IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW

MARC IMHOTEP CRAY, M.D./Last updated 06-08-12

IVMS LEARNING OUTCOMES –
HORIZONTALLY INTEGRATED RAPID OVERVIEW

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IVMS LEARNING OUTCOMES -HORIZONTALLY INTEGRATED RAPID OVERVIEW 1


1. CELLULAR & MOLECULAR STRUCTURE & FUNCTION
Animations, 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
1.2.2.1 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

1.2.2.2 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



Levels of organization (primary, secondary, tertiary and Organization of secondary structural elements into
quaternary) structural and functional domains: specific
Organization and properties of alpha-helix, Beta-sheet, examples, e.g. ABC proteins, 2 units of 6  helices
and loop/turn in membrane; nicotinic acetylcholine receptor
Structural and functional domains
Hetero- and homo-oligomeric multi-subunit proteins Comparison of the structure and properties of
Functional 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, structural
1.2.3 Structural Proteins: Structure and Function
1.2.3.1 Collagen
Structural 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 imperfecta
1.2.3.2 Histones
Structural 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 H1
1.2.4 Enzymes And Enzymatic Catalysis

1.2.4.1 Concepts of Biochemical Reactions and Enzymes



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
1.2.4.2 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)

1.2.4.3 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-enzymes

1.2.4.4 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

1.2.4.5 Regulation of Enzyme Activity



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 1.2.4.2)
1.3 LIPIDS
1.3.1 Types Of Lipid In The Body
1.3.1.1 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)



1.3.1.3 Sterols
Outline structure of cholesterol
Cholesterol derivatives: bile acids and steroid hormones
1.3.2 Roles Of Lipids
Energy 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 IP3
1.4 CARBOHYDRATES
1.4.1 Types Of Carbohydrates
Monosaccharides: e.g. glucose, fructose, galactose L- and D-glucose: ―dextrose‖ as a common clinical
Disaccharides: e.g. sucrose, lactose term for D-glucose
Polysaccharides Structure and formation of 1,4 and 1,6 glycosidic
bonds
Glycogen, starch, cellulose
1.4.2 Roles of Carbohydrate in the Body
1.4.3.1 Structural
Proteoglycans in the extracellular matrix (see 5.2) Examples and functions of hyaluronic acid,
chondroitin, dermatan, keratan.
1.4.3.2 Energy Sources
Roles of glycogen, starch, cellulose Inability of mammals to digest cellulose.
(Details of metabolism as outlined in 2.3)
1.4.3.3 As Biosynthetic Precursors
Role of carbohydrates in synthesis of amino-acids, fatty
acids and nucleotides
1.4.3.4 In Conjugates



Glycoproteins and glycolipids Cell surface carbohydrates in blood groups
1.5 STRUCTURE AND FUNCTION OF MEMBRANES
1.5.1 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 model
1.5.2 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 nature

1.5.3 The Fluid Mosaic Model of Membrane Structure



The fluidity of membranes Implications of the model for membrane function and
Modes 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 behaviour
1.5.4 Functions of Membrane Proteins
1.5.4.1 Transport through Lipid Membranes
See 1.2.5 and 1.6.1
1.5.4.2 Vesicular Transport
Membrane proteins:
promote and regulate vesicle formation
determine the destination of vesicles and their contents
(see 1.9)
1.5.4.3 Signalling
See 4.2.1 and 4.2.3
1.6 SUB-CELLULAR ORGANELLES
Structure 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
microfilaments
Metabolic compartmentation: see 2.5
Vesicle and protein trafficking: see 1.9

1.7 THE NUCLEUS



Size and structure of nucleus Chromatin structure: the packing of DNA (a long
Nuclear 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 DNA
The interphase nucleus: euchromatin and
heterochromatin
Constitutive and facultative heterochromatin (Barr body)
Concept of condensed chromatin and gene inactivity
Nuclear envelope: defines eukaryote Structure and functions of the nuclear envelope
Two way communication between nucleus and cytoplasm inner and outer membrane, perinuclear space,
The nucleolus: the site of ribosome production nuclear lamina
nuclear pores
1.8 TRAFFICKING
Vesicle trafficking routes Transport of vesicles: role of cytoskeleton
From endoplasmic reticulum to the Golgi apparatus,
thence:
to the plasmalemma or to lysosomes
Trafficking to the plasmalemma adds material to it or
allows secretion into the extracellular space:
constitutive and regulated secretion
Receptor mediated endocytosis Ligand–receptor binding, clustering of receptors
Transcytosis Coated pits and vesicles: clathrin
Low pH in endosomes: significance
Principle 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 pathways

1.9 THE CELL CYCLE: MITOSISAND CELL DIVISION



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 division
1.10 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 40.3.1.3)



Regulation 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)

1.11MEIOSIS
1.11.1 Principles
Creation of offspring with new combinations of genes by
sexual reproduction
Haploid 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 chromosome
Meiosis II:
Follows meiosis I with no intervening S-phase
Resembles mitosis – chromatids separate to form new
nuclei
One primary gametocyte can thus produce 4 gametes
(e.g. spermatozoa)
1.11.2 Gametogenesis



Spermatogenesis: see 13.3.1
Oogenesis: 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 fertilisation

1.12 LIGHT MICROSCOPY
Resolution: 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 embedding
General 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 grey
Localization of specific molecules by Use of fluorescence microscopy on living cells
immunocytochemistry
1.13 ELECTRON MICROSCOPY
Resolution: 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



2. CELLULAR METABOLISM
2.1 GENERAL PRINCIPLES
The 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 production
2.1.1 Principles of Metabolic Control
Short-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
regulation
2.1.2 Oxidation–Reduction Reactions
Oxidation 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



Substrates 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 heme
Significance of ―anaplerotic‖ reactions to maintain
concentrations of TCA cycle intermediates
Operation 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
concentration
2.1.4 ATP Production and its Control
Near-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
glycolysis
2.1.5 Pathways Of Mitochondrial Oxidation
2.1.5.1 The electron transport chain
Main 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 chain
2.1.5.2 Reoxidation of reduced cofactors in the mitochondrion



Reoxidation 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 NAD
2.1.6 Mitochondrial ATP Synthesis
2.1.6.1 The Chemiosmotic Mechanism
Oxidative 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 Nystatin

2.1.6.2 Uses of the Proton Gradient



ATP 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 synthase
Inner 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 pyruvate
Thermogenesis in brown adipose tissue Outline of mechanism. Importance especially in
neonates (who can‘t shiver).
2.1.7 Body Energy Supplies
Stores: relative stores of fat, carbohydrate (as liver and
muscle glycogen and as blood glucose), and protein
Intake (see 2.6): relative intake and energy values of fat,
carbohydrate and protein
2.2 FAT AS A METABOLIC FUEL
2.2.1 Overview
Advantages and disadvantages of fat as a metabolic fuel.
Contribution to total energy production (about 35%)
2.2.2 Assimilation of Dietary Fat
Assimilation, emulsification, absorption, packaging as Direct transport of medium chain length fatty acids
chylomicrons. via blood to liver and peripheral tissues
Transport in lymph to peripheral tissues. Lipoprotein
lipase in release of fatty acids from chylomicrons
Uptake and resynthesis of intracellular triglyceride in
adipose tissue
Utilization of triglyceride by skeletal muscle, heart and
renal cortex



Release and transport of NEFAs. Hormonal regulation of
lipolysis
Plasma NEFA levels under different metabolic conditions
2.2.3 Metabolic Fuels and Tissues
Heart‘s preference for NEFAs and endogenous triglyceride
Skeletal muscle and use of free NEFAs, glucose and
glycogen during different forms of exercise
NEFA use in renal cortex
2.2.4 Oxidation of Fat
Production 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 deficiency
2.2.5 Fatty acid metabolism in the liver
2.2.5.1 Oxidation
See 2.2.4
2.2.5.2 Biosynthesis
Production 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)
2.2.5.3 Ketogenesis



Role in fasting and starvation Structures of common NEFA-derived ketones and
Use of ketone bodies in peripheral tissues. steps in their synthesis
Ketone bodies as signals for availability of energy
substrates
2.2.6 Integration of Fatty Acid Metabolism
Effects 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 carboxylase
2.3 GLUCOSE AS A METABOLIC FUEL
2.3.1 Overview
Storage and availability of glucose. Relative use of Glucose delivery to the fetus
glucose by different tissues: brain, skeletal muscle, red
blood cells, renal medulla
2.3.2 Glycolysis
2.3.2.1 Significance
Overall scheme and importance in generating ATP in Measurement and concentrations of intermediates
different tissues under anaerobic conditions.
Production of lactate
2.3.2.2 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)
2.3.2.3 Trapping energy: formation of ATP in glycolysis


Substrate-level phosphorylation: quantity of ATP per Principal points of ATP formation
molecule of glucose
2.3.2.4 Control of glycolysis
Glycolysis 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-bisphosphate
Isozymes 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 kinase
2.3.2.5 Utilization of other monosaccharides
Galactose and fructose: importance as fuel Galactosaemia - typical pattern of presentation;
metabolic problems
Hereditary fructose intolerance - presentation;
metabolic problems

2.3.3 Aerobic Oxidation of Glucose
Pyruvate dehydrogenase as key regulatory enzyme Control of activity in relation to metabolic state of
mitochondrion
Importance of aerobic glucose oxidation in the brain
Pentose 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 anaemia
2.3.4 Storage of Glucose
Glycogen synthesis in liver and muscle
Cost of synthesis



Mobilization: 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 Glucogenesis
Quantitative importance and sites of synthesis Why we can‘t make glucose from fatty acids
Common 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 corticosteroids
2.4 AMINO ACID METABOLISM
2.4.1 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 acids
2.4.1.1 Amino acids
Amino acids essential in diet, arginine as an essential
amino acid produced by endogenous synthesis.
Consequences of dietary lack
Incorporation into body proteins or derivatives (e.g.,
hormones, neurotransmitters), oxidation, conversion to
glucose or fatty acids
Categories of amino acid:
glucogenic via pyruvate, glucogenic via TCA cycle
intermediates; ketogenic;
mixed
2.4.1.2 Amino Acid Metabolism
2.4.1.2.1 Oxidation
Transamination; role of -ketoglutarate and glutamate Pyridoxal phosphate in transamination



Significance of glutamate dehydrogenase. Fate of
ammonia generated
Transport of ammonia from peripheral tissues. Metabolism
of glutamine in intestinal cells and renal cortex
Nitrogen excretion as urea or as ammonium ions;
implications for pH regulation
2.4.1.2.2 Urea synthesis
Principal steps in formation of urea from ammonia Hepatic intracellular compartmentation of the urea
Site (periportal cells of liver lobule) cycle

Control 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 24–36h
2.4.1.2.3 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 cycle
2.5 CELLULAR ORGANIZATION OF METABOLISM
2.5.1 Overview
The major pathways of metabolism in relation to sub-
cellular architecture
2.5.2 Mitochondria
Role 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)



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 Apparatus
Outline of role in biosynthesis of lipids, complex
carbohydrates and glycoproteins
Role in detoxification: significance of cytochrome P450
2.5.3 Lysosomes
Outline of role in recycling of building blocks of Range and importance of lysosomal diseases
macromolecules (especially extracellular matrix
components). See also 1.9
2.5.4 Peroxisomes
Outline of role in substrate processing Role in biosynthesis: plasmalogens, bile acids
Significance of peroxisomes as revealed by
peroxisomal diseases
2.5.5 Protection Of Cells Against Reactive Oxygen Species
Mechanism of generation of O2– and H2O2 Glutathione, vitamins C and E
Superoxide dismutases, catalase, glutathione
Existence of specific ‗antioxidant‘ enzymes that remove
peroxidase (need for selenium)
these toxic species
Glutathione reductase, need for NADPH
2.6 BIOCHEMICAL PRINCIPLES OF NUTRITION
Energy 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 weight
Biochemical 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



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 ill
2.7 CLINICAL BIOCHEMICAL MEASUREMENT
Measurement of gases, ions, pH, osmolarity, metabolic
substrates, hormones and enzymes: principles and
clinical importance
Uses 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 2.3.2.4)
Recognition of enzyme deficiencies
Use of enzymes to measure biologically-important Glucose assays
molecules
3.MOLECULAR AND MEDICAL GENETICS
3.1 PRINCIPLES OF MOLECULAR GENETICS
3.1.1 What Genes Do
Genes 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 Of
Genes 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 proteins
3.1.3 Connection between Gene Structure and Function



Molecular structure of DNA Physical evidence for DNA structure. Simple
Nucleic acid bases, nucleosides and nucleotides treatment of X-ray diffraction
5‘-3‘ polarity of DNA strands; base pairing rules
DNA replication as a semi-conservative process Evidence from electron microscopy and
identification of enzymes needed for replication
Synthesis of DNA; proof-reading functions of
enzymes
How genes code for proteins: key features of the genetic Evidence for the nature of genetic code
code Identification of individual codons, stop and start
Role of tRNAs and aminoacyl-tRNA synthase signals
3.1.4 Regulation Of Gene Expression
Regulation of expression of genes by other genes: RNA polymerases and their roles in mammalian
concept of structural and regulator genes cells
Roles 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 of
Chromatin condensation and gene activity (see 1.8) postulated factors
3.1.5 TRANSCRIPTION, RNA PROCESSING AND TRANSLATION
Products 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 synthesis
Outline of ribosome structure and of translation
Intracellular sites of protein synthesis and the signal
hypothesis (see 1.9)
3.1.6 Organization Of The Genome



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
fragments

Principle 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



3.4 GENETICS OF DISEASE
Single gene disorders
Autosomal dominant — segregation, expression in
heterozygotes, penetrance, expressivity, risk to
offspring
Autosomal recessive — transmission, expression in
homozygotes, carrier status, risk to siblings Basis of rare occurrence of X-linked disease in
X-linked — transmission, hemizygous males, carrier females
females Mitochondrial disorders: heteroplasmy
Mitochondrial inheritance
Polygenic disease: concordance in twin studies, relative
risk, susceptibility genes
3.5 GENES IN POPULATIONS
Ethnic differences in disease frequencies
Hardy-Weinberg equilibrium
Assortative mating, genetic drift, selection and mutation
The concept of polymorphism
3.6 THE HUMAN GENOME, MAPPING & DIAGNOSIS
3.6.1 DNA Polymorphisms
Restriction fragment length polymorphisms (RFLP)
Minisatellites and microsatellites (VNTR)
Use of DNA polymorphisms as genetic markers
3.6.2 Genetic linkage
Concept 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



ethical considerations.
3.7 MUTATION AND HUMAN DISEASE
Effects 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 changes

4.PRINCIPLES OF DRUG ACTION
4.1 TYPES OF PHARMACOLOGICALLY ACTIVE AGENTS
Acting 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 inhibitors
Drugs acting on membrane transporters or ion channels
e.g. calcium channel blockers, potassium channel
blockers
4.2 RESPONSE
4.2.1 Cell -Surface Receptors
Proteins as receptors
Three 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 interactions
4.2.2 Drug Action



The log-dose/response curve Principle and uses of bioassay
Affinity, efficacy, potency: definitions and chemical basis
Types of antagonism: competitive, non-competitive, Radioligand binding studies
irreversible, physiological
Effects on log-dose/response curve
4.2.3 Receptor–Effector Coupling
Concept of second messengers: principle of amplification;
G-proteins
Cyclic 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 extrusion
Gap junctions: passage of ions and small molecules
(second messengers) between adjacent cells e.g.
linking epithelial, cardiac and some smooth muscle
cells
Desensitization (tachyphylaxis)
4.2.4 Modulation
Interactions at receptor site and intracellularly
4.2.5 Receptor Regulation
Up- and down-regulation in response to agonists and
antagonists
4.2.6 Intracellular Receptors



Intracellular 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 Administration
Main routes of administration:
oral, sublingual, rectal, topical (skin, eye, by sniffing),
inhalation,
and injection (intravenous, subcutaneous,
intramuscular, intraspinal) Concept of bioavailability
Factors 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 Action
Lipid 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 fat
Binding to plasma proteins: Drug interactions through competitive
reduces free drug able to diffuse into tissue fluid; displacement from plasma proteins
reduces renal clearance of drugs
Carrier-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 urine
4.3.3 Drug Metabolism And Excretion



Principles of drug metabolism (see also 10.1.4) Metabolism may activate some agents - concept of
Chemical modification usually abolishes activity: ‗pro-drugs‘
hydrolysis, e.g. acetylcholinesterase (see 6.4.4.1); Drug metabolites may be toxic - severe
oxidative deamination e.g. MAO (see 6.4.4.2); 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 excretion
Renal excretion of drugs
Glomerular 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: enterohepatic
Tubular 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 drugs
5.TISSUE TYPES: STRUCTURE & FUNCTION
5.1 EPITHELIAL TISSUES
Classification by cell shape and organization:
simple (squamous; cuboidal; columnar;
pseudostratified); stratified; transitional
Classification by function: secretory, absorptive,
mechanical
Stem cells and differentiated cells EM appearance of intercellular junctions
Basement membranes: structure and function in epithelial
anchorage, polarity and differentiation
Functions of intercellular junctions:
desmosomes - mechanically linking cells
gap junctions - allowing intercellular communication



by ions and small molecules
junctional complexes - determining trans-epithelial
transport:
leaky and tight epithelia (see 11.3.3)
Polarity: apical and basolateral surfaces
Functions: 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 TISSUES
Types of macromolecules making up the extracellular
matrix (ECM), a simple appreciation of their nature and
properties:
e.g. collagen (see also 1.2.3.1), elastin, proteoglycans
Cell 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 storage
Tendons, ligaments, aponeuroses, fascia, cartilage and
bone: their mechanical properties and functions;
organisation as joints
Adipose tissue: storage and thermal insulation
Cartilage: 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



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



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: Leucocytes
You 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.
5.4.2.1 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
5.4.2.2 Monocytes
Blood cells that give rise by migration to macrophages,



both resident macrophages (e.g. Kupffer cells) and those
freshly migrated from the blood at sites of inflammation
Macrophages 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 bodies
5.4.2.3 Lymphocytes
Stem cells in bone marrow, primary development along two
lineages, ‗B‘ cells and ‗T‘ cells. ‗T cells‘ mature in thymus,
self-sustaining in the periphery
Proliferate 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 response
Large lymphocytes (lymphoblasts): activated, dividing,
developing to effector cells
Immunological memory resides in lymphocytes
5.4.2.4 Platelets See 10.3
5.4.3 Hemopoietic Stem Cells



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 SYSTEM
Principles of the peripheral organisation of the somatic motor and sensory nervous systems, and of the autonomic
nervous 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



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 viscera

6.3 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



Role of K+ and Na+ diffusion in generating the Effects of varying external K+, Na+, or Cl– on membrane
membrane potential potential
6.3.2 Action Potential
Ionic mechanism of the action potential Experimental evidence for the Hodgkin-Huxley model.
Conduction of action potential Explanation of voltage-clamp, patch-clamp and gating
Role of myelination in saltatory conduction currents. State-diagrams for Na+ and K+ channels
Range 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 sclerosis
6.3.3 Local Anesthetics
Examples of local anaesthetics e.g. lignocaine Cocaine
Mechanisms of action. Local, regional, spinal, epidural anesthesia
Duration of action: dependence on lipid solubility, use Risks of accidental systemic administration
of vasoconstrictors
Sequence of blockade: pain first, then general sensory
and then motor last.
6.3.4 General Anesthetics
Principles of action of general anaesthetics
Distribution of anesthetic drugs between alveolar air (for Physical and chemical characteristics of the ―ideal‖
inhalational agents), blood, tissues and CNS general anesthetic
Factors influencing duration and depth of anesthesia.
6.4 SYNAPTIC TRANSMISSION
6.4.1 Neuromuscular Transmission
Morphology and function of neuromuscular junction Structure of ACh-activated cation channels; two ACh
(nmj) receptor sites per channel. High signal-to-noise ratio



Synthesis, storage, release and action of ACh of synapse. Choline recycling. Drugs interfering with
Hydrolysis of ACh vesicular release: botulinum toxin
Mechanisms 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 block
6.4.2 Interneuronal synapses
Variety of neurotransmitters (including ACh,
catecholamines, glutamate, GABA and glycine) and
receptors
Excitatory and inhibitory synapses
EPSPs and IPSPs Pre-synaptic inhibition
Concept 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 junctions

6.4.3 Autonomic Synapses
Synapses on cardiac and smooth muscle (en passant
junctions, varicosities): structure and function in
comparison with neuromuscular junction.

6.4.4 Autonomic Transmission
6.4.4.1 Cholinergic
Nicotinic and muscarinic receptors: distribution and Existence of receptor subtypes M, N1,, N2: ganglionic vs.
function neuromuscular nicotinic receptors
Local 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



Acetylcholinesterase
Examples and effects of anti-cholinesterases.(e.g.
neostigmine)
Therapeutic use of anticholinesterases in myasthenia
gravis
6.4.4.2 Catecholaminergic
Synthesis, 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-
DOPA
Adrenoceptors: 1, 2, 1, 2; distribution and function Therapeutic applications of selective antagonists: in
relative potency of NA, Adr, and isoprenaline on 1, asthmatics
1, 2
Local and systemic effects of agonists and antagonists
Therapeutic use of selective agonists and antagonists
e.g:
 -agonists in asthma
1 -blockers (e.g. atenolol) in cardiovascular disease
Reuptake of transmitter and subsequent degradation:
MAO, COMT
inhibitors of reuptake (amphetamines);
inhibitors of degradation: MAO inhibitors

6.4.4.3 Other autonomic neurotransmitters
Other transmitters and neurotransmitters e.g. nitric
oxide (NO), ATP and neuropeptides e.g. VIP

Concept of co-transmission Putative functions of co-transmitters
6.5 MUSCLE AND INNERVATION
6.5.1 Structure and Function: Overview
Skeletal 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



(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-tubules
Cardiac muscle:
branching mesh of cells joined and electrically
coupled by intercalated disks (desmosomes and gap
junctions)
autonomic innervation
Smooth 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 innervation
6.5.2 Skeletal Muscle
Muscle action potential as the trigger for muscle fibre Length–tension curve of muscle
contraction Electron microscopy of muscle. 3-D arrangement of
Grading 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+-release
Cross-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 Muscle
Heterogeneity, roles, and basic ionic mechanisms of the
cardiac action potential
Role of Ca2+ entry (during the long AP) and sr Ca2+



release in e/c coupling
Mechanism 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
beat
Inotropic effect of cardiac glycosides (see also 8.6.7)
6.5.4 Smooth Muscle
Neurogenic and myogenic activity Types of smooth muscle:
Role of the action potential (when present) (i) electrically excitable: driven entirely through nervous
Role of Ca2+ entry and sr Ca2+ release in activating activity e.g. vas deferens, arterioles
contraction (ii) spontaneous electrical activity modulated by nervous
Role 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 LIMBS
Principles of skeletal organisation; bone as a tissue (see 5.2)
Long, flat, and short bones; adaptations to strength and force transmission
As examples, the bones of the upper limb, their functional adaptations; comparisons



with bones of the lower limb
Shoulder 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 femur
Forearm: ulna and radius; comparison with tibia and fibula
Small bones of hand (carpal; metacarpals; phalanges); comparison with foot (tarsus,
metatarsals, phalanges)

7.2 JOINTS OF THE LIMBS
Principles of the structure and function of fibrous, cartilaginous, synovial joints
Relationships between stability and mobility
For 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 muscles
Compare the structural specializations of the hand (dexterity and grip) with foot
(stability and support)
7.3 MUSCLES AND MOVEMENTS OF THE LIMBS
Principles of the organisation, function and innervation of functional muscle groups
The attachments, functional grouping and movements of the muscles of the upper
limb; comparisons with the lower limb; control of tendons at joints
Muscles groups acting on the shoulder girdle and shoulder compared with those
acting at the hip
Muscles groups of the flexor and extensor compartment of the arm (acting on the
elbow) compared with those acting at the knee
Muscles groups involved in pronation and supination of the forearm
Muscles groups acting to produce inversion and eversion of the foot
Muscles groups of the forearm involved primarily in flexion and extension of wrist and
fingers compared with ankle and toes
Movements of the hand compared with the foot



7.4 BLOOD SUPPLY TO THE LIMBS
Basic 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 joints
7.5 NERVE SUPPLY OF THE LIMBS
Principles 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 development
Brachial plexus and lumbosacral plexus
The 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, sciatic
Anatomical basis of common reflex arcs: significance in mapping injuries to spinal
nerve roots
7.6 SPINE
Basic 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 body
Components 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



Intervertebral joints: movements possible at different regions of the spine;
intervertebral discs
Curvatures of the spine: lumbar and sacral lordoses. Transmission of weight through
the spine
Major features of the development of the segmental structure of the body
7.7 LIVING ANATOMY
Major bony landmarks (esp. around shoulder, elbow, wrist). Vertebral prominences
Principal arterial pulse points. Measurement of systemic arterial pressure
Points of access to veins for venepuncture
Nerve function: muscle action and power, tendon reflexes (e.g. biceps, knee jerk); Electromyogram
sites to test sensation to determine damage to nerve roots and main peripheral
nerves
7.8. IMAGING
Plain radiographs: principal bony landmarks
CT and MRI: principal structures and landmarks
Contrast imaging: angiograms - principal arteries, veins, lymphatics Arthrograms
8. BREATHING AND CIRCULATION
8.1 THORACIC ANATOMY
Principal features of the living, gross and radiographic anatomy, including CT and MRI appearance of the thorax.
You should be able to identify major named structures on the living body, a dissection, or a clinical image, and
to define their major functions.
8.1.1 Thoracic Cage
Structure of thoracic cage in relation to movements of respiration, protection of thoracic contents, and
examination of heart, lungs and chest wall.
8.1.1.1 Living anatomy of the thorax
Surface markings on the chest of the apex beat and
borders of the heart, the diaphragm
Relative expansion of the upper and lower chest in
anteroposterior and lateral dimensions; descent of
diaphragm on inspiration
Percussion of the chest wall to detect dullness due to
heart and liver, or resonance of gas-filled cavities i.e.


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