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  • Pharmacokinetics & Drug Metabolism Lecture

    Diunggah oleh

    Joseph Chan
    192 tayangan78 halaman
    This document summarizes key principles of pharmacokinetics and pharmacology. It discusses: 1) The importance of maintaining appropriate drug concentrations at the site of action over time. Factors like dosage, formulation, and patient characteristics influence absorption and concentrations. 2) Drug metabolism and elimination occurs mainly through the liver and kidneys. Biotransformation makes drugs more soluble for excretion, though some drugs require these transformations to become active. 3) Alcohol is absorbed through the stomach and small intestine and distributed throughout the body. It is mainly metabolized in the liver by alcohol dehydrogenase and acetaldehyde dehydrogenase. Metabolic byproducts can be toxic and cause organ damage with chronic use.

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    This document summarizes key principles of pharmacokinetics and pharmacology. It discusses: 1) The importance of maintaining appropriate drug concentrations at the site of action over time. Factors like dosage, formulation, and patient characteristics influence absorption and concentrations. 2) Drug metabolism and elimination occurs mainly through the liver and kidneys. Biotransformation makes drugs more soluble for excretion, though some drugs require these transformations to become active. 3) Alcohol is absorbed through the stomach and small intestine and distributed throughout the body. It is mainly metabolized in the liver by alcohol dehydrogenase and acetaldehyde dehydrogenase. Metabolic byproducts can be toxic and cause organ damage with chronic use.

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    © All Rights Reserved
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    192 tayangan78 halaman

    Pharmacokinetics & Drug Metabolism Lecture

    Diunggah oleh

    Joseph Chan
    This document summarizes key principles of pharmacokinetics and pharmacology. It discusses: 1) The importance of maintaining appropriate drug concentrations at the site of action over time. Factors like dosage, formulation, and patient characteristics influence absorption and concentrations. 2) Drug metabolism and elimination occurs mainly through the liver and kidneys. Biotransformation makes drugs more soluble for excretion, though some drugs require these transformations to become active. 3) Alcohol is absorbed through the stomach and small intestine and distributed throughout the body. It is mainly metabolized in the liver by alcohol dehydrogenase and acetaldehyde dehydrogenase. Metabolic byproducts can be toxic and cause organ damage with chronic use.

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    dari 78

    Lecture1.1.

    2Principlesofpharmacokinetics
    Somebasicprinciplesunderpinningdrugdosing
    Deliverappropriate(therapeuticallyeffective)concentrationofdrugtositeofaction
    Maintainappropriateconcentration
    Clinicalpharmacology
    Rightdrug,patient,dose,doseformandtiming

    Concentrationeffectrelationship
    Doseresponsecurveissigmoidaltoxicitywillstartatsomepointintheeffectcurve.
    Safetymarginiswhentoxicityandsafetyisbalanced
    Plasmaproteinsareasitefordrugbinding
    Theratiooffreeandbounddrugdependsontheaffinityofthedrug
    Effectiscausedbyfreedrug

    Freedrugcanbeexcretedoritcanbemetabolised
    COncentraitoncurveisdependentonrateofdeliveryandexcretion

    Timeofonsetofeffectconvenience,physiochemicalproperties,expense,localaction
    Concentraitontimeprofilesintravenousvsextravasculardosecurvesdiffer

    Lignocainehasmanyroutesofadministration(intravenous,topicaletc)

    Glyceryltrinitrate(GTN)cannotbegivenorally,butcanbeabsorbedviaotherroutes(maybeaffectedbyfirst
    pass)

    Factorsaffectingtherate/extentofdrugabsorption
    Formulationordrugcharacteristics(tabletdissolution,influenceofexcipients)
    PKcharacteristicsofdrugfirstpasseffect(metabolismbybacteria)
    Patientcharacteristicsgastricandintestinaltransittime,influenceofdisease
    Oraldoseforms
    Conventional,coated,entericcoated,sustainedrelease,controlledrelease
    Controlledformsgoodforminimizingrepeatdosing

    EntericcoatingpHdependentrelease(preventdegradationinstomach),protectstomachfromirritantdrugs,
    shouldneverbecrushed
    Controlleddissolution

    Barrierstodrugabsorptionwhentakenorally
    FlumenxFgutwallxFportalxFliver=F
    Bioavailabilityextentofabsorptionafteradministrationofanextravasculardose
    Definitionfractionoftheadministereddosethatreachesthesystemiccirculation

    Lowbioavailabilityduetoextensivefirstpasshepaticelimination
    Doxorubicin,nicotine,testosterone,papaverine

    Nicotinehighfirstpasseffect,notactiveafteroraldiministratione.g.transdermalisbetter

    Gastricemptyinglimittime
    STimualtesgastricacidsecretion,chelatetoforminsolublecomplexes,increaseabsorptionbyhelpingtosolubilise
    insolubledrugs,generallyslowsabsorptionrate.
    Routesofelimination
    Metabolicbiotransformationliver,intestine,kidney,lung
    Exhalation,urine,faces

    Biotransformationatliver
    Oxidation,reductionorconjugationmakesdrugsmoresolublesoitcanbeexcreted
    INsomecasesprodrugneedsthesemetabolicbiotransformationscodeine

    Renalelimination
    Filtration(glomerulus)allunbounddruginplasmaisfiltered
    Secretion(proximaltubule)carriermediated,drugsmayinteractforthesamecarriere.g.amoxicillinprobenecid)
    Passivereabsorption(distaltubule)relativelyinsolubleandunchargeddrugsundergopassivereabsorption

    Renalfunctionisveryimportantforclearanceofdrugs
    TOtestthisweusecreatinineclearance
    CLcreathasaformula
    Asweage,functiondeclinesandisalsoaffectedbyweight
    eGFRelectronicallyreportedGFRnotagoodmeasure

    Cefotaximegoodfunctionis0.71.3hours
    CLcreat3.5hours
    Clearance=organbloodflowxextractionratio

    CListhemostimportantclinicalpharmacokineticparameterbecauseitdeterminestheaverage.
    Albumin(foracidicdrugs),acidglycoproteins(basicdrugs),lipoteins(forlipophlicdrugs)
    Acidicdrugsaremorehighlyboundwarfarinfb>99%
    Volumeofdistribution
    Smallvolumesofdistributionhighlyproteinbound
    Highvolumesofdistributionhighlytissuebound

    Clearanceisdose/areaunderthecurve
    Lecture1.2.3BiochemistryofAlcohol
    Ethanolcontenttypically0.789gpermL
    Standarddrinkis10grams

    AbsorptionofalcoholMouth,Stomach,SIandLI
    GastricADHsiteoffirstpassmetab
    Rateofabsorption=gastricemptying

    Fateofalcoholportalblood
    Liveristhemajorsiteofbreakdown,somefirstpassmetabolism
    Distributedwidelyinsystemicbloodrapidlyequilibratesacrosscellmembranes

    Distributionofethanolwholebodywater
    Intracellularconcentration=extracellularconcentration
    Detectedinexpiredair,urine,sweatandblood
    BACisexpresseding/100mL1
    0.05%=10mmoLveryweakdrug

    Breathalyzeroxidation/reductionreaction
    90%isbrokendownbyliver,10%eliminatedinexpirations(sweat,urine,air)

    Ethanolacetaldehydeaceticacid

    HepaticbreakdownAlcoholdehydrogenase
    EthanoloxidiseNADtoNADHAcetaldehyde

    Minorpathwaystohepaticbreakdown
    Microsomalethanoloxidisingsystem(MEOS)SER,cytochromep4502E1(Inducible)
    Catalaseperoxisomes
    Km=10mMforMEOSusuallyutilizedinbingedrinking
    Acetaldehydemutagenic,toxigenic,carcinogenic
    Formsadductswithproteins,bindstoSH/lysinesidechains,inducesdepletionofglutathione(impairsresistanceto
    oxidation),Damagesmitochondria,enhanceslipidperoxidation,damagescellmembranes,genotoxic
    Acetaldehydedehydrogenase(ALDH)
    AcetaldehydeNADtoANDHaceticacid

    ALDHforms,ALDH1,2,3MostimportantisALDH2
    PolymorphisminALDH2laedstotwomajorforms*1and*2(lowactivity).

    Japanese40%havelowALDH,only5%alcoholdependenthavelowALDH
    LowlevelsofALDHprotectagainstalcoholdependence
    ALDH2*2flushingsyndromeunpleasant,nausea,palpitationscanprotectpeoplefromalcohol
    Heterozygotesmildflushingcanbepleasant
    Antabuse(Disulfiram)inhibitorofALDHinducesflushingsyndrome

    Ethanolacetaldehyde(CYP2E1)
    AceticacidconversiontoAcetylCoAthisdrivesCitricacidcycle
    AlcoholdrivesgenerationofNADHNADHisusedtomakeupATP
    Metabolicconsequences
    NADHincreases,NADdecreases,ATPsynthesis(emptycalories),decreaseFAutilizationduetoNADdepletion,
    increasedFAaccumulation,supressedglycolysis,conversionofpyruvatetolactatebyNADH
    Increasedsusceptibilitytohypoglycaemiaindiabtesoninsulin
    Alcoholemptyofvitamins,minerals

    Thiaminesmeat,greenveges,legumes,corn,brownrice

    Wernickeencephalopathyorganicbrainsyndrome(disorientation),acuteparalysisofextraocularmuscles,ataxia
    Korsakovspsychosispersistentmemoryloss,destructivechanges(thalamus,hypothalamus)
    Thiamineactivationthiaminepyrophosphate(TPP)conversiondonebydephosphorylationofATPtoAMP
    TTPactsascoenzymefor
    Pyruvatedehydrogenase(conversionofcarbohydratestoaCOA)
    aketoglutaratedehydrogenasecatalysesessentialstepforgenerationofNADHincitricacid
    Transketolaserequiredtoconverthexosestopentoses
    Endocrinefunctionnotpredictable
    hormonesecretion(StimulatedHP*adrenalaxiselevatedACTH,cortisol
    SupressedHPgonadalaxissexualdysfunction
    Impairedgrowthhormone

    Hormonesensitivity
    ResistancetoinsulinandIGF1restinghyperglycemia

    Ethanolmetabolismcanformphosphatidylethanolintestinalhyperplasia
    IntoxicationdepressiveCNS,reduceNMDAactivity,increasedGABA,reducedVOCCa2+channel
    ChronicchangesincreasedNMDA,increasedVOCCandreducedGABA
    Alcoholwithdrawalsyndromehyperexcitability
    Anxiety,agitation,paranoidideas,formication,seizures
    Lecture1.2.4CentralNeurotransmitters
    Neuronscellbodyinmiddle
    Dendritesseriesthatgointothecellbody
    Axonlinkagetonextneuron

    DendritesreceiveinputsAllinputsaresummatedattheaxonhillockthisgeneratestheAP
    Myelinsheathcoverstheaxon
    Apicaldendritesreceiveinputs

    Postsynapticdensityscaffoldingproteinslinkingimportantproteinstogether

    ClassicsynapsesAxodendriticoraxosomaticsynapseaxonterminalsynapsesontodendritesorcellbody
    Axoaxonicsynapsesregulateswhathappensonanotherbouton
    Autoreceptorsneurotransmittersactonthesamebouton
    Complexsynapsesinvolvingmultipleneurotransmittersdifferentaxonsacting(axoaxonicandaxodendritic)

    Allcellsyouhavesodium/potassiumATPaseenergyderivedfromhydrolysisofATP
    MajorityofATPisusedbythispumpthispumpmaintainstheIongradient

    K+channelsopen,butslowerthanNa+channels
    NeuronesinbrainhavereceptorsforglutamateandGABA
    About50%ofneuronesreleaseglutamateasexcitatory
    About3040%ofneuronesreleaseGABAasaninhibitory
    Neuronescanreleasecanreleasemorethanoneneurotransmitters(e.g.inhibitorsthatuseglycineandgaba)

    Fastneurotransmissionionotropicreceptor(ligandgated)
    Glutamatesodiumandcalciumchannelscausingdepolarization
    GABAreceptorschloridechannelscausinghyperpolarization
    SlowneurotransmissionGPCR
    Metabotropicmetabolismofthecell(altersit)
    ReceptorssitinthecellagonistbindsGPCRcausesGTPtoexchangewithGDP
    AlphasubunitactivatesadenylatecyclaseconvertsATPtocAMPcanalteractivityofgeneexpression
    Betaandgammasubunitsactivateownsetofproteinse.g.calciumchannels

    Glutamate
    IonotropicNMDA,AMPA,Kainaite
    Metabotropic8differenttypes
    NMDArequireglutamateandglycinesloweractivation
    AMPAsmalleronlyrequireglutamatefasteractivation
    GABA
    IonotropicGABAA,C(CombinationofsubunitsthereforelotsofGABAareceptors)
    MetabotropicGABAB1,B2

    Ethanolinfluencesmanyligandgatedionchannels
    CanblocksomeNMDAreceptors
    EnhancesactivationofGABAareceptors(mostobviouseffect)
    Ethanolcanreduceexcitationandincreaseinhibition
    Barbituates,Benzodiaepines

    EthanolisfairlyhydrophobicdiffusewithinmembraneassociateswithtransmembranedomainsofGABAar
    Thismakesthechanneltoopenfareasierethanolstaysintherebecauseitisassociatedwithtransmembraneand
    notaqueous

    Ethanolatsedative/motoruncoordinatingdosesactselectivelyonGABAareceptors
    Atlowdoses(5mM)actonGABAacontainingdeltasubunit

    Menarelesssensitivethanwomen,sexdifferencesareoftennotedindrugsactingonGABAreceptors

    Changesinbalanceofneuronalexcitationandinhibitonmayleadtoadaptivechangesinnervoussytemfunction
    Needtodrinktobringbackbalance

    ChronicethanoladministrationleadtochangesinexpressionofcertainreceptorsforglutamateandGABA

    Combiningsedativeswithethanolcanbedangerous
    Suddenlystopusingsedativesinsomnia,anxiety,convulsions
    Lecture1.2.5Theoriesofsubstanceabuse
    MISSING
    Initialtheoriesofsubstanceabuse
    Moralfailureandstigmatisation
    Modernalternatives
    Biopsychosocial
    Spiritual
    Biologicaltreatments
    Addicitonisabraindiseaseflushershavelowratesofalcoholismlookatgenetics
    Alcoholpharmacotherapiesarecontributory
    Harmreductionandabstinencehavebasesbothmodelsaregoodtouse
    CanstudyaddictionusingFMRIstudybrainswhenatriskofrelax
    Psychological
    Learnedandreinforcedbehaviourslearnedbehaviourthatalcoholrelievesstress
    Therapistshaveamajorroleintreatment
    CBT(cognitivebehaviouraltherapy)isgoldstandard
    MI,ACT,DBT,TSFnewertherapies
    Social
    SubstanceshaveasocialcontextAustraliahasanalcoholculture.
    Currentlylegaldrugskillmorepeoplethanillegaldrugs
    Doctorshaveimpactonsocietye.g.seatbeltsandRBTEBMtotheproblemsofaddiction

    Spiritual
    Liveswithhappiness,meaningandpurposetendnottobepronetosubstance
    MaybeoxytocinthathelpthereisEBMformeditation
    1930sifpeopleweremorerelaxedlesslikelytorelapse
    Twomodesofinheritance
    Type1themorecommonaffectsmalesandfemalesequallyrequiresanenvironmentalprecipitant
    Type2isamoresevererarepatrilinealformassociatedwithadolescentonset
    Therearedefinitelyserotoningeneticsthataffectdrinkinghighertoleranceofdrinksandmorelikelytobingedrink
    Nucleusaccumbensisveryimportantinaddiction
    Relapsecausedbystress,cues
    Preludetopassiontherearecuestorelapseunseencuesbutshowactivationonfmri

    Alcoholdependencesyndrometolerance,repeatedwithdrawalsymptoms,reinstatmentafterabstinence

    Treatbility
    Neurplasticitynewlearning,newbehaviours
    Braindiseasebuttreatable

    Lecture1.2.6Drugmetabolism
    Lipophilicchemicalscaneasilypermeatelipidcellmembranesandaccumulatewithincells
    Genotoxicity,carcinogenicityandtoxicity

    Toxicmoleculesdealingwiththese
    Phase1Oxidativemetabolism(CYPenzymes)
    Phase2Conjugativemetabolism(transferases)
    Phase3Transport(usuallyABCtransporters)
    Metabolismistorendercompoundsmoresolubleforexcretion

    Liverpredominantmetabolisingorganforphase1and2
    Gutalcoholdehydrogenaseinstomach,CYP450inSI
    Circulationplasmacholinesterases,proteases
    Othertissuelessimportant

    Specializedvascularepitheliuminliversinusoids
    Phase0Uptaketransporters
    Phase1,2
    Phase3biliarycannalicus

    Generalpropertiesofdrugmetabolizingpathways
    Highlyconservedthroughevolution
    Enzymeshavemultiplesubstratescopewithdiversityofxenobioticspresentintheenvironment
    Severalenzymesareinducible

    Phase1altermoleculesstructure/reacitivtymainlycytochromep450
    Phase2conjugationtoendogenousmoleculemainlytransferases(glucuronidation,sulphation)

    Somedrugsonlygothroughphase2morphine
    Somegothroughbothphase1and2phenytoin

    Metabolismcangiverisetolessormoreactivecompounds(Codeineglucuronideormorphine)
    Metabolismcangiverisetolessandmoretoxiccompounds(NAPQIGSHandNAPQI)

    CYP450actasmonooxidases

    ImportantP450s
    CYP1A2caffeine
    CYP2D6codeine
    CYP2E1paracetamol/ethanol
    CYP3A4cyclosporine

    Otherphase1enzymes
    ADH,xanthineoxidases,MAO,plasmacholinesterases,plasma/tissueesterases

    FirstpassmetabolismPortalveinliver
    Fractionextractedandmetabolised
    Fractionescapingextraction(1E)
    Bioavailabilityfractionofdrugreachingthesystemiccirculationintact
    FororaladministrationdependsonfractiondrugabsorbedbygutandFirstpassbyliver

    Whatdeterminesrateofliverdrugmetabolism
    1.Intrinsicclearanceaffinityofliverenzymesfordrugs
    2.Liverbloodflow
    3.Bindingtoplasmaproteins

    Highclearancedrugslignoicainebloodflowmatters(intrinsicclearance,bindingdoesntmatter)
    Intermediateclearancedrugsparacetamoleverythingmatters
    Lowclearancedrugswarfarin,phenytoinbloodflowdoesntmatter(Intrinsic,proteinbindingmatter)
    Inhibitionofp450mediatedmetabolism
    Twomainmechanisms
    Reversibleinhibitorcompeteswithdrugforp450
    Metaboliteintermediatecomplexationmetabolitesofinhibitorsequesterp450inaninactiveform.
    Inductionorinhibitionofmetabolismmaygiverisetosignificantdruginteractions
    LECTURE1.2.7EBMDesigns1
    PICOformat
    Population(inwhomarewelooking),Intervention(whatisbeingdone/orexposedto),Comparator(placebo),
    outcome(whatareyouinterestedin)

    AnalyticvsDescriptivestudies
    Descriptivestudiesoftencrosssectionalorcaseseriestrytodisplaythefrequencyofaproblemwithoutan
    attempttolookinaquantitativewaytheeffectofastudyfactoronthatproblem.E.g.infectionsin2.1%of
    operations.

    Analyticstudies
    ExperimentalASmanipulatingthedrugintakeorexposure
    ObservationalOSmeasureoutcomesbutcantmanipulateCohort/Casecontrol/Crosssectionalanalytic
    Aimstoquantifystudyfactorwithoutcomes
    Randomizedcontroltrial(RCT)randomlyassigningparticpantstointerventionorcomparator
    Cohortstudyismeasuringwhetherreceivedexposureorcomparator
    Exposureismeasured/allocatedTHENoutcomesSUBSEQUENTLYmeasuredafteraperiod
    CasecontrolstudytakeoutcomesthenlookintopastWORKINGBAKCWARDS
    AnalyticcrosssectionalstudyWemeasureoutcomesandexposuressimultaneouslyoccursatONETIMEpoint
    AetiologyQuestion
    onlycertaintypesareusefulRCTsystemicreview,cohort,casecontrol
    Otherssuchascross/sectionalandcaseseriesnotuseful
    BestevidencewoulduseRCTorsystematicreview

    TherapyQuestionRCTandsystemicreviews
    PrognosisquestionCohortstudy
    DiagnosisRCTandAnalyticalcrosssectionalstudy

    Confounderhasanassociationwithbothexposureandoutcomemayalteroutcomes
    BYrandomizingconfoundersaremadeequalbetweengroups
    RCTneedstoberepresentativeoftargetpopulationandhavesufficientsamplesize
    Intervention/Comparator
    Interventionmustbedescribedadequatelycomparatorshouldbecurrentgoldstandard
    Methodsofrandomization
    UnequalgroupsizesarepossibleUsePermutedblocks
    QuasirandommethodsNOTGOODcanbecorrupted

    Allocationconcealmentisessentialexaggerationcanoccurotherwise
    Stratificationseparaterandomizationofcertainpredefinedsubgroups
    Blindingnotknowingwhichstudygrouptheparticipantisin

    Intentiontotreat
    Notallpatientswhoarerandomizedreceivetheinterventiontheywererandomizedto
    Expandsamplesizetodealwithdropoutrates/crossoverrates
    Itisrecommendedthatpatientsreceiveinterventionassoonaspossible
    Compliancehasabigeffect

    Measuresofoutcome
    RR,OR,relativeriskreduction,absoluteriskreduction,numberneededtotreat
    Howprecise?Confidenceintervals

    Lecture1.5.2Actionsofopioids
    Opioidsaredrugsthatactontheopioidreceptors
    Opioidalkaloidsarestillharvestedfromopiumpoppies(includesmorphine,codeine,thebaine)

    Actionsofopioidsanalgesia,euphoria,impairedcoughreflex,constipation,respiratorydepression,nauseaand
    vomiting,dependence

    Opioidreceptorsmu,k,delta
    MorphinecausesGDPexchangewithGTP

    ActivationGproteininhibitscalcium,activateK+channelsforittoleave
    InhibitsAdenylatecyclaseATPtocAMP
    Inhibitsneurotransmitterrelease

    kopioidreceptor
    kagonistsproduceanalgesiabutmostdrugs(pentazocine)aremixedupartialandkagonists.
    Mechanismforanalgesiaunresolved.
    Producesimilarsideeffectstomorphinebutalsodysphoria,includinghallucinationsanddiuresis

    deltaopioidreceptor
    Producesomeanalgesia,mayproduceseizures,hamperedbylackofgoodpharmacologicaltools,receptorsmaynot
    usuallyresideoncellsurface

    opioidreceptor
    Agonistsatreceptorproducestronganalgesia,constipationmosteffectseen
    Morphineandothercommonanalgesicsacthere
    Morphinebindfarbetteratmuthanatdeltaorkappa

    HeroinreplacesOHwithanacetylgrouptogetherwithitsmetabolitearemorelipophiliccrossesintoBBBfaster

    Opioidreceptorsareexpressedthroughoutthebrain
    Opioidsactonseveralpartsofthebrain
    Antitissuive,respiratory,depressionmedulla
    AnalgesiaPAGandspinalcord

    Endogenousopioids
    Proenkephalin(nervecells,adrenal)
    Prodynorphin(nervecells)alphaneoendorphin,dynorphinAandB
    Proopiomelanocortin(pituitary,brain)ACTH,betaendorphin

    Activationofnociceptionneuronprojectstothalamusandcortexpain
    DescendingpathwayPAGdescendinginhibitionofneuronthatprojectsup

    InhibitioneffectactsatRVMinthemedullaandcausesinhibitionatdorsalhorn
    Opioidreceptorsexpressedonmanynociceptorsreduceglutamatereleaseinthedorsalhorn
    OpiotescauseeuphoriapresumablyfromincreaseddopamineviatheVTAtonucleusaccumbens

    RespiratorydepressionchangesthecellsinmedullarespondtoCO2dontbreathedeath
    Constipationismajorprobleminchronicopiodusers(receptorsinGIT)
    Opioidantagonists
    Naloxoneshortacting,loworalbioavailability,usedforreversalofopioidoverdose,usedincombinedtherapywith
    agonisttoreduceconstipation
    Naltrexonelongacting,highoralbioavailability,reducescravinginalcoholdependence
    Lecture1.5.3Neuroadaptationanddependence
    Generalfactorsinaddictionbiologicalactions,environmental,personalityandgenetics

    AddictionisCharacterisedbycompulsivedrugseeking,repetitiveuse,tolerance,withdrawal,craving/association
    Cangethighcravinginalldrugs,butsomedrugsdontcauseseverewithdrawal

    Mechanismsoftolerancemetabolic
    Acutetolerance
    HighdoseofnicotinedesensitizeNAchannelsquickinductionandreversibility
    Chronictolerancemassiveincreaseinnicotinicacetylcholinereceptorscounteradaptation

    AcuteactionBindingtoopioidreceptors
    GPCRcauseskinasestophosphorylateintracellulardomains
    Receptorsbecomedesensitized

    Opioidtolerancedensitizationbecausephosprylatedatintracellulardomainsnotgoingtocausemucheffector
    functioncancauseuncoupling
    Opioidtolerancephosphorylatedformcancausebetaarrestinlinkermoleculesdragopiodreceptorsintocell
    Reducedeffect

    Proteinisdraggedintocellproteinisdegradedvsrecycled
    Nuclearsignallingdownregulation

    Withdrawalfromalcoholcanbeworsethanheroinseizures

    Counteradaptatationadaptationthatcountertheacutedrugactionmayunderlydrugwithdrawal
    Canoccuratmolecular,cellularornetworklevel

    Benzodiazepinewithdrawalrebound
    Acuteactionanxiolytic,sedative,somnolence,anticonvulsant,musclerelaxation
    Withdrawalanxiety,irritability,insomnia
    CounterbalancevsDesensitization

    Thelocuscoeruleusaxonalprojectionstoallpartsofthebrain

    AcutemorphinedecreasedcAMPdecreasedexcitability
    OpioidwithdrawalincreaseinadenylatecyclaseincreaseexcitabilityincreaseinCREB(xcriptionF)

    Heroin,nicotine,stimulantsexcitecontainingnervecellsinrewardsystemsVTAtonucleusaccumbenstoPF
    cortex

    Molecularswitchforaddiction
    DopamineincreasedsensitizationmorecAMPandPKA

    IncreasedPKAphosphorylateCREMwhichincreasestranscriptionfactorofBDNF(increasesdrugseeking)
    CREBalsoincreasesddeltaFosB(CDk5)
    Effectsonstructurallyrelatedgenes?BDNFenhancesdendriticspinedensity
    Lecture1.5.4Integratedcare
    Communityservices,obstetrics,drughealthandaboriginalhealth
    Helpwithinformationondruguse,treatment,antenatalcare
    Offerassistancewithhealthissues,hepC,housing
    Substanceusehistoryestablishingrapportisveryimportant
    Referralsourcesself,drugtreatmentprograms,antenatalclinic
    Benzodiazepineepisodicheavyuse(wholepacket)anxiousandtermors
    Managementreinstituteinstabledailydoseregulatethedispensing(dailydosing)
    FASmissingpalpebralgroove,smallhead,smallnarroweyes

    TreatmentofHepCisteratogenic

    Childreporting
    94%ofchildrenknowntodocsbeforedeaths
    Majorityaged4andunder,significantnumberofcaseshadrelationswithdomesticviolenceandsubstanceabuse
    NSWchildrenandyoungpersonsact1998
    Childrenslegislationamendmentact2009
    Changetothresholdriskofsignificantharm
    AddditonofriskfactorforROSHfailuretomakearrangementsforchildseducation
    seriesofactsthattogethermayestablishapatternofharm
    Section44assumptionofcareministertakescare
    8areasofactneglect,medical,physical/sex/illtreatment,domesticviolence,psychological,prenatalreportwhere
    motherfailstominimizerisk,seriesofacts
    AssessingharmThechild,Theparents,theNetworks
    Opportunityforharm,Sourceofharm,healthcaseplan
    Parentingleadstothedevelopmentofaninfantswellbeing
    Importanttransitionperiodfordrugusers
    Interventionreducechildprotectionconcernsbyaddressingtheissuesimpactingparentingcapacity
    Lecture1.5.5Clinicalpharmacologyanddispositionofopioids
    Kappareceptorsspinalanalgesia,dysphoriaandsedation
    Physicaldependenceofopiatestachycardia,tremors,sweats
    Psychologicaldependencecraving,drugseekingbehaviour

    Analgesiaacuteandchronicpain,notveryeffectiveforneuropathicpain
    Euphoriasenseofcontentment,wellbeing,alsosedation,IVrush
    Respiratorydepressionoccurswiththerapeuticdoses

    GITincreasedsphinctertone(decreasedmotility),constipation(Treatdiarrhoea)
    Coughreflexnotrelatedtoanalgesia,codeineeffectiveinsubtherapeuticdoses
    Pupillaryconstrictionmu,kappareceptorsinocculomotornucleus(III),reversedbyIVnaloxone
    Nauseaandvomitingareapostrema(medulla)chemotriggerzone,40%(nauseus),usuallytransientwith
    repeatedadministration

    MedicationsClass,mechanism,PK,Metabolsim&excretion,sideeffects
    Morphinebioavailability2030%,halflife:23hours,sustainedrelease
    Kapanolisapolymercoatedpellets(8hours)
    Oralmorphinecomesinwaves;chronicpainshouldbetreatedwithsustainedrelease
    Morphinemetabolismconjugatedwithglucoronicacid
    M6glucuronide(M6G);2xpotencyofmorphinewhengivensystemically

    Morphineoral,subcutaneous,intrathecal/epidural(monitorresprateduetoc4/c5)

    Codeine3methylmorphinehighoralbioavailability(lesspotent),lesseuphoria(lessaddiction),produces
    constipation(antidiarrhoea),coughsuppression

    Codeinemorphine(8%ofpeoplecant)ViaCYP2D6
    Geneticpolymorphisms(Ems),codeinetomorphine
    Poormetabolisers(PMs)710%caucasians

    Extensivemetabolisersareabletoconvertfarmorecodeinetomorphine
    CodeineisineffectiveinPmscodeinesanalgesiaduetoconversiontomorphine
    CoadministrationofinhibitorsofCYP2D6(fluoxetine)willreduceanalgesiaofcodeine

    Oxycodonenotaprodrugbindsdirectlytoopiatereceptors,goodoralbioavailability(endone)4,5hours
    Formualtedasasustainedreleasepreparation(oxycontin),12hoursduration

    Fentanylsyntheticopioidmuagonist
    6080xpotencyofmorphinehighlipidsolubility
    Shorthalflife3hoursusedinanaesthesia,patientcontrolledanalgesia,transdermalpatches

    Buprenorphinereceptoractivity
    Partialagonist(mu,kappareceptor,deltareceptor)

    Tramadol
    Analgesiaduetoweakmuagonist,inhibitionofneuronalNORuptake
    Goodoralbioavailability(70%)livermetabolismCYP2D6,3A4poormetabolisersmaygetlessanalgesia
    Sideeffectslessconstipation,respiratorydepression
    Pethidinedontuseit
    Differentchemicalstructure,similaractionstomorphine,rapidonsetandshorthalflife
    Livermetabolism(oxidativeenzymes)metabolitenorpethidinemaycauseconvulsions,potentialdruginteractions
    Methadonesimilaractionstomorphine
    Littleeuphoria,slowrelease(oncedaily),mostcommonagentusedinoralmaintenanceprograms

    Heroindiacetylmorphine
    MorerapidtransportintoCNS,deacetylatedintomorphine
    Opioidactiosnblockedbynaloxone

    Lecture1.5.6CommunityagenciesMISSING
    StepsinAA
    Meetings,workbooks
    Calmingdownmeditation,yoga

    Ifyouaredependentondrinkingcontrolleddrinkingdoesnotwork

    ProjectMATCHlargesteverstudyofpsychotherapy
    NodifferencebetweentherapybutlongertermAAwasbetter

    Minnesotamodel
    Addictionisadisease,abstinenceisnecessarybutnotsufficient,12steps,peerinvolvement

    Fullrecoveryisareality
    ResidentialrehabreportedmoreabstinenceandmoreAAattendance

    Lecture2.2.2Principlesofpharmacologicalmanagementfordrugdependence
    Alcoholandtobaccohighest
    Cannabisishighestalmostashighastobacco

    Therapeuticnihilismdrugusersdonotcareabouttheirhealth,donotwanttostopgenerallyuntrue
    Addictioninvolvessomeneurobiologicaldysnfunctionnotsimplybehavioural
    InitialdrugusemaybevoluntaryandAddictionislikeachronicdisease
    Thereissoundevidenceinsupportofsometreatmentse.g.methadone
    Complianceproblemswithtreatments
    Bloodpressuremedicationandbehaviourcomplianceisverysimilartoalcohol
    EngagementassessmentMotivationalenhancementgoalsetting,treatmentwithdrawalmaintenance
    Managementtreatmentofestablisheddependence
    Detoxificationremovaloftoxins,rarelyworks,longtermrelapseisdifficulttoreduce
    PlannedWithdrawalmotivatedtoreducedruguselesssevere
    Incidentalwithdrawalverysevere
    Precipitatedwithdrawalopioidantagonistinduceseverewithdrawalextremesofvomiting/diarrhoea

    Establishgoals,stopuse,monitorwithdrawalsymptoms,medicaltherapytocontrolthese,reducedosesteadily

    Benzodiazepine
    Benzodiazepinewithdrawaltimeofonsetdependsondurationofdrug>3tabs/dayfor>3months
    Donotsuddenlystopbenzodiazepinethiswillcauseseizures
    Switchtodiazepam(longacting)stabilizeusingequivalentofhalfusualdose
    Weansteadilyensuresafesupply
    Opiatesfordetoxification
    Methodoneeffective
    Buprenorphinemosteffectivebecauseitspartialagonistnottotal
    90%completedetoxification.Dailydoseforaboutaweek
    Permitstransitiontomaintenancetreatments
    Alcoholwithdrawalmanagement
    Thiamineprophylaxis(treatmentofcomorbidity),identifyatriskofwithdrawal
    Drugofchoicediazepamcrosstolerancebutnotdirectagonist
    Cannabisnosetgoldstandard

    Pharmacotherapyforrelapseprevention
    Theycanreducecraving(acamprosate),Canblockthedrugofabuse(naltrexone),Aversivetreatment(disulfiram)
    Treatmentadherence
    Supervisionoftreatmentbypharmacyorcarers,Depotmedications
    Abstinenceorientedtreatmentnotpharmacological
    Highlysoughtafter,counselling(rarelyeffectiveforopioiddependence)
    Therapeuticcommunitieshavehighdropoutandrelapse
    Methadone
    Legaldrug,longacting,oncedailydosing,relativelysafe
    Improvedfunctioningreducedcomplications,stigmatised

    AustraliaMethadoneprogram
    Whenunstablestartsasstrictsupervision(notakeaways,publicclinicdosing)laterbecomesminimalsupervision
    butisnolongerfree($30/50aweek)

    Buprenorphine
    Longduration,partialagonist,highreceptoraffinity,highfirstpassmetabolism

    Abusedeterrentpreparations
    Combineagonistandantagonistinsame
    Suboxone(Buprenorphine+naloxone)reducesabuse

    Naltrexone
    Longactingorallyaciveantagonistbutexpensiveandunsubsidised
    Associatedwithdropoutrates,rapidopioiddetoxification

    PrescribedheroinillegalinAustralia
    Naltrexoneretentionis4%comparedtomethadone/buprenorphine(~40%)
    AcamprosatealtersCNSneurotransmissionreducesrelapseofalcoholdependence
    Antabuseriskyifolderpatientorhascardiovasculardiseasefewstudiesshowbenefit
    Lecture2.2.4Injectingdruguseinthecommunity
    Supervisedinjectingcentreprovidesequipmentbutnotdrugs

    NUAApreventbloodborneviruses
    Projectplansforpeergroups
    PeersupportforhepCtreatment

    Savingoflivesequalssavingmoney

    Nationalactionplanonharmminimalization
    Supplyreduction,demandreduction,harmreduction
    Justicehealthprovideshealthservicesto10,100fulltime
    22%maleinmatesareaborigines
    45%offemalesand28%ofmaleinmatesarehepatitisC

    80%ofinmatesreportpastillicitdruguse
    Lecture2.5.2Theautonomicnervoussystem
    AutonomicnervoussystemvsSMS
    Somaticisrapid,accurate,peripheral,commandsonlyskeletal
    ANSisslow,wide,graded,commandsalltissueandorgans,outsideCNSdisynaptic

    SMSsomaticmotorneuronsinsideCNSinnervateskeletal
    AMSneuronsinautonomicgangliapreandpostganglionicfibresinnervatemusclesandglands
    ANS
    Sympatheticdivisionincreasedheartrateandbloodpressure,increasesweating
    Parasympatheticslowheartrate,increasedigestion
    Sympatheticshortpreganglionic
    Parasympatheticlongpreganglionic
    SYMPTHETICNERVOUSSYSTEMentiretyofthebody
    PreganglionicneuronsofSNSisonlyfoundinsympatheticsystemT1toL2/3Foundinlateralhorn(between
    dorsalandventralhorns)onlyfoundint1toL2/3
    Dorsalrootsensorynervescomeinhere
    Ventralrootmotornervescomeinhere
    Rootsjointoformspinalnerves

    Rootssplittoformventralanddorsalramus
    Dorsalramussupplystructuresoftheback,Ventralanterior2/3rdsofthebody
    SMSencountersgangliaparalleltospinalchord
    Sympatheticchain
    Entirelengthofvertebralcolumn,gangliaassociatedwithvertebrallevels
    Paravertebralgangliaeachganglionisassociatedwithanemergenceofaspinalnerveexceptforcervical
    vertebrae
    Cervicalareassociatedwiththreelargegangliasuperior,middleandinferior

    Sacralgangliafusetoformterminalganglionimpar
    Prevertebralgangliaarefoundusuallyonabdominalaorta
    SupplyoflocalstructuresTravelinventralrootstospinalnervesynapseonsympatheticpostganglioniccell
    thenleaveandenterspinalnerveenterdorsalandventralramisupplystructures
    Supplyofdistantstructuresleavelateralhornventralrootsympathetictrunkandgonorth/southsynapse
    therewithpostganglionic

    Supplyofmedialvisceralstructures
    Joinspinalnerveentersympatheticganglionpreganglionicfibrestoparavertebralgangliaandsynapse
    splanchnicnerves
    EXCEPTION:isheartpostganglioniccellsinheart(onlyt1,2,3)
    Parasympatheticnervoussystem
    Decreasedheartrate,decreasedsweating,erection,inhibitsmicturition

    TravelwithcranialnervesVagusnervesuppliesmostorgans
    sympatheticfibresoriginateinthoracicspinalchord
    Parasympatheticofheartoriginateinvagusoriginatefromnucleusambiguousanddorsalmotorvagalnucleus
    Regulationofparasympatheticisregulatedbyhigherbrainregionssuchasmidbrain,highcorticalregions

    Lecture2.5.3bloodpressureandtisfluctuations
    Sizeofdifferencebetweensystanddiastolicpressureiselasticityofchamber(aorta;moreelastic=lesser,
    morestiff=higher)andstrokevolume
    Atherosclerosisandelasticdegradationcanleadtostiffervesselsleadtolargerpulsepressure
    SeveralcomponentstodropinBP;whenaorticvalvecloses,thereisadicroticnotch.Thenrunoffphaseas
    bloodrunsofffromdilatedaortathatiselasticintoallarteriesandvessels.GradientofBPdecreasehere
    reflectsthetotalperipheralresistance;thelower,thefasteritrunsout;ifhigh,thesloweritrunsout.
    QRScomplexwhenventriclesstartcontractingandpushbloodintoaorta
    Armupandbackdownmanoeuvre;columnsoffluidproducespressure;furtherdownincolumnisgreater
    pressure;rho*g*h(density=rho,h=heightofcolumn)
    BPmeasuredlowerdowninbodyishigherproportionaltoheightofcolumnofblood;hydrostaticeffects
    duetoposture
    BP=CO*TPR.Sobloodflow=BP/TPRbutoversimplification.Arterialpressurecominginandvenous
    pressurecomingout.Bloodflow=PaPv/TPR.Puttingarmupalsochangesvenouspressurebysame
    amountasarterialpressure.AndsoalthoughPagoesupwithhandsdownandPvdoestoo;sonoeffecton
    bloodflow.Soitismisconceptionthatputtingarmupnecessarilygiveslessbloodflowormorewitharm
    down.
    Youwouldnotexpectposturalchangestoaffectbloodflowbutwouldonarterialandvenouspressure.
    CyclemuchshortersinceHRgoesupwithexercise.BPincreasestoo.
    HRincreasesduetosympatheticnervoussystem.Twomechanismscentralcommandbrainknowsyou
    areexercisingandsendsviaSNSforhearttospeedup(canstartbeforeexercisesonotfeedback)since
    needsmorebloodflow;andchangesinBPandchemoreceptors,feedbackfrommuscles,joints(arrayof
    sensoryinformation).
    Largefallindiastolicpressure,largeincreaseinsystolicpressureandpulsepressureexercise.SVgoesup
    sincevenousreturnincreasesCO,andcontractilityincreasesofheartinc.bySNSsoheartcontractsmore
    forcefullyallincSVthatgivespulsepressurerise.TPRdropsoffalotinrunoffphasesolowerdiastolic
    Again,BP=CO*TPR;letssayexerciseincCO2folds,butBPdidntdoublebecauseTPRprobablyfellbyfactor
    of2;sosamemeanpressure,buthighersystolicandlowerdiastolicpressure.
    DeepinspirationandexpirationBPchangeswithbreathingduetoCO.Breathinginmakesintrathoracic
    pressurelowerandbringsmorebloodintoheart;andthisvenousreturnincreasesCObyStarlingslaw.And
    thusincreasesBPwithinspiration.
    HRgoesuptoo.
    BPmeasuredinfootwouldbehigher.BPmeasuredatarmwouldbeatlevelofheartsononeedfor
    correction
    TPRdependsonconstrictioninarterioles
    Anotherposturalchangefromsittingtostanding.BPfellbothsystolicanddiastolicthenrecovered.
    Whenlyingflat,BPissameinchestandhisfeetandhead.Whenstandingup,youaddcolumnofbloodto
    BP;soaddspressuretoarterialandvenouspressureintoes.Noeffectonbloodflowthough.ReducesPa
    andPvinbraintoo.IncinPvwillincreasevolumeofveinbystandingup.Veinexpansionandfilledupand
    lessbloodreturningtoheart.Sohalfliterofbloodtransferredfromchestintolargeveinsofleg.Soitisnot
    aneffectondirectpressureinarteryandveins(thatcancelout),itisbecauseveinsswellduetoincin
    pressureandsomorebloodstoredherethannormal.HencelessvenousreturnandlessCOandsolessBP.
    SobaroreceptorsdetectthisandactivatereflexesthatincreaseHR,andthusincCOandthusrecoversyour
    BP.Takesa1015secondsforfeedbacklooptooperate.

    Lecture2.5.4shockanoverview
    Circulatoryshock
    Definedasageneralinadequacyofbloodflowthroughoutthebody
    Cardiovascularsystemitselfbeginstodeterioratebecomemoresevere

    Causesofcirculatoryshock
    Hypovolaemicseverehaemorrhage/vomiting/diarrhoea
    Cardiogenicshockdecreasedcardiacpumping
    Vasogenicshocksepticoranaphylactic(vasodilationleadingtodecreasedvascularresistance)
    Neurogenicshockdecreasedvasomotoractivityvasodilation

    Decreasedbloodvolumedecreasedcardiacfillingatrialreceptoractivityincreaseinsympatheticnerve
    activity
    DecreasedcardiacfillingdecreasedCOdecreasedMAParterialbaroreceptorsympatheticnerve

    Sympatheticnerveactivityvasoconstriction,vasoconstriction,cardiacrateandcontractility
    Vasopressin/Antidiuretic
    FallinArterialpressure,bloodvolumeunloadingofarterialbaroreceptors
    Leadstovasoconstrictionandreabsorptionofwaterandsaltinkidneyincreaseinbloodvolume
    Reninangiotensinaldosterone
    Reninrelasedfromjuxtaglomerularcells
    AngiotensinogenA1ACEinlungsA2bloodvesselsconstriction,kidneys,adrenalcortex,brain

    Inhaemorrhagevasoconstrictionoccursinvascularbedsbutnotcoronaryorcerebralbeds
    Skinappearspaleandbloodflowtovisceraisalsoreduced
    bloodflowtocoronaryandcerebralbedscontrolledlargelybylocalmetabolicfactors(autoregulation)not
    sympathetics
    Autoregulation
    DecreaseinArterialBPdecreaseinflowimbalanceinnutrients/wasteCo2increasesvasodilation,
    coronarybloodflow
    Autoregulationbetween50150mm
    Longertermresponsestohaemorrhage
    Lossofplasmaproteinsiscompensatedin34days
    ProductionofRBCinitiatedbyEPOrestoredoverweeks
    2,3DPGisincreasedtomakehaemreleasemoreoxygen
    Severehaemorrhagecausingprogressiveshort
    Bloodpressurefallslowenoughautoregulationnolongerworks
    Thiscausesheartfailure,depressofvasomotorcentre,reducedbloodflowtoothertissues

    Otherconsequencesofseverebloodloss
    Acidosis(increasesriskofbloodclotsandviscoscity),capillaryhypoxicdamageafterhours,GITbreakdown,Organ
    failure
    Treatment
    Besttreatmentisbloodtransfusion
    Plasmaisgoodalternative
    Plasmasubstitutesuchassolutioncontainingdextran(similarosmoticpressure)
    Salinealoneisnotsufficient

    Lecture3.2.1NaturalhistoryofhepatitisC
    WHOhealthreport,HCCisrisinginincidenceandburdenduetoviralhepBandC
    25%infectionsdisplayovertclinicaldisease
    Chronicinfectionin70/85%
    40%ofchronicinfectionswilldevelopcirrhosiswithin10years,20%willhavehepatocellularcarcinoma
    MajorcauseofHCCisHCVinfection
    Limitedtissueculturesystemtopropagatethevirus,infectsprimates

    HepC+vestrandRNAvirus,vestrandintermediate
    HCVisareceptormediatedendocytosis,processingandreplicationisatER
    ReceptorthoughttobepossiblyCD81/claudin1/scavengerreceptorB1
    Approximatelyonemutationpervirion

    Differentgenotypesindifferentplacesintheworld
    PrevelencehighinAfrica,westpacificandeastMediterranean
    PrevalanceifHCVishighinmiddleagepeople

    Incubationperiodis67weeksonaverage
    Acuteillness(<20%)seenasjaundice
    Fatalityrateislow,mortalityis3%fromCLD
    Injecting,bloodborne,birthandsexaremajorfactorsininfection
    HCVserologyELISA(sensitivityandspecificitynowgood),RIBA,RNA,PC

    InChronicAntiHCVincreasingbutRNAcontinuetobeproducedwithfluctuatingALT
    InAcutewithrecoveryAntiHCVincreasing,HCVRNAstopsproducingandsymptomsgoaway
    Naturalcourse,someresolvesomehavestablechronicdisease,somehavestablecirrhosis
    Fromtimeofinfectionuntilmortalityorcarcinoma(<20years),madeworsewithalcoholandcoinfections
    HCVinfectioncanleadontocirrhosis/deathfasterwithHBVandHIV
    HCVlesslikelytoclearifmale,transfusionrequired
    AcuteHCVmostlikelyin20sto30sandin1950/60birthcohort
    Race,haemachromatosis,schistomiasis,obesitycanallmakeHCVprogressionworse

    InjectingdrugusecanleadtoHCVduetocontamination
    30%prevat3,>50%at5years
    Verticaltransmissionis6%,probablynottransmittedfrombreastmilk(VLnotknown)
    Rarebetweenlongtermsteadypartners
    Householdtransmissionisrare,occursthroughexposuretoblood
    HepCincreasing
    Pretreatmentworkup
    History/physicalexam
    Bloodandchemistry,liverpanelincludingPT
    TFT,HCV,HCVRNA,liverimagingandbiopsy

    IndicationsfortreatmentpersistentelevatedALT,abnormalliverbiopsy,dectectableHCVRNA
    NotrecommendedPersistentlyabnormalALTadvancedordecompensatedcirrhosis,excessive
    alcoholuse,contraindications
    UnclearelevatedALTbutnormalhistology
    TreatmentconsistsofIFN,orcombinedIFNribavirin,pegylatedIFNincreasesefficacy
    TreatmentmostlyeffectiveforGenotype3amdmpt1
    Predictorsofafavourableresponse
    Genotype2or3
    LowHCVviralload(<2million),nooronlyportalfibrosis,female,<40yearsold
    Postexposuremanagement
    Ig,antiviralsnotrecommendedtestsourceforantiHCVtestworkerforantiHCV(46monthslater)referto
    specialistformanagementifpositive
    IL_28Bassociatedwithclearance,treatmentresponse

    Lecture3.2.2Boneandtoothstructureandfunction
    BonemineralconsistsofmostlycalciumandphosphateHydroxyapatitecrystal
    Trebechularbonebonemarrow
    1unitofcorticalboneishaversiansystemcentralccanalhasartery,veinandnervesupply

    Osteocytessitinlacunae(hole)connectwithcentralcanalthroughcanaliculae
    Aroundoutsideofhaversiansystemcementline(distinguishesonesystemfromanother)
    Cellsthatsensemechanicalstrainareosteocytes
    Mostbonematrixconsistsoftype1collagen(osteoid)minieralize(fullbone)
    Thereareconcentricringsofcoarellagen
    Pagetsdiseaseenhancedboneturnover
    Trebecularbonelaidinparallebundles
    Spineismostlytrabecular,sometrabecularatwrist
    shaftismostlycorticalbone

    Collagenismainproteinmakingupbonematrixtype1lamellarvswovenbone
    Noncollagenousproteinsalkalinephosphatase(importantinmineralization),proteoglycans(structural),growth
    factorsinbonematrix
    Bonemineralcalciumandphosphatelaiddownincrystallinestructureknownashydroxyapatite>
    compressivestrength
    Compressivestrengthinsufficientmineralbowlegs

    Boneresorbingcellsosteoclast
    Microcracksosteoclastenterduetosignallingthisresorbsthebone
    Osteoblastslaydownbonematrixafter21daysthisbecomesmineralized
    Osteocytes90%ofbonecellpopulaton
    Osteoblastsareboneformingcellscomefromboneformingcells
    Activeosteoblastsmakelargeamountsofproteinthatdeposit

    Osteoblastsboneformingcells,linebonesurfaces,activesynthesisofmatrix
    Liningcellsflatennedosteoblastsliningbonesurface
    osteocytesosteoblastsembeddedinbonematrix
    Osteoclastsmultinucleatedgiantcellssecreteacidandproteolyticenzyme;enzymesdisassociatesgrowth
    factorsfrominactiveprotein.
    Boneturnover
    Shapechangesofboneinresponsetochanglingload(moreboneindominanthand/arm).
    Boneshapeissuchthatittakesthemostforce

    osteoclastscomefrombloodvesselsinhaversiancanalBoneiscut(cuttingcone)andresorbed
    Newosteoblastscomeinandstartlayingdownnewboneeventuallyitsmineralizedembeddedintoboneas
    osteocytes.
    Turnoverishigherintrabecularthancompactbone
    Couplingingeneralboneresorbed=volumeofbonereplaced

    Growthfactorconceptofcouplingchemotaxis,proliferation,differentiationandmineralizationisinfluencedby
    growthfactorssuchasTGFb

    osteoblastexpressonsurfacecalledRANKligand
    RANKreceptorisexpressedonpreosteoclastmeetingwithosteoblastdifferentiationintoosteoclast

    osteoprotegerindecoyproteinbindstoRANKligand(preventsinteractingwithpreosteoclastrankreceptor)
    preventsdifferentiation

    OPGandRANKLexpressionisindelicatebalance
    parathyroidhormoneinfluencesthis

    monoclonalanibodyagainstRANKLreducesrateofboneresorption

    Rateofboneformationdependson
    Osteoblastnumbers,activity,lifespan

    Rateofboneresorptiondependson
    Osteoclastnumbers,activity,lifespan
    Sexsteroidsalterosteoblastandosteoclast(lossofestrogencausesosteoclaststolivelongeranderodebone)
    Teethariseinboneofthejaw
    Dentineissimilartoboneinthatitisacollagenbasedmaterial.
    Pulpchamberissimilartotheideaofhaversiancanal
    Enamelcapsthetoothveryhighlymineralized

    Enamelisanoutpouchingoftheepithelium
    Ameloblastslaydownenamel
    Odntoblastslaydowndentine
    Osteoblastsalveolarbone

    Ameloblastslaydownenamelbeforetootheruptsverydensematrixveryresistanttoacidcloselypacked
    collagenandlargecloselypackedhydroxyapatitecrystals
    Calcium,fluorideareadsorbedtocrystals

    Odontoblastslaydowndentine
    Osteoblastsandosteoclastsinalveolarbonealveolarboneremodelling
    Caries
    Bacteriaandfoodsticktoteethcreateafilmonteethcalledplaquecarbdependent
    Anaerobicaciddisolvesmineral
    Fluoridefromthetapisadsorbed

    Asessingbonebonedensitometry,ultrasound,biopsy

    Asessingbonemassbonemineraldensity(assumenormalmineralization),noosteophytes,consideraortic
    calcification
    Bonebiopsyveryinvasive
    Othermeasurementsmicroarchitecture,celldeathhardtotest
    Osteoporosispresenceorhistoryofalowtraumafracturefractureisnotrequiredfordiagnosislowerthan
    acceptablebonemineraldensitymachine

    Boneteststandarddeviationscore
    Tscorecomparesbonemineraldensitywithmeanpeakbonemassusedtoassessfracturerisk(SDrelatinship)
    ZscorewhereSDofyourmeasurementcomparedtoage/gendermatched

    normalTscore1.0andabove,lowbonemass(1.0to2.5),osteoporosisisbelow
    FRAXage,sex,priorfragilityafterageof50,historyofcorticosteroiduse,parentalhistoryofhpfracture,RA,
    secondaryosteoporosis(t1diabetes,prematuremenopause),currentsmoker,alcoholuseofgreaterthan2units
    daily,BMI
    Lecture3.2.3Geneticsandepidemiologyofalcoholdependence
    Alcoholdependence
    3+criteriatolerance,withdrawal,impairedcontrol,awarenessofcompulsiontodrink,alcoholtakeshigherpriority,
    continueddrinking

    Alcoholdependencemenhavehigher(2to1)
    Alcoholabusedisorderissignificantlyhigherinyoungergroups.
    Alcoholicisnotforlife
    Lifetimealcoholdependencehigherinbabyboomergeneration

    Riskfactorsofalcoholavailabilityofalcohol,gender,yearofbirth,smoking
    Availabilityofalcoholwhentheresnoalcoholitshardertogetanalcoholproblem

    DeathsfromcirrhosisfelldramaticallyduringprohibitioninUS
    Alcoholconsumptionandalcoholismreducedgreatlyduringww2

    Smokingisariskfactorfordrinking
    Lifetimenicotinedependence50%lifetimealcoholdependent
    Withoutnicotinedependenceonly20%alcoholdependence

    Geneticcorrelation0.7andenvironmental0.2

    Alcoholflushreactionprotective
    Subjectsthatalwayshadadversereactionstodrinkingdranklessfrequentlyhowevernotprotectedagainst
    alcoholdependence.

    Thosethataresensitivetoalcoholarelesslikelytobedependent(metaanalysisofvariousstudies)
    Adoptionstudiesrelativeriskofdependenceinchildrenofalcoholics

    Multiplegeneticandenvironmentalfactorscombineinadditive/interactiveway
    Alcoholicratsandmicecanbeselectivelybredforalcoholpreference.

    Linkagestudies
    Associationstudiesgenomewidescan,orspecifiedagainstcontrol(candidate)
    Significantresultsneedbiologicalplausibilityandreplication

    R47HassociatedwithAsiansbutlowfrequencyinEuropeanscannotcontributetorisk
    Geneticvariationinmetabolizingenzymesaffectsriskofalcoholdependence
    KnownvariantsmainlyaffectriskinAsians
    NeurotransmitterreceptorsinvolvedinalcoholeffectsGABA,opioids,serotonin,dopamine
    GABAgammaaminobutyricacid,brainsnaturalDampingeffect

    SignificantassociationwithGABAa2withalcoholism

    GABAreceptora2alsoaffectchildhoodconductdisorder,illicitdrugdependceinadults,antisocialpersonality

    Geneticstudieshaveaddressedalcoholpancreatitisandalcoholicliverdisease
    Culture,useanddiseasearelinked
    Lecture3.2.4Adolescenceandyoungadulthood
    WHOdefinitionofadolescence101920%ofworldpopulation85%indevelopingcountry
    Onlyuniversaldefinitionisthatadolescenceisaperiodoftransition

    Eriksonstagesofdevelopment
    Adolescenceisstage5
    atage1220identityvsroleconfusiondevelopingpersonalityandsexualidentity,occupationalchoice
    Youngadulthoodisstage6
    2035yearsoldintimacyvsisolation
    Ifpeopledontmoveontonextstagetheygetstuck
    HavinghurstsDevelopmentaltasktheory
    Adolescence1218achievingagendersocialrole,acceptingonesphysique,preparingformarried
    life/economiccareer,acquiringasetofvalues
    Earlyadulthoodselectingamate,gendersocialrole
    Piagetlevelofformaloperationsisachieved
    Achievedbyafewchildrenbyage12andby35%of1617somepeopleneverachievethis
    20%diagnosablepsychopathology,25%smoothtransition,remainderhaveperiodsofconflict

    NonEuropeanculturesgothroughsamestagesbutatadifferentrate
    Universityofinformaleducationorderoftaskdifficulty
    Adolescentturmoilpsychologicalupheaval
    Mutliplestressorsandpressure,academicworkismoredemanding,morediversepeergroup
    Indicatorsofyoungadultsuccess
    Physicalhealth,psychologicalwellbeing,lifeskills,healthyfamilyandsocialrelationships,educationalattainment

    Transitiontoadulthoodespeciallydifficultforadolescentswithchronicdisease(movefrompaedstoadult)
    Riskybehavioursmayfulfilapositivefunctionintransitiontoadulthood

    Asthmatreatmentisaffectedbyrisktakingleadstononcompliance
    Deathsfromasthmaconflict,depression,familydysfunction
    182420%havebeenphysicallyassaulted
    Girls1019highestriskofsexualassault

    Whatcontributestorisktakingbehaviour
    Intergenerationalinfluenceshealth/social/economiccosts
    Physicalhealth,growthandearlydevelopmentsubstanceabuse,alcohol,prenataldiet
    Beingborntoadolescentparents
    Aggression,antisocialbehaviour,cognitiveability
    Dualsystemmodelsofriskingtaking
    PiagetmaysaysinglefactorbutNotjustadolescentcognitiveprocess
    Affectiveprocessesarealsocrucialmaturesrapidlyatadolescence
    Lecture3.2.5HCVcaseconference
    HepAhasincubationperiodof60days,upto90days.
    DiagnosisofacuteinfectionofantiHAVigM

    HepAserology2080%communityis+ve

    HepatitisBcircularDNAvirusintolerantofmanymutations
    Incorporatesintogenomecantclearonceinfected

    Chronicphase(3types)noviralparticlesbeingproduced,viralparticlesbeingproduced,pathogenicity
    HBcoreproteinallowsutodifferentiatebetweenvaccineandacuteinfectionantiHBCIgM
    HBsurfaceantigenindicatessurfaceantigenproductionorviremia
    HBsAbpastinfection
    HBVDNAmarkerofreplication
    HBcABpastinfection
    HBeAGviralreplication,negativeinmutantvirus
    HBeAbnonreplicativephase

    HepCchroniccourse60%
    Selflimitngcourse(40%)

    HepCtestELISAfollowedbyPCR

    ElevatedALTdoesnotneccesarilyindicateliverfailureorinflammation.LevelsofotherproteinssuchasAlb
    important
    PEGINF/Rwasstandardtreatmentnownewtreatmentincludesproteaseinhibitors
    ProteaseinhibitorsareeffectiveforG3aswellasGenotype1
    GS7979effectiveagainstallviruses

    Genotype3(depositionoffatinliver)notseeninG1
    Directactingantivirals(DAAs)nucleotideanalgoues,HepCtargets(proteases),tripletherapy
    EvolutionincarefromIFNtotripletherapyeffectivenessishigherfor3,butcanstillworkfor1
    IL28BpolymorphismsencodesIFNlambda3
    Prevalencegoodalleleishighercorrelatedwithrespondingtotherapy
    Intermediatephenotypefrom2
    MajoradverseeventsreportedwithIFNa
    flulikesymptoms,injectionsitereactions,myalgiaandarthralgia,nausea,anorexia,weightloss,thyroidsyfunction,
    bonemarrowsuppression.
    Majorsideeffectsofribavirinteratogenic,haemolyticanaemia,skinrash,cough,insomnia

    Jaundiceisyellowingduetobilirubin
    (1)Toomuchredcellbreakdown
    (2)notenoughconjugationandexcretionbyliver
    (3)obstructiontobiliaryducts

    Livercelldamage
    cellcontentsreleasedtobloodstream(RaisedALT,AST,GGT)
    Lossoffunctions:Bothsecretionandexcreition(lowserumalbumin)
    Collateraldamageacuteswellingobstructsbilecanaliculae

    IfelevatedALT,ASTandlowalbcouldbeindicativeofsyntheticliverfailurefromhepatitis
    Chronicityalbuminhashalflifeof3to4weeks.(Ifstilllowafterthisperiodsuggestschronicity)

    Viruses,drugs,alcohol,NAFLD,cardiacfailure,uncommoncausescanallcauseheptatis
    Takeclinicalfeaturesandhistory(travel,contacthistory)

    Epidemicsduetopracticesinegypt(schistosomiasistreatment,initalyhomeinjections)
    a)Whetherhehasacute/chronichepatitis
    b)thesourceofhisinfection?

    HepatitsCPCR,assessFBC,ultrasound,liverbiopsy,alphaferroprotein
    LargemassandextremelyelevatedaFP(564normalis3to7)

    Chronicinfectionnoclearanceoncepersistenceisestablished

    ChronichepC
    1)Assessthevirus(PCR,RNA,genotype)
    2)Assesstheliverdamage(clinical,noninvasive,fibroscan)
    3)AssesspossibilityofcomplicationsliverCT/MRI

    InvestiagtionsofrhonicCcansuggestliverfailureandhepatocellularcarcinomabesttreatmentistransplantbut
    verylimited

    ManagementVeryearlystagecirrhoticscanbetreatedwithantiviral(butencephalopathicandtummyswelling
    oftencontraindicated)

    Needlesticktransmissiondependsongaugeofneedle
    HepBbloodborneriskabout50%ifnonimmune
    HepCriskabout2%
    HIVriskabout0.3%
    AcutehepCOutcomes98%viralclearance,40%spontaneousclearance

    PreventionofhepCtransmissioninhospitalandhealthcare

    Lecture3.5.4Fallsintheelderly
    Unintentionallycomingtotheground
    1in3aged>65atleast1fallayearhighinhostels
    Theconsequencesofafallarethereasonfor2025%ofallpatientsage>65

    Complicationsoffallsheadinjuries,softtissueinjuries,longlie(pressureulcers),disability

    Causeoffallsclearlyexternalcauseandinternalcausebutmultiplereasons

    Predisposeddementia/cognition,vision,gait/balance,muscleweakness,proprioception
    Precipitatingmedications,acuteillness,displacingactivity(carrying),environment
    Testinneurologyrhombergstesttestofproprioception(tellthemtocloseeyes)
    Peoplegetolderlosedepthperception,changeperceptionincolours,10%decreaseinproprioception,reduced
    reactiontime
    Differentdiseasescanaffectsensoryinput,musculoskeletalsystem,centralprocessing
    Diabetescanreduceproprioception
    Psychoactivemedicationshighlyassociatedwithfalls,alsopolypharmacy
    Symptomsandsignsinfallen
    Syncopemanycausesarecardiovascularorneurogenic
    dizzinessandunsteadinessvertigo,lightheaded
    Orthostatichypotensionhypovolemia,prolongedbedrest,postprandial
    Gait
    CardiovascularTIA
    Neurological
    Neurallymediatedsyncopefaint,orthostaticBP
    Whotoassessindetail
    Recurrentfalls>2inlast6months
    Difficultyinwalking/balance
    Fearoffalling
    Presenttoemergencywith>1fall
    Fallprevention
    Multifactoralinterventionsworkbest
    GoodevidenceExercise,psychotropicdrugwithdrawal,homevisitandfollowup,hipprotectors
    NotmuchevidenceWithouttargetedmanagement,dementia,cognitivebehaviouraltherapy
    Visionexpeditedcataractsurgeryisgoodinpreventingfalls

    Fallsinhospital
    Delerium,medications,deconditioning
    Lecture3.5.4Mineralhomeostasis
    Averagepersonhas1.1Kgofcalcium99%inbone/teethmorecalciuminECFthencytoplasmic
    Bloodcalciumis2.32.5m/molhalfisionisedandhalfalbuminbound
    Changesincalcium
    Consequencesdependonseverityandsudden/longtermchange
    Decreaseincalciumsodiumpermeabilitychangespartialdepolarizationmusclespasm,pinsandneedles,
    seizures
    Increaseincalciumhyperpolarizedneurologicaldysfunction,cardiacarrhythmias,constipationlongterm
    kidneystones
    Phosphate0.81.4mmolLessimportant
    Highsofttissuemineraldeposition
    Lowinadequatebonemineralization
    Dietsource
    Calciumistakenupingutfromdiet
    Calciumisfilteredatthekidney
    Calciumisstoredinbones
    PTHcomesfromparathyroid
    PeptidereleasedbylowcalciumviaCSR,alsodecreasedbycalcitriolandhighcalcium

    VitaminDcalcitriol
    Shortexposuresarebetterthanlongexposures
    Exposure15%to1/3MEDmostdaysinsummer6/8minutesinmorning
    FortifyfoodwithvitaminD25ug

    25hydroxylvitaminDisactuallywhatsactuallytested(notwellregulated)
    Convertedtocalcitriolinkidney
    FGF23
    Producedinboneactsinkidneysincreasesphosphatewasting,decreasescalcitriolproductionandincreases
    degradationofcacitriol
    FGF23stimulatedbycalcitriol,PTH,highphosphate
    Calcitonin
    Ccellsofthyroidgland
    releasedbygastrichromones,pentagastrinandalsobyhighlevelsofcalcium
    Switchesoffboneresorption
    Gutsourceofingestedcalciumandphosphate
    Sourcesofcalciumdairy1000mgperday

    Bone
    Calciumandphosphatehydroxyapatite
    Actsasastoreofcalcium
    CalciumandphosphatereleasedfrombonebyPTHtriggersresorbtion
    YouneedvitaminDtoactivatethis

    Mainfunctionofcalcitriolistoincreasecalciumandphosphateabsorptionfromdietsoyoudontneedtobreak
    bone
    Kidney
    modulatescalciumandphosphatelosses
    Calciumishighhighcalciumurinelossmaybeenoughtostopbloodcalciumincreasing
    Normally98%reabsorbedhelpedbyPTH
    Phosphateisresorbedbyphosphatetrnasportersthereisamaximumability
    PTHdumpsphosphateinurine
    PTHaffectscalciumandphosphatedifferentlyinkidney
    Extracalciumpumpedintobloodwillbeconserved
    Extraphosphatebeingupumpedintobloodwillbedumpedintourine
    Calcitriolmajoreffectisongutnotonbone(minor)

    HighPTHhypercalcemia
    LowPTHhypocalcemia
    LowmildvitDcausesincreasePTHmaintainsbloodCaatexpenseofboneresorption,mayseedecreasein
    phosphate
    SeverelowvitDcantresorbbonerickets/osteomalacia
    Lecture3.5.5Osteoporosis
    Bonemass
    Resorptionformation(coupling)

    Bonemassdeterminantsgenetics,environment,biomolecules

    Peakbonemassage30
    Fracturethresholdarbitraryjustincreasedrisk

    Peakbonedensitydeterminedbyalotofthings
    Bonemassinadultdependsonpeakbonemassandrateofloss
    Meanwallthicknessdecreasewithageinbones

    Contributorstofracturerisk
    Bonemass(density)Tscore<2.5(osteoporotic)
    Bonequalitydeadcellsmicrofractures,connectivity
    Bonegeometry
    Propensitytofallmusclefunction,coordinator
    Adequateexercise,calciumintake,vitaminD,normalsexsteroidsavoidsmoking,alcoholandglucocorticoids
    Mechanicalloading
    Resistancetodeformityresponsemorebonealteredposition
    osteocytes=90%bonecells

    Mechanicalloadingimprovesbone
    Osteocytes=90%bonecells
    Secretesclerostin=negativeregulatorofbonemassINHIBITSwntpathway
    Withdeformityofbonesclerostinsecretionisreduced
    WNTpathwaysignallinginhibitedbysclerostin
    Wntsignallingpromotedleadstoincreasedtranscriptionofgenesinvolvedinboneformation
    Adequatecalcium
    AdequatevitaminDtomineralizebones
    >25mmolvitaminD

    VitaminDdeficiencysomeincreasedPTH,osteoporosis,impairedmusclefunction
    SeverevitaminDimpairedca/pogutabsorptionmuchincreasedPTHboneresorptionisimpaired
    phosphateislostinurineduetoincreasedPTHlowbloodcalciumandphosphateinsufficienttomineralize
    boneosteomalacia
    VitaminDwhoisatrisk
    Reducedmobility,darkskin,modestdress
    Verylowcalciumosteomalacia
    IIntermittentPTHstimulatesboneformationmaystopsclerotin
    Sexsteroidshelptomaintainnormalbalanceincoupling,alsotokeepbonecells
    Estrogenareimportantinmen
    Androgensgivemenmechanicallystrongbones

    Mechanicaladvantageoflargercylinderdiameter

    Sexsteroidhormonesincreasedresorptionlessboneformation
    Sexsteroiddeficiencyinanorexia,congenitaldeficiencies,alcoholism,menopause
    Glucocorticoidscatabolicdecreasecalciumabsorptionsupressosteoblastviability

    Lecture3.5.6MSKinthecommunity
    Backandboneproblemsurveysshowequallyimportantindevelopedanddeveloping
    8Essentialquestions
    1.Howcommonistheproblem
    2.Whatcausestheproblem
    3.Prevention
    4.Management
    5.Evidencestrength?
    6.Personaleffects?
    7.Societaleffects?
    8.Societalresponse
    InAustraliaVerygooddataonhipfractures,fewoncollesfracture,noneonOAofthehip
    Reasonwhyisadmissionratesofhipfracturesisalmost100%

    FracturesinAustralia
    Wrist,vertebral,humeralfracturesadmissionrateisnothigh
    Projectionofhipfracturesincreasewithincreasingelderly
    Fracturesinthethousands
    Prevalenceofosteoarthritis
    AtHandsandkneesveryhigh(85/30)butlowinthehips(10)
    40%ofpeople1yearafterhipfracturedeadorinnursinghome

    Physicalfunctiondecreaseswithage,butmentalhealthdoesntseemtochangewithage
    Badhipfracture80%wouldratherbedead

    Lowbonemineraldensitylowestquartile8.25RR
    Evidenceofpreventinghipfractures
    VitD+calcium,hipprotectors,bisphosphonates,HRT,strontium
    20%ofmenin70agegrouphaveosteoporosis,byage9050%;only10%whengivenbisphosphonate
    CostperQALY

    WEEK4Lectures
    Lecture4.2.1PrinciplesofRehabilitation
    Ruleofquartershipfracture(1/4die,recover,havepersistentdisability)
    Recoveryisuncertain
    Bestpredictoroffunctionalstatusisprehospitalizationfunctionalstatus
    Returninghomeisdependentonsocialsupport

    Barthelindexestablishesafunctionalindexofdailyliving
    010scale

    RehabilitationGoalorientatedandtimelimitedprocessenablesimpairedpersontoreachanoptimalfunctional
    level

    Involvemeasuresintendedtocompensateforlossoffunction
    Internationalclassificationoffunctioning,disabilityandhealth

    ICFimpairmentisalossofabnormalityofbodystructureorofaphysiological/psychologicalfunction
    Activityistheexecutionoftaskbyanindividualatagenerallevel
    Participationisinvolvementinalifesituationataspecificlevel(sustainingaconversation)

    9domainsofICF
    (1)Learningandapplyingknowledge(2)Generaltasksanddemands(3)communication(4)mobility(5)selfcare(6)
    domesticlife(7)interpersonalinteractions(8)majorlifeareas(9)communityandciviclife

    Environmentalfactorsmakeupthephysical,socialandattitudinalenvironmentinwhichpeoplelive
    Personalfactorsarespecificidentifyingdetailsabouttheperson
    Rehab13days
    Healthcondition(typeofhipfracture),othercomorbidillnesses

    Rehabplan
    Impairments(abnormalities)e.g.Fractures,limitedmovement,confusion,incontinent
    Activitylimitationse.g.mobility,selfcare,domesticlife,generaltasks
    Environmentalfactorse.g.Familysupport,housingaccessfacilities,adaptiveequipment
    Otherhealthprofessionals
    Physiotherapistmobilization,respiratorystatus
    Nursefamilysupport,skin,fluidintake

    Rehabplanday3
    Managementofhealthconditions,treatimpairments,reduceactivitylimitations,willrequireadmissiontorehab
    ward

    Minimentalstateexamination
    Orientation
    Memoryregistration
    Attentionandconcentration
    MemoryRecall
    Language
    Geriatricdepressionscale(shortform)

    Mobilizationiskeytorehabilitation
    Oralnutritionalsupplementsmaybenecessary

    Physiotherapistmayhelpwithgymnasium
    Occupationaltherapisthelpswithbathing,cleaning
    Mealsonwheelsmayalsobeusedtodeliverfood
    Posttreatmentmonitoringbynurse

    Treatmentofosteoporosisandhipprotectorshelppreventfromhavingreoccurance

    Lecture4.2.2Biochemicalsynthesis
    Biochemicalspeciesthatcannotbesynthesized
    VitaminsexceptionvitaminD,Essentialaminoacids,essentialfattyacids

    evolutionarilyspeaking;
    Ifsynthesisisnotsupporteddietmustreliablysupplykeyspecies
    Ifsynthesisissupporteddietmayneverhavebeenreliable

    EssentialAALysine,histidine,threonine,methionine,phenylalanine,tryptophan,isoleucine,leucine,valine

    GlutamateprecursorforotherAAsglutamine,proline,arginine

    Importantcarriersinsynthesisoffattyacids
    coenzymeA
    Acylcarrierprotein(ACP)importantlyphosphopantetheineGroup

    Synthesisoffattyacids
    AcetylCoAmalonylCoA
    2Carbongroupand3carbongroupjoinandcondensetoform1carbon+4carbon
    Chainlengthincreasesby2carbonseachcyclemaximumlenthviaFASis16C

    Overallreactionofpalmitatesynthesis
    8acetylCoAbecomespalmitate(NADP+CoA+someotherstuff)
    Namingfattyacids
    Carboxylcarbonisincluded
    2
    nd
    carbonisknownasalpha,3
    rd
    isbeta
    Conversely,omegaiswheredoublebondis

    Majorconfigurationinnatureiscis
    Kinkeddoublebonds(cis)meltingtemperaturedrops
    Unsaturatedfattyacidsarenormallyliquid
    Dietarysourcesofessentialfattyacids
    n6linoleatesafflower,grapeseed,poppyseed
    n3alphalinolenatechia,kiwifruitseeds,flax
    SynthesisofHMGCoA
    (a)AcetylCoAreleaseCoAacetoacetylCoA
    (b)AcetylCoA+AcetoacetylCoAreleaseCoAHMGCoA

    HMGCoAreleaseCoAmevalonate

    StatinsinhibitHMGCoAreductaseinhibitcholesterolsynthesis
    C2eventuallybecomescholesterolC27
    Howeverinbetweenthereareimportantintermediates
    Mevalonate(C6),IsopentenylPpi(C5),C10,C15(FarnesylPpi),C30(Squalene),C27(Cholestrol)
    C15proteinprenylation,hemeAcoenzymeQ10

    SynthesisofC10and15issupressedbyNbisphosphonatesthesealsosupressformationofosteoclastsinbone

    Steroidsandbilesaltsaresynthesizedfromcholesterol
    Interactionsbetweenunsaturatedfattyacidsandcholesterol
    1.FattyacidsregulateuptakeofcholesterolrichLDLs
    2.Fattyacidsregulatecholesterolsynthesisattranscriptionallevel

    Glucosealdosereductasesorbitolsorbitoldehydrogenasefructose

    Pentosephosphatepathway/shuntalternativefateforglucosesynthesisofribosemaintainingGSHinreduce
    stateGSHprotectscellproteinsfromoxidation
    Glucose6Pribulose5pribose5pnucleotides
    Howeverribulose5palsohasconnectionbacktoglycolysis

    MajorconsequencesofpentosephosphatepathwaysynthesisofRibose5P,synthesisofNAPDH
    DifferentialfluxthroughbiwaysindependentcontrolofRiboseandNAPDHsynthesis
    Glutathionesynthesisandroleasanantioxidant
    yglutamatecysteinylglycine(G)+SHGlutathione(GSH)(reducedform)
    GSH+GSHGSSG+water

    PentosephosphatepathwayregeneratesGSHbyprovidingNAPDH

    G6PdehydrogenasedeficiencyfailureofNAPDHsynthesis
    Acutehaemolysis(GSHnormallyprotects),Jaundice,Anemia
    Drugscanalsotriggercrises
    InadequateNAPDHexposescellstolyticdamagee.g.inFAVISM
    Lecture4.2.3HealthLaw3Consent,knowledgeandpower
    Typesofconsentexcessorimplied
    Actuallybodilyharmisnotcoveredbyconsent

    Medicaltreatmentasanexception

    Elementsofconsent
    Voluntary,specific,identity,understandingnatureofact
    Righttorefuseconsent(evenifdeatheventuates)
    Righttorefusefeeding

    Advanceddirectivescanbeusedtorefusehelp

    Capacitypresumptionofcapacityinadultspresumedtobecompetentunlessshownbytheevidence
    Functionaltestsifunconsciousisobvious
    Howeverifconsciousneedtocomprehendandhaveinformationretention,believeinformationandweighit
    againstotherfactorstoreachadecision

    Slidingscaleapproach
    1.Illness,drugs,fatigue
    2.Metalillnessordisorder
    3.Undueinfluencestrengthofthewillofpatient,relationshipwiththepersuader
    NSWgillickcompetencyis14,

    Consentintheprovisionofinformationattemptedtogiveit(ifrefused)thatissatisfactionofduty
    Whatisthestandard?
    Diagnosisandtreatment
    Reasonablepersonstandardthetestisstandardoftheprofession

    Bolamtestallowednewknowledgeandpractisestodevelopwithoutfearonlyneedonebodyofdoctorsto
    agreethatthestandardisenough

    InAustraliathereisanobligationtoprovideallinformationthatisrelevant

    CivilliabilityactStandardofcareforprofessionalsisdeterminedbythebodyoftheprofession,howeverliability
    doesnotextendifprofessionalhasnotexplainedrisksinvolved
    Guardianshipactconfirmstherightsofadultswithadisabilitytomaketheirowndecisionswherepossible
    Containsspecialpowerswhenapersonisatrisk,neglectedordetained
    Confirmsthatmedicalpractionerscanprovidetreatmentwithoutconsentwhenitisneededtosavethepersonslife
    orpreventseriousdamage
    Enduringguardianshipanadultcanappointapersonashisenduringguardiantotakeeffectlater.
    Lecture4.2.4UpperlimbClinicalanatomy
    Problemsyoucanseeinthoracic/armarea
    brachialplexuslesions,stenosisofarteryandocclusionofvein
    C7cervicalribjoinsontot1ribcancausethis
    Subclavianocclusioncausesthromboemboligangreneindigits

    Clavicleisthestrutthatholdsthearmoftenbroken
    Middlethirdofclavicleiswhereitbreaks

    Coracoclavicularligamentverystrong
    coracoacromialligamentverystrongonlywaydamagedisbyrupturetakesalongtimetoheal
    Dislocatedshouldersomethinghastohappentorotatorcuffjoints
    Anteriordislocationoftheshoulderisthemostcommon
    posteriordislocation
    AxillarynervecaneasilybedamagedbydislocationMUSTidentifyifithasbeendamagedbeforerepair
    Supraspinatussyndrome
    Subacromialandsubdeltoidcommonbursaproblem
    Supraspinatusholdshumerusintoglenoidinjectsteroidstoalleviatethis
    InvestigationofthisiswithMRI
    Humerusandsupracondylarfractures
    Dangerousfracturesaresupracondylarracturesabovethecondyles
    Mustmakesurebrachialarteryisnotoccludedinchildrenverydangerous

    Radius,ulnaandhumerusdislocationsandfractures
    Iffractureofradiusoccursatneck,theheadcandie
    Removaloftheheadorprosthesisinsertcanhelpbringbackfunction
    Iffractureofulnarisinproximalthirdplasteringneedstobeputinmostsupineposition
    Iffractureofulnarisindistalthirdplasteringcanbedoneinneutralposition
    CollesFractureoftheDistalRadius
    Radialandulnarstyloidprocessneedtobefixed
    Dorsallyangulatedfixedinflexion,fixedulnardeviationbackslabtostartwiththenshortarmplaster

    Carpalbones
    Fracturesofscaphoid
    Deepinsnuffboxiswherethescaphoidboneis
    Nutrientforaminaproximalfracturesofthescaphoidmaynothaveenoughnutrientsupplydieinfracture

    Carpaltunnelsyndrome
    Compressionofmediannervecausesnumbnessof3fingers
    Lossoffeelingorneuralgiacanoccurifnervesaredamagedduringoperationwhencarpalligamentareseparated

    Passingthroughthecarpaltunnelare10structuresnobloodvessels
    Flexorpollicislongustendon,4tendonseachoftheflexordigitorumsuperficialisandprofundusmusclesandthe
    mediannerve

    Axillarydissection
    Apicalgroup,central,anterior,posteriorandlateralgroupoflymphnodes
    Stage11degreebelowPecminor
    Stage2nodesbehindpectoralisminor
    Stage3abovepecminorapicalgroup
    Mostsurgeonswilldostage3

    Longthoracicnervemustbeprotectedserratusanteriorwinging
    Thoracodorsalnervesupplieslattisimusdorsi

    Waiterstippositionerbduchenneparalysisc5,6,7,compressionbirth
    C8,T1Klumpkesparalysis(clawedhand)
    Mediannervelesion
    Mediannervesupplies3fingersandthetips
    Testingisbyopposingthumbandpinky
    Lesionmonkeyshandcantopposemediannervepalsy
    Ulnarnerve
    Cutaneousdistributionofulnarnervefanfingers
    Ulnarnervepalsyclawhand

    Radialnervesuppliesonlydorsumputwristsup
    Radialnervepalsywristdrop

    Cubitafossa
    MediancubitalveinBrachialarteryisbehinditmediannervebesideit

    SixPsofacuteischaemia
    Pallor,paraesthesia,pain,paralysis,pulselessnessandpoikilothermia(cold)

    Allenstest
    Squeezehandthenoccludebothulnarandradialarteriesthenreleasehandreleaseonearteryallofhand
    shouldgopinkifthereisadominantartery(neverdoasurgicalprocedureondominantartery)

    Synovialsheathbecomesinfectedthenbecomesstiff
    Witlowinfectionindistalpulpspacemustberelievedotherwiseinfectioncanspread
    Lecture4.2.6EBMII
    Lecture4.5.4Osteoathritis
    Dontusethetermdegenerativeorosteoathrosiswhenreferingtoosteoathritis

    Osteoathritistheydohaveinflammationofsynovialjoint
    Osteoarthritis(Impat)
    Mostcommonjointdiseaseintheworld22.8%Australianshavearthritis(20%ofthesehaveosteoarthritis)
    Accountsfor95%ofkneeandhipreplacements

    Osteoathritisdoesntaffectjustcartilageaffectsalltissuesinsynovialjointqqq
    Cartilagedoesnthavenerves

    EverybodysjointhasabilitytorepairAnabolismvscatabolism
    Inosteoarthritisanabolismoutweighscatabolism

    Disruptionofcollagentype2whichbringsinwaterswelling
    Firstpersonpresentswitharthritisthereisswelling

    Oseophytejointtryingtorepairitselfdoesnotrepairattheweightbearingpartbutonthemargins

    Osteoathritiscanoccurinanysynovialjointships,knees,jointsofhandand1
    st
    metatarsaljoint
    70%ofpeopleover65havefeaturesconsistentwithosteoarthritis

    Candiagnoseosteoarthritisbasedonhistoryandexamination
    Crepitis,stiffness,bonytenderness,age,50years
    XrayisonlyusedtorefutediagnosisdefinitelydontneedaMRI
    CriteriaforHipOA
    Hippainandatleast2ofthefollowing;ESR<20mm/hour,radiographicfemoral/acetabularostephytes,radiographic
    jointspacenarrowing
    ESR=erthyrocytesedimentationrate

    HandOAdiagnosishandpain,achingstiffnessandofthefolloiwngfeatures
    hardtissueenlargement,hardtissue
    Osteoathritistwiceaslikelyinwomen,(morelikelyinmen<50yearsold)

    HandOA26%ofwomen,135ofmenagedover70
    Multifactoralgenetics,mechanicalfactors,obesity,priorinflammatoryjointdisease
    Leadstoreducedgripstrength,writing,Carryingweight

    KneeosteoarthritisOftenasaresultoflandinginthewrongposition(Innoncontactsports)

    RiskfactorsforOsteoarthritissystemicriskfactors(familyhistory=4x),Age,gender,ethnicity(HipOAnon
    existentinchina),Dietaryfactors

    Obesityandjointinjurycandrivetheprogressionofdisease
    Varusmalalignmentmedialtibial
    Valgusmalalignmentlateralfemoral

    Whydoesithurt?Periostealandsubchondralbone,synovium,softtissues

    Osteoahtritisaffectseachpersondifferentlyprogressesquicklyslowlyovermanyyears
    UsuallyOAdevelopsslowlyjointsmayacheafterphysicaworkorexercise
    Laterindiseasejointmaybepainfulatrest

    Stiffnessisusuallyshortlivedlasts30minutes
    Othersymptomscrepitus,limitedfunction,jointwelling,reductioninjointrange,maypredisposetobuckling

    Othertypesofarthritisthatmayinvolvehipkneeorhand
    RA,psoriaticarthritis,otherseronegativespondyoarthropathies,sarcoidosis,alsoGOUT

    OApresentsashand,hiporknee
    ReferredpainfromL1and2
    Excessivealcoholuse,bloodclotting,abnormaitiesmaypredisposetoavascularnecrosis
    Lookattheknee,bicompartmental
    Mostcommonispatellafemoralandmedialtibiofemoraljointcompartments
    f
    Othercommoncausesofkneepain
    BursitisITbfrictionsyndrome,patellaatendonitis,patellofemoralpainsyndrome

    RighthiOA,showsfixedflexiondeformiyswolleneftkneewithvarusandfixedflexiondeformity

    Othercommoncausesofhandpain
    DeQuervainstenosynovitis,CarpelTnnelsyndrome,flexortenosynovitis,ulnarnervecompression
    Squaringdeformitylossjointspaceandosteophyteforming

    Heberdens(DIP)andBouchards(PIP)nodes
    ProximalanddistalphalangealjointOAoftenjustcosmeticbutnotfunctional
    LaboratorytestsOAisoftendescribedasanoninflammatoryarthritisandassuchlaboratorytestingisnon
    contributory
    ConsideraspirationaswollenjointifadiagnoissotherthanOAisconsideredsynovialfluidshouldbeclearand
    viscouswithaWCC<2000mm3
    Radiographiccriteria
    Osteophyteformation,jointspacenarrowing,subchondralsclerosis,subchondralcysts
    Lectureimages
    OAacetebullumnarrowingspace,jointthickening
    MoreadvancedJointspacedisappears,headthickens,cystsform,mishappen
    Femurcartilageinkneecapandjointaregone
    Carpal/metacarpaljointosteophyteformingatbaseofthumbjointspaceisdiminished
    Heberdensnodeosteophytewillformatmarginsofjoint,lossofjointspace
    OAoccursbetween4and10jointallDIPandPIPareaffected

    ErosiveOA
    in510%centralerosioncanoccurfeaturecauseserosiveosteoarthritis
    Treatmentoferosiveosteoarthritisdiseasemodifyingagents,changesettingofthechange
    Usuallyaffectsnotjustonejointbutanumberofjoints

    NaturalhistoryofOA
    Initiationofdiseaseprocessbeginsatage18
    mRI/Biomarkers(chanesincompositionofbonecartilage)mri/us(structuralchangesinbone,cartilage)Xray
    (structuralchangesinbone)Endstagedisease(i.ejointdeath)
    Researchnowistofindbiomarkersthatcanallowustotargetearlyon

    CartilageisnotcentraltowhydiseaseworsensorsymptomaticOA
    Lecture4.5.5PhotobiologyUVandtheskin
    OverreactivetoUVMelasma
    Lupus,olarurticaria,porphyria

    GoodeffectsVitamiD,UVphototherapy,photodynamictherapy,serotonin,circadianregulation
    UVCusuallyfilteredbyatmosphere
    UVBerythemogenicsunburning
    UVA2
    UVA1
    Visible

    SolarradiationmolecularoxygenandozoneabsorbalotofUVCandUVB

    Loweratmospherescattering,absorptionbyparticulatesandclouds
    50%ofradiationisdiffusebackscatteredhatsgiveonlylimitedprotectiontothelowerface

    Overviewofskinstructure
    Stratumcorneum,epidermis
    melanocyteseffectiveatabsorbingsunlight
    50%ofUVAwillgointodermishigherthewavelengththemorelikelytopenetrate
    Chromophoreabsorbsspecificenergypackets

    Excitedstate
    Photoproducs,photosensitization,emissionofightorheat

    DNAabsorbingUVC(260nm,porphyrins(400420nm),hemaglobin

    Melaninabsorbsmosteffectivelyat335nmalsoabsorbsbrown
    Actionspectrum=themosteffectivewavelengthrsforproducingacertainresponse

    Sunburnlowerwavelengtharealotfasteratcausingsunburn(lowerMED)
    Thereisablipat360380nminUVANOTCOMPLETELYUSELESSATcausingsunburn
    Totalenergywillcausebiologicalresponsenottimetaken
    Sydneysummersun1MEDis510min

    DNAdamageinnormalhumanepidermisafter1/3ofanMEDs
    UVBandUVAdifferentpatternsofDNAdamage
    DirectdnadamageCPDs
    oxidativeDNAdamage8oxog
    ActionspectrumforCPDssameasactionforsunburntanning,SCCinduction
    DNAdamagealsoinducesUVimmunosuppressionsuppressiveeffectsoncells(langerhancells,Tcells,mastcells)
    suppressivechemicals,cytokines,neuropeptides

    UVsuppressiveresponsesCHS,DTH,decreasedtumourrejection
    Mantouxtestissuppressed
    UVandUVAhavedifferenteffectsonimmunesystem

    UVimmunosuppressionenhancedcarcinogenesis,infections(HSV),TB,malaria

    Immunosupressiontoactionspectrum360/380blipisimportant
    Skinthickenanimportantdefenceforpalepeople
    Epidermal>dermalthickening
    MelaninabsorbsUV,visible,freeradicalquencher
    MelanosomesscatterincomingUV

    Sunburnsensitivityisdeterminedbymelanin(andskinthickness)
    SusceptibilitytoUViunosupressionispartyrelatedtoskincolourbutonlyweakcorrelation(skinthicknessismore
    important)
    DNArepairCPDs
    DNAdamageCPDsreducedafterselfrepair
    Defectivenucleotideexcisionrepairveryeasilysunburnt

    Xerodermapigmentosum,orXP,isanautosomalrecessivegeneticdisorderofDNArepairinwhichtheabilityto
    repairdamagecausedbyultraviolet(UV)lightisdeficient

    MelanocyteshopelessatDNAdamage

    VitaminDnotverymuchindiet
    Prolongedsummersunexposureveryhigh
    MinimumamountofUVisnotknown

    VitaminDdeficiencyinAutralianursinghome,tasmania,sunprotecting,skincancerpatients
    UVBtreatmentpsoriasis,vitiligo,cutaneousTcelllymphoma
    UVAEczemasceroderma,SLE
    VisiblephototherapyneonataljaundicenewisomerscantcrossBBb
    Deliberatelyapplyporphoryin(Photosensitization)causephotochemicalreactiontreatmentofsuperficialskin
    cancer

    PDTcureratesgoodbutcanreoccur
    PDTishighlyimmunosuppressive
    Photosensitizationwithlotionhugelyimmunosupressive

    Tumourtype,subtypethickness
    Fractionationradiotherapysinglemassivedose,overanhourbadsideeffects
    Fractionizingsmalldosesoveracourselesssideeffects

    Deliverlightmoreslowlyno/lessimmunesuppression
    DNAdamageisakeytriggerforphotoimmunosupression
    Importanttoknowwhattypeofradiationisbeingused
    Ocularvisiblelightexposurecircadianrhythm(melatonin)
    Immuneeffects,reproductiveeffects,psychologicaleffects

    Lecture5.2.1Nondrugmanagementofosteoarthritis
    Peopleonosteoarthritisareoncomplementarymedicine
    Omega3acids,VitaminD,Kallwork
    Glucosaminesulphatedoesnotwork
    Synviscinjectionsofhyaluronicaciddoesnotprovideanysignificanteffect
    Currentpracticedontprescribeglucosamine,butdontdeterifstarted(placebo)

    Pharmacologicalapproach
    Paracetamolistheoralanalgesicofchoiceformild/moderatepain
    Shouldnotprescribemorethan4gmshouldideallyprescribe3gm/day
    NSAIDSshouldbeaddedorsubstitutedinpatientswhorespondinadequately
    TopicalformulationsofNSAIDSandcapsaicinhavebeenshowntobeahelpfuladjuncttosymptommanagement
    NSAIDsversusparacetmol
    Intraarticularsteroidsofonlyshorttermbenefitbecauseitisachronicdisease

    Intraarticularhyaluronicacidisnotsignificantlymoreeffectivethanaplacebo

    MainbodyoforthopaedicsurgeonsinusRecommendationagainstperformingarthroscopywithdebridementor
    lavageinptientswithprimaryOA

    Placeboeffectisgreaterifexpectationoftreatmentishigher

    Indicationsfortotaljointreplacementnightpainunresponsivetoantiinflammatorydrugs
    Majorinabilitytoperformdailyactivities
    Unacceptablereductioninabilitytowork/walkhowevertryothertherapiesfirst

    Currentmanagementfeaturesmultiplehealthcareproviders
    Focusonmechanicsweightloss,strengtheningandorthoses

    MedialTFOAweightloss,musclestrengthhipadduction,Brace,orthoticforsubtalarneutral
    LateralTFOAweightloss,musclestrength,brace,alsousemedialwedgedorthoptic

    PFOAPFmalalaignmentisassociatedwithincreasedpain,reducedfunctionstrengthenvastusmedialis,
    correctoverpronation,patellataping,userealigningsleeve

    Currentlywearejustpreventingsymptomsweshouldmodifydiseaseprogression
    Currentanumberofphase3andphase2thesemodifythediseasee.g.calcitonin,strontium

    Weshouldimprovecareforthosecurrentlywithdisease,preventionstrategies(weightloss)
    HalfthepatientsthathaveOAdontknowincreaseOAdiseaseawareness

    Conclusions
    Typicallymanagementiswoefulpainmanagementstillunmet
    Needfortreatmentstoimpactprogression,butfocusonmechanicalriskfactors
    Lecture5.2.2Preventionofskincancers
    Thingsarepreventable
    Semmelweissshowedthathandwashingwaskeyinreducingmaternalmortality

    skincancer
    LifetimeriskinAustraliais50%,4timesascommonasallothercancerscombined

    Tumourthicknessisagoodindicatorofmelanomaprognosis
    Basalcellcarcinomamostcommonskincancer,slowgrowingandalmostnevermetastasize
    Manytypessuperifical(nodular),micronodular(infiltrating)

    Actinickeratosissunspots>60%ofAustraliansover40
    Premalignantcanprogresstosquamouscellcarcinomasmayspontaneousresolve

    SCC23timeslesscommonthanBCC,canmetastasizetonodes,lungsandbone

    Whatcausesskincancer?DNAdamage

    Melanomariskfactors
    Acute,intermittentUVexposureinchildhood,adolescenceandadulthood
    SomeriskwithchronicUV,immunosuppression,defectiveDNArepair
    Geneticpredisposition,allskincancer(paleskin)

    BCCriskfactors
    EpisodicUV,sunburns,immunesuppression,genetic,arsenic

    SCCriskfactors
    ChronicUVexposures,80%fromAKs,immunosuppression(farmoreimportantinSCCthanBCC),HPV

    Actinickeratosispremalignancycanprogresstosquamouscellcarcinoma
    Surrogatemarkerforskincancerrisk

    DNAdamage,immunosuppressioncancauseskincancer
    Skincancerpreventionprotectskinimmunity,preventDNAdamage,enhanceDNArepair
    MinimizeUVexposure,sunscreens,chemoprevention
    Sunglassesareneededtopreventcataract
    Solariaincreasesriskofmelanoma
    Sunscreenscanabsorbenergy,orbackscatterit
    Canbechemicalabsorbersorphysical(zincoxide)blockers

    Measuringprotectionfromerythema(mainlyUVB)
    SPF=MEDofsunscreenprotectedskin/MEDofunprotectedskin

    Differentingredientsinsunscreencanaffectprotectionbecauseofdifferentproperties

    SPFdependsonsunscreenfilmthickness,spectrumofUV,skintype(darkerskin,lowerspf)photodecayofsunscreen

    UVimmunosuppression
    ImmunosupressionincreasesskincancerriskevenlowUVdosessuppressskinimmunity
    UVimmunosuppressionplaysakeyroleinskincancerdevelopment
    RecommendationishighestSPFandbroadspectrumsunscreens
    Sunscreensaregenerallybetteratpreventingsunburnthanimunosupression

    sunscreensreduceAKsby40%in2years

    AdverseeffectsofsunprotectionvitaminDdeficiency
    Osteoporosis,autoimmunedisease,cardiovasculardisease,internalcancer
    BriefsunexposuresareneededtomaintainvitaminDlevels
    Nanoparticlesnotallarethesameharmfulifinhaled
    Nanoparticlesinsunscreendontpenetratenormalstratumcorneum

    highfatdietincreasessccriskinanimals,halfingfatreduces
    Obesityandmelanomariskarepositivelycorrelated,andsccriskdecreaseswithleafygreenintake

    Chronicstressincreasesphotocarcinogenesis(duetoimmunosuppression)

    Smokingandskincancer
    Surgicalsideeffects,2xriskofAKsandSCCs,

    Sometimessunscreenisntenoughchemoprevention

    Retinoids(acitretin)helpsabithaslotsofsideeffects

    CyclooxygenaseinhibitorstopicalNSAIDSdiclofenac
    decreasedNMSCandmelanomainpeopletakingaspirin/NSIDS,45%reductioninBCC/SCC

    T4N5liposomesenhanceDNArepair,decreaseAKBCC,butexpensive

    NIcotinamideprecursorofNADeasytotake
    NicotinamideprotectanimalsfromUVimmunosuppressionandphotocarcinogenesis
    ProtectsagainstbothUVAandUVBimmunosuppression(canalsoworkasatablet)

    NicotinamideworksbecauseitsinvolvedIncellularenergy
    DNArepairrequiresenergysunlightdepletescellsoftheseNicotinamideincreasescellularenergy
    UVBcausesCPDsor8oxoG

    Nicotinamideincreasesrepairofbothdirect,UVBandoxidativeDNAdamage

    OralnicotinamideforAKsmassivereductioninprecancres
    Preliminarystudyhasshownthatnicotamidemayreduceskincancerby75%

    Publiceducationisimportanthastobeconstantnotaoneoff

    Lecture5.2.3Autoimmunity
    Tolerancespecificinabilityoftheimmunesystemnottorespondtoselfantigens
    1.Centraltolerancedeletionofautoreactivelymphocytesintheprimarylymphoidorgans
    2.PeripheraltolerancecontroloftheactivationoftandBcellsinsecondarylymphoidorgans

    MechanismsofTandBcelltolerance
    1.Deletionofautoreactivetandbcellsinthymusandthebonemarrow(ImportanceofAIREgene)
    2.ControlofactivationofTcellsrequirementofcostimulation,controlofexpansion
    Breakdowninselftolerance
    Precipitatedbyinteractionofenvironmentalfactorswithageneticallysusceptiblehost(Infection/drugs60%)in
    geneticallysusceptiblehost(40%)
    thereisautoimmunediseaseforeverytissueinthebodycollectivelythirdhighestcauseofmorbidity
    Step1developmentofanautoimmuneresponsewhichmaybeshutdown
    Step2developmentofclinicalautoimmunediseasefailureofselftolerance

    Combinationofgenetics,environmentandimmuneresponseautoimmunity

    Certaintypesofautoimmunediseasesseemtoruninfamily
    SequenceofhumangenomeSNPscancausediseasecompareSNPsofindividualswithdiseaseandwithout

    inHumangenomethereareabout3millionvariantsmayoccuringenesthatareimportantforimmuneresponse

    ManhattanplotsentiresequencesLookatSNPSbetweenpopulationgroups(seeveryhighpeak).
    Chromosome6HLADRismostimportantinTcellsexplainsapartofRA
    Chromosome1Phosphataseimportantintype1diabetessignallingmechanim

    MHC/Hlavariationandimmunedisease
    AnkylosingspondylitisHLAb27relativeriskisveryhigh(90)
    HLAdifferencesareimportantinalotofautoimmunediseases

    Rheumatoidarthritis
    1.HLADRB1locus,2.Alleleinproteintyrosinephosphatase(PTPN22),turnsoffsignalling
    3.PossiblyCTLA4,IL2,TNF

    Howeverenvironmentalisalsoimportantlookingattwins.
    Antigensinmicroorganismcrossreactivewithselfproteins(molecularmimicry),Viralorotherinfectionsactivate
    dendriticcells,smokingisassociatedwithanticyclicpeptide(changesargininetocitrulline)

    Susceptibilitygenespredisposetoselftoleranceeffectofgenesisquitesmall.NeedmultipleSNPs
    Foxp3importantinIPEXsyndrome

    SingletissuedamageorganspecificE.g.Type1diabetes,addisonsdisease(adrenalfailure)
    Nonorganspecific(Systemic/lupuscluser)RA,SLE,sjogrenssyndrome)

    Thyrogastricclustervslupuscluster

    Commoncharacteristicsofautoimmunediseasescombinationofsomeofallofthefollowing
    Genes,females,chronicfluctuatingcourse,presenseofautoantibodies,lymphoidcellinfiltratesoftissues

    mostcausedbyTcells,notautoantibodies

    Antiinflammatorydrugsdampeneffect
    Immuosuppressivedrugstargetsthecause

    Thyroidantibodies,antinuclearantibodiesbothincreasewithageoftenlowtitreandnonpathogenic
    (presencedoesnotindicateautoimmunedisease)
    Lymphoidinfiltrationinsublingualglandssjogrenssyndromethiscausesdecreasedsecretionofsalivalymphoid
    takesovertissuebecomingalymphnode(insomecases)

    Type2Antigenintissues/cellsurfaceactivatescomplementtissuedamagefromneutrophils/macrophages
    Type3antigenissolubleimmunecomplexactivatescomplementrecruitcellstositesofimmunecomplex
    depositsintissues(knownasserumdisease)

    APatternsofautoimmuneTDsantibodydriven
    SLEshightitreautoantibodiesdirectedatnucleus(Type3hypersensitivity)
    RelatedconditionswithSLEsjogrenssyndrome,scleroderma(butterflyrash)

    CellsarebeingturnedovernuclearfragmentsarereleasedprocessedbydendriticcellscanbepresentedtoT
    cells
    UVirradiationincreasesapoptoticcellsthereforeDNAincirculation
    Infectedbyviralinfectiontype1IFNincreasedTcellhelpfollicularhelperTcell

    TH2cellsmaybeactivatedprovidehelpforBcellsantibodiesproduced

    inSLEreducedclearanceofapoptoticcellsandnuclearAg

    Immunecomplexesdepositinjointscausingdisease,alsoactivatecomplement
    Immunecomplexescandepositinglomerulibecausecannotbefiltereddepositioncancauseimmunedisease
    Anticollagenantibodiescancausegoodpasturesdisease

    SLEcandevelopautoantibodiesagainstawholerangeoftissues
    AntiENA,AntiACA

    2.Tcell/cytokinedrivenimmunedisease
    ChronicinflammationdrivenbyTcells
    Infilitratingantigensuncertaincitrullinatedpeptidessmokinginducesmodificationofargininetocitruline
    Selfproteincanbedamagedcreatesaneoantigen
    CitrullinatedpeptidesbindtocertainHLAallelesactiatTcellswhichhavenotbeendeleted
    highlevelsofproinflammatorycytokines(TNF,IL6)stimulateacutephasereactiveproduction(creactive
    protein,serumamyloidprotein)

    CRPisasurrogatemarkerforproinflammatorycytokines

    SelfproteinpresentedbyDC(recentinfectioncanupregulatecostimulation)activateth1tellMpsto
    producecytokines/chemokines
    Bcellsrecgoniseselfproteinantibodiesaremadethatrecogniseselfprotein
    RACCPabanticycliccitrullinatedpeptideshighlyspecific
    RhematoidfactorsIgmantiIgGantibodypresentinsynovialfluid/serumspectrumofCTdiseases

    Processresultsincollectionoflymphocytesandmacrophagesinfiltratingthecartilageofjointcalledhammus?

    KeycytokinedrivingprocessofRAisTNFinhibitorsofTNF(canswitchoffproductionofcytokineproduction0,can
    switchofsynovitis

    TNFisadominantcytokine
    TNFtreatmentneedstobemaintained(biologicaltherapy)

    Lecture5.2.4Substitutedecisionmaking
    Childrencompetence,parentalpower,specialtreatments
    Incompetentadultsenduringguardianship,guardianship,personresponsible,parenspatriae
    Ageofminority18

    Decisionmaking
    Thebestintereststesttreatmentoptionsconsideringreligiouspreference,sexualorientationfearoflitigation
    Futility?notgoingtoworknotgivingtreatmenttopeoplewithdownsyndrome(statisticallynotsurviving)
    Qualityoflife?aftertreatmentwilllifebebetterafterthetreatment
    childrenwithseverementalanddevelopmentalissuesthatshouldbeallowedtodiesincetheirqualityoflifewill
    stillbehorrible.
    Impracticality?
    problems?

    Decisionmakingsubstitutedjudgement
    Ifthepatientismentallyincapableofmakingadecisionsomeoneelsewithpatientsinterestatheartcandecide
    Problemswedontknowthepersonstrueopinionsontheissuethatistobedecided
    Acombinedapproachisbestcombiningtheopinionsofpersonsguardians+government

    Childrenandcapacity
    SpecialtreatmentMarionscase
    Sterilizationofa16yearoldgirlbyparents
    Thecomplexityofthequestionofconsentnontherapeuticdecisionmakesquestiondifficultbecauseparents
    canmaketherapeuticdecisions,medicalprofessionsoftheareacannotbetrusted,inherentconflictinparents
    decision(makingitforthemselves,notforchild)familieswithdisabledchildrentendtobepoor(orbecomepoor
    duetocosts)

    centralroleplayedbythemedicalprofessionbothindecisionmakingandintheperformanceoftheprocedure
    Theclashofinterestsdecisionsinvolvethepossiblyconflictingthroughlegitimate,interestofthechild,the
    parents,carersandotherfamilymembers.
    Limitsonparentalpower,parentscantbetrustedNSWsterilizationcanonlybedonewhenlifeisotherwise
    threatened
    Whentherapeuticdonotneedcourts

    Statelegislationdoneeneedstobeparentorimmediatefamily?
    Somethingswhicharenontherapeuticwhichfallwithinparentalresponsibilitycircumcision,earpiercing
    Genderdysmorphiadangerofchoosingthewronggender
    Genderdysphoriafeelingthatyoureinthebodyofthewronggenderreversiblehormonaltherapiesnoneed
    togocourtbecauseoftherapeuticcase

    Abortionsomecourtinterventionsbutonlyifwardofthestate
    QLDjudgeallabortionsforchildrenshouldbeapprovedbycourt(howeveroverload60kabortions)
    QLD,NSWabortionisillegalunlesstherapeutic

    Femalecircumcisionisillegal
    Experimentaltreatmentallowedifchildwilldieanyway

    Cosmeticsurgery
    Heathlegislationinqueenslandmadelawthatsaidthatatreatmentcouldonlygoaheadifitsinthechildsbest
    interest

    Withdrawaloftreatmentanddoubleeffectmanagingababysdeathcanbedecidedatafamilyleveltherapeutic
    decision
    LegislationNSWNeccesaryasamatteryofurgencytocarryutthetreatmentonchildtosavechidslife(special
    (infertilitycontraceptionmenstrualregulation,vasectomy,occlusion,drugsofaddicitonmorethan10/30days,
    experimentalmedicaltreatmentnonconformingwithnHRMC

    Dataover1000girlshadbeensterilizedwithoutcourtapproval

    Incompetentadults
    Theycanappointguardianenduringguardianship
    Guardianshiptribunalcanappointsomeonetoappointsomeonetolookafteryou

    Personresponsible(nextofkiniswrong)issomeonewhocanconsentifyoureincompetent
    Startswithguardian,spouse(closeandcontinuing0,whoeveriscaringforyou,closefriendorrelative

    Onlygivethetreatmentwhenitistomaintaintheirhealth

    Emergenciesnecessityonitsownwrongnecessarytoavoidworseoutcome
    Candoemergencieswithoutconsent
    Nonemergenciescannotfindpersonofconsent
    Minortreatmentscanbeprovidediftreatmentisnecessaryifitisimportantformaintaininghealthandwellbeing

    1.Isthereanadvanceddirective
    2.Hasacourt/guardianshipauthoritymadeorders
    3.Hastheptientcreatedanenduringguardianship
    4.Istheresomeoneresponsible
    5.Isthetreatmentinthepatientsbestinterestandnecessarytosavelifeorpreentinjuryordamage
    6.IsthetreatmentcoveredbyGuardianshipact1987s37
    Lecture5.2.5Osteomyelitisandsepticarthritis
    Infectionofboneandjoints

    infectionofthebone,usuallycausedbypyogenicbacteriaormycobacteria
    Usuallysubclassified
    Causativeorganism,theroute(haematogenous,contiguous),duration(acutetreatedwithantibiotics/excision,
    subacute,chronic),Anatomicallocation

    Haematogenouslongboneosteomyelitis,osteomyelitisassociatedwithopenfractures,vertebralosteomyelitis,
    osteomyelitisassociatedwithdiabetes
    Posttraumatic,vascularinsufficient,haematogenousseeding
    Common(>50%)staphylococcusaureus,coagulasenegativestaphylococci(relatedtoprosthetics)
    Ocassionallyencounteredstreptococci,enterococci,(gramnegative),rarelyanaerobes
    RarelyencounteredTB,nonTBmycobacteria,brucella,salmonella
    Osteomyelitisboneresistanttobacterialcolonizationhoweverdisruptionofboneintegritycanintroduce
    infection,neutrophilmigrationleadstoinflammationandoedema
    Symptomsfever,chills,fatigue,inflammationdetailedhistory

    Investigationsinhospital
    ESR,andCRPusuallyelevatedCRPisnowbetter,lessfalsepositiveandfaster
    IncreaseWCCbutoftennormalinchronicosteomyelitis
    Bloodculturesimportanttoguidediagnosisnotpositivefrequentlyinlocalizedinfection(unlesshaematogenous)
    BonebiopsyconsiderwheneverpossibleinelderlycouldbeUTIgramnegative
    Localswabsfromsuperficialwoundsandsinustractoftendoneoftenmisleading

    PlainXrayhelpfulfirststepifchronicity,periostealelevation,boneirregularity,osteolysis
    Nuclearimagingtechnetium99mbonescan,highsensitivity,butlesserspecificity
    CTscanrevealarticularsurface,bonechanges,morespecific,assesssofttissue

    CTscanimageshowschewing,marginationwithmanyfragments,psoasmuscleisswollen
    Nextimagewholevertebralcomponenthasbeenfragmentedwilltakelotsofhealing
    MRIpusgeneratedustgosomewherebloodstream(leastresistance,throughtoskin)

    MRI
    Detectsbonemarrowabnormalities
    Highestsensitivity
    Changespresentearlier
    TypicallydecreasesignalonT1weightedimagesandincreasedsignalonT2weighted

    MRIimageuptakeinpericlavicularpus

    Hematogenousosteomyelitismostcommonlycausedbystaph
    Alsocausedbybetahaemolyticstrept
    Enterobacteriacaemorecommoninelderlyorimmunecompromised
    Riskfactorsintravascularsource,immunocompromised,oldage(UTI)
    ininfants,childrenusuallyinvolvesmetaphysisprimaryinfectionmorecommon
    Inadultsthevertebraemostcommonlocation
    Haematogenouslongboneosteomyelitismostcommoninchildren,usuallytibiaorfemur

    Vertebralosteomyelitis
    Elderly,IVDUseedingfromIVdevices,endocarditisorUTI
    Ofteninsidious,abruptonsetofseverefocal,localizedbackpainradiationunrelievedbyanalgesics
    Neurologicaldeficitssecondarytovertebralbodycollapseorepiduralabcess
    Treatedwithprolongedantibioticsmayrequiresurgicalexcisionmicrobiologyiscrucial
    ConsiderTBespeciallyifsymptoms

    Mayfollowspinalsurgeryorepiduralcatheter

    Osteomyelitisimagediscitishasthecausedvertebralbodiestocollapse

    Osteomyelitisisassociatedwithopenfracturesimportantinmotorvehicleaccident
    Usuallylowerlimborganismsmaybeenvironmentalorcommensalflora
    Leadstoinfectednonunion,oftenwithsurgicallyimplanteddevicessuchasscrews,plates,bonegrafts
    Vascularinsufficiencyindiabetesorpatientswithperipheralvasculardiseasepoorvascularsupply
    Inadequatelocaltissueresponsetoinfection=poorhealingcapacity.
    Minortraumaleadstoulcersthatspreadtobone
    Baselineperipheralneuropathydelayedrecognitionofulcers,cellulitis,softtissueinfection
    Typicallypolymicrobialstpah,strep,enterococci
    Diabeticfootosteomyelitismanagement
    Earlyaggressiveandfrequentdebridementmanagementofpressureareas
    Deepcultures,IVantibioticsfor24weeks,healingwillnotoccurunlessgoodvascularsupply(fempopbypass)
    Chronicosteomyelitisoftenatendsofthelongbones
    Persistentinfectionrefractorytoantimicrobialtherapy
    Changesofacuteosteomyelitisbonesclerosisanddeformity
    Chronicinflammationleadingtofibrosis,vascularthrombosisandnecrosisofbone
    OftennoconstitutionalsymptomsorleucocytosishoweverCRPelevated
    Antibioticssurgicalexcisionmaybenecessaryandmayleadtoamputation
    TBosteomyelitis
    90%spinal(pottsdisease)othersitesuncommonbutseeninfeet,clavicle
    Chronic,lowgrade,deforming,TBtherapyhighlyeffective
    Septicarthritis20%havenoidentifiablepredisposingrisk
    Bacterialarthritisdestructionandlossoffunctionifuntreated
    Viraloftenmultiplejoints,generallydoesnotleadtolongtermmorbidity
    TB/fungiusuallyascrhonic,lookforsystemicorlocalinfectionatremotesites
    DDreactivearthritis,gout
    Bacterialarthritisusuallyhaematogenousendocarditis,meningococcus
    Synovialmembranevascularitybacterialdeposition
    Otherroutesofinfectiondirectioninoculation,percutaneous,contiguousspread
    Bacteremiawillseedoftenpreferentiallytoprostheses
    Septicarthritispresentingsymptomsonly50%havefever
    Arthritis,pain,lossoffunctionover12weeks,decreasedrangeofmotion,inflammation,focalpain,
    O/Efocaljointtenderness,inflammationandeffusion,active/passivemotion

    Microbiologystreptococci,staphpaeruginosa
    Bacteriallyme,tb
    ViralarthritisHIVcanbeinvolved(importanttoremember)

    Staphaureusmultifocalthinkendocarditis
    N.gonorrhoeaedisseminatedin053%ofmucosalgonotwosyndromes
    1.Arthritismono/oligoarthritis
    2.Tenosynovitis,dermatitisandmigratorypolyarthralgia

    Septicarthritisdiagnosis
    WCC,culture,bloodcultures,specificPCRs,serology

    Imagefemur(totallydestroyed)movedaside
    TBswellingandeffusionsinus(pouringpus)coldabcess
    Treatmentwashoutaidstreatmentandantibioticdiffusionintojoint
    Adults46weekstherapy(IVandoral),ChildrenlittleIVneeded(oralisenough)

    Successofjointreplacementdependsonwhethertissuecellsorbacteriawinracetosurface
    1/3occurinfirst3monthsafterprosthesis
    1/3occurinfirstyear

    10yearsasepticlooseningdifferentiationfrominfection/looseningrequired

    Biofilmneedstoberemovedsoitcanbetreated

    Classificationofprosthesisrelatedinfections
    stage1earlypostop(24weeks0acutestaph,coagnegstaph
    stage2chronic(124months)insidiousonset,persistentpanCoNS,pacnes,anaerobess.aureus
    stage3haematogenous(>2years)acutefever,inflammationstrept,staph,GNBs

    Intervention/surgery
    Determinedbypresentation,durationofinfection,typeofinfection,conditionofbone/softtissue,organism
    virulence,antibioticsusceptibilitypatientsagemorbidities

    Treatment
    1.Debridementwithretention
    2.Removalofimplant1stageexchange
    3.Removalofimplant2stageexchange
    4.Removalofimplantnoreimplantion(girdlestonehip,kneearthrodesis)

    Lecture5.5.1Uricacidandmedications
    EtiologyofGoutcrystallizationofuricacidinjoints(monosodiumurate)
    Crystalsinducelocalinflammation
    Neutrophilinvasionandphagocytosisofcrystals
    Tissuedamagefromreleaseofenzymesandoxygenradicals

    StructuresofuricacidandurateKetoandenolform
    Enolformformsurate

    Uricacidisderivedfrombreakdownofpurinenucleosidesandnucleotides(e.g.adenosineandATP)
    Serumurate(0.250.42)inwomen(0.180.38)differencesarelikelyduetogeneticdifferences
    Crystallizationisclosetoserumlevel
    UricacidactsascavengerofROSantioxidant
    Uricacidmaybeimportantinprotectingtissues

    Eliminationofuricacidrenalsecretion,filtered,secretedandreabsorbed

    Uricaciddependsonpurinesynthesis,breakdown,intakeandexcretionrates
    Therearesalvagepathwaysthatrescuepurinebasesbacktonucleotides
    Salvagepathwaysareimportantinlimitingurate

    controlofdenovopurinenucleotidesynthesisPRPPpositivefeedforwardeffect

    Salvagepathwaysdivertpurinebasesfromuricacidsynthesis
    Adeninephosphoribosyltransferase(APRT):Adenine+PRPPAMP+PPi
    HypoxanthineGuaninePhosphoribosyltransferase(HGPRT)=blockingleadsxanthinetouric
    Rolesofsalvagepathwayenzymesminimizeuricacidproduction,recoverpurinebasesforuseaspurine
    nucleotidesneededforneurotransmittersinbraine.g.dopamine

    LechNyhansyndromexlinked(deficiencyofsalvagepathwayenzyme)
    CNSeffectsofsyndromementalretardation

    thereisalink
    EthanolincreaseacetatelevelsAmpIMPuricacid

    Clinicaleffectsofhyperuricemia
    Acuteattacksofgoutyarthritis,tophi,renalcalculi

    Chemicalcontextsinwhichuricacidloweringtherapyisdesirable
    Preventacuteattacks(uricacid<0.36mmol),eliminatetophi,reversehyperuricemiainIHD

    TreatingacutegoutNSAIDS,Cox2,colchicinesupressesacuteinflammation
    Loweringserumuricacidlevelsdoesnothelpduringacutegout

    Managementofgoutaimistopreventattacksortreattophi
    Lowerserumuricacidlevels,blockuricacidsynthesis,converttoallantoin,promoteurinaryexecretion

    Xanthineoxidaseifthisisblockeduricacidsynthesisisblocked
    Xanthineoxidasecanbeblockedbyallopurinolhypoxanthineanalog
    AllopurinalisconvertedtoalloxanthinebyXanthineoxidasealloxanthineremainsboundtoactivesitexanthine
    undergoessuicideinhibition

    Xanthineoxidaseinhibitorfebuxostat

    Alternativeapproachestoloweringuricacidlevels
    1.Uricosuricspromoterenalexcretionbyblockingreabsorptione.g.probenicidgreaterriskofrenaldeposition
    2.Uricasehumanslackuricase,uricaseconvertsuricacidtoallantoin,highlyeffectiveinmobilizinguricacidfrom
    tophi,alsoeffectiveincontrollinguricacidlevels

    Goutcrystalarthropathyduetoelevatedserumuricacidlevels
    Uricacidlevelsincreaseifhighdiertaryintakeofpurines,denovosynthesisactive,purinebreakdownaccelerates,
    salvagepathwaysofpurinenucleotideslow

    Lecture5.5.2Meettheexpertosteoarthritis
    Maincellularconstituentofcartilageischondrocyteswhichisformationofcollagenandproteoglycans
    Majorcomponentofproteoglycansisaggrecanhydrophilicprovidessomefunctionofcartilage
    Cartilageismademostlyofaggrecanandtype2collagencanholdalotofwater

    Collagenisameshthatholdsaggrecan+waterthisallowscompressiveforcetooccur
    Meshofcollagenallowsdistortionbutifcollagenisdisruptedwatercanbeattractedtoproteogyclansandswell

    Paracetamolisnotsafeifusedabout3.5g/day
    Acetaminophenisusedasanadjunct,canbetoxic
    NSAIDSaremoreefficaciousthanparacetamol

    NSAIDshavedifferenttoxicityprofilesbasedonCox1orCox2selectivity
    Injuryphospholipidsarachidonicacidsleukotrienesandprostaglandins
    Cox1(constitutional)cytoprotectivePG
    Cox2(inducible)inflammatoryPG

    Cox2haveeffectsonbloodvesselsusefulingastricandcardiovascular
    DifferentantiinflammatorieshaveCOX2specificitiesavoidsideeffects
    Morecox2specificlessgastricsideeffects
    ShouldscreenpatientsforGIT/cardioproblems

    CommonadverseeffectsofNSAIDS
    Plateletdysfunction,gastritisandpepticulcerationwithbleeding

    NSAIDsisahugeriskfactorformorbidity
    GIcomplicationsarecomingwithcorrectprescription
    Cox2highercauseofcardiovasculardeath

    Arthroscopiesshouldonlybeperformedonpeopleunder35(becausemeniscusstillvascularised)

    Lecture5.5.4Nervestructureandconduction
    Nervefibres/axonslongthinprojectionsformneuroncellbody
    Nerveimpulses/actionpotentials/spikes:briefdepolarisationoftherestingmembranepotential

    65mVisnormalstateofapolarizedneuronActionpotentialcausesthistobecome+ve
    RestingmembranepotentialVm

    Twoopposingconcentrationgradientspowerthenervepotential
    Chemicalgradientofsodiumcausesittorushintothecellwheneverithastheopportunity

    Thereissteadydiffusionofpotassiumacrossthecellatrest(K+leakagechannelsallowingsomeK+todiffuseout)
    Ifpotassiumalonewasdiffusingeventuallyelectricaldrivingforcethatitgenerateswouldcanceloutitsoutward
    chemicaldrivingforcenernstpotentialforK+

    Sodiumionsalsoinfluencetherestingmembranepotential
    Na+hasaninwardchemicaldrivingforce,Na+leakagechannels
    Nernstpotentialforhealthyneurons
    NPforK+is75mV
    NPforNa+is55mV
    NernstpotentialforClis60mV

    k+leakagechannelshave20xhigherpermeabilitybutweakerdrivingforc
    Na+haslowerpermeabilitybutstrongdrivingforce
    Smallriseinmembranepotentialtoathresholdtriggershodgkinscycle
    Voltagegatedsodiumchannels3states(closed,activated,inactivated(refractoryperiod))
    PropagationofAPcontinuouspropagation,salutatorypropagation

    Immatureneuronscontinuouspropagationcontinuousspreading(worksinsmallanimals)
    Fasterpropagationrequiredinlargeranimals
    Slowcontinuouspropagationisunmyleinated

    Myelinsheathcanpropagatemuchfaster(100m/secvs1m/sec)
    Nodesofranvierallowsignaltobeboostedalongtheway
    Internodepassivelyconductselectricalsignal

    Demyelinationcanbetestedslowpropagation

    Nerveinjuryischaemic,compressioncut,widespread/systemic(e.gdemyelinationdisease)
    Concentrationgradientofsodium/potassiumacrossthemembranearemaintainedbyna/K+ATPase

    Na/K+pumpworkstomaintainconcentrationgradientsdamageleadstoslowdepolarization
    Physical/ischaemicdamagesidneysunderlandgrades

    Axonmembranedamagedaxonwillbeeatenawaydestroyedlikeapoptosisregenerationislikely
    (1mm/day)
    Ifendoneuriumisalsodamagedhardertorepair

    1
    st
    gradetemporaryblockofpropagationwithoutaxondamagee.g.compressionofbloodvessels
    2
    nd
    gradeaxonseverancebutendo/peri/epineuriumundamaged
    3
    rd
    5
    th
    degreeaxonseverancewithdamage

    Lecture5.4.5Lowerlimbdevelopment
    Mostcommoncongenitalabnormalitiesarelimbdefects
    Asthelimbformsitformsabagofmesodermthisissurroundedbyexternaljacket
    Therearelimbbudsthatformatcertainlocations

    Specifichoxgenesdeterminethelocationoflimbsthisissameinalotofanimals
    Addinghoxgenescancauseextrawingstogrowondrosophila
    Usinganimalmodelswecandeterminehelocationoflimbs

    Removetheectodermalridgeearlyonlygetproximalstructures
    FGF8isimportantandneedstobeexpressedontheectodermalridge
    Anteriorposterioraxisknockoutindividualgenesandseewhathappens
    Zoneofpolarizingactivitycausesgradientofactivity
    Lmx1
    wnt7akopalmsreversed
    TBX5forelimb
    TBX4hindlimb.
    PiTX1hindlimb
    Usinganimalmodelstostudyprocesses

    Digitsformbyprogrammedcelldeath
    By8weeksdigitforms
    Programmedcelldeathsculptsthelimb
    Migrationfromotherpartsofthebodyintothelimbprovidesnervesandbloodvessels
    Bonesareoriginalcartilaginouseventuallycalcify
    Bonesaregraduallyformandthelongbonesformtheshaftanglesandby12weekshaveossificationcentres
    Growthplatesallowbonestolengthenduringgrowth

    Firstbloodvesselsforbyvasculogenesisparticularbranchesareselectedtoforthemajorvessels
    INtiiallywehavefinecapillarynetwork
    Angiogenesisissproutingvesselsaslimbgrowthesevesselsfor.
    nervesmigrateintothelimbsoccursduringthefifthweektheymigrateintothemesenchymeofthelimb
    Youwouldhaveseethatpartofthedermatomeisirregularinthelimbsparticularlythehindlimbs
    Upperlimbsrotatelaterally90degreeslowerlimbsrotatemedially180

    Mechanismsoflibformation
    migrationofmuscleprecursors
    lbx1directsmigrationofmuscleprecursorcells

    IFweknockoutlbx1limbsformbutmusclesareformed
    Limbanomaliesmajoranomalies2per1000newborns

    Causeoflimbanomaliesvasculardisruption,drugs,environmental
    Whenbabygetslargerlessroomformovementimpairedmovementcausesvariousabnormalities

    Congenitalhipdysplasia
    Lecture5.5.6Radiationsafetyinmedicalapplications
    Largestcontributortoradiationexposureofthepopulationmedicalradiation
    CThasa1in1000chanceofcausingcancer

    Radiationionizingandnonionizing
    Ionizinginvivodiagnosisandtherapyradiology,nuclearmed,radiotherapy,dental
    Invitroradiolabellingtechniques,bloodirradiation
    NonionizingMRI,ultravioletlight,lasers,radiofrequency(TUNA)

    Longtermrisk,riskofradiationeffects
    Radiotherapydeepxrayunit

    Radiotherapyprecisepositioning,accuratedosimetrypotentialforaccidents(overdose)
    Highdoseratebrachytherapyunithotradiationobjectlowereddownintoorificeoftenforlunguncontrolled
    radiation

    NuclearmedicineSPECTemissionimagesliceslikeCTGives3dimensionalimage
    PET/CTpositronemissiontomographydose

    RadiationdoseunitsSievert
    Acutelethaldose5/7sv
    Annualbackground2.3mSV

    CTisbecomingthelargestsinglecontributorofradiation
    Damagedonebyradiationphysical,physicochemical,chemical,biological
    Stochasticeffectsprobabilityofeffectincreaseswithdose

    Controllingradiationthedose,useshieldingforstaff,distance(inversesquarelaw)
    Staffwhoworkregularlywithradiationrequirepersonalmonitoringhospitalstaffuse20%ofinternational
    limits
    Thisequatestotwicenaturalbackgroundradiationlevels
    Indicatedmedicalresearchexcludedfromdoselimitsresearchisseparateprocess
    Regulaoryobligationsfordoctor
    RegulatorybodyinNSWisEPA
    nonradiologistswantingtousefluoroscopymusthavealicenselicenseisalsoneededforresearch

    Donotoveruseradiation
    ICUpatientsshouldnothavemorethan2CXRadayor>10CTs
    Justificationandoptimisation(onlyusewhenneeded)
    Lecture6.2.1Radiologyvertebralcolumn
    Overlappingprojectionofeverythingbetweenxraytubeandfilm
    4distinguishabletissueattenuations
    Air,fat,water/softtissue,calcium/bone,metallicforeignmaterial
    Cannotdistinguishbetweendifferenttissuesinthekidneyforexample,becauseallofsametypesofttissue
    Radiographcanbeusedbyitselforwithacontrastmedium

    Contrastmedia
    Negativeagentsair,carbondioxide(absorbedmorequickly)
    Positiveagentsiodinecontainingwatersolublemedia,barium,oilmedia(myodilusedforspinalroots40years
    ago)

    Invertebralcolumn
    Xraywithcontrastmediumcanbemyelogram(theca)anddiscogram(indisc)
    Radioactivetracerisbonescintigramorisotypebonescan
    OthertypesofimagingareMRI,CT,spinexray

    XrayCTwillshowubonebutalsoshowusofttissuecanshownerverootsandthecalsack
    CTmyelogramcanshowspinalrootsallowscontrastbetweenspinalcordandCSF
    MRIbonesaredark(tissueswithoutwaterwillnotshownup)
    MRIt1andt2weightingcanmakewaterwhiteorblack
    t1fluidisblack,t2fluidiswhite
    Corticolboneisblackvertebralbonehaslotsoffat(thatswhyitswhite)
    BonescintigramWhenboneisabnormalrepairhappensosteoblastsincreasethiswillshowupinbonescan

    Anatomy
    Bonejointanatomy
    Discanatomy,neuralanatomycanseeduralspaces,courseofroots,lowerspinalcord

    Nervecompressionsiteofcompressionintramedullaryorextramedularlly,extradural,outsidespinalcanal
    Somepeoplearebornwithspinalstenosiswheretheresnoroomfornerve

    Sourceofbackpain
    Discdegeneration(inyoung),spondylosisdeformans(theold),alteredalignment(spondylolisthesis,scoliosis,
    kyphosis)Primarybonepathologyfracture,inflammation,tumour

    Diagnosticsieve
    Congenital,Traumatic,inflammatory,neoplastic,metabolic,degenerative,vascular,psychogenic
    Findthingsthatwhenweimagearenotthecauseofthepain
    Imagingguidedneedlesforpain
    Medialbranch,sacroiliacjointanaesthesia,discstimulationbyinjection
    Therapeuticinjectionse.g.epidural
    Middleagefindingsimportantbutnoteasyotsee
    Imagingiswarrantedifsuspicionofbonepathology,historyofcancer,highESRalsoifthereisnervecompression
    orsuspicionofsuspicionofspinalcordcompressionandacutetrauma
    Lecture6.2.2Synaptictransmissionandneuromuscularjunction
    Compoundnerveactionpotentialstimulationandrecordingelectrodes
    InformationfromCNAPrecordingsrateofAPpropagationmayindicatedamage
    ChangesinshapeofCNAPmayrevealalteredproportionsofdifferentclassesofnervefibres

    compoundsmuscleactionpotentialplacerecordingelectrodesontopofmuscle
    RepetitivestimulationmayrevealfatiguingCMAP

    Voltagegatedsodiumchannelsinmuscleissimilartonerve
    APdepolarizesnerveterminalvoltagegatedCA2+openthistirggersAchAchdiffusesacrosssynapticcleft
    andbindsNaCHrAchcontainsacationchanneldepolarizationopensvoltagegatedsodiumchannels

    WEcanreliablytriggeramusclepotentialmostofthetime
    Minatureendplatepotential(MEPP)smallamplitude,spontaneouspostsynapticevents

    InlowcalciumsmallamplitudeEPPeventswerequantized
    AmplitudesofsubthresholdEPPsfellintoquantitiesof0.4

    Achisreleasedfromnerveterminalsinquantalamounts
    MEPPrepresentararerandomexocytosisofAch
    EPPhaslargeamplitude(70mV)producedbysimultaneouslyreleaseofmanyquantathisiscoordinatedbyinflux
    ofcalciumintonerveterminaldependsonvoltagegatedchannelsinnerveterminalandhighextracellularCa2+

    Lamberteatonmyasthenicsyndromeantibodiesattackvoltagegatedcalciumchannels
    ReducedcalciuminfluxfewerquantaofAchreleasedsmallerEPPfailuretoreachthreshold
    HOWEVEReveninnormaltissues,fatiguehappenswcwnruLLY

    EPPneedstoreachthresholdtogenerateAP
    1mVisthemostcommonvalueyougetinMG,mostcommonwas0.2mV

    INcontrolpatientsCMAPsameeverytime
    Indiseasewithautoantibodiesthereisadecrementalresponse

    Eveninhealthymusclesthenumberofquantareleasedeclinesinresponsetosuccessivenerveactionpotentials
    EPP=quantalamplitudexnumberofquantareleased(declinesnaturallyduringtetanicactivation)

    Myastheniagravisimmunosuppressantdrugs,thymectomy,plasmaexchange
    Anticholinesterase(neostigmine)inhibitcholinesterasesenhanceEPP
    Lecture6.2.3Introductiontonuclearmedicine
    Radiopharmaceuticals/tracers
    Radioactiveisotypeshowswhereitisinbody,pharmaceuticaldeterminesbiodistrubitioninbody
    tcMDPisusedforbonescans

    Gammacameraheadcollimatorchannelsgammaraysthenhitcrystalswhichscintillatesensorisdetectedand
    multipliedtoproduceimage

    Planarimaging2Dimage
    SPECTgivesa3Dimage,similartoXrayvsCT

    SPECT/CThybridsymptomsarenowavailable

    FusionimagingusesverylowdosesforCTallowsanatomicallocationsothattc99mcanbeoverlaid
    Traceruptakeonbonescanreflectsosteoblasticactivity

    Normalbonescanuptakereflectsbonymetabolismosteoblasticactivity

    Bonescanoccursin3phases
    Bloodflow60secondscancapturebloodflowtoareas
    Bloodpool15minutesshowstissuevascularityrelevantininfection,trauma,inflammation
    Delayed24hoursbonymetabolism

    Bonescansarehighlysensitivityalmostallpathologicalprocessesinboneareassociatedwithalteredbonemetab
    Functionalchangesoccurearlierthanstructural(xray/ct)
    Bonescansarehighlysensitive
    Specifictycomesfromlocationandappearanceofabnormality,clinicalsetting
    Correlationwithradiologicalapperances,SPECT/CT

    Imagingisusedinavarietyofdiseases,injuries,prostheticcomplications

    ScaphoidfracturecanberadiologicallyinvisibleIncreaseuptakeatscaphoidcanshowfracture
    Pelvicfracturecanbeveryeasilyseeninabonescan

    Talardomefractureisimportantorcanleadtoarthritisofteninvisibleinradiography

    Bonescansincontextofcancer
    Staginginvestigationformetastaticbonedisease,assessingmetastasisandcandiscovermetastasis

    Bonemetastasesradiologicallyosteoclasts/blastscanbeactivated
    Thyroidandprostatecancerscancauseopposingactivation
    Osteoblastic/lyticmetastasisimportantinbreast,prostate,lung
    Osteolyticmetastasisdominatebonescanlesssensitivethyroid,renal,myeloma
    3050%ofpatientswithsecondarieshavenoknownpain
    BonescanisabnormalearlierthanCT

    Widespreadmetastaticdepositsareveryobvious

    Multiplepathologiescanbespottedinabonescan
    DeQuervainstenosynovitis

    Complexregionalpainsyndromesympatheticsupplytohandcancauseincreasedvascularity

    Galliumscan67scan
    Halflifeis6daysanalogueofferriciron
    inflammatorycellsarepackedwithlactoferrinimagingover24,48,57days

    Galliumtakenupinliverandspleen,alsotakenupbyglands
    Galliumscanshowsdiffusearoundareasofinflammationshowingthatitisinfection,whennormalBSisntclear
    LabelledWBCscraqns
    Leukocytesmigratetoareasofinfection,bloodsamplewithdrawn
    WBCsseparatedandradiolabelledwithTc99m
    Requireshighstandardofasepticconditions
    Betterforacuteoverchronicosteomyelitisandgoodforassessingperipheral

    Osteomyelitisbonescan
    osteomyelitismightusebonescanandWBCscan
    IninfectionmightaddagalliumorlabelledWBContopofbonescan
    InspineMRI,(canusegalliumbutdontuseWBC)
    WithprosthesesCTmightnotbegood

    Lecture6.5.3Nonsteroidalantiinflammatorydrugs(NSAIDS)
    Aspirin,naproxenibuprofen
    Cox2selectivecelecoxib,lumiracoxib,meloxicam

    NSAIDSaredifferentfromCORTICOsTEROIDS
    ProstaglandinsE2+histaminelostofexudation
    NSAIDSinhibitcycloxygenaseinhibitssynthesisofprostaglandins(PGs)reducespotentiatingactionsofPGs
    COXingastricmucosacytoprotectionthereforecanleadtoGITulcers

    ArachidonicacidCoxprostanoidsrenal/plateletfunction,protectgastroduodenalucosa,mediate
    inflammation,painandfever

    NSAIDSpharmacologicallyantinflammatory,antipyretic,analgesic,antiplatelet
    NSAIDSmayhaveeffectonchemotaxisandoxygenfreeradicals

    PharmacokineticsofnsAIDSgoodoralabsorption,95%albuminbound(smallvd),formmostlyinactivemetabolites
    NSAIDSthereisvariationbetweenpatients

    TypicalNSAIDsideeffects
    GITdyspepsia(Discomfort),ulceration,gastritis(redness)
    Plateletfunctionreduceaggregation (notimportantgenerally)
    Renalimpairmentdecreaseinsodium/waterexcretion(CFheartfailure)
    Respiratoryaggravateasthmainaspirinsensitiveasthmatics

    Cox1constitutive,producesprostanoidsimportantingastricmucosa,kidney,platelets
    Cox2inducedatsitesofinflammationmediatespain,fever,inflammation

    Cox2celecoxib,parecoxib(IVformulationprodrug),meloxicam,rofecoxib(vioxx),lumiracoxib(prexige)

    ConventionalNSAIDSequallyactiveoncox1andcox2
    Meloxicambitofactivityoncox2andcox1
    Rofecoxib(vioxx)cox2selective
    Inhibitingcox1increasedmucosalulceration
    COXinplateletscontaincox1andnotcox2ThromboxnaeA2isimportantinducesaggregationyoullbleed

    Celecoxib,rofecoxibhadincreasedCVrisk

    parecoxib
    LowdoseasprinwillinhibitcoxinhibitplateletaggregationbeneficialcanbeCVDandCerebralVD

    Physiologicalactivity
    EndotheliumPGI2vasodilator,inhibitsplateletaggregation
    PalateletscoxTxA2proaggregatory
    Thereisabalancebetweenendotheliumandplatelets
    LowdoseaspirininhibitsTXA2inhibitsproaggregation
    Highdoseinhibitsbothendotheliumandplateletthereisnobenefitofdoingthissinceantiaggisalsoinhibited.

    Atheromatousplaquecox2involvedcanleadtoplaqueocclusion
    Cox2isinducedneededtosytnhesizePGI2(thusincreased)PGI2isprotectiveagainstthrombosis,cox2
    selectivedrugsinhibitPGI2synthesis(henceheartattacks)
    LongtermRxincreasesriskofCVandthromboticadverseeffectslongtermdosageshouldnotexceed200mg/day

    Lecture6.5.4Autoimmuneserologyformedicalstudents

    Autoantibodiestestforpathogenicornottransplacentaltransferofdisease

    Systemiclupuserythamatosus(SLE)Breakdownintoleranceandmultipleautoantibodiesarthritis,serositis,
    haemolyticanaemia,glomerulonephritis,skidisease,CNSdisease
    Sjogrenssyndromediseasemostlydirectedatexocrineglandssicca,drymucosa,mostly>40swomencan
    beprimaryorsecondarytootherimmunediseases
    Mixedconnectivetissuediseasewaxylikechangestofingers,sicca,arthralgias
    SclerodermasystemicautoimmunediseasecharacterisedbyfibrosesandvascularalterationsDividedinto
    CRESTandgeneralised(whichincludesrenal,vascularandgangreneinvolvement)
    Schirmerstest<5mmbotheyescanindicatesicca

    Antinuclearantibodies(ANA)antibodiesdirectedatcellnuclei
    Screeningtestforantibodiesagainstmultiplecomponentsofthecellmarkersforimmunedysfunction
    SerumdiluteduntiltestbecomesnegativeLowtitres1:40/1:160commoninpopulationusuallynothing

    ANAindirectimmunofluorescence
    Thehigherthetirethemorelikelytobesignificant
    ANApatternlikelyautoantigenictargets

    ENAantibodiestoextractablenuclearantigensinitiallydefinedbybreakingupnuclei,extractingtheproteinsand
    detectingprecipitatingantibodies

    Antigenspecificitydeterminedbyidentitywithreferenceantisera
    ELISAandLIAareusednow

    dsdNAantibodiesaddantibodiestodsDNAthathavebeenconjugatedwithradioactivityprecipitatecomplexes
    withammoniumsulphatecountradioactivity

    Inmayautoimmunediseasesyouonlygetafewautoantibodies
    butfeatureofSLEisautoantibodiesagainstmanytissues
    AlotofANAnegativepeoplestillhaveautoimmunediseases
    ENAscreenisimportantpositivityfromascreen+LIAisalikelydiagnosis
    dsDNAtestisimportantinbackingupdiagnosis

    Granulomatosiswithpolyangiitisformerelyknownaswegenersgranulomatosis
    systemicgranulomatousvasculitis
    Affectsrespiratorytract(limited)upper,lug
    Kidneyrapidlyprogressive

    ANCAtest+vevasculitisincldeswegeners,churgstrausssyndrome,microsclopicpolyangiitis
    cANCAPR3granulomatosiswithpolyangiitis
    PANCAMPOChurgstrausssyndrome
    GoodpasturesantiGBMdiseaserareconditiondetectablewithdirectimmunofluorescence
    SerologicaltestingforcoeliacsdiseaseGliadinEMA/TTG
    TTGIGA

    Rhematoidarthritisantibodiestocycliccitrullinatedpeptides(antiCCP)highlyspecificforRA(muchbetterthan
    RF)predictsmoreerosivediseasepartofdiagnosticcriteria

    Antiphospholipidsyndromeprocoagulatnmanifestedbythrombosissecondarytolupus
    Antibodiestophospholipidsanticardiolipin

    Lecture6.5.5Part2
    Methodsinusehavearangeofspecificityandsensitivitymosttestsarenowautomated

    PVVproportionwithpositivetestwhohavedisease
    NPVproportionwithnegativewhodonothavedisease
    Lecture7.2.1Antiinflammatorydrugs
    Paracetamol(analgesic)notantiinflammatorybutusedinmildarthritis
    NSAIDScox1and2antiinflammatorytreatment
    Diseasemodifyingantirheumaticdrugs(DMARDs)methotrexate,leflunomide
    Antiinflammatorycorticosteroidshydrocortisone

    Antiinflammatorycorticosteroids
    Manyclinicalindications,usedininflammatorydisorders,asthma,skindiseases
    Cancauseimmunosuppressionusefulinorgantransplantation

    Majorgroupsofcorticosteroidstwomajorgroups
    Mineralcorticoidsfludrocortisone(analogofaldosterone)usefulforsodiumconservation
    GlucocorticosteroidsPrednisone(analogofcortisol)glucose,proteinandfatmetabolism

    Prednisolonesomemineralcorticoidbutispredominantlyglucocorticoid
    Dexamethasonenomineralcorticoidactivity

    GlucocorticoidsentercellbindtoGRi(whichisflankedbyHSP90s)glucocorticoidthendiffusesintocellandgoes
    tonucleustobindtoglucocorticoidresponseelement(GRE)
    CortisolbindingglobulinGCSisboundtoitdiffusesintocellandthenontoGREcausing
    transcription/translation

    Transactivationsynthesisofantiinflammatoryproteins
    Transrepressionswitchoffmanyinflammatorygenes
    PostgenomiceffectsdestabilizesproinflammatorymRNA
    ActivationofHDAcswindingofDNA(noreadingofinflammatorygenes)

    Transactivation
    Antiinflammatoryproteinsannexin1(lipocortin)inhibitingPA2,Secretoryleukoproteaseinhibitor(SLPI)
    Phospholipidsphospholipase(annexininhibitsthis)

    ChromatinDNA+basicproteins
    InrestingcellsDNAtightlywoundacetylationofhistonesunwindsthisproinflammatoryhaveintrinsicHAT
    activity

    TransrepressionproinflammatorytranscriptionfactorssuchasNFkBhaveintrinsicHAT
    GRssupressHATactivitydoesntorequireGRtobindtoGRE
    Steroidreceptorcomplexinteractswiththispathwayandtransactivation

    Postgenomiceffects
    mRNAissusceptibletodegradationbyribonuncleases,mRNAisstabilizedbyproteins,proteininhibitedbyCS

    ActivationofHDAC
    AcetylationofhistonesunwindingofDNA
    HDACSdeacetylateacetylatedhistoneswindingofDNA,genesilencing

    Sideeffects
    GRsbindtonegativeGREsosteocalcinproducedbyosteoblasts
    Antiinflammatoryeffectsinhibitbothearly(redness,heatpain)andlatemanifestationofinflammation(wound
    repair)

    Pharmacokineticsplasmaandbiologicalhalflifes(biologicalislonger)cortisol(1.5plasma),prednisone(3.3),
    dexamethasone(5hours).preferabletouseprednisoneotherwisebuidlupwhenusingdexa

    Lowdosephysiological(7mgprednisone)
    Intermediatedose(1520mg)antiinflammatory
    Highdose(50100mg)immunosupressent

    Prednisoneaprodrugundergoesreductionfromketonetohydroxyl
    Prdednisolonegetsmetabolisedinlivertoprednisolone

    CSsideeffects
    Relatedtodoseandduration
    Shorttermcoupleofweeksveryfewshorttermeffects
    Highdosesweightgain,moodchanges,increasedbloodglucose,hypokalaemia,transitoryHPAaxissuppression
    howeverreversibleoncessation

    Longtermsideeffects
    Mineralcorticoidsodiumretention,oedema,weightgain
    Glucocorticoid:
    Osteoporosisproteincatabolism,calciumlossandlessabsorption,suppresspituitarygonadalaxis(dueto
    decreassinsexhormones)
    Increasedbloodglucose
    Musclewastingandthinskin(proteincatabolism)
    Infectionviral(CMV,herpes),fungal(candida),tuberculosisthesearemostlyopportunistic
    ToavoidReducedoseslowlyafterlongtermtreatment

    HPAaxishypothalamusCRFACTHadrenalglandssecretecortisolnegativefeedback
    Cushingssyndromedevelopsimilarsymptomsasthoseoncorticosteroids
    Recombinantproteinsasdrugs
    TNFainducesproinflammatorycytokines
    Increasesadhesionmoleculesonendothelialcells,activatesneutrophils,increasesconcentrationsinRA
    TNFainfliximabisantibodyagainstTNFaneutralizesTNFa
    UsedinRAandcrohnsdisease
    Givenasinjections(IVorsubcutaneous)

    ToclizumabmABagainstIL6RAnotrespondingtoothertreatments(DMARDsandantiTNFa)
    RituximabagainstCD20onBcellsusedwhenothersnotresponding

    Lecture7.2.2physiologyofmuscle
    Skeletalmusclelargesttissueinthebody
    Importantformovements,posture,breathing
    Lossofmusclefunctiondeaththroughrespiratoryfailure

    Topicsofimportance
    Structureofmuscle,centralinnervation,neuromuscularjunction,excitationcontractioncoupling,crossbridge
    cycling,energysupply
    TtubulescarriesAPdowntheextracellularspacealongsurfacemembraneintomuscle
    Sarcoplasmicreticulum(SR)intracellularmembranesystem

    Ttubulesaffectsarcoplasmicreticulum
    ThereisvoltagesensorinTtuble(SMCachannel)_makephysicalcontactwithcalciumchannelinSrmembrane
    (ryanodinereceptors)

    ThereisSRcalciumpumprelaxationpumpthatpumpssodiumbackintoSR.
    Mytoniafailuretorelax(cancontractthough)abnormalitiesinsodium/chloridechannels
    causedbyCTGorCCTG(microsatelliteexpansions)

    Malignanthyperthermia(CausedbymutationstoRyR1)rare(familialdisease),triggeredbyanaesthesiaSRCa
    channelsopenedbyvolatileanaesthetics(e.g.halothane)allmusclesgointocontracturedeaththrough
    respiratoryfailure
    DantroleneblocksSRCAreleasevaluabletreatment

    Mutationsinthecontractileproteins(Actinandmyosin)areoftenlethalnonlethalmutationscanbeassociated
    withmuscledamagereducedforceproductioncanleadtohypertrophy

    MuscleconsumeATPforcrossbridgecycling,SRCapump,NApump
    SourcesofATP(1)ATP(2)phosphocreatine(3)glycogen(4)aerobicglycogen
    McArdlesdiseaselackofmyophosphorylaseenzymewhichbreaksdownglycogen
    Normalstrengthrapid,painfulfatiguegentleexerciseOK

    Mitochondrialmyopathiesverypoorexercisetolerance,severemetabolicacidosis
    Histologicallyshowmultipledamagedmitochondria

    Skeletalmuscleisquiteresistanttoischaemia(contrasttocardiac)notactiveatrest,reasonablesupply
    ofanaerobicpathwaysorthopaedicsurgeonsapplytourniquetstolimbstoworkinabloodlessfield

    IfischaemiasufficientlylongcyclingXBscannolongerdetachrigormortis
    Musclesareplasticcanchangetheirformwithtraining

    Atrophymusclesbecomesmallerandthinnerwithdisusenumberofcellsconstantlesscontractileproteins
    withineachcell
    Hypertrophyweightlifterstriggeredbyrelativelysmallnumberofmaximalcontractions
    Endurancemarathonrunnerscausesfastfibrestoconverttoslowfibresthinnermoreaerobicandfatigue
    resistant
    Rapidgrowthareaanddrugstoencouragehypertrophyinskeletallmuscleanddiscourageitintheheart

    Lecture6.2.3Exerciseandmuscle
    Somediseasesarecharacterisedbyreversibleweakness
    Runningdownamountainmusclesgetweakattheendoftheactivitymusclesaresore,stiffandtender(DOMS)
    recoverytakesseveraldays.

    MetabolicchangesduringfatigueATPbreakdownexceedsATPresynthesis
    DuringmusclecontractionunderischaemicconditionsATPremainsthesame,butPCRdecreases
    LacticacidtheoryofmusclefatiguelowerpHlessforceforsamecalcium
    ProblemwithLATisthatfatigueoccurswithoutacidosisalsoat37Cthecurveshiftdisappears
    Calciumreleasefailurecausesfatigue

    TherearechannelsinSRwhicharepermeabletophosphate
    NormallyphosphateislowinSRinfatiguePhosphateishighinextracellularspaceentersintoSRCaPiis
    thenformedandtrappedinsideSRsothereisadecreaseincalcium

    ROSareproductsofmitochondriawhichcancauseoxidativedamageelsewhereinthecell
    Casensitivityofcontractileproteinsdecreaseafterfatigue
    ROSscavengerscanpreventcalciumsensitivity

    Delayedonsetmusclesoreness(DOMS)isaformofmuscledamagereduceforce(takesdaystorecover),lossof
    muscleenzymes(membranedamage),mainlyoccursincontractionsinvolvestretch,EMappearanceof
    overstretchedsarcomeres
    Sarcomeresareunstableonthedescendingpartofthetension/lengthcurvebecauseneighbouringsarcomeres
    becomingstrongerasoverstretchedonebecomesweaker
    Satellitecellsarespecializedcellsthatrepairdamagedmuscle
    Satellitecellsarestemcellswhenmuscledamagedstemcellsactivatedbycytokines/inflammatorycells
    Activatedcellsformmyoblastsdivideandfuseformingmyotubes
    myotubeseventuallyrepairandreplacethedmagedregionofamusclecell
    Centralnucleisuggestsrepair

    Duchennemusculardystrophy1in3500malebirths
    Musclesarenormalatbirthincreasingmuscleweaknessshowdamageandregeneratingnucleiinbiopsy
    Degenerationpredominatesleadingtodisability
    Alsoaffectscorticalfunctionmildintellectualimpairment
    Cardiacinvolvementandrespiratoryfailurenoeffectivetreatment

    Histologyfromearlytolateshowscentralnucleithendestructionandlossofmusclefibres

    Dystrophinproteinthatconnectszlinetomembranes
    Dystrophinmuchmoresusceptibletostretchinducedmuscledamage
    Absentdystrophinleadstoexcessivemovementresultingintearsallowingenzymestoleakouttothemfibres

    Dystrophincouldbetargetedbygenetherapybutlargemusclemasstoinfect,geneistoolargeandprotein
    recognisedasforeign.
    Lecture7.5.1MeettheexpertRheumatoidarthritis
    Aspirationcanbedonebutdoesnotnecessarilyindicateanything
    Synovialfluidcanexcludecertainddxe.g.infectionofjoint

    PannusmeansclothtypicalofRAbutisnotlimitedtoRAcollectionofthings
    RheumatoidfactornotlimitedtoRAcanbeseeninanumberofotherautoimmunediseases
    HighquantitesofRFinearlystagesiscorrelativewithworseoutcomes
    Erosions,extraarticulardisease,lotsofjointsinvolvedearlyonindicativeofbadoutcome

    510%ofpeoplewithRAcanaccessbiologics
    Ifthepatientsjointsarenotpainfulorswollen,ifnonewsymptomsremission
    Patientsinremissionxraycanstillshowsubclinicalsynovitis

    Lecture7.5.2
    Criteriafordiseasediagnosis4outof7
    6weeks:Morningstiffness>1hour,Arthritisof>3joints,arthritisofhandjoints,symmetricalarthritis
    Rheumatoidnodules,serumrheumatoidfactor,radiographicchanges
    50%slow,25%acuteonsetMeantimeofdiagnosisis9months
    Nosinglepathognomoniccriterionpoordiseaseunderstanding
    Treatmentiscurrentlypalliativenotyetpreventativeorcurative

    Infectiousagentinsynoviumtwopossiblities
    ArthritogenicantigenThereisapeptidethatiscrossreactivewithantigenfromsynovium
    ContinuedpresenceofsuperantigenCouldbeEBV,TB?
    DRB1hasallelicdoseresponseonlyneed1alleletogetantigenresponse
    Etiologicaltheories
    Altered/aberrantTcellreactswithselfTcellsthatattackMHCIIarenotdeletedindevelopment
    inabilitytocontrolclonalexpansiondownregulationinTregs
    Bcelletiologyantibodiesagainstanticitrullinatedpeptides
    ACPAcitrullinationispartofnormalcelldeathPADenzymeunfoldsproteinslossofcellularintegrity
    leakageofcitrullinatedpeptidesnotcontainedbymacrophages
    HLADRB1MHCIIinteractswithACPtoenableAGpresentationtoCD4
    Triggerleadstomassivecelldeathpoorclearanceoftissue
    ACPAareanearlyassociationwithRA
    Assay95%specific,75%sensitivitybutnotallRApatientshaveACPA

    Insynovialfluid
    TypeAsynoviocytemacrophagetypeofcellresideinsynovialfluidcomesfrombonemarrowandpopulates
    synoviumcanbeactivatedandcanproducecytokinessuchasTNFinsamewaysasmacrophages

    TypeBsynoviocytesfibroblasticproducesynovialfluid

    SynovialtissueTherearemacrophagesandthereareafewlymphocytesanddendriticcells

    SynovialcellstakeonlyonelayerDenseconnectivetissueunderneath
    Acutechangesincreasevascularflow,oedemaandfibrin(ricebodies)
    Endothelialactivationincreasedadhesionmolecules,leukocyteadhesion,leukocytetransmigration
    Vascularproliferation

    ReplicationoftypeBsynoviocytesandrecruitmentoftypeAsynoviocytes
    Fusionofbothintogiantcells(IFNy,GMCSF)
    Tissueproliferationheapingsynovialvilliformingpannus
    ALLimmuneresponmseelementspresentallhavetoberecruited
    Macrophages,lymphocytesheapintosynovialtissue
    Chronicchanges
    Cellbiologicalresponsesleadstorecruitmentviachemokines(anumber)
    RemodellingresponsesMMPsandTMPs
    Reducedapoptosisofsynoviocytesdecreasedp53function
    Formationofpannus,Erosionofcartilageandbone
    XRAY:Jointnarrowing(lossofcartilage),Erosionsadjacenttocartilage,Osteopaenia

    IncreasedpressurefromPannusHypoxicintypeBsynoviocytesHIF1aVEGF
    IL1,TNFstabilizeHIF1a
    Systemicdiseases
    Keratoconjunctivitissicca(25%)
    Respiratorypleurisy(50%),fibrosis,cicrcoarytenoidinflammation
    Vasculitis(2025%)rheumatoidnodules
    Entrapmentneuropathy(20%)
    Cardiacpericarditis(3%)
    HaematologicalFeltyssyndrome(Neutrapenia)(2%)
    Amyloidosis(110%)

    Lecture7.5.3
    Pelvicfractures(13%offractures)
    60%malemajorityisMVAmortality1015%
    Pelvicfractures
    Lateralcompressionfracturethroughsacramandpubicramus
    APcompressionfracturethroughpubicsymphisis,throughpubicbones,openupSIjointtornligaments
    Verticalshear(happensoftenduetofallfromheight)shearinginjurytopelvis,displacedvertically
    Associatedinjuries75%haemorrhage,urological12%,neurological8%
    Proximalfemurfractures
    Bloodsupplyiscriticalifbloodsupplyislostleadstoiscahemia
    Mainsupplyisvialateralandmedialcircumflexarteries
    Riskofischaemiadependsonlocation,degreeofdisplacement,age
    Subcapital,transcervical,intertrochanteric
    AbductortendonpathologyTornawayfrominsertion

    Osteoarthritis
    featureschondralloss,jointspacenarrowing,cysts,maginalosteophytes,subchondralscleroses
    Osteophyteprojectionsareahomeostaticresponsetoincreasesurfaceareaandstabilizethejoint

    Lipohermarthrosisfatisfrommarrowconfirmingafracture
    Fatfluidinterface

    Attheanklejointringofbones
    WeberA,B,Ctypesofinjury
    Inverttheankletallustwistsyougetanavulsiveinjurytransversetypeoffractureobliquetypefracture
    WeberBisEversioninjury
    AnythingabovethelevelofprofoundisaweberC

    Maisonneuvefracturespiralfracturegoesupforcegoesupthroughtheinterosseusmembraneandoutmore
    proximally

    7keyareasforankletrauma
    Malleoli,Lateralprocessofthetallus,talardome,5
    th
    metatarsalbone,Anteriorprocessofcalcaneus,Posterior
    processoftalus,Calcanealfractures

    Calcanealfractures(suprasurfaceofcalcaneusand)boehlersanglenormally2040degrees

    Tendonsoffoot

    Peronealbrevisandlongustakea90degreeturnthroughatunnel

    Anteriortendonsanterioribial,extensorhallicuslongus,extensordigitorumlongus
    Lecture7.5.4clinicalanatomyofthePNS
    Neuropathy
    Diffusediabetes,hereditary(CMTdemyelinatingneuropathy),chemotherapy(willgetneuropathybecause
    affectsmicrotubules).
    Focalsingleperipheralnerves (lesionofasinglenerve)
    Multifocalmononeuritismultiplex(commonestisleprosyintheworldbutnotinaustralia)

    Mononeuropathies
    Trauma,iatrogenic,externalpressure,ischaemiatakingahistory(always)
    Howdidtheneuropathyarise?

    SymptomsNumbness,weakness,lossofcontrol,pinsandneedles,insects(Frenchsaylesformis),electricity,
    circulation
    Examineforpatterns
    Examinefordifferencesbetweenthemidline,examineacrossthepointofdifference,
    Radicular,dermatomeareachangingperipheralnerveterritory
    Knowyourpatterns
    modalityspecificchangesmall(painandtemperature),large(discriminatorytouch)
    Diffuse(axonal,dyingback,lengthdependent)nervesthatarelongestaremostaffectedattheirdistallocations
    Whereistheproblemandwhatisit?

    Knowfunctionsofulnar,median,radial,axillarynerve
    Carpaltunnel

    Lowerlimbs

    Lecture8.2.1Principlesofmanagementofbackpain
    Levelsofevidence
    NHMRCLevel1toLevel4
    Acutebackpain
    Bedrestnoteffective8/10showedbedrestnomoreeffectiveorworsethancontrolbedrestisbad
    Stayingactiveisbetter
    simpleanalgesicsnoteffective>5outof6outcomes
    NSAIDseffectiveforshorttermreliefbutnotforsciaticaornerverootcompression
    Spinalmanipulationworksbutnomoreeffectivethanexerciseorpainmedications
    CochranereviewofSMTshowssmallstiasticallysignificantbutclinicallyirrelevant
    Exercisenotmoreeffectivethanotherconservativemeasuresincludingnointerventionforacutelowbackpain
    BeneficialSTAYACTIVE

    QueenslandstudyMedications+multifidusexercises
    ShorttermincreasedmusclesizeActivegroup12timeslesslikelytosufferrecurrence,9timeslesslikelytosuffer
    recurrence

    NSAIDsandmusclerelaxantsTradeoff
    Bedrestharmfulorineffective
    SubacuteLowBackPain612weeks
    Largescalestudyinscandanavia
    Asessment,functionalassessment,exerciseandjustresassuringpeoplewasenoughtohalfbackpain
    LikielihoodRatioof1meansthereisnoeffect,2meanstwiceaslikely
    Age,sex,smoking,overweightLR1
    HigherworkloadLR1.41.5
    Highlevelsofmaladaptivebehaviours2.5
    Lowgeneralhealthstatus1.8
    Lowlevelsoffearavoidance0.39,Lowbaselinefunctionalimpairment0.3
    Chroniclowbackpain>12weeks
    15%SIJreliefwheninjected,40%disc,15%zjoint,30%noresponsetoanyinterventions

    DiscjointIDDnoneofthetreatmentshaveanygoodevidence
    Zjointsarthritis,tearscorticosteroidsdontworknervedenervationwork
    StrongestevidenceisExercisetypicalyinsettingoffunctionalrestorationprogramwithbehaviouralelements
    Psychosocialinterventionsaddressfears,beliefs,attitudes
    CBTlevel1evidenceImprovedonpainexperience,coping

    Massagedisabilityscorehelpsonlywithmassagenotacupuncture,butbothersomescorewasnotsignificant
    FORCHRONICbackpain
    BeneficialBackexercises,intensivemultidisciplinarytreatmentprogrammes
    Noteffectivelumbartraction

    Lecture8.2.3Lowerlimbclinicalanatomy
    Subcapitalfracture,Cervicalfracture,basalfracture,pertrochantericfracture
    Treateddifferentlyduetobloodsupply
    Somesupplyvialigamentumteres,butmostlythroughneckviamedullaandcapsularretinacula
    Subcapitalfracturemostofbloodsupplylostreplacethehead
    Pertrochantericfracturebloodsupplyretainedputascrewthrough
    Disolocationofthehip
    Ligamentofbigelowwomenhavesmalleronecanthyperextendbigelow
    Majorityofdislocationsoccurattheback

    Sciaticnerveisinthemidpointbetweentrochanterandischialtuberosity
    Femoraltriangledamage

    Femoralfractures
    Whenbrokenattheshaftinsertanintermedullarynailgoodhealing
    Platingafemurwontworktoomuchweightbearing

    Supacondylarfractureatkneepoplitealarterycanbetraumatised00>needstobefixedwithscrews

    Bursaeawayfromknee
    Clergymanskneebelow,Housemaidskneeattheknee

    Patellaandfracturearoundknee
    Muscleskeepthepatellainplace
    Kneejointisheldtogetherbyseveralligamentsalongwithcruciateligaments
    ACLresistsforwardmovementoftibiaonfemur
    PCLresistsbackwardmovementoftibiaonfemur
    Osteochondritisdessicanscancauseavascularnecrosis

    Tibialshaftfractures
    Opencompoundtreatedwithafixiter

    Anklefracturesalwaysfracturedislocations

    TarsalfracturesSpringligamentcalcaneus(heel),5
    th
    metatarsal
    Bilateralhalluxvalgus
    Tendocalcaneusplantarflex
    Midpointofinguinalligamentvsmidinguinalpoint
    Nervearteryveinlymphinfemoralcanal

    Femoraltrianglepenetratinginjuriestomedialthighareverydangerous
    Subsartorialcanal
    PoplitealfossaTibialnerve,peronealnerve
    Compartmentsyndromecanhappenbecausetheyreinfibrouscompartments
    Takeoutsegmentoffibulawillhelpdecompress

    CharacteristicsofmelanomaAtoH
    Lecture8.2.4ImagingtheMSK
    Casepresentation
    1.PatientsNameandDOB2.Anatomicalregion3.Critiqueimagequality4.Interpretimage
    Basicorthopaedics1
    Whenafractureisidentifieddescribeit

    BasicorthopaedicsIIRuleof2s
    2views,2joints(aboveand/orbelow),2limbs(lookatbothsides,epiphysealplatescanbedifficult),2injuries(high
    energytraumamaycausemorethanoneabnormality),2occasions

    8.2.4.5MISSEDLECTUREBIOCHEMICALTESTING
    Lecture8.2.5Honesty
    Typesofcertificatesbirth,death,diving(requiredforscubadiving),attendance(carerstoattendpatients),travel
    (areyoufittotravelcanyoutakecertaintypesofinsurance),centrelink

    Differenttypesofcertificatetypes
    Sicknesswork,study,centrelink
    Fitnessdriving,diving,preemployment,travel
    Entitlementdisabledparking
    legalbirth,death
    Certificatesbenefitpatient,communityandtodoctor(financial)
    Deathcertificate

    Healthcarenormallyoperatesinthezoneofillegalnormal

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