QUANTITATIVE ENGR PHYSIOL I
QUANTITATIVE ENGR PHYSIOL I BME 365R
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Date Created: 09/06/15
BME 365 Quantitativ Physiology A Lecture 14 Control of Movement Reflexes Integrated Control Review of Lecture 13 Propagation of Action Potentials Synapse Structure of Skeletal Muscle Living Crystal I Myofibrils Muscle Contraction Overview Excitation Contraction Coupling Length Tension Relationship Summation and Recruitment ATP blindm nuclenlhiebln ing m an m ym uyoun than dlswclnlulmm m nlmmnv c n Mas r ms nu nmrs mkz n me nweuxmke an my he mm m mm mumquot Mum m H912 8 rThe mo ecu ar basws of Contracuon hffn39lwww ri rl 39 A Rellxed mu h B Inlllallon o1 ounltacllnn Power stroke Imv 1 nquot kquot 39 In In an Emu 1 Indln III on GIml 4 Gaclln mm 6 o 12 wwwscisdsuedu m vies actin m osin ifhtm Fig 129 Regulatory role of tropomyosin and troponin Silvenhorn 2 d Ed Axon germinal oi smnano motor neuron Mum mm Anion pmmial T mnula Sarcaplasmiv reticulum Myasln llcklllumem 2 Ca hlndn Ac n fllamem moval la nopanln Inward M line asln D mad Myolln mickllllmem povoel caul iuakl Distance aclln moves L39 Fig 1210 Excitationcontraction coupling Silve horn 2quotd Ed Run at sure mefe lengms In burly Tension dmlnped by comrammg muscle percent 1 maxlmum o a 1 6mm 26mm 13mm Damesad lenglh lncmued Ianglh Normal restan length 0 muscle 391214 SHvenhom 2quot Ed Outline Reflexes Integrated Control Outline Reflexes Integrated Control Reflexes a Re ex Integration of sensory information into an involuntary response 1 Basic components of a reflex Stimulus activates a sensory receptor Receptor sends information via AP to CNS CNS selects appropriate response and initiates AP in efferent neurons to muscles andor gland 3 Feedback an important part of many reflexes Ways to Classify Reflexes By efferent division of nervous system that controls response Somatic reflexes Involve skeletal muscle Autonomic reflexes Involve autonomic neurons all are polysynaptic By the CNS location where the reflex is integrated Spinal reflexes integrated in spinal cord Cranial reflexes integrated in brain By whether they are innate or learned By the number of neurons in the pathway Monosynaptic Involves 2 neurons afferent sensory and efferent motor Polysynaptic reflex a Monosynapue re ex Spinal cord megralmg be e quot mskalml muscle 4 by w amp Somatic Q mmornaumn R55an N Tar equal ram quot9 r b Polysynaptic somatic motor reflex Mr synapse Sensory naumn 135m E erelit 0W quotmmquot pg 1317 Monosynapnc and powwnapuc re exes SHvenhom 2quotd Ed Pre angllonlc an onomic neuron Fostgangllnnlc anionomic Auionmnic neuron gangllan Fig 13 2 r Autonomic re exes Si venhom 2quot Ed Skeletal Muscle Reflexes a How do they work Receptors in muscle send info to CNS CNS decides should muscle contract or relax in response CNS sends appropriate signal via somatic motor neurons 3 Somatic motor neurons are always excitatory CNS activates if contraction is right response CNS inhibits if relaxation is right response Receptors Muscle receptors Sense muscle length andor tension Two types of stretch receptors Muscle spindles Golgi tendon organs Receptors Muscle spindles Small elongated structures are parallel to muscle fibers Spindle has outer connective tissue sheath Inner group of intrafusal fibers 4 Respond to stretch a Modified muscle fibers that lack myofibrils in their center position u Ends do not contain contractile elements 7 Muscle spindle Gamma quotID DI neurons fmm CNS Ta CNS Sensory neumns Centralregion a myollbrlls 5 r a 5 s 39 a Gamma motorneumns tv lromCNS Muscle spindle 1 Viam Extrafusal fiber Muscle Spindle lnlrafusalliber Extrafuaal muscle fibers Exlrnlusnl muscle bers Afferent neuron Golgl tendon organ 1Endcn Fig 133 Sensory receptors in muscle Silverlhorn 2quotd Ed Receptors Golgi tendon organs Found at junction of tendon and muscle fibers In series with tendons and muscle fibers Respond to stretch and contraction of muscle Skeletal Muscle Reflexes a How do receptors send info to CNS Via sensory motor neurons 3 How is info sent back from CNS Via alpha motor neurons Innervate normal contractile fibers of muscle a How does this all work together to form reflexes Muscle spindles Figure 134 135 Golgi tendon organs Figure 136 Muscle Spindles a Sensory neurons wrap around middle of intrafusal fibers 3 Fire when intrafusal fiber stretches a They are tonically active so that muscle has tone at rest a Increase firing rate when muscle stretches m Causes muscle to contract in response to stretch Sensory neuron ls tonlcaily amlve Exiraiusal muscle fibers at ruling lenglh 593mm Sense neuro 39I earn as unct an en ings lntrafusal title 01 muscle spind Extrafusal quotbe gt Iriaintlaln aecertaln Alpha mater neurons in extrafusal fibers are tonlcaIly active Increased Increased effmnlu m r H39 m Muscle aire rsgtp l39gnalu tarsus n mn 33823 stretches cord gammy Muscle langlil Muscle muscle watches contracts V V Membrane l I I IBIISCWVHBUIO A A Time Fig 134 Muscle spindle functions Silverthorn 2nd Ed How is stretch reflex maintained as muscle contracts a When muscle contract doesn t muscle spindle get shorter so that firing rate increases No gamma motor neurons innervate the contractile ends of muscle spindle The are coactivated with alpha motor neurons They cause ends of spindle to shorten with contraction so that central portion remains stretched a Sgindle funciloll wilhoul g mma molar neuron amivlty G Alpn mmr naumn llre Lesa Milan on oanler ol Imrmnl quotbars 9 Flrln me oi Emil neumn decreases Muscla Denim Mumle V length Anion polenlial Membrane I Polenllnl l fol 5amp1 Muscle summers neuron 39I1me gt Flg 13 5 r Gamma motor neurons n Ayrhagamma coac vation wl h gamma motor neuron actlvlty a Alpha Inmor nwmn nros and gamma molar nwmn llros clng l Gamma motor neuron lire L r Ends of inllrafusal 2 bers conlracl and snonen Conlors ul inlrngqsnl oors slmoh llnng role ol n aranl nouron mmalns conslnnl M I M I38 K lllleulncle Y lm 39rfr39 n39l manglanyl39nan 9m Membrane Flrlng rule remIns oonsunz WSWquot H H H H H wlndla A sensory Muscle Contact aura mn Sllvenhom 2 Ed Golgi Tendon Organs a Composed of Nerve fiber endings that wind between collagen fibers inside connective tissue capsule a If muscle is stretched Free nerve endings are pinched and they fire a Activation of Golgi tendon organs Inhibits alpha motor neurons and decreases muscle contraction Muscle spindle re ex Sensory neuron Spl nd le a Add load to muscle Golgi tendon reflex Inhibiting interneuron Muscle contracts l Muscle contraction stretches Golgi tendon organ Fig 136 Muscle re exes Reflex contraction initiated stretch as am drops by muscle spindle restores arm posmon Muscle and muscle spindle CD Neuron from Golgi tendon organ fires C2 Motor neuron is inhibited Muscle relaxes Load is released ll excessive load is placed on muscle Golgi tendon reflex is activated ca relaxation thus protecting muscle Silverthorn 2nd Ed Outline Reflexes Integrated Control Control of Movement Movement around flexible joints is controlled by Synergistic Antagonistic Muscles that act in a coordinated way Myotactic Unit Collection of pathways controlling a joint Knee Jerk Reflex a Simplest reflex in a myotactic unit Monosynaptic stretch reflex eg Knee jerk reflex a Tap patellar tendon Activate muscle spindle stretch receptors Send AP to spinal cord Synapses directly on motor neuron that controls contraction of quadriceps monosynaptic Also produces reciprocal relaxation of hamstring polysynaptic F SHEDme g Emmi pm 2 Imemeumn Inhibiting Minnie mmar neumn n W m mum39 u1m39i g mm all reclpmillnhllm on H913 7 rThe kneejerk re ex SHverthom 2 Ed Types of Movement Reflex Least complex Primarily integrated in spinal cord Voluntary Most complex Requires integration at cerebral cortex Can be initiated without an external stimuli Rhythmic eg walking or running Rhythmic Movement Combination of Voluntary movement Reflex movement Must be initiated or terminated by input from cerebral cortex Can be sustained without further input from brain Rhythmic activity Maintained by groups of spinal interneurons Known as central pattern generators Alternater contract and relax muscles in repetitive fashion until told to stop A dln lh lo lln quotquotquot 33 WWLIIJJ 33quot ourmy Inu Palmul x mulul Emmian mm 7 Flaxan mmrm Exmsuls mum u mmlng m nwny welgm mm In Ian lag hum painful mmum Flmrl nlllhltgd Hg 13 8 r F ex on re ex and he Crossed extensor re ex SHvenhom 2 Ed Hg 13 9 r ntegrauon of musde re exes SHvenhom 2 Ed V I n r v m o u a y mo ems s Cerebral conical motor areas Planning 923 T L Postural re exes hand and eye movements Spinal re exes Fig 1310 7 Higher Center Control of movement Silvenhom 2 Ed INITIATING MOVEMEN EXECUTIN t MOVEMEN Basal ganglia Cortjcal Idea 355 c393 lon gt Motor arlex Movemenl areas V i n Cerebellum Cerebellum4 gt Feedback pathways Hg 13 M rCNS COHUO ofvohmtary movement SHvenhom 2 Ed Brain initiates 305V moves dlsturbed Posture adjusted quotquotquotquotquotquotquotquotquotquotquot quot rvyard Feedback for c unanticipated postural ce Posture is Feedfo for anti Ipated postural disturbance dlsturban Fig 1312 r Feedforward re exes and feedback of information during movement Siivennom 2 Ed Summary Reflexes Integrated Control Poem of the Day BME 365 Quantitative Physiology Review of Lecture 6 I Synthesis of Biomolecules I The Cell Cycle Lecture 7 I Epithelial Tissue I Apoptosis Cancer Cell Cycle IHow owekno Studying Cell Cycle I Can study in cell culture I Mammalian cells ll i culture will undergo 25740 divisions men growth arrest I Replicauve senescence I Immortalized cell line I Uri ergo mutauon to overcome replicauve cell n repli ted I vvnen telomeres reach criucal iengm cell division stops I Telomerase can swi esize telomeric DNA d w where cells are in cell cycle I Pulse of 3H thymdirie I Flow cytomeiry ceu numnsr 00 El 61 El 5 m I GzM 240 160 an V 125 255 DNA mmam Cell Cycle Control I 2 classes of proteins l Cyclin dependent protein kinases Cdk Levels are consrantrhroughout simplest cell cycles I Bind to Cdk molecules and control their ability to phosphorylate larger promins Undergo cycle of synthesis and degradation with eac cell cyc e l CyclinCdk complexs Induce a variety of downstIeam evens by phosphorylat39ng seletIed proteins Cell Cycle Cyclin Cdk Complexes Interactive Biology Video Control of Cell Cycle I Control system responds to I Intracellular signals I Extracellular signals I Can arrest cell cycle progression when I Cell fails tn complete an ssential cell cycle 5 proc s I Cell encounters unfavorable environmental con itions Targets of CyclinCdk Complexes I Retinoblastoma protein pr h39 hood hereditary eye cancer I Loss of both copies of Rb gene lads tn excssive cell proliferation in immature retina I Rb protein is important in restraining cell division I CyclinCdk complexs phosphorylate pr reducing its activity and enabling progression I through G1 checkpoln Targets of CyclinCdk Complexes I p53 I DNA damage leads tn activation ofgene regulatory protein p5 I p53 stimulates transcription ofseveral gens thse gene products inactivate CyclinCdk c p exs and prevent entry into S p ase I Prevents replication of cells with damaged DNA I Mutations of p53 gene occur in half of uman tumors Cull C IEII Cnnuni m ms mm m l lil Apoptosis Hogrammed cell death lfcells are no longer needed they commit suicide by activating intracellular death program important in developmental biology in 3 E m quot3 am 5 m 2 Cell death due to acute injury Mes I induces in ammation Apoptotic Death Hocess I Cell shrinks and condenses Cytoskeleton collapses Nuclear envelope dr sassembl es DNA breaks into fragments Cell surface altered so cell is rapidly phagocytosed by neig ors Caspases mediate apoptosis Bcl2 family of proteins important in activating cas a deo of apoptosis Outline I De nitions I Epidemiology I Molecular Biology ofTumor Growth I Biology ofTumor Growth I Tumor Heterogeneity I Diagnostic Approaches I Therapeutic Approachs Outline I Epidemiology I Molecular Biology of Tumor Growth I Biology ofTumor Growth I Therapeutic Approaches Definitions I Neoplasia New growth Abnormal mass of tissue Growth exceeds that of normal tissue Growth persists after stimuli initiating it cease Purposeless and preys on host I Tumor neoplasm Tumor Components Types of Tumors l Proliferating neoplastic cells I Benign l Parenchyma I Malignant l Supporting stroma I Differ in four main ways I Connective tissue and blood vessels l Differentiation and anaplasia l Rate of growth I Local invasion l Metastasis Differentiation and Anaplasia Benign vs Malignant I Benign tumors I Well differentiated I Malignant tumors Range from well no poorly drferentiamd I Hallmarks ofanaplasia cells and nuclei show pleomorphism ceiis conmin abundant DNA coarse clumped chromatin Large Nc ratio 11 rather mm 14 Large nucleoli www web atholo com cate 2 I U lt In Precancerous condition in epithelial tissue Anaplastic cells in epithelium Dysplasia does not always progress to cancer Rate of Growth Local Invasion I Benign tumors I Benign tumors I Generally grow slowly over a period of years I g ow as cohesive expanding masses that remain localized to site of origin I Malignant tumors I Do not have capacity to metastasize m distant sites I Grow rapidly at an erratic pace I Frequently are surrounded by a brous cap I Malignant tumors I G w with progressive in ltration invasion and destruction of host tissue I Poorly demarcated from surrounding normal tissue Metastasis I Tumor implanis that are discontinuous from the primary tumors I 30 of newly diagnosed patienis with solid tumors prsent with metastass I How do cancers spread I Direct seeding of body cavities or surfaces 0v CA I Lymphatic spread carcinomas I Hematogenous spread sarcomas m i is Mmmmm mm Outline I De nitions Epi e ogy I Molecular Biology of Tumor Growth I Biology ofTumor Growth I Tumor Heterogeneity I Diagnostic Approaches I Therapeutic Approaches Epidemiology I 2 d leading cause ofdath in the US I Major cancers IColori 11 mmummmmmwmm mm Wm Outline I De nitions I E 39demiol I Biology ofTumor Growth I Tumor Heterogeneity I Diagnostic Approaches I Therapeutic Approaches Molecular Basis of Cancer I Carcinogenesis I Result ornonelelnal geneuc damage I m rnasses resultfrom one clonal expansorl of single progenitor cell mar nas lncurred geneuc da I Genetic damage resullsi I o cogene acuvauorl gall l offurlcuorl a rnage or suppressor gene funcuorl loss of funcuorl I Abnormal DNA repair rnecnanlsrns I Lack of senescence ln mmor cells Molewlaf ADDVOEcheSln caser Yherap y Ea39luerFeaIure Molacularlafgets Yherav es Dneavene n 5 warns FameSyHlansVelase mm mm AM zor Recev al m w snemse a2 m slamses lnhlbnms r ersenrr a inssa umm nampmere Gene heiivv aleslale suppresmeres naimalsuvviessalvene Wm summons DNAmsmalchlevall Gene heiivv aleslale repquot neermns enzyme naimal enzyme may W m Yelamelase Yelamelase molars umalcelb Anvlaveness ror veer mar w 47 Helms lnlevvln reeeplm Melenses Melallavmkases rraiesenrrms Carcinogenesis MultiStep Process stepWIs I Phenotypic level I Genetic level I Tumor characteristics acquired in e fashion 39 l rmaesnnmmenmammal Newx 6 Capabilities of Cancers I Selfsuf ciency in growth signals I Insensitivity to growth inhibitory signals I Evasion of programmed cell death I Limitless replicative potential I Tissue invasion and metastasis I Sustained angiogenesis Oncogenes and Cancers I Protooncogens Tumor Suppressor Genes amp Cancer I Physiologic function I Cellular genes that promote normal growth I Apply brakes to cell proliferation I Oncogens I Loss is key event in many human tumors I awange in gene st39u ture I Cenical canc I Syndnesze abnormal gene product Widn abnormal functon I Change in gene promoter I Ennanced producton of normal growdn i I Sexually transmitted di promotng prot sease I Caused by infection with human papiloma vlrus HPV I HPV infection is necessary but not sufficient co dition for development of cervical cance HPV and Cervical Cancer irl gz il5tgli gangster L39 0 62quot 7132322 Sii239 i a WWW My ins I ds circular DNA with 8000 bps I Low grade cenical precanc r A I HPV DNA present as free ext39achromosomal circle episome39 I High grade cenical precance I ral DNA integrated i to eg a drives h ted production of viral proteins that ost cell into S phase ome I Disrupis control of expression of viral genes I Lhr u amen mmwvl ml min mounmtm mama HPV and Cervical Cancer I Two viral proteins of interest I E6 HPV and Cervical Cancer I Two viral proteins of interest I Alters cell growdn dnrougn errece on p53 39 Alters Ce grown Tough 665 0 PRb I E6 targee 353 for degradaton 39 WW I in normal cells followll39lg DNA damage 353 induces growdn arrest in ct to allow cell to repalr damage I in transfer med cells increased E6 le ds t decreased 353 D I pRl a ternates betyam anosanoiylated and nuns phosphorylated state in every cell cycle I vvnen not anospncr lated pRl bind regulatory produce and premts tn nucleus to drive cell prolireation I Transformed cells I E7 laimd eyels unregulated cell cycle rogression and accumulaton of DNA damage s strongly to gene em rrom acting in s to pRl and pryme it rrom binding to gene regulatory pro uce I Leads to increeed transoipton of molecules that drive cell prolreation mammalian lacwr mm m milmm mum We mum Wm u 0 m1 PRoLiFEnAnDN ACl lVATED av om mus Limitless Replicative Potential I Telorneres Ends of eukaryouc chromosomes I Telorneric DNA Shortens continuously throughout lire When it reaches a critical length cells senesce and i I Cancer cells ck and conunue to divide merase Length n if telorneres u m 8 3 gm 3 3 Q 90 of hu man cancers activate telornerase Tissue Invasion I Metastasis causes 90 of cancer dath I How do tumors invade I Detach from primary tumor own regulauon ofErcadherin expression I Attach to matrix componenls Degrade ECM Secrete proteolyuc enzymes I eg Matrix metallorproteases Migrate mime mama Wm mummmw mmmmnxWWW mm Outline I De nitions I Epidemiology I Molecular Biology ofTumor Growth Biology ofTumor Growth I Tumor Heterogeneity I Diagnostic Approaches I Therapeutic Approachs Biology of Tumor Growth I Natural hx of most cancers has 4 phases I Malignant transformation in target cell I Growth of transformed cells I Local invasion I Distant metastases I Factors affecting tumor growth I Kinetics of tumor cell growth I Tumor angiogenesis I Tumor progression and heterogeneity Outline I Definitions I Epidemiology I Molecular Biology of Tumor Growth I Biology of Tumor Growth I Diagnostic Approaches I Therapeutic Approaches Tumor Heterogeneity I Over time I Tumors become more aggressive I Acquire malignant potential I Related to I Sequential appearance of subpopulation of cells that i er in p enotype I Although tumors are monoclonal in origin their cells are extremely heterogeneous I Due to multiple mutations that accumulate in different cells I Growing tumors I Enriched in subclones that beat the oddsquot Outline I Definitions I Epidemiology I Molecular Biology of Tumor Growth I Biology of Tumor Growth I Tumor Heterogeneity I Diagnostic Approaches I Therapeutic Approaches The Cancer Problem I 2nd leading cause of death in US I 1 of every 4 deaths is from cancer I 5year survival rate 59 IAnnual costs 107 billion The Cancer Problem I Importance of screening for early disease I Five Year Relative Survival Rates Local Regional mam quotMm bunhausomn ijilhmln lbunjmwily 4mm Cervical Cancer Detection 339d most common cancer in women worldwide Leading cause of cancer death in women worldwide Cervical precancer curable precursor Advanced stages hysterectomy chemoradiation Developed world Screening programs costty amp cumbersome Developing world Resources for screening not available Many young women die of a preventable olsease Epithelial Pre Cancer Detecting Cervical PreCancer Current Patient Care Strategy Pz znl has Pzpaniuhu war Wmtsfaxl weeks Cuhusmpy and dixetl hinpg39s Wmtsfaxl weeks In Vivo Molecular Imaging of Cancer I Vision I Topical application or injection of contrast agent I Low resolution 2DHigh resolution 30 optical imaging I Battery powered pensized microscope I Challen e I Requires coordinated advances in Nanotechnology e Sate bngnt obbcal labels Biotecnnologv e ngn af nity brobe molecules cal lVE ex enslve 5e Drug delivery 7 Targeted ef cient labeling MS 7 In b nsors How to Make a Contrast Agent Choose a Biomarker EGFR MMPs Telomerase Integrins Select a specific probe molecule Monoclonal antibodies Peptide and nucleic acid aptamers Select an optically interrogatable marker Fluorescent dyes Metal nanoparticles Quantum dots Develop a delivery formulation Scattering of Gold Nanoparticles In ll Strong scattering no photobleaching Inert biocompatible Complex formation simple stable amp well understood Can We Deliver Contrast Agent No Penetration 10 PVP Enhancer 10 DMso 10 PVP Higher Mag TEM Gold Particles Sllver and Gold Nanopartlcles m it Confocal microscopy a OCT Photon Migration US Aggregates Isolated Can We Image EGFR In Human Tissue Re ectance 647 nm excitation Abnormal Normal Sokolov et al Cancer Research 2003 11 Outline I De nitions I Epidemiology I Molecular Biology of Tumor Growth I Biology ofTumor Growth I Tumor Heterogeneity I Diagnostic Approaches Therapeutic Approaches Therapeutic Approaches I Cancer therapy exploils genetic instability of tumors I Drugs and ionizing radiauon to damage DNA I Normal cells would stop diyiding and repair damage I Turmr tells mntlnue to multiply and die immediately I Cancers can evo ve resistance to therapy I ceneuc instability leads to nign mutation rate I Tumor cell neterogeneity makes treatment Winn one drug dlf cult I cells exposed to one drug often deyelop resistance to other drugs that they naye neyer been exposed to I Viral thera I Tu Some New RX Approaches Some tumors overproduce one protein I Block acuyity of protein I Breast cancer I Block actiyity arnaz protein With manaclanal Al I Infect cells Winn vlrus that can only replicate in p53 de clerlt cells yiral inrecuon kllls tumor cells I Angiogenesis In I I I Tumor vessel I39S s naye unique markers I Gleevec I Targee BcrnAbl protein pyerproduced in leukemlas Gleevec Gleevec HOW lT WORKS Summary I De nitions I Epidemiology I Molecular Biology of Tumor Growth I Biology ofTumor Growth I Tumor Heterogeneity I Diagnostic Approaches I Therapeutic Approaches Poem of the Day BME 365 Quantitative Physiology Lecture 8 cDNA Microarrays to Exprssion Review of Lecture 7 I De nitions I Epidemiology I Molecular Biology ofTumor Growth I Biology ofTumor Growth I Tumor Heterogeneity I Diagnostic Approaches I Therapeutic Approachs Molewla ADDVOachesin caaer Ynerapy Therapeutic Approaches I Cancer therapy exploits genetic instability of tumors I Drugs and ionizing radiation to damage DNA I Normal teiis would stop dividing and repair damage I Tu mar cells EDNUHUE to multiply and die immediately I Cancers can evolve resistance to therap I ceneuc instapiiitvieads to nign rrutation at I Tu or cell neterogeneitv makes treatrnent Winn one drug dif cu t I Cells exposed to one drug ome s that mev nave often deveiop resistance to r drug d never been expose to Molewlar raraeis rnerapemies n i Fainesyl iiensieiese mm Uncavene r ateirs mm AM someeemii m rviamemse aamsiekime mm nt ensemm a tnssattumai naenmavene oeneiaeiapvteiesiaie suppresaivenes quotaimisuppiessaivene Wm AbnaimalDNA DNA meme repair Genetneiivytn iestaie repair meerema enzvmes Mimi enzyme may reiameiese imam a reiameiae Mai ells Anviavenesa Fer veer mm w 47 mar lntEViin ieeemge Metallaviateases Fiatuseinhibnms Meiauses Some New RX Approaches I Some tumors overproduce one protein I Block acuvitv of protein I Breast cancer I aiatk attivitv ofHeQ protein With nanatianai Al I Viral therapy I u I lnfect cells Winn virus that can oniv repiicate in p53 de cient cells viral infection kills tumor cells I Angiogenesis inhi itors I Turnor vessels have unique markers GI evec e I Targee BcrnAbl protein overproduced in leukemias Gleevec Gleevec HOW IT WORKS Outline I Overview I Printing Microarrays I Experimental Design I Reading Microarrays I Use of Microarrays I Studying Cell Cycle Control I Cancer Diagnosis Prognosis Choice of Rx Outline I Overview I Printing Microarrays I Experimental Design I Reading Microarrays I Use of Microarrays I Studying Cell Cycle Control I Cancer Diagnosis Prognosis Choice of Rx Gene Expression Analysis I Human Genome I 40000 unique genes I Which genes are active I DNA Microarrays I Tool to study gene expressnon I Which genes are turned on or of as cells grow divide respon to hormones etc What is a DNA Microarray I Glass slide I Large number of DNA fragments I Each contains nucleotide sequence to probe for a specific gene I Short oligos synthesized on surface of glass wafer I Large DNA fragments generated by PCR and spotted onto slide by robot I Each gene has unique physical address on slide How Do We Use a DNA Microarray I Extract mRNA from cells under study Convert mRNA to cDNA Label cDNA with fluorescent probe Incubate labeled cDNA with microarray Wash slide to remove unbound cDNA Scan slide with laser scanning fluorescence microscope Determine which genes are expressed 39 in test sample Outline I Oveniew rintin Microarra s I Experimental Design I Reading Microarrays I Use of Microarra s I Studying Cell Cycle Control I Cancer Diagnosis Hognosis Choice of Rx Printing Microarrays I Virtual eld trip I Dr shy Iyer39s lab at UT Austin Science Project Ideas I Build your own arrayer I hm1cmgmstanfordedulpbrownlmguidel I Array Camp I hmImeetingscshloi39ngOO4l2004carraxshlm Outline I Oveniew Printin Microarra s I Reading Microarrays I Use ofMicroarrays I Studying Cell Cycle Centre I Cancer Diagnosis Hognosis Choice of Rx Goal Molecular Portraits J ii hung et ai Maleculav Puma af amen Nature Genetics Supplement 32 533 zuuz Wm M I Experimental Design mA A a umm e 4mm 7 e m udmlm unit I g l 5 7 l 33 E a a g menu Fundammtals of EXDaimmtal Design for DNA Microarrays Namve Gmencs Smolenent 32 490 2on2 Sources of Variability Biological Variation Intrinsic to all organisms Technical Variation Introduced during extraction labeling and hybridization Measurement Error Reading fluorescent signals Dealing with Variability Biological Variation Biological Replicates Technical Variation Technical Replicates Statistical Tests Are differenoes statistically significant Large number of variables small sample size Experimental Design new A A a malngial Dy mm mm l menu Fundamentals of EXDEimmtal Design for DNA Microarrays Namve Gmencs Smolenent 32 490 2on2 Outline Oveniew Printing Microarrays Experimental Design Use of Microarrays Studying Cell Cycle Control Cancer Diagnosis Prognosis Choice of Rx Reading Microarrays Slide scanner htt wwwaff metrixcom roducls instrume nlslsgecificlscanner 3000affx Gridding Microarrays Gridding Microarrays Outline I Overview I Printing Microarrays I Experimental Design I Reading Microarrays I Use of Microarrays I Studying Cell Cycle Control I Cancer Diagnosis Prognosis Choice of RX Holloway et al epuons 7 from start to nish rfor obtaining data from DNA Microarrays Nature Geneucs Supplemmt 32 481 2002 Study Cell Cycle Paper 1 I Singular Value Decomposition for GenomeWide Expression Data Processing and Modeling I O Alter P Brown D Botstein I PNAS 971010110106 2000 From Molecular Biology of the Cell Goal Data l Budding yeast I Saccharomyces cerevisiae l Monitor genome wide mRNA levels I 6000 genes I Monitor gene expression on genomic scale I Develop mathematical tools I Adaptable to large quantities of data 39 Reduce compleXltY I I Every 30 minutes for 390 minutes I Make them C0mPI EhEDSIble I In synchronized yeast culture I Reveal expression patterns I Relative to asynchronous yeast culture I 14 microarrays I Previous analysis using clustering I 784 genes related to cell cycle regulation Methods Singular Value Decomposition I Each microarray of N genes I Can express any matrix as I vector of data Nx1 I eu6V I Data matrix e 39 3111 I Assemble 14 vectors to form matrix Nx14 I V Vd I I Elements e I 8 IS Iagona E mf m m I I SVD is a lineartransformation I xpresswn 0 n gene In m samp e I from N genes X M arrays Space I to L eigengenes x L eigenarrays I each eigengene is decorrelated from other eigengenes Results Singular Value Decomposition Rig ulxlyl Em llasn a Mamas mam I First eigengene I accounts for 90 of variance I Relatively constant across cell cycle I Underlying processes are weak perturbation of steady state expression Eigengenes representindependent pl reguamrv progams or processes Res u Its a miuiwl imiml r x meamn Lev I 239 3rd and 4th eigengenes I Show oscillations during cell cycle I 3 1 and 05 of overall relative expression Study Tumor Type chung et al Molecular Portraib omecer Nature Genetics Supplement 32533 2002 Study Tumor Type chung et al Molecular Portraib omecer ature Genetics Supplement 32533 2002 Paper 2 I Variation in Gene Expression Patterns in Follicular Lymphoma and the Response to Rituximab l S Bohen et al I PNAS 1930 2003 Goal I Can gene expression profiling predict which patients with follicular lymphoma will respond to rituximab Follicular Lymphoma I gt10000 new casesyr in US I Responds to Rx but rarely curative Rituximab I Monoclonal Ab against B cell antigen CD20 I 50 rsponse rate in Phase II trials I Mechanism of action unclear I Mechanism of resistance unclear Methods I Tumor samples I 24 patients I Frozen lymph node biopsies before treatment I Patient histories response to Rx available I Sample processing I mRNA extracted I Experimental cDNA probe with Cy5 dye I Common reference cDNA I Panel of cancer cell lines Cy3 dye Methods I Arrays tanford human arrays with 38431 DNA spols I Hybridize samplereference cDN I Data Analysis I Hierarchical cluster ana ysis I Firs a mpt 2 clusters segregated by date I Due to differences in two different scanners I Used SVD to remove pattern containing artifact Results Results Summary I Oveniew I Printing Microarrays I Experimental Design I Reading Microarrays I Use ofMicroarrays I Studying Cell Cycle Centre I Cancer Diagnosis Hognosis Choice of Rx Poem of the Day This is Just to Say William Carlos Williams 1 have eeteh Poem of the Day This is Just to Say EricaLynn Gambino 1 have lust eveh thauqh which Wu were Wabale saving thauqht far breakfast Iwauld name me quwe me they were deliciaus u were 5a sweet amihg a h e ihsehe Due Dates Tuesday September 28th Egtltam One Covers Lectures 19 Reading HWs 14 Practice Exam Posted on Class Website BME 365 Quantitativ Physiology A Lecture 21 Heart Failure Review of Last Time How do we treat coronary artery disease CABG PTCA I Stent Prevention Progression of Heart Disease High Blood Pressure High Cholesterol Levels Heart Failure Atherosclerosis Heart Attack Ischemia Outline What is Heart Failure Treatment of Heart Failure Heart Transplant Cardiac Assist Devices Total Artificial Heart Outline What is Heart Failure I Treatment of Heart Failure Heart Transplant Cardiac Assist Devices Total Artificial Heart Heart Failure 1 Heart failure Occurs when left or right ventricle loses the ability to keep up with amount of blood flow Can involve the heart39s left side right side or both sides Usually affects the left side first 1 About 5 million Americans are living with heart failure a 550000 new cases diagnosed each year Quantifying Heart Performance 1 Ejection Fraction EF Fraction of blood pumped out of ventricle relative to total volume at end diastole EF SVEDV Normal value gt 60 Measured using echocardiography a Normal echocardiogram nttlovvwvvnlltumcedukumcnedscardloloovmovlesn llondecnolabelednntml a Dilated cardiomyopathy nttpvvvvvvlltumcedulltumcpedscardioloclvmoviess ssmoviesdilcardlomvoosssnntml Left Sided Heart Failure Involves left ventricle Systolic failure Left ventricle loses ability to contract Can39t push enough blood into circulation Diastolic failure Ventricle loses ability to relax muscle has become stiff Can39t properly fill during resting period between beats Pulmonary edema Blood coming into left chamber from lungs quotbacks upquot causing fluid to leak into the lungs As ability to pump decreases blood flow slows causing fluid to build up in tissues throughout body edema Congestive Heart Failure Illahi Hand and bran Mina Rimming 51ner Hananwax 7 Fulmmary 7 Eight atrium F quot 39 Ahdnmlrnl uu lnfnrlnr Hana pram win ig th 1TH Hana arta I Ful ll Inga Symptoms of Heart Failure Symptom Why It Happens People May Experience Shortness of breath also called dyspnea Blood quotbacks upquot in pulmonary veins the vessels that return blood from the lungs to the heart because the heart can39t keep up with the supply Causes fluid to leak into lungs Breathlessness during activity at rest or while sleeping which may come on suddenly and wake them up Often have difficulty breathing while lying flat may need to prop up upper body and head on pillows Persistent coughing or wheezing Fluid builds up in lungs Coughing that produces white or pink bloodtinged phlegm Buildup of excess fluid in body tissues edema As flow out of heart slows blood returning to heart through veins backs up causing fluid build up in Ussues Swelling in feet ankles legs or abdomen or weight gain May find that shoes feel tight Symptoms of Heart Failure Symptom Why It Happens People May Experience Increased heart rate To quotmake up forquot loss in pumping capacity heart beats faster Heart palpitations which feel like the heart is racing or throbbing Confusion impaired thinking Changing levels of blood substances such as sodium can cause confusion Memory loss and feelings of disorientation Lack of appetite nausea Digestive system receives less blood causing problems with digestion Feeling of being full or sick to their stomach Tiredness fatigue Heart can39t pump enough blood to meet needs of tissues Body diverts blood away from less vital organs limb muscles and sends it to heart amp brain Tired feeling all the time and difficulty with everyday activities such as shopping climbing stairs carrying groceries or walking Heart Failure Video Outline What is Heart Failure Treatment of Heart Failure Heart Transplant Cardiac Assist Devices Total Artificial Heart Heart Transplant 19605 First heart transplants performed 19805 Antirejection meds became available Cyclosporine Today About 80 of heart transplants are alive two years after the operation I 50 percent survive 5 years Need 4000 patients are on the national patient waiting list for a heart transplant Only about 2300 donor hearts become available for transplantation each year Surgical Procedure httpwwwpbsorgwgbhnov aehearttransplantwavehtml Rejection a Risk of rejection is highest right after surgery In one study first year after transplant 37 of patients had no rejection episodes 40 had one episode 23 had more than one episode a Induction therapy Use of drugs to heavily suppress immune system right after transplant surgery 1 Patients keep taking some antirejection drugs for the rest of their life Preview of Immune System How Do T Cells Identify Virus Infected Cells Antigen Presentation All cells have MHC molecules on surface a When virus invades cell fragments of viral protein are loaded onto MHC proteins a T Cells inspect MHC proteins and use this as a signal to identify infected cells MHC Receptors 1 Two types of MHC molecules Class I MHC molecules are found on all nucleated cells Class II MHC molecules are found on antigen presenting immune cells a SelfTolerance T cells which recognize class I MHCself antigens are destroyed early in development a When this fails autoimmune disease Type 1 diabetes t5 Anlifnpreaenling muralth mime dliEp aw aniigen fragments an surface msentum Mariamage Maurapha 39 antigen in 5115 Antign fragment Antigenpresenting cell Antigenpresenth cell binds to T Iymphncyte TBEII reneptur Signal transductinn activates T Iymphnwte T lympnnnyte Donor MHC Matching a The greater the difference in peptide sequences of MHC receptors between donor and recipient The stronger the immune response The greater the chance of organ rejection 1 Matching 200 different histocompatibility antigens Each person has a certain quotset Odds that 2 unrelated people will have the same set are about 1 in 30000 Transplant coordinators try to match histocompatibility antigens of the donor and the recipient as well as possible to minimize rejection lmmunosuppressive Rx Cyclosporine azathioprine and lowdose steroids Reduce T cell activation T helper cell CT L activity Immunocompromised state Recipient susceptible to virusrelated diseases Bcell lymphomas EpsteinBarr virus Squamous cell carcinomas human papilloma virus Kaposi39s sarcoma a herpes virus Viral infections cytomegalovirus Graftversushost disease Caused by aoreactive T cells within the donor tissue that can cause tissue damage in the recipient Routine heart biopsies to monitor for rejection How To Become An Organ Donor Three steps 1 Speak with your family about your decision to donate Make sure they know about your wish to be an organ donor 2 Sign a Uniform Donor Card and have two family members sign the card as witnesses 3 Carry the card in your wallet at all times Uniform Donor Card Department of Public Safety where you obtain drivers licenses Download the Uniform Organ Donor Card littleWwwutdllustateutxuusaoleDbecomeantm Uniform Donor Card Telephone Why Inform Your Family If you haven t told your family you re an organ and tissue donor you re not Sharing your decision with your family is more important than signing a donor card In the event of your death health professionals will ask your family members for their consent to donate your organs and tissues This is a very difficult time for any family and knowing your wishes will help make this decision easier for them They will be much more likely to follow your wishes if you have discussed the issue with them Remember signing an organ donor card is NOT enough Discuss your decision with our famil More About Organ Donation httpwwworgandonorgov httpwwwtdhstatetxusagepbecomehtm httpwwwifeqiftorCIdefaulthtm httpwwwlifegiftorgUD Organ Donationhtml httpwwwshareyourlifeorq History of Cardiac Devices a 19505 and 19605 Heartlung machine Prosthetic materials to close holes between heart chambers Replacement valves Implantable pacemakers Coronary angiography to diagnosetreat coronary artery disease Intraaortic balloon pump IABP 1 19705 and 19805 IABP gains wide acceptance as temporary cardiac a55i5t 5y5tem Cyclosporine an antirejection drug makes human heart tran5p ants feasible PTCA to treat coronary artery disease with a balloon catheter External amp implantable ventricular assist devices enter clinical trials D 19905 External and implantable left ventricular assist devices approved for temporary support as a bridgetotran5plantation Requirements of Mechanical Support Nonthrombogenic blood contacting surface Pumping action that avoids blood trauma Variable output Small enough to fit in chest cavity Reliable Types of Mechanical Support Temporary LVADs Give heart muscle a chance to restrecover Bridge to transplantation Failure is not catastrophic Permanent Total Artificial Heart Replace damaged heart muscle Failure is catastrophic Em IKEaim mum1 r i l39iii mg 111 1339 LEA i axmrn 39l mail if 3251 I I I I E L I i 5 39 w 39 I j 7 J H E 7 inQHur ir Wm Mquot kin liriu Axial Flow Pumps cam Tam Hun Mum I Small Continuous nonpulsatile flow Artificial Heart History April 4th 1969 Haskell Karp became first human to have an artificial heart implanted Surgeon Denton Cooley performed operation Artificial Heart History 1 Denton Cooley Mr Karp has regained organ function indicated the mechanical heart is feasible 1 Mrs Shirley Karp He could not say anything I don t think he was really conscious One day they removed the tube from his throat they put a sheet over all the apparatuses in back of him and had they media take their pictures Immediately after this was done they put back the tube and opened up everything that had closed up Artificial Heart History Karp survived 5 days with artificial heart Human heart transplant was performed Karp died 14 hours later Artificial Heart History 3 Dr Debakey Led team testing artificial heart in animals a Dr Liotta Principal scientist developing artificial heart a Liotta s proposal Even though 4 of 7 calves died after implant Implant heart in human Debakey rejected proposal Liotta secretly went to Dr Cooley who agreed IRB was not informed Artificial Heart History a Dr Cooley Dr Debakey seemed to show little interest in ever using it Dr Liotta thought he was just wasting his years in a laboratory The time had come to really give it a test and the only real test would be to apply it to a dying patient In those days I didn t feel like we needed permission I I needed the patients consent I think if I had sought permission from the hospital I think I probably would have been denied and we would have lost a golden opportunity Artificial Heart History I Dr Debakey I was in Washington when I read in the morning pagers about the use of this artificial heart I I was shocked I didn t know he had taken it from the laboratory Artificial Heart History I No more human trials until the 19805 History of Artificial Heart httpwwwcnncom 200 1 H EALTHconditions07 03artificialheart June 2001 httpdiscovernprorqfeat uresfeatureihtmwfId11 23833 August 2001 httpdiscovernprorgfeat uresfeaturejhtmwfId11 27758 November 2001 httpdiscovernprorqfeat uresfeatureihtmwfId11 33260 History of Artificial Heart 0 1958 0 1965 Designed by Drs Willem Kolff Dr Willem Kolff and Tetsuzo Akutsu Silicone rubber heart Polyvinyl Chloride device Tested in a calf Sustained a dog for 90 minutes History of Artificial Heart 0 1969 0 1982 Dr Domingo Liotta Drs Willem Kolff Donald Olsen First to be implanted in human as and Robert Jarvik bridge to transplant Jarvik7 Patient survived for 3 days with First to be implanted in a human as artificial heart and 36 hours more destination therapy with transplanted heart Afti i l Heart Sy tam Mtl nlall Heart Enhanlsam WIIirE I tEES Energy transfer System E arnal Military Pauk mum HWEthf M n J 1 Int r al Rachargabla Baum Internal Euntrsnlllar llln AbioCor Artificial httpwwwheartpion eerscomnewsimaces htm Cost 70 100k Surgical Procedure 1 Surgeons implant energytransfer coil in the abdomen 3 The chest is opened and patient is placed on a heart lung machine Surgeons remove the right and left ventricles of native heart This part of the surgery takes two to three hours a Atrial cuffs are sewn to native heart39s right and left atria a A plastic model is placed in the chest to determine the proper placement and fit of the heart in the patient Grafts are cut to an appropriate length and sewn to the aorta and pulmonary artery The AbioCor is placed in the chest Surgeons use quotquick connectsquot sort of like little snaps to connect heart to the pulmonary artery aorta and left and right atria a All of the air in the device is removed a The patient is taken off the heartlung machine httDwwwDbsorcIwclbhnovaehearttranleantwavehtml BM E 365 Quantitative Physiology Overview I Drug and Device Regulation Re u n to Disaster Tragedy and Misfortune 906 Lecture 22 First federal regulauon or drugs en on FDA to PROVE it is UNSAFE FDA Reguiation of New Food Drug and Cosmetlc Act Drugs and Medical Prerrnarket NOTIFICATION I 1962 DEV39CES Drug amendments to FDampC Act Prerrnarket APPROVAL I Medical Device Amendrnens to FDampC Act Using Gold to Detect Cancer Using Gold to Feel Better How long do you think it will be before we can test this in patients I m wwwalchemistsworkshopcom my coleOOgALLPOLITICSl10102 offbeatblue candidate How long do you think it will be before we can test this in 39 t3 pauen g Vitamin Mineral HerbalSupplements Zantrex3 I Thousands sold in the US little is known about most Remarkably I WW nccom I39O w ducts I 6 out of 10 Americans take one or more ents a day I Americans spent 19 billion on dietary supplements in 2003 One of the most popular weight loss supplements currently sold in the US One month39s supply 350 I Millions of bottles sold Hit US market in March 2003 I Sold at39 GNC CV5 RiteAid WalerIart internet eBay onta ins t I ree common South American herbs that act as sumulans Zantrex Marketing I Don Atkinson I VP of Sales for Basic Research I Company that distIibutes Zantrexs3 I When I train salspeople1 say to them Do you know what people are calling you for It isn39t the pill They are calling you for hope That is rally what they want from you quot I I love my job And do you know why Because when I get up in the morning I know somebody39s life is better because we are here Somebody today got some hopequot hQIZZISOOQBEChSLD mlzantrexlcomboht mlsiteid ia cT7QKp 9k iDlg G4hCZyoEaxIX139 DS 5g 1994 Dietary Supplement Health amp Education Act I Congress deregulated supplement i dustIy Benefits of Supplements I Companies are not re quot I Vitamin C to prevent scurvy qulred to prove produCE are effective Mdlsm m or even safe before marketing them 39 39 cequot 39Y Scurvy kllled more Brrush sallors than War I Companies CANNOT Blatandylle I Folic acid to prevent neural tube defects Claim to have a cure for a specl c dlsease Cancer dlabetes Alos I Calcium to prevent osteopoross I Companies CAN say without evidence Productls deslgrled to supporta healthy heart 39 V39tam39 B12 to Prevent dement39a I CardlAll I Protect cells from damage LNerlte l m rove runcuon or Compromlsed lm murle system I Almost no smndards that regulate how pills are made I Not msted once they are m History of Supplements Lydia Pinkham s Vegetable Compound I 1793 I A Positive Curequot for all those Painful Complaints 39 and Weaknsses so common to our female I Patenlgeglslauon that perr ltte I I populationquot manu tuners m more t e ormu anons I 1914 AMA analyzed Pinkham39s compound I Did not require that they work 20 pure alcoho 39 Early 18005 I sonn pure vegetable extrace WN WNW I Number of newspapers in US published I Many supplements laced with increased dramatically I Cocaine 3 g I Early 19005 39 Caffeim 39 I Patentmedicine business accounted for mor 39 Mp39u h newspaper ads than any other kind of product 39 mp 39quote History of Supplements 1906 Pure Food and Drug Act Reaction to The Jungle by Upton Sinclair or misleading advertising History of Supplements 19 Sulfanilimide antibiotic for streptococcal infections used safely as a pill for years Most children can39t swallow p39lls One com ny in Tennessee found they could dissolve drug in ethylene glycol antifreeze Tested for flavor appearanoe fragrance NOT for toxicity Shipped it all over the country Within weeks scores of children were dead Sulfanilimide 137 children died Severe abdominal pain nausea vomiting convulsions Even the memory of her is mixed with sorrow for we can see her little body tossing to and fro and hear that little voice screaming with pain and it seem as though it would drive me insanequot Letter to FDR from woman describing the death of her child History of Supplements 1938 Food Drug and Cosmetic Act Gave FDA authority it needed to regulate such products I 1940519605 I 19705 History of Supplements Line between foods and drugs was fairly clea If manufacturers made a disease relate claim for a supplement FDA would go after them Government started telling Americans to alter diets if they wanted to have longer healthier lives Heart disease diabetes cancers 9 eat less salt fat add fiber eat more fruits amp table Kellogg s All Bran 1984 I Launched campaign with N I AllBran cereal illustrated how lowfat high fiber diet might reduce risk of certain cancers ht wwwkello scom rand allbran Today I CANNOT mention disease make claims that food can affect structure of function of body I Examples I CANNOT say that a product reduced cholesterol but CAN say it maintains healthy cholesterol levels I CANNOT say echinacea cures disease but CAN say it has natural antibiotic activities and is considered an excellent herb for infections r all Ilian Echinacea I One of the most commonly used cold remedies in US I ClinicalTrial 400 chlldren Wlth common colds over 4 months Compared placepo to echlnacea Placebo worked pat as well chllden takhg echlnace a were more llkely to develop a rash Ephedra I Was most popular supplement in US I Brought in more than Byear 39 al sa s I Risks of ephedra use when used with caffeine Increased rlsk of heart attack stroke palpltatlons anklety psychosls death I Steve Belcher 23 year old pltcher tor Baltlmore D39lole Dled February 2003 of heamtroke tollowlng ta khg an menthercounter procLlct that contalned eph da I h jwwwcnncom20031HEALTH1230cnna thompson Q BllE 3 Today uantltatlve y5lo ogy Misfortune I Congress Conslderlng a blll that would modlfy 1994 law so that d Isaste r amp many unregulated botanlcal supplemenm would be treated more llllte drugs than ll oo We put dlsclalmens ln our ads and we owe people the resulm ot the stcdles and a moneyrback guarantee What more could you Want Don t prevent people from ushg thelr Judgment Let them try lt If lt doesn t work retum lt Tha s whats talr That s whats Ame Lead to reforms in drug and device tragedy regulation FDA I Regulates products whose annual sales account for 394 of consumer spending in US I Responsible for ensuring SAFETY and EFFICACY of CHEMICAL BIOLOGICAL agents and sophisticated medical DEVICES I Safe I Probable bene ts to health for intended use outweigh any probable risk of harm I Effective I Device dos what it is supposed u do in a reliable History of Regulation I 1906 I First federal regulation ofdrugs I Food and Drugs Act I 1938 I Food Drug and Cosmetic Act I 1962 I Drug amendments to FDampC Act I 1976 I Medical Device Amendments to FDampC Act 1906 I Food and Drug Act I Label could not contain any statement regarding therapeutic effect which is false and fraudulent I FDA could act only after drugs were marketed I Was not enough to show that product did not work I Had to show that seller knew the claims it made were false 1938 I Food Drug and Cosmetic Act I New Drugs I Could not be marketed without rst notifying the FDA and allowing agency time to assss safety I Beginning ofera in which it is illegal to marketa new drug without FDA approval I Sellei s belief regarding product s value was no longer relevan I Issue does the product really work 1962 I Drug Amendments to FDampC Act I FDA must review evidence of drug safety and effectiveness I Converted premarket notification system into premarket approval system I Evidence of safety and efficacy must come from wellcontrolled investigations by qualified experts I FDA has the authority to prevent harm before it occurs Drug Approval Process I Preclinical testing cell animal occurs first I Assess togtlticity I Investigational New Drug IND I Human clinical trials allowed with IND I Phase 1 2 3 clinical trials I Manufacturer files NDA New Drug Application for permission to market new l7ch Drvnommr AND APPROVAL Pnouss Phases of Clinical Trials I Phase 1 I Goal safety of compound I Low doses administered to small group of healthy volunteers I 20100 volunteers I Phase 2 I Goal effectiveness of compound I 100300 patients who suffer from condition 3 IPh ase I Final step before seeking FDA approval I 39 39 39 trial PostMarket Surveillance I Phase 4 I Study longer term effects of drug exposure I Report adverse effects to FDA Not Many Drugs Make It I For every 500010000 drugs that enter preclinical testing I ONE makes it to market I Cost ofdeveloping one new drug I 360 million500 million Regulation of Medical Devices I FDA did not rnglate devices before 1938 I 193839 I FDA could only challenge sale of producB lt belleved were unsafe I Could only remove them from the market after pauent ll iJLlrleS I 19605 I Rapld lnnovauon ln medlcal technology I Trled to 9 late rn y sdr gs contact lenses lUDs I Catastrophlc fallures of heart valves and pacemakers I 19705 d recognluon that dlfferent rules were needed to reclul ate devl ces 1976 I Device amendments to FDamp Act I No single policy would work for all devices I Tongue depressor I Aru clal heart 1976 Device amendments to FDampC Act Three classes of devices Class I Pose least risk to patient Not ire sustaining ch proper record keeping required 30 of evices Xsray film tongue depressors stethoscopes l Class II Not ire susmining but must meet performance standards Blood pressire monitors Catheter guide wires 50 of devices I Class III Pose greatest risk to patient r se in supporting or susmining human life 10 of devices stems heart valves LVADs Require GMP failure modes analys39s animal mss human clinical studies under IDE Role of CDRH Ensure that products coming to market have more benefit than risk Ensure that products are labeled so that practitioners and patients know what to expect from their use Regulates 1700 types of devices 23000 registered manufacturers 1996 received 20236 device related submissions Device Approval Process Device intended use considered together Manufacturer submits request for marketing approval Advisory panel One consumer representative nonvoting One industry representative nonvoting Physicians and scientis s FDA not required to follow recommendations of panel although they usually do IDE Investigational Device Exemption Enables experimental use of high risk device Must have positive engineering and animal data First give approval for feasibility studies with small number of patients Then proceed to multicenter trials Larger data sets frequently show results from small sample sets are not true Humanitarian Use Exemption Device designed to treat or diagnose condition that affects lt4000 patientsyear Device would not otherwise be available without exemption No comparable device is available Patients will not be exposed to unreasonable or significant risk of injury or illness by device Medical Device Reporting System to detect device related problems in a timely manner Serious injuries or deaths that may have been caused by or related to a a medical device must be reported to the manufacturer of the device within 10 days Must be reported to the FDA within 10 days Recently Approved Devices I httpwwwaccessdatafdagovscriptscdr h cfdocslchopiclM DAlmdaIistcfm ist 1 I NIR ex Stent System I hm wwwfdagovlcdrhMdaldocslpozoow html I hmjwwwmedinolcornmirflexhtml Dkuc stuommr AND Arrnuvu Pnouss hm www39fda39gov cdrh PDFZEOZOMOalgdf I m wwwldagovlcdrhlPDFQPOZOMOhtmI 400500 million to develop one drug Pancreatic Cancer I Incidence I 31860 people in the US will be found to have pancreatic cancer in 2004 I Mortality I 31270 will die of the disease in 2004 I Fourth leading cause of cancer death in men and women Gm mom39 I Survival I one year surviv I Five year surviv Detection of Pancreatic Cancer Treating Pancreatic Cancer Early demtion i5 difficu39ti I 3 main types of treatment for cancer of I Pancr a is eepl the o v cannot see or feel tLlrnors during a rouune physlcal exam the Pancras I No blood tesB or other tests that can nd on cancer Surgery I Radiation therapy early ll l people Wlmour symptoms I By the time a person has symptoms the tumor has cancer may have Chemotherapy often reached a large slze and Spread t her We I Depending on the stage of the cancer 2 I Late symptoms or even 3 of thse types of treatment I Jaundlce am could be given either at the same time I vvelgnt Loss or one after the other I Dlgestlve Problems New Chemotherapy Vinblastine I Phase I clinical trials 10 patients I One year survival New Chemotherapy Vinblastine I Phase II clinical trials 100 patients I 5 lived one yar with new drug I One year survival I 20 for hismrical controls I 45 with new drug I Immediate treatment related mortality I Agematched controls standard treatment 17 I 2 patients had shortterm fatal drug reaction with I Immediate treatment related mortali Vinblastine 13 of dpatients had nearterm fatal drug raction to new rug I 2 of patients had n earterm fatal drug racu39on to standard treatment New Chemotherapy Vinblastine FDA Panel Meet39ng 39 Vinblastine I Randomized Phase III clInIcal trIals 300 patients I Cast of Characters I One year survival I Panel MDs I42 with new dru I 18 with standard treatment I Immediate treatment related mort 39 I Panel Pharmacologists a Ity I 10 ofgatiems had immediate fatal drug reaction to new rug I Pancreatic Cancer Patient I Family member of patient who suffered fatal I 1 of patient had immediate fatal reaction to druQ reacrlon In phase III shmcal trlal standard tratment I Drug company representative I FDA Officer Real FDA Decision Real FDA Decision I httpwwwcnncomHEALTH990326re Z I Lquot 11 KiNb I IL quot4120 ulinreview02 011119disputeddrughtm I Rezulin I Intergel I Drug to treat adult onset type 2 diabetes I Intended to reduce adhesions following gynecologic surgery internal scar tissue that I sensmzes b dY t0 lnSUlln can cause chronic pain or intestinal I Often given when patients fail other therapies obstruction I Taken by more than 750000 Americans I 281 women o I Associated with liver failure and death 55 0 ntergel recipients suffered infection at surgical site I Taken off the market in Britain I 29 of women who received standard surgical n treatment suffered an infectio NanoparticleLaser Robotic Surgery I Phase I clinical trials 10 patients I One year survival I 5 lived one year with new surgery I 20 for historical controls I Immediate treatment related mortality I 1 patient died due to surgical complications with new system NanoparticleLaser Robotic Surgery I Phase II clinical trials 100 patients I One year survival I 46 with new surgical system I Agematched controls standard treatment 17 I Immediate treatment related mortality I 13 of patients died on the table due to surgical complications with new system I 2 of patients had nar term fatal drug reaction to standard treatment NanoparticleLaser Robotic Surgery I Randomized Phase III clinical trials 300 patients I One year survival I 48 with new surgical system I 18 with standard treatment I Immediate treatment related mortality I 12 of patients died on the table due to surgical complications with new system I 2 of patient had immediate fatal reaction to standard trmtment FDA Panel Meeting Nanoparticle Robotic Surgery I Cast of Characters I Panel MDs I Panel Biomedical Engineers I Pancreatic Cancer Patient I Family member of patient who suffered fatal complication in phase III clinical trial I Medical device company representative I FDA Officer Summary I Drug and Device Regulation I Rmction to Disaster Tragedy and Misfortune 1906 I First federal regulation ofdrugs I Burden on FDA to PROVE it is UNSAFE 1938 I Food Drug and Cosmetic Act I Premarket NOTIFICATION 1962 I Drug amendments to FDampC Act I Premarket APPROVAL 1976 I Medical Device Amendments to FDampC Act Due Dates I Tuesday November 23rd I Egtltam Three I Wednesday November 24 h I Project Due e mail url I Thursday December 2nd I Presentation of top 6 projects BME 365 Quantitative Physiology Review of Lecture 1 I Course Overview I Introduction to Physiology I I Cells and Tissues I Pathophysiology Lecture 2 Intro to Modeling amp Review of Electrical i Circuiis Outline Outline Introduction to Modeling Introduction to Modeling I Review of Electric Circuits I Levels Of MOdeling sing the Accuracy of a Model mtions of Modeling I Review of Electric Circuiis Introduction to Modeling Experiment of the Day I Levels of Modeling I Picmrial Relationship I Cause and Effect lrrportant lneracuons and Mechanistic Analogy to Well Understood Physical System Quantimtive Description Analytic vs Numeric I 10 volunteers Introduction to Modeling n E ect I IrnD rtant Interactions and Mechanisms I Analogy to ell Understood Physical System I Quantitative Description I Analytic vs Numeric Assessing Model Accuracy Assessment Metrics I Comparison to Measured Physiologic Data I ModelBased Predictions 9 Suggest New Experiments 9 Compare to Measured Data Limitations of Modeling I GIGO I Simplifying Assumptions I Physiologic Parameters Outline Ies cnarge Current Voltage Resistance COn uctance Capacitance I Analysis Methods I KVL Arili I RC CircuiE Physical Quantities Charge Q Units Coulomb I Charge on electron 716 x 10quot9 C cnarge on proton 1 o x 10399 c xamp e I Ions inside and outside of cell Insi e DuEide Nat Ci39 IQJ LhitS lAmp loouornbs I Exam le Physical Quantities rrent 1 Flow or Charge o rrom one regon m another can 3 t dt equillbrium Flow orsmaii amount or charge dQ past a portin reference dream in one at Has magnitude and dream Posmve current is ow or posmve charge in rererenoe direcuon Flow ofiors into or ootora cell via rm dnanriels or pumps Physical Quantities Physical Quantities I V ltage I Resistance I Work required to move charge through ckt element s pe of quotmags v5 current curve vvv I One type of voltage source is a battery I For Ohmic materials V IR R VI Reamu Units I Other circuit elements such as capacitors and inductors also serve as voltage sources and store charge 39 1 9 1 WA Units at Example 1 v 1 Jc MW I Resistance of ion channels Exampe I Conductance I Membrane potential I Reciprocal of resistance I Units l 1 mho 1 AN Physical Quantities Analysis Methods PARALLEL PLATE CAPACI ro I Capacitance 1 l KCL I Two conducting regions I Conservation of charge separated by an insulator I I Sum of current entering branch p0int I Ability to store charge Sum of current egtltiting branch p0int cunning M Mle Eletmmty Water analogy g muuv Wm in l quot2 15A 5A lSIJs 5U E mumTi gltmlrmxe 39 i v up i IDA 10115 in Analysis Methods Analysis Methods I KVL 39 I Nodal Analysis I Conservation 39 Idem quotwas 1 Point Where 3 or more B5 of energy 3 Q Wires mee B2 I Sum of I Identify branches Bl B4 VOItage drops 1 y I Choose one node to be n quot N3 around any the reference ground B3 closed loop is node zero 2 Q I Write KCL at each node B6 I Express currents in terms 4 of node voltag I Solve for node voltages Nodal Analysis Nodal Analysis i 5 a 10 a 4 lo 5139 3051 09 109 3 1qu 09 we 20 Wire Nodal Analysis Special Circuits Voltage Divider N1 N3 we or more resistors connected in series mg 13 Q u 0 across a voltage source Often used to supply voltage that is different a 5 359 from available source innov quot1ElDDV 120an ZDDD 30 D 40 D N2 N4 Special Circuits Voltage Divider mm mm BERWink BEHAVKUR umEe LUAD mam 1hr inaned mi v mm mm VV k m Vt R w v u R A i i lurnum Lirtul Special Circuits RC Circuit In Switch 5 a charging process Switch 5 b discharging process Special Circuits I RC Circuit Simulation hgo llwebohysicsoavidson edumhyslet reso I hm webphysicsdavidsonedulphyslet reso urceslhu seme erllcll RChtm Summary I Introduction to Modeling I Review of Electric Circuits I hQllmathonwebcomlhelplbackgdlhtm I hlhxp rphyslcsphr ashgil edulhbaselelechiclvoldiv html Poem of the Day Billy Collins I Forms US Poet Laureate 2001703 I New York StaE Poet Laureate 2004705 Professor ofEngllsh Lehman College CCNY rmaquot Due Dates I Tuesday September 7 quot Homework 2 Lecture 1 Introduction to Physiology kortumbme365 Fat call 50450 um While bland cell l5 pm 1 Red blond I 9 cell 75 mu 6 Smonm muscle cell Sperm cell 15200 um long 5 um long Neuron m b sun4m pm wme S venhum 2nd Ed F932 S venhom 2 Ed H9315 F g 31b SHvenhom 2 Ed 30 w 40 929303 Ma Ma composed a nnmambrannu J mganelles Exlracelluiar uid EXTRACELLULAR FLUID Glycnpmhln Hg 3 5 rThe CeH membrane SHVerthom 2 Ed Endopllsmll mlculum Small sumnu Large subunit Hg 3 E r Rmusumes S venhum 2quotd Ed Hg 3 7b rThe cytoske eton Mlcrofllamems Micmtubule Inlermedlale lament SHverthom 2 Ed Microvilli Micmlilaments Hg 3 7a 7 Mmrumaments suvenhum 2quot Ed Omar mmmna Cytoplasm cum quotmum 0 cell o1 miwchondrion Oulslde M V Mamx cuma ouwr membrane Hg 3 a r Munchundna S venhum 2nd Ed Rlbosomes 7 Raugll umaplumlc mlculum smoom endoplasmlc mlculum 4 r A N v fwgw quot9 an L k 3 3 Hg 3 1n rm endumasmm vencumm S venhum 2nd Ed Secretary veal2m Mmurln 9 face Transport Fnrmlng m vesmles H3311 rThegmgwappavams suvenhumszu Inner mamhnne of nuclear envelop Broken ad a M outer mam una Omar memhlane of nunlanr envelope S venhum 2quotd Ed Hg 3 131m nuc eus e U S S T nlm d In 1 p E 1 i h 15 gervrlcg a quot I W 3 L n A O W F J E 1 m a u T U V A fl r u L 1 l a a a a a iir K Wu a PrbaCan er I 9 mi 39 Normal Cervical Tissue I II V ii q 7 39 AL A L L Rexiculur bers Melauncyla V V hers Mast call Elaslh Fran macrophage Collagen bers Fbrablasl Fm macrophage Whlie bland Dell The release at eeetyleheline at the r ieuremueeular MOW quotE39Jr n junetien causes an electrical impulse to be Acelylwmme generated in the muesle tsetl plasma membrane Electrical 1743quot impulse 5 395 The electrical impulse tux r l is carried ten the cell39s interior by the T tubules T tubule SarceplaSrriic reticulum I The electrical impulse triggers the release it Ca3 from the eereepleemie reticulum L39r 7 Muscle cell a i plasma membrerie Myelibn39ls Copyright 2001 Beryemin Cummings an impnnt 0t Addlson Wesley Lengman Inc 6IHEdmon I I PA 1 391 101 JGK OHARRISON S BASIS of quspxsp y ilmsw Ll Ii ln VquotI1ll1h In II tum 39 4quotquot s Kaspar araunwald Feud Mauser Lnngo Jarnanon BME 365 Quantitative Physiology 9 Lecture 1 1 Hodgkin Huxley Model Review of Lecture 10 I Organization of Nenous System I Constituent Cells of Nenous System I Electrical Signals in Neurons I Source of Resting Membrane Potential 0 Channels I Qualitative Dscripu39on of Action Potential I Graded Potential I Action Potential I Refractory Period rgxsruazmmmi simmauz m Outline I Revised circuit model of membrane I Hodgkin Huxley Model ofAP HodgkinHuxley Model I Hodgkin and Huxley I Developed rst quantitative model of propagation of electrical signal down giant squid axon I Most important model in all of physiologic literature Space Clamp Technique I Thread a wire through axon eliminate voltage gradienls along axon I Now V is a function of t ony mp HlHSlde salve eduwalshneumn wq History I 1902 Bernstein believed at rest v 770 rnV during acuvrty v o Before 1939 Merrbrane potenual importantbut no Way to measure it I 1940 Cole and Cums obtained evidence of increase ll i conductivity during AP Postwar Space clamp technique History 194s Hodgkin Hu ey and Katz record transient ionic uxes over physiological v 1949 Recognition Na K important explained overshoot 1952 Presented experimental data hypothesis t of model to experimental data and prediction of time course of the AP Voltage clamp Key to sorung out conductance Nobel prize Outline d cu model ofmembrane Rev se I odgkin Huxley Model ofAP Circuit Model of Membrane ul m iiwumnuu mmmmnto rummen 58 W 21m llrr m aslirrmcnie tum s mm out Lnnmiclmm llndimlorl in m urnm m a tll in mr uru or ilmmgh mt wudtttmte in ur mum nulw mimbmm ummllal but no wvm mhlt Lhaimt m lllL39 nilnitrmnc mumm rlgn cunnilinva smurmm rim mus um During m mm Circuit Model of Membrane I Membrane I Capacitor in parallel with ionic current I Membrane Voltage I vtvrnsaavwsaa m l I VEq Resting pot l ill xlquot xllt 39VN3NaN9I39nStpOtE LEM9Nth EVE gr vK K Nernst pot quot Tf I VL Leak Nernst pot I Transmembrane 1 quot1 I IImIKIL Circuit Model of Membrane Voltage Clamp I I ICIN KIL rm l I determining conductances a J l t dVIdt1lt mIgv vVN 9KV39V 9tVVt II dQCdtINaIKIL E lip if 3 Voltage clam a a K l I A plv voltage source v across membrane u I Fixes merrbrane potenuai at v 39 Qt cmV I dVdt0 IlungNaV39VN59KV39VKQVVL Then make a rapid step of v I Measure current mat rrust be supplied to keep voltage constant I I CmdVdtgNaVVNagKv39VKQLV39VL I Supplied current ransmemprane current I 19 VVV g VVV g VVV 39 dVdt 1CmI QNaV VNagKV VKgLV VL I IlweNsaepalrvaate erfectKof differLent channels then I To get any further need I Measure 1N2 Kasa runcuon or voltage GM Gown GM arajr lg Reference lground electrode Separating Ion Channels I Ion substitution I Sodium current zero when VVNa I C nge Na concentration to vary VNa and keep Valiage clamp device I Measure changes in potassium conductance Ion Channel Conductance I Potassium channels gK36n I 4 open n gates which work together I n is a ume dependent propaprlrtv mat anv one gate is open mm an open 17 n n XMV closed I op voltage dependent rate constanB dndt UnV139rl39Bnrl Ion Channel Conductance Sodium channels gNa120m3h Two types of gates l Three m gates 9 open I One hquotgate 9 close HMV HMV gt gt 17 m m 17 h h mW hV dhdt uhV1hl3hVh mm umv1m hvm Solutions All have the same form ntnm qliexprn2q am quotma2quot anVBnV rm an V B V Hodgkin and Hugtltey determined I an M 0 n mm M HH Measurements 0cm 01V35exp01V35 1 3quot 4expV6018 ah 007exp005V60 3h 11exp001V30 an 001V50exp001V50 1 3n 0125exp00125V60 Outline Revised circuit model of membrane Hodgkin Huxley Model of AP HodgkinHuxley Equations Major equations used by HodgkinHuxley to mathematically model action potential Cdedt35n4VVK120m3hVVN303VVL dmdt amVm1mi3hVmm dndtunVm1nl3nVmn dhdt ahvm139h39 hvmh Four coupled ODEs with highly nonlinear terms Cannot solve analytically Difficult to motivate solution in intuitive way Hodgkin 1977 Finally there was the dif culty of computing the action otentials item the equations which we had develo ed e had settled all the equations and constants by arch 1951 and hope to get these solve on the Cambridge to feel at we ad no wasted the many months that we had spent in analysing the records Huxley 1964 The computations were done by hand Tm Was a iaburiuus business a membrane action potentiai tank a manerufdaystu compute and a propagated aetiun p a atter er e permeabiiity Wuuid the membrane putentiai getaway mm a spike or me in a subthreshuid usmiiatiun Very often my expecta n turned Dune be Wrong and an important iessuri i iearned from these manuai computations Was m umpiete inadequacy er une s intuition in trying in deai With a system enms cumpiexity HodgkinHuxley Equations I Can we get intuitive sense for why system behavs in the way that it does I HH Simulator W I m ww tan 0rd du1af0dor1HHMode him Summary Poem of the Day Due Dates I Thursday October 7 h I HWS BME 365 Quantitativ Physiology A Lecture 22 FDA Regulation of New Drugs and Medical Devices Overview Drug and Device Regulation Reaction to Disaster Tragedy and Misfortune 1906 I First federal regulation of drugs Burden on FDA to PROVE it is UNSAFE 1938 Food Drug and Cosmetic Act Premarket NOTIFICATION 1962 Drug amendments to FDampC Act Premarket APPROVAL 1976 Medical Device Amendments to FDampC Act Using Gold to Detect Cancer a Antibody A How long do you think it will be before we can test this in patients Using Gold to Feel Better 1 WEEDZfWWWnaHChEWlStSWQFkShQDEC m 1 h pszwwwncnncomZlQQEALLPQLETECS1 f 2 offbeatublueucancliolate How long do you think it will be before we can test this in patients Vitamin Mineral HerbalSupplements Thousands sold in the US Remarkably little is known about most httpwwwndnecomproducts 6 out of 10 Americans take one or more supplements a day I Multivitamins Amino acids Weightloss cures Herbal tonics Americans spent 19 billion on dietary supplements in 2003 Zantrex 3 One of the most popular weight loss supplements currently sold in the US One month s supply 50 Millions of bottles sold Hit US market in March 2003 Sold at GNC CVS RiteAid WalMart internet eBay Contains I Caffeine Green tea Three common South American herbs that act as stimulants Found in Cosmo Glamour and Parade DISCUVEI Ed In Britney39s purse w I 5 he pills Revealed htt1800atchesco Emmy mzantrexcomboht mlsiteidia QKQ M Q fHDlG4hCzoEaXIX39 DSSg Landon SQDtcmber 3 03 e amney spears nkqs shnn ng mus a 2n mnmtmu her sexy shape atcarmhq m s anusquot mm avSpawn m pap DVVKQSS has muted um drawing a mm m burningquot tables as Landau s Haammw Anvm yesterdlv e hufm39e baardwq s mm a Les memes Vimtngmphs m we Lundnnrhnsnd mw Expmss Shaw Kruney mum m a mum ban n whuh we ab md mms m hnvn dqnnhm ss mm e s mm m d1ltf suvv Ement Zantrex Marketing 1 Don Atkinson VP of Sales for Basic Research Company that distributes Zantrex3 a When I train salespeople I say to them Do you know what people are calling you for It isn t the pill They are calling you for hope That is really what they want from you a I love my job And do you know why Because when I get up in the morning I know somebody s life is better because we are here Somebody today got some hope 1994 Dietary Supplement Health amp Education Act Congress deregulated supplement industry Companies are not required to prove products are effective or even safe before marketing them Companies CANNOT Blatantly lie Claim to have a cure for a specific disease cancer diabetes AIDS Companies CAN say without evidence Product is designed to support a healthy heart M Protect cells from damage Events Improve function of compromised immune system Rt LSi Almost no standards that regulate how pills are made Not tested once they are made Benefits of Supplements Vitamin C to prevent scurvy Mid18th century cl Scurvy killed more British sailors than war Folic acid to prevent neural tube defects Calcium to prevent osteoporosis Vitamin B12 to prevent dementia History of Supplements 3 1793 Patent legislation that permitted manufacturers to protect their formulations Did not require that they work a Early 18005 Number of newspapers in US published increased dramatically 3 Early 19005 Patentmedicine business accounted for more newspaper ads than any other kind of product Lydia Pinkham s Vegetable Compound A Positive Cure for all those Painful Complaints and Weaknesses so common to our female population 1914 AMA analyzed Pinkham s compound I 20 pure alcohol 80 pure vegetable extracts Many supplements laced with Cocaine I Caffeine l Opium ad a V H tlT HLH WHPWE l Morphlne Iil mu r 3 up lquotf lllfl 39LT1 History of Supplements I 1906 Pure Food and Drug Act Reaction to The Jungle by Upton Sinclair Permitted Bureau of Chemistry to insure that labels contained no false or misleading advertising History of Supplements 3 1937 Sulfanilimide antibiotic for streptococcal infections used safely as a pill for years Most children can t swallow pills One company in Tennessee found they could dissolve drug in ethylene glycol antifreeze Tested for flavor appearance fragrance NOT for toxicity Shipped it all over the country Within weeks scores of children were dead Sulfanilimide m 137 children died Severe abdominal pain nausea vomiting convulsions 1 Even the memory of her is mixed with sorrow for we can see her little body tossing to and fro and hear that little voice screaming with pain and it seems as though it would drive me insane Letter to FDR from woman describing the death of her child History of Supplements I 1938 Food Drug and Cosmetic Act Gave FDA authority it needed to regulate such products History of Supplements 1 1940519605 Line between foods and drugs was fairly clear If manufacturers made a disease related claim for a supplement FDA would go after them 1 19705 Government started telling Americans to alter diets if they wanted to have longer healthier lives Heart disease diabetes cancers 9 eat less salt fat add fiber eat more fruits amp veetables Kellogg s All Bran I 1984 Launched campaign with NCI AllBran cereal illustrated how lowfat high fiber diet might reduce risk of certain cancers httpwwwkelloggsc0mbrandallbran Today a CANNOT mention disease a CAN make claims that food can affect structure of function of body 3 Examples say that a product reduced cholesterol but say it maintains healthy cholesterol levels N say echinacea cures disease but iiiiiiliahl say it has natural antibiotic activities and is considered an excellent herb for infections Echinacea One of the most commonly used cold remedies in US I Clinical Trial 400 children with common colds over 4 months Compared placebo to r V i V echinacea gamma Cl39lllltl39f Ami Placebo worked Just as well Children taking echinacea were more likely to develop a rash Ephedra Was most popular supplement in US Brought in more than lByear 10 of supplement industry annual sales Risks of ephedra use when used with caffeine Increased risk of heart attack stroke palpitations anxiety psychosis death Steve Belcher 23 year old pitcher for Baltimore Orioles Died February 2003 of heatstroke following taking an overthecounter product that contained ephedra a httpwwwacnncom2003MEALTHX1230cnna1 thompsonz Today a Congress Considering a bill that would modify 1994 law so that many unregulated botanical supplements would be treated more like drugs than like foods 1 Supplement manufacturers Assault on first amendment We put disclaimers in our ads and we give people the results of the studies and a moneyback guarantee What more could you want Don t prevent people from using their judgment Let them try it If it doesn t work they can return it That s what s fair That s what s Americanquot BME 365 Quantitativ Physiology A Misfortune disaster amp tragedy Lead to reforms in drug and device regulation FDA 1 Regulates products whose annual sales account for 14 of consumer spending in US a Responsible for ensuring SAFETY and EFFICACY of CHEMICAL BIOLOGICAL agents and sophisticated medical DEVICES a Safe Probable benefits to health for intended use outweigh any probable risk of harm a Effective Device does what it is supposed to do in a reliable fashion History of Regulation 1906 First federal regulation of drugs Food and Drugs Act I 1938 Food Drug and Cosmetic Act I 1962 Drug amendments to FDampC Act I 1976 Medical Device Amendments to FDampC Act 1906 a Food and Drug Act Label could not contain any statement regarding therapeutic effect which is false and fraudulent 3 FDA could act only after drugs were marketed 3 Was not enough to show that product did not work 1 Had to show that seller knew the claims it made were false 1938 Food Drug and Cosmetic Act I New Drugs 1 Could not be marketed without first notifying the FDA and allowing agency time to assess safety 3 Beginning of era in which it is illegal to market a new drug without FDA approval Seller s belief regarding product s value was no longer relevant Issue does the product really work 1962 a Drug Amendments to FDampC Act FDA must review evidence of drug safety and effectiveness Converted premarket notification system into premarket approval system Evidence of safety and efficacy must come from wellcontrolled investigations by qualified experts 1 FDA has the authority to prevent harm before it occurs Drug Approval Process 3 Preclinical testing cell animal occurs first Assess toxicity 3 Investigational New Drug IND a Human clinical trials allowed with IND Phase 1 2 3 clinical trials 3 Manufacturer files NDA New Drug Application for permission to market new drug Disemewf Pt39ectliiiieeit Testing Titheirs Iii5 Teet Laljlzlraten anti F w iti n animal eturliee ears egge eaten Fiwnp ee Imelmglml activity and iierrnulatinzne Seeeese Eiuu Haite mmpeunrle evaluatefl Ftte IND at FDA Ctnicell Triatlle Pt iaise Phase Pheee I II III 1 5 2L3 h 7 JLJ i UL it ELL i LILU ti EMIIJLJ healthy patient lznaitient 39eIiLll39ItEFE39IS mlunteele autnlunteere Determine EmlLlente Centirm E39ITFE39EH39IEE39HE39SE safety elilietiveneeeng nmnit r fi39e39E39IEE39 and leak liar I39E39Ellfiillll39lfa tram tlcueage SifiE e39lilienrte Icingterm LISE39 L enter triele Hie MBA at F t FDA Ptiaiee LS Eeei ew p n teest apprm39n I I pp lave 39i w39i39itlflitiel i Eli peet ITI mketing testing reqLIiIetl byFDA THE 0in EVEt eMEM AND APPMML Peecees Phases of Clinical Trials 3 Phase 1 Goal safety of compound Low doses administered to small group of healthy volunteers 20100 volunteers 3 Phase 2 Goal effectiveness of compound 100300 patients who suffer from condition a Phase 3 Final step before seeking FDA approval Randomized clinical trial PostMarket Surveillance Phase 4 Study longer term effects of drug exposure I Report adverse effects to FDA Not Many Drugs Make It For every 500010000 drugs that enter preclinical testing ONE makes it to market Cost of developing one new drug 360 million500 million Regulation of Medical Devices FDA did not regulate devices before 1938 1938 FDA could only challenge sale of products it believed were unsafe Could only remove them from the market after patient injuries 19605 Rapid innovation in medical technology Tried to regulate many as drugs contact lenses IUDs Catastrophic failures of heart valves and pacemakers 19705 Broad recognition that different rules were needed to regulate devices 1976 Device amendments to FDampC Act No single policy would work for all devices Tongue depressor Artificial heart 1976 Device amendments to FDampC Act a Three classes of devices I Class I Pose least risk to patient Not life sustaining GMP proper record keeping required 30 of devices X ray film tongue depressors stethoscopes I Class II Not life sustaining but must meet performance standards Blood pressure monitors Catheter guide wires 60 of devices I Class III Pose greatest risk to patient For use in supporting or sustaining human life 10 of devices Stents heart valves LVADs Require GMP failure modes analysis animal tests human clinical studies under IDE Role of CDRH a Ensure that products coming to market have more benefit than risk 3 Ensure that products are labeled so that practitioners and patients know what to expect from their use 3 Regulates 1700 types of devices a 23000 registered manufacturers a 1996 received 20236 device related submissions Device Approval Process 3 Device intended use considered together a Manufacturer submits request for marketing approval 3 Advisory panel One consumer representative nonvoting One industry representative nonvoting Physicians and scientists 3 FDA not required to follow recommendations of panel although they usuall do IDE 3 Investigational Device Exemption Enables experimental use of high risk device Must have positive engineering and animal data First give approval for feasibility studies with small number of patients Then proceed to multicenter trials Larger data sets frequently show results from small sample sets are not true Humanitarian Use Exemption a Device designed to treat or diagnose condition that affects lt4000 patientsyear 3 Device would not otherwise be available without exemption 3 No comparable device is available in Patients will not be exposed to unreasonable or significant risk of injury or illness by device Medical Device Reporting 1 System to detect device related problems in a timely manner a Serious injuries or deaths that may have been caused by or related to a a medical device must be reported to the manufacturer of the device within 10 days 1 Must be reported to the FDA within 10 days Cliwiul Irixls Dixcmnry Hum mm Phase Prlcliniczl tailing I m mu 5 15 2 35 20 m m mumsuu luu0la5uuu ml labmm ml ham pallenl pallenl Pnpulzlmu annual males 9 mlunleers mllmleers allle 5 Assess mm 3 Dem wme mums Purpnsu lnloluglml snlelv ensnwem mumlm mm 2 mm ml g ml lmk ml resinous How mnmllallons mge ms ellezls lungm use sucms Spun 5 mm zumpmmds mluml enlerlllals THE DRUG DEVELOPMENT AND APPROVAL PROCESS 400 00 million to develop one drug Recently Approved Devices 3 mmfiwwwneceeeedatenfdauelevScrDECSCm hiefdeCSC ep cMAimde ietcfm st m NIRerX Stent System httpwwwufdangevCdrhmdadecsp2 4 u htm httpWWWQmedme ucemimr exnhtm httpwwwfdanqevCdrhPFZPQZWeEmnpdf httpwwwfdanqevCdrhPFZPmm thtm WW mum Pancreatic Cancer Incidence 31860 people in the US will be found to have pancreatic cancer in 2004 Mortality 31270 will die of the disease in 2004 Fourth leading cause of cancer death in men and women Survival One year survival 1520 Five year survival few percent Detection of Pancreatic Cancer 3 Early detection is difficult Pancreas is deep inside the body cannot see or feel tumors during a routine physical exam No blood tests or other tests that can find this cancer early in people without symptoms By the time a person has symptoms the tumor has often reached a large size and cancer may have spread to other organs a Late symptoms Jaundice I Pain Weight Loss Digestive Problems Treating Pancreatic Cancer a 3 main types of treatment for cancer of the pancreas Surgery Radiation therapy Chemotherapy 1 Depending on the stage of the cancer 2 or even 3 of these types of treatment could be given either at the same time or one after the other New Chemotherapy Vinblastine Phase I clinical trials 10 patients n One year survival a 5 lived one year with new drug 1 20 for historical controls Immediate treatment related mortality u 2 patients had shortterm fatal drug reaction with Vinblastine New Chemotherapy Vinblastine Phase II clinical trials 100 patients n One year survival 3 45 with new drug d Agematched controls standard treatment 17 Immediate treatment related mortality a 13 of patients had nearterm fatal drug reaction to new drug a 2 of patients had nearterm fatal drug reaction to standard treatment New Chemotherapy Vinblastine a Randomized Phase III clinical trials 300 patients n One year survival 42 with new drug 18 with standard treatment Immediate treatment related mortality 10 of patients had immediate fatal drug reaction to new drug 1 of patient had immediate fatal reaction to standard treatment FDA Panel Meeting Vinblastine Cast of Characters Panel MDs Panel Pharmacologists Pancreatic Cancer Patient Family member of patient who suffered fatal drug reaction in phase III clinical trial Drug company representative FDA Officer Real FDA Decision ai HxANMWMCWW IM HEALTHV932WZ UHEWJQVEEW Z a Rezulin Drug to treat adult onset type 2 diabetes Sensitizes body to insulin Often given when patients fail other therapies Taken by more than 750000 Americans Associated with liver failure and death Taken off the market in Britain Real FDA Decision 3 httpWWWUusatodavucomnewsnealtl iZf 1a1119 lisoutedndruguhtm a Intergel Intended to reduce adhesions following gynecologic surgery internal scar tissue that can cause chronic pain or intestinal obstruction 281 women 56 of Intergel recipients suffered infection at surgical site 29 of women who received standard surgical treatment suffered an infection NanoparticleLaser Robotic Surgery Phase I clinical trials 10 patients n One year survival a 5 lived one year with new surgery 1 20 for historical controls Immediate treatment related mortality a 1 patient died due to surgical complications with new system NanoparticleLaser Robotic Surgery 3 Phase II clinical trials 100 patients n One year survival 46 with new surgical system Agematched controls standard treatment 17 Immediate treatment related mortality 13 of patients died on the table due to surgical complications with new system 2 of patients had near term fatal drug reaction to standard treatment NanoparticIeLaser Robotic Surgery a Randomized Phase III clinical trials 300 patients n One year survival 48 with new surgical system 18 with standard treatment Immediate treatment related mortality 12 of patients died on the table due to surgical complications with new system 2 of patient had immediate fatal reaction to standard treatment FDA Panel Meeting Nanoparticle Robotic Surgery 3 Cast of Characters Panel MDs Panel Biomedical Engineers Pancreatic Cancer Patient Family member of patient who suffered fatal complication in phase III clinical trial Medical device company representative FDA Officer Summary Drug and Device Regulation Reaction to Disaster Tragedy and Misfortune 1906 I First federal regulation of drugs Burden on FDA to PROVE it is UNSAFE 1938 Food Drug and Cosmetic Act Premarket NOTIFICATION 1962 Drug amendments to FDampC Act Premarket APPROVAL 1976 Medical Device Amendments to FDampC Act Due Dates Tuesday November 23ml Exam Three Wednesday November 24th I Project Due email url Thursday December 2nd Presentation of top 6 projects Lecture 19 Models of CV System Heart Disease BME 365 Quantitative Physiology m Outline I Compliance and Cardiac Output I Model 1 I Single chamber heart I Resistive closed loop I Model 2 I Slnglechamber hea t s ternlc resistance I Compliant I Heart Disea lt arteries and Vell is se U a U E 1 m 2 I Heart Attack Outline I Slnglecnamber heart I Resistive closed loop chamber heart I Systemic resistance I Compliant arteries and veins I Heart Dis e I o veins I As pressure increases they can expand v VD CF I C gtgtC arteries ea cl bal burden art Attack I Pathophyslology I Pathophyslology planners Dl osls Compliance Cardiac Output I Blood vssels are elastic I Think of hart as compliance vessel I V VDt CtP I Diastole I Heart is at rest I Very compliant I Hessure venous pressure I Systole I Heart contracting I Much less complia e nt I H ssure aortic pressure m mm im ll a s rlguzsr ammurpuumrm clalgualiilgmaummmt sum 7 a Cardiac Output I VDt CtP I Diastole I VED mx CDPV I systole P I vES mm CXP I cxltltcD v V I Stroke Volume We ia I vim vm 7 VW CDPVV CSPJ I Cardiac Output I co Hmv m I Mostly determined by P Starling39s Law Outline 1 irigle chamber heart esisuve closed loop I oe I Singlechamber heart I Systemic resistance I Compliant arteries arid veins I Heart Disease I Pathuphysiulugy I Dimnesis Model 1 I Heart I Single chamber I Com iant I Circulation I Resistive I Diagram Model 1 Q PamR Q HRVH Copy CsPa I Two ow rates must match in steady state I Unknowns I P3 PW Q I Dos not uniquely determine solution I We have not allowed the circulatory loop to be a compliance vessel Outline I Compliance and Cardiac Output Model 1 I Singlechamber heart I Resistive closed loo Model 2 I Single chamber heart I Systemic resistance I Compliant arteries arid veins ear Isease I Global burden I Heart c I Pamuphysiulugy I Dignesis Model 2 I Heart I Single chamber I Compliant I Vminvmagtlt I Circulation I Systemic rsistance I Compliant arteris and veins I Diagram Model 2 Q HRCDPV Q PamRs va capa vvcVPV va vv vT I System of 5 linear equations Model 2 I Flow rates Q HRCDPV Q PaPvRs I Arteries and veins are linear compliance vessels with zero volume at zero pressure I Va CaPa I VV CVPV I Total blood volume is constant vavv vT Model 2 I As HR increass I summon Pa increasesm vca 7 1 HRCDRS VT I As HR decreass CV 1 HRCBRJCH Pa decreases m vcvca I As HR decreass A PV increases to vcvca CV 1 HRCpRQCa I In heart failure 41 PV pfpa gt no flow Q7 HRCDV CV 1 HRCDRSW39I I Increase In R5 ase PV Shift of blood from venous to armrial sysmm Outline I Compliance and Cardiac Output I Model 1 I Single chamber heart I Rsistive closed loop I Model 2 I Single chamber heart I ystemic rsistance I Com iant arteris and veins I Heart Disease I Global burden I Hart Attack Pamophysiology Diagnosis Global BurdenCardiovascular Disease I In 1999 I CVD contributed to a third of global deaths I In 2003 I 167 million deaths due to CVD I By 2010 I CVD is estimated to be the leading cause of death in developing countries 2002 Worldwide Mortality Mortality in Developing Countries i ii umiii Quill Burden of CVD United States VD bout 61 million Americans almost Va of population have CVD I ccounE for more than 40 of all deaths 950000 Americans die of cardiovasmlar disease each year Two main forms o CVD ischemc heart disease Stroke Ischemic Heart disas Leading cause of death in us Coronay heat disease is a leading cause of premature permanent disability among working adulE troke I Third leading cause of death 39n the US Cost of CVD dismse 351 billion 209 billion for health care expenditures I 1i Ullll ii i i US Burden of Heart Attack I Consequences of ischemic heart disease I Caused by a narrowing of the coronary arteries that supply blood to the heart I Often resulB in a heart attack I Each year I 11 million Americans suffer a heart attack I 460000 of those heart attacks are fatal I Half of those deaths occurwithin 1 hour of symptom onset before person reaches hospital Early Detection of CVD Risk Factors I Tobacco use I Low levels of physical activity I Inappropriate diet I High blood prssure Over 70 not under control I High cholesterol Over 80 not under control Screening for CVD I Mmsure BP annua y 1213 point reduction in blood pressure can reduce heat cks by 21 I Check cholsterol every 5 mrs 10 drop in cholesterol can reduce heart attacks by 30 Of Those With High BP Percentage of Americans with Uncontrolled High Blood Pressure by Race and Ethnicity 90 Percent Aiiican Mexican While Total us Aineiimii Aiiieiicaii Pdpulatlan Serum Ch olesterol Levels 2 LDL causes hateshemt m hum up msrde Maud vesse s HDL actuaHV vemaves ha estem m the watts ar Maud vesse s ma hvmqs rt hack m the my m be safE V excvaed H ea rt Attacks Pa wophysro ogy Dragnosrs I Treatment M mm mm m M a w m m 5mmquot Wu a m a m Mmm m m a m m 5mmquot mm m x W mm M m aquot m m wt W W tquot m w m W b 2 bane 2wakm Mm hamtn eev Nthauqh hemed In M mama m at up M mm r M mam amt m W m In M d my zrngmmixgzrn W m mm W m g i Mm zmavdrxzamhnrnmxzmvxbut Mmquot my m m W m Mum Jim mm g 2 x m 2 wRVSCE me W 53W SEW NW een 2nd m M mug wuqh 2nd Mutt WNW mgquot humhummasmKnuauezhejnun Early Warning Signs of Heart Attack Mawheavtattiksstavtstaw w S wmmsmanmeand qa Chest msmm fmt Max M nka mw vldmamfon For m thzn zkw mmutex mm mmquot on feet We mammmtpymm mueexr m the my Mum m hm Immame We quot1 mum m m Drsmmfmt m athev areas ar the HDDEV hadY cquot mdud mm mm m m mm m m m m 12w Shmtnessafhveath om mm m m m drxzamfon a t m an auuvbefom m mmquot 0mg 5 pm Mmmdude mm m m 2 HM wt New ham Mam Heart Attack Signs W dryu m Tunan media TI Ink1 advnnmia Heart Attack Video I httg www heart comattackguidan cf m Tissue Plasminogen Activator Tissue plasminogen activator lPA A thrompoiyuc agent can dissoiye blood cioB Approved tor use in certain pauenB haying heart atiz or SlTO clinical studies m and other ciotrdissoivirig agenB can reduce the amount ot damage to the heart muscie and saye iiyes To be ettectye they must be giyen Wi in a ew hours atter symptoms pegin Administered through an intrayenous iv the in the arm by hospital personnei 30 NB treated Wilhii i 90 minutes after O set of chestpain are on yenth as iikeiy to die compared Thrombolytics I Risks of thrombolytics Intraaaniai hemorrhage ninoeased risk in those gt age 70 PatienE may requ39re further inmrventr39on I Costs of thrombolytics streptok39nase 320 Effectiveness of Thrombolytics I Clinical Trial in 15 countries and 1051 hospimis 41021 pauenB With eyoiying myocardiai intarcton Randomly assigned to 4 different strategies I vamkinase and subcutarimus Hwavin I vamkinase and IV Hwavin I Accelerated nssue Diasmintum acnvami WA 2rd IV Hwavin I Ctme cf svewt kinase Dius hi YA with IV hEDaiiri Primary end pointwas Bonday mortality eillt strepmkinase amp subcut heparin 7 2 stroke 0 49 strepmkinase amp W he arin 7 4 stroke 0 54 Aoceierated EPA amp W heparin s 3 stroke 0 72 CostEffectiveness of BME 365 Quantitative Physiology Lecture 21 Heart Failure Review of Last Time I How do we treat coronary artery disease I CABG PTCA x I Stent I Prevention Progression of Heart Disease High Blood Pressure High Cholesterol Levels Heart Failure Atherosclerosis Heart Attack Ischemia Outline I What is Heart Failure I Treatment of Heart Failure I Heart Transplant I Cardiac Assist Devices I Total Arti cial Heart Outline I Treatment of Heart Failure I Heart Transplant I Cardiac Assist Devices I Total Artificial Heart Heart Failure I Heart failure I Occurs when left or right ventricle loses the ability to keep up with amount of blood ow I Can involve the heart39s left side right side or both sides I Usually affects the left side rst I About 5 million Americans are living with heart failure I 550000 new cases diagnosed each year Quantifying Heart Performance I Ejection Fraction EF I Fractim of blood pumped out of ventricle relative to total volume at end diastole I EF SVIEDV I Normal value gt 60 I Measured using ecnocardiograpny I Normal echocardiogram I wwikumciedu umc eds cardiolo movies n mm I Dilated cardiomyopathy I ntt 1 wwwikumciedu umc eds cardiolo movies s Left Sided Heart Failure I Involves left ventricle I Systolic failure I Left ventricle loses ability to contract I Can t pusn enough blood into circulation I Diastolic failure I Ventricle loses ability to relax muscle has become stiff I Can t properly fill during resting period between beats I Pulmonary e ema I Blood coming into left cnamber from lungs backs up causing fluid to leak into the lungs I As ability to pump decreases blood flow slows causing fluid to build up in tissues throughout body edema I Congestive Heart Failure Symptoms of Heart Failure Symptoms of Heart Failure Heart Failure Video Outline I What is Heart Failure l Treatment of Heart Failure I Heart Transplant l Cardiac Assist Devices l Total Artificial Heart Heart Transplant I 19605 I First heart transplant performed I 1980s I Antirejection meds became available Cyclosporine I Today I About 80 of heart transplant are alive two years er the operation I 50 percent survive 5 years I Need I 4000 patients are on the national patient waiting list r a heart transplant I Only about 2300 donor hearts become available for Surgical Procedure I httDwwwDbsorqwthnov aeheartltransplantwavehtml Rejection I Risk of rejection is highest right after surgery I In one study rst year after transplant I 37 of patients had no rejection episodes I 40 had one episode I 23 had more than one episode I Induction therapy I Use of drugs to heavily suppress immune system right after transplant surgery I Patients keep taking some antirejection drugs for the rest of their life Preview of Immune System I How Do T Cells Identify Virus Infected Cells I Antigen Presentation I All cells have MHC molecules on surface I When virus invades cell fragments of viral protein are loaded onto MHC proteins I T Cells inspect MHC proteins and use this as a signal to identify infected cells MHC Receptors I Two types of MHC molecules I ClassI MHC molecules are found on all nucleated cells I Class II MHC molecules are found on antigen presenting immune cells I SelfTolerance I T cells which recognize classI MHCself antigens are destroyed early in development I When this fails autoimmune disease I Type 1 diabetes 1 w 3quot aquot lm many Antigenpresenting nail bln s in T lymphoma Anllgen nagmem A Antigenpresenting cell Signal llansductlun nubalas 1 ymmmcv 7 T lymphocyte Donor M HC Matching The greater the difference in peptide sequences of MHC receptors between donor and recipient The stronger the immune response The greater the chance of organ reiection Matching 200 different histocornpatlbiiity anugens Each person has a certain set dds that 2 unreiated peopie Wiii have the same set are about 1 in 30000 Transpiant coordinators try to mat ch histocorrpatlbiiity antigens of the donor and the recipientas weii as possipie to minimize reiecuon Immunosuppressive RX Cyclosporine azathioprine and lowdose steroids I Reduce Trceii activation Trheiper eii cn itivi Immunocompromised state Recipient suscepubie to virusrreiated diseases Bteii iymphnmas Ep einraa39r Virus Equamuus eii cartinum human papiiiama Virus ynsi s sarmma a herpes Virus v Graftversushost Isease I Caused by aiioreactive Trceiis within the donor tissue t can cause ussue damage in the recipient Routine heart biopsies to monitor for rejection How To Become An Organ Donor l Three steps 1 Speak with your family about your decision to donate Make sure they know about your wish to be an organ 2 Sign a Uniform Donor Card and have two family members sign the card as witnesses 3 Carry the card in your wallet at all times Uniform Donor Card Department of Pubiic Safety where you obtain drivers iicenses Downioad the Uniform Organ Donor Card t S a e h 9 www tdh stateDlt u i g pibecorne htrn Why Inform Your Family If you haven t told your fanin you re an organ and tissue donor you re not Sharing your decision with your family is more important than signing a donor ca d n the event of your death halth profssionals will ask your family mem or their consent 0 ona e your organs and tissues This is a very dif cult time for any famil and knowing your wishs will help make this decision msier for hem They will e much more likely to follow your wishs ifyou have discussed the issue with them Remember signing an organ donor card is NOT enough Discuss your deci ion with Vour familvl More About Organ Donation I httpwwworgandonorgov I httpwwwtdhstatetxuslagegzbecomehtm I httpwwwlifegiftorgdefaulthtml I httpwwwlifegiftorgUD Organ Donationhtm I httplwwwshareyourlifeorgl History of Cardiac Devices I 19505 and 19605 I Heartrlun machine I Prosthetic materials to close holes between heart chambers Replaceme yaiyes Implantable pacemake Coronary angiograpny to diagnosetreat coronary artery disease IABD map gains Wide acce ance as temporary cardiac assist system cyciosporine an antrrejection drug makes human heart transp anE feasible DTCA to treat coronary artery disease With a balloon catheter S External and impiantapie left yentricdiar assist deyices approved for temporary support as a bridgertortransplantation I External amp implantable ventricular assist devices enter clinical trials Requirements of Mechanical Support I Nonthrombogenic blood contacting surface I Pumping action that avoids blood trauma I Variable output I Small enough to fit in chest cavity I Reliable Types of Mechanical Support I Temporary LVADs I Give heart muscle a chance to restrecover I Bridge to transplantation I Failure is not catastrophic I Permanent Total Artificial Heart I Replace damaged heart muscle I Failure is catastrophic Ml m Whatn Mm may mmm vE mu 7 antiwar air m KM sxn liriu Axial Flow Pumps awn mum I Small Artificial Heart History I April 4 1969 I Haskell Karp became first human to have an artificial heart implante I Surgeon Denton Cooley performed operation Artificial Heart History I Denton Cooley I Mr Karp has regained organ function indicated the mechanical hart is fmsible I Mrs Shirley Karp I He could not say anything I Idon39t think he was really conscious I One day they removed the tube from his throat they put a sheet over all the apparatuss in back of him and had they media take their picmrs I Immediately after this was done they put back the tube and opened up everything that had closed up Artificial Heart History I Karp survived 5 days with artificial heart I Human heart transplant was performed I Karp died 14 hours later Artificial Heart History I Dr Debakey I Led team testing artificial heart in animals I Dr Liotta I Principal scientist developing artificial heart I Liotta s proposal I Even though 4 of 7 calves died after implant I Implant heart in human I Debakey rejected proposal I Liotta secretly went to Dr Cooley who agreed I IRB was not informed Artificial Heart History I Dr Cooley I Dr Debakey seemed to show little interest in ever using I l r Liotta thought he was just wasting his years in a laboratory l The time had come to really give it a test and the only real test would be to apply it to a dying patient I In those days I didn t feel like we needed permission I I needed the patients consent l I think ifI had sought permission from the hospital I thinkI probably would have been denied and we would have lost a golden opportunity Artificial Heart History I Dr Debakey I I was in Washington when I read in the morning pagers about the use of this artificial heart I I was shocked I I didn t know he had taken it from the laboratory Artificial Heart History I No more human trials until the 19805 History of Artificial Heart I httpwwwcnncom200 IZHEALTHZconditions107l 031artificialheartl l June 2001 I htgldlscoyerngrorglfeat ureslfeamrehtml7wfld11 23833 I August 2001 I thUdlscoyerngrorglfeat ureslfeature html7wfld11 27758 I November 2001 I thUdlscoyerngrorglfeat uresfeal1lre html7wfld11 3260 History of Artificial Heart 958 1965 DeslgnedbyDrs willern Kolff Drwillern Kolff andTetsuzoAkutsu Slllconerubberheart Polyvinylchlnrldedevlce Testedlnacalf Sustalnedadogforg mlnutes History of Artificial Heart 969 1982 DrDomlngoLlotta Drszllem KolffDonaldOlsen Flrsttobelmplantedlnhumanas andRobertJanlk brldgetotransplant naiieiii Ii ieeiei ua iiii i artificial heart and 36 hours more destlnatlon therapy With transplanted heart AbioCor Artificial Heart The Abiocor Arki clal ean I htt wwwheart ion sym39quot 39 1 eerscomnewsimages quot mm 39 39 html mam I I Cost 70100k VIIIlulu mth mm rumI lnnllul heer anagram Imuy n Surgical Procedure I Surgeons implant energytransfer coil in the abdomen The chest is opened and patient is placed on a hart ung machine Surgeons remove the right and left ventricles of native heart This part of the surgery takes two to three hours I Atrial cuffs are sewn to native heart39s right and left atria A plastic model is placed in the chest to determine the proper placement and t 0 the heart in the patient Gra s are cut to an appropriate length and sewn to the aorta and pulmonary artery The AbioCor is placed in the chest Surgeons use quotquick onnectsquot sort 0 like little snaps to connect heart to the pulmonary artery aorta and left and right atria h I h h I All of the air in the device is removed quotn WWW quot m I The patient is taken off the heartlung machine Due Dates I Tuesday November 23rd I Egtltam Three I Wednesday November 24 h I Project Due e mail url I Thursday December 2nd I Presentation of top 6 projects BME 365 Quantitative Physiology Lecture 16 Cardiovascular System Outline Overview of CV System Funcuons lernervB Factors Affecting Blood Flow I Cardiac Muscle arid the Heart The Heart I Cardiac Muscle Heart as a Pump I Coordinated Electrical Contraction EKG Factors Arrecung Cardiac mum Outline Overview of CV System Doris Factors A Heart as a Pump I Coordinated Electrical Contractori EKG Factors Arrecung Cardiac Output Overview of CV System I Fu nctions Cells need oxygen nuh39ienls Oxygen can diffuse a limited distance Solution evolution of a circulatory system I Elements Heart Blood vessels Blood rlguerumianmyamecmmWMIm 5mm 251 Outline Overview of CV System uncuorvs F Elemene eart as a Pump I Coordinated Electrical Contractori EKG Factors Arrecung Cardiac mum Factors Affecting Blood Flow I Flow rate F o APR I Resistance to flow R e 8Lnn Velocity of ow I v Fcross secuonal area I Terms I F ow rate volume orbiood passing point in system per unit urne Lrnin pressure gra lent esistance to ow vasoconsmcuondilauon uid VlSCOSltV l I r vesse radius v velocity or ow The Heart I Four chambers encased in pericardium I Compose of I Cardiac muscle myocardium I Thin layer of epithelium and connective tissue I Semilunar valves separate ventricles and sels I Coronary arteries Supply myocardium with blood rguwamux siuemanznm Blood Pressure I My blood pressure 10368 I The higher systolic nurnber represene the pressure while the heart is beaung I The lower diastolic nurnber represene the pressure when the heart is resting between beaB I Normal blood pressure I Varies frorn rninute to mnute I Varies With changes in posture I Should be lt 12080 mm Hg for an adult I Hehypertension I Blood pressure that stays between 120713980789 I Hypertens39on I Blood pressure above 14090 rnrn Hg How Do We Measure BP I Sphygmomanometer I Increase cuff pressure until it is higher than systolic pressure I Blood flow into arrn stops I Gradually release pressure I When curr pressure systolic pressure I Bland begins ti flaw again I Hear Kurutkurrsuund assailated Witn mrbulent flaw thruugh artery I When curr pressure diastolic pressure I Artsy is nu lungs umpre sad I Nu lunger hear Kurutkurr eund How Do We Measure Blood Pressure Cardiac Muscle I Most cardiac muscle is contractile I Striated muscle with contracule bers organized into sarcomeres I Smaller than muscle cells I Have single nucleus bloo 2X amount extracted by other D I 1 of myocardial cells are specialized I Generate APs spontaneously I Called autornytnrnlc cells or pacemakers I Do not have sarcorrieres I Give neartaplilty to contract Wo ouelde signal dr a I Cardiac rnuscle extrace mezzoaa ofoxygen dellyered by ssues rummamnm smmra Cardiac Muscle I Intercalated disks I Cardiac muscle cells branch and join neighboring cells end to end at these disks I Interdigitating membranes tightly linked by desmosom I Allow force created in one cell to be transmitted to adjacent cell I Also contain gap junctions ked transmembrane proteins I Allow direct movement ofions from one cell to net cell I Electrically couple neart rnuscie so dnatwayes or depolarizau on can contract almost slrnultaneously Contraction in Cardiac Muscle I Occurs via sliding filament movement as in skeletal muscle I An AP is required to initiate contraction I AP opens yoitage gated calcium cnanneis I Calcium enters cell 0 E E I Reiaxanon occurs when caiclurn unbinds from troporiiri I Calcium transported back to SR Witn nelp of calcium ATPaSe 932 Graded Cardiac Muscle Contraction Single cardiac muscle fiber can vary amount of force it generate I Skeletal muscle ls all or none Force generated 4 active crossbridges Number or a ss is determried by cytosollc calcium concentration Regulated by epinepnrine and norepinepnrine For both cardiac and skeletal muscle Force or conbacuon depends or sarcomere length at beginning of contraction Depends on overlap between min and mick lamene BUT in cardlac muscle stretcning can also allow forceful addltlonal calclum to enter a more Fgullrmhmubllm tranmuasama sluemanz m CONUBCUON APs in Cardiac M uscle 1m skalml muscle 5 l Myocardial contractile cells g Similar to APs in neurons and skeletal muscle 5 5quot Rapid depol due to Na a an mm quotmm Steep repol due to avl g Main difference Lengthening of AP due to 5 calcium e tr so m so an inn Sareamere length 94 oi maxlmum l Stable resting potential of 90 mV I Wave ofdepol comes in from neighboring 5 cells via gap junction WmlmllKlmw s WuHr zmlwumlavaummwllnzlkul Sluemanz m APs in Cardiac Muscle AP opens voltage gated Na enannels Na entry arapig depol to 20 mV Doubly gated Na enannels close K v ugn open K enannels cell begins repol AP attens into plateau due to betraasea K permeaiiti as rast K channels lose Increase in EalElum pamemility due to opening ofvoltage gated altlum Channels Calcium enannels close and slow K enannels open K eXlB and cell repolarlzes In ux ot calcium lengthens AP 1 u ce ms Cardiac cell 200 ms 9 prevenls tetanus FiguisrMumupemalxxehulamummmuw sluemanz m Autorhythmlc Cells Unstable membrane potentia Stare at 750 mV and slowly ante up wnen it reaches threshold AP is red Different ion channels At 7 5 Bath w Nat dwawnels are upen Lthannels Nat influx gt efflux Sluwly depularlzes tell As membrane potenual becomes more posmve harm ls luse up n many atthreshnld lnum depularlzes tell Calciumthawnels El se Slaw K Ehanneb upen Repnlarlzatlnn atturs Timing of Autorhythmic APs Overview of CV System Funcuons Elements Factors Affecting Blood Flow ac lVLlscle and the Heart Heart as a Pump I Coordinated Electrical Contracuon EKG Factors Affecung Cardiac Output quotmumm uwu mmmwgmm quotquot t Awe Sensitive to s w mm Altered ion channel permeability 5 l Norepinephrine and epinep r39 it Increase If and calcium channel permeability 5 a i w J Varan X WM Increase rate of AP fIrIng mm 1 r 1m meme rammmm mama Outline Heart as a Pump Coordinated elech39icalconduct39 n utornymmrc cells form an The nonnconbactl a anatomic pattern in tne neart SA node Group of cells rn Set pace of near Internodal pathway Connecs SA node to AV node top of ngnt amum t node Group of cells near oor of ngnt atrium S Bundle 0 H Purkinje fibers m we Etmiwmlmn in m Heart as a Pump I SA node initiates wave of atrial contraction I Fibrous skeleton ofheartat AV Jui iCDOi i prevents Uai ismissioi i of APs except to AV node I APs from AV node initiate ventricular contraction I AV node de a I Ventricular contraction always follows atrial Coi m achoi i A node I Highest rate of spontaneous AP generauon I Sets heart rate EKG I Recording of electrical activity of heart I Made from electrodes placed on skin surface I Signals wmk buy the time they rach skin surface I 100 mV at heart I 1 mV at skin I EKG h ws sum of electrical potentials generated by all cells of heart at any time Flgiuienuhmmhgm smmma EKG of One Cardiac Cycle I F wave I Atrial depolarization I QRS complex I Ventricular depolarization I T wav e I Ventricular repolarization muzzeoummm My mum m mum in mum ace Slum 7 a Cardiac Cycle I 1 Hart at rest I Atria filling with blood from veins I Ventricles have just completed a contraction s open I Blood flows from atria to ventricles lt m x q a a m 3 a 2 gt lt E 2 m I Push blood into ventricles Cardiac Cycle I 3 AV node res I Ventricles begin to contract I Forces AV valves closed 1St heart sound I Semilunar valves still c osed I Isovolumic contraction I Atria begin to repolarize and fill I 4 Ventricles complete contraction I Force SL valves open I Blood exils to arteries Cardiac Cycle I 5 Ventricles relax I SL valves close 2nd heart sound WW 11quot 7 7 x i m ll i ii memmmmm 5mm in mm ngzsr unmlubllivuxlmmllma mammammm Slum 7 I Quantifying Cardiac Performance Venh39icles ED end diastolic volume N135 rnl E v systoiic volume 55 rnl Stroke volume I SVEDV7ESV I Amount coriU39acu m 2 1 ofblood purrped by 1 yenmcie ii i 1 on gtlt SV Amount ofblood purrped per yenmcie per dmt urne I NSL rniri Normal blood volume is N St Quantifying Heart Performance Ejection Fraction EF I Fracuori of blood umped out of ventricle relative to total volume at erid diastole I EF SVEDV I Normal value gt 60 Measured usirig ecnocardiograpny Normal echocardiogram mm Dilated cardiomyopalh I htt www ku Y g 1 rnc edukidrncgedsicardiolog rnoviesi Factors Affecting CO Heart rate Paras mpadneuc acuyity decreases HR Sympatn c acuyity incre ses R Stroke v e Depends on rorce generated by cardiac rruscle during corit racuori Eorce is arrected by Lengtnetmsiun reiatinn A5 sartamere lengthens tensiari during anhactian increases Sterling s law CDritreEtili centmied by nervous and EridDEririe systems centramiity inErE ES as available EalEiurn inErE ES riguz Naming 4 menan awn 4 riguziemwmw iagm simmered Outline Overview of CV System Furicuoris ElerneriB Factors Affecting Blood Flow I Cardiac Muscle arid the Heart Tine Heart I Cardiac Mus i CDritraEtiDri Atticn Putmtials Heart as a mp I Coordinated Electrical COi iU aCDOi i EKG Eactors Affecurig Cardiac Q put Poem ofthe Day Due Dates Tuesday November 2nd Homework 8 BME 365 Quantitativ Physiology A Lecture 15 DeMyelinating Disorders Review of Lecture 14 Reflex Integration of sensory information into an involuntary response Basic components of a reflex Stimulus activates a sensory receptor Receptor sends information via AP to CNS CNS selects appropriate response and initiates AP in efferent neurons to muscles andor gland Feedback an important part of many reflexes Outline Overview Diagnosis I What is MS MRI Epidemiology Evoked Potentials Role ofmyelin Treatments Pathologic Features Interferon Plaques in CNS Copolymer 1 Pathophysiology Treatment of I Immunology Symptoms Symptoms Presenting symptoms Disease course Outline Overview Diagnosis I What is MS MRI Epidemiology Evoked Potentials Role ofmyelin Treatments Pathologic Features Interferon Plaques in CNS Copolymer 1 Pathophysiology Treatment of I Immunology Symptoms Symptoms Presenting symptoms Disease course Impact of MS I remember well the day that l was diagnosed My wife and I had been married for twelve years both with good jobs and living in a nice house Now the doctor sitting across the desk from me said Well John I hate to be so blunt but you either have a brain tumor or you have Multiple Sclerosis It was like getting hit between the eyes with a brick There l was in the prime of my life with everything going for me and now suddenly faced with a lifechanging illness There l was a relatively young man working full time in a great career with nothing but a bright future ahead Now suddenly the picture was changing drastically httpwwwmsactivesourcecomapplicationmsasdest2Fportals2Fmsas2Flw ms2FconLWMSDetailjspampdocl DlwmslwmssamplemynameisjohntxtamplwmsFro mfeatampJSPBASEUNIQUEURLCREATOR1067089092805 Case Study 1 Margaret is a 32 year old nurse Three years ago she had a baby Four weeks after delivery she began to feel very tired and had some difficulty passing urine She then developed a heavy sensation in her legs and her husband noticed that she was dragging the left leg While taking a shower one morning she noticed that she could not discriminate between hot and cold water on the right leg Ten years priorto this she had noticed that the vision deteriorated in her right eye although it recovered over a period of one month She had not sought medical attention for this Margaret saw a neurologist She was brought into hospital where she undenvent an MRI scan and a lumbar puncture A diagnosis of relapsing remitting MS was made Margaret39s aunt also suffers from MS as does her first cousin Margaret commenced on betainterferon and has been well for the past three years httpwww brainresearch ieprofilecndmul htm Case Study 2 httphealtholoqvhealinqwellcomfocus i ndexaspfm sclerosis The Story of a Doctor with MS Case Study 3 httpwwwnprorqtemplatesstorvstorvp hpstorvd1148988 What is MS Slowly progressive CNS disease characterized by disseminated patches of demyelination in brain amp spinal cord resulting in multiple varied neurological symptoms amp signs usually with remission and exacerbations Characterized by chronic inflammation demyelination amp scarnng a MS lesions disseminated in time and space a Disease variable in severity and course ranges from benign illness to rapidly evolving and incapacitating disease Probably autoimmune disease triggered by environmental exposure in genetically susceptible host Herpes virus6 causes roseola 90 of adult American population exposed to HHV6 Reactivation of virus may cause breakdown of myelin Epidemiology m Affects 350000 Americans 3 million worldwide a Strikes predominantly young adults 2040 a Most frequent cause of neurologic disability in young adults 1 Women twice as susceptible as men a Twice as common in Caucasians as African Americans m 5 times more prevalent in tropical climates childhood exposure to warm climate is most important Cell Baldyr Buma Dendrites equot I Had uf Flamrim 391 fl Nucleus s 39 L Axon Myelin Presynaptic Terminal Outline Overview Diagnosis I What is MS MRI Epidemiology Evoked Potentials Role ofmyelin Treatments Pathologic Features Interferon Plaques in CNS Copolymer 1 Pathophysiology Treatment of I Immunology Symptoms Symptoms Presenting symptoms Disease course Plaques in CNS Multiple scarred areas visible on macroscopic examination of the brain plaques Plaques vary in size from 12mm to several cm Lesions evolve over time Initially contain T lymphocytes and macrophages which infiltrate areas of demyelination As lesion evolves macrophages scavenge myelin debris Then scar tissue forms MS lesions are typically more numerous than anticipated based on clinical symptoms Correspondence between number and size of plaques and severity of clinical symptoms is not precise Pathophysiology Demyelination can have either positive or negative effects on axonal concluction Negative Effects Slowed axonal conduction due to loss of salutatory conducUon Can treat using blockers of voltage gated potassium channels that become exposed in internodal axon membrane following myelin loss Variable conduction block due to axonal transaction Positive Effects Ectopic impulse generation Can treat using calcium channel blockers to reduce the threshold for impulse generation Abnormal crosstalk between demyelinated fibers Immunology 1 Autoimmune disease modulated by T lymphocytes Etiology not completely understood much of what we know comes from animal models of experimental allergic encephalomyelitis another dymelinating disease a Etiology Neural antigens are processed by antigen presenting cells in lymph nodes and presented to T cells Sensitized memory T cells migrate to the CNS where they are reactivated by antigen presenting macrophages Proinflammatory cytokines are secreted Enhance expression of adhesion molecules by vascular endothelium alter permeability of the bloodbrain barrier and induce a second wave of inflammatory cell recruitment Inflammatory response leads to localized demyelination a Autoantigen is most likely a myelin protein An ipewpresanfing call A sirmyte Antibzdy k 1 Ufgodendrocyie B39ooc vcsssl IIyelm she th Mychn antgcn CEHmwgratun Somme mematurs cytmnes hemkmes e pruteases h39TrD 39 4349 Dicture3gif Basement memb from Hailfab Brain 1997 MS 101 Multiple Sclerosis 101 Outline Overview Diagnosis I What is MS MRI Epidemiology Evoked Potentials Role ofmyelin Treatments Pathologic Features Interferon Plaques in CNS Copolymer 1 Pathophysiology Treatment of I Immunology Symptoms Symptoms Presenting symptoms Disease course Symptoms Characterized by CNS dysfunction with remissions and recurring exacerbations Presenting Symptoms a Visual disorders optic neuritis blurring of central visual field loss of brightness in one eye eye pain a Movement coordination and balance problems a Numbness and tingling paresthesia and dyesthesia a Spacticitiy Tremors Weakness and fatigue Bladder and bowel disorders Diagnosis by exclusion Percent in E Pain Dementia Vismalj i033 Facial Malay Impetmc My nkymia Epilepsy sis mammary Table 3761 Harrison s Principles of Internal Medicine Videos of Symptoms httpmedstatmedutahedukwmsvideo html Course 1 Clinical course is highly variable a Four general courses of disease Figure 3761 I Relapsingremitting MS Attacks generally evolve over days to weeks Followed by complete or partial within weeks to months No progression of neurologic impairment between attacks Secondary progressive MS most common form Progression between attacks May begin shortly after disease onset of delayed for years or decades Primary progressive MS No distinct relapses between attacks Affects less than 15 of all MS patients I Progressing relapsing MS Rare Tlma n mlapsingrcmming c n FIGURE 3764 Clinical pallenls of MS 39 E F Hg 3754 Hamsun s Pvmmmes u mevna Medmme lt lllgtuao Stabe Reapse ngressiml MS Classifications was 1 Benign Multiple Sclerosis 1 AAA 2 Relapsing Remitting Multiple Sclerosis 3 Secondary Chronic Progressive 4 Primary Progressive 10 r 20 of patients TIMEH Course I The longer a cohort is followed the smaller the portion of patients with mild disease I 15 years after diagnosis 20 of MS patients have no functional limitation 70 are limited or unable to perform major activities of daily living 75 are not employed Outline Overview Diagnosis I What is MS MRI Epidemiology Evoked Potentials Role ofmyelin Treatments Pathologic Features Interferon Plaques in CNS Copolymer 1 Pathophysiology Treatment of I Immunology Symptoms Symptoms Presenting symptoms Disease course Diagnosis 1 No clinical sign or diagnostic test finding is unique to MS Usually easily made in a young adult with relapsing and remitting symptoms referable to different areas of CNS white matter a Diagnosis divided into Probable MS Definite MS I At Risk for MS Table 3762 quotExamination musi nva Ulijc39i39lii39l ubuumlzllilics of mu CNS lnvulvnmenlmusirencciprcdo i mlydiseuuofwhilmanerlnngimcts 39 1w hicercbellarpaillwuysic men I 1 I mulluncl gin dill longimdina fasciculus d npli ne xnminniiun orh rvz and c pas erior co l mus Islury mum impllcule invlllvcmcni ur Wu or more mu 3N1 CN u MRI may be used ID dnaumcni n Jet39mul lesion when only one site of lbni Aconlinuninry mm ulil 39 bean demunslruble oli exllmlnaimn r lesium invnlving the while runner or irce lcsiuns rm y musl have uilJIer ml ll39onl is perilmilieu muuonn Acuupin man 3 mm in mama Fur paliems older allowing cr en mun Iilsn be met lul lesion size gt5 min b ldsinns Ibul me hudius uf um Imam vullu iuiea uuu it leuuulnl rumm in mu n les 39xllusi be grcnler him so ycats m39n n he mica nxnmlunuuu a cllmulll puuzm mun cunsisi of zli iwn ur mum separate ennuim ul39 rimming involving lhffel tll 39lne CNS cnch lnsunz u lens 24 n Indvccllnim m lensl 1 mulllh upm or b gradual ur slupu u m mn ou 51mm low 6 monihs if uccnmpunind by incrczlied csr lgG synthesis or poslerlm u vb EYukEd mpumu Inning may be med 0 dncumtnl 11 mm Icaiun rim vi cm on c 39 o c n Ag ofunsel heween l5 um 60 years n s nuumiugic ummiuuu mum um hemr ix zilLribulcd ID nnmher u Lnlmm ury csiing thin may be xdvisnblc in ccnnin cuses includes CSF mmlysi h MRI urine head nr spine in serum vilumin 13 level A human T cell iymphmmpil virus type i v1 limn iL39 crydu ocyle Mimenlunion run in rheumuloui i uclur ununucluun unliDNA lmubudjzs 5113 g scrum VDRL h angimcminvtonvenin enzvme imrcnidosis i l nnzliii scrulogy iLynua dismal 0 very in ngL any ldsiu rennv ysl unhyluiidlilscmm nrlmu musciu hinpynrmimllmn 39Illial DNA Amulvus m m hmld m disorders GNOthC CATEGORIES pe nlle Ms All sh criieriu ful lledu 39Pmbnbin MS All six main ful lled umpl a Only on ablative abnur u svmpmmauc episode or lb only un symplomuul sadl dcspllc lwu or more ublccuvc ubnurmnlilicn rtdknrMS All six cri crin ll lledcxceplonly one sympmmalic epimde one objccliv nbuurmnluy W um Table 3762 Harrison s Principles of internal Medicine Diagnostic Techniques 3 MRI plaques in CNS T2 weighted images show bright foci in CNS a Evoked Potentials Record electrical response evoked in the nervous system following repetitive sensory auditory visual or motor stimuli arms or legs Shows slowed or abnormal conduction in visual auditory somatosensory or motor pathways Thought to result from loss of salutatory conduction along demyelinated axons MRI Analysis of MS Lesions httpspwebbwhharvardedu8000pagesppmarkmsmshtml Lesion Evolution Over Time httpsplwebbwhharvard edu8000pagesppImarkmsmshtml SG rinse P DD w ave Latency ED mam Pi wam Latency 134 m ser Outline Overview Diagnosis I What is MS MRI Epidemiology Evoked Potentials Role ofmyelin Treatments Pathologic Features Interferon Plaques in CNS Copolymer 1 Pathophysiology Treatment of I Immunology Symptoms Symptoms Presenting symptoms Disease course Treatment Kurtzke Expanded Disability Status EDSS used to measure neurologic disability Table 3763 Important to track overtime to make therapeutic decisions EDSS 01 No disability minimal signs in one functional system FS 12 Minimal disability in 1 FS 23 Moderate disability in 1 FS or mild disability in 34 FS though fully ambulatory 34 Fully ambulatory with aid up and about 12 hoursday despite relatively severe disability able to walk with aid for 500 meters 45 Ambulatory with aid for about 200 meters disability impairs full daily activities 56 Intermittent or unilateral constant assistance required to walk 100 meters with or without resting 67 Unable to walk beyond 5 meter even with aid essentially restricted to wheelchair wheels self transfer alone 78 Essentially restricted to bed or chair or perambulated in wheelchair but may be out of bed much of day retains selfcare functions generally effective use of arms 89 Helpless bed patient can communicate and eat 995 Unable to communicate effectively or eatswallow 10 Death due to multiple sclerosis Treatment to arrest disease process a Two chronic treatments available I Interferon Downregulates expression of MHC molecules on surface of antigen presenting cells actions of cytokines expression of vascular endothelial adhesion molecules Inject 1Xweek side effect flulike symptoms Copolymer 1 Induce antigen specific suppressor T cells competitive binding to MHC molecules on surface of antigen presenting cells Inject side effects flushing chest tightness palpitations anxiety Both therapies reduce exacerbation rates by 13 Many patients develop neutralizing antibodies against interferon Steroid to relieve inflammation in acute relapses Why Start Treatment httphealtholoqyhealinqwecomfocus i ndexaspfm sclerosis Making a Plan for MS Why Start Treatment Interferon Side Effects httphealtholoqyhealinqwecomfocus i ndexaspfm sclerosis Help with Interferon Therapy Tips from MS Nurses New Treatments httpwwwnprorgtemplatesstorystory phpstoryId898856 Treatment of symptoms Muscle relaxants to treat spasticity Treat depression Hallpllng Form a us I Memmvexmm or 21 Azalhlanrinu m Mumylpmdntsorany S m Cydmhosnhmde pvadmsune ac HQ 3764 Hamson s Pr nc p es of ntema Med cme Outline Overview Diagnosis I What is MS MRI Epidemiology Evoked Potentials Role ofmyelin Treatments Pathologic Features Interferon Plaques in CNS Copolymer 1 Pathophysiology Treatment of I Immunology Symptoms Symptoms Presenting symptoms Disease course Poem of the Day Due Dates Tuesday October 26th Exam II BME 365 Quantitative Physiology g Review of Lecture 8 I Printing Microarrays I Experimental Design I Human Genome l 40000 genes Tool to study 9 expression which 9 r mmed f s cells grow divide respond to hormones etc Lecture 9 I Reading Microarrays I Use ofMicroarrays omics Studying Cell Cycle Control I Cancer Diagnosis Hognosis Choice of Rx Gene Expre mm M We on WWW edu zW excellence HEP HEP m vateduvehtm Study Cell Cycle me Malemlev Bialaqy ar the Cell a Predict Tumor mm 1 U RX Response 39 E l i 39 L i E I Ethical Issues I httpwwwnprorgfeaturesfeaturephp wfId1690425 I httpwwwnprorgfeaturesfeaturephp w d1897199 Outline I The Big Picture I Laser Capture Microdissection I Tissue Microarrays I Proteomics I Metabolomics Outline I Laser Capture Microdissection I Tissue Microarrays I Proteomics I Metabolomics Central Dogma Gene ATGAGTAACGCG Nontemplate strand TACTCA I I GCGC Template strand Transcription mRNA AUGAGUAACGCG Translation note in MetSerAsnAla Orders of Magnitude I 3 billion nucleotides I 3000040000 human genes I 50000300000 human proteins I only 1020 found in a given cell omics Genome Total genetic material of an organism Organism s complete DNA sequence Constant feature of an organism Proteome Entire protein complement expressed by a genome or by a cell or tissue type Dynamic Metabolomics Small molecules found in biological fluids Flow of Biological Information DNA 9 mRNA 9 Proteins 9 Modified Proteins Genome Transcriptome Proteome Level of Analysis Term Methods of Analysis Genome Genomics Systematic DNA seq uencing Transcriptome Transcriptom ics Hybridization arrays History 1986 Genomics 1995 Proteomics 2000 Human genome sequenced SAGE Proteome Proteom ics 2D PAGE Mass spec Metabolome Metabolomics NM spectroscopy Outl i n e u The Bi Picture Laser Capture Microdissection Tissue Microarrays Proteomics Metabolomics Laser Capture Microdissection Tumors are heterogeneous Cell types undergoing similar molecular changes may constitute less than 5 of the volume of tissue biopsy Laser Capture Microdissection Procedure for procuring pure cells from specific microscopic regions of tissue sections mm mmquot mum nu w w mm Whole Biopsy gas A Tumor Cells Onlyr if 1 I k 2 wwwm mun um g Wmummpmllv mmmm mu 9 I Q i 5 mm mm hmnwuumh What is LCM Inverted microscope with low power near IR laser Tissue sections mounted on glass slide 100 micron thick ethylenevinyl acetate film placed over dry section Laser focused to 7 pm spot on cells of interest Laser melts thermoplastic lm binding it to targeted ces Film absorbs energy so molecules not damaged Film amp adherent cells are removed Cells lysed for analysis of DNA RNA or protein LCM I Lecture Videos lcmmov I wwwarcturcom Outline I The Big Picture I Laser Ca ture Microdissection I Proteomics I Metabolomics Tissue Microarrays I Multiple slides that contain hundreds of individual tissues I 600 spoBslide I 700800 micron spacing I Relocate tissue from conventional blocks I Use a needle biopsy I Re embed them in arrayed master block I Histochemical amp molecular detection techniques for regular sections can be used with microarrays Figure l Figure 2 h WWW ale am or EPTresearcn cCrMA usarra ntm Commercial Tissue Microarrays I httpwwwthe scientistcomyr2004 marltools 040315ht m Outline I The Big Picture I Laser Capture Microdissection I Tissue Microarrays I Proteomics I Meta o omics complexity Goal of Proteomics I Levels of protein expression do not always correlate with mRNA levels I Identi cation of each protein I Proteins are expressed at different levels different times different forms I Posttranslational modi cations I Types and sites I Much more complex than genomics Proteomics I Separation of individual proteins I 2D polyacrylamide gel electrophoresis I 2D PAGE I Identi cation by mass spectrometry 2D Gel Electrophoresis I First Dimension I lsoelectric focusing wmw immobilized pH gradiens I Separate by charge 7 V 7 I Second Dimension I SDSVPAGE I Many spDE mam more than me pmtein up n 4n Mass Spectrometer What is Mass Spectrometry I Chemically pure sample I Bombard with electron beam of suf cient energy to fragment mo ecu e I Positively charged fragments produced are celerated in vacuum through magnetic eld and sorted on basis of masstocharge ratio I Most ions produced carw unit positive charge I Value mcharge is equivalent to molecular weight of fragment I Analyze by reassembling fragments working backwards to generate original molecule TOF Mass Spec I Create gasphase ions I Separate ions in space or time based on masstocharge ratio I Measure quantity of ions of each massto charge ratio laser beam lOI39I 9955 M llssue vwwvsumemamm ionization exnadloquot drill tube re ectron chamber detector Time of Flight Mass Spec I 12 mv2 qV I V ZqVm12 I The transit time t through the drift tube is LV where L is the length of the drift tube tL2Vmq12 Abundance Sample Data isomu Violas 11w 15cc vim 1400 150 150 quot111 Outline I The Big Picture I Laser Capture Microdissection I Tissue Microarrays I Proteomics I Metabolomics Metabolomics I Small molecule omics I Low MW compounds Lipids I Carbohydrates I Vitamins I1 I Measured in bio uids I Spinal fluid I Can sene as indicators of disease Ihtt ubsacsor cen coversto 8048 804 i icture Metabolomics I Two techniques to quantify I NMR spectroscopy I Mass spec http pubs acs orgcencoverstory804EprintEOAEpnarmaceuucaiA ntm Metabonomix I htt wwwmetabometrixcom r005htm Summary I The Big Picture I Laser Capture Microdissection I Tissue Microarrays I Proteomics I Metabolomics Poem of the Day I Poem to Be Read at 3 AM I Donald Justice Due Dates I Tuesday September 28 11 I Exam One I Covers Lectures 19 Reading HWs 14 I Practice Exam Posted on Class Website BhAE 365 Quantitativ Physiology A Lecture 7 Cancer Review of Lecture 6 Synthesis of Biomolecules The Cell Cycle Epithelial Tissue Apoptosis Cell Cycle 39lndefinite eriod Studying Cell Cycle 1 Can study in cell culture Mammalian cells in culture will undergo 2540 divisions then growth arrest Replicative senescence a Immortalized cell lines Undergo mutation to overcome replicative cell senescence Telomeric DNA not replicated When telomeres reach critical length cell division stops Telomerase can synthesize telomeric DNA a How do we know where cells are in cell cycle Pulse of 3H thymidine Flow cytometry
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