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  1. 1. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 IVMS LEARNING OUTCOMES – HORIZONTALLY INTEGRATED RAPID OVERVIEWVIEWING INSTRUCTIONS FOR THIS COMPONENT:Once you download, and open in MS word: go to View> NavigationPane. You will see a hot-linked index of this resource. Hyperlinks to major curriculum topics are also embedded. This function, aswell as the embed hyperlinks in the map, is only limited in this demonstration. Nonetheless, this document will provide you will acomprehensive sequenced vocabulary/ medical terminology of IVMS Courseware learning objective. It is an excellent tool tocross reference with our Basic Medical Terminology-PROGRAMMED INSTRUCTION downloadable resource. N.B.-An extensively hyperlinked to IVMS online RLOs (Reusable Learn Objects/aka, SCOs/ Sharable Content Objects using SCORM Terminology) is available to enrolled learners and/or at cost for those learners/teachers non-enrolled IVMS is the ultimate medical student Web 2.0 companion. This SDL-Face to Face hybrid courseware is a digitally tagged and content enhanced replication of the United States Medical Licensing Examinations Cognitive Learning Objectives (Steps 1, 2 or 3). Including authoritative reusable learning object (RLO) integration and scholarly Web Interactive PowerPoint-driven multimedia shows/PDFs. Comprehensive hypermedia BMS learning outcomes and detailed, content enriched learning objectives. IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 1
  2. 2. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 1. CELLULAR & MOLECULAR STRUCTURE & FUNCTIONAnimations, Movies & Interactive Tutorials 1.1 GENERAL PRINCIPLES OF BIOCHEMICAL STRUCTURES Macromolecular organization as the basis of biological structure and function Concept of stereoisomerism 1.2 PROTEINS 1.2.1 GENERAL PRINCIPLES Functional types: structural proteins, enzymes, transporters, regulatory proteins 1.2.2 Protein Composition and Structure Amino Acids and the Peptide Bond Principles of structure of amino acids: details of Protein sequencing: basic principles and application functional groups of individual amino acids not of required The functional types of amino acid side-groups: basic, Difference between mammalian and bacterial use of acidic, hydrophilic, hydrophobic, ―structural‖ (proline) stereoisomers. Antibiotics as mimics of D-amino acid structures The peptide bond: features, significance in secondary Significance of stereoisomerism in drug development structure Importance of stereoisomerism in influencing shape of proteins and hence interaction between molecules Principles of protein structure Factors stabilizing protein structure: Van der Waal‘s Reversible and irreversible denaturation of protein. forces, hydrogen bonds, hydrophobic forces, ionic interactions, disulphide bonds IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 1
  3. 3. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Levels of organization (primary, secondary, tertiary and Organization of secondary structural elements into quaternary) structural and functional domains: specificOrganization and properties of alpha-helix, Beta-sheet, examples, e.g. ABC proteins, 2 units of 6  helices and loop/turn in membrane; nicotinic acetylcholine receptorStructural and functional domainsHetero- and homo-oligomeric multi-subunit proteins Comparison of the structure and properties ofFunctional significance: allosteric (intra-protein) hemoglobin and myoglobin regulation; protein–protein regulation: e.g. cAMP-dependent hemoglobin as an example protein kinase Post-translational modifications disulphide bonding, cross-linking, peptidolysis non-peptide attachments: glycosylation, phosphorylation, adenylation, farnesylation roles: regulation, targeting, turnover, structural1.2.3 Structural Proteins: Structure and Function1.2.3.1 CollagenStructural protein of tendons and ligments: Repeating amino-acid unit favours left-handed helix fibrous protein, triple coils of extended helices, formation assembled staggered and cross-linked for strength Hydrogen bonding by glycines as the stabilizing force of the triple helix Ehlers-Danlos syndrome; osteogenesis imperfecta1.2.3.2 HistonesStructural protein of chromatin: globular, associate in Need for histones: packaging of DNA (saves space octamers to form nucleosomes around which DNA is and protects it) wound Significance of the cationic nature of histones. Packaging role of H11.2.4 Enzymes And Enzymatic Catalysis1.2.4.1 Concepts of Biochemical Reactions and Enzymes IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 2
  4. 4. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 Definition of catalysis, definition of enzyme Energy of reaction and reaction intermediates. Transition-state complex Classes of biochemical reaction: hydrolysis, ligation, condensation, group-transfer, redox, isomerization Structure and Function of Enzymes Importance of active site for catalysis and specificity Domain organization Multimeric enzymes: Mechanisms of catalysis illustrated by serine ranges of isozymes e.g. LDH proteases, carboxypeptidase A and lysozyme multienzyme complexes e.g. pyruvate dehydrogenase (see 2.3.3) regulation of activity by allostery, and by subunit dissociation (e.g. cAMP-dependent protein kinase) Co-Factors Importance of co-enzymes and trace elements in enzyme Examples of co-factors e.g. from glycolysis, TCA action cycle, fatty acid oxidation and synthesis Vitamins as precursors of co-enzymes1.2.4.4 Kinetic Parameters Dependence of rate of reaction on substrate concentration and amount of enzyme Simple steady state reaction kinetics: Michaelis constant Km, maximal velocity Vmax and turnover number Principles of competitive, non-competitive and irreversible inhibition Regulation of Enzyme Activity IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 3
  5. 5. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 Allosteric control pH and temperature sensitivity of enzymic catalysis Covalent modification e.g. phosphorylation 1.2.5 Transporters: Structure And Function Types with examples (see 1.6.1): Common features: e.g. transmembrane segments and channels energy-producing domains carriers - passive and active (i.e. pumps) Amphipathic nature of transmembrane segments Specificity due to interaction between solute and channel Polar/ionic inner surface of pores or carrier Passive transport in channels: gated channels undergo conformational change to open or regulate the channel Saturation of carriers at high solute concentrations Carriers: undergo cyclical conformational change to transport ligands across the membrane Flipases, P-glycoprotein Consequences of structural perturbation: e.g. misfolding and intracellular retention of CFTR, the cystic fibrosis transmembrane-conductance regulator 1.2.6 Regulatory Proteins: Structure And Function Examples: proteins that regulate gene expression (see Ligand-induced structural changes (illustrated by the 3.1.4) steroid hormone receptor) affect binding to DNA regulatory subunits of enzymes (see LIPIDS 1.3.1 Types Of Lipid In The Body Fatty Acids and Glycerides General structure of fats and fatty acids Sources of fatty acids (dietary and de novo synthesis) Concept of essential fatty acids 13.1.2 Phospholipids Outline structure of phosphatidyl compounds Structure and classes of sphingolipid (sphingomyelin, gangliosides, cerebrosides) IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 4
  6. 6. MARC IMHOTEP CRAY, M.D./Last updated 06-08- SterolsOutline structure of cholesterolCholesterol derivatives: bile acids and steroid hormones1.3.2 Roles Of LipidsEnergy sources (see 2.2)Structural: as diffusion barriers (in lipid bilayers - see 1.6), and to stabilize fat : water interfaces (bile salts in the gut, and phospholipid and cholesterol in plasma lipoproteins)Signalling molecules Extracellular signalling molecules derived from extracellular: e.g. steroid hormones arachidonic acid: eicosanoids Intracellular signalling molecules (second messengers) derived from the phopholipid PIP2: e.g. diacylglycerol and IP31.4 CARBOHYDRATES1.4.1 Types Of CarbohydratesMonosaccharides: e.g. glucose, fructose, galactose L- and D-glucose: ―dextrose‖ as a common clinicalDisaccharides: e.g. sucrose, lactose term for D-glucosePolysaccharides Structure and formation of 1,4 and 1,6 glycosidic bonds Glycogen, starch, cellulose1.4.2 Roles of Carbohydrate in the Body1.4.3.1 StructuralProteoglycans in the extracellular matrix (see 5.2) Examples and functions of hyaluronic acid, chondroitin, dermatan, keratan. Energy SourcesRoles of glycogen, starch, cellulose Inability of mammals to digest cellulose.(Details of metabolism as outlined in 2.3) As Biosynthetic PrecursorsRole of carbohydrates in synthesis of amino-acids, fatty acids and nucleotides1.4.3.4 In Conjugates IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 5
  7. 7. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Glycoproteins and glycolipids Cell surface carbohydrates in blood groups1.5 STRUCTURE AND FUNCTION OF MEMBRANES1.5.1 Solutes, Membranes, and Membrane Transport Principles of solubility, osmosis, and diffusion Fick‘s Law of diffusion Transmembrane passage of gases and water Passage of charged and uncharged solutes through artificial lipid membranes Membrane transport: channels, carriers and pumps for Structure of membrane channels, carriers and pumps the passage of ions and substrates such as glucose (see 1.2.5) Channels: voltage-gated e.g. for Na or for K ligand-gated e.g. by ACh Carriers: primary active transport e.g. Na/K-ATPase secondary active transport e.g. Na/Ca exchange, the Na-glucose symporter facilitated diffusion e.g. Cl‘/HCO3‘ exchange Simple kinetic properties of channels and carriers Cellular ion homeostasis (see also 6.3.1) The pump-leak model1.5.2 Composition of Membranes Roles of lipids (including cholesterol), proteins and Comparison of micelles, bilayers and monolayers carbohydrates (including glycoproteins and Variation in membrane properties with different types glycolipids). of lipid constituents Biosynthesis of phospholipids and glycoproteins: involvement of CTP and dolichol Structural aspects of membrane proteins: alpha- helical content and amphipathic nature1.5.3 The Fluid Mosaic Model of Membrane Structure IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 6
  8. 8. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12The fluidity of membranes Implications of the model for membrane function andModes of association of proteins with the lipid phase: behaviour: e.g. mobility of receptors, recirculation surface proteins, transmembrane proteins, anchored of membrane constituents proteins Range of motions for membrane components: rotational and translational; lipid translocation and asymmetry Limitations of the fluid mosaic hypothesis: alternative hypotheses of membrane behaviour1.5.4 Functions of Membrane Proteins1.5.4.1 Transport through Lipid MembranesSee 1.2.5 and Vesicular TransportMembrane proteins: promote and regulate vesicle formation determine the destination of vesicles and their contents (see 1.9) SignallingSee 4.2.1 and SUB-CELLULAR ORGANELLESStructure and function of the cell membrane and sub-cellular organelles: rough and smooth endoplasmic reticulum, ribosomes, Golgi apparatus, mitochondria, lysosomes; and the cytoskeleton: microtubules, intermediate filaments and microfilamentsMetabolic compartmentation: see 2.5Vesicle and protein trafficking: see 1.91.7 THE NUCLEUS IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 7
  9. 9. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Size and structure of nucleus Chromatin structure: the packing of DNA (a longNuclear functions: (see also section 3) molecule) into a compact structure - histones - gene replication and repair, genetic transcription, solenoids - loops ribosome production Chromatin structure related to functions of DNAThe interphase nucleus: euchromatin and heterochromatinConstitutive and facultative heterochromatin (Barr body)Concept of condensed chromatin and gene inactivityNuclear envelope: defines eukaryote Structure and functions of the nuclear envelopeTwo way communication between nucleus and cytoplasm inner and outer membrane, perinuclear space,The nucleolus: the site of ribosome production nuclear lamina nuclear pores1.8 TRAFFICKINGVesicle trafficking routes Transport of vesicles: role of cytoskeletonFrom endoplasmic reticulum to the Golgi apparatus, thence: to the plasmalemma or to lysosomesTrafficking to the plasmalemma adds material to it or allows secretion into the extracellular space: constitutive and regulated secretionReceptor mediated endocytosis Ligand–receptor binding, clustering of receptorsTranscytosis Coated pits and vesicles: clathrin Low pH in endosomes: significancePrinciple of the targeting of newly synthesized proteins Details of protein trafficing in endoplasmic by signal sequences reticulum/Golgi and import of proteins into mitochondria or nucleus Role of chaperonins Genetic defects of trafficking pathways1.9 THE CELL CYCLE: MITOSISAND CELL DIVISION IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 8
  10. 10. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 Phases of the cycle: Interphase : G1, S (nuclear DNA replication), G2 — G0 Demonstration of cell-cycle phases by 3H-thymidine non-cycling cells Centrosome, centrioles, aster, spindle Mitosis: M (i.e. nuclear division) Centromeres and interaction with spindle appearance of the chromosomes and separation of the chromatids prophase, metaphase, anaphase, telophase Cell division1.10 CONTROL OF CELL GROWTH AND DIFFERENTIATION 1.10.1 Cell Growth and Division Growth in development, morphogenesis (see 15) Growth after birth Renewing tissues: e.g. skin, gut epithelium - continually dividing stem cells Resting tissues: e.g. liver, cells multiply only to repair damage Non-dividing tissues: e.g. neurones do not multiply after birth Maintenance of normal tissue structure and function: Characteristics of normal fibroblast growth in vitro cell growth and division, controlled by extracellular Experimental demonstration of platelet-derived growth factors, and balanced by cell loss and cell death fibroblast growth factor (PDGF) Apoptosis (programmed cell death) Physiological hypertrophy: e.g. of skeletal muscle Cancer a disease of excessive cell multiplication Physiological hyperplasia: e.g. skin, erythropoiesis (see 40.3) 1.10.2 Differentiation Selective gene expression as the basis for producing cells with different functions Totipotent stem cells, pluripotent and unipotent cells Principles of the establishment of tissues: progressive Mosaic vs regulative decisions in cell type specification restriction of developmental potential The stability of cell differentiation Abnormal differentiation in tumors (see IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 9
  11. 11. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Regulation of tissue structure and function by hormones Role of retinoids in normal and abnormal differentiation and growth factors (affecting gene expression and cell (e.g. of epithelia) multiplication and turnover)1.11MEIOSIS1.11.1 PrinciplesCreation of offspring with new combinations of genes by sexual reproductionHaploid gametes are formed by two special cell divisions ‗meiosis‘(Chromosome abnormalities through faults in meiosis: see 3.3)Meiosis I (‗reduction division‘): Follows a normal S-phase in primary gametocytes Prophase I: The stages of prophase I: role of the synaptonemal pairing of homologous chromosomes complex chromatids ‗cross-over‘ (exchange of maternal and Molecular mechanism of recombination: paternal genes) Concepts of strand invasion, Holliday junction, Anaphase I: branch migration maternal and paternal chromosomes separate at Reciprocal vs non-reciprocal recombination random to form daughter nuclei Result: two secondary gametocytes, each with only one chromosome of each pair, and with new combinations of maternal and paternal genes on each chromosomeMeiosis II: Follows meiosis I with no intervening S-phase Resembles mitosis – chromatids separate to form new nucleiOne primary gametocyte can thus produce 4 gametes (e.g. spermatozoa)1.11.2 Gametogenesis IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 10
  12. 12. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Spermatogenesis: see 13.3.1Oogenesis: see also 13.3.2 Primary oocytes arrest in prophase I during fetal life, build up stores of RNA and protein and then rest until puberty At puberty, cohorts of oocytes mature by completing meiosis I (giving one secondary oocyte and a polar body): ovulation occurs Meiosis two (with the production of another polar body) is completed on fertilisation1.12 LIGHT MICROSCOPYResolution: can show bacteria, and details within Reveals structures commensurate with one wavelength nucleated cells such as mitochondria and storage of light ‗granules‘ (gross appearance only)Simple appreciation of the steps needed to prepare tissue Artefacts of specimen preparation e.g. usually, lipid is for light microscopy: fixation, sectioning and staining dissolved and lost from the specimen during fixation and embeddingGeneral histological appearance of an ‗H & E‘ stained ‗Basophilic‘ structures, such as nucleic acids, bind section basic dyes (e.g. purple Hematoxylin); ‗acidophilic‘ nuclei (and structures rich in nucleic acids) stain structures bind pink Eosin purple Specific stains e.g: Van Giesson‘s stain renders most proteins stain pink (in particular, the cytoplasm of collagen fibres vivid pink muscle, and red blood cells, and many epithelial cells) orcein stains elastin greyLocalization of specific molecules by Use of fluorescence microscopy on living cells immunocytochemistry1.13 ELECTRON MICROSCOPYResolution: shows structure within organelles, lipid membranes, viruses and macromolecules (e.g. DNA and proteins)Appearance of the main cell organelles Scanning EM to study surfaces of as listed in 1.7 in transmission EM cells and organelles IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 11
  13. 13. MARC IMHOTEP CRAY, M.D./Last updated 06-08-122. CELLULAR METABOLISM2.1 GENERAL PRINCIPLESThe overall strategy and logic of human metabolism: Free energy, entropy partial and complete oxidation; trapping of energy as ATP; coupling of ATP hydrolysis to energy-requiring Structure of ATP and its energy content reactions; CO2 and water production2.1.1 Principles of Metabolic ControlShort-term controls: allosteric effects (milliseconds), covalent modification (seconds to minutes)Long-term controls: enzyme induction / suppression (hours to days)Cycles between organs (e.g. Cori cycle): principle that control of metabolism includes (i) delivery (i.e., anatomy, functioning circulation) and (ii) transmembrane movement (i.e. membrane transporters) of substrates, as well as enzyme regulation2.1.2 Oxidation–Reduction ReactionsOxidation and reduction by NAD+/NADH, FAD/FADH2, Key examples of linked oxidation and reduction: oxidation of glyceraldehyde-3-phosphate, and NADP+/NADPH implications for energy transfer by substrate-level phosphorylation.2.1.3 Role and Control of the TCA Cycle IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 12
  14. 14. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Substrates and products of the cycle. Significance of a Entry to TCA cycle of carbon skeletons of amino cyclic (as opposed to a linear) pathway: catalytic acids, odd chain length fatty acids effects. Connection with other metabolic pathways: as substrate (e.g. acetyl CoA) or as intermediate (e.g. - ketoglutarate)Use of TCA cycle intermediates for biosynthesis, esp. of Succinyl CoA as precursor of glucose, fatty acids and some amino acids porphyrins and hemeSignificance of ―anaplerotic‖ reactions to maintain concentrations of TCA cycle intermediatesOperation related to demand for ATP, not to substrate Reguln.of TCA cycle by calcium: activation of availability pyruvate dehydrogenase, isocitrate dehydrogenase and  -ketoglutarate dehydrogenase in response to an increase in intra-mitochondrial calcium concentration2.1.4 ATP Production and its ControlNear-constancy of intracellular ATP concentration; Signals of ATP utilization: relative concentrations of ATP, ADP and AMP rising ADP as a signal to mitochondria rising AMP as a cytoplasmic signal to regulate glycolysis2.1.5 Pathways Of Mitochondrial Oxidation2.1.5.1 The electron transport chainMain components and outline organization of the electron Structure and function in the chain:- transport chain Large protein complexes linked by smaller, more mobile intermediates. Multiple centres allowing sequential oxidation/reduction reactions with increasing redox potential Function of specific examples of oxidation/reduction centres: haem, iron-sulphur centres, ubiquinone, copper (in cytochrome oxidase) Stoichiometry of the electron transport chain2.1.5.2 Reoxidation of reduced cofactors in the mitochondrion IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 13
  15. 15. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Reoxidation of mitochondrial NADH (diffusible in the Reoxidation of cytoplasmic NADH: shuttle systems matrix) and FADH2 (enzyme-bound) in the transfer reducing equivalents through mitochondrion mitochondrial membrane (impermeable to NAD/NADH) Significance of different redox states of cytoplasmic and mitochondrial NAD2.1.6 Mitochondrial ATP Synthesis2.1.6.1 The Chemiosmotic MechanismOxidative phosphorylation: an indirect coupling of energy Mitochondrial matrix as a closed environment, with release by oxidation to the synthesis of ATP inner membrane impermeable to H+. Extrusion of- Flow of electrons down the respiratory chain drives H+ H+ creates a pH and electric potential gradient. extrusion from the mitochondrion Experimental evidence for the chemiosmotic- Flow of H+ back into the mitochondrion via a protein hypothesis complex drives ATP synthesis includes uncouplers that short circuit the proton gradient e.g. lipophilic weak acids such as 2,4-dinitrophenol, salicylic acid Discharge of proton gradient as regulator of the electron transport chain and hence of substrate oxidation: ―respiratory control‖ Analogy to bacterial power supply. Some antibiotics act as uncouplers e.g. topical antifungal ionophores such as Nystatin2.1.6.2 Uses of the Proton Gradient IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 14
  16. 16. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12ATP synthesis F1 F0 components, role of transmembrane proton flow leading to ATP release Co-operativity and stoichiometry (about 3 H+ per ATP) of the enzyme. Reversibility of ATP synthaseInner membrane transport Examples: mitochondrial uptake of ADP and extrusion of ATP (most ATP is made in the mitochondrion yet used in the cytoplasm) Mitochondrial uptake of Ca2+, and of substrates such as pyruvateThermogenesis in brown adipose tissue Outline of mechanism. Importance especially in neonates (who can‘t shiver).2.1.7 Body Energy SuppliesStores: relative stores of fat, carbohydrate (as liver and muscle glycogen and as blood glucose), and proteinIntake (see 2.6): relative intake and energy values of fat, carbohydrate and protein2.2 FAT AS A METABOLIC FUEL2.2.1 OverviewAdvantages and disadvantages of fat as a metabolic fuel. Contribution to total energy production (about 35%)2.2.2 Assimilation of Dietary FatAssimilation, emulsification, absorption, packaging as Direct transport of medium chain length fatty acids chylomicrons. via blood to liver and peripheral tissuesTransport in lymph to peripheral tissues. Lipoprotein lipase in release of fatty acids from chylomicronsUptake and resynthesis of intracellular triglyceride in adipose tissueUtilization of triglyceride by skeletal muscle, heart and renal cortex IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 15
  17. 17. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Release and transport of NEFAs. Hormonal regulation of lipolysisPlasma NEFA levels under different metabolic conditions2.2.3 Metabolic Fuels and TissuesHeart‘s preference for NEFAs and endogenous triglycerideSkeletal muscle and use of free NEFAs, glucose and glycogen during different forms of exerciseNEFA use in renal cortex2.2.4 Oxidation of FatProduction of fatty acyl CoA; carnitine ―shuttle‖ and its Cytoplasmic fatty-acid-binding protein, transport to control mitochondrial membrane -oxidation of fatty acyl chain. Site of reaction Enzymes of fatty acid oxidation: VLCAD, LCAD, (mitochondrial matrix) MCAD, SCAD Oxidation of other fatty acids: unsaturated fatty acids, very long chain fatty acids, odd-chain- length fatty acids, branched-chain fatty acids Defects of fatty acid oxidation - relative frequency, biochemistry and clinical symptoms of MCAD deficiency, carnitine deficiency2.2.5 Fatty acid metabolism in the liver2.2.5.1 OxidationSee BiosynthesisProduction of triglyceride from excess sugars and amino Outline of structure and function of fatty acid acids synthase complex. Key differences between fatty acid biosynthesis and beta-oxidation: enzymes, cofactors, subcellular compartments Balance between oxidation and synthesis, regulated by concentration of substrates (and of TCA cycle intermediates) Ketogenesis IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 16
  18. 18. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Role in fasting and starvation Structures of common NEFA-derived ketones andUse of ketone bodies in peripheral tissues. steps in their synthesisKetone bodies as signals for availability of energy substrates2.2.6 Integration of Fatty Acid MetabolismEffects of insulin, glucagon, adrenaline and thyroxine on Regulation: synthesis, breakdown, uptake and release of fatty acids of lipoprotein lipase (clearing-factor lipase) of mobilization of NEFAs from adipose tissue, and of acetyl CoA carboxylase2.3 GLUCOSE AS A METABOLIC FUEL2.3.1 OverviewStorage and availability of glucose. Relative use of Glucose delivery to the fetus glucose by different tissues: brain, skeletal muscle, red blood cells, renal medulla2.3.2 Glycolysis2.3.2.1 SignificanceOverall scheme and importance in generating ATP in Measurement and concentrations of intermediates different tissues under anaerobic conditions. Production of lactate2.3.2.2 Glucose uptake (transport and phosphorylation)Glucose uptake requires transport and phosphorylation Glucose transport:Tissue differences: GluT1–5 transporters, kinetics and tissue Uptake dependent on plasma glucose concentration distribution of different glucose transporters, - in liver (appropriate for glycogen or fat synthesis) insulin-induction of GluT4 expression - in endocrine pancreas (to control hormone release) Phosphorylation: insulin-independent glucose transport by GluT2 hexokinase in peripheral tissues Uptake elsewhere (in ‗peripheral‘ tissues) depends on glucokinase in liver, pancreas ( -cells) energy needs of tissue and is regulated in tissues that physiological significance of differences in their can also use non-carbohydrate energy substrates: properties (Km values and inhibition) importance of the insulin-dependent glucose transporter (GluT4) Trapping energy: formation of ATP in glycolysis IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 17
  19. 19. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Substrate-level phosphorylation: quantity of ATP per Principal points of ATP formation molecule of glucose2.3.2.4 Control of glycolysisGlycolysis is regulated by the energy needs of the cell: Points of regulation: hexokinase, this regulation is of specific importance in type IIb phosphofructokinase, pyruvate kinase skeletal muscle fibres Phosphofructokinase as principal control point of glycolysis: fructose-2,6-bisphosphateIsozymes of glycolytic enzymes and their significance in Variation of isozyme expression in different tissues; clinical diagnosis correlation with different metabolic function of different tissues, e.g. lactate dehydrogenase, pyruvate kinase2.3.2.5 Utilization of other monosaccharidesGalactose and fructose: importance as fuel Galactosaemia - typical pattern of presentation; metabolic problems Hereditary fructose intolerance - presentation; metabolic problems2.3.3 Aerobic Oxidation of GlucosePyruvate dehydrogenase as key regulatory enzyme Control of activity in relation to metabolic state of mitochondrionImportance of aerobic glucose oxidation in the brainPentose phosphate pathway: Reaction sequence of the pentose phosphate significance as a generator of NADPH and for the pathway synthesis of various carbohydrates, including pentoses Glucose-6-P dehydrogenase deficiency - for nucleic acids significance and metabolic consequences; Role in antioxidant pathways (see 2.5.5) prevalence (common); mechanism of damage to rbc; development of acute haemolytic anaemia2.3.4 Storage of GlucoseGlycogen synthesis in liver and muscleCost of synthesis IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 18
  20. 20. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Mobilization: phosphorylase and debranching enzyme The ―glucose–fatty-acid cycle‖Control of glycogen synthesis and breakdown in muscle Hormone receptors on hepatocytes. Role of and in liver; roles of adrenaline, glucagon and insulin autonomic nervous system in hepatic metabolism. Calmodulin as subunit of phosphorylase kinase.2.3.5 GlucogenesisQuantitative importance and sites of synthesis Why we can‘t make glucose from fatty acidsCommon substrates: lactate, alanine, glutamine, glycerol Comparison between glucogenesis and glycolysis and other sugars Control: acutely: by metabolites and hormonal signals e.g. glucagon chronic adaptation: in response to insulin, glucagon and corticosteroids2.4 AMINO ACID METABOLISM2.4.1 Protein digestion (see also 9.5.4 and 9.5.5)Dietary intake; digestion by pepsin, trypsin, chymotrypsin. Enterokinase Uptake of di- and tripeptides by intestinal cells; Pancreatitis conversion to amino acids2.4.1.1 Amino acidsAmino acids essential in diet, arginine as an essential amino acid produced by endogenous synthesis. Consequences of dietary lackIncorporation into body proteins or derivatives (e.g., hormones, neurotransmitters), oxidation, conversion to glucose or fatty acidsCategories of amino acid: glucogenic via pyruvate, glucogenic via TCA cycle intermediates; ketogenic; mixed2.4.1.2 Amino Acid Metabolism2. OxidationTransamination; role of -ketoglutarate and glutamate Pyridoxal phosphate in transamination IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 19
  21. 21. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Significance of glutamate dehydrogenase. Fate of ammonia generatedTransport of ammonia from peripheral tissues. Metabolism of glutamine in intestinal cells and renal cortexNitrogen excretion as urea or as ammonium ions; implications for pH regulation2. Urea synthesisPrincipal steps in formation of urea from ammonia Hepatic intracellular compartmentation of the ureaSite (periportal cells of liver lobule) cycleControl of the urea cycle: Fate of urea: n.b. renal concentrating mechanism acute: regulation of enzyme activity; carbamyl- phosphate synthetase as the controlling step chronic: induction of urea-cycle enzymes over 24–36h2. Tissue-specific amino acid metabolism Amino acid metabolism in specific tissues: liver, intestine, skeletal muscle, renal cortex Distribution of urea-cycle enzymes between gut and kidney The glucose–alanine cycle2.5 CELLULAR ORGANIZATION OF METABOLISM2.5.1 OverviewThe major pathways of metabolism in relation to sub- cellular architecture2.5.2 MitochondriaRole in energy generation; in generation of NADH and Separate mitochondrial genome encodes some metabolic intermediates; final common pathway of components of the electron transport chain chemical energy production, electron transport chain complexes and oxidative phosphorylation Mitochondria as ―symbionts‖ Mitochondrial biosynthesis. Density of mitochondria in cells (increases in hypoxia) IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 20
  22. 22. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 Clinical manifestations of mitochondrial disease. Maternal inheritance of mitochondrial DNA. Mitochondrial DNA mutations and their expression (see 3.4)2.5.2 Endoplasmic Reticulum/Golgi ApparatusOutline of role in biosynthesis of lipids, complex carbohydrates and glycoproteinsRole in detoxification: significance of cytochrome P4502.5.3 LysosomesOutline of role in recycling of building blocks of Range and importance of lysosomal diseases macromolecules (especially extracellular matrix components). See also PeroxisomesOutline of role in substrate processing Role in biosynthesis: plasmalogens, bile acids Significance of peroxisomes as revealed by peroxisomal diseases2.5.5 Protection Of Cells Against Reactive Oxygen SpeciesMechanism of generation of O2– and H2O2 Glutathione, vitamins C and E Superoxide dismutases, catalase, glutathioneExistence of specific ‗antioxidant‘ enzymes that remove peroxidase (need for selenium) these toxic species Glutathione reductase, need for NADPH2.6 BIOCHEMICAL PRINCIPLES OF NUTRITIONEnergy balance and body weight regulation: meaning of Obesity and its treatment dietary ―energy‖; components of energy balance; physical activity vs. energy intake as determinants of body weightBiochemical basis of nutritional guidelines: contribution of Epidemiology of coronary heart disease in relation carbohydrate, protein, fat to dietary intake; the to nutritional patterns nutritional role of different fatty acids; types of dietary carbohydrate and their effects on metabolism IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 21
  23. 23. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 Principles of clinical nutrition: energy and nutrient requirements in illness vs. health; means of supplying energy and nutrients in the sick; metabolic effects of parenteral delivery of nutrients. Amino acid supply in the critically ill2.7 CLINICAL BIOCHEMICAL MEASUREMENTMeasurement of gases, ions, pH, osmolarity, metabolic substrates, hormones and enzymes: principles and clinical importanceUses of enzyme measurement in clinical practice Assessment of tissue damage: Cardiac enzymes and liver enzymes as examples in the assessment of tissue damage (see also Recognition of enzyme deficienciesUse of enzymes to measure biologically-important Glucose assays molecules3.MOLECULAR AND MEDICAL GENETICS3.1 PRINCIPLES OF MOLECULAR GENETICS3.1.1 What Genes DoGenes as inherited units of information, specifying Identifying amino-acids changed by mutation phenotype at a gross level (e.g., morphological characteristics) or at a molecular level (e.g., genes representing polypeptides).Mutation: types of mutation and their consequences; harmless variants vs disease-causing mutations (see 3.7)3.1.2 What Genes are Made OfGenes as nucleic acid Transfer of genetic information to cells in vitro shows that genes can be extracted from cells, making chemical identification possible Confirmation that genetic information is carried by DNA and RNA but not by proteins3.1.3 Connection between Gene Structure and Function IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 22
  24. 24. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Molecular structure of DNA Physical evidence for DNA structure. SimpleNucleic acid bases, nucleosides and nucleotides treatment of X-ray diffraction5‘-3‘ polarity of DNA strands; base pairing rulesDNA replication as a semi-conservative process Evidence from electron microscopy and identification of enzymes needed for replication Synthesis of DNA; proof-reading functions of enzymesHow genes code for proteins: key features of the genetic Evidence for the nature of genetic code code Identification of individual codons, stop and startRole of tRNAs and aminoacyl-tRNA synthase signals3.1.4 Regulation Of Gene ExpressionRegulation of expression of genes by other genes: RNA polymerases and their roles in mammalian concept of structural and regulator genes cellsRoles of gene regulation in mammalian cells: Essential features of bacterial operons and key transient - e.g. for response to steroid hormones genetic experiments which demonstrate them. stable, long-term - e.g. cell differentiation Biochemical confirmation by isolation ofChromatin condensation and gene activity (see 1.8) postulated factors 3.1.5 TRANSCRIPTION, RNA PROCESSING AND TRANSLATIONProducts of gene expression: mRNA, ribosomal RNA, Assembly of the initiation complex. Recruitment of tRNA, snRNA. RNA polymerase.RNA bases; relationship between a DNA coding strand and Termination and release of the transcript. Nature of its transcript cap, role of cap and poly-A.Outline of production and processing of mammalian Discovery of introns. Mechanism of splicing. mRNA: Alternative splicing. Ribozymes. transcription, capping and polyadenylation Details of translation at the ribosome; initiation, introns, exons and splicing elongation and termination of protein synthesisOutline of ribosome structure and of translationIntracellular sites of protein synthesis and the signal hypothesis (see 1.9)3.1.6 Organization Of The Genome IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 23
  25. 25. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 The mammalian genome: Information content of different genomes: single copy sequences Comparison between simple, non-redundant multiple-copy genes (e.g for histones and the genes for genomes of bacteria and viruses and the complex ribosomal RNA) genomes of eukaryotes. highly repeated non-coding sequences Coding/non-coding ratio in the mammalian genome 3.1.7 Characterization of genes at a molecular level Meaning of ‗cloning a DNA sequence‘ Elementary cloning of genes for known proteins Principles of DNA cloning Northern blotting Use of restriction enzymes & simple cloning vectors; Expressed sequence tag (EST) libraries polymerase chain reaction Examples of uses for cloned genes and probes in Separation of DNA fragments according to size by fundamental research, and for diagnostic and electrophoresis therapeutic applications Southern blotting and the use of DNA probes to identify fragmentsPrinciple of DNA sequencing 3.2 GENERAL CONCEPTS OF MEDICAL GENETICS Impact of genetic disease on public health Relationship of genes and environment Mendelian fundamentals: character, gene, allele, genotype, phenotype, dominant and recessive traits 3.3 CHROMOSOMES Chromosome structure and the normal chromosome complement Sex determination Chromosomal abnormalities, with examples of their occurrence and effects Deletions, inversions Numerical: aneuploidy, monosomies, trisomies Structural: balanced and unbalanced translocations, duplications IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 24
  26. 26. MARC IMHOTEP CRAY, M.D./Last updated 06-08-123.4 GENETICS OF DISEASESingle gene disordersAutosomal dominant — segregation, expression in heterozygotes, penetrance, expressivity, risk to offspringAutosomal recessive — transmission, expression in homozygotes, carrier status, risk to siblings Basis of rare occurrence of X-linked disease inX-linked — transmission, hemizygous males, carrier females females Mitochondrial disorders: heteroplasmyMitochondrial inheritancePolygenic disease: concordance in twin studies, relative risk, susceptibility genes3.5 GENES IN POPULATIONSEthnic differences in disease frequenciesHardy-Weinberg equilibriumAssortative mating, genetic drift, selection and mutationThe concept of polymorphism3.6 THE HUMAN GENOME, MAPPING & DIAGNOSIS3.6.1 DNA PolymorphismsRestriction fragment length polymorphisms (RFLP)Minisatellites and microsatellites (VNTR)Use of DNA polymorphisms as genetic markers3.6.2 Genetic linkageConcept of genetic linkage and the principle of its use in Construction of genetic linkage maps genetic mapping Mapping genetic diseases with and without biochemical or cytogenetic clues Localizing genes by somatic cell hybridization and by fluorescent in situ hybridization (FISH) Long range mapping with cosmids and YACs. Identification of genes: open reading frames (ORFs),Moving from a linkage marker to a disease locus: use of CpG islands, use of mRNA, cDNA libraries and the human genome sequence zoo blots Pre-natal and pre-symptomatic diagnosis, including IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 25
  27. 27. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 ethical considerations.3.7 MUTATION AND HUMAN DISEASEEffects of single-base changes, deletions and unstable Molecular basis of mutant phenotypes with repeat units (anticipation); with examples some examples e.g. sickle-cell anaemia and resultant genetic diseases thalassaemia as examples of recessive disease; collagen disorders as examples of dominant disease Notation for single amino-acid changes4.PRINCIPLES OF DRUG ACTION4.1 TYPES OF PHARMACOLOGICALLY ACTIVE AGENTSActing via receptors: Endogenous agents: e.g. hormones (see 14); neurotransmitters (see 6.4); growth factors; vaso-active factors (such as endothelin) Exogenous agents, ‗drugs‘, that modify the effect of endogenous agents: agonists or antagonists acting at the receptor for the endogenous agent; drugs that act indirectly (e.g. by physiological antagonism, by effects on release, metabolism, or reuptake of endogenous agent)Enzymes and enzyme inhibitorsDrugs acting on membrane transporters or ion channels e.g. calcium channel blockers, potassium channel blockers4.2 RESPONSE4.2.1 Cell -Surface ReceptorsProteins as receptorsThree types of cell surface receptor: ion-channel-linked, Types of enzyme-receptors (e.g. tyrosine kinases, G-protein-linked, enzymes guanylate cyclases)Kinetics of ligand-receptor interactions4.2.2 Drug Action IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 26
  28. 28. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12The log-dose/response curve Principle and uses of bioassayAffinity, efficacy, potency: definitions and chemical basisTypes of antagonism: competitive, non-competitive, Radioligand binding studies irreversible, physiologicalEffects on log-dose/response curve4.2.3 Receptor–Effector CouplingConcept of second messengers: principle of amplification; G-proteinsCyclic 3‘,5‘-AMP (cAMP) Control of adenylate cyclase by G-proteins, Produced in response to e.g.  -adrenoceptor including inhibition of adenylate cyclase e.g. by stimulation muscarinic receptor activation Action: cAMP-dependent protein kinase (PK-A) Other cyclic nucleotides as second messengers: regulates specific enzymes cGMP for atrial natriuretic peptide (ANP) Degradation: phosphodiesterases (inhibited by methylxanthines)Intracellular calcium Coupling of receptor stimulation to production of Raised by:- release of Ca2+ from intracellular stores (e.g. inositol trisphosphate (IP3) and diacylglycerol  -adrenoceptor 1 (DAG) stimulation); or by opening of Ca2+-channels in cell IP3releases intracellular calcium, DAG activates membrane protein kinase-C Action: activates specific enzymes Role of calmodulin Lowered by reuptake to stores or extrusionGap junctions: passage of ions and small molecules (second messengers) between adjacent cells e.g. linking epithelial, cardiac and some smooth muscle cellsDesensitization (tachyphylaxis)4.2.4 ModulationInteractions at receptor site and intracellularly4.2.5 Receptor RegulationUp- and down-regulation in response to agonists and antagonists4.2.6 Intracellular Receptors IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 27
  29. 29. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Intracellular receptors & nuclear actions of steroid hormones, T3, retinoic acid (a vitamin A derivative), 1,25-dihydroxycholecalceriferol (derived from vit. D)4.3 PRINCIPLES OF DRUG ADMINISTRATION, AVAILABILITY AND ELIMINATION (PHARMACOKINETICS)4.3.1 Routes Of Drug AdministrationMain routes of administration: oral, sublingual, rectal, topical (skin, eye, by sniffing), inhalation, and injection (intravenous, subcutaneous, intramuscular, intraspinal) Concept of bioavailabilityFactors governing choice of route: rate of absorption of drug from site of administration & ‗Enteric coated‘ preparations transport to site of action desire to administer drug close to its desired site of action (see 6.3.3) susceptibility of drug to degradation by digestion or metabolism desired time-course of action (see also 4.3.3)4.3.2 Distribution Of Drugs In The Body: Factors Affecting The Concentration Of A Drug At Its Site Of ActionLipid solubility: needed for simple diffusion across epithelia; effect of pH Drug transfer across the blood-brain barrier, and differences across epithelia on the distribution of the placenta ionisable drugs (e.g. absorption of weak acids from the stomach; renal effect: see 4.3.3); partition into body fatBinding to plasma proteins: Drug interactions through competitive reduces free drug able to diffuse into tissue fluid; displacement from plasma proteins reduces renal clearance of drugsCarrier-mediated transport: Binding of tetracyclines to calcium (effect on uptake of some drugs from the gut, and excretion into absortion from gut, discolouration of teeth) bile and urine4.3.3 Drug Metabolism And Excretion IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 28
  30. 30. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Principles of drug metabolism (see also 10.1.4) Metabolism may activate some agents - concept ofChemical modification usually abolishes activity: ‗pro-drugs‘ hydrolysis, e.g. acetylcholinesterase (see; Drug metabolites may be toxic - severe oxidative deamination e.g. MAO (see; hepatotoxicity in paracetamol overdose introduction of functional groups by mixed-function Drug interactions through induction of hepatic cyt. oxidases (cytochrome P450 system) - inducible in liver P450 system (see 10.1.5)Conjugation: addition of polar groups hastens excretionRenal excretion of drugsGlomerular filtration: most drugs are freely filtered (unless Adjustment of urinary pH to regulate the renal bound to serum proteins); filtered drugs may be elimination of some drugs passively reabsorbed or trapped in urine according to Secretion of conjugated drugs into bile, their lipid solubility and tendency to ionise deconjugation in gut, reabsorption: enterohepaticTubular secretion and reabsorption (e.g. secretion of recirculation penicillin)Simple consideration of time profiles of drug Effect of physical from of drug on its absorption concentrations after: and distribution a single oral dose (absorbed rapidly or slowly) (particle size, crystalline form, e.g long-acting a repeated oral dosage regimen insulin formulations) continuous intravenous infusion Depot formulations e.g. oily suspensions of antipsychotic drugs5.TISSUE TYPES: STRUCTURE & FUNCTION5.1 EPITHELIAL TISSUESClassification by cell shape and organization: simple (squamous; cuboidal; columnar; pseudostratified); stratified; transitionalClassification by function: secretory, absorptive, mechanicalStem cells and differentiated cells EM appearance of intercellular junctionsBasement membranes: structure and function in epithelial anchorage, polarity and differentiationFunctions of intercellular junctions: desmosomes - mechanically linking cells gap junctions - allowing intercellular communication IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 29
  31. 31. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 by ions and small molecules junctional complexes - determining trans-epithelial transport: leaky and tight epithelia (see 11.3.3)Polarity: apical and basolateral surfacesFunctions: trans-epithelial transport; synthesis and Epithelial morphogenesis in the embryo (e.g. secretion; protection; generation of movement over the neurulation - see 15) and later (e.g. mammary apical surface (ciliated epithelia) gland)5.2 CONNECTIVE AND SKELETAL TISSUESTypes of macromolecules making up the extracellular matrix (ECM), a simple appreciation of their nature and properties: e.g. collagen (see also, elastin, proteoglycansCell types and their functions in soft connective tissues: fibroblasts - synthesis of ECM macrophages – phagocytosis and degradation of ECM, role in immunity mast cells, lymphocytes - role in immunity adipocytes - triglyceride storageTendons, ligaments, aponeuroses, fascia, cartilage and bone: their mechanical properties and functions; organisation as jointsAdipose tissue: storage and thermal insulationCartilage: chondrocytes as sole cell type (chondroblasts as ECM of hyaline cartilage: proteoglycans and type II stem cells secretion and degradation of ECM collagen (plus elastin in elastic cartilage; or type-I collagen in fibrocartilage)Bone: ECM - collagen, hydroxyapatite, proteoglycans ECM of bone: osteoid, type I collagen cells - osteoblasts, osteocytes (bone formation), Osteoporosis osteoclasts (bone removal)Compact and spongy (cancellous) bone (adaptations for strength and lightness)Lamellar structure of bone; Haversian systems, blood Repair of fractures IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 30
  32. 32. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 supply Marrow cavities (fat storage and haematopoiesis) Bone as a highly vascular living tissue, constantly being remodelled Growth of long bones: remodelling; epiphyseal and appositional growth (accretion) Bone salts as a store of calcium and phosphate Overview of endocrine effects on bone: STH, PTH, vit. D metabolites, calcitonin, oestrogens, androgens (detailed endocrine regulation of calcium & phosphate in 2nd year) Joints: structure & function of fibrous; cartilaginous; synovial joints (see 7.2) 5.3 SKIN Functions e.g. protective (water, infection, UV), sensory, thermoregulation. Epidermis: cell types and functions (epithelial, melanocyte, Langerhans); epidermal layers; nails and hair Dermis: sweat glands, sebaceous glands. Blood supply of skin; Nerve endings (see 6.1)5.4 BLOOD CELLS 5.4.1 Red Blood Cells: Erythrocytes The shape, and size and contents of rbc in relation to their Changes in erythrocyte characteristics in globin function in oxygen and carbon-dioxide transport diseases e.g. sickle-cell anemia (see 3.7) Deformability for passage through capillaries; role in Erythrocyte cytoskeleton. Crenated erythrocytes anomalous viscosity of blood Normal hematocrit and red blood cell count. Normal turnover time. (see 10.1.6 Catabolism of heme) Recognition and destruction of ‗aged‘ rbc by macrophages in the spleen Red bone marrow: location Pernicious anaemia in the elderly through lack of IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 31
  33. 33. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 Production of rbc: stem cells (erythroblasts), normoblasts, intrinsic factor. Megaloblastic anaemia in folate reticulocytes deficiency Control of erythropoiesis: erythropoietin (14.8.1), bone Use of exogenous EPO marrow hyperplasia e.g. in response to prolonged (see also 10.1.3 Iron transport and storage) hypoxia, or hemolytic anaemia Role of folate and B12 in erythropoiesis Anemia through insufficiency of iron, or vitamins (folate, or vitamin B12) 5.4.2 White Blood Cells: LeucocytesYou should know the roles and normal abundance and turnover times of neutrophils, eosinophils, basophils, monocytes, lymphocytes and platelets; and the appearance of these cells in blood films. You should be aware of the role of stem cells in their production. Granulocytes Neutrophils (PMNs; polymorphonuclear leucocytes, Reserve stores, growth factors specific for each type ‗polymorphs‘) of leucocyte Increased production in acute bacterial infection Adhere to vascular endothelium and migrate into tissues at sites of acute inflammation. Phagocytic: ingest, kill and digest micro-organisms, particularly bacteria.form pus (see also 10.4.1) Eosinophils Increased production in chronic allergic conditions or parasitic infection May protect against damaging effects of long-standing allergic reactions Basophils Granules contain vasoactive substances including histamine Related to tissue mast cells which release histamine (increases blood flow and vascular permeability) in one type of allergic response Monocytes Blood cells that give rise by migration to macrophages, IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 32
  34. 34. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 both resident macrophages (e.g. Kupffer cells) and those freshly migrated from the blood at sites of inflammationMacrophages phagocytose and kill organisms; remove tissue debris (they secrete enzymes e.g. collagenase) Macrophages may cause tissue damage known as allowing effective repair; and are involved in tissue ‗chronic inflammation‘ homeostasis and remodeling – they phagocytose e.g. in TB apoptotic bodies5.4.2.3 LymphocytesStem cells in bone marrow, primary development along two lineages, ‗B‘ cells and ‗T‘ cells. ‗T cells‘ mature in thymus, self-sustaining in the peripheryProliferate in secondary lymphoid organs - lymph nodes, Peyer‘s patches and spleen.‗B cells‘ e.g. mature into antibody producing cells (plasma cells: see 10.4.1)‗T cells‘ play a role in regulating the immune response, or else act to kill cells directly (e.g. virus infected cells)Third type of lymphocyte: Natural Killer (anti-viral and anti- tumor roles)Small lymphocytes: quiescent, non-dividing, awaiting activation by antigen Re-circulate continuously through tissues by migration through post-capillary venules and via tissue-fluid, lymphatics and lymph nodes back into the blood thus monitor tissues for presence of antigens Respond to specific antigens (presented by antigen- presenting cells) by mounting a specific immune responseLarge lymphocytes (lymphoblasts): activated, dividing, developing to effector cellsImmunological memory resides in lymphocytes5.4.2.4 Platelets See Hemopoietic Stem Cells IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 33
  35. 35. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 As classic example of well-studied cellular differentiation Markers of differentiation: proteins (e.g. cell surface lineage markers); mRNA (= cDNA) profiles. Specialized protein synthesis, e.g. globin, immunoglobulin Self-renewal of stem cells Location in adult red bone marrow Experimental basis of determination of hemopoietic Sensitivity to ionizing radiation, and to cytotoxic drugs, e.g. function those used in chemotherapy of cancer (see 40.3.4) 6.EXCITABLE CELLS: NEURAL COMMUNICATION 6.1 TISSUES OF THE PERIPHERAL NERVOUS SYSTEM Structure of a peripheral nerve: epineurium; fascicular Perineurium, endoneurium arrangement of axons; myelin sheaths, nodes of Ranvier; unmyelinated axons Ganglia: dorsal root, sympathetic and enteric ganglia Structure and distribution of nerve endings: sensory terminals (e.g. Meissner, Ruffini, Merkel, Pacinian, free), motor end-plate, sympathetic varicosities 6.2 DIVISIONS OF THE PERIPHERAL NERVOUS SYSTEMPrinciples of the peripheral organisation of the somatic motor and sensory nervous systems, and of the autonomicnervous system 6.2.1 Somatic Nervous System Somatic motor fibres (efferent): cell bodies in spinal cord, terminate directly on muscle at motor end plates Somatic sensory fibres (afferent): sensory endings in tissues, cell bodies in dorsal root ganglia, synapse to other neurons inside central nervous system, convey information from receptors e.g. in skin (touch, pain, temperature), in joints (position sense, pain), in muscle and tendons (reflex control of movement) Motor and sensory fibres typically run in the same peripheral nerves – ―mixed nerves‖ Fibres of the somatic nervous system are mostly myelinated with fast to medium velocity (see 6.3.2); slow ‗C-type‘ pain fibres unmyelinated IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 34
  36. 36. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 6.2.2 Autonomic Nervous System Efferent system for involuntary control of body functions. Two major efferent divisions: sympathetic and parasympathetic Cell bodies in CNS send pre-ganglionic fibres (mostly myelinated, slow to medium velocity) to synapse on ganglion cells outside CNS. Pre-ganglionic transmitter: ACh Parasympathetic outflow: cranial, e.g. vagus nerve for thoracic and most abdominal viscera; and sacral for lower gut and urogenital system Sympathetic outflow: thoracic and lumbar (T1-L2) Ganglion cells send post-ganglionic fibres (non-myelinated slow) to cardiac and smooth muscle and glands Parasympathetic ganglion cells: typically within end-organ, release ACh Sympathetic ganglion cells: typically in discrete ganglia with long post-ganglionic fibres e.g. paravertebral chain, coeliac ganglion; most release noradrenaline adrenal medullary cells are modified symp. ganglion cells that secrete adrenaline into the blood. Visceral afferents (from stretch and chemoreceptors) often run with autonomic nerves: may elicit involuntary autonomic reflex (e.g. baroreceptor reflex), or may give sensation and mixed autonomic and voluntary somatic effects (e.g. micturition) Enteric nervous system: sensory, motor and secretomotor neurons in plexuses in the gut wall Coordinates activity of gut Modulated by pre-ganglionic parasympathetic fibres and post-ganglionic sympathetic fibres See also specific sections on e.g. autonomic transmission, and nervous control of thoracic and abdominal viscera6.3 NERVE CONDUCTION 6.3.1 Membrane Potential General ion distribution across membranes Double-Donnan distribution (osmotic-equilibrium) Role of Na/K pump in generating Na+ and K+ distribution Nernst equation, constant field equation IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 35
  37. 37. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Role of K+ and Na+ diffusion in generating the Effects of varying external K+, Na+, or Cl– on membrane membrane potential potential6.3.2 Action PotentialIonic mechanism of the action potential Experimental evidence for the Hodgkin-Huxley model.Conduction of action potential Explanation of voltage-clamp, patch-clamp and gatingRole of myelination in saltatory conduction currents. State-diagrams for Na+ and K+ channelsRange of nerve fibre sizes (non-myelinated and Effects of ion-channel blockers e.g. tetrodotoxin (TTX) myelinated) and their conduction velocities: and tetraethylammonium ions (TEA) compound action potential in a peripheral nerve Electrical circuit model of membrane potential Passive electrical constants of membranes (length constant, time constant) Wallerian degeneration Degenerative disorders: axonal death as a cause of disease -Motor Neurone Disease; vincristine neuropathy as an example of the effect of failure of the cytoskeleton demyelinating diseases - multiple sclerosis6.3.3 Local AnestheticsExamples of local anaesthetics e.g. lignocaine CocaineMechanisms of action. Local, regional, spinal, epidural anesthesiaDuration of action: dependence on lipid solubility, use Risks of accidental systemic administration of vasoconstrictorsSequence of blockade: pain first, then general sensory and then motor last.6.3.4 General AnestheticsPrinciples of action of general anaestheticsDistribution of anesthetic drugs between alveolar air (for Physical and chemical characteristics of the ―ideal‖ inhalational agents), blood, tissues and CNS general anestheticFactors influencing duration and depth of anesthesia.6.4 SYNAPTIC TRANSMISSION6.4.1 Neuromuscular TransmissionMorphology and function of neuromuscular junction Structure of ACh-activated cation channels; two ACh (nmj) receptor sites per channel. High signal-to-noise ratio IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 36
  38. 38. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12Synthesis, storage, release and action of ACh of synapse. Choline recycling. Drugs interfering withHydrolysis of ACh vesicular release: botulinum toxinMechanisms of action of neuromuscular blocking Modern analogues of tubocurarine. drugs: Advantages and disadvantages of tubocurarine vs. competitive non-depolarising (tubocurarine) suxamethonium. Pseudocholinesterase deficiency depolarising (suxamethonium)Methods of reversing neuromuscular block6.4.2 Interneuronal synapsesVariety of neurotransmitters (including ACh, catecholamines, glutamate, GABA and glycine) and receptorsExcitatory and inhibitory synapsesEPSPs and IPSPs Pre-synaptic inhibitionConcept of synaptic integration Idealised model of a nerve cell (input and output regions; summing point) Concept of spatial and temporal summation Synaptic plasticity; facilitation and depression Electrical synapses, gap junctions6.4.3 Autonomic SynapsesSynapses on cardiac and smooth muscle (en passant junctions, varicosities): structure and function in comparison with neuromuscular junction.6.4.4 Autonomic Transmission6.4.4.1 CholinergicNicotinic and muscarinic receptors: distribution and Existence of receptor subtypes M, N1,, N2: ganglionic vs. function neuromuscular nicotinic receptorsLocal and systemic actions of agonists (e.g. nicotine, Hexamethonium vs. decamethonium as evidence for muscarine) and of antagonists (e.g. tubocurarine, structural differences between N1 and N2 subtypes atropine)Therapeutic use of antimuscarinics in e.g. asthma, urinary incontinence IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 37
  39. 39. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12AcetylcholinesteraseExamples and effects of anti-cholinesterases.(e.g. neostigmine)Therapeutic use of anticholinesterases in myasthenia gravis6.4.4.2 CatecholaminergicSynthesis, storage and release of catecholamines Actions of experimental toxins to interfere with synthesis (dopamine, noradrenaline, adrenaline) Effect of reserpine DA as a transmitter in brain, gut and kidneys: use of L- DOPAAdrenoceptors: 1, 2, 1, 2; distribution and function Therapeutic applications of selective antagonists: in relative potency of NA, Adr, and isoprenaline on 1, asthmatics 1, 2Local and systemic effects of agonists and antagonistsTherapeutic use of selective agonists and antagonists e.g:  -agonists in asthma 1 -blockers (e.g. atenolol) in cardiovascular diseaseReuptake of transmitter and subsequent degradation: MAO, COMT inhibitors of reuptake (amphetamines); inhibitors of degradation: MAO inhibitors6.4.4.3 Other autonomic neurotransmittersOther transmitters and neurotransmitters e.g. nitric oxide (NO), ATP and neuropeptides e.g. VIPConcept of co-transmission Putative functions of co-transmitters6.5 MUSCLE AND INNERVATION6.5.1 Structure and Function: OverviewSkeletal muscle. Functional and metabolic characteristics of different Gross structure: fascicular arrangement; myofibres fibre types in skeletal muscle. Distribution of different controlled in groups fibre types between muscles IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 38
  40. 40. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 (motor units) by somatic nerves ending at motor end plates (see 6.4.1) Ultrastructure: sarcolemma, sarcoplasm, sarcoplasmic reticulum, myofibrils, myofilaments (organisation of muscle proteins), mitochondria, T-tubulesCardiac muscle: branching mesh of cells joined and electrically coupled by intercalated disks (desmosomes and gap junctions) autonomic innervationSmooth muscle: distribution and functions Relationship between ultrastructure and function in all Gross and microscopic structure in relation to three muscle types: comparisons between types function; cell-cell connections – mechanical and Limitations on regeneration and repair following damage communicating autonomic innervation6.5.2 Skeletal MuscleMuscle action potential as the trigger for muscle fibre Length–tension curve of muscle contraction Electron microscopy of muscle. 3-D arrangement ofGrading of contraction depends on motor unit myofilaments. Relation of sliding-filament theory to recruitment and frequency of nerve (and, therefore, length-tension relationship muscle) action potentials:- T-tubules and triads in e/c coupling: ‖one-to-one transmisssion‖; twitch summation; link between t-tubules and sarcoplasmic reticulum - tetany Ca2+-releaseCross-bridge cycling and sliding filament theory of Troponin/tropomyosin inhibition of cross-bridge cycling: contraction disinhibition by a rise of intracellular Ca++Role of sarcoplasmic reticulum and Ca++: e/c coupling and muscle relaxation (sr Ca2+-ATPase)6.5.3 Cardiac MuscleHeterogeneity, roles, and basic ionic mechanisms of the cardiac action potentialRole of Ca2+ entry (during the long AP) and sr Ca2+ IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 39
  41. 41. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 release in e/c couplingMechanism of relaxation.Regulation of contraction: Length–tension curve of cardiac muscle cellular basis of Starling‘s Law of the heart Effects of methyl-xanthines role and mechanisms of autonomic input in controlling the amplitude and frequency of the heart beatInotropic effect of cardiac glycosides (see also 8.6.7)6.5.4 Smooth MuscleNeurogenic and myogenic activity Types of smooth muscle:Role of the action potential (when present) (i) electrically excitable: driven entirely through nervousRole of Ca2+ entry and sr Ca2+ release in activating activity e.g. vas deferens, arterioles contraction (ii) spontaneous electrical activity modulated by nervousRole of cAMP in inhibiting contraction activity:Regulation of contraction: pacemaker depolarizations and spikes e.g. bladder, excitatory and inhibitory autonomic innervation some gut muscle stimulation or inhibition by a variety of hormones and or basic slow wave activity e.g. most gut, uterus locally produced compounds (iii) electrically inexcitable: regulated through receptors acting via second messengers (not via Em) e.g. respiratory tract, many blood vessels Patterns of innervation of these types of smooth muscle Control of contraction by the action of myosin light chain kinase (Ca2+ activates, cAMP/PK-C inhibits)7.MUSCULOSKELETAL ANATOMY Basic principles of living, gross and radiographic anatomy, (including CT and MRI) of the principal features of the musculoskeletal system. You should be able to identify major named structures on the living body, a dissection, or a clinical image, and define their principal functions.7.1 BONES OF THE LIMBSPrinciples of skeletal organisation; bone as a tissue (see 5.2)Long, flat, and short bones; adaptations to strength and force transmissionAs examples, the bones of the upper limb, their functional adaptations; comparisons IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 40
  42. 42. MARC IMHOTEP CRAY, M.D./Last updated 06-08-12 with bones of the lower limbShoulder girdle: clavicle; scapula (coracoid, acromion, spine, glenoid fossa); comparison with pelvic girdle (pubis, ischium, ilium )Arm: humerus (head, neck, lesser and greater tuberosities, shaft, epicondyles); comparison with femurForearm: ulna and radius; comparison with tibia and fibulaSmall bones of hand (carpal; metacarpals; phalanges); comparison with foot (tarsus, metatarsals, phalanges)7.2 JOINTS OF THE LIMBSPrinciples of the structure and function of fibrous, cartilaginous, synovial jointsRelationships between stability and mobilityFor each joint you should know its structural and functional classification, the type and range of movements, and main muscle groups acting at the joint. Compare the movements and structural specializations of the shoulder girdle (sterno-clavicular and acromio-clavicular joints) and pelvic girdle, shoulder and hip, elbow and knee, forearm (radio-ulnar) and wrist compared with the leg (tibio-fibular) and ankle.Role of the rotator-cuff musclesCompare the structural specializations of the hand (dexterity and grip) with foot (stability and support)7.3 MUSCLES AND MOVEMENTS OF THE LIMBSPrinciples of the organisation, function and innervation of functional muscle groupsThe attachments, functional grouping and movements of the muscles of the upper limb; comparisons with the lower limb; control of tendons at jointsMuscles groups acting on the shoulder girdle and shoulder compared with those acting at the hipMuscles groups of the flexor and extensor compartment of the arm (acting on the elbow) compared with those acting at the kneeMuscles groups involved in pronation and supination of the forearmMuscles groups acting to produce inversion and eversion of the footMuscles groups of the forearm involved primarily in flexion and extension of wrist and fingers compared with ankle and toesMovements of the hand compared with the foot IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 41
  43. 43. MARC IMHOTEP CRAY, M.D./Last updated 06-08-127.4 BLOOD SUPPLY TO THE LIMBSBasic principles and general organisation of arterial supply and venous and lymphatic drainage (structural adaptation of blood vessels: see 8.5.2)Upper limb arteries (subclavian, axillary, brachial, radial, ulnar, palmar arches) compared with lower limb (external iliac, femoral, popliteal, anterior and posterior tibial, dorsalis pedis, plantar arch)Superficial and deep venous drainage of upper (axillary and subclavian veins) and lower limb (venae comitantes; popliteal and femoral veins)Communicating veins: normal flow from superficial to deep. Effects of gravity on venous return from legs, roles of muscle pump, fascial compartments.Lymphatic drainage follows venous drainage; superficial and deep nodes; principles of central drainage via successively more central nodes, axillary lymph nodes - role in drainage of breast.Principle of anastomosis around joints7.5 NERVE SUPPLY OF THE LIMBSPrinciples of the origin and distribution of the motor (multiple spinal levels of origin for nerves involved in limb movements), sensory (dermatomes), and autonomic nervous systems (see 6.2.2)Principles of organization of limb plexuses in relation to their developmentBrachial plexus and lumbosacral plexusThe nerve supply to the flexor and extensor compartments of the limbs, and the muscle groups supplied: Upper limb: musculocutaneous, median, ulnar, radial Lower limb: femoral, obturator, gluteal, sciaticAnatomical basis of common reflex arcs: significance in mapping injuries to spinal nerve roots7.6 SPINEBasic principles of development of the spine (sclerotome formation) and of its structure sufficient to understand its functions as the central, flexible, weight- bearing axis of the bodyComponents of a typical vertebra. Regional specializations for function at cervical, thoracic, lumbar and sacral levels; the atlas and axis; fused vertebrae in sacrum and coccyx IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 42