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.



lung fields and gas in stomach

8.1.1.2 Skeletal and soft-tissue framework of the thorax
Sternum, manubrium, xiphisternum, sternal angle, ribs
and costal cartilages
Diaphragm, external and internal intercostal muscles,
phrenic nerve (C3,4,5)
Movements of the ribs: expansion of transverse diameter
by movement of the lower ribs; movement of the upper
ribs give lesser expansion of anterior-posterior and
transverse diameters; role of intercostal muscles,
diaphragm
8.2 PULMONARY MORPHOLOGY
Structure of the lungs, airways and pleural cavity in relation to respiration
8.2.1 Pleura and Pleural Cavities
Pleural sac. Parietal and visceral layers of pleura.
8.2.2 Upper Airway
Role of the nose: olfaction, and warming, cleaning, and Sites of impaction of inhaled bodies
humidifying inspired air
Naso-, oro-, and laryngopharynx
Movements of mouth, tongue, soft palate and pharynx
during breathing
Epiglottis, larynx and phonation
8.2.3 Airway And Lungs
Airway: trachea left and right main bronchi; division into
lobar bronchi
Principles of lobar organization and bronchopulmonary
segmentation
Structural feature of the lungs in relation to gas exchange
Principles of pulmonary and bronchial arterial supply and
venous drainage of the lungs
Afferent and efferent autonomic innervation of airways
and lungs



Principles of lymphatic drainage of airway

8.2.4 Tissues of the Respiratory System
General structure of mucous and serous membranes; the Accumulation of viscous secretion in cystic fibrosis
mucous membranes of the respiratory tract
Epithelial cell types and their functions in the airways: Brush cells, Clara cells, small granule-containing cells
ciliated cells, goblet cells
Development and cellular structure of alveoli: surfactant Respiratory distress of the new-born
production Effects of smoking on respiratory epithelia
Type I and type II pneumocytes, alveolar macrophages, Role of growth factors in differentiation and
alveolar capillaries morphogenesis
elastic fibres

8.2.5 Imaging
Appearance on radiographs, angiograms, CT and MRI of
normal lung parenchyma and pulmonary vasculature

8.3 RESPIRATORY PHYSIOLOGY

8.3.1 Overview Of Pulmonary Function
Total ventilation. Respiratory dead space and alveolar
ventilation
Concept of partial pressure and its units of measurement
Resting oxygen uptake and carbon dioxide production Respiratory quotient
Normal alveolar partial pressures of oxygen and carbon The alveolar gas equation
dioxide
8.3.2 Respiratory Mechanics - Statics
Tidal volume, vital capacity, functional residual capacity, Other lung volumes and their measurement
and their measurement
Negativity of intra-pleural pressure: pneumothorax Measurement of intra-pleural pressure and lung
compliance
Concepts of compliance, surface tension Regional ventilation
Surfactant Laplace‘s equation



Atelectasis in Respiratory Distress Syndromes
8.3.3 Respiratory Mechanics - Dynamics
Concept of airways resistance Distribution of airways resistance
Turbulence of airflow leading to wheeze Relation of airways resistance to lung volume
Measurement of airways resistance
Peak expiratory flow and its measurement Forced expiratory volume in one second (FEV1)
Work of breathing
Distinction between obstructive (e.g. asthma) and
restrictive (e.g. pulmonary fibrosis) lung disease

8.3.4 Diffusion Of Respiratory Gases
Concept of diffusion and of the diffusing capacity of the Fick‘s law of diffusion
lung
Factors influencing the speed of diffusion Perfusion and diffusion limitation of gas transfer
Pathologies affecting diffusion e.g. pulmonary fibrosis, Measurement of diffusing capacity using carbon
pulmonary edema, emphysema monoxide
8.3.5 Oxygen Transport
Normal value for systemic arterial partial pressure of Measurement of arterial partial pressure of oxygen
oxygen
Role of hemoglobin in oxygen transport Contribution of dissolved oxygen to oxygen
Concept of saturation transport
Measurement of arterial pressure oxygen saturation
by pulse oximetry
Shape of the oxy-hemoglobin dissociation curve The Hill equation and cooperative binding
Myoglobin: role of myoglobin comparison with
Shift of the curve by CO2 and pH (Bohr effect) hemoglobin,
Effect of temperature and 2,3-DPG concentration on
oxy-haemoglobin dissociation
Varieties of hemoglobin: e.g. foetal, sickle cell
Delivery of oxygen to the tissues and factors affecting it Oxygen stores and the effect of apnoea
hypoxic hypoxaemia, cyanosis
Cyanide and carbon monoxide poisoning, oxygen
therapy



8.3.6 Carbon Dioxide Transport
Normal value for systemic arterial partial pressure of
carbon dioxide
Role of bicarbonate in carbon dioxide transport Contribution of dissolved carbon dioxide to oxygen
Concept of buffering: its importance in carbon dioxide transport
transport The Henderson-Hasselbalch equation
role of hemoglobin in buffering H+ from dissociating The CO2/blood dissociation curve: the Haldane effect
H2CO3 The Davenport diagram showing the
Additional role of haemoglobin in CO2 transport by interdependence of plasma bicarbonate, pCO2,
formation of carbamino compounds and pH in oxygenated and deoxygenated blood
Role of carbonic anhydrase in red cells; the chloride shift Body stores of CO2; the effects of apnoea
8.3.7 Pulmonary Perfusion And Ventilation/Perfusion (V/Q) Matching
The pulmonary circulation as a low pressure circulation Regional distribution of flow and its measurement
Effect of mismatch of perfusion to ventilation on Regional differences in ventilation/perfusion ratios
pulmonary gas exchange (including consequences of and alveolar gas composition
the shape of the oxyhemoglobin dissociation curve) The three-compartment model of the lung: shunt,
Concept of pulmonary shunt ideal alveolus and dead-space
Hypoxic pulmonary vasoconstriction and acute pulmonary Pathological examples of V/Q mismatch: pulmonary
hypertension embolism, pneumonia
8.3.8 Control Of Breathing
Generation of breathing rhythm within brainstem Structure and function of the carotid body
Effect of ventilation on alveolar pressures of oxygen and
CO2
Central chemoreceptors: their location, normal stimulants,
and role
Peripheral chemoreceptors: their location and normal Innervation of peripheral chemoreceptors
stimulants
Pulmonary stretch receptors Hering-Breuer reflex. Pulmonary irritant and J
Autonomic innervation of the bronchi receptors
Innervation of pulmonary receptors via vagus nerve
8.3.9 Acute Airways Obstruction
8.3.9.1 By Foreign Bodies
Consequences of acute airway obstruction by foreign Anatomy of bronchial bifurcation: favoured path



bodies: upper and lower airways followed by inhaled foreign bodies
8.3.9.2 In Unconsciousness and Sleep
Consequences and relief during basic
resuscitation of upper airways obstruction
8.3.10 Pharmacology Of Breathing
8.3.10.1 Effects of drugs on respiratory control
Effects of opiates on cough reflex and respiratory Effect of salicylate overdose on respiratory control
drive Use of respiratory stimulants (doxapram) after
general anesthesia
8.3.10.2 Asthma and its pharmacology
Asthma: role of inflammatory response Mucus formation. Intrinsic plexus
Drugs used to treat asthma: Potential disadvantages of pharmacological
bronchodilators;  -adrenoceptor agonists e.g. intervention: receptor down-regulation, adverse
salbutamol, adrenaline (for its effects on mucus viscidity (beta-agonists)
 -agonism), cholinoceptor antagonists (e.g. Antileukotrienes in asthma therapy
ipratropium), xanthines Sodium cromoglycate; inhibition of mast cell
(e.g. aminophylline) degranulation
Steroids: actions and adverse effects (see also 34.1.1; Other transmitters of bronchial plexus as possible
27.5.2) therapeutic targets
Cromoglycate Use of humidification and mucolytics

8.4 CARDIOVASCULAR SYSTEM: MORPHOLOGY
8.4.1 The Heart
Structure of the heart in relation to its action as two pumps, left and right. 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.
8.4.1.1 Exterior of heart
Fibrous pericardium; serous pericardium
Principal venous structures draining to the heart (superior
and inferior venae cavae and pulmonary veins)
Principal arterial structures leaving the heart: aorta and
pulmonary trunk



8.4.1.2 Interior of heart
Atria and ventricles: structural adaptation to function
Right (tricuspid) and left (mitral) atrioventricular valves,
pulmonary valve, aortic valve
8.4.1.3 Blood supply of heart: distribution of supply
Principles of coronary vascular supply; angiographic Angina. Myocardial ischemia; consequences of
appearance occlusion of the major coronary arteries
Principles of blood supply to myocardium: coronary
arteries as functional end arteries, coronary perfusion
during diastole, coronary sinus
8.4.1.4 The Conducting System (see also 8.6.1)
Principles of conducting system of the heart
Sinu-atrial and atrioventricular nodes. Atrioventricular Referred pain from the heart to central chest, neck
bundle: right and left branches and left arm; from diaphragm to shoulder (C4)
Autonomic innervation.
8.4.2 Histology of Blood Vessels
Structure and functions arteries, arterioles, capillaries, Arterio-venous anastomoses
venules and veins: Atherosclerosis - degenerative process narrowing
endothelium; tunica intima, media, vasa vasorum, arterial lumen and weakening walls (details to be
adventitia; elastic and non-elastic vessels covered in 2nd year)
Portal systems (in liver, kidney, and pituitary gland)
Structure and function of different types of capillaries:
non-fenestrated and fenestrated capillaries, sinusoids,
‗tight‘ capillaries
8.4.3 The Great Vessels
Major arteries and veins carrying blood from, and returning it to, the heart.
Aorta: ascending, arch, descending
Aortic arch baroreceptors, aortic body chemoreceptors Sensory fibres in vagus nerve: Cr. X
Brachiocephalic artery, subclavian and common carotid
arteries; carotid bifurcation Sensory fibres in glossopharyngeal nerve: Cr. IX
Carotid sinus baraoreceptors, carotid body
chemoreceptors



Pulmonary artery. Ligamentum arteriosum
Brachiocephalic veins, superior and inferior vena cava
8.4.4 Mediastinum
Position and function of the major structures within the chest, and their relationship to the heart and lungs.
Major aspects of organisation of the mediastinum. Sites
of major structures: heart, great vessels, trachea,
oesophagus, phrenic, and autonomic nerves
Thoracic duct draining lymph to left subclavian vein
8.5.5 Autonomic Innervation of Thoracic Viscera (see also 6.2.2)
Sympathetic nervous system: origin of preganglionic
fibres from T1 - L2 of cord; Sympathetic chain of
ganglia; effects on heart and airways
Parasympathetic system; preganglionic fibres in vagus Horner‘s syndrome (damage to sympathetic trunk at
nerves; effects on heart and airways head of first rib)
Visceral afferent (sensory) fibres with vagus and
sympathetic nerves
8.4.6 Imaging
Appearance on radiographs, angiograms, CT and MRI of
normal heart and mediastinum

8.5 CARDIOVASCULAR PHYSIOLOGY
8.5.1 Electrical Activity In The Heart: The Electrocardiogram
Pacemaker and conducting system
relative conduction velocities in parts of the conducting
system
Key components and origin of the 3-lead ECG The heart as a dipole in a volume conductor
P, QRS, T waves Historical appreciation of the contributions of
Einthoven and others to understanding the ECG.
12-lead ECG
Elementary examples of clinical abnormalities
diagnosed on ECG

8.5.2 The Heart as a Pump



Role of papillary muscles in valve function
1st and 2nd heart sounds 3rd and 4th heart sounds
Cardiac cycle: pressure and volume changes in relation to
the ECG
Jugular venous pulse in relation to the cardiac cycle
Physiological significance of the Frank-Starling Law of the Historical appreciation to the Frank–Starling Law
Heart Concept of cardiac work
Determinants of cardiac output Measurement of cardiac output: the Fick principle,
Neural and chemical factors affecting the inotropic and and dilution technique; echocardiography
chronotropic state of the heart

8.5.3 Properties of the Vascular System
Functions of the circulation: systemic and pulmonary
divisions
Distribution of cardiac output to main organs of the body
Structure and roles of arteries, arterioles, capillaries, & Arterio-venous anastomoses
veins (see 8.5.5)
Relation between flow velocity and total cross-sectional Poiseuille‘s equation; distinction between laminar
area of vessel bed and turbulent flow
Blood volume and its distribution with respect to vessel Laplace‘s law: the importance of elastic tissue in
type maintaining the stability of resistance vessels
Effect of vessel radius on its resistance to flow
Anomalous viscosity of blood
Fluid balance across capillaries (Starling forces)
Production of vasoactive substances by endothelium
8.5.4 Hemodynamics
Measurement of arterial blood pressure; Korotkoff sounds Appreciation of the history of the circulation (Galen,
Harvey)
Pulse pressure, mean arterial blood pressure, diastolic Pulse wave transmission speeds
and systolic blood pressure Differences between peripheral and central pressure
waveforms
Determinants of arterial blood pressure (cardiac output
and total peripheral resistance)



Use of the jugular vein for assessment of central venous
pressure.
Effects of posture and gravity on pressure and volumes in
the circulation
8.5.5 The Control Of Regional Blood Flow
Autoregulation
Factors affecting local vascular control: Stretch-activated ion channels
temperature, metabolic, myogenic, autacoids, nitric Evidence for role of nitric oxide
oxide
Reactive hyperaemia
Neural and hormonal control
Distinguishing features and the control of circulation in
the major organs:
skeletal muscle, coronary, pulmonary, cutaneous,
cerebral, renal
8.5.6 Sensory Receptors And Reflexes
The integrative processes involved in blood pressure regulation will not be examined until the second year
Arterial baroreceptors: location and function Classes of baroreceptor fibre and their thresholds for
firing
Afferent and efferent pathways Effect of arterial chemoreceptor stimulation on the
circulation
Low pressure cardiopulmonary receptors Significance of blood pressure regulation
8.5.7 Pharmacology of Cardiac Contractility
Principles of influence of drugs on cardiac contractility: Effects on cardiac contractility of coronary and
direct effects on heart, indirect effects through peripheral vasodilators (e.g. ACE inhibitors,
changing vascular tone hydralazine, nitrates)
Cardiac glycosides: possible mechanism of action Risk that drugs increasing cardiac contractility may
Positive effect of adrenoceptor agonists e.g. dobutamine precipitate ischaemia and dysrhythmia
( agonist)
- Calcium sensitizers as possible new positive
Negative effect of adrenoceptor antagonists e.g. inotropes
propranolol
8.5.8 Cardiac Dysrhythmias And Heart Block
Examples of common dysrhythmias Possible causative mechanisms:



Effects of ischemia, electrolyte
imbalance
Structural causes, e.g. hypertrophic
obstructive cardiomyopathy
aberrant conducting pathways as in
Wolff-Parksinon-White syndrome
Examples of antidysrhythmics, e.g: Dysrhythmogenic effects of
lignocaine, propranolol, amiodarone, antidysrhythmic drugs.
verapamil, adenosine; brief outline of
possible principles of action
Types of heart-block Possible iatrogenic origins of heart-
Secondary pacemakers block:
Therapeutic use of antimuscarinic drugs use of cardiac glycosides or Ca++
(atropine) channel antagonists
8.5.9 Integration of Regional and Systemic Regulation of the Circulation
Examples of coordinated regulation see: Exercise Physiology (section 8.7)

Local metabolic and myogenic effects on regional Cellular mechanisms of metabolic vasodilation:
circulation ATP, adenosine, pH, K+, osmolarity, temperature,
Distinction of functions of metabolic and myogenic ATP-sensitive K+ channels, L-type Ca2+ channels
responses Cellular mechanisms of myogenic response: stretch-
Action of regional regulatory changes on cardiac sensitive cation channels
output through Starling's Law Role of endothelial nitric oxide in ascending
vasodilation
(n.b. other locally acting mediators: see Anti-
Inflammatory Drugs 27.5)
Experimental demonstrations of autoregulation of
local blood flow
Venous occlusion plethysmography
in situ studies of vessels, countercurrent
communication from venules to arterioles
Effects of posture on capillary pressure of the human
foot



Short-term reflex control of arterial blood pressure Rate sensitivity of carotid sinus baroreceptors
Pathways of the reflexes: role of the brainstem
stability of ABP independent of local flow

mechanisms

High pressure (arterial) and low pressure (atrial)
reflexes
8.5.10 Cardiovascular Regulation in Critical Illness
Symptoms and signs of cardiac failure Classification of disorders of the circulation
Examples of causes of left and right ventricular Effects of haemorrhage and vasoconstriction or
failure, failure of the arterial and venous dilation on cardiac and vascular function curves:
circulations, and losses of circulating volume Guyton‘s analysis
Arterial and venous compliances. Mean circulatory
pressure
Definition of shock: symptoms and signs of shock. Principles of treatment of shock
Features of hypovolemic, cardiogenic and septic Anaphylactic and spinal shock
shock
Neural and endocrine responses to shock
8.5.11 Pharmacology of Cardiac Failure
Symptomatic treatments: diuretics; actions on Advantages and disadvantages of different
vasculature and on circulating volume approaches to therapy
Vasodilators: nitrates, converting-enzyme inhibitors Therapeutic and possible adverse effects of diuretics
through reduction in venous return
Positive inotropes: glycosides
8.5.12 Pharmacology of Blood Pressure
8.6.12.1 Central Effectors
Sympathetic influences in CNS. Other possible sites
of control
Clonidine,  -methylDOPA
8.5.12.2 Peripheral Vascular Effectors
8.5.12.2.1 Sympathetic



Alpha and beta antagonists in the treatment of Possibility of sub-groups of hypertensives responsive
hypertension to beta-blockade
Adverse effects of alpha blockade: postural
hypotension Possible mechanisms of action of beta-blockade
Adverse effects of beta blockade:
lethargy/depression, exacerbation of asthma,
digital vasoconstriction
8.5.12.2.2 Nitrates
Existence of EDRF (nitric oxide) and its receptors. Failure of endogenous nitrate vasodilator (EDRF)
Nitrate vasodilators: glyceryl trinitrate, isosorbide. mechanism as a postulated cause of hypertension
Frusemide and thiazides as vasodilators Use of inhaled nitric oxide in treatment of pulmonary
hypertension
8.5.12.2.3 Calcium channel blockers
Dihydropyridine derivatives block Ca2+-channels Adverse effects: flushing, headaches
preferentially in smooth muscle (as compared with
cardiac): causes vasodilatation
8.5.12.3 Peripheral Endocrine Effectors
8.6.12.3.1 Adrenals (cortex and medulla)
Influences of aldosterone, cortisol, adrenaline on Use of aldosterone antagonists (e.g. spironolactone)
vascular tone and circulating volume Cortisol excess (e.g. Cushing‘s syndrome) and
aldosterone excess (Conn‘s syndrome - rare) as
causes of hypertension
8.5.12.3.2 Renin–angiotensin-aldosterone system
Angiotensin-converting-enzyme inhibitors: enalapril Contribution of renin-angiotensin system to normal
Angiotensin receptors; effects on vascular tone blood pressure regulation: overactivity of this
system as a possible cause of hypertension. Renin
antagonists; angiotensin receptor antagonism
8.5.12.3.3 ADH
Existence of receptors for
ADH/vasopressin, effects on vascular
tone
8.6 EXERCISE PHYSIOLOGY
8.6.1 Energy Metabolism And Oxygen Consumption During Exercise



Changes in metabolic rate and oxygen consumption Measurement of the severity of exercise. Efficiency of
during exercise exercise.
Measurement of oxygen consumption Distinction between sprinting and endurance
Power supply: the energy value of basic body fuels; exercise. Energy & fuel requirements. Muscle fibre
respiratory quotient types involved. Substrate cycling and glycolysis.
Use of carbohydrate, fatty acid and phosphagen
stores.
Balance between fuels for maximum aerobic power
output in marathon compared to
ultra-short-distance runners
8.6.2 Physiological Changes During Exercise
Changes in cardiac output and heart rate with Changes in stroke volume and systolic & diastolic
increasing exercise pressures with increasing exercise
Factors which contribute to venous return, Relation between oxygen consumption, blood flow
including the muscle pump and venous oxygen saturation for exercising
muscle and the whole body during exercise
Matching of ventilation to severity of exercise Changes in tidal volume and respiratory rate with
Stability of blood gases increasing exercise
Possibility of diffusion limitation to pulmonary gas
transfer in extreme exertion
Changes in plasma lactate concentrations during Changes in plasma catecholamine and potassium
exercise concentrations

8.6.3 Control Of Physiological Changes During Exercise
Exercise limitation in normal subjects and in patients The effects of training. The three phases of change in
with cardiopulmonary disease ventilation on starting steady exercise
Sources of feedforward and feedback control in the
regulation of breathing during exercise
Role of the autonomic nervous system in the Relative importance of sympathetic neural and
cardiovascular response to exercise. Skeletal humoral cardiac drive
muscle work (chemo) receptors



Symptoms and signs related to exercise limitation in
disease: angina, claudication, dyspnoea.
Exercise ECG testing. Limitations on exercise at
altitude.
9. DIGESTIVE SYSTEM
9.1 ABDOMINAL ANATOMY
Principles of the living, radiological and gross anatomy, including CT and MRI appearance of the principal features
of the abdomen and pelvis. You should be able to identify major structures as appropriate on the living body, a
dissection, or a clinical image, and to define their functions.
9.1.1 Anterior Abdominal Wall
Basic structure of the anterior abdominal wall in relation to
its function
Surface projections of the major organs Inguinal hernias; congenital umbilical hernias
Consequences of deficiencies in the abdominal wall e.g.
the inguinal canal
9.1.2 Posterior Abdominal Wall
Basic structure of the posterior abdominal and pelvic
walls
Distribution of vessels and nerves to organs and the lower
limbs
9.1.3 Peritoneal Cavity and Peritoneum
Major compartments of the peritoneal cavity in relation to Spread of infection and fluid within the abdomen
abdominal organs. Visceral and parietal peritoneal
layers. Peritoneal cavity: greater sac, lesser sac. Pelvic
cavity
9.1.4 Spleen
Position of the spleen in the peritoneal cavity. Arterial
supply and venous drainage of the spleen
Roles of spleen: turnover of red blood cells

9.2. MOUTH, PHARYNX AND ESOPHAGUS
Mouth and mastication, teeth and tongue
Salivary glands: parotid, submandibular, and sublingual



Naso-, oro-, and laryngopharynx. Functions of soft palate,
oesophagus
Movements of mouth, tongue, soft palate and pharynx
during swallowing
9.3 THE GASTRO-INTESTINAL TRACT
Principles of the structure, vascular supply, innervation of the abdominal alimentary tract in relation to its
movements, secretions and absorptive functions.
9.3.1 Morphology Of Gastro-Intestinal Tract
Abdominal oesophagus; gastroesophageal junction and Hiatus hernia
‗sphincter‘ mechanism
Stomach: fundus, body; pyloric region (sphincter); greater and Pyloric stenosis; Gastric ulceration
lesser omentum
Duodenum; entry of biliary and pancreatic ducts Duodenal ulcers
Jejunum, ileum, attachment to small bowel mesentery
Cecum; appendix; ascending, transverse, descending and Appendicitis
sigmoid colon; rectum, anal canal
9.3.2 Vasculature Of Alimentary Tract
Distribution of major arteries to the gut and associated organs, venous drainage to hepatic portal vein, and
portal/systemic anastomoses.
Major features of organisation related to development.
Coeliac artery – foregut derivatives
Superior mesenteric artery to midgut derivatives
Inferior mesenteric artery to hindgut derivatives
Arrangement of arterial supply to gut Volvulus, intussusception, and consequences of
ischemia
Control of gut arterial supply by sympathetic nerves
Drainage of veins to hepatic portal vein Consequences of portal hypertension
Venous drainage of the rectum Hemorrhoids
Principles of lymphatic drainage
9.3.3 Autonomic Innervation of Abdominal Viscera (see also 6.2.2)
Sympathetic, and parasympathetic (vagal and sacral),
supplies to abdominal organs



Effects on motility, sphincters and secretion
Visceral afferent (sensory) fibres with vagus and
sympathetic nerves

9.3.4 Histology of the Digestive Tract
Basic structure of gut wall and its regional modifications:
mucosa (i.e. epithelium, lamina propria, muscularis
mucosae); Mucosal immune system: M cells, dendritic cells, gut-
submucosa; submucosal nerve and vascular plexus; associated lymphoid tissue
muscle layers; myenteric plexus; gut-associated Paneth cells
lymphoid tissue; serosa.
Types, functions and turnover of the various epithelial
cells (enterocytes, goblet cells, enteroendocrine cells -
see 14.6)
Stomach: structural, functional and cellular specializations
of the fundus, cardiac and pyloric regions. Gastric pits
and glands
Small intestine: structure of villi, lacteals, brush border of
absorptive epithelium,
crypts - replacement of epithelial cells by division,
migration and differentiation of stem cells
Large intestine: crypts, no villi, predominance of goblet
cells, taeniae coli
Innervation of the gut: enteric nervous system (see 6.2.2)

9.4 LIVER AND PANCREAS
Principles of organisation of the liver in relation to its processing of venous drainage of the bowel, secretion of
plasma proteins etc., production of bile and its storage and transport to the intestine
Principles of organization of the pancreas and drainage of its secretions (exocrine and endocrine)
9.4.1 Liver and Biliary Tract
Porta hepatis, hepatic portal vein, hepatic artery, hepatic
veins, portal-systemic venous anastomoses
Biliary system: hepatic ducts, gall bladder and cystic duct,



common bile duct, sphincter of Oddi.
Liver as common site for metastatic tumors
9.4.2 Histology of Liver and Biliary System
Liver: major functions; histological structure - sinusoids,
space of Disse, bile canaliculi, portal triads, functional
subunits (lobules)
Kupffer cells as an example of the mononuclear phagocyte
system
Biliary system: bile-resistant epithelium, the gall bladder.
Gallstones
9.4.3 Pancreas
Head, neck, body, tail and uncinate process of pancreas
Exocrine role: main pancreatic duct, sphincter of Oddi
Endocrine role: see 14.5
Principles of vascular supply
9.4.4 Histology of Salivary Glands and Pancreas
Microscopical anatomy of the salivary glands and
pancreas in relation the secretion of saliva and
pancreatic juice; zymogen granules
Salivary glands: myo-epithelial cells, serous cells, mucous
cells; control of secretion
Exocrine and endocrine components of pancreas:
exocrine acini and ducts, endocrine islets (14.5)

9.5 GASTROINTESTINAL PHYSIOLOGY

The physiological functions of the various parts of the gastrointestinal tract in relation to its functions in
digestion, absorption, and excretion of components of a meal; function in maintenance of salt and water
balance; and function as a protective/immune system.
9.5.1 Activity of the alimentary tract following a Meal
Cephalic, gastric, intestinal phases of activity
Integration of intrinsic and extrinsic neural control and local
hormones in regulation



9.5.2 Alimentary Tract Motility
Movements of different parts of the alimentary tract and their co-ordination. Relationship to abnormal
bowel movements. Effects of drugs
Swallowing
Esophageal sphincters
Gastric motility and emptying — its control Gut motility controlled according to contents by:
Importance of stomach as a storage organ; formation of chyme (i) hormones released by specialised epithelial
cells
(ii) stretch receptors acting via the enteric
nervous system
Gall bladder motility
Small intestinal motility: segmentation and pendular activity
Large intestinal motility: peristalsis (stimulated by distension Electrical slow waves, migrating motor complex
via enteric nervous system) (MMC)
Role of enteric nervous system NANC (non-adrenergic, non-cholinergic nerves)
Influence of drugs on motility: anti-emetics, laxatives,
antidiarrheal drugs
parasympathomimetics, opiates
Influence of diet on motility Importance of dietary fibre
Defaecation: voluntary and autonomic control Common motility disorders: e.g. constipation,
irritable bowel syndrome
9.5.3 Gastrointestinal Secretion
Salivary secretion: mechanisms and regulation. Components
of saliva
Gastric secretions: Experimental pouches, innervated and vagally
acid (see 9.5.3.1); enzyme (pepsinogen); mucus; denervated.
intrinsic factor - role in vitamin B12 absorption Sham feeding experiments.
Pernicious anaemia
Pancreatic secretion: enzyme, chloride and bicarbonate Abnormalities of chloride secretion in cystic
components fibrosis
Biliary secretion; entero-hepatic recirculation of bile salts Entero-hepatic recirculation of drugs
9.5.3.1 Gastric Acid Secretion and Peptic Ulceration
Mechanism of gastric acid secretion:



parietal cells, role of the H+-K+ ATPase in maintaining a large
pH gradient
Interactions of vagal stimulation, histamine and gastrin in
control of gastric acid secretion
Peptic ulcer: possible causes and therapy with antacids Adverse effects of antacid therapy
direct antacid agents e.g. aluminium hydroxide Evidence for association of Helicobacter pylori
histamine antagonists e.g. ranitidine with peptic ulceration: chemotherapy for
blockers of H+-K+ ATPase e.g. omeprazole Helicobacter
Also used, but rarely for peptic ulcer:
antimuscarinic agents e.g. pirenzepine
9.5.4 Digestion in the Alimentary Tract
Contributions of saliva, gastric secretion, pancreatic secretion Diversity of proteases, amylases and lipases
and bile to the digestion of protein, carbohydrate and lipid. Use of pancreatic enzymes in substitution
Enterokinase as an activator of intestinal peptidases therapy in pancreatic malabsorption
Role of brush border peptidases
Role of brush border disaccharidases Inability of humans to digest cellulose
Composition, concentration and secretion of bile
Emulsion and micelle formation and the role of bile salts
9.5.5 Absorption by the Alimentary Tract
Absorption of the major digested products of proteins, carbohydrates and fats; absorption of water- and
fat-soluble vitamins; absorption of water and electrolytes
Integration of nutrient digestion and absorption The unstirred layer
Role of active and passive epithelial transfer
Absorption of amino acids and peptides in the small bowel
Intracellular peptidases
Active absorption of D-glucose and D-galactose by Na- Minor passive components:
dependent secondary active transport; hexose exit from the uptake of fructose by facilitated diffusion
epithelium Role of glutamine as an intestinal fuel
Oral rehydration solutions: notably isosmotic salt/glucose
solution
Fate of unabsorbed carbohydrate Osmotic diarrhoea due to carbohydrate
malabsorption; Lactase deficiency
Intracellular triglyceride resynthesis. Chylomicron formation



and passage via lymph
Absorption of water-soluble and fat-soluble vitamins
Absorption of water and minerals, especially calcium and iron Toxin-induced diarrhoeas
(see also 10.1.1.3)
Intestinal electrolyte transport: Cystic fibrosis
tight and leaky epithelia and segmental variation
apical and basolateral transporters for Na+, Cl‘, K+, HCO3‘,
and short-chain fatty acids
regulation of ion transport
9.5.6 Gastrointestinal Hormones (see section 14.6)
The role of hormones (e.g. gastrin, secretin, cholecystokinin) in integrating the secretory, digestive and
motile functions of the alimentary tract
9.5.7 Protective/Immune Functions of the Alimentary Tract
The role of the different components of the alimentary tract in protecting the body
Taste as a protective mechanism
Gastric acid as a protective mechanism; sterility of small Achlorhydria: bacterial overgrowth as a cause of
bowel contents fat malabsorption
Epithelial barrier functions; protective role of mucus
Concepts of mucosal immune system
10. BIOCHEMISTRY: INTEGRATIVE ASPECTS, DEFENSE & DISEASE
10.1 ROLES OF THE LIVER
10.1.1 Overview
Roles of the liver in glucose homeostasis, fat metabolism, Effects of acute and chronic liver disease
amino acid metabolism and urea synthesis (see preceding
sections)
Functions in plasma-protein synthesis, trace-element
homeostasis, detoxification, alcohol metabolism,
vitamin/cofactor metabolism, and storage (see examples in
following sections)
10.1.2 Hepatic Protein Synthesis: Examples
10.1.2.1 Albumin



Significance in osmotic balance between vascular and edema of malnutrition
interstitial compartments; origins of oedema and ascites as
signs of severe (usually chronic) liver disease
Role in transport of hormones, fatty acids and drugs.
Example of another transport protein: transferrin (see 10.1.3)
10.1.2.2 Vitamin-K-dependent clotting factors
Proteases that, when activated, act on one another Identity: prothrombin (Factor V), and Factors VII,
sequentially: ultimate product is insoluble fibrin IX, X
Significance of clotting defects in liver disease
Action of these and other plasma proteases is inhibited by  -carboxyglutamate residues:
other proteins produced in the liver e.g. the protease role in metal-ion binding
inhibitor a-1-antitrypsin made by a vit K-dependent post-translational
See also ‗Hemostasis‘ (10.3) modification
of clotting factors
inhibition of that process by coumarin
anticoagulants
10.1.3 Iron Transport And Storage
Iron absorption, transport and distribution: roles of transferrin Causes and manifestations of iron deficiency
and transferrin receptors and iron excess
Homeostasis: storage forms, dietary intake (including dietary
sources, ease of absorption of haem vs non-heme iron),
forms of loss
Iron storage in cells: role of ferritin Coordination with transferrin receptor synthesis
10.1.4 Detoxification
Conversion of toxic, lipophilic compounds to polar, more
water-soluble derivatives for excretion, by oxidation,
reduction and conjugation
Oxidation/reduction reactions: significance of Dehydrogenases (e.g. alcohol dehydrogenase),
oxidation/reduction reactions in detoxification, reductases, oxidases. Mono-oxygenases –
activation of xenobiotics (to carcinogens), activation of cytochrome P450; function as electron donor
prodrugs Flavin-containing mono-oxygenases



Conjugation: functional groups introduced by Conjugation with sulphate, acetyl groups, amino
oxidation/reduction subsequently used to increase acids
water-solubility by conjugation, esp. with glucuronic
acid
10.1.5 Alcohol Metabolism
Role of the liver in alcohol metabolism Major pathways of hepatic ethanol metabolism.
Resultant susceptibility of liver to alcohol-induced Roles of alcohol dehydrogenase, cytochrome
damage P450 mono-oxygenase, peroxisomal catalase.
Metabolic effects of alcohol: hypoglycaemia, lactic Effects of ethanol metabolism on NADH levels.
acidosis, hyperuricaemia Significance of differing rates of alcohol
metabolism in different individuals, and their
possible relation to alcohol tolerance
Significance and subtypes (I–IV) of acetaldehyde
dehydrogenase; recognition of variations of
acetaldehyde dehydrogenase between races;
significance for alcohol tolerance.
Cellular effects of acetaldehyde; acetate; metabolic
consequences of increased NADH on fatty acid
metabolism and gluconeogenesis. Effect on
collagen synthesis (hepatic fibrosis in alcoholism)
Concept of modification of drug metabolism by alcohol A consequence of induction of the cytochrome P450
system; increased metabolism and decreased
activity (e.g. phenobarbitone, warfarin) and
increased activation with risks of hepatotoxicity
(e.g. paracetamol)
10.1.6 Catabolism Of HemE
Origin from red cells; conversion to bilirubin; transport to Competition with drugs for binding sites on albumin
liver bound to albumin; conjugation in liver to render it
water-soluble.
Bacterial metabolism of gut bilirubin to urobilinogen;
some oxidized to urobilins. (Significance of colour
of faeces and urine in bile-duct obstruction: see
9.4.1)



Jaundice as a sign of hyperbilirubinaemia. Significance of Toxicity of bilirubin
conjugated and unconjugated bilirubin in liver function
tests in investigation of causes of jaundice. Common
causes of elevated levels of conjugated and
unconjugated bilirubin
Kernicterus. Effects of light on bilirubin:
significance for phototherapy of neonatal jaundice
10.2 LIPOPROTEINS
Lipoproteins as transport vehicles for lipids: major Examples of single-gene inherited dyslipidemias:
lipoprotein fractions familial hypercholesterolemia, type I
hyperlipoproteinemia
Outlines of the metabolism (origin and fate) of chylomicrons, Possible significance of HMG CoA reductase in
VLDL, LDL and HDL atherosclerosis; inhibition of cholesterol
synthesis in the management of
atherosclerosis
The LDL receptor and its regulation Treatment of inherited dyslipidemias
10.3 HEMOSTASIS
Hemostasis:
vasospasm; formation of haemostatic plug by platelets
coagulation of the blood; subsequent clot resolution and
repair
Blood vessel endothelium: properties and interactions with Leukotrienes, chemokines, EDRF (NO)
blood components
Tunica media: smooth muscle, properties (structure of vessel
walls: see 8.5.2)
Platelets Phosphoinositides, von Willebrand‘s factor
granule constituents (ADP and 5-HT). Aggregation and
degranulation
functions in hemostasis: vasoconstriction, platelet plug,
activation of fibrin deposition (stabilises plug), initiation of
vascular and other repair processes (PDGF)
Blood coagulation: clotting cascade and its control:
extrinsic and intrinsic pathways, major coagulation factors Hemophilias and other bleeding disorders



(tissue factor, factor VIII, prothrombin, fibrinogen). Vit. K- Thrombosis: intravascular coagulation (details
dependent clotting factors: see 10.1.2.2 2nd year)
Fibrinolysis and role of plasmin Endogenous anticoagulants

10.4 ANTIBODIES AND COMPLEMENT
10.4.1 Antibodies: Immunoglobulins
Produced by plasma cells (which differentiate from B
lymphocytes: see 5.4.2.3)
Plasma cells derive clonally from a lymphocyte and produce
an antibody recognising a specific antigen characteristic
for that lymphocyte. Plasma cells as sites of
immunoglobulin synthesis in gut, mammary gland,
lymphoid organs and bone marrow
Role of antibodies:
bind to microorganisms and prevent their entry into
body/cells
bind to organisms and bind also to phagocytes
assists phagocytosis (‗opsonization‘) and activates
phagocytes
neutralise bacterial toxins
on binding to antigen activates complement and induces
inflammation (see 10.4.2)
membrane-bound form as receptor for antigen on B
lymphocytes
Antibody (i.e. immunoglobulin) structure: glycoproteins;
molecular size in relation to distribution in body fluids;
heavy and light chains
Variable and constant regions: the Fab region; the Fc region Structural basis of classes and sub-classes
Classes of immunoglobulins, the number of binding sites (isotypes)
they have for antigen Secreted vs cell surface determined by alternative
Secreted and cell surface forms of antibody mRNA splicing
Antibody function: Affinity, avidity. Structural basis of specificity:
Antigen binding region (Fab) for specificity complementarity determining residues (CDRs)



Fc region:
complement activation
binding to receptors on various cell types, e.g:
to macrophages and neutrophils, triggers phagocytosis
(opsonization) and activn.
to mast cells (IgE), triggers degranulation
to epithelial cells for transepithelial secretion:
IgA into tears, saliva, colostrum, the gut, etc.
IgG across the placenta
Turnover time of immunoglobulins as plasma proteins.
Relationship to neonatal protection by maternal antibody
10.4.2 Complement
System of neutral proteinases secreted into plasma by the
liver (also by macrophages) Alternative pathway for activation: IgA or certain
Cascade activated by immunoglobulin (IgG or IgM) bacterial cell walls (‗endotoxin‘)
associated with its antigen (classical pathway): feed-
forward amplification, control by inhibitors
Roles:
activated complement fragment C3 bound to antibody acts
as an opsonin
released fragments mediate inflammation (e.g. stimulate
migration of phagocytes,
increase venule permeability)
on antibodies bound to cell membranes, activated
complement assembles a pore that
causes cell lysis (e.g. can kill a microrganism, or a cell
producing virus)

10.5 DIABETES MELLITUS
Types of diabetes: insipidus; mellitus Types
1 and 2



Mechanisms of Type 1 and Type 2 diabetes
mellitus: insulin deficiency (from b-cell
destruction) vs. insulin resistance
Major metabolic disturbances in diabetes Biochemical principles underlying
mellitus (Types 1 and 2): polyuria, the treatment of type-I diabetes
polydipsia, dehydration, fatty acid Complications of diabetes mellitus
mobilisation, ketoacidosis, hypoglycemia
Glucose tolerance test
10.5.1 Endocrinological Aspects Of Growth
Hormones and prenatal growth, postnatal growth and the
pubertal growth spurt. Role of growth hormone, insulin-like
growth factors, human chorionic somatomammotrophin, T3,
sex steroids
10.5.2 Metabolic Homeostasis
Uptake and storage of nutrients: control by insulin, growth
hormone and IGF-1;
multifactorial control of insulin release
Mobilization and utilization of energy substrates; roles of
glucagon, catecholamines, T3, growth hormone/IGF-1 and
corticosteroids
Gluconeogenesis; regulation by glucagon, corticosteroids and
T3
10.5.2 Malnutrition And Obesity
Hormonal responses to malnutrition
Control of body weight, leptin. Hormonal aspects of obesity
10.6 INBORN ERRORS OF METABOLISM
Importance of these individually relatively rare diseases in the Examples: glucose-6-phosphatase deficiency,
population. A logical scheme for understanding any phenylketonuria (including maternal PKU),
individual disease: site of the enzyme defect and an urea cycle defects
understanding of the relevant biochemistry. Rational Form of notation used to indicate single amino
approach to treatment acid substitutions
11. URINARY SYSTEM
11.1 URINARY TRACT MORPHOLOGY



Principles of the living, radiological and gross anatomy, including CT and MRI appearance of the urinary tract. You
should be able to identify the major structures on the living body, a dissection, or a clinical image (radiograph,
endoscopic image etc.), and to define their functions.
11.1.1 Kidney and Ureter
Asymmetry of left and right kidney, relationship with adrenal
glands
Hilus of kidney, renal veins and arteries; renal pelvis, major
and minor calyces; cortex and medulla; kidney capsule
Ureter
11.1.2 Urinary Bladder
Position of bladder in abdomen, structural features relating to
bladder function e.g. sphincters
Principles of autonomic and somatic innervation (11.4)
11.2 HISTOLOGY OF THE URINARY TRACT
Structure of glomerulus and filtration barrier: podocytes,
basement membranes, capillary fenestrations, Bowman‘s
capsule, afferent and efferent arterioles
Structure and relationship to function of proximal and distal Cortical and juxtamedullary nephrons
convoluted tubules,
component parts of the loop of Henle, collecting ducts
Blood supply to the medulla: vasa recta
Juxtaglomerular apparatus, macula densa (see also 11.3.3)
Urothelium (‗transitional epithelium‘) of lower urinary tract Specializations of bladder epithelium for
distension
Structure and function of wall of bladder and ureter
11.3 RENAL PHYSIOLOGY
11.3.1 Role Of The Kidney
Overall functions of the kidney: regulatory; excretory; Consequences of renal failure:
endocrine (erythropoietin secretion, vitamin D activation) loss of ability to deal with volume and salt
General mechanism of urine formation: loading disturbances of electrolyte balance
glomerular filtration, tubular re-absorption and secretion (e.g. hyperkalemia) and mineral metabolism,
Magnitude of: renal blood and plasma flows, glomerular metabolic acidosis,
filtration rate (GFR), range of urine flow rate uremia, loss of endocrine functions



Role of the kidney in salt and water homeostasis
11.3.2 Glomerular Filtration
Concept of ultrafiltration and components of filtration barrier; Experimental evidence for ultrafiltration
driving forces for filtration and determinants of GFR; Concept of filtration pressure equilibrium
concept of filtration fraction
Definition of renal clearance and use of inulin and creatinine Para-amino hippurate (PAH) clearance to
clearance to measure GFR measure Effective Renal Plasma Flow (ERPF):
Autoregulation of GFR: myogenic response, tubulo-glomerular the Fick Principle
feedback Differential regulation of the afferent and
efferent arterioles (e.g. by angiotensin II and
by atrial natriuretic peptide ‗ANP‘)
11.3.3 Tubular Transport
Principles of epithelial transport: active versus passive
transport processes; leaky and tight epithelia; transcellular
versus paracellular route
Importance of basolateral Na/K-ATPase in driving solute and
water reabsorption
Mechanisms of apical sodium entry (coupled transporters and
channels)

Main functions and transport mechanisms of the different Composition of the tubular fluid along the
parts of the nephron nephron
Proximal tubule: Glomerulo-tubular balance in the proximal
Isotonic reabsorption of the bulk of filtrate. Concept of Tm tubule
and glucose ―overspill‖
Secretion of endogenous and exogenous organic cations
and anions
(e.g. uric acid, penicillin)
Loop of Henle: urine dilution (see 11.3.4)
Distal tubule and collecting duct:
Fine-regulation of renal electrolyte and water output

Juxtaglomerular apparatus Consequences of hyper- and



Renin-angiotensin-aldosterone system hypoaldosteronism on renal tubular
Action of aldosterone on Na+ re-absorption and K+ and H+ transport and body electrolyte balance
secretion
11.3.4 Formation Of Dilute And Concentrated Urine
Range of urine osmolarity
Establishment of corticopapillary interstitial osmotic gradient
by countercurrent multiplication in loops of Henle (role of
NaK2Cl co-transport and role of urea)
Regulation of tubular water permeability by ADH (i.e. V2 receptor; aquaporins
antidiuretic hormone, vasopressin) to concentrate urine (site Diabetes insipidus: central and nephrogenic
and mechanism of action) Effect of ADH on urea permeability in the inner-
Role of the vasa recta in countercurrent exchange medullary collecting duct
11.3.5 Diuretics
11.3.5.1 Loop diuretics (e.g. furosemide)
Mechanism of action: Secreted by the proximal convoluted tubule,
inhibition of the NaK2Cl transporter in the thick ascending and acts on the loop of Henle from within the
limb disrupts the osmotic gradient needed for urine lumen
concentration Treatment of oedema e.g. in congestive heart
failure
Adverse effects: e.g. K+ loss, volume depletion Peripheral vasodilator effects
11.3.5.2 Thiazides (e.g. hydrochlorothiazide)
Mechanism of action: Treatment of hypertension and edematous
inhibition of NaCl transporter in the distal tubule conditions
Comparison with loop diuretics: less potent, smaller loss of K+ Can precipitate gout through competitive
inhibition of uric acid excretion
11.3.5.3 Osmotic diuretics (e.g. mannitol)
Mechanism of action: Treatment of cerebral edema and prophylaxis
osmotic activity in tubule diminishes fluid reabsorption of acute renal failure: adverse effects: e.g.
volume-overload
11.3.5.4 Potassium- sparing diuretics
Aldosterone antagonists e.g. spironolactone Adverse effects: e.g. hyperkalemia
Inhibitors of the epithelial Na+ channel in the collecting duct



e.g. amiloride
11.3.5.5 Carbonic anhydrase inhibition (e.g. acetazolamide)
Mechanism of action: inhibition of bicarbonate reabsorption in Not considered useful as a diuretic, but used to
the proximal tubule treat glaucoma and as prophylaxis against
mountain sickness
Adverse effect: e.g. hypokalemia and acidosis
11.4 BLADDER CONTROL AND URINARY CONTINENCE
Nervous control of bladder (parasympathetic), and of internal
and external urethral sphincters (sympathetic and voluntary
control: see also 6.2.2)
Muscarinic antagonists for incontinence due to overactive
bladder
 -antagonists for outflow obstruction
1

BODY FLUIDS(14)
12.1 VOLUME, ELECTROLYTE COMPOSITION, OSMOLARITY

Body fluid compartments and their volume: Measurement of the volumes of
Total body water body fluid compartments
Extracellular fluid ‗ECF‘ (plasma and
interstitial fluid)
Intracellular fluid ‗ICF‘
Transcellular fluid e.g. exocrine secretions
into gut (cerebrospinal fluid, intra-ocular
fluids)
Electrolytes: Concept of salt and water balance
reference values in ECF for the Causes and consequences of
concentrations of sodium, chloride, water and electrolyte depletion
bicarbonate, potassium, calcium, and for (e.g. diarrhoea)
pH Causes of salt and water overload
approximate intracellular values for (e.g. iatrogenic fluid overload,
sodium, potassium, calcium and pH drugs)



Serum osmolarity and its determinants
12.2.1 Regulation Of Body Fluid Volume and Osmolarity
Normal water intake and losses Abnormalities of water balance and
Feedback control of the release of antidiuretic hormone (ADH) regulation
in regulating blood volume and serum osmolarity:
hypothalamic osmoreceptors and vascular volume receptor
mechanisms - their relative importance in control of ADH
release. The major contribution of sodium to osmolarity;
regulation of plasma sodium: the renin-angiotensin-
aldosterone system. Long-term regulation of blood
pressure.
12.2.2 Regulation of Plasma Potassium
Distribution and total body content of K+. Normal plasma Functional consequences of exercise-
concentration at rest and during exercise induced hyperkalemia e.g. skeletal
Consequences of hypo/hyperkalemia. Normal dietary balance muscle hyperemia
Non-renal handling of potassium. Hormonal effects on Na-K fatigue
ATPase (insulin, catecholamines) myocardial stability (e.g. interaction of
effects of adrenaline and hyperkalemia)
Abnormalities of K+ balance, including diarrhoea and renal
failure and the consequences on systemic function (e.g. on
the heart)
12.2.3 Regulation of Plasma Calcium
Assumes a knowledge of the effects of PTH, calcitonin and calcitriol on bone, gut and kidney



Distribution and total body content of Ca2+: plasma Ca2+ Mechanisms of absorption in gut
Mechanisms of excretion/reabsorption in
level; cell Ca2+ kidney
Functions of Ca2+: consequences of hypo/hypercalcemia Formation and reabsorption of bone,
osteoblasts, osteocytes and osteoclasts
Whole body Ca2+-fluxes, intestine, kidney, bone: dietary
intake vs requirements
Bone resorption in malignancy — PTH-RP
Special considerations: development, pregnancy, lactation
Abnormalities of Ca2+-regulation e.g. rickets, osteoporosis,
hypo/hyperparathyroidism, pseudohypoparathyroidism,
cancer, diuretics, renal failure
Glucocorticoids — as cause of osteoporosis Effects of thyroid hormone, growth hormone
Sex steroids — post-menopausal osteoporosis & IGFs, local growth factor
12.3 ACID–BASE BALANCE
12.3.1 Maintenance Of Intracellular And Extracellular PH
Importance of the maintenance of constant intracellular and Role of Na+-H+ exchange, HCO3‘ transporters,
extracellular pH and other membrane transporters (e.g.
Three lines of defence against acidosis/alkalosis: H+-ATPase) in controlling intracellular pH
(i) buffers; (ii) ventilatory mechanisms; (iii) renal with respect to extracellular pH
mechanisms
Concept of a buffer
Main intracellular and extracellular buffers
12.3.2 Renal Contribution to Acid-Base Balance
Renal regulation of plasma HCO3‘ Metabolic acidosis in chronic
concentration by: renal failure
(a) reabsorption of filtered HCO3‘ Clinical usefulness of adjusting
(b) generation of new HCO3‘ urinary pH to hasten drug
(c) distal tubular secretion of HCO3‘ excretion e.g. alkalinize the
Sites, mechanism and regulation of H+ urine to remove salicylate from
secretion and HCO3‘ the body
re-absorption/secretion
Urinary buffers (e.g. phosphate)
Adaptive changes (e.g. in NH4 synthesis) to



maintain acid-base balance
12.3.3 Integration of renal and respiratory mechanisms of control
Examples of common causes of acid-base disturbance (see also
8.7; 15.4)
Adverse effects of acidosis
Changes in ventilation and in renal bicarbonate and glutamine
handling in acid-base disturbance. The Davenport plot
Respiratory compensation and renal correction of metabolic
acidosis
Renal compensation in respiratory acidosis
13. REPRODUCTIVE SYSTEM
13.1 ANATOMY OF THE GENITAL SYSTEMS

13.1.1 Anatomy Of The Pelvis And Perineum
Bony and soft-tissue of structure of the pelvis, pelvic floor Prolapse of pelvic organs after damage to
Principles of distribution of nerves and vasculature to pelvis, pelvic/perineal floor; incontinence
perineum and lower limb
Urogenital triangle in the male and female
13.1.2 Reproductive Tract Differentiation And Development
Source and migration of germ cells
Role of the Y-chromosome in sex determination SRY gene
Formation of female and male gonads; their migration
Formation of female and male internal reproductive tracts and Bicornuate uterus, imperforate hymen,
external genitalia recto-vaginal fistula
Effects of androgens and of Müllerian inhibiting factor on Genetic disorders affecting sexual differentiation:
sexual differentiation testicular femininisation syndrome, 5- -
reductase deficiency
absence of Müllerian inhibiting factor
Maldescent of testis Appendices of testis and epididymis
Cysts derived from mesonephric duct in female;
torsion of ovary; ovarian cysts

13.1.3 Male Genital System



Testis, seminiferous tubules, vasa efferentia
Epididymis, vas deferens. seminal vesicles, common
ejaculatory duct; relations to pelvic peritoneum, inguinal
canal. Penis - erectile tissue
Arterial supply and drainage of testis and external genitals;
pampiniform plexus
13.1.4 Female Genital System
Ovary: position. Fallopian tubes. Uterus: body, fundus,
cervix, vagina
Arterial supply and venous drainage of ovary and uterus;
anastomotic supply to uterus

13.2 HISTOLOGY OF THE REPRODUCTIVE TRACT
Testis: germinal epithelium = Sertoli cells + the various stages
of development of the male germ cells; interstitial (Leydig)
cells
Epididymis, seminal vesicles, prostate
Ovary. Ovarian follicles in various developmental stages: Corona radiata
primordial, antral, pre-ovulatory, atretic. Theca interna and
externa, granulosa cells, oocyte and zona pellucida. Corpus Corpus albicans
luteum.
Fallopian tube: epithelium and muscle coat
Uterus: myometrium, endometrium in different stages of the
menstrual cycle - endometrial glands, spiral arteries,
endometrial stroma
Cervix and vagina
Correlation of the structure of the female tract with the
endocrinological status

13.3 REPRODUCTIVE FUNCTION

Relevant pituitary hormones are described further in 14.2.2.3; 14.2.2.4; 14.2.3.2
13.3.1 Production of Male Gametes



Dual function of the testis: production of gametes and sex
hormones
Spermatogenesis: spermatogonium to spermatid; the
significance of meiosis; maturation of spermatids to
produce spermatozoa
Functions of Leydig and Sertoli cells
Control of testis function by gonadotrophins (LH, FSH) and
testosterone
Gonadal hormone feedback to pituitary, hypothalamus
Effects of testosterone on genital tract, secondary sexual
characteristics
Functions of the epididymis, seminal vesicles, prostate
Erection, emission, ejaculation; neural control – erection Male infertility; impotence, Viagra; priapism
parasympathetic; emission sympathetic; ejaculation Contraception in the male
somatic.
13.3.2 Production of Female Gametes
Dual function of the ovary: production of gametes and sex
hormones
Maturation of primordial follicles to pre-ovulatory follicles;
follicle ‗rescue‘, selection, atresia
Functions of granulosa and theca interna cells
Control of ovarian function by gonadotrophins (LH, FSH) and
estrogen
The hypothalamo-pituitary axis; endocrine control of
menstrual cycle; gonadal hormone feedback
The ovum and its covering layers at ovulation; process of
ovulation
Formation of corpus luteum; secretion of progesterone,
oestrogen; luteolysis
Female infertility Suppression of ovulation in starvation, severe
Contraception and strategies for the treatment of infertility; in exercise, emotional stress
vitro fertilisation
13.3.3 Coitus, Fertiliation, Implantation and Pregnancy



Coitus and orgasm
Fertilisation and preparation of the uterus for pregnancy
The process of implantation; status of the foetus as an
allograft
Structure and function of the placenta; placental villi
Production of estrogen, progesterone, gonadotrophin during Human placental lactogen. Possible role of foetal
pregnancy; roles of these hormones in the maintenance of steroids: concept of the feto-placental unit
pregnancy
Mechanism of parturition; hormonal control - role of oxytocin
and prostaglandins
Premature and delayed parturition
13.3.4 Mammary Gland and Lactation
Structure of the mammary gland at different ages.
Breast development in pregnancy and lactation, and its
hormonal control
Lactogenesis: roles of prolactin and other hormones
Milk-ejection reflex: role of oxytocin
Consequences of lactation and raised prolactin levels on
fertility
Pituitary tumors and galactorrhea
13.3.5 Age Changes in Reproductive Status
Growth during childhood
Puberty: role of pituitary hormones Adrenarche, gonadarche, menarche
Ageing of the female reproductive tract; the menopause
Precocious puberty; delayed puberty

13.4 PHARMACOLOGICAL ASPECTS OF THE FEMALE SEX HORMONES



Replacement therapies: use of estrogens and Anti-progesterones - 'abortion pill' (RU-486)
progesterones Adverse effects of combined pill: preferred use of
Anti-estrogens: tamoxifen and estrogen-dependent progesterone only in older women
breast cancer Post-coital contraceptive pills. Fertility
Oral contraceptives: progesterone only and combined treatments.
pill Endometriosis: therapy with danazol as an
inhibitor of gonadotrophin output

ENDOCRINOLOGY
14.1 PRINCIPLES OF ENDOCRINOLOGY
14.1.1 Principles Of Hormone Action
For any particular hormone, you will be expected to know:
its chemical class & broad structure; site and mechanism of
production & release
stimuli that cause or inhibit its release; pattern of secretion
into the blood/ecf
mechanism of transport in the blood/ecf (general principles
of half-life and clearance:
see section 4)
distant action: endocrine (or local action: paracrine and
autocrine)
principal target tissue(s) & receptors; mechanism of action
in target tissue(s)
principal effects
major effects of excess, deficiency, hormone resistance in
target
The mechanisms of action of hormones, their distribution in
the body
14.1.2 Main Regulatory Roles Of Hormones
in homeostasis, including anticipatory responses; stress
responses
in control of reproduction



in development, growth and differentiation
14.1.3 Characteristics of Main Classes Of Hormone
Hormones synthesized and stored in endocrine glands:
protein, peptide, bioactive amine, steroid, thyroid
Structure of cells that synthesize and store these hormones
Order of normal concentration in plasma: protein and Methods of assay: distinction between free and
polypeptide hormones, typically nanomolar; steroids, total (including protein bound) hormone
typically sub-micromolar
Secretion may be in pulses, rhythms (diurnal, reproductive)
Hormones produced enzymatically as they are needed:
prostaglandins (see 13.3.3);
nitric oxide (see 8.6.5); angiotensin II (see 11.3.3)
14.2 PITUITARY
14.2.1 Components of Pituitary
Development of pituitary gland
Gross and microscopic structure of pituitary and component
parts: adenohypophysis, neurohypophysis
Adenohypophysis: anterior part Tuberal and intermediate (vestigial) parts.
endocrine cells: thyrotrophs, corticotrophs, gonadotrophs, Folliculo-stellate cells
lactotrophs, and somatotrophs
control of adenohypophysis: Concept of feedback regulation at hypothalamic
(a) by CNS: neurosecretion of specific releasing factors and pituitary levels
from hypothalamus via hypothalamo-hypophysial portal
vessels;
(b) by negative feedback of target hormones and effects
local and systemic effects of tumors of the
adenohypophysis
Neurohypophysis: nerve endings of hypothalamic Concept of neurosecretion
neurosecretory neurons

14.2.2 Hormones Of The Adenohypophysis
Symptoms of excess or insufficiency mostly resemble those of over- or under-activity of the target endocrine
organs



14.2.2.1 TSH = thyrotrophin (from thyrotroph cells)
Glycoprotein Two subunits:  common to TSH, LH, FSH; 
Promotes thyroid gland growth and synthesis and secretion of specific
thyroid hormones Acts by raising cAMP in thyroid; effects on
Negative feedback by T3 and T4; hypothalamic control various aspects of thyroid gland metabolism
Released in pulses: diurnal rhythm Danger of withdrawal of thyroid hormone therapy
14.2.2.2 ACTH = corticotrophin (from corticotroph cells)
Polypeptide Produced by cleavage from a protein precursor
Promotes adrenal cortical steroid secretion and growth (pro-opiomelanocortin ‗POMC‘)
increases mostly glucocorticoid production (some increase Acts by raising cAMP in adrenal cortex
in adrenal sex steroids)
Negative feedback by glucocorticoids; hypothalamic control Danger of sudden withdrawal of glucocorticoid
(hypoclycaemia, stress); released in pulses: diurnal rhythm therapy
Nelson‘s syndrome increased pigmentation
(melanocyte stimulation by high ACTH)
14.2.2.3 LH = luteinizing hormone; FSH = follicle-stimulating hormone (from gonadotroph cells)
see also 13.3
Both are glycoproteins Subunit structure (see 14.2.2.1)
Actions on ovary in female: Both act by raising cAMP
FSH stimulates follicle development and ovulation
LH stimulates progesterone secretion by corpus luteum
Actions on testis in male:
FSH acts on Sertoli cells to initiate and maintain
spermatogenesis
LH stimulates interstitial cells (of Leydig) to secrete
testosterone
Released in pulses: hypothalamic control and feedback from
gonadal hormones
Cyclical variation in LH and FSH in menstrual cycle (see 13.3.2)
Dysfunctions: infertility, precocious puberty
14.2.2.4 Prolactin = mammotrophin (from lactotroph cells)
Protein Receptor - tyrosine kinase



Promotes growth and development of breast and milk Inhibitory to gonads; lactational amenorrhoea
production
Control: only pituitary hormone whose principal control is Inhibition of release is by DA
inhibition by the hypothalamus
dysfunction: prolactinomas Dopamine agonists (e.g. bromocryptine)
suppress lactation
14.2.2.5 Growth hormone = somatotrophin (STH: from somatotroph cells)
Protein Receptor - tyrosine kinase
Actions on growth: direct and indirect via IGFs; metabolic Wide-ranging metabolic effects - promotes
actions protein synthesis, but raises blood glucose
Release (pulsatile) controlled via hypothalamus by
metabolites; stress, sleep, exercise
Dysfunction: short or excess stature, acromegaly; diabetes
mellitus

14.2.3 Hormones Of The Neurohypophysis
14.2.3.1 Antidiuretic hormone (ADH) = vasopressin
Affects body fluid volume and osmolarity by regulating water
reabsortion in the kidney (see 11.3.4). Diabetes insipidus
14.2.3.2 Oxytocin
Role in parturition, milk-ejection (see 13.3.3; 13.3.4)
14.3 THYROID GLAND and IODOTHYRONINES
Development, gross and microscopic structure of thyroid; Structure of thyroid hormones
vasculature; colloid
Synthesis and storage of thyroglobulin, secretion of thyroid Plasma transport, long half lives of T4, T3
hormones; iodine economy of the thyroid; action of TSH
Peripheral metabolism of T4 to T3 and rT3 by liver, kidney; Different deiodinases; interactions with
clearance of iodothyronines autonomic nervous system; euthyroid sick
syndrome
T3 as the metabolically active hormone; T3 receptors Action on gene transcription by intracellular
receptor
Actions of T3 on basal metabolic rate (protein, carbohydrate &



lipid metabolism), development and growth
Catabolic versus anabolic effects; negative feedback of T3, T4
on pituitary and hypothalamus
Control: via TSH, iodine
Dysfunction: excess – thyrotoxicosis; deficiency - cretinism,
myxoedema
Goitre in iodine deficiency. Thyroid resistance
14.4 ADRENAL GLAND
Development of cortex and medulla; foetal zone of cortex
Gross and microscopic structure of adrenal cortex and
medulla; vasculature, innervation
14.4.1 Adrenal Medulla
Synthesis of adrenaline and noradrenaline; storage in
chromaffin granules
Catecholamine receptors and their distribution in tissues (see
6.4.4.2)
Actions on cardiovascular system, respiratory system,
gastrointestinal tract, metabolism (see appropriate
sections). Mediation of effects: cAMP, or IP3/calcium (see
4.2.3)
Control by autonomic nervous system
dysfunction: effects of pheochromocytoma
14.4.2 Adrenal Cortex
14.4.2.1 General principles
Synthesis of glucocorticoids and mineralocorticoids from Inherited disorders of steroid synthesis (general
cholesterol principles)
Steroid action: intracellular receptor controls gene
transcription
Congenital adrenal hyperplasia
Plasma transport of corticosteroids; clearance by liver
14.4.2.2 Cortisol
Widespread action on many tissues: induces enzymes, favours Other effects:
fat mobilisation, protein catabolism, gluconeogenesis (i.e. immunosuppressant (at therapeutic doses)



opposes insulin) some mineralocorticoid effect (adverse effects
Dysfunction: adrenal insufficiency (Addison‘s) and excess of therapy)
(Cushing‘s)
14.4.2.3 Aldosterone
See 11.3.3
14.4.2.4 Adrenal androgens
At most times a very minor component of secretion Route for synthesis of sex steroids: action of
adrenal androgens in fetus and at puberty
Adrenal sex steroid production in inherited
disorders
14.5 ENDOCRINE PANCREAS
Development and microscopic structure of islets of Blood and nerve supply of islets
Langerhans
14.5.1 Insulin

A protein synthesized in -cells Synthesis as proinsulin with C-peptide
Receptor: tyrosine-kinase
Secretion stimulated by: raised blood glucose, amino acids, Mechanism of stimulus-secretion coupling:
hormones e.g. GLP (glucagon-like peptide - sensitises  - role of ATP-inhibited K+ channels; action of
cells to glucose), nervous inputs sulphonylureas
GIP: Glucose-dependent insulinotrophic peptide
hormone secreted by cells in small intestine in
response to glucose - sensitises  -cells to
glucose
Widespread actions to promote anabolism; lowers raised
plasma glucose
Diabetes mellitus: type I and type II
14.5.2 Glucagon
Metabolic effects of glucagon to be examined in more detail in Biochemistry: see e.g. 2.2.6; 2.3.4; 2.3.5
Polypeptide hormone synthesized in  -cells
Released in response to hypoglycemia Somatostatin, pancreatic polypeptide
Acts on liver via cAMP to promote glycogenolysis and



gluconeogenesis; promotes lipolysis in adipose tissue
Synergism of actions with catecholamines, glucocorticoids,
growth hormone
14.5.3 Somatostatin
Paracrine peptide produced in -cells; inhibits insulin release Also a negative paracrine modulator in the gut,
salivary glands and pituitary
14.5.4 Endocrine Tumors of Pancreas
Insulinoma (rare) multiple endocrine neoplasia
gastrinoma (see 14.6.1: ectopic gastrin
production - no feedback from stomach acid to
limit gastrin secretion: Zollinger-Ellison
syndrome)
14.6 GASTROINTESTINAL HORMONES
Endocrine cells scattered in gut epithelium sense contents of Origin of gut endocrine cells from endoderm
lumen
Peptide hormones released by exocytosis
Integrated role of gut endocrine and nervous systems to
control motor, digestive, vascular activity of gut
Concept of two families of gut hormones:
gastrin-like (includes CCK) gastrin-like hormones act via intracellular calcium
secretin-like (includes glucagon) secretin-like hormones act via cAMP
14.6.1 Gastrin
Produced in gastric antrum Gastrinomas (pancreatic gastrinoma free from H+
Stimuli for gastrin secretion; H+ negative feedback feedback much more common than gastric
Actions: pepsin secretion; gastric acid secretion (see also gastrinoma see 14.5.4)
9.5.3.1)
14.6.2 Histamine
Secreted by ECL cells of stomach in response to stretch or
vagal stimulation
Paracrine action to stimulate gastric acid via H2 receptors on
oxyntic cells (see 9.5.3.1 for more detail)
14.6.3 CCK (Cholecystokinin )
Produced in duodenum and jejunum



Stimuli for secretion: protein and fat products in duodenum
Actions: stimulation pancreatic enzyme secretion and gall
bladder contraction
14.6.4 Secretin
Produced from duodenum to ileum
Stimuli for secretion: acid in duodenum
Actions: stimulation of HCO3‘ secretion from pancreas and Action of secretin via cAMP and CFTR on Cl‘
liver conductance stimulates Cl‘/HCO3‘ exchange
14.7 HORMONES INFLUENCING CALCIUM, PHOSPHATE, BONE

14.8 OTHER HORMONES
14.8.1 Kidney
Erythropoietin: stimulates erythropoiesis in response to Erythropoietin replacement therapy (and dialysis)
hypoxia or anaemia needed after severe renal damage (see also
Renin-angiotensin-aldosterone system 5.4.1)
14.8.2 Heart: ANP
ANP = atrial natriuretic peptide
Produced in atrial myocytes, released by atrial
distension
Reduces salt and water content of body (see
11.3.2)
14.8.3 Adipose Tissue

14.8.4 Prostaglandins
Widespread production and roles: esp. actions on uterus (see
13.3.3)
15. EMBRYONIC DEVELOPMENT
Subjects for study are chosen to provide (i) an essential understanding of the principles of developmental
biology, (ii) a background with which to understand some congenital abnormalities (including genetic and
non-genetic conditions), and (iii) a knowledge of the embryonic origins of adult gross anatomy. Key
developmental principles to be covered include: multipotentiality and restriction of potential; inductive
tissue interactions; the concept of organizers, signalling centres, and pattern formation.
15.1 FERTILIZATION TO IMPLANTATION



See also: 1.10; 1.11; 1.12; and 13.3.1 - 13.3.3
Fertilization, the zygote, cleavage of blastomeres, totipotency, IVF
formation of blastocyst (inner cell mass and trophoblast), Specific maternal and paternal contributions to
implantation, bilaminar germ disc (epiblast and hypoblast). development
Amniotic cavity & amnion. Formation of umbilical cord, Ectopic implantation
placenta.
15.2 FORMATION OF THE BASIC BODY PLAN
Axis/primitive streak formation, gastrulation, tissue Hemivertebrae
interactions leading to formation of definitive germ layers Kyphoscoliosis
(ectoderm, mesoderm, endoderm) from the epiblast;
formation of and derivatives of notochord, somites,
intermediate and lateral plate mesoderm, segmentation
Teratogenesis, sensitive periods
15.3 MORPHOGENESIS AND INITIATION OF THE ORGANS
Neurulation, neural patterning, neural crest; embryonic
folding, formation of the gut (foregut, midgut, hindgut) and
coelomic cavities (pericardial, pleural, peritoneal cavities);
septum transversum, formation of the diaphragm; initiation
of lung development (see also 8.2.4)
Diaphragmatic hernia, esophageal atresia/tracheo-esophageal Hirschsprung‘s disease
fistula, spina bifida
15.4 LIMB DEVELOPMENT: AN ILLUSTRATION OF KEY PRINCIPLES AND CONCEPTS
Induction of limb buds at specific axial levels; outgrowth and Polydactyly, syndactyly
patterning in proximodistal, anteroposterior and Thalidomide
dorsoventral axes; migration of myotome into the limb;
segmental innervation of skin and muscles
15.5 DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM
15.5.1 The Early Heart Tube
Formation and fusion of the left and right heart tubes;
structure of the early heart tube (myoepicardium, cardiac
jelly, endocardium); the mesocardium and transverse sinus;
asymmetric morphogenesis to form atria, ventricles, conus
cordis, truncus arteriosus; the onset of contractile activity;



changing pattern of the aortic arches
15.5.2 Development Of The Fetal And Postnatal Heart And Circulation
Septation of the atria, ventricles and outflow tract; the role of
haemodynamic forces, deformability of the heart wall, and
cell proliferation
Development of the venous system: bias of venous inflow into
the right atrium prior to septation
The definitive fetal circulation; changes at birth
Congenital abnormalities of the heart, especially septation Tetralogy of Fallot
defects
15.6 DEVELOPMENT OF THE GUT AND ASSOCIATED STRUCTURES
The endodermal epithelial lining of the gut and its derivatives;
buccopharyngeal and anal membranes; septum
transversum.
Foregut/midgut/hindgut formation and their blood supply Meckel‘s diverticulum
Epithelial-mesenchymal interactions leading to region-specific Recanalization of the gut
differentiation and morphogenesis of the gut wall; gut
diverticula undergo branching morphogenesis to form liver,
pancreas (and lungs - see 5.3; 8.2.4)
Spleen from mesenchyme only
Neural crest origin of enteric neurons
Rotation and fixation of the gut
15.7 DEVELOPMENT OF THE URINARY SYSTEM
Pronephros, mesonephros, metanephros form from Evolution of metanephric kidney for life on land
intermediate mesoderm in craniocaudal sequence and show
increasing complexity
Formation of metanephros (definitive mammalian kidney) from
ureteric bud and surrounding mesenchyme
Branching of ureteric bud to form ureter, pelvis, major and
minor calyces, collecting tubules; ampullae at apex of
branches induce formation of excretory tubules and
glomeruli from mesenchyme
Ascent of kidneys



Formation of bladder (from lower allantois), urethra, prostate,
urachus
Congenital abnormalities, including polycystic kidney,
oligohydramnios, hydronephrosis, kidney agenesis, horse-
shoe kidney
15.8 DEVELOPMENT OF THE GENITAL SYSTEM
See 13.1.3 Reproductive tract differentiation and development
15.9 DEVELOPMENT OF HEAD AND NECK
Cranial neurulation and neural crest migration
The embryonic pharynx: pharyngeal (branchial arches),
pouches and clefts, and their derivatives; nerves, muscles,
arteries and skeletal elements
Development of the facial processes and secondary palate;
cleft lip and palate
16. HEAD & NECK

16.2 OSTEOLOGY
16.2.1 Skull
16.2.1.1 Sutures: Development
Functions (deformation in birth)
Identification on a skull or plain radiograph of the following Fontanelles: relative times of fusion
sutures: coronal, sagittal parieto-occipital; bregma, lambda, Results of premature fusion
pterion
16.2.1.2 Bones of the vault
Identification on a skull or plain radiograph, and as surface Tympanic plate
landmarks (where appropriate) of the following bones: Eroded posterior clinoids as a sign of
frontal, occipital, parietal,; squamous and petrous temporal, pituitary enlargement or as a sign of
external acoustic meatus, zygomatic, greater and lesser raised intracranial pressure
wings of sphenoid, cribriform plate, clinoid processes; and Localizing signs of skull fractures. CSF
the pituitary fossa, and anterior, middle and posterior cranial leakage: otorrhoea, rhinorrhea
fossa Common sites and consequences of skull
fractures
16.2.1.3 Cranial nerve foramina


Identification on a skull or plain radiograph or CT scan of the following foramina,
and a knowledge of their principal contents: rotundum (maxillary V), ovale
(mandibular V), spinosum (middle meningeal art.); jugular foramen (IX,X,XI + int.
jugular); foramen magnum (spinal cord+ vertebral arts.); carotid canal (Int.
Carotid), stylomastoid foramen (VII), hypoglossal canal (XII); optic foramen (II+
ophthalamic art.), superior and inferior orbital fissures ( III,IV,VI, ophthalmic V);
internal acoustic meatus ( VII, VIII + labyrinthine art.)
16.4 BLOOD SUPPLY
16.4.1 Arterial Supply
16.4.1.2 Arterial supply to central nervous system, related meninges and soft tissues
To be able to identify the following major vessels on angiograms and on wet specimens, to describe their course
and to relate this to the functional areas and fibre tracts they supply and the deficits caused by occlusion of
main vessels

Common carotid, external carotid, middle meningeal, internal Arterial anastomoses
carotid; anterior, middle and posterior cerebral; vertebral
(and its subclavian origin), basilar; striate; pontine; posterior
inferior cerebellar; anterior and posterior spinal; Anterior inferior cerebellar artery
reinforcement of spinal supply (artery of Adamkiewitz). Circle Choroidal arteries
of Willis
Important relations of arteries:
Circle of Willis - subarachnoid haemorrhage
Middle meningeal to pterion - extradural haemorrhage
Internal carotid to middle ear, cavernous sinus
16.4.1.3 Pulse points - surface markings
Carotid; facial; superficial temporal
16.4.2 Venous drainage
16.4.2.5 Venous drainage of the brain
Superior sagittal sinus, great cerebral vein, transverse and Inferior sagittal sinus; inferior petrosal
cavernous sinuses; sigmoid sinus; internal jugular vein sinus
Venous haemorrhages; sub-dural space

16.5 SPECIAL AREAS



16.5.2 Orbit And Eye
16.5.2.1 Orbit and associated structures
Bones of orbit: frontal, sphenoid, zygoma, maxilla, lacrimal
Optic canal, superior and inferior orbital fissures, lacrimal
fossa and nasolacrimal canal
Eyelids, tarsal plates, tarsal glands, levator palpebrae,
orbicularis oculi
Attachments and function of external ocular muscles, Orbital fat; medial and lateral check
suspensory ligament of the eyeball ligaments
Lacrimal gland, puncta and nasolacrimal duct, conjunctival sac. Puncta, conjunctival sac
Tarsal plates
Lacrimation reflex: afferent - ophthalmic V (emotional stimuli)
efferent - parasympathetic facial, pterygopalatine ganglion,
lacrimal gland
Levator palpebrae: innervation by III and by sympathetic fibres
Ptosis: failure of autonomic or oculomotor nerve (III)
Lesions of sympathetic supply (Horner‘s syndrome). Carcinoma of apex of lung (Pancoast‘s
Intracranial lesions tumour)
Blink reflex: afferent - ophthalmic V; efferent - facial to
orbicularis oculi
16.5.2.2 Development of the Eye
Development of the eye as an outgrowth of the forebrain Development and envelopment of lens vesicle
Hyaloid artery
16.5.2.3 Gross Morphology of the Eyeball
Cornea, sclera, conjunctiva; iris, pupil, retina, optic disc,
fovea, central artery of the retina; lens, ciliary body, Disorders of the lens: cataract
suspensory ligaments, ciliary muscles; anterior and ciliary nerves and arteries
posterior chambers, ciliary processes; optic nerve
Optic nerve and its surrounding extension of
subarachnoid space; ocular signs of raised
intracranial pressure
Aqueous humour: drainage; raised intraocular pressure
(glaucoma)



Ophthalmoscopy: appearance of the normal retina Common abnormalities - papilloedema, cataract,
abnormal blood vessels
16.5.2.4 Internal muscles of the eye
Functions and innervation of ciliary muscles, and of
dilator and sphincter pupillae Pupillary reflexes: see
21.7
16.5.2.5 Oculomotor, Trochlear and Abducent Nerves; Movements of the Eye: see 21.6
16.5.4 The Ear
16.5.4.1 Development of the ear
Origin of inner ear from the otic placode/vesicle
with neural crest contributions
Sensitivity of the organ of Corti to viral infections
(e.g. rubella) in early pregnancy
Eustachian tube and tympanic cavity from 1st
pharyngeal pouch
Ext. acoustic meatus and pinna from 1st
ectodermal cleft
Malleus and incus (Vth nerve to tensor tympani)
from 1st branchial arch
Stapes (VII th nerve to stapedius) from 2nd arch
16.5.4.2 Functional Anatomy of the ear
External ear: pinna, tragus, external auditory meatus, Features of tympanic membrane visible on
tympanic membrane examination
Innervation of external auditory meatus by V and X, with Wax production and removal. Otitis media.
VII contributing at the tympanic membrane Perforated eardrum.
Sound conditioning: role in monaural sound
localization
Referred pain in ear from e.g. sore throat
Vomiting and cardiac depression with syringing
of external meatus (X nerve stimulation)
Ramsay-Hunt syndrome (Herpes zoster of
geniculate ganglion)



Middle ear: malleus, incus, stapes; stapedius, tensor Mastoid antrum
tympani; pharyngotympanic tube; round and oval Infection spread through middle ear to middle and
windows posterior cranial fossae, causing meningitis
Function of auditory ossicles: impedance matching and brain abscesses
Hyperacusis from VIIth nerve damage
Connection with mastoid air cells; importance as a route Innervation: middle ear and pharyngotympanic
of infection tube: IX (tympanic branch); tympanic plexus
Inner ear: temporal bone, internal acoustic meatus; Tinnitus, vertigo. Sensory/conduction deafness
cochlea, cochlear nerve, spiral ganglion (see also Connections between perilymph and CSF
20.4.2; 20.4.4); semicircular canals, utricle and saccule
17. EMBRYONIC DEVELOPMENT NERVOUS SYSTEM
17.10 DEVELOPMENT OF THE CNS
Neuroectodermal origins of neural and glial cells, basal Neural cell determination; cell migration
(motor) and alar (sensory) plates; neural crest and its A general understanding of the process of axon
derivatives; mechanisms of axon growth; no mitosis outgrowth and formation of connections:
of mature neurons critical periods, synaptic plasticity, neural cell
death and growth factors
Neural tube formation, the flexures of the brain,
expansion of the telencephalon
Abnormalities: spina bifida, anencephaly Cell migration defects; heterotopias, dysplasias
18. CNS MORPHOLOGY
18.1 CNS COMPARTMENTS
18.1.1 Blood-Brain Barrier
Histological appearance of astrocyte: endothelial surface; Chemical and physical interruption of
selective transport through barrier; significance for receptor-mediated transport across blood-
drugs, infection, immune system brain barrier
18.1.2 Cerebro-Spinal Fluid



Production (choroid plexus), composition relative to CSF cisterns: magna, interpeduncular, ambiens,
plasma, and absorption via arachnoid granulations pontine, lateral fissure, and superior.
Circulation: CSF-vascular shunts
the cerebral ventricles (lateral ventricles, third
ventricle, aqueduct and fourth ventricle) and their
relationships to structures in 18.2.1 and 18.2.2.
Hydrocephalus
CSF cisterns. Lumbar puncture
18.2 NEUROANATOMY

You should be able to identify major structures (set out below) on CT and MRI scans, and major tracts on
histological sections, i.e., online atlases. You should know their major afferent and efferent connections,
their function and the likely effects of a lesion.
18.2.1 Forebrain
18.2.1.1 Cerebral Hemispheres
Lobes - frontal, parietal, occipital, temporal Pre-central, post-central, collateral sulci
Gyri - calcarine, superior temporal, pre-central, post-central,
insula, uncus, parahippocampal, hippocampal
Wernicke‘s and Broca‘s areas
Sulci - longitudinal (sagittal), lateral, central, parieto-occipital,
calcarine and cingulate
Origin, course and major terminations of fibres in the: corpus Origin, course and major terminations of
callosum, internal capsule, fornix fibres in the anterior commissure,
Classification of commissural, association, projection fibres stria terminalis, and cingulum
18.2.1.2 Basal Ganglia and Diencephalon
Caudate, putamen, globus pallidus, amygdala, thalamus,
hypothalamus, mamillary bodies, pineal, pituitary. See also
21.4.1
18.2.2 Brainstem and Cerebellum
Medulla, pyramids, olive, pons, cerebellum, cerebellar
peduncles, midbrain, cerebral peduncles, tectum (superior
and inferior colliculi)



Brainstem nuclei: dorsal column nuclei, pontine nuclei, Raphé nuclei
olivary nuclei
Periaqueductal grey
Cranial nerve nuclei: Edinger-Westphal, III, IV, VI, trigeminal Mesencephalic nucleus of V
(main motor and spinal nuclei), facial, cochlear, vestibular, Subdivisions of vestibular nuclei
nucleus ambiguus, nucleus of the solitary tract, vagal,
hypoglossal
Tracts: corticospinal, corticobulbar, corticopontine, dorsal
column, internal arcuate, medial lemniscus, lateral
lemniscus, anterolateral column (spinoreticular,
spinomesencephalic, spinothalamic), medial longitudinal
fasciculus, spino-cerebellar, ponto-cerebellar, superior
cerebellar peduncle, spinal tract of the trigeminal
Cerebellar hemispheres, vermis, flocculo-nodular lobe, supr., Tonsil, uvula, pyramids, nodule; other deep
mid., inf. peduncles; spinal/vestibular/cortical divisions; nuclei
deep nuclei (esp. dentate)
18.2.3 Spinal Cord
18.2.3.1 Gross Structure
Dura, arachnoid, sub-arachnoid space, pia. Dorsal and ventral Subarachnoid septum
roots, dorsal root ganglia, cauda equina, filum terminale, Denticulate ligaments
lumbar and cervical enlargements; connections to Radicular arteries and veins
sympathetic chain. Vessels: anterior and postero-lateral
spinal arteries
18.2.3.2 Internal Organization
Dorsal horn, posteromarginal zone, substantia gelatinosa,
main sensory nucleus, thoracic nucleus; motor pools
(medial and lateral); lateral horn
Fibre tracts and the consequences of lesions: corticospinal, Rubrospinal and tectospinal tracts
dorsal columns, anterolateral columns, spino-cerebellar,
Lissauer‘s, vestibulospinal, reticulospinal
18.2.4 Spinal Nerve Exit Foramina and Intervertebral Discs
Anatomy and MRI appearance of exit space
Consequences of compression of the spinal nerves



19. PRINCIPLES OF NEURONAL FUNCTION
19.1 METHODS OF STUDY OF THE NERVOUS SYSTEM
Basic histological techniques (Nissl, Golgi, Weigert)
CT, PET, MRI scans; and EEG: the information each can
provide
19.2 STRUCTURE AND FUNCTION OF NEURONES AND GLIA
Characteristic appearance and functions of projection and
inter-projection neurones
Excitatory and inhibitory neurones
Neuroglia: appearance and function of astrocytes,
oligodendroglia, microglia
19.3 NEURONAL DEGENERATION
Wallerian degeneration, demyelination Multiple sclerosis. Motor Neurone Disease
CNS degenerative disorders e.g. Alzheimer‘s, Parkinson‘s (see Vincristine peripheral neuropathy as an
24.6.2; 21.4.3) example of a failure of the neuronal
cytoskeleton
19.4 NEURONAL REPAIR AND REGENERATION
Comparison of PNS and CNS regeneration Factors affecting CNS regeneration: glia,
growth factors, cell survival,
renavigation, microglia
Possible application in Parkinson‘s
Disease. Neural transplantation
19.4.1 Neuronal Plasticity
Concept of neuronal plasticity. Possible role in learning Neuronal plasticity in recovery from stroke
19.5 SYNAPTIC TRANSMISSION
19.5.1 Excitatory Transmission in the CNS
Glutamate: some sites of action and putative functions; NMDA receptors and synaptic plasticity
glutamate receptors
Differences between AMPA, NMDA, and metabotropic receptors Molecular genetics of receptors and
channels.
Excitotoxicity in stroke and ischaemia
19.5.2 Inhibitory Transmission in the CNS



GABA: synthesis and degradation. Drugs that inhibit GABA Glycine
breakdown and drugs that mimic GABA actions
Mechanisms of action: GABA receptors, chloride channels,
hyperpolarization. Action of benzodiazepines at
GABA-receptor complex
19.5.3 Neuromodulation
Concept of neuromodulation Pre-synaptic modulation at autonomic
synapses. Wider role of
neuromodulation in CNS
19.5.4 Regulation of Receptor Action
Up- and down-regulation of receptor numbers, and receptor Tachyphylaxis. Possible mechanisms:
desensitisation, after chronic stimulation or blockade. changes in receptor structure or affinity;
Long-term potentiation, long-term depression second messengers
19.6 EPILEPTIC DISCHARGES
Concept of epilepsy as uncontrolled CNS discharge
19.6.1 Anti-Epileptic Drugs
Pharmacological mechanisms for suppression of epileptic
activity:
Acute (status epilepticus): diazepam;
Chronic/prophylactic: phenytoin, carbamazepine as local Use of carbamazepine in treatment of
anaesthetics / antidysrhythmics; valproate as GABA agonist. trigeminal neuralgia
Newer anti-epileptics: lamotrigine; vigabatrin
20. SENSORY SYSTEMS
20.1 SOMATOSENSORY PATHWAYS
20.1.1 Receptors
Classification and morphology of receptors (mechano, Impulse generation and coding
thermo, noci) Sensory transmitters
Classification and characteristics of nerve fibres (myelinated
vs. unmyelinated)
Mechanisms of sensory transduction and adaptation 2-point discrimination
20.1.2 Spinal Pathways
20.1.2.1 Dorsal Column Systems



Modality and somatotopy (dorsal columns, dorsal column
nuclei and VPL thalamus)
Sensory coding: receptive fields, lateral inhibition Corticofugal control
20.1.2.2 Anterolateral System
Dorsal horn laminae: termination of primary sensory neurones
Spinoreticular, spinomesencephalic and spinothalamic
projections
20.1.2.3 Consequences of spinal cord lesions
To be able to work out the level of a spinal cord lesion from
the signs: complete
transection; Brown-Sequard; partial lesions at different
levels; syringomyelia
20.1.3 Somatosensory Cortex
S1 maps; columnar organization; S1 lesions in humans Cortical processing. Stereognosis. S2
Development and adult plasticity of S1.
Phantom limb
20.2 PAIN
20.2.1 Role and Neurophysiology
Protective function Features of absence of pain perception
Receptors and peripheral pathways Types of pain, possible correlation with
fibre type
Central pathways: Central representation of pain
Dorsal horn gate, enkephalin interneurones, descending
control (periaqueductal grey)
Variability of pain perception: hyperalgesia, psychological
modulation of pain, anatomical basis of ‗referred‘ pain
20.2.2 Pain Relief



Analgesic drugs and techniques:
Peripherally-acting analgesics: aspirin and other NSAIDS Transmitters in the pain pathway
(see 27.5.1), local anesthetics (mechanisms of action: first Sub-classes of opiate receptor
year) Acupuncture. Placebo effect
Centrally-acting analgesics: opioids. Anxiolytics in the
management of pain
(See also General Anaesthesia 24.1.2)

20.3 VISION
20.3.1 Structure of the Eye (See 16.5.2.3)
20.3.2 Histology of the Retina
Functional histology of retina: distribution of rods and cones
20.3.3 Visual Transduction
Visual pigments: defects of colour vision
Visual transduction: dark current, transducin cascade, light Bipolar and ganglion cell receptive fields
adaptation
20.3.4 Visual Pathways
Bipolar and ganglion cells, optic nerve, chiasm, and tracts; Magnocellular and parvocellular pathways
lateral geniculate nucleus; optic radiation; other sub- in terms of function rather than details of
cortical projections - superior colliculus, suprachiasmatic, anatomy
pretectal nuclei Meyer‘s loop
20.3.5 Visual Cortex
Striate cortex. V1. Columnar organization. Orientation. Ocular Development and plasticity of the visual
dominance system.
Effects of amblyopia, strabismus
Two visual outflows: V4 to inferotemporal
cortex for colour and pattern, visual
agnosia; V5 to posterior parietal cortex
for location and motion, space sense
20.3.6 Visual Fields



Visual field representation from eye to cortex; consequences
of lesions of optic nerve, optic chiasm, optic tract and Field defects due to optic neuritis, retinal
visual cortex; visual field examination arterial emboli
Binocular vision: distance perception, disparity and
stereopsis
20.3.7 Visual Function : Optical and Neural Determinants
Acuity, intensity, wavelength discrimination Cortical determinants
Optics; refractive errors; myopia, and hypermetropia, and their Diffraction. Emmetropization during
effects on visual performance; visual testing development
Optical and neural determinants of contrast
sensitivity
Effects on visual performance of glaucoma,
cataract, macular degeneration
20.4 AUDITION
20.4.1 Peripheral Structures
See 16.5.4.2 Physics of sound
20.4.2 Inner Ear
Cochlea: gross structure and histology. Formation and
composition of endolymph and perilymph
Hair cells and transduction Inner hair cells as resonators; outer hair
cells as motors
Olivocochlear bundle and centrifugal
control
20.4.3 Auditory Function
Audiometry. Frequency resolution, sound localization (by Sound pressure level thresholds
binaural timing and intensity differences) Speech sounds and speech perception
Monaural cues to sound localisation
Causes of deafness Deafness in ageing. Tinnitus
Conduction vs. neural deafness: tuning fork tests (Weber & Drug-induced ototoxicity: e.g., gentamicin,
Rinne) frusemide, aspirin
20.4.4 Auditory Pathways



Spiral ganglion, auditory nerve, dorsal and ventral cochlear Tonotopicity, phase locking, VIIIth nerve
nuclei, trapezoid body, superior olive, inferior colliculus, tuning curves
medial geniculate nucleus. Projections to cortex: superior Binaural interaction in superior olives for
temporal gyrus A1 sound source localization
20.4.5 Speech and Language
Aphasias: Wernicke‘s area and sensory aphasia; Broca‘s area Arcuate bundle. The dyslexias
and motor aphasia. Hemispheric specialization Aphasia c.f. dysarthria
20.5 VESTIBULAR SYSTEM
Otoliths (linear acceleration, head position); semicircular Mechanisms of vestibular transduction
canals (angular acceleration)
Vestibular pathways: vestibular nuclei, vestibulo-spinal, and
vestibulo-ocular tracts
Vestibulo-ocular reflexes: reflex stabilizes gaze Relations with cerebellum; cerebellar
Vestibulospinal reflexes calibration
Placing and neck reflexes
20.5.1 Disorders of Equilibrium
Vertigo, motion sickness, nystagmus Drugs for motion sickness: hyoscine,
antihistamines
20.6 SMELL AND TASTE
Olfactory system: chemoreceptors in nasal mucosa, Importance of smell to limbic system
afferents (I) via cribriform plate; olfactory bulb, Genetics of olfactory and taste receptors; their
olfactory tract, primary olfactory cortex of temporal turnover
lobe (see 22.1.1)
Taste system: taste receptors, projections via VII and
IX to nucleus of the solitary tract, to the
hypothalamus and orbitofrontal cortex
20.7 SENSORY INTEGRATION
20.7.1 Auditory-Visual Integration
Superior colliculus organisation: inputs,
topography, multimodality
Function: orientating eye (saccadic), head and
body movements
20.7.2 Association



20.7.2.1 Posterior parietal cortex
Inputs: visual, somaesthetic, auditory, motor, limbic Superior parietal lobule; integration of sensory
Outputs: frontal cortex, basal ganglia, cerebellum motor and motivational signals for
Multimodal sensorimotor association area for direction representation of body image and ―active
of attention, movement, speech and reading touch‖
Inferior parietal lobule; visual ―where‖ and eye
movement signals integrated for ―active sight‖
and representation of visual space
Lesions give neglect syndromes and acquired Hemispheric localization and lesions:-
dyslexias. Right hemisphere - visuo-spatial (lesion gives left
neglect)
Left hemisphere - language and reading (lesion
gives acquired dyslexia or apraxia)
Concerned with egocentric space (as opposed to
the hippocampus which is concerned with
allocentric space
20.7.2.2 Prefrontal cortex
Reciprocal connections with limbic, visual systems Medial (orbitofrontal): receives limbic and visual
and basal ganglia ―what‖ signals, assessment of significance
Functions: working memory, intention, decision Lateral: receives visual ―where‖ signals, also input
from basal ganglia, choice of behaviour
Lesions: perseveration, indecisiveness,
impulsiveness c.f. schizophrenia
21. MOTOR SYSTEMS
21.1 LOWER MOTOR NEURONE POOLS
Motor units: the size principle, temporal and spatial
facilitation, reciprocal inhibition, pattern generation
Lesions: flaccid paralysis in lower motor neurone lesion

21.2 MUSCLE STRETCH REFLEX



Muscle spindle, primary and secondary spindle afferents; Contribution of spindle and joint receptors to
 -efferent control position sense
Reflexes: tendon jerk; monosynaptic component; tonic Transcortical stretch reflex
stretch reflex for posture; spinal interneurones (Ia
inhib. and Renshaw). Flexion reflex
21.3 UPPER MOTOR NEURONES
21.3.1 Descending Pathways To Spinal Cord
Functional anatomy of pathways to spinal cord: Rubrospinal and tectospinal tracts
corticospinal, vestibulospinal, reticulospinal Lamination of motor cortex and tracts
Lateral and medial descending systems
Effects of damage to descending tracts at different levels
on voluntary movement, muscle tone, spinal reflexes
Decerebrate preparation. Hemiplegia. Hemiparesis,
paraplegia, spasticity, rigidity
Babinski response
21.3.2 Cortical Control Of Motor Activity
Motor cortex (Area 4) – functional anatomy
Inputs: supplementary motor area, premotor and
somatosensory cortex, VL and VA thalamus (from
cerebellum and basal ganglia respectively)
Outputs: corticospinal tract, corticostriate,
corticobulbar (to cerebellum, red nucleus, reticular
formation, cranial nerves)
Premotor cortical areas:
Premotor cortex (lateral area 6) for sensory guidance
of movements and postural adjustments
Supplementary Motor Cortex (area 6) for planning
spontaneous movements
21.4 BASAL GANGLIA
21.4.1 Components, Connections And Functions



Nuclei: Neostriatum - caudate & putamen; Globus pallidus Limbic components: nucleus accumbens,
(internal & external); ventral striatum and pallidum
Subthalamic nucleus; Substantia nigra (compact and
reticular)
Subcortical loops back to cortex and to brainstem via BG;
nigrostriatal loop
Direct and indirect pathways. Effect on thalamic, VA and VL
nuclei
Functions: selection and control of expression and execution Function with limbic system: selection and
of internally generated motor programmes control of expression of emotions
21.4.2 Neurotransmitters And Pharmacology
Principle neurotransmitters: Limitations of L-DOPA therapy (systemic
Excitatory (glutamate) inputs from cerebral cortex to striatum side-effects, involuntary movements,
Inhibitory (GABA) from striatum and globus pallidus receptor desensitization, continuing
Dopaminergic from compact substantia nigra to striatum neuronal degeneration). Use of other
activates direct and inhibits indirect pathways dopaminergic agonists as adjuncts
Dopaminergic neurones degenerate in Parkinson‘s Disease: use (bromocriptine)
of L-DOPA
Other possible therapies: muscarinic
antagonists (benztropine). MPTP as
model
Example of possible application of neural
transplantation
21.4.3 Consequences of Lesions
Involuntary movements and inability to make voluntary
movements: akinesia, bradykinesia
Tremor and rigidity of Parkinson‘s Disease; chorea in striatal
lesions (Huntington‘s chorea); ballism in subthalamic
lesions
21.5 CEREBELLUM
Cytoarchitecture:
three layers: molecular layer (parallel fibres), Purkinje cell
layer, and granule cell layer



Inputs: Long-term depression of Purkinje cell
Mossy Fibres: pontocerebellar, spinocerebellar, synapses by climbing fibres.
vestibulocerebellar (simple spikes)
Climbing Fibres from the inferior olive (complex spikes)
Deep nuclei and outputs:
medial (fastigial nucleus) to vestibular system; intermediate
(globose and emboliform nuclei) to red nucleus and
descending spinal systems; lateral (dentate nucleus) to VL
thalamus, thence to motor cortex
Function: motor coordination: calibrating, learning and
automating motor skills
Lesions: incoordination, postural ataxia, intention tremor,
nystagmus
21.6 LOCOMOTION
Walking: brainstem and spinal pattern generators, Swing and stance phases
proprioceptive feedback
Abnormal gaits: freezing and festination (i.e. small steps) in
Parkinson‘s disease; limping in hemiplegia; abnormal gaits
due to absent proprioception in syphylis (tabes dorsalis)
and peripheral neuropathy
21.7 EYE MOVEMENT CONTROL AND PUPILLARY REFLEXES
Cranial nerves: III, IV, VI: origins and course; consequences of
lesions (see also 22.1.3)
Eye movements: vestibular, pursuit, saccadic, vergence.
Central control: nuclei of III, IV, and VI; medial longitudinal Clinical disorders of oculomotor control
fasciculus; Effects of myasthenia: ptosis, diplopia
role of posterior parietal cortex, frontal eye fields, superior
colliculus, vestibular nuclei
Pupillary reflexes: light response and accommodation reflex; Argyll-Robertson pupil
parasympathetic and sympathetic control.
Lesions of the sympathetic supply; ptosis and Horner‘s
syndrome
22. CRANIAL NERVES



The following should be known for each cranial nerve: function(s); origin; emergence from CNS; intra- and
extra-cranial course; peripheral distribution; testing of function; consequences of lesions at different
levels; control and interrelations of cranial nerve nuclei. Classification of fibres into: sensory fibres
supplying somatic tissues, viscera; motor fibres to striated muscle; autonomic fibres to glands and smooth
muscle. Particular points for each nerve are listed below.
You should also know the related sympathetic cervical ganglia; parasympathetic ganglia (ciliary,
pterygopalatine, submandibular, otic), the control of sweating, lacrimation, salivation, and eyelid and
pupillary reflexes (see 21.7)
22.1 SPECIFIC CRANIAL NERVES
22.1.1 Olfactory (I)
See 20.6 Anosmia after skull fracture. Kallman‘s
Test: examine sense of smell syndrome
Medial and lateral olfactory striae; septal
olfactory area; inputs to limbic system
22.1.2 Optic (II)
See 20.3.4 Tests: visual field tests
22.1.3 Oculomotor, Trochlear, Abducent (III, IV, VI)
See control of eye movement: 21.7 Position of nerves in cavernous sinus
Tests: examine pupillary reflexes and eye movements Relation of nerves to internal carotid
artery
Damage to III: loss of upward, downward and medial rotation
of eye; prosis; pupillary dilatation
Damage to IV: diplopia on looking down and medial
Damage to VI: loss of lateral rotation of eye, diplopia on
looking to side
22.1.4 Trigeminal Nerve (V)
Motor to muscles of mastication Motor to tensor tympani, tensor palati
Sensory to face, floor of mouth, teeth and tongue
ophthalmic and maxillary V afferents in coughing and
sneezing
Trigeminal ganglion; principal sensory and spinal sensory Mesencephalic nucleus of V
nuclei; motor nucleus



Lalateral medullary syndrome: loss of pain and temperature
sensation
Tests: examine sense of touch in cornea and face; check that On opening, jaw deviates towards side of
jaw closes symmetrically any paralysis
22.1.5 Facial Nerve (VII)
Motor supply to muscles of facial expression, stapedius; motor Facial colliculus (fibres of VII around Vi
nucleus nucleus)
Sensory supply via chorda tympani (taste to anterior 2/3 of Hyperacusis
tongue);
geniculate ganglion, nucleus solitarius
Autonomic parasympathetic supply to lacrimal glands, nose
via pterygopalatine ganglia; and to floor of mouth via
submandibular ganglion
Tests: examine control of facial muscles, check symmetry of Unilateral and bilateral cortical control
expression
Bell‘s (facial) palsy
22.1.6 Auditory Nerve (VIII)
See 20.4.4 Acoustic neuroma
Tests: audiometry, use of tuning fork to distinguish
sensorineural and conductive
hearing loss
examine vestibular function with caloric or rotational tests
and
observation of nystagmus
22.1.7 IX, X, XI
Sensory supply to oropharynx, carotid sinus, carotid body (IX);
and to foregut and midgut derivatives (X), projection to
nucleus of solitary tract
Motor fibre supply from nucleus ambiguus (IX, X, XI) to
muscles of palate, larynx, pharynx
Role of the afferents and efferents in coordinating swallowing Disorders of swallowing with fractures
(also XII) through the jugular foramen
Actions of sternomastoid and trapezius muscles (XI)



Autonomic: preganglionic parasympathetic fibres from inferior
salivatory nucleus of IX to parotid gland, and dorsal motor
nucleus of X to pharynx, larynx and all of the
gastrointestinal tract derived from fore- and mid-gut
Tests: gag reflex (IX and X)
palatal movements (X)
actions of sternomastoid and trapezius muscles (XI)
22.1.8 Hypoglossal Nerve (XII)
Motor supply to muscles of the tongue; hypoglossal nucleus
Tests: observe tongue for paralysis and wasting - tongue
deviates on protrusion towards paralysed side
23. THALAMUS AND HYPOTHALAMUS
23.1 THALAMUS
Functions. Reticular, perireticular, pulvinar and
Afferent and efferent connections of the following thalamic dorsomedial nuclei.
nuclei: anterior (limbic); ventral anterior and ventral lateral
(motor), ventral posterior medial and lateral
(somatosensory), lateral geniculate (visual), medial
geniculate (auditory). Afferent relay to cortex, topographical
organization, reciprocal connections with cortex
23.2 HYPOTHALAMUS
Note also Body Temperature Regulation: section 15.3
Structure and connections of the hypothalamus as a basis for Role in sleep-wake cycle
the physiological control of internal systems via the
autonomic and endocrine systems; the biological clock;
reproductive functions
23.2.1 Components and Connections Of The Hypothalamus



Principal nuclei and functions of: Subdivisions: (anteroposterior)
suprachiasmatic nucleus (biological clock); chiasmatic; tuberal; posterior;
supraoptic / paraventricular nucleus (posterior pituitary (mediolateral) periventricular, medial,
neurosecretion, lateral
oxytocin/vasopressin); Preoptic / anterior hypothalamic area
mediane eminence/arcuate nucleus (control anterior Lateral hypothalamic area. Posterior
pituitary) hypothalamic area
ventromedial nucleus (feeding, satiety) Dorsomedial nucleus, lateral tuberal
mamillary body (memory) nucleus (very wide GABA projections,
cf. raphe, locus coeruleus), medial
mamillary nucleus, lateral mamillary
nucleus
Sensitivity of neurones to osmotic pressure, temperature, Periventricular organs:
glucose, hormones Organum vasculosum of lamina
terminalis (OVLT)
Subfornical organ (SFO) - thirst,
osmoreception
Sexual dimorphism of some hypothalamic
nuclei
Role of hypothalamus in sexual behaviour
and orientation
Neural connections: large fibre bundles - fornix, Stria terminalis
mamillothalamic tract, and medial forebrain bundle. Largely
reciprocal
largely reciprocal
Afferents: from sensory receptors, visceral (via reticular
formation and solitary tract); from brain stem (locus
coeruleus, raphe, periaqueductal grey); higher centres
(hippocampal formation, amygdala, orbitofrontal cortex via
mediodorsal thalamus)
Sensitivity of neurones to osmotic pressure, temperature,
glucose, hormones.



Efferents: endocrine control via posterior pituitary, and
anterior pituitary via portal system; descending control of
autonomic centres in brain stem and spinal cord;
mamillothalamic tract
Vasculature of hypothalamus and pituitary from internal Superior and inferior hypophyseal arteries
carotid, capillary plexus in median eminence; portal vessels Long and short portal vessels
to anterior pituitary; direct supply to posterior pituitary
23.2.2 Functions
Roles in homeostasis, rhythms, development (e.g. puberty),
metabolism, control of autonomic nervous system and
endocrine control
Monitoring of plasma levels of hormones, metabolites,
osmolality
Coordination of regulation of blood pressure and volume
Control of the anterior pituitary by secretion of: Effects of adrenalectomy on production of
releasing hormones: GnRH, GHRH, TRH, CRH melanocyte stimulating hormone, and
release-inhibiting factors DA, somatostatin effect on pigmentation
Secretion of oxytocin and vasopressin from posterior pituitary
Negative and positive feedback by peripheral hormones and by
metabolic signals

Control of autonomic nervous system:
neural outputs to brain stem and spinal cord centres
effects of hypothalamus and of hypothalamic lesions on
autonomic functions in eye
(pupil, lacrimation); osmotic regulation and cardiovascular
system; thermoregulation;
alimentary system (salivation, peristalsis); genital system
(erection and emission);
urinary system; sleep-wake; aggressive behaviour (sham
rage)
Autonomic and endocrine components of the stress response



Hypothalamo-pituitary-gonadal system (principles of endocrine
contraception: see 13.4)
Effects of pituitary tumors
23.3 EPITHALAMUS
Pineal: control by postganglionic
sympathetic fibres;
melatonin production, day-night rhythm;
habenular nuclei
23.4 HUNGER, THIRST AND REWARD
Peripheral receptors vs. central control signals; interaction
with mesolimbic reward system
24. HIGHER CEREBRAL FUNCTIONS
24.1 CONSCIOUSNESS
24.1.1 Coma
Coma. Persistent Vegetative State The ―binding problem‖. Neuronal oscillation and
synchronization
24.1.2 General Anesthesia
Postulated mechanisms of action
Adjuvant drugs in general anaesthesia: inhibitors of
secretion (e.g. atropine), anxiolytics (e.g. diazepam,
opiates); analgesics, muscle relaxants
(tubocurarine, suxamethonium)
24.2 SLEEP
EEG stages of sleep, reticular activating system,
non-specific inputs to cortex; role of 5-HT, NA, ACh,
peptides, endogenous rhythms, paradoxical, REM;
sleep and dreaming
24.3 COMPONENTS AND CONNECTIONS OF THE LIMBIC SYSTEM
Circuit of Papez: cingulate gyrus, parahippocampus
(reciprocal connections with most association
cortex), hippocampus, dentate gyrus, fornix/fibria,
mammillary bodies, mamillothalamic tract, anterior
thalamus



Amygdala: links with olfactory system, association
cortex, and hypothalamus
Orbitofrontal cortex
24.4 FUNCTIONS OF THE LIMBIC SYSTEM
Functions of frontal lobe Self-stimulation studies of Old
Amygdala and fear ‗Face‘, ‗food‘, ‗error detection‘ neurones
Effect of lesions of hippocampus and amygdala in man Learning: one-trial, multi-trial
24.5 MEMORY
Classical conditioning
Types of memory: associative, declarative and
procedural memory
Short- and long-term memory
Hippocampal LTP responsible for spatial or episodic Synaptic plasticity in hippocampus
memory, cf cerebellar LTD for automaticising skills Human amnesia, bilateral hippocampectomy,
Korsakov‘s disease
Alzheimer‘s Disease, basal forebrain cholinergic Anticholinesterase treatment for Alzheimer‘s
systems disease
24.6 DEVELOPMENT AND AGEING
24.6.1 Aging and Dementia
Normal ageing and Alzheimer‘s Disease Neuropathology of Alzheimer‘s Disease. Varieties
of dementia
24.6.2 Individuality
Individual differences. IQ Basic dimensions of personality.
Difference between personality and temperament
Connections to abnormal psychiatric states
Genetic and developmental evidence for theories
of personality.
Personality and personality disorders.
25. PSYCHOLOGICAL DISORDERS AND PSYCHOPHARMACOLOGY
25.1 EMOTION, STRESS AND ANXIETY
Human emotion: cognitive factors; clues from Emotion in animals
functional imaging



Stress - its consequences for human anxiety and Stress in animal models
depression; panic disorder; post-traumatic stress
disorder
Eating disorders
25.2 DEPRESSION
25.2.1 General
Definition and types of depression Hypotheses of cause
Drug-induced depression
25.2.2 Anti-Depressant Drugs
Classes of anti-depressants: Possible mechanisms of action of anti-
tricyclics, 5-HT antagonists, selective 5-HT depressants
(serotonin) re-uptake inhibitors (‗SSRIs‘), MAO ―Atypical antidepressants‖, e.g. mianserin
inhibitors, lithium and their adverse effects Indications from drug therapy for ideas of cause of
(including psychological and physical dependence) depression: validity of evidence
25.2.3 Anxiolytic Drugs
Benzodiazepines: see 19.5.4
25.2.4 Other Treatments
Electroconvulsive therapy as a treatment for
depression
25.3 SCHIZOPHRENIA
Definition and major symptoms; DMS criteria Neurobiology of psychoses: ideas and clues from
neuropharmacology, brain imaging and
genetics
25.3.1 Pharmacology of Anti-Psychotic Drugs
Dopamine antagonists, e.g. chlorpromazine: possible Possible role of newly-identified transmitters in
mechanisms of action in schizophrenia; adverse schizophrenia; therapeutic possibilities.
effects, incl. effects on motor control.
25.4 SOCIAL DRUGS AND ADDICTION
Dependence Neurobiology of addiction
26. OVERVIEW OF INFECTION AND IMMUNITY
This section summarizes key concepts in infection and immunity that are elaborated in following sections.
26.1 IMPORTANCE OF INFECTIOUS DISEASE
26.1.1 Relative Importance Of Infection As A Cause Of Morbidity And Mortality



Differences between the West and developing countries. Comparison with
cancer and cardiovascular disease
Age distribution of infectious disease
Illustrative examples: tuberculosis, malaria, HIV and AIDS, tetanus,
poliomyelitis
26.2 PATHOGENS AND THEIR DISEASE-CAUSING PROPERTIES

Concept that pathogens have evolved to evade and avoid host defense
mechanisms
26.2.1 Bacteria
Pathogenic bacteria fall into the following major groups
Pyogenic (pus-forming) e.g. Staphylococcus and Streptococcus
Enteric bacteria e.g. Salmonella and Vibrio
Exotoxin producers e.g. Clostridium and Vibrio
Facultative intracellular parasites (e.g. Mycobacterium) that provoke a
disease-causing immune response
26.2.2 Viruses
Viruses are obligate intracellular parasites which can cause disease by:
inducing inflammation, causing cell death, increasing the likelihood that a
tumour will develop
26.2.3 Eukaryotic Parasites
Malaria, schistosomiasis
26.2.4 Fungi
Importance in immunosuppressed individuals
26.2.5 Non-Pathogenic Micro-Organisms
Normal body flora; usually-harmless organisms; role in protection from
pathogens
Cause disease in immunosuppressed individuals: e.g. people with AIDS
patients immunosuppressed with drugs after transplantation
people with inherited defects of the immune system
26.3 DEFENSE AGAINST INFECTIOUS DISEASE
Natural defence is often inadequate e.g. poliomyelitis, tuberculosis, tetanus,
rabies, AIDS.



26.3.1 Innate Mechanisms
Can act without help from the specific immune response
Barriers to infection: skin, mucus, gastric acid, bile salts, normal flora
Internal mechanisms:
Cells - opsonin-dependent: neutrophils, macrophages
opsonin-independent: natural killer ‗NK‘ cells
Molecules - complement, interferons and other secreted molecules
26.3.2 Specific Immune Response
26.3.2.1 Induction
Depends on lymphocytes. Involves recognition of an antigen. Response is
specific for an individual antigen. Different lymphocytes recognise
different antigens
The specific response arises by the selection, clonal expansion, and
differentiation of lymphocytes that recognise the antigen
Immunological memory for a specific antigen
the primary response to an antigen
the secondary response (faster and more effective) to the same antigen
26.3.2.2 Effector mechanisms
B-cells differentiate to antibody-secreting cells (plasma cells)
Antibodies: prevent entry of pathogens (e.g.viruses and mucosal
bacteria),
neutralize bacterial toxins, opsonize bacteria, initiate acute inflammation
T-cells: help B-cells grow and differentiate to plasma cells
kill cells directly (e.g. virus-infected cells)
secrete cytokines which e.g. activate macrophages and NK cells
(so improving the effectiveness of innate immunity)
26.4 PREVENTION AND TREATMENT OF INFECTIOUS DISEASE
Importance of public health measures - developing world
Immunization: examples of success and limitations
- smallpox, polio, tetanus, measles; as compared with HIV, malaria,
tuberculosis
Antibiotics: principles of action; development of resistance
27. INFLAMMATION, CELL DEATH AND REPAIR



Host response to infection and tissue damage
27.1 NECROSIS AND APOPTOSIS
Necrosis: damage to the cell raises intracellular calcium and
activates hydrolytic enzymes. Result: cell death and the
release of inflammatory mediators
Apoptosis: ―programmed cell death‖ directed by the Mechanism and regulation of apoptosis
expression of specific genes; produces no inflammation. Role of Fas, caspases, and bcl-2
Roles: normal tissue homeostasis, embryonic
morphogenesis and deletion of self-reactive lymphocytes
27.2 ACUTE INFLAMMATION
27.2.1 Function in Defense
Lasts minutes to days (but see 27.2.9)
Combats pyogenic infection by recruiting neutrophil
polymorphonuclear leucocytes (PMN) and by
facilitating phagocytosis by PMN

27.2.2 Cardinal Features
Heat (vasodilation) Redness (vasodilation)
Swelling (oedema) Pain (chemical mediators) Leads to loss
of function

27.2.3 Histology
Vasodilation, oedema, adhesion of PMN to venule walls
Cellular infiltration by PM N (major) and macrophages (minor)
Formation of pus. Abscesses: structure, formation and fate

27.2.4 Leucocytes
You should know the appearance and normal abundance of neutrophils, eosinophils, basophils,
monocytes, and lymphocytes, and you should know the significance of increased blood counts of
neutrophils and eosinophils.
27.2.4.1 Neutrophils (PMNs; polymorphonuclear leucocytes, ‘polymorphs’)
Site of production, lifespan and morphology Reserve stores, stimulated production
Colony stimulating factors



Adhesion to vascular endothelium Rolling (selectins), firm adhesion
(integrins)
Diapedesis Chemokines and their receptors
G-protein coupled receptors
Migration and chemotaxis along gradients of CD31
inflammatory mediators
C5a, leukotrienes, bacterial peptides, chemokines
Cell biology of chemotaxis
Phagocytosis Zipper mechanism
opsonization by Ab and complement Other opsonins and receptors for phagocytosis
lysosomal fusion (lectins)
killing and digestion of micro-organisms Respiratory burst (NADPH oxidase)
Non-oxygen-dependent killing mechanisms
Defects: chronic granulomatous disease; Ig and
complement deficiencies
Tissue damage Degranulation
Frustrated phagocytosis, cell death
Secreted and released enzymes
27.2.5 Macrophages
27.2.5.1 Life history and distribution
Derived by differentiation of blood monocytes (which are M-CSF, GM-CSF
ultimately bone marrow-derived)
Two major classes: resident (e.g. Kupffer cells); Other tissue-macrophages: e.g. splenic, alveolar,
inflammatory Langerhans cells
Adhesion of monocytes to vascular endothelium, T-cell factors, MCP, Rantes
migration and chemotaxis Chemokine receptors (see HIV)
- as for PMN
Long lived. Giant cell formation
27.2.5.2 Functions
Defence Leishmania, leprosy
killing facultative intracellular pathogens, e.g. TB, Cytotoxic mechanisms: oxygen metabolites, nitric
(dependent on activation by interferon-) oxide
Activation alternatively by TNF and IL-4



activation by endotoxin Cytokines (TNF-, IL-1, IL-6, L-10, IL-12)
clearing of virus from blood Other secretory products: hydrolytic enzymes,
secretion of cytokines complement components
Role in Th-1 development
Tissue homeostatis: remodelling and repair Removal of apoptotic and necrotic cells
Pathology: chronic inflammation (section 27.3)
27.2.6 Mast Cells (see also Section 34.1.1)
Morphology and distribution Types of mast cell, biochemistry of mediator
synthesis
Release of inflammatory mediators e.g. histamine (from Role of FcR on mast cell membrane
vesicular stores) Other triggers: C5a and C3a, trauma
Triggering of release, role of IgE Preformed mediators (histamine) and mediators
synthesized by triggered mast cells
(leukotrienes, prostaglandins): biochemistry of
mediator synthesis
27.2.7 Mediators Of Inflammation
27.2.7.1 Complement
Sequential activation of neutral proteinases with feed- Role of C3, C3a, C5a
forward regulation Individual components, regulation of activation,
Principle of amplification: need for control by inhibitors deficiencies
Initiation of classical and alternative pathways Interaction with coagulation, kinin and fibrinolytic
cascades
27.2.7.2 Other mediators
Products of coagulation cascade; Roles of Hageman factor and thrombin
Products of fibrinolytic cascade; Activation of plasminogen
Kinins, prostaglandins and leukotrienes role of plasmin in producing other mediators
27.2.7.3 Effects of mediators on cells
Effects on vascular endothelium, PMNs,
macrophages, mast cells, fibroblasts
27.2.7.4 Regulation of acute inflammation
Concept of inactivators for active mediators 1-anti-trypsin and emphysema
C1 esterase inhibitor and angio-oedema



27.2.8 Systemic Effects of Acute Inflammation
Acute phase response; fever. Roles of IL-1, TNF- and NO
Septic shock, role of endotoxin (see 8.6.10.2) Acute phase proteins (C-reactive protein)
Role of lipoteichoic acid (cell wall component of
Gram-positive bacteria with effect like
endotoxin)
27.2.9 Persistent Or Repeated Acute Inflammation
Results from an inability to clear pathogenic bacteria
(normal mechanisms may be impeded by dead tissue
or by a foreign body) or from repeated episodes of
pyogenic infection
Frequently classified in textbooks as ―chronic
inflammation‖, but the mechanism is as for acute
inflammation

27.3 CHRONIC INFLAMMATION
27.3.1 General
Lasts weeks to years
Mononuclear cell infiltrate i.e. macrophages (may
include giant cells and epithelioid cells) and
lymphocytes
Absence of PMNs and pus
Vascularization and collagen deposition (may become
excessive), but little oedema
27.3.2 Pathogenesis: Non-Immune
Toxic, non-antigenic, particles activate and kill
macrophages
Stimulates further recruitment and death of
macrophages
Mediators released by macrophages cause persistent
repair reaction leading to fibrosis and loss of
function.
27.3.3 Pathogenesis: Immune-based



T-cell-mediated immune response to persistent Animal models
antigens Role of CD4+ T-cells and macrophage activation
Structure of a granuloma and its evolution Role of IFN- and TNF-
Macrophage as a secretory cell causing tissue damage Reasons for antigen persistence
Genetic basis for susceptibility (and evidence
Examples: from mice)
tuberculosis (see section 29.5.4), rheumatoid Sarcoidosis, systemic lupus erythmatosis (SLE)
arthritis, and other auto-immune diseases, contact
schistosomiasis (see section 32) sensitivity
27.4 REPAIR
Histology of repair of a clean incision
27.4.1 Cellular basis of repair
Granulation tissue (do not confuse with ‗granuloma‘)
Roles of blood and lymphatic vessels, blood platelets,
endothelium, macrophages and fibroblasts.
27.4.2 Regulation of repair
Roles of cytokines (PDGF), proteases, fibrinolysis
Resolution, organization and fibrosis. Scar formation
Repair in epithelia
Factors inhibiting repair — infection, vascular
insufficiency (e.g. varicose ulcers, diabetes)
malnutrition

27.5 ANTI-INFLAMMATORY DRUGS
27.5.1 Aspirin and Other NSAIDs
Mechanism of action:
cyclo-oxygenase (COX) inhibition blocks prostanoid Aspirin as a non-specific COX-inhibitor
synthesis Development of new, COX-2 specific, anti-
Systemic effects. inflammatories
Adverse effects: gastrointestinal haemorrhage (COX-1
inhibition: see 36.8.2) Other potential targets for anti-inflammatory
Use in rheumatoid arthritis action:
Awareness of other drugs used in rheumatoid arthritis complement and complement fragments



(DMARDS - disease modifying anti-inflammatory kinins, reactive oxygen species
drugs)
Note: Paracetamol has no anti-inflammatory action (it inhibits a specific COX and has analgesic and antipyretic
effects only)
27.5.2 Steroids
Mechanism of action: modulates protein synthesis and Lipocortins
results in a reduced activity of phospholipase A2 -
effect to reduce production of prostaglandins,
leukotrienes and platelet activating factor. Systemic
effects on inflammatory processes
Use in allergic conditions including asthma: see e.g.
8.3.10.2
Adverse effects:
immune depression increasing susceptibility to viral
infection
hypertension via effects on fluid and electrolyte
balance
bone resorption; diabetes; peptic ulcers; effects on
the skin
27.5.3 Anti-inflammatory Histamine Antagonists (H1 blockers)
Role of histamine in inflammation: uses and limitations
of anti-histamines in therapy
Anaphylaxis: principles of cause and treatment,
including use of anti-histamines (see 34.1.1)
28 SPECIFIC IMMUNE RESPONSE
28.1 STRUCTURE AND PHYSIOLOGY OF THE IMMUNE SYSTEM
28.1.2 Primary lymphoid organs
Sites of lymphocyte production, not activation Overproduction of lymphocytes and apoptosis in
Thymus - T cells primary organs
Bone marrow- B cells Histology and embryology of thymus and bone
marrow
Differentiation sequences of lymphocytes. Allelic
exclusion


28.1.2 Lymphocytes
Major surface molecules of T-cells Schematic structure of these molecules
T cell Ag receptor, CD3, CD4, CD8, adhesion molecules, Individual adhesion molecules, selectins,
cytokine and chemokine receptors (e.g. IL-2R) integrins, CD40, CD28, Fas-ligand and Fas
Major surface molecules of B-cells Individual adhesion molecules, selectins,
surface Ig, MHC class II, adhesion molecules, chemokine integrins,
and cytokine receptors and Ig co-receptors
28.1.3 Secondary lymphoid organs
Where immune responses start - sited to monitor pathogen Common mucosal system - importance for neo-
entry natal immunity
Lymph nodes - monitor solid tissues High endothelial venules as site of lymphocyte
Spleen - monitors blood exit from blood
Peyer‘s patches and equivalents - monitor mucosa Recirculation allows accumulation of Ag-specific
Basic structure of secondary lymphoid organs lymphocytes at sites exposed to Ag - amplifies
T and B cell areas response
Routes of Ag entry Differential expression of molecules on
Lymphocyte recirculation lymphocyte and endothelium determines sites
of exit - selectin, chemokines, integrins
Resting and activated lymphocytes have
different migratory properties
28.2 INDUCTION OF IMMUNE RESPONSES
28.2.1 The Nature Of Antigens
Factors affecting antigenicity: size, shape, degree of Antigenicity and immunogenicity
foreignness
Concept of antigenic epitopes
Antigen processing, antigenic peptide fragments:
exogenous proteins (taken into cells by
endocytosis) are degraded into peptides
and the fragments presented on MHC class II
endogenously synthesized proteins (including host
proteins but also viral TI-1 and TI-2 antigens: role of spleen
proteins) yield fragments displayed on MHC Cellular and molecular pathways of antigen
class I processing



Haptens and carriers
Concept of thymus-dependent (T-dependent) and T-
independent antigens
28.2.2 Antibody Structure
Immunoglobulins: heavy and light chains; variable and
constant regions Complementarity determining residues (CDRs)
‗Y-shaped‘ structure: 2 antigen-binding sites (e.g. on IgG),
and the Fc region Structural basis of sub-classes (isotypes)
Classes and valency of immunoglobulins
Secreted and cell surface forms of antibody
28.2.3 Antibody Function
Antigen binding region (Fab) Affinity, avidity
specificity, diversity
Fc region
complement activation Molecular mechanisms of complement
binding to receptors on various cell types: activation
to macrophages and neutrophils, triggers phagocytosis by the classical pathway, IgM & IgG
(opsonization) and activn. by the alternative pathway: IgA or endotoxin
to mast cells (IgE), triggers degranulation
to epithelial cells for transepithelial secretion - IgA into
tears, saliva, colostrum, the gut, etc.; transplacental
migration of IgG
28.2.4 Clonal Selection
Each lymphocyte expresses many copies of one Ag- Only about 1 in 105 lymphocytes react to any
receptor (Ig or TCR) one Ag Evidence for clonal selection
Wide diversity of Ag-receptors
Ag selects those lymphocytes that can bind Ag sufficiently
strongly
These are stimulated to divide and produce clones of
effector/memory cells
28.2.5 Physiology Of The Immune Response
Ag is transported to secondary lymphoid organs by
dendritic cells or free in lymph



Antigen-specific T cells adhere to dendritic cells and receive
activation signals
Activated lymphocytes leave secondary lymphoid organs
and become effector/memory cells
28.2.6 Activation Of T Cells
T cell activation is essential for most immune responses Evidence from immunodeficient humans and
T cells recognize peptides bound to MHC molecules animals
nature of T-cell receptor Basic structure of MHC molecules
CD4+ T cells recognize MHC class II Structural basis of peptide binding
CD8+ T cells recognize MHC class I Signals are transduced via CD3. Ca2+ and DAG
Naive T cells require co-stimulatory signals pathways
Activation of NF-B
Nature of co-stimulation, B7 (CD80, CD86),
CD28, CTLA-4, differential signaling
pathways, anergy induction in absence of co-
stimulation.
Activated T cell can be stimulated by other
APCs (B cells, macrophages etc.)
Activated CD4+ T cells express IL-2R and
secrete
IL-2: IL-2 is a growth factor for T-cells
Danger theory
28.2.7 Regulation Of Immune Responses
Activated CD4+ T cells (―Helper Cells‖) secrete cytokines IL-10, IL-12, functions of cytokines
that promote
the growth and differentiation of other lymphocytes and
that activate Evidence for Th1/2 polarization. Factors
macrophages: e.g. IL-2, IL-4, IFN- influencing polarization. Il-12, IL-10. Some
Cytokine secretion by CD4+ T cells can be polarized into antibody is secreted in Th1 responses. Th2
Th1 and Th2 types: responses stimulate IgE secretion.
Th1 secrete IL-2 and IFN- and stimulate cell-mediated T cell memory may or may not be Ag-dependent
immunity
Th2 secrete IL-4 and stimulate antibody synthesis



Clinical relevance : e.g. Th2 response ineffective in leprosy
T cell memory is usually long-lasting
28.2.8 Activation Of B Lymphocytes
Response to polysaccharides (e.g. to bacterial capsules) Types of T-independent Ags, mechanisms of
doesn‘t involve T-cells and is consequently weak and activation, characteristics of response
short-lived: relevance to vaccination (typically IgM)
Antibody synthesis to protein Ags needs CD4+ T cell help B cells can act as APC for primed T cells - these
and produces stronger responses then activate the B cell
Multiplying B-cells may switch from producing IgM to the Mechanisms of B cell APC activity, nature of
other Ig isotypes, and they may change to produce signals involved in B-T collaboration
antibodies with increased affinity (―affinity maturation‖) Mechanisms of affinity maturation; somatic
Antibody-secreting cells (plasma cells) are present in hypermutation, germinal centres
secondary lymphoid organs, mucose (IgA) and bone Considerations of effect of binding and
marrow dissociation rate changes on affinity during
maturation
Mechanisms of B cell memory, follicular
B-cell memory can last for many years dendritic cells, retention of Ag/Ab complexes.
tetanus immunization is repeated every 10 years Evidence for Ag-dependence of memory
28.2.9 Immunological Tolerance
Ag specificity of newly-formed lymphocytes is randomly Positive and negative selection in thymus,
generated mechanisms of central and peripheral
Some will have receptors for self antigens tolerance, incomplete nature of tolerance in T
These are inactivated in thymus - central tolerance, or and B cells
periphery - peripheral tolerance Evidence for different theories of tolerance:
deletion, anergy, active suppression
28.2.10 Monoclonal Antibodies
Principles of production and use of monoclonal antibodies Details of monoclonal antibody technology:
fusion partners; cell cloning techniques
methods for labeling, detecting and
engineering monoclonal antibodies
28.3 IMMUNOGENETICS
28.3.1 Antibody And TCR Genes
Basic principles of generation of diversity of antigen- Basic structure of Ig and TCR genes



binding sites Numbers of gene segments (V, J or V, D, J)

Production of receptors in lymphocytes by
combinatorial association of different genes –
heavy and light (B cells) or  and  chains (T
cells) – and constituent gene segments
Junctional diversification
Secondary diversification of Ig but not TCR genes
(affinity maturation)
Basic molecular genetics of diversification
including somatic hypermutation after B cell
activation
Oligoclonality of germinal centres
28.3.2 Major Histocompatibility Complex
Allelic polymorphism of MHC genes leads to preferential Reasons for MHC polymorphism, immune
presentation of certain antigens and may lead to response genes
disease association e.g. insulin-dependent diabetes,
rheumatoid arthritis
28.4 EFFECTOR MECHANISMS IN IMMUNITY TO INFECTION
28.4.1 Antibody
28.4.1.1 Defense Against Infection
Elimination of infection; opsonization, initiation of acute
inflammation
Resistance to reinfection:
prevention of pathogen binding to host cells
neutralization of bacterial products, including
exotoxins
28.4.1.2 Mucosal Immunity
Mucosae as the major site of pathogen entry Need to protect against infection but not make
Concept of common mucosal immune system harmful responses to food. Oral tolerance
Secondary lymphoid tissues - Peyer‘s patches Mechanisms of IgA synthesis and transport
Functions of IgA Regulation of IgA synthesis
28.4.2 CD8+ T-Cells



Recognize MHC class I + peptide Secrete perforin, homology with complement
Cytotoxic: induce apoptosis in target cell; can kill virally- factor 9, polymerizes to form non-specific pore
infected cell and abort infection in plasma membrane, entry of granzymes,
Secrete IFN-: activates macrophages activate caspases - leads to apoptosis
28.4.3 Natural Killer Cells
Part of innate immune system but activity increased by Receptors on NK cells; killer inhibitory receptors
the specific immune response (―KIRs‖), recognition of lack of MHC class I
Do not express TCR or Ig. May kill virally-infected cells Molecules activating NK cells; IL-12, IL-2, IFN-
Secrete IFN-. Activate macrophages early in response Human NK cell deficiencies
28.4.4 Macrophages
Part of innate immune system but properties changed by
the specific immune response
Recruited to sites of infection Molecules involved in recruitment; adhesion
Activated by IFN- molecules, chemokines
When activated:-
kill facultative intracellular parasites in O2-dependent When activated: express MHC class II; can act as
way APC for CD4+ T cells
- e.g. Mycobacteria, Leishmania Molecules secreted by activated macrophages;
secrete toxic molecules: can cause tissue damage H2O2, enzymes - collagenase, elastase, other
- chronic inflammation proteases
Genetic basis of resistance to infection; twin
studies, inbred strains of mice
29 BACTERIOLOGY
29.1 BACTERIAL STRUCTURE
Size: typically 1m - i.e., much smaller than eukaryotic Properties and functions of essential cellular
cells structures: - nucleoid, ribosomes, cytoplasmic
Bacteria are prokaryotes: differences between bacterial membrane
and eukaryotic cells
The schematic structure of the bacterial cell wall: Chemical description of peptidoglycan structure
peptidoglycan, teichoic acids, lipopolysaccharides, Differences between cross-linking in different
mycolic acids species
The differences between Gram-positive, Gram-negative
and acid-fast cell walls



Plasmids, pili, flagella, capsule, endospores: their
functions in antimicrobial resistance and virulence (see
29.3.3; 29.5)
29.2 BACTERIAL GROWTH AND DISINFECTION
Measurement and simple description of growth phases in Likely differences between growth phases in vivo
batch culture and in vitro
Environmental factors affecting bacterial growth (e.g. Different modes of bacterial nutrition: autotrophy
availability of nutrients, pO2, temperature, iron) and the vs. heterotrophy; free-living, facultative and
relevance of these factors to bacterial growth within a obligate parasitism
host organsim Bacterial need for iron: host sequestration of iron
Principles of disinfection and sterilization Methods of sterilization. Ultrafiltration, dry heat
Aseptic techniques and steam. Common disinfectants and their
mode of action
29.3 ANTIBIOTICS
29.3.1 Prinicples Of Selective Action
Examples of the mechanism of action of specific classes Comparison of bacteria and eukaryotic parasites
of antibiotic: (e.g. fungi) as targets
inhibitors of cell-wall synthesis (e.g. penicillin) Beta-lactam structure. Penicillin-binding proteins
inhibitors of protein synthesis (e.g. aminoglycosides) Target for aminoglycosides is A-site on 16S rRNA
inhibitors of transcription (e.g. rifampicin) Further examples of antibiotics and their action:
inhibitors of DNA synthesis (e.g. sulphonamides) cephalosporins, tetracyclines, chloramphenicol,
Trimethoprim, quinolones
29.3.2 Practical Considerations
Use of antibiotic with appropriate spectrum of activity, Appropriate prophylactic use of antibiotics e.g. in
before and after microbial diagnosis surgery and for prevention of meningitis
Ability of antibiotic to reach target tissue
Dangers of indiscriminate use: drug resistance and
elimination of natural flora
Synergism and antagonism between antibiotics
Hypersensitivity to antibiotics
29.3.3 Principles Of Antibiotic-Resistance
Genetic mutation Mechanisms of antibiotic resistance:
Effect of selection pressure target site insensitivity: e.g. mutations in gyrase



Vertical and horizontal transmission leading to quinolone resistance
enzymatic modification of antibiotic: e.g.
beta-lactamases and aminoglycoside
phosphotransferases
cell wall impermeability to antibiotics: e.g.
mutations in Gram-negative porins
Pharmaceutical responses to resistance: newer
synthetic beta-lactams, beta-lactamase
inhibitors (e.g., clavulanate, tazobactam)
29.4 BACTERIAL DIAGNOSIS
29.4.1 Isolation Of Presumptive Pathogen
Safe handling of potentially pathogenic micro-organisms Koch‘s postulates
Isolation, culture and purification of bacteria from clinical
specimens
The use of selective media
29.4.2 Principles Of Identification
Gram staining, and colony and cellular morphology in Phage typing, PCR-based methods, serology
preliminary identification (exemplified by reference to
pathogens in 29.7)
Tests for antibiotic sensitivity
Knowledge of the appropriate use of catalase, coagulase, The principles of diagnosis by multiple
oxidase tests, Streptococcal carbohydrate antigen fermentation tests, where appropriate
grouping and MacConkey agar, to discriminate core
pathogens listed in 29.7
29.5 BACTERIAL PATHOGENESIS
29.5.1 Normal Flora
Blood, lymph and CSF are normally sterile; skin and
colon are not
Species of bacteria normally found on skin and in the Adaptations for growth on the skin and in the gut
colon: -
commensals or symbiotic; usually harmless
opportunistic pathogenesis (‗opportunism‘)
Other sites for commensals: mouth, vagina



29.5.2 Bacterial Adhesion
Adhesion of bacteria to body surfaces as a prelude to Mannose-resistant adhesins of Enterobacteria
colonization (adhesins not blocked by mannose)
example: role of the Type 1 Enterobacterial pilus Use of cystic fibrosis transmembrane regulator
(CFTR) as a cellular receptor by Vibrio cholerae
and by Salmonella typhi
29.5.3 Intracellular Uptake And Survival
Invasion of cells by Mycobacteria and Salmonella Induction of cellular uptake by bacterial adhesion
Structure and function of siderophores, and the
cycle of iron-uptake
29.5.4 Tissue Damage
Locally-acting exoenzymes and toxins of Staphylococcus Mechanism of action, schematic structure and
and Streptococcus physiological consequences of exoenzymes
and toxins
Distantly-acting exotoxins of Vibrio cholerae and Shiga toxin, botulinum toxin, pertussis toxin,
Clostridium tetani E. coli LT (labile toxin) and ST stable toxin,
staphylococcal TSST-1 (toxic shock syndrome
toxin-1), streptococcal erythrogenic toxin,
Clostriudium perfringens  -toxin
Systemic action of endotoxins, esp of Salmonella Lipoteichoic acids as endotoxins
(see also 27.1.5; 27.1.7; 27.1.8)

Induction of hypersensitivity and autoimmune reactions Bacterial endocarditis
by Streptococcus Acute glomerulonephritis, rheumatic fever
Induction hypersensitivity and chronic inflammation by
Mycobacterium (see 27.3)
29.5.5 Bacterial counter-measures against the immune system
Avoidance of phagocytosis by capsules (esp. Composition of capsules in group A
Streptococcus) Streptococcus, pneumococcus, Bacillus
anthracis
Action of leukocidins, Ig proteases
Survival within neutrophils by Staphylococcus, and in
macrophages by Salmonella typhi and Mycobacterium



29.6 GENETICS OF VIRULENCE AND ANTIBIOTIC-RESISTANCE
Plasmids as repositories of additional genetic information Prophages and transposons
Mechanisms of genetic transfer in bacteria:
transformation, transduction, conjugation
Antibiotic-resistance is most often determined by genes Examples of adhesins, aggressins (e.g. toxins)
on plasmids and antibiotic resistance genes carried by
Resistance is transferable between bacteria. Multiple mobile genetic elements
drug resistance
Genetic responses to environmental variables:
selection of favorable mutants, induction of
gene expression
Expression of virulence determinants may be
regulated by environment: e.g. in group A
Streptococci by CO2
29.7 SPECIFIC PATHOGENIC BACTERIA
Differential identification, pathogenesis, basis of treatment, and prophylaxis in the following examples:-
Streptococcus pyogenes: (Group A Strep.) pharyngitis, Streptococcus pneumoniae: primary lobar
cellulitis, rheumatic fever pneumonia
Staphylococcus aureus: abscesses, surgical wound and Corynebacterium diphtheriae
burn infections, food poisoning Listeria monocytogenes
Bacillus cereus, Bacillus anthracis
Salmonella spp.: enteric fevers, food poisoning Enteropathogenic, enteroinvasive and 0157 strains
of Escherichia coli
Vibrio cholerae: cholera Klebsiella spp.
Mycobacterium tuberculosis: tuberculosis Shigella spp.
Clostridium tetani: tetanus Haemophilus influenzae
Bordetella pertussis
Neisseria gonorrhoeae
Pseudomonas spp.
Campylobacter jejuni
Legionella pneumophila
Treponema pallidum
Chlamydia



Rickettsia
30 MYCOLOGY
30.1 FUNGI OF MEDICAL IMPORTANCE
Yeasts e.g. Candida (a commensal in the mouth,
gut, vagina – cause of thrush); Pneumocystis
and Cryptococcus
Filamentous fungi such as Aspergillus and Mucor
Dermatophytes
Importance of health of host in resistance to
fungal infection.
Aspergillus as an example of the effect of the
host upon disease: no disease, allergic
bronchopulmonary aspergillosis, aspergilloma
in lung cavities, invasive aspergillosis in
neutropaenics and severely
immunocompromised
Chemotherapy of fungal disease
31 VIROLOGY
31.1 EXAMPLES OF VIRAL DISEASES
Symptoms, pathogenesis, basis of treatment, and prophylaxis in the following examples and the replication and
structure of the causative viruses:-
Influenza (influenza virus) Paramyxoviridae: measles virus, mumps virus,
respiratory syncytial virus
Poliomyelitis (polio virus) Picornaviridae: Rhinovirus – common cold
Rhabdoviridae: rabies virus
AIDS (HIV-1) Rous sarcoma virus

Viral Hepatitis and hepatocellular carcinoma (HBV) Reoviridae: rotavirus- childhood diarrhoea
Herpesviridae: Human cytomegalovirus, HSV-1
(labial and genital herpes), Varicella-Zoster
virus (chicken pox and shingles)
Infectious mononucleosis, Burkitt‘s lymphoma, Papilloma virus associated with warts, cervical
nasopharyngeal carcinoma (EBV) carcinoma



Flaviviridae: Dengue virus, yellow fever virus,
hepatitis C virus, West Nile virus
Togaviridae: rubella virus
31.2 LABORATORY DIAGNOSTIC METHODS
Viremia. Detection of virus in blood (or c.s.f.) indicates Visualization by electron microscopy
current infection. Methods for detecting virus (or virus
fragments) include: ELISA, PCR (or RT-PCR), plaque (or
other infectious centre) assays, hemaglutination.
Serology. Existence of serum antibody to virus indicates
prior infection. Depends on specificity of immune
response. Methods for detecting specific antibody
include: ELISA, hemagglutination Inhibition
31.3 VIRION STRUCTURE AND CLASSIFICATION
Small size (20–300nm)
pass through bacterial filters; not visible by light
microscope
Simplicity — protein and nucleic acid (RNA or DNA) (lipid
and carbohydrate). Numerous, infect all types of host.
Diversity of structure. Cause diverse diseases
The enigma of prions

Nucleocapsid: protein that packages virion nucleic acid Capsomers. Helical symmetry: e.g. rabies
virus, influenza virus
Icosahedral symmetry: e.g. polio virus
Envelope (in some viruses): lipid bilayer derived from host
cell;
contains viral attachment proteins; destroyed by
detergents e.g. bile
Nucleic acid: Single-stranded (ss) or double stranded (ds)
RNA or DNA; may be segmented; positive or negative Linear or circular; size range: 3-300 kb
polarity Finer viral classification is based on structure,
Nucleic acid type (and replication strategy) determine serology and sequence homology
―Baltimore Classification‖ Families, subfamilies, genera, species, strains.



ssDNA viruses

31.4 VIRUS REPLICATION
Obligate intracellular parasites. Unique mode of replication.
Eclipse phase

Entry into cells
the concept of virus attachment proteins and their Particle/pfu ratios
cellular receptors: EBV gp340 and CD21. Polio virus receptor
HIV-1 gp120 and CD4; influenza haemagglutinin and (PVR)
sialic acid HIV-1 co-receptors (chemokine receptors
Specificity and tropism CXCR4, CCR5)

Penetration:
envelope fusion at plasma membrane (HIV) Capsid transformations at cell surface and
envelope fusion in endosomes at low pH (influenza) endosomes (polio virus)
Nuclear localization (flu, HIV-1, EBV) and
integration (HIV-1)

Viral gene expression
Principle of subversion of cell metabolism to manufacture Temporal and quantitative control of gene
of virus components expression
(poliovirus effects on the ribosome) Latency-associated transcription (EBV)
Tat and Rev in regulation of HIV-1 expression

Nucleic acid replication
Involves viral polymerases and other viral enzymes (drug Strategy for production of genomic and
targets: see 31.8) messenger nucleic acids
RNA viruses need viral RNA polymerises. Retroviruses Viral enzymes:
need reverse Essential, e.g. DNA and RNA polymerases,
transcriptases reverse transcriptase
Genetic resortment and recombination (e.g. antigenic Non-essential, e.g. thymidine kinase,
shift in influenza virus) ribonucleotide reductase, virulence factors



Assembly and release
budding of enveloped viruses (HIV-1, EBV) Self-assembly of capsids and virus-like particles
cell lysis to release naked viruses (poliovirus) Prolonged shedding during persistent
infections
Specific lysis proteins
Role of viral proteases in virus maturation (poliovirus, HIV-
1) and as drug targets (see 31.8)
31.5 CELLULAR AND SYSTEMIC CONSEQUENCES OF INFECTION
Not all viruses are pathogenic
Mechanisms by which viruses produce disease in whole Effect of dose of infectious agent on outcome
organism Effect of host factors on probability of infection:
Outcome of infection influenced by viral and host factors age, health, immunosuppressive drugs
(see immediately following sections) (including steroids)

31.5.1 Cell Death
Cytopathic effects of polio virus (anterior horn cells) and Cytoskeletal changes: changes in cell shape,
HIV-1 (CD4+ cells). loss of cell adhesion (notable in vitro)
Role of apoptosis (see 27.1). Chromosome destruction
Role of cell-mediated immunity in viral hepatitis (see 34.3)
31.5.2 Cellular Transformation
31.5.2.1 Transformation By DNA Viruses
EBV normally causes only infectious mononucleosis, but Papilloma virus: gives common warts (benign
predisposes to Burkitt‘s lymphoma (BL) and tumors) and certain strains predispose to
nasopharyngeal carcinoma (NPC). Other cofactors cancer of the uterine cervix
required. Geographical incidence of BL and NPC: its
implications
Chromosomal translocations in BL: c-myc with
Ig light or heavy chain loci. Interactions of
virus proteins with products of tumour-
suppressor genes
Kaposi‘s sarcoma and HIV 8
HBV can give rise to hepatocellular carcinoma following Viral transforming proteins:



chronic infection Adenoviridae, E1A and E1B
Papovavirdae (SV40 and polyoma) large T
antigen
31.5.2.2 Transformation by RNA viruses
Cellular transformation by retroviruses:
Adult T-cell leukaemia/lymphoma (ATLL: rare)
occurs only in carriers of HTLV-1 (and only in
1/1000 of them). A virally encoded
transcription factor can activate cellular
growth-promoting genes
Retroviruses oncogenic in animals:
e.g. RSV, AMV, MLV (see 38.3.3.3)
31.5.3 Cellular and Clinical Latency
Cellular latency is the persistence of viral genomes in cells Latent infections by herpes viruses
without overt expression of new viruses. Observed in HSV (cold sores, genital herpes); reactivation
Herpes viruses and retroviruses. during immunosuppression,
Clinical latency is the temporary absence of symptoms in e.g.transplantation surgery
spite of infection. This may be the result of cellular Human cytomegalovirus
latency, active immunity, etc.
Varicella-Zoster virus: chickenpox and zoster
(‗shingles‘)
Retroviruses The integrated provirus, can
become transcriptionally silent, in response
to host cell quiescence: possibility of germ-
line transmission
31.5.4 Dissemination In The Host
Local spread
Symptoms due to cytopathic viruses appear after a short Restriction of virus replication to local site by
incubation period e.g. influenza, rotavirus polarized shedding to apical surface of
Spread to local lymph nodes epithelium (e.g. flu)
Spread to lymph nodes as free virus or within
phagocytes
Systemic infection Virus in blood may be free in plasma or within



Viremia enables infection of distant sites leukocytes
Effect of virus on distant tissues becomes evident after a Secondary viremia results from the release of
longer incubation period, e.g. poliomyelitis virus from secondary sites into the blood
Penetration of vascular barrier by viruses (to
reach secondary sites esp. CNS) may be
within recirculating leukocytes or by
replication in endothelial cells
31.5.5 Fever, Malaise etc
Overlapping spectrum of symptoms found in many virus Arthopathy, myalgia, headaches, vomiting,
infections. Most symptoms result from release of dizziness, depression.
mediators of inflammation (27.2.7). Fever: elevated Post-viral syndromes (ME)
temperature due to change in hypothalamic set point
(15.3) as a result of chemical mediators (prostaglandins,
1lL-1, TNF) released by neighbouring macrophages.
31.5.6 Resolution
Acute infections
Virus replication sometimes restricted by local Action and induction of interferons
production of / interferons
Virus-infected cells cleared by immune system, chiefly
CD8+ lymphocytes
(see 28.4.2)
Free virus cleared by antibody + complement
Re-infection prevented by plasma IgG and secretory IgA

Persistent and chronic infections
HIV, leading to AIDS: attack on CD4+ lymphocytes, Measles, subacute sclerosing panencephalitis
antigenic variation (SSPE)
Epstein-Barr virus: asymptomatic, or glandular fever, Immunomodulatory viral proteins of EBV, other
both followed by persistent infection: role of CMI in herpes and pox viruses: blockage of
control and symptoms (see also 31.6.2) complement, interferon, inflammation, fever,
HBV - leading possibly to liver cancer MHC I-Ag presentation
31.6 POPULATION VIROLOGY
31.6.1 Routes of Transmission



Feco-oral route (polio) Mammal bites: rabies virus in saliva
Respiratory droplets (influenza) Skin: by scratches (e.g. papilloma)
Saliva (EBV) Arthropod bites: yellow fever; Dengue, West
Genito-urinary transmission (HIV) Nile viruses
Transfusion, blood products, i.v., drug abuse (HIV, HBV) Concept of animal reservoirs, zoonoses
Veterinary eradication / slaughter policies
Transfusion hepatitis (usually HCV)
31.6.2 Vaccination (See section 33)
31.6.3 Antigenic Variation
Mutability of virus (esp RNA virus) genomes Error rates of RNA-dependent nucleic acid
polymerises
Structural constraints on virus evolution
Neutralizing antibody as a selection pressure CTL as selective agents
Antigenic drift (e.g. influenza and HIV) Concept of virus quasispecies
Antigenic shift (e.g. influenza) Role of avian and porcine hosts in pandemic
Antigenic conservatism (e.g. polio) shifts
Implications for vaccination regimes
31.6.4 Therapy of Viral Diseases
31.6.4.1 Antiviral therapy
Limited choice of targets compared to bacteria (intimacy
of parasitism)
Viral target enzymes: Herpes virus thymidine kinases: acyclovir and
HIV reverse transcriptase - zidovudine (azidothymidine, gancyclovir
AZT) chain terminator Use of RT inhibitors in HBV
HIV protease - Saquinavir , substrate peptide analogue Possibility of interfering with virus/cell receptor
Influenza virus M2 ion channel - amantadine recognition
31.6.4.2 Palliative therapy
Problem of lack of effective drugs Interferons
Problem of lack of specific diagnosis: similarity of Cytokine therapy
symptoms
Anti-inflammatory drugs (see 27.5)
32 PARASITOLOGY
Worldwide significance of protozoal and helminth infections



Protozoa: Plasmodium sp. Basic life-cycle and Leishmania spp., amoebae, Trypanosoma spp.,
pathogenesis Toxoplasma, Cryptosporidium, Giardia
Helminths: Schistosoma sp. Basic life-cycle and Ascaris spp., hookworms, Taenia spp.,
pathogenesis Echinococcus spp.
33 IMMUNIZATION AGAINST INFECTIOUS DISEASE
33.1 PASSIVE IMMUNIZATION
Immunoglobulin, e.g. for Hepatitis B Advantage: instant effectiveness
Disadvantage: short-lasting, serum sickness
(response to foreign protein)
33.2 LIVE VACCINES
Attenuated form of virulent organism (e.g. measles, Other examples of attentuated organisms: rubella,
Sabin polio vaccine) yellow fever 17D vaccine
Immunologically related organism (e.g. vaccinia) Advantages: long-lasting
inexpensive manufacture
easy administration
induce both cell-mediated and antibody
response
Disadvantages: may revert to virulence (rare)
more severe reactions than with dead
vaccines
- (life-threatening infections in immune-
incompetent)
vaccine may be shed into environment
storage difficulty (e.g. heat lability)
Immunization with virulent organism (variolation)
33.3 DEAD VACCINES
Antigen preparation chemically treated to inactivate Advantage: safety
infectivity and toxicity: Disadvantages: multiple administration
Whole organisms e.g. cholera, pertussis needed (may need adjuvant)
Subunit vaccines e.g. influenza vaccine, genetically shorter-lasting immunity than with live
engineered protein sub-unit from HBV vaccines
Inactivated exotoxin e.g. tetanus toxoid (boosters needed)
less cell-mediated immunity



expensive
33.4 EPIDEMIOLOGY AND PUBLIC HEALTH
Principles of prevention and control of infections
diseases: The need to develop new vaccines
prevention of exposure; quarantine (e.g. rabies) New strategies for vaccine development
immunization DNA vaccines
control of reservoirs (e.g. rabies); control of vectors recombinant viral vaccines
(e.g. yellow fever)
Concept of herd immunity
34 IMMUNOPATHOLOGY
Concept that immune responses can cause harm to the
host and are central to many clinically important
diseases
34.1 HYPERSENSITIVITY
34.1.1 Anaphylactic (Type 1)
Allergic responses (hay fever, asthma, food allergies Distribution of mast cells, ways of triggering
(peanuts) mast cell degranulation, other mediators
Central role of IgE in triggering mast cell degranulation released from mast cells
Histamine, leukotrienes - effects on smooth muscle of Physiology of anaphylaxis
blood vessels and bronchi and on mucosae Genetic basis of allergies and asthma
Treatment: immediate: anti-histamines, adrenaline Relationship to Th2 responses
long-term: cromoglycate, glucocorticoids, anti-
histamines
34.1.2 Cytotoxic (Type 2)
Mediated by antibody  complement - cell lysis or
opsonisation
Transfusion reactions - the ABO and Rhesus blood
groups
Haemolytic disease of the new-born; pathogenesis and
prevention
Hyperacute allograft rejection
34.1.3 Immune Complexes (Type 3)
Antigen/antibody complexes activate complement,



initiating acute inflammation
Local - complexes in specific sites - e.g. inhaled Ag -
Farmer‘s lung
Diffuse - circulating complexes - deposition in
microvasculature of joints, kidneys e.g. systemic lupus
erythematosus (SLE) which involves autoantibodies
34.1.4 Delayed Type Hypersensitivity ‗DTH‘ (Type 4)
T cell-mediated - Ab has no role Genetic basis of DTH
Develops slowly as cells accumulate Animal models of DTH
Roles of T cells and activated macrophages
Role of persistent Ag: e.g. mycobacteria, self Ag in
autoimmunity Details of pathogenesis of contact sensitivity
Examples: Mantoux test, contact sensitivity
34.1.5 Stimulatory Hypersensitivity (Type 5)
Mediated by autoantibody acting as agonists on cell
curface receptors
e.g. Graves‘s Disease (hyperthyroidism)
34.2 BACTERIAL IMMUNOPATHOLOGY
Role of DTH in tuberculosis Ulceration by Salmonella typhi
Role of antibody-mediated reactions in pathogenesis of
rheumatic fever and glomerulonephritis
(Streptococcus)
34.3 VIRAL IMMUNOPATHOLGY
Hepatitis B virus: cell killing largely due to cytotoxic T- Lymphocytic chorio-meningitis virus
cells Antibody-enhanced infectivity: Rabies early
death syndome;
Subacute sclerosing panencephalitis
34.4 PARASITE IMMUNOPATHOLOGY
Schistosomiasis
34.5 AUTOIMMUNITY
Concept that immune responses may be initiated by self- Hypotheses to explain existence of self-reactive
Ag lymphocytes
Implication that self-reactive lymphocytes exist in the Hypotheses to explain activation of these



periphery lymphocytes in autoimmunity
Concept and examples of privileged sites Genetic basis of autoimmunity
Examples of autoimmune disease, brief details of Experimental models of autoimmune disease
pathogenic mechanisms: non-obese diabetic (NOD) mice
Cell-mediated - insulin-dependent diabetes, experimental autoimmune encephalomyelitis
rheumatoid arthritis (EAE)
Antibody-mediated - myasthenia gravis, Graves‘s
disease (hyperthyroidism),
and rheumatic fever
34.6 TRANSPLANTATION IMMUNOLOGY
The need for tissue and organ transplantation
Autografts: no immune response
Allografts: characteristics of allograft rejection; Xenografts
hyperacute, acute and chronic rejection (their Rejection mechanisms
histology) Behaviour of different types of graft - kidney and
first and second set rejection bone-marrow
Immune basis of allograft rejection, memory and Experimental studies of mechanisms of graft
specificity rejection
Antigens responsible for allograft rejection Experimental induction of tolerance to allografts
blood group Ags Blood transfusion effect
major and minor histocompatibility Ags Initiation of response - passenger cells
Prevention of rejection (dendritic cells)
MHC matching
Immunosuppressive drugs e.g. cyclosporin A,
corticosteroids Tacrolimus
35 IMMUNODEFICIENCY AND IMMUNOSUPPRESSION
35.1 IMMUNODEFICIENCY
35.1.1 T-Cell Deficiencies
Cause susceptibility to infections by viruses and
facultative intracellular pathogens Adenosine deaminase (ADA) deficiency
Inherited: e.g. thymic aplasia (lack of T-cells) Loss of cell-mediated immunity due to measles
Acquired: e.g. loss of CD4+ T-cells due to HIV: results in
AIDS



35.1.2 B-Cell Deficiencies
Cause susceptibility to pyogenic infections
Inherited: e.g. agammaglobulinemia
35.1.3 Deficiencies Of The Non-Specific Immune System
Causes susceptibility to pyogenic infections
Cellular defects e.g. involving PMN Chronic granulomatous disease; Chédiak-
Deficiencies of secreted molecules e.g. of a complement Higashi syndrome
component
35.1.4 Treatment
Replacement therapy e.g. give immunoglobins Gene therapy (e.g. attempted correction of ADA
deficiency)
Bone-marrow transplantation
Antiviral chemotherapy e.g. in AIDS
35.2 IATROGENIC IMMUNOSUPPRESSION
As a complication of the use of cytotoxic drugs or
irradiation in tumour therapy
Therapeutic immunosuppression (i.e. intentional) after
transplantation surgery or to control auto-immune
disease
36. CARDIOVASCULAR PATHOLOGY
36.1 HEMOSTASIS
Vasospasm. Formation of hemostatic plug by platelets (section
36.3)
Coagulation of the blood: subsequent fibrinolysis (section 36.4)

36.2 STRUCTURE AND FUNCTIONS OF ARTERIAL WALL
Endothelium, intima, media, adventitia; vasa vasorum
Endothelium: properties and interactions with blood leukotrienes, chemokines, EDRF (NO)
components
Media: smooth muscle cells, properties, control of migration and
proliferation

36.3 BLOOD PLATELETS



Origin and lifespan. Granule constituents (ADP and 5-HT). Phosphoinositides, von Willebrand‘s
Aggregation and degranulation factor
Functions in haemostasis — vasoconstriction, platelet plug,
activation of fibrin deposition (stabilises plug), initiation of
vascular and other repair processes (PDGF)
36.4 BLOOD COAGULATION
Extrinsic and intrinsic pathways, major coagulation factors Hemophilias
(tissue factor, factor VIII, prothrombin, fibrinogen)
Fibrinolysis — role of plasmin, inhibitors of fibrinolysis.
Endogenous anticoagulants
36.5 THROMBOSIS
―Hemostasis in wrong place‖. Differences between arterial
and venous thrombosis. Risk factors in venous thrombosis:
venous stasis, surgery, childbirth. Evolution of a thrombus.
Effects of thrombosis — stenosis, ischaemia, infarction,
embolism.
36.6 EMBOLISM
Types of embolism — most are thrombi (others: fat, air, pus,
material from atheromatous plaque)
Pulmonary embolism: its main consequences
Systemic embolism: infarction
Possible healing reactions in an embolised thrombus
Possible enhancement of collateral circulation
36.7 ATHEROSCLEROSIS
Epidemiology — age, sex, geographical distribution
Structure and distribution of lesions — fatty streaks, fibro-fatty Cellular and molecular mechanisms of
plaques, complicated lesions. pathogenesis
Animal models: apoE and LDLR knock-out
mice
Pathogenesis: reponse to endothelial injury vascular gene transfer
Risk factors — Smoking, diabetes, genetic (LDL receptors), Apolipoprotein E.
endocrine (sex), hypertension, hyperlipidaemia (raised LDL
as opposed to HDL), oxidised LDL, Lp(a)



Clinical manifestations: angina, myocardial infarction,
claudication, embolism, aneurysm
36.8 PREVENTION AND TREATMENT OF CV DISEASE
Lifestyle choices:
smoking, obestity, physical activity, blood pressure, diet
Anti-thrombotic drugs
aspirin and its action; thrombolytic agents eg streptokinase,
tPA
Anti-coagulant drugs
heparin and warfarin: their action and its reversal
Lipid-lowering drugs:
action of the statins
Surgical intervention:
ballon angioplasty, stenting, coronary bypass
37. DEGENERATIVE DISEASE DUE TO ABNORMAL PROTEIN DEPOSITION
37.1 NON-TRANSMISSIBLE
Amyloidoses
Alzheimer‘s disease
37.2 TRANSMISSIBLE
Neuropathies associated with prions - transmissible
spongiform encephalopathies (TSE):
Creuztfeld-Jacob disease (CJD), and Variant CJD,
Bovine spongiform encephalopathy (BSE)
38. GROWTH AND FUNCTION OF TISSUES AND ORGANS
38.1 DECREASED GROWTH
Elementary classification with physiological and
pathological examples:-
38.1.1 Developmental
Agenesis
complete failure to develop — e.g. ovaries in Turner‘s
syndrome
Hypoplasia
partial failure to develop — e.g. testes in Klinefelter‘s



syndrome
38.1.2 Progressive
38.1.2.1 Physiological Atrophy (involution)
e.g. branchial clefts in embryogenesis, ductus arteriosus
after birth, thymus at puberty.
38.1.2.2 Pathological Atrophy
General: affecting many different tissues or organs - e.g.
wasting in starvation, old age and in malignant disease
(―cachexia‖)
Tissue-specific: affecting a particular tissue of the body brown atrophy (in neurones and cardiac
e.g. osteoporosis (due to post-menopausal hormonal muscle)
changes, prolonged
recumbency, or vit. C deficiency).

Local: through various causes —
disuse — e.g. bone and muscle of an immobilized limb
ischaemic — e.g. due to pressure exerted by a cyst,
tumour or aneurism; or
due to vascular disease (a cause of cerebral atrophy)
neuropathic — e.g. muscle wasting after nerve injury or
polio
idiopathic — e.g. the neuropathies in Parkinson‘s and in
Alzheimer‘s diseases
38.2 INCREASED GROWTH
Definitions, with examples and their causes
38.2.1 Hypertrophy
Increase in a tissue or organ by an increase in cell size
typical of ‗permanent‘ tissues (e.g. skeletal, smooth and
cardiac muscle)
Characteristics of hypertrophy
38.2.2 Hyperplasia
Increase in a tissue or organ by cell multiplication
typical of ‗renewing‘ tissues e.g. bone marrow; or



‗resting‘ tissues
e.g. the thyroid and other endocrine glands, and
regeneration of the liver
Characteristics of hyperplasia: distinction from neoplasia
38.3 NEOPLASIA (TUMOUR GROWTH)
38.3.1 Pathology
38.3.1.1 General
Characteristics of neoplastic growth (and distinction from
hyperplasia)
A simple overview of the range and nomenclature of
benign and malignant tumors
38.3.1.2 Benign Tumors
Characteristics of benign tumors
Examples of benign tumors: warts; gliomata; adenomata teratoma, hydatidiform mole
(e.g. colonic polyps); fibroids (uterine leiomyomata);
lipoma
Possible damaging effects eg bleeding, pressure,
endocrine toxicity, and possible progression to
malignancy
38.3.1.3 Malignant tumors (i.e. ‘Cancer’)
Characteristics of malignant tumors (including invasion,
metastasis and progression): distinction from benign
tumors
38.3.1.4 Spread of Malignant Tumors
Local invasion: routes for invasion (including infiltration Factors involved in invasiveness
and permeation)
Metastasis — a common and serious problem (but
variable) Experimental study of metastasis
Routes for metastasis The inefficiency of metastasis, the steps
Preferred sites of secondaries — the anatomical view, involved and specific interactions that may
and the notion influence it
of ‗seed and soil‘



38.3.1.5 Consequences of Malignant Tumors
Local effects — pressure, occupation of space (e.g. intra-
thoracic or intra-cranial), obstruction of vessels or
ducts, intussusception of the gut, haemorrhage,
infection
Systemic effects: cachexia (weight loss, nausea, anorexia, Role of TNFin cachexia
lethargy); hormonal effects (over-secretion, ectopic
secretion, or destruction of endocrine tissue); marrow
destruction in leukaemias leading to infection
(neutropenia), bleeding (thrombocytopenia), or anaemia
38.3.1.6 Tumors and the Immune System
The immune system does little to prevent tumour growth. Tumour associated antigens seen as self and
The very limited effect of immunodeficiency or so provoke no immune response
immunosuppression on tumour incidence (other than that Oncofetal antigens, differentiation antigens,
of lymphoid tumors) and their use in diagnosis
Experimental demonstration of tumour-
specific transplantation antigens —
rejection of experimental tumors by T-cell-
mediated immunity (induction of apoptosis)
Comparison of metastasis in nude mice and
beige mice: role of NK cells
Experimental demonstration of anti-tumour
role of activated macrophages:
experimental production of microvascular
damage in tumors by TNF
38.3.2 Regulation of Cell Growth
38.3.2.1 Normal and Abnormal Cell Growth
The phases of the cell cycle - mitosis (M, nuclear division), Measurement of phases of the cell cycle
cell division and interphase (G1, S, G2)
Arrest of normal cells in G0, or induction of apoptosis, by Experimental demonstration of the ―restriction
absence of growth factors point‖ in G1
Characteristics of normal fibroblast growth in
vitro



Experimental demonstration of platelet-
derived fibroblast growth factor (PDGF)
The concept of cellular transformation, in particular: Other characteristics of transformed fibroblast
independence from growth factors growth
the potential for unlimited cell division (‗immortality‘) Transformed growth as typical of explanted
tumour cells
Experimental in vitro transformation
Transformation as contributor to (yet alone insufficient Experimental assay for tumorigenic cells
for) malignancy
Factors that limit tumour growth: most cells in a tumour Cell cycle analysis in tumors in vivo
are in G0, cellular differentiation, death (ischaemic lysis
or apoptosis), cell loss (e.g. from skin and gut, or
shedding into the circulation)
38.3.3 Genetic Basis of Malignancy
38.3.3.1 Somatic mutation and malignancy
Rarity of tumors expressed on a per cell basis
Monoclonality of tumors Experimental evidence for monoclonality
Age-incidence data suggest a need for the accumulation of
several independent events
Epidemiology of tumors in man — examples indicating the The ‗Ames test‘: role of microsomal
importance of chemical and physical mutagens metabolism; the conversion of ‗pro-
carcinogens‘ to mutagenic ‗ultimate
carcinogens‘.
Implication that malignancy develops through cells in the Examples of accumulated genetic changes in
body accumulating changes to their genes e.g. activation carcinogenesis e.g. the development of
of oncogenes, and loss of tumour suppressor genes carcinoma of the colon
38.3.3.2 Chemical carcinogenesis in experimental animals
Experimental evidence for the distinction
between initiation and promotion.
Initiation involves mutagens, promoters need
not be mutagens: possible genetic
significance
38.3.3.3 Oncogenes


The concept of viral oncogenes as cancer-inducing genes Ability of RSV and SV40 to cause
within oncogenic viruses. transformation in vitro and tumors in vivo.
Integration of viral oncogenes into cellular
DNA, and their role in the maintenance of
transformation and tumorigenicity.
Evidence from studies with temperature-
sensitive mutant oncogenes

Cellular oncogenes — cellular genes whose normal role is Relationship between cellular and viral
most likely to regulate normal cell growth, death or oncogenes
differentiation, but which contribute to malignancy Examples of oncogenes and the functions of
when mutated, or inappropriately or over-expressed their products in the intracellular
transduction pathways for hormones and
growth factors
The detection of ‗morphologically
transforming‘ oncogenes in tumour cell
DNA by the 3T3 transfection assay, and the
demonstration of other, ‗immortalising
oncogenes‘, as an additional requirement
for transforming normal fibroblasts
38.3.3.4 Tumour suppressor genes
Tumour suppressor genes normally prevent tumour Evidence for tumour suppressor genes: -
growth and are mutated or lost in malignant tumors recessivity of tumorigenicity in hybrid cells
made by fusing normal and malignant cells
‗inherited‘ tumors resulting from somatically
acquired homozygosity for a mutant or
deleted tumour suppressor gene (e.g.
inherited bilateral retinoblastoma)
Inherited susceptibility for many types of human tumour Mechanisms for the acquisition of
Role of somatically acquired homozygosity in the homozygosity, and evidence for its
occurrence and progression of non-inherited tumors importance
Examples of tumour suppressor genes and
suggested roles of their products: evidence



from transgenic mice
Testing for predisposition to tumour
development
38.3.4 Cancer Chemotherapy
Principles of action of drugs used against neoplasms. Mechanisms of resistance to chemotherapy
Difficulty of selectivity: adverse effects on host. (e.g. methotrexate resistance and multi-drug
Alkylating agents, e.g. cyclophosphamide; cytotoxic resistance). Strategies for avoiding or
antibiotics, e.g. doxorubicin; antimetabolites, e.g. reducing resistance.
methotrexate.
Drug resistance and its development
39. RADIOBIOLOGY
39.1 GENERAL
Distinction between ionizing and non-ionizing radiation. Radon as hazard
Concept of isotope
- and X-rays in relation to diagnosis Medical X-rays as hazard
-particles,  particles and neutrons in relation to
radiotherapy
Relative contributions of different ―background‖
exposures: natural versus man-made
Concept of physical half-life of decay: distinction from
biological half-life; and the combined concept of
effective half-life
39.2 EFFECTS OF IONIZING RADIATION ON TISSUE

Absorption of ionizing radiation by tissue
Linear energy transfer (LET) and the nature of damage Double-strand versus single-strand DNA
Chromosomal damage breaks
Constraints on repair
Relationship between dose level and damage (qualitative)

39.3 CLINICAL ASPECTS



Fractionated versus single-dose in radiotherapy
Relative radiosensitivities of different tissues and cell types
e.g. neural tissue insensitive, lymphocytes sensitive
Radiosensitization
oxygen effect and use of hyperthermia
radiosensitisation by drugs
Symptoms of radiation overexposure
Radiation as carcinogen

40. ABNORMALITIES OF GROWTH
40.1 DECREASED GROWTH
Elementary classification with physiological and pathological examples and their causes
40.1.1 Developmental
Agenesis
complete failure to develop — e.g. ovaries in Turner‘s
syndrome
Hypoplasia
partial failure to develop — e.g. testes in Klinefelter‘s
syndrome
40.1.2 Progressive
Physiological atrophy (involution) e.g. thymus at puberty
Pathological:
General: affecting many different tissues or organs - e.g.
wasting in starvation,
and in malignant disease (―cachexia‖) Brown atrophy (in neurones and cardiac
Tissue-specific: e.g. osteoporosis muscle)
Local atrophy - through various causes: disuse — e.g. bone
and muscle of an immobilised limb
ischemic — e.g. cerebral atrophy
neuropathic — e.g. muscle wasting after nerve injury or
poliomyelitis
idiopathic — e.g. the neuropathies such as Parkinson‘s



40.2 INCREASED GROWTH
Definitions, with examples and their causes:
40.2.1 Hypertrophy
Increase in a tissue or organ by an increase in cell size
Characteristics of hypertrophy
Typical of ‗permanent‘ tissues
May be physiological e.g. skeletal muscle in exercise;
or be caused by a pathology e.g. bladder smooth muscle in
prostatic enlargement;
and may predispose to disease e.g. cardiac hypertrophy
40.2.2 Hyperplasia
Increase in a tissue or organ by cell multiplication
Typical of ‗renewing‘ tissues e.g. bone marrow; or ‗resting‘
tissues
e.g. the thyroid and other endocrine glands, and
regeneration of the liver
Ranges from physiological to seriously pathological
Characteristics of hyperplasia: distinction from neoplasia
40.3 NEOPLASIA (TUMOUR GROWTH)
40.3.1 Pathology
40.3.1.1 General
Characteristics of neoplastic growth (and distinction from
hyperplasia)
A simple overview of the range and nomenclature of benign
and malignant tumors
40.3.1.2 Benign Tumors
Characteristics of benign tumors
Examples of benign tumors: warts; gliomata; adenomata (e.g. teratoma, hydatidiform mole
colonic polyps); fibroids (uterine leiomyomata); lipoma
Possible damaging effects e.g. bleeding, pressure, endocrine
toxicity, and possible progression to malignancy
40.3.1.3 Malignant tumors (i.e. ‘Cancer’)



Characteristics of malignant tumors (including invasion,
metastasis and progression; pleomorphism, anaplasia):
distinction from benign tumors
40.3.1.4 Spread of Malignant Tumors
Local invasion: routes for invasion (including infiltration and Factors involved in invasiveness
permeation)
Metastasis — a common and serious problem (but variable)
Routes for metastasis Experimental study of metastasis
Preferred sites of secondaries — the anatomical view, and The inefficiency of metastasis, the steps
the concept of ‗seed and soil‘ involved and specific interactions that may
influence it
40.3.1.5 Consequences of Malignant Tumors
Local effects — pressure, occupation of space (e.g. intra-
thoracic or intra-cranial), obstruction of vessels or ducts,
intussusception of the gut, hemorrhage, infection
Systemic effects: cachexia (weight loss, nausea, anorexia, Role of TNFin cachexia
lethargy); hormonal effects (over-secretion, ectopic
secretion, or destruction of endocrine tissue); marrow
destruction in leukaemias leading to infection (neutropenia),
bleeding (thrombocytopenia), or anaemia
40.3.1.6 Tumors and the Immune System
Slight effect of immunodeficiency or immunosuppression on
general incidence of tumors (with some notable exceptions:
lymphoid tumors, certain skin tumors; some virally
associated tumors)
40.3.2 Regulation of Cell Growth
40.3.2.1 Abnormal Cell Growth
This section assumes a knowledge of normal cell growth and its control (see 1.10 1.11)
The concept of cellular transformation, comparison with Other characteristics of transformed fibroblast
normal cell growth growth
In particular: Transformed growth as typical of explanted
independence from growth factors tumour cells



the potential for unlimited cell division (‗immortality‘) Experimental in vitro transformation
Transformation as contributor to (yet alone insufficient for) Experimental assay for tumorigenic cells
malignancy
Factors that limit tumour growth: most cells in a tumour are in Cell cycle analysis in tumors in vivo
G0, cellular differentiation, death (ischemic lysis or
apoptosis), cell loss (e.g. from skin and gut, or shedding
into the circulation)
40.3.3 Genetic Basis of Malignancy
40.3.3.1 Somatic mutation and malignancy
Rarity of tumors expressed on a per cell basis
Monoclonality of tumors Experimental evidence for monoclonality
Age-incidence data suggest a need for the accumulation of
several independent events
Epidemiology of tumors in man — examples indicating the The ‗Ames test‘: role of microsomal
importance of chemical and physical mutagens metabolism; the conversion of ‗pro-
carcinogens‘ to mutagenic ‗ultimate
carcinogens‘
Implication that malignancy develops through cells in the body Examples of accumulated genetic changes in
accumulating changes to their genes e.g. activation of carcinogenesis e.g. the development of
oncogenes, and loss of tumour suppressor genes carcinoma of the colon
40.3.3.2 Chemical carcinogenesis in experimental animals
Experimental evidence for the distinction
between initiation and promotion
Initiation involves mutagens, promoters need
not be mutagens: possible genetic
significance
40.3.3.3 Oncogenes
The concept of viral oncogenes as cancer-inducing genes Ability of RSV and SV40 to cause
within oncogenic viruses. transformation in vitro and tumors in vivo.
Integration of viral oncogenes into cellular
DNA, and their role in the maintenance of
transformation and tumorigenicity.
Evidence from studies with temperature-



sensitive mutant oncogenes
Cellular oncogenes — cellular genes whose normal role is Relationship between cellular and viral
most likely to regulate normal cell growth, death or oncogenes
differentiation, but which contribute to malignancy when Examples of oncogenes and the functions of
mutated, or inappropriately or over-expressed their products in the intracellular
transduction pathways for hormones and
growth factors
The detection of ‗morphologically
transforming‘ oncogenes in tumour cell
DNA by the 3T3 transfection assay, and the
demonstration of other, ‗immortalizing
oncogenes‘, as an additional requirement
for transforming normal fibroblasts
40.3.3.4 Tumour suppressor genes
Tumour suppressor genes normally prevent tumour growth Evidence for tumour suppressor genes: -
and are mutated or lost in malignant tumors recessivity of tumorigenicity in hybrid cells
made by fusing normal and malignant cells
‗inherited‘ tumors resulting from somatically
acquired homozygosity for a mutant or
deleted tumour suppressor gene (e.g.
inherited bilateral retinoblastoma)
Inherited susceptibility for many types of human tumour Mechanisms for the acquisition of
Role of somatically acquired homozygosity in the occurrence homozygosity, and evidence for its
and progression of non-inherited tumors importance
Examples of tumour suppressor genes and
suggested roles of their products: evidence
from transgenic mice
Testing for predisposition to tumour
development
40.3.4 Cancer Chemotherapy
Principles of action of drugs used against neoplasms. Mechanisms of resistance to chemotherapy
Difficulty of selectivity: adverse effects on host. Alkylating (e.g. methotrexate resistance and multi-drug
agents, e.g. cyclophosphamide; cytotoxic antibiotics, e.g. resistance). Strategies for avoiding or



doxorubicin; antimetabolites, e.g. methotrexate reducing resistance.
Drug resistance and its development
41 MEDICAL SOCIOLOGY FOR MEDICAL STUDENTS
Long-term trends in health
Social status and health
Life events, social support and health
The influence of class, gender, ethnicity, and age on health
Impact of illness on patients; illness behaviour; assessment of health status and health-
related quality of life
The consultation; strategies of doctor and patient; patient satisfaction and compliance
Comparative health-care systems: evaluation, structure and finance
42. MEDICAL STATISTICS
42.1 DESCRIPTIVE STATISTICS
Types of data: binary, categorical, continuous
Summary statistics: means, medians, proportions and
standard deviations
Frequency distributions
42.2 THE NORMAL DISTRIBUTION
The Normal curve from continuous data
42.3 STATISTICAL INFERENCE
Sample statistics and population parameters.
Distribution of the means of repeated random samples from the
same population
(i.e. sampling distribution of a mean)
Sampling distribution of the difference between two means:
standard errors of means
42.3.1 Estimation
Confidence intervals for a single mean and the difference
between two means
42.3.2 Hypothesis Tests
The null hypothesis. The test statistic. The p-value
Test of statistical significance for comparing two means
Assumptions of methods


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