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,[Link]

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,[Link])
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([Link])

Fastneurotransmissionionotropicreceptor(ligandgated)
Glutamatesodiumandcalciumchannelscausingdepolarization
GABAreceptorschloridechannelscausinghyperpolarization
SlowneurotransmissionGPCR
Metabotropicmetabolismofthecell(altersit)
ReceptorssitinthecellagonistbindsGPCRcausesGTPtoexchangewithGDP
AlphasubunitactivatesadenylatecyclaseconvertsATPtocAMPcanalteractivityofgeneexpression
[Link]

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
[Link]

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
[Link]
[Link]
[Link]

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
[Link]
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%[Link]
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,[Link]
[Link]
reflectsthetotalperipheralresistance;thelower,thefasteritrunsout;ifhigh,thesloweritrunsout.
QRScomplexwhenventriclesstartcontractingandpushbloodintoaorta
Armupandbackdownmanoeuvre;columnsoffluidproducespressure;furtherdownincolumnisgreater
pressure;rho*g*h(density=rho,h=heightofcolumn)
BPmeasuredlowerdowninbodyishigherproportionaltoheightofcolumnofblood;hydrostaticeffects
duetoposture
BP=CO*[Link]=BP/[Link]
[Link]=PaPv/[Link]
[Link];sonoeffecton
[Link]
down.
Youwouldnotexpectposturalchangestoaffectbloodflowbutwouldonarterialandvenouspressure.
[Link].
[Link]
areexercisingandsendsviaSNSforhearttospeedup(canstartbeforeexercisesonotfeedback)since
needsmorebloodflow;andchangesinBPandchemoreceptors,feedbackfrommuscles,joints(arrayof
sensoryinformation).
Largefallindiastolicpressure,[Link]
sincevenousreturnincreasesCO,[Link]
[Link]
Again,BP=CO*TPR;letssayexerciseincCO2folds,butBPdidntdoublebecauseTPRprobablyfellbyfactor
of2;sosamemeanpressure,buthighersystolicandlowerdiastolicpressure.
[Link]
pressurelowerandbringsmorebloodintoheart;[Link]
thusincreasesBPwithinspiration.
HRgoesuptoo.
[Link]
correction
TPRdependsonconstrictioninarterioles
[Link].
Whenlyingflat,[Link],youaddcolumnofbloodto
BP;[Link]
[Link]
[Link]
aneffectondirectpressureinarteryandveins(thatcancelout),itisbecauseveinsswellduetoincin
[Link].
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

[Link]
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
[Link]
[Link]
[Link]
[Link]
[Link]?
[Link]?
[Link]?
[Link]
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)[Link],limitedmovement,confusion,incontinent
[Link],selfcare,domesticlife,generaltasks
[Link],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
[Link]
[Link]

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
[Link]
Lecture4.2.3HealthLaw3Consent,knowledgeandpower
Typesofconsentexcessorimplied
Actuallybodilyharmisnotcoveredbyconsent

Medicaltreatmentasanexception

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

Advanceddirectivescanbeusedtorefusehelp

Capacitypresumptionofcapacityinadultspresumedtobecompetentunlessshownbytheevidence
Functionaltestsifunconsciousisobvious
Howeverifconsciousneedtocomprehendandhaveinformationretention,believeinformationandweighit
againstotherfactorstoreachadecision

Slidingscaleapproach
[Link],drugs,fatigue
[Link]
[Link],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([Link])
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
[Link],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
[Link]
[Link]

MechanismsofTandBcelltolerance
[Link](ImportanceofAIREgene)
[Link],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,[Link](PTPN22),turnsoffsignalling
3.PossiblyCTLA4,IL2,TNF

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

[Link]
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

[Link]/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

[Link]
[Link]/guardianshipauthoritymadeorders
[Link]
[Link]
[Link]
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
[Link]/oligoarthritis
[Link],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,[Link]
stage3haematogenous(>2years)acutefever,inflammationstrept,staph,GNBs

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

Treatment
[Link]
2.Removalofimplant1stageexchange
3.Removalofimplant2stageexchange
[Link](girdlestonehip,kneearthrodesis)

Lecture5.5.1Uricacidandmedications
EtiologyofGoutcrystallizationofuricacidinjoints(monosodiumurate)
Crystalsinducelocalinflammation
Neutrophilinvasionandphagocytosisofcrystals
Tissuedamagefromreleaseofenzymesandoxygenradicals

StructuresofuricacidandurateKetoandenolform
Enolformformsurate

Uricacidisderivedfrombreakdownofpurinenucleosidesandnucleotides([Link])
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
[Link]

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
[Link]
[Link],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([Link])
Concentrationgradientofsodium/potassiumacrossthemembranearemaintainedbyna/K+ATPase

Na/K+pumpworkstomaintainconcentrationgradientsdamageleadstoslowdepolarization
Physical/ischaemicdamagesidneysunderlandgrades

Axonmembranedamagedaxonwillbeeatenawaydestroyedlikeapoptosisregenerationislikely
(1mm/day)
Ifendoneuriumisalsodamagedhardertorepair

1
st
[Link]
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
[Link]
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([Link])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
[Link]

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
[Link]
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