cell movement, puts pressure on posterior capsule. Accomodation lens, looses barrier but not fixed focus.

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cataract and PCO

anti-inflamation - raised protein levels following surgery contribute to PCO, steroids and anti-inflammatory drugs dont help reduce PCO, histamines could be important. pharmacologcail intervention: inhibit migration, cell division and wrinkling and kill all cells. drug delivery important could damage other tissues. 

calcium signalling - thapsigargin inhibits ER caATPase - decreased cell growth and protein synthesis - kills cells (apopotis) - can coat intraocular lens in thapsigargin. capsular bag model - cataract surgery in culture where dead eye not on person so can experiment on it. 5-FU not as effective as TG

Visual perception - rhodopsins, rods and cones, phototransduction, retinal processing of visual info, the visual cortex. retine has 2 light sensitive cells - rods and cones. Rods - cisual sensation of light intensity from black to gray and white, used in low lighting. Cones - vision, 3 types red blue and green. 4 receptors possess a distinct photopigment which possesses diff absorbance spectrum. optic nerve - blind spot and macula lutea most high quality vision. 

phototransduction - rhodopsin and retinal opsin react with light causing transduction of G protein causing cGMP to break down and release neurotransmitter in synapse. cis to trans state, photopigment wrap around rods and cones. Need to go from cis to trans quickly. retinal dissassociates from opsin to RPE where converted to cis-form, returns back to combine with opsin to form rhodopsin

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eye 3

photoreceptor in dark is naturally depolarised - Na channels are open causing Ca to be open in pre synaptic knob triggering exocytosis of transmitter glutamate causing graded potential in bipolar cell. when light hits its absorbed by photopigment, retinal and oppsin disassociate, transduction is activated, phosphodiesterase is activated, cGMP levels in cystol decrease, sodium channels close. Calcium channels close due to hyperpolarisation, transmitter glutamate release is decreased, graded potential to bipolar cells gets smaller. 

receptive field - antagonistic across retina and in ganglion cells. bipolar and horizontal cells - depolarising and hyperpolarising cells, some have excitatory or inhibitory receptors. H bipolar cells - horizontal cells contacts lots of cells, releases GABA, inhibits release of glutamate, hyperpolarised 

Visual information pathway - stimulus (light) - rods and cones - bipolar cells - ganglion cells - optic nerve - thalamus (lateral geniculate nucleus) - pathway - cortex - visual cortex and visual association cortex. left eye to right side of brain and vice versa. 

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glaucoma filtration surgery

glaucoma - intraocular pressure damages retinal ganglion cells, once nerve cells are damaged they dont regrow. Aqueous flow - front of eye, aqueus humour is the liquid between anterior chamber/conjunctiva and the lens. Increased liquid pushes pressure on lens which puts pressure on nerve cells. Cannal of schlemm drain it, too much liquid not enough drainage = blocked trabecullar network and cannal of schlemm.

surgery - increase volume of eye, bleb failure can occur. Make openning so fluid can drain, space between conjunctiva and schlera to relieve pressure on anterior chamber. peel back lens make incision and place lens back. failure - increased migration, proliferation and matrix deposition leads to reduction of spare volume increasing pressure again.

therapies - agens to prevent scaring. current drugs - 5-FU and mitomycin C but are very crude prone to leakage and infection and cystic blebs. research into targetting TGFbeta, MMPs and CTGFs. drug development - identify theraputic target, utlise agent that affects it, determine effective conc using cell cultures, small scale animal studies, compare with current drugs, human clinical trials. 

potential target: transforming growth factor beta. associated with wound-healing/fibrosis, levels elevated in gluacoma, increased matrix deposition is trabecular meshwork, expressed in normal conjunctiva

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glaucoma therapies

TGFB - promotes proliferations, 2D and 3D contraction assays, fibroblast proliferation assays and fibroblast migration assays show this. IC50 value - find 50% inhibitory value anf get ratio between ligand and antibody. Use TGFB-B2 antibody to treat TGFb overexpression. increased bleb survival and height and area. 5-FU causes lots of corneal epitheliopathy compared to CAT-152 and no treatment. CAT-152 caused less avascularity aswell. 

potential target: connective tissue growth factor. herapin binding protein, expression greatly induced by TGFb, CTGF reported to mediate number of TGFb actions including matrix contraction. causes contraction and regulates TGFb induced contraction. 

MMPs, matrix metalloproteinases - matrix degrading proteases, expresseion modified by injury, play role in cell migration and matrix contraction. involved in CTGF/TGFb induced contraction. inhibits it which supresses contraction. inhibitor. increases bleb survival and intraocular pressure. better than Mitomycin C as doesnt disrupt epithelium. 

current therapies to prevent bleb failure are crude need more selective replacements. TGFb, CTGF and MMPs provide alternate theraputic targets for novel drug therapies. Neutralising antibodies, pharmacological antagonists and antisense provide theraputic options. 

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skeletal and cardiac - striated. smooth control movement and regulates internal flow. tendon connect muscle to bone, muscle = bundles of fassicles = bundles of myofibrils. Dark A band and light I band. Z disc is dark line in I band, m line is light line in A band. 1 myosin surrounded by 6 actins. H zone is only actin and gets shorter during contraction. z lines come closer together. actin - F and G actin molecules. myosin - crossbridges, actin and ATP binding sites, heavy and light chains. 

Titin - largest protein keeps muscle shape. I bands shorten aswell in contraction. crossbridge - binding - phosphate is released - power stroke - ADP released (low energy state) - New ATP binds releasing head - cocking of head (high energy form)

Excitation contraction coupling - action potential at neuromuscular junction, many action ps summate to make stronger contraction due to short action p time. Ca important binds to troponin to move tropomyosin. Sarcoplasmic reticulum and transverse tubules for connection. lots of mitochondria, and nuclei. triads have Ca channels in and t tubules link sarcoplasmic reticulums. Dihydropyridine receptor has Ca channels which respond to depolarisation - L type channles. Sarcoplasmic Ca Atpase pumps to restore Ca resting potenital in cytoplasm

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muscle 1

3 sources of ATP in skeletal muscle - Glycolysis, Oxidative phosph and creatine phosphate. Creatine - creatin kinase uses ATP to make creatine phosphate - immediate source of energy before ATP synthesis, Fatty acids used for long distance. 

Type 1 fibres = MYH-slow - hydrolyses ATP slowly, oxidative phosph, long distance, lots of blood vessles, myoglobin and mitochondira, slow ATPase small fibres. Type 2 - MYH-2A - hydrolyses ATP fast, rapid contraction, fast glycolytic and fast oxidative, tire rapidly, heavy liftin, low myoglobin mitochondria and capilaries. High myosin ATPase. larger fibres

single motor neuron innervaes many muscle fibres. Slow oxidative fibres contract first, then fast oxidative then fast-glycolytic depending on contraction strength needed. 

myotonic dystrophy - commonest. nuclei found in cells not surrounding fibres, mostly small fibres. loss of myosin type 2 (strong fast fibres). myotonia - cant relax muscles. Chloride channels allow resting state activation after depolarisation. mutation means muss less stimulus needed for action potentials so multiple occur

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Heart 1

Pulmonary - lungs systemic circulation - body. deoxiginated blood in through superior and inferior vena cava to right atria and ventricle to pulmonary artery to lungs. Oxygenated from lungs in pulmonary veins to left atria and ventricles then to aorta to body and head. between epicardium and pericardium - fluid filled space to reduce friction. Left ventricle bigger. 

cardiac muscle - gap junctions hemijunction between cells for connects for powerful contractions and electrical coupling. Use Ca for contraction. intercalculating discs in gap junctions. macula adherens (desmosomes) - join intermediate filaments to stop cells separating during contraction. Cx43 - main connexin in heart, high density in intercalculating discs. Coronary artery source of o2 for heart, heart doesnt get o2 from blood inside itself. resting membrane potential - More negative inside. -70mV. lots of K in not much Na. electrical, chemical and electrochemical driving forces. Na/K pump maintain gradient. 

Conduction of heart - SAN - AVN - electrical seperation of ECM - Bundle of his and purkinji fibres. Atrial systole, ventricular systole (QPR), diastole (T wave) depolaration. Ventricular myocytes rapid depolaration due to permeability to Na, K then brings Na back down so Ca can flow in. Long QT disease - gap between Q and repolarisation is larger, repolarisation is delayed so next contraction cant start so they overlap - ventricular fibrulation. caused by mutated Na channels. 

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heart 2

Pacemaker potential - SAN, no resting membrane potential always depolarising. funny current - sodium channles more likely to open at negative potentials - 'funny current/channels'. in skeletal muscles there is a short refracting period for rapid long contractions, high frequency of A. potentials summate to long contractions. Longer refractory period in heart so no summation, cant restimulate A.potentials. 

2 sources of Ca in heart to regulate Ca levels. Membrane channels and Sarcoplasmic reticulum channels. Membrane Na/Ca pumps and CaATPase pumps to get rid of Ca. Mitochondria also take it up. depolarisation - openning of plasma membrane L-type Ca channels in T tubules - Influx of Ca - Binds to receptors on SR - openning of Ca channels so more Ca flows into cystol - contraction. 

stroke volume x heart rate = cardiac output. Sympathetic pathways main control of heart thoracic nerves 1-5. Parasympathetic constantly reducing heart rate, very dominant. Para - acetylcholine to M receptors, symp = Norepinephrine to Beta receptors. Adrenal glands release epinephrine into blood by chromatin cells. Dont use synapses but varicosites. Both act on G proteins, AcH - muscarinic cholinergic receptor. NE - Adrenergic receptor. Ach decreases CAMP, NE increases it. G protein binds GTP, Gi is inhibitory, Gs - stimulatory. AcH increases K channels to hyperpolarise cells.

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heart 3

funny channel - hyperpolarisation-activated cyclic nucleotide-gated channels. Inward Na channel. Activation at -45mV, causes depolarisation of SAN, acitvation by cAMP, slow activation/depolarisation. cAMP increases current. HCN channels. Mice without it develop bradycardia (low heart rate) and heart block. 

drugs which target sympathetic path - use G protein receptors e.g inhibits muscarinic receptor (M2) antagonists and removes inhibition of cAMP e.g Atropine. Drugs which affect para - Beta blockers, antagonists, affect B receptors in mucles aswell as heart e.g Propranolol. Calcium channel antagonists - voltage gated Ca channel blocker to treat arrhythmias. Glycosides - target Na/KAtpas pumps to increase contraction force, every cell in body has these pumps, agonist, used to treat atrial fibrulation.

Muscarine is muscarinic receptor agonist, antidote is atropine, causes bradycardia. glycosides - increase force of contraction, longer phase 4 of cardiac AP, slower heart rate. Na not being removed K not coming in so increased Na and Ca in cells. 'pure' heart rate lowering drugs - direct f current directly - block channel directly, linked to heart attacks, longer diastole. 

sympathetic nerve input - increases stroke volume in ventricular myocardium. Both act of SAN to regulated heart rate. stroke volume - ventricular contractibility, end-diasolic volume and afterload

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heart final

ventricular contractility - cAMP activates protein kinase PKA which phosphorylates targets. e.g L-type Ca channels - increases their openning porbability. Ryanodine receptors - increases their openning prob. Speeds up dissasociation of Ca from troponin. Increases SERCA activity and Ca re-uptake into SR. 

End-diastolic volume - Increase in end diastolic v causes stroke volume to increase. Frank-starling effect due to length-tension muscle relationship. Example of intrinsic control. Factors that influence SV - increased venous return meands increased EDV means increased SV. Increased sympathetic activity or adrenaline means increased contractibility meaning more SV. Decrease in Arterial pressure (afterload) affects SV. 

flow and pressure - flow = pressure gradient/ resistance. Cardiac output = Mean arterial pressure/ total peripheral resistance. Arterioles control blood flow to individual organs and mean arterial pressure - main source of resistance. Act as pressure reservoir and MAP is driving force for blood flow, systemic resistance causes loss of pressure. arterioles very muscular, contraction of blood vessel increases resistance, vasodilation decreases it. Radius, Length and blood viscosity affect this. control of arteriolr blood flow to organs - intrinsic controls - active hyperimia, flow autoregulation, reactive hyperimia, response to injury. Extrinisic - Sympathetic/para nerve and hormones. 

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heart final 2

activer hyperemia - increased tissue metabolism as needs lots of o2 e.g pins and needles. relaxes smooth muscle to increase blood flow. flow autoregulation - reduced arterial pressure in organ, reduced blood flow, less o2 more metabolites, arteriol dilation, restoration of vlood flow. Adrenal medulla secretes adrenaline into blood - increased plasma epinephrine - acts on alpha receptors for vasoconstriction and beta cells for vasodilation. Sympathetic postganglionic neurons to skeletal muscles arterioles releases norepinephrine - increased NE in extracellular fluid - affects alpha receptors causing vasoconstriction. 

61% blood in veins. sympathetic, alpha adrenergics and vascoconstriction affect peripheral venous pressure. increased venous pressure - increased venous return - increased arterial pressure - increased end diastolic volume - increased SV. 

regulation of systemic arterial pressure - all cahnges must be because of changes in cardiac output or total peripheral resistance. short term - baroreceptor reflexes, chemoreceptors and thermoregulation. Long term- regulation of blood volume. cardiovascular control centre in medulla oblongata. baroreceptors - on aortic arch and carotid sinus give afferent neurones to cardiovascular control centrel. Stretch receptors, decreased frequency of action potentials for receptors increases sympathetic activity. exercise - large decrease in arteriolar resistance

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Kidney 1

excretion of metabolic waste e.g ammonia is converted to urea to be removed. depends on flow size of product. Therefore drugs need to be coupled to large proteins so stays longer in blood stream. small proteins, glucose, urea, salts, water, acids, antibiotics and hormones are secreted. many hormones e.g insulin are degraded in kidneys. kidneys also help: regulate arterial blood pressure, synthesis of glucose, regulate water and ion balances. 

Nephrons for kidney filtration secretion and reabsorption. afferent arteriole to glomerular capillary where filtration of blood happens to efferent arteriole. glomerulus = filtration. Tubules = transport, secretion and reabsorption. glomerular unit has capillary endothelial cells, Glomerular basement membrane (Collgen IV stable network, laminins non covalent gel like polymer and perlecan oligomers), slit membrane (Nephrin crosslinkers) and podocytes. Alports syndrome linked with defects of collagen4 affects kidney by not filtering blood so found in urine, abnormal GBM structure. 

Glomerular filtration - fluid flows from capilaries into bowmans capsule, fluid entering has same ionic composition as blood, small ions can pass through easily. Size and charge affect it. Cellular barrier - endothelial cells and podocytes. Size barrier - GBM and slit diaphragm. Filtration driven by blood pressure. very low presssure = insufficient elimination of waste, too high = increased loss of solutes. 

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kidney 2

glomerular filtration controled by vascular smooth muscle cells. Decreased GFR by constriction of afferent arteriole or dilation of efferent one and vice versa. 

tubules - proximal convoluted, proximal straight, descending loop of henles, ascending loop, distal convoluted, cortical collecting duct and medullary collecting duct. Close contact to blood vessels, tight junction and cell adhesion molecules. only 10-20% renal blood flow in filtered in glomeruli, most passes to peritubular capillaties, so secretion is needed. Secretion moves unflitered substances from blood to tubule. most water, glucose and sodium is reabsorbed. most water and Na reabsorption in proximal tubule, more Na reabsorbed in henles loop and more water in distal and collecting duct. 

proximal tubules most metabollically active cells in kidney. sodium reabsorption linked to complete reabsorption of glucose and amino acids. High water permeability across epithelial cell layer. lots of mitochondria, and high surface area on brush border. Na-K ATPase lowers intracellular Na conc which generates low electrochemical gradient to tubular fluid so water rushes out. Need Na pump from tubules to capilaries so gradient is maintained to drive reabsorption of glucose etc. 

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kidney 3

Na H antiporters to remove acids from body. HCO3 (bicarbonate buffer) needed in blood for pH control. Blood flow keeps gradient high. Cl is transported into blood with K. Aquaporins allow water through. Shunt pathway driven by electrical gradient across the membrane, hydrostatic pressure gradient. Solute concs change along proximal tubules but not conc of Na. 

loop of henle - Lots of aquaporins on descending limbs no active transport of ions, lots of water reabsorption. ascending limbs no aquaporins lots of reabsorption of NaCl, K etc into interstitium to raise osmolarity there. generates steep Na gradient in the medulla from the cortex. Descending limb starts isotoninic at bottom its hypertonic, cortical collecting duct - hypotonic medullary collecting duct hypertonic. 

Vasopressin controls water transport, collecting duct and distal convoluted tubule ony part of kidney you can control water reabsoprtion. 2 types of epithelial cells there, intercalated cells balance the acidity and pH by excreting H and reabsorbing HCO3. glomerulus - ultrafiltration controlled by staling forces (pressure). Proximal tubules - bulk reabsorption of solutes and water, secretion of solutes controlled by active transport of solutes and passive water reabsorp. Loops - establish medullary osmotic gradient and secretion of urea. descending - bulk reabsorption of water, ascend - reabsorption of NaCl controlled by active trans. distal and cortical collecting - fine tuning of reabsorp controlled by aldosterone. Cortical and medullary - fine tuning and reabsorp of urea controlled by vasopressins.

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kidney control of solutes

no sodium sensing receptors, alterations of Na changes osmolality of extracellular fluid and volume of fluids affecting blood pressure. Detected by osmoreceptors by specialised neurons in the hypothalamic supraoptic and paraventicular nuclei are osmoreceptors. Produce ADH in neurons which are stored in pituitary gland and released into bloodstream, regulated retention of water by increasing water permeability of distal tubule generating concentrated urine and ADH increases permeability to urea in medullary collecting duct. Anti-diuretic hormone e.g vasopressin. 

nd baroreceptors (pressure) info on glomerular filtration and fluid levels. high pressure receptors in aortic arch and caotid sinus. low in heart/atrium and lung. triggered by stretching of vessel wall. impulse frequency of afferent nerve increases with pressure. nervous signals: Renal sympathetic activity activates ADH (vasopressin) and ANP . e.g Excess H20 - decreased body fluid osmolarity - decreased firing by hypothalamic osmoreceptors - posterior pituitary which decreases vasopressin secretion - collecting ducts decrease tubular permeability to H2o decreases h2o reabsorption - increased h20 excretion. 

vasopressing receptors have diverse functions in diff tissues and diff signalling cascades e.g cAMP and calcium. 

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kidney control

changes in plasma volume e.g Diarohea so loss of Na and H20 - decreased venous pressure  - decreased ventricular end diastolic V - decreased SV and cardiac output and arterial blood pressure so renal sympathetic nerve acts by constricting renal arterioles decreasing GFP by lowering blood pressure so less Na and H20 excreted. 

Renin-angiotensin system (RAS) regualted blood pressure and water balance. Can be activated by loss of blood volume or drop in blood pressure. Sensors in carotid sinus stimulating macula densa cells to signal juxtaglomerulat cells to release renin. results in - vasoconstriction of arterioles. glomerular arterioles : greater effect on efferent arterioles increased glomerular filtration rate. Tissue arterioles: contriction increases arteriolar pressure, rasing systemic arterial blood pressure and decreases blood flow. Decrease of medullary blood flow decreases washout of NaCl and urea in kidney medullary space. Release of aldosterone which increases reabsorption of Na/H20 increasing blood volume and pressure. Release of ADH/vasopress stimulares water reabsorp. 

decreased plasma volume - decreased GFR so deecreased flow to macula densa - decrease NaCl conc in macula densa - increased renin secretion from renal juxtaglomerular cells increases angiotensin II - adrenal cortex increases aldosterone secretion - cortical collecting ducts increase sodium reabsorption so less sodium excretion

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kidney final

renin-angriotensins system - increased symp activity, tubular Na cl reabsorption and K excretion and H20 retention caused by increased alsosterone secretion from adrenal gland cortex, increased arteriolar vasoconstriction and blood pressure, increased ADH from pitiutary gland, increased h2o absorption in collecting duct. increased plasma volume - increses ANF secretion - dilates afferent aterioles and constricts efferent one, reducing Na reabsorption and increases GFR - increasing sodium excretion. 

Potassium regulation. Main intracellular space cation. most reabsorbed in proximal tubule. factors regulating K secretion in cortical collecting ducts - high Adlosterone, K and Ph in blood. High sodium delivery rate, high luminal flow rate and negative lumen potential diff in tubules affect K. increased K intake increases aldosterone which increases K excretion and decreases Na excretion.

Calcium regulation - PTH stimulates bone reabsorption, increases Ca reabsorp by kidneys. needed for storage in bone. Acid-base balane controls H conc. Metabolic reactions sensitive to pH. extracellular buffer - Co2 and HCO3. intra - proteins and phosphates. Bicarbonate buffer system - CO2 + H20 ( lung )-> H2CO3 (carbonic acid) -> HCO3 + H (Kidney). Gain on H - decreased pH increased acidity - generation of Co2 oxidative phosph, metaoblism of proteins, anaerobic metabolism. Loss of H - metabolsm of organic anions - loss in vomiting, urine and hyperventilation

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Lungs 1

functions - breating pulmonary ventilation, gas conditioning (warming, humidifying and purifying), produce sounds, olfactory sensation and protection from pathogens. conducting zone: trachea, bronchi and bronchioles, rigid pathways to warm, moisten and filter air lots of cartilidge rings. Respiratory zone: respiratory bronchioles, aveolar ducts, alveolar sacs, site of gas exchange, large surface area. lots of capilaries, alveoli pores for connection.

lots of type 1 cells with lots of cytoplasm for gas exchange. type II cells - epithelial, form layer between air and body, secrete alveolar fluid, lung stem cells, secrete surfactant to maintain tension, sit on basement membrane for close association. emphysema - type I cells damaged so no elastin-elasticity, smaller gas exchange area so cant recoil. surfactant - phospholipids and proteins, increased by big breath, means alveoli dont collapse under pressure.

Pulmonary ventilation- ventilation of air between alveoli and atmosphere. Air moves out because alveolar pressure is greater than atmosphere. boyles law. diaphragm relaxes thoracic volume decreases. Intraplueral fluid lubricated pleural surfaces, pressure causes lungs to move in and outtogether during breathing. intrapleural pressure always less than intrapulmonary pressure and atmosphere pressure so lungs dont collapse. greater the complience of lungs easier it is to expand them in response to change in transpulmonary pressure. determined by stretchibility of lung tissue and surface tension at air-water interfaces.  

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lungs 2

surface tension is attraction of liquid to one another at liquid-gas interface. alveoli lined by surfactent which decreases cohesive forces between water molecules on alveoli therefore lowering surface tension increasing lung complience. respitory distress syndrome where type II cells dont produce enough. fibrosis - loss of ECM deposition, thick stiff walls, less gas exchange decreased complience. COPD and emphysema - degenration of alveolar wall increases compliences, decreasing pressure. asthma - hyperactive airway muscles lead to excessive airway narrowing - normal complience. 

airway resistance very small: radius, tube length, interaction between gas molecules. radii changes due to chemical, physical and nueral faactors. asthma - inflamation make smooth muscle hyperresponsive and causesit to contract strongly, goblet cells also secrete more mucus reducing airways. anti-inflammitory and bronchodilator drugs. COPD = emphysema and chronic bronchitis. causes difficulties in ventilation and oxygenation of blood. chronic bronchitus - excessive mucus production in bronchi and chronic inflammatory changes in airways

measure lung function using spirometer. tidal volume - amount of air inhaled in one breath. inspiratory and expiratory reserve - using maximum effort. residual volume - keeps alveoli inflated and mixes with fresh air. vital capacity - inspiratory + expiratory reserve. Functional residual capacity - amount left after normal expiration. Total lung capacity.  

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lungs 3

capilaries from pulmonary artery and vein surround alveoli. Lymphatics surround the blood vessels. ventilation normally = 4.2L/min. Perfusion normally 5L/min. 50% goes to each lung. when mismatched e.g in COPD the right lung overventilated the left under ventilated by perfusion stays the same. results in decreased O2 pressure increased co2 pressure in arterial blood. to compensate hypoxia induced vasoconstriction in under ventilated lung, causing increased ventilation means decreased CO2 pressure in over ventilated lung - raising pH which increases local airway resistance. 

Globin 4 protein chains each surround heme group. Iron containing porphyrin ring. binding of O2 to HB relied on PO2. sigmoid curve- affinity for o2 increases after each o2 is bound. o2 diassociated and is used by cells with less o2. High alkaline pH makes o2 have higher affinity for Hb. Low temp means higher affinity for Hb. Lower CO2 pressure means higher affinity for Hb. Increase in any factor e.g PCO2, H+, temp and 2,3-DPG decreases ability of Hb to bind to O2. bohr effect. CO2 and H alter confirmation of Hb by binding to globin. 2,3 DPG reversibly binds with Hb lowering affinity for O2. increase in CO2 increases H+. 

bohr effect - decrease in blood pH (increase in H) or increase in CO2 conc in blood will resuly in hB releasing loads of o2 and a decrease in CO2 or increase in pH will result in Hb picking up more o2.

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lungs 4

Co2 transport - CO2 + H2O -> HCO3 (bicarbonate) + H+ (proton). carbonic anhydrase is the enzyme, H2CO3 is the intermediate substance. 30% carbamino Hb -CO2 in cells bind to Hb, causing a chloride shift which is used in Cl/HCO3 antiporter ATPase. 60% as bicarbonate. 10% in solution.

Haldane effect - in tissues deoxygenated Hb has higher affinity for CO2 than o2 does. In high CO2 presence CO2+H20 - H + HCO3 applies. Deoxygenated Hb is better proton acceptor so H is taken up by Hb and o2 is released into tissue. This enhances removal of CO2 from o2 consuming tissues. In the lungs there is high PO2 in pulmonary capillaries. Oxygenation of Hb promotes dissociated of H from Hb, the increase in H shifts the bicarbonate buffer equilibrium towards CO2 formation. HCO3+H - CO2 and H20 so CO2 is realeased from red blood cells.

If alveolar PCO2 increases e.g emphysema - respiratory acidosis occurs. Hyperventilation leads to Respiratory alkalosis due to decrease in PACO2. Increase in blood H - metabolic acidosis. Loss of acid e.g vomiting - metabolic alkalosis. Changes in PCO2 are detected by central and peripheral chemoreceptors. in the medulla in the brain stem. Central respond to changes in H and PCO2 in brain extracellular fluid. Much slower responce to H change as it doesnt cross blood brain barrier. Response to increased PCO2 - increased ventilation. peripheral - carotid and aortic bodies respond to changes in arterial blood. 

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GI tract

Digestion starts in mouth with salivary amylase and lingiunal lipases. No further digestion in esophagus. Then to stomach where pH is very acidic: 2. Gallbladder gives out bile to stomach from liver whcih digests fat and pancreas gives out enzymes. in stomach, cheif cells in gastic mucosa secrete pepsinogen, converted to pepsin a protease by the acidity in stomach so that the enzyme wont degrade anything on its way to the stomach. Then to the small intestine where majority of absorption occurs. then to colon and cecum then to rectum and anus.

Main digestion in stomach to small intestine bit. Lots of secretion from blood into stomach. Lots of absorption and secretion in small intestine. More GI tract motility at colon and rectum than mouth. All minerals and nutrients absorpbed by blood from the GI passes through the liver through the hepatic portal vein.

Small intestine - large layers of longitudinal then circular smooth muscle for peristalsis to move food along. inner layer folded into villi and have microvilli brush border on top. all villi replaced every 5 days. surface area of 300m2. EPIthelium layers on villi and cripts and cover organs. ENDOthelium cells cover blood vessels. Villi only found in small intestine. Cirpts at bottom of villi contain stem cells and the cells move up the villi and die when reach the top the be replaced by cells at bottom. protects the villi from mutations which cause bowel cancer. only 1 cell thick so small diffusion pathway 

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digestion 2

apical membrane faces lumen, basil membrane faces cystol, lateral membrane connects cells and has tight junctions. gives cell polarity are ions movement is controlled, causing electrostatic gradient is formed. microvilli brush border on apical membrane. digestion occurs in lumen and on apical membrane. electrostatic gradient pulls positive ions into cell as cell more negative on inside. 

starch - glucose polymer, amylose alpha 1-4, amylopectin alpha 1-4 and 1-6 (branched). glycogen another glucose polymer. sucrose - glucose and fructose, lactose - galactose and glucose. starch digested by glucoamylase and alpha dextrinases, uses SGLT1. Glucose/Na ATPase also can use galactose. Fructose has own carrier into cystol. GLUT2 transports glucose into interstitual fluid to then go into capillaries. Low conc of Na in cells, -55mV on membrane. 

Proteins - 8 essenital amino acids, 14 unessential ones. 'ogen' e.g pepsinogen means inacitve form. enteroendocrine cells secrete CCK hormone into blood when small peptides and amino acids are liberated in stomach and are sensed by duodenum, causing pancreatic peptidases to be released from the pancreas. exocrine - secretes substances into duct e.g bile duct to carry digestive enzymes into duodenum, endocrine - into blood. Endopeptidases - cleave the middle of the peptite e.g trysinogen and pro-elastase. Exopeptisaes hydorlise amino acids from carboxyl end of peptide e.g carboxypeptidase A and B.  

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digestion 3

proenzymes - inacitve. enteropeptidase protease activates inacitve endopeptidases e.g trypsinogen - trypsin by removing 6 aa from N terminal, which then activates pro-enzymes. other digestive enzymes - aminopeptidases, carboxypeptidases and dipeptidases. 

amino acid and peptide transporters on brush border, polar and co transporters and aqueous soluble peptides need transporters. Peptide trans HPEPT1 - coupled with H ions as cells remove H protons all the time to keep cell pH so brush border outside is very acidic causing conc gradient which peptides use. H waste product of resp. Antibiotics use HPEPT1 for uptake into blood. cystolic peptidases then amino acid transports on basal membrane to blood. 

iron daily intake 15-20mg, 1mg absorbed, haem and non-haem. 60% in haemoglobin, 25% in storage in liver, 8% in myoglobin in muscles and 5% in enzymes. Iron from diet reduced to Fe2+ by ferrireductase and then co-transported in with H protons (DMT1) using acidic microenvironment on brush border. Heam transporters. Ferritin binds to iron or storage. Fe2+ oxidised to Fe3+ by ferroxidase and then transported into blood by ferroportin. Transferrin transports iron around body. 

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more digestion

lipids - glycerol backbone and 3 fatty acid chains. triglycerides, cholesterol, cholesterol esters and phospholipids. pancreatic lipase cleaves FAs from triglycerides to produce 2 FAs and a monoglyceride. Colipase is used for lipase to bind to emulsion droplets in the presence of bile acids. Cholesteral esterase cleaves ester bond to form free cholesterol and 1 FA. Bile acid forms hepaticites which pancreatic duct takes into stomach. fat droplet covered in emulsion droplets, fat and bile salts. 

Absorption - micelles diffuse into unstirred layers. FAs diffuse, Phospholipids diffuse, cholesterol and monoglycerides all diffuse in. All come together to form chylomicron with lipoprotein coat from smooth ER. Exocytosis out of cell into lymphatic system. Fat droplets emulsified by bile salts and PLs into micelles which are digested by pancreatic lipases. Chylomicrons are then processed and traffiked into cell and then lymph system and adipose tissue. 

stomach - fundus is upper end, antrum is lower. epithelium cells. oxyntic gladnular mucosa on inside acid producing cells, pyloric glandular mucosa on outside. links oesophagus to duodenum. sterile acid enviro to kill bacteria, breakdown protein to peptides with pepsin. gastric mucosa - lined with gastric glands and surface epithelial calles. parietal cells secrete HCL amnd intrinsic factors essential for absoprtion of Vit B12. cheif cells secrete pepsinogens

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endothelial cells come to juxtaposition with epithelium cells in gastric pit. parietal cells in fundus, ucous secreteing cells in pyloric region. gastric juice - salts (Ch, K, Na), water, HCL, pepsins, intrinsic factors and mucous. thinking, smellnig or eating food stimulate onset of proton (H) secretion and NA lowers so electroneutrality stays. pH-2 acidic more H ions. bicarbonate neutralised H by producing H2o and CO2. 

people with gastric ulcers have less HCL and those with duodenal ulcers secrete more. pariatel cells have lots of tubulovesciles and internalised intracellular canaliculous with membranes inside cells which join to outside membrane. tubulovesciles fuse with membrane of intracellular cannaliculus which is opne to lumenn of the gland and lined with microvilli when the cell starts secreting acid. intracellular cannaliculus fused with apical membrane. 

Cl enters stomach lumen through epithelial cell from capillary through CFTL channels. H2CO3 from red blood cells and carbonic anhydrase split to leave lots of protons and bicarbonate moecules leave into capilary. H/K electroneutral ATP pump pumps H to stomach and K into cell. K then exits cell back into stomach through K channel. cell more negative inside than in stomach. gastric mucosal barrier of HCO3 and mucus to keep edge of stomach more pH neutral so acid doesnt erode. contains sticky mucin glycoprotein s from mucous neck cells. K and HCO3 secreted by surface epithelial cells. secretion stimulated by stimuli that enhance acid and pepsinogen secretion

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stomach final

parietal cells - gastin, histame and Ach inducing receptors on basal membrane facing capillary. somatostatin inhibitory receptor. all activate secondary messengers e.g Ca and cAMP. Ach - muscarinic receptor. stimulate formation of canaliculi which causes H acid secretion. when stomach has been empty for hours the acid secretion is incresed 10%.

cephalic phase is elicited by sight taste etc in mouth - salivation, vagus efferent nerve in autonomic sympathetic pathway to parietal cells to release Ach and to G cells to release Gastrin. Gastric phase - gastric distenstion (food in stomach) - local and vago-vasal sensory relfexs to parietal and G-cells in antrum. Intestinal phase caused by protein degradation in duodenum causes intestinal G cells to release Gastrin and intestinal endocrine cells to produce entero-oxytin. 

inhibition - antrum, duodenum and jejunum. Stimulus includes Ph<3, hyperosmotic, fatty acids and monoglycerides. GIP inhibits gastrin release. CCK, Enterogestrone inhibit acid secretion by parietal cell. 

ulcer - protective - mucous and HCO3. aggressive - acid and pepsin activity. ulcer when too acidic, rantidine block H2 receptor and K/H ATPAse. H.Pylori bacterium shown to cause ulcers. Treatment with antibacterial bismuth longer remission. triple therapy Bismuth, antibiotics and PPis. 

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endocrine system

endocrine - results take long, hromones released into blood,  nervous - certain parts release hormones into blood, rest release neurotransmitters excite or inhibit nerve, muscle and gland cells. exocrine gland: secrete products into ducts, swear, oil, mucous and digestive glands. endocrine glands: pituitary, thyroid, parathyroid, adrenal and pineal, secrete hormones into bloodstream, other organs secrete hormones as 2nd function e.g hypothalamus, thymus pancreas, ovaries etc. 

endocrine: reproduction, growth, development, defense, water electrolyte balance, energy balance,, cellular metabolism. negative feedback - opposiste direction to initial change e.g calcium in blood - parathyroid hormone released by parathyroid gland stimulates osteoclasts to resorb bone releasing calcium - clacitonin hormone released by thyroid gland which inhbits osteclasts to resorb bone and encourages calcium salt deposit in bone marrow - decreased Ca in blood. positive - same direction, amplify cascades - e.g hypothalamus makes pituitary gland secrete oxytoxin - uterine contractions - delivery - neural electrcal impluses stimulate hypothalamus again.

other endocrine stystems - brain, atrium, liver, kidney, immune cells, adipose tissue. pancreas -insulin. thymus gland - thymosins. pineal body - melanin. Pituitary - FSH, LH, oxytocin. most hormone secretion by hypothalamus and pituitary gland.  

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endocrine system

endocrine - results take long, hromones released into blood,  nervous - certain parts release hormones into blood, rest release neurotransmitters excite or inhibit nerve, muscle and gland cells. exocrine gland: secrete products into ducts, swear, oil, mucous and digestive glands. endocrine glands: pituitary, thyroid, parathyroid, adrenal and pineal, secrete hormones into bloodstream, other organs secrete hormones as 2nd function e.g hypothalamus, thymus pancreas, ovaries etc. 

endocrine: reproduction, growth, development, defense, water electrolyte balance, energy balance,, cellular metabolism. negative feedback - opposiste direction to initial change e.g calcium in blood - parathyroid hormone released by parathyroid gland stimulates osteoclasts to resorb bone releasing calcium - clacitonin hormone released by thyroid gland which inhbits osteclasts to resorb bone and encourages calcium salt deposit in bone marrow - decreased Ca in blood. positive - same direction, amplify cascades - e.g hypothalamus makes pituitary gland secrete oxytoxin - uterine contractions - delivery - neural electrcal impluses stimulate hypothalamus again.

other endocrine stystems - brain, atrium, liver, kidney, immune cells, adipose tissue. pancreas -insulin. thymus gland - thymosins. pineal body - melanin. Pituitary - FSH, LH, oxytocin. most hormone secretion by hypothalamus and pituitary gland.  

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hypothalamus and pituitary

both master endocrine glands. influenced by emotions and metabolic status. controls pituitary gland with 9 diff horomones. hypothalamus - secretion of hypophysiotrophic hormones - influenced by emotions, delivered to the anterior pituitary. synthesis of diff anterior pituitary hormone by diff cell populations. Thyrotropin by thyrotropes. anterior lobe - hormones secreted to control other endocrine glands. Production of ADH and oxtocin by hypothalamus into neruone to posterior lobe of pituitary. hypo control symp and parasym output to adrenal medulla which secretes epinphrine. 

growth hormone - bones. Prolactin - mammary glands. TSH - thyroid. thyroid stimulating hormones triggers release of thyroid hormones which increase metabolic rate. posterior PG - hormones synthesised in hypothalamus and transported down axon and stored in nerve ending, neurons release oxytocin and vasopressin (ADH) into capillaries. when body needs water, receptors in hypo sense increase of solute conc in blood and releases ADH from pituitary gland which works on distal nephron tubule increasing permeability to water so more water moves out and back into ciruclation. 

pituitary disorders - hyposecretion - underactivity e.g pituitary dwarfism not enough GH or diabetes - no ADH, can treat both with hormone replacement therapies. hypersecretion - overactivity - gigantism or acromegaly. 

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thyroid gland

rich blood supply. T3 and 4 = from follicular cells - synthesis of protein, breakdown of fats. increase rate of o2 uptake and basal metabolic rate. enhance effect of symp stimulation increasing heart rate, blood pressure. help maintain body temp. Calcitonin from parafollicular cells - build bone and stop reabsorption of bone - lower levels of calcium. 

disorders - congenital hypothyroidism - infant stunting, low body temp, retardation. myxedma - adults, low metabolic rate, sleepish, weight gain, constipation. Goiter - englargement of thyroid gland. endemic goiter - lack of iodine necessary for TH, pituitary no feedback so extra TSH, Toxic goiter - autoimmune disease - abnormal antibodies mimic TSH - nervous, no sleep, weight loss, abnormal sweat. 

parathyroid glands - parathyroid hormone. raise blood calcium levels increase activity of oseoclasts increased reabsorption of Ca by kidney, inhibits reabsorption of phosphate, opposite to calcitonin. high level Ca in blood stimulates PTH release from thyroid gland which releases Ca from bone matrix to blood, PTH also stimulates kidneys to release Calcitriol which increases absorption of Ca - increased blood Ca levels. Low levels - parathyroid gland to release calcitonin - promotes deposition of blood Ca into bone matrix. removal of parathryoid glands - hypoparathyroidism - lower Ca levels - death. hyperparathyroidism - caused by tumour - more Ca soft bones. 

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adrenal glands

kidney - cortex produces 3 diff hormones. medulla produces epinephrine + norepinephrine. glomerulosa secretes aldosterone. fasciculata - cortisol. reticularis secretes androgens. mineralocorticoids -  aldosterone - regulate Na retention and K loss, hypersecretion - tumour producting aldosteronism - high blood pressure due to renetion of Na and water in blood. glucocorticoids -  cortisol, help regulate metabolism - increase rate of protein catabolism and lipolysis, converts amino acids to glucose, raise BP by vasoconstriction, anti-inflamitory effects reduced. androgens  - small amoutn of male hormone.

adrenal medulla - chromaffin cells recieve direct innnervation from symp nervous system produce epinephrine and norephine. acetylcholine increase hromone secretion. adrenaline -increase heart rate + blood pressure. noradrenaline - constricts arterioles. crushing syndrome - adrenl tumour, excess ACTH, hyperglycemia + hypertension. addison disease - hyposecretion of glucosteroids and mineralocorticoids - hypoglycemia - Na/K inblanace, weight loss dehydration. 

pancreas - islets of langerhans. endocrine - B cells - insulin. Alpha - glucagon. exocrine - pancreatic acini - alkaline enzyme rich fluid. ovaries + testis - estrogen, progesterone, testosterone. pineal gland - melatonin - sets biological clock. Thymus gland - maturation of T cells. kidney - calcitrol, erythropetin - production of red blood cells, renin - renin-angiotensin system. ANP - atrial cells in heart reduce blood volume + pressure. 

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hyperglycemia - too much sugar. hypo - less than 60mg/dL. increase in glucose - converted to glycogen + triglyceride. decrease - glucose made by gluconeogensis + fat converted to fatty acid and glycerol. metabolically active tissues - skeletal muscle + liver. Metabolically inacitve - adipose and fat. glucose dependant tissue - brain, blood cells, eye, kidney. proteins, keto acids, glycerol, ketone bodies all feed into krebs cycle to create ATP. pancreas - 99% exocrine - digestive enzymes delivered to duodenum by pancreatic duct. rest endocrine organ produces glucagon and insuin. glucagon activates G-protein coupled receptor and stimulates glycolysis and gluconeogensis

diabetes mellitus - insulin deficiency - hyperglycemia. primary - type 1 insulin dependant diabetes. type 2 non insulin dependanr. secondary - islet pathology - infectious, tumours, drugs. type 1 - low or no insulin production - autoimmune disorder. type 2 lack of response to insulin. complication - angiopathy, nephropaty, neuropathy. microangiopathy - glucose with protein e.g collage in blood vessels, excess deposotpn in basemenet membrane, thick and leaky blood vessels - organ damage. 

diagnosis - dip-stick method after fasting. oral flucose tol. overnight fasting, lots of glucose, monitor glucose levels in blood. HBA1c test. drugs - stimulate B cells, improve insulins ability to move glucose, makes cells more senstiive to insuline. pancreas transplants, islet cells transplants + stem cells. 

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biological clock

circadian function - regular bodily rhythms occur on 24 hour cylce. internal biological clock - pacemaker cells: cryptochrome protein and clock genes. Clck and cycle proteins bind and increase production of PER and TIM which accumulate and when enough is there they inactivae CLOCK-CYCLE complex. rhytms also affected by sunlight, alarm clock etc. some endogenous. e.g levels of melatonin that rises in your body during night and falls during day. 

endogenous - 24.5 hours e.g activity, temp, waking sleeping, hormones secretion, eating and drinking. zeitgeber - stimulus that resets biological clock e.g light, exercise, temp. human sleep wake cycle in entrained and constant - light in entraining cue, light speed up clock, can change by one hour, jet lag. 

circadian rhys link to endocrine - core body temp, secretion of cortisol, melatonin and TSH, physiological, behavioural, sensitivity to drugs. role of endogenous clock: suprachiasmitic nucleus (SCN). light picked up in eye by specialized ganglion cells to retinohypo-thalamic tract. existance of photoreceptors not specialised for visual function - entrainment of circadian rhys. retinohypothalamic pathway - Per2 promoter linked to GFP expression. 

endogenous (internal) pacemaked is SCN. small group of cells in hypthalamus, lies above optic chiasm. 

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biological clock

circadian function - regular bodily rhythms occur on 24 hour cylce. internal biological clock - pacemaker cells: cryptochrome protein and clock genes. Clck and cycle proteins bind and increase production of PER and TIM which accumulate and when enough is there they inactivae CLOCK-CYCLE complex. rhytms also affected by sunlight, alarm clock etc. some endogenous. e.g levels of melatonin that rises in your body during night and falls during day. 

endogenous - 24.5 hours e.g activity, temp, waking sleeping, hormones secretion, eating and drinking. zeitgeber - stimulus that resets biological clock e.g light, exercise, temp. human sleep wake cycle in entrained and constant - light in entraining cue, light speed up clock, can change by one hour, jet lag. 

circadian rhys link to endocrine - core body temp, secretion of cortisol, melatonin and TSH, physiological, behavioural, sensitivity to drugs. role of endogenous clock: suprachiasmitic nucleus (SCN). light picked up in eye by specialized ganglion cells to retinohypo-thalamic tract. existance of photoreceptors not specialised for visual function - entrainment of circadian rhys. retinohypothalamic pathway - Per2 promoter linked to GFP expression. 

endogenous (internal) pacemaked is SCN. small group of cells in hypthalamus, lies above optic chiasm. 

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biological clock 2

diff rhys in diff organisms. CYC/CLK-dependant gene expression responsible for controlling biological and endocrine output from SCN = all depends on instrinsic stability of CLOCK family proteins. fluctuating gene products - day - less protein degradation, more RNA production, night opposite. 

drosophila - light effects genes to mediate hatching or molting etc. clock genes whose products regulate clock - per, tim and vri. all promoters are bound by protein transcription factors: CLOCL endoded by gene clk and CYCLE encoded by cyc. can set clock using CRY which causes TIM to break down ending its inhibition of CYC/CLK, if this happens when PER/TIM levels are rising (late in day) it sets clock back. if it happens when levels are declining (late in night ) it sets clock ahead. 

in mice light acts through retina and direct neural pathways to SCN to stimulate per gene expresiion. ganglion cells have dendrites that contain melanopsin, when exposed to light the ganglion cells depolize and send signal to SCN. circadian rhys of gene expression in liver become entrained to meal times. clocks present in other organs e.g heart and lung and interact with central SCN. 

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circadian rhythm disorders

caused by mismatch between external and internal time, e.g jet lag, day shift to night shift at work. can relate to dsyfunctional photic input e.g blindness. circadian 'dysentrainment e.g sleep disorders and insomnia. 

familial advanced sleep phase syndome (FASPS) - inherited, wake up several hours earlier than normal, mutation in PER2 gene so PER2 protein build sup more rapidly than normal triggering earlier feedback inhibition. delayed sleep phase syndrome - delayed sleep-wake cycle gene cause not clear could be PER3. 

jet lag and shift work - light box treatment, melatonin resets rhyth.

endogenous pacemaker (SCN) and exogenous zeitgebers.  

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hormone form pineal gland. controls body temp and release of endocrine hormones from hypothalamus. promotes sleep, depresses activity of gonads, affects thyroid and adrenal cortex functions. Seasonal affective disorder - too much melatonin. Melatonin drops 75% before puberty. also in retina, bone marrow, skin etc. Night - 200pg/ml, day - 10. blocks synthesis of skin pigment melanin. after birth - not much, 6-8 wekks more, 3-5 years max. low levels seen in old age. 

pineal gland - inhibit reproductive functions, protect against free radicals, set circadian rhythms. amine hormone from tryptophan. melanopsin photopigment produced by ganglion cells in eye when no light. the suprachiasmatic nuclei in brain detects light and is central biological clock system. light - eye- glutamate - SCN. rhythmic melatonin secretion is driven by a poly-synaptic output pathway from SCN. release of noradrenaline stimulates pineal AA-NAT expression at night. AA-NAT is enzyme that stop melatonin biosynthesis. 

melatonin is made from serotonin, when melatonin low, serotonin high. light makes more serotonin - SAD. 4 receptors -  MT1a - SCN of hypo, pituitary gland. also MT1b -retina, MT2/3 kidney and brain. major - MT1a/b, G protein coupled receptors. link to cAMP inhibition. lowers calmodulin and linoleic acid uptake that create tumours. tryptophan - serotonin ( AA-NAT enzyme) - melatonin. 

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melatonin action

MT3 receptor - intracellular QR2 detoxifying enzyme, decreases cancer risk. reduces free radicals and increases antioxident enzymes. antiprolifferation to stop tumours. potential uses - 1000-100,000 times increase to treat cancer and can impair sleep and circadian rhythms. antioxidant properties. too much light can be detrimental (LAN). some studies show link to leukaemia and melatonin protect against oxidative damage in haemopoietic systems. humans took 300mg of melatonin and had 50-70% reduction in damage in lymphocytes. 

LAN - exposure to light at night suppresses nocturnal production of natural anti-cancer agent. night shift workers more at risk. melatonin shown in study to reduce blood pressure slightly. low levels also associated with heart disease. 

in US melatonin sold as dietart supplement for jet lag and insomnia. 

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bones and joint

joints - skeleton mobility and hold it together. fibrous - fixed e.g skull. cartilaginous - slightly moveable lots of cartilage. synovial - very movable, most common, have capsule and synovial fluid for lubrication. synovial joints all have - articular cartilage, synovial cavity, articular capsule, synovial fluid and reinforcing ligaments. 

rheumatoid arthritis - thinning of cartilage, inflamed tendon sheath and synovium across joint surface, erosion into corner of bone. osteoarthritic joint - bone angulation, little remaining cartilage, tight thickened capsule, inflamed synovium, thickened bone with no covering cartilage. connective tissue - adipose - subcutaneous in palms and soles, loose connective tissues - surrounds organs and tissues, dense CT - tendons cartilage, ligaments, joint capsule etc.

ECM - collagens, elastin, proteoglycans and glycoproteins e.g laminin and fibronetin. collagen elastin and proteoglycans provide strength, elasticity and compressibility. matricellular proteins e.g tenascin for cell-ECM interaction. cell surface receptors such as integrins and HSPG for signalling and binding. proteinases and inhibitors for ECM turnover e.g MMP and ADAMTS. 

ECM proteoglycans - glycosaminoglycan side chain e.g aggrecan, hold water in tissues for viscoelasticity. collagen - staggered collagen molecules packed and crosslinked in triple helix. firbil forming - I,II,II,V etc. meshwork - VIII, X, basement membrane - IV, anchor = VII, 

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bones and joints

skin - 60% collagen I, 30% III. tendon - 90% I, 5% III, parrallel fibres. bone - 90%- I form sheets. cartilage - 90% II, 10% aggrecan meshwork. insertion tendons have collagen II, IX and XI and aggrecan and biglycan. connective tissue cells types - fibroblasts in skin tendon ligament etc. Chondrocytes in cartilage, osteocytes in bone and stem cells. 

ECM turnover - MMPs collagenases - inhibited by TIMPs and ADAMTS aggrecanases - inhibited by TIMP-3. MMPs - transcription control - ytokines, cell-matrix interaction and mechanical load, pro-MMP inactive, other MMPs activate it, TIMPs inactivate it. IL1 and TNF control transcript. ECM turnover highly regulated

joint disease - osteoarthritic - degenerative, increased matrix degeneration. rheumatoid arthritis - inflammatory, increased matrix degredation, decreased synthesis. tendiopathy - same. loss of proteoglycan, collagen fibrillation. 

osteocyte to osteoblasts by mechanical stress and DMP1, to osteoclasts by systemic factors by cytokines and CSF-M. 206 bones. store calcium phosphate etc, haemopoeisis, immunity. lamellar - mature bone, strong, collagen fibres in lamellae sheets. woven - immature, healing, meshwork of collagen, replaced by lamellar. 

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lamellar and woven

lamellar contain cortical and trabecular bone. cortical - in long bones, large cortex. trabecullar - in vertebrae, trabeculae with connectivity to increase compressive stress resistance, thin cortical shell. bones - periosteum is fibrous membrane rich with capillaries. cortical 80% of total outer layer, strong. trabecular - 20% bone mass, internal region, resists compression. medullary cavity contains bone marrow rich in blood vessels site of blood cell formation. proximal epiphysis - diaphysis - distal epiphysis. 

haversian system (cortical) - lamellae arranged in rings surround each haversian canal which has blood vessels, lymphatics, connective tissure inside, each unit - osteon. osteon - osteocyte lacunae and canaliculi (network of transverse canals). 

intramembranous ossification - flat bones, forms within fibrous membrane. formation of ossification centre within membrane, secretion of osteoid which mineralises to calcify bone matric, formation of woven bone and periosteum by condensing mesenchyme, formation of compact bone and marrow. 

endochondral ossification long bones - cartilage replaced by bone. catrilage model forms, blood vessels invade and primary ossification sites develop, trabecullar bone develops at secondary oss sites, cavity formed by blood vesssels, compact bone contains osteocytes, growth plates promote longitudinal growth at ends of bone. 

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bone diseases

strength determined by - rate of turnover, collagen matrix, size, structure and mineral density. osteogensis imperfecta - mutation in collagen genes. sclerosteosis - excessive bone formation, osteoporosis - loss of bone, bone mineral density reduced, hormone replacement therapy. sclerosteosis may lead to new treatments. 

bone remodelling - continuous cycle. response to mechanical forces, calcium, vit D, PTH GH oestrogen, cytokines, growth factors and signalling molecules. Wnt signalling pathway essentail. PTH raises serum calcium and Vit D levels. Vit D raise serum calcium and phosphate levels while decreasing PTH. PTH and vit D = major calcitropic hormones. Uv light makes vit D go to liver then kidney to release Ca from there. 

mechanical or biochemical stimuli - lining cells retract and matrix metalloprotinases remove the membrane, osteclasts fuse and digest and reabsorb the surface bone lining then reversal with macrophages, then osteoblasts form the new osteoid which is calcified. 

osteocytes - regulatory cells. 90% bone cells, terminally differentiated, derived from osteoblasts, encased in bone matrix, communicate through canaliculi. mechanosensory cells regulate bone structure and mass. ostecytogenesis - effected by matrix stifness, structure composition?

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more bone

osteclasts - bone reabsorbing cells. derived from circulating macrophages. multinucleated, dependant on 2 cytokines: RANK ligand and M-CSF. monocytes recruited by M-CSF and RANK which ahere and differentiate into osteclasts. RANK stimulate activation. Secretion of H and lytic enzymes: TRAP and CATK. 

osteoblasts - derived from stem cells, present on endosteum (bone lining), lay down new matrix (osteoid) which later becomes mineralised. stimulated to divide and differentate by hormone and cytokines, formation regulated by growth factors, insulin, TGFB1/2, transcription factors etc. 

Wnt B-catenin signalling essential for bone formation. When no Wnt ligand - B catenin phosphorylated by GSK-3, targeted for degradation in proteosome, doesnt translocate to nucleus, no expression of genes. in presence of Wnt ligand - Wnt binds to LRP, B catenin not phosphorylated, translocated to nucleus, activates genes.

sclerosteosis - genetic defect in SOST gene. Van buchem disease - both autosomal recessive, increased bone growth, resistance to bone fracture, reduced sclerostin. deletion in regulatory region of gene, reduced transcript. Sclerostin inhibits Wnt signalling so reduced osteoblast formation. only produced by osteocytes, negative regulator of bone formation, anti-sclerostin antibody being developed. 

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