Q J Med 2001; 94: 643-656
© 2001 Association of Physicians
Annual General Meeting |
The Association of Physicians of Great Britain and Ireland 2001
Ninety-Fifth Annual General MeetingThe Ninety-Fifth Annual General Meeting was held in Edinburgh on Thursday and Friday 5 and 6 April. The attendance book was signed by 178 ordinary members and 34 senior members.
The President, Dr N.D.C. Finlayson, took the chair.
The Minutes of the last Annual General Meeting, having been published in the Quarterly Journal of Medicine (November 2000), were taken as read, confirmed and signed. The following Officers and Executive Officers were elected:
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The following Honorary, Senior and Ordinary Members were elected:
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Ordinary Members
Cappuccio, Francesco Paolo, MBBS, MD, FRCP, MFPHM. Professor of Primary Care Research & Development/Consultant Cardiovascular Physician, Department of General Practice and Primary Care, St George's Hospital Medical School, Cranmer Terrace, London SE17 0RE
Conlon, Christopher Peter, MBBS, MRCP, MD, MA. Consultant Physician & Honorary Sr Lecturer, Infectious Diseases & Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU
Dean, John CS, MB ChB, MA, FRCP. Consultant in Medical Genetics, Department of Medical Genetics, Medical School, Foresterhill, Aberdeen AB25 2ZD
Dornhurst, Anne, BM BCh, DM, FRCP, MRCPath. Consultant Physician/Hon Sr Lecturer, Department of Metabolic Medicine, Division of Investigative Science, 6th Floor Commonwealth Building, Imperial College at Hammersmith Campus, London W12 0NN
Douglas, John Graham, MB ChB, FRCPE. Consultant Physician, Department of Respiratory Medicine, Aberdeen Royal Hospitals Trust, Foresterhill, Aberdeen AB25 2ZD
Elborn, Joseph Stuart, MB BCh BAO, MD, FRCP. Hon Sr Lecturer in Medicine, QUB/Visiting Professor (Health Sciences), Department of Respiratory Medicine, City Hospital, Belfast BT9 7AB, N. Ireland
El-Omar, Emad, MB ChB, MRCP, MD. Professor of Gastroenterology & Hon Consultant Physician, Department of Medicine & Therapeutics, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD
Friedland Jonathan S, MB BS, PhD, FRCP. Reader & Hon Consultant in Infectious & Tropical Diseases, Department of Infectious Diseases, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN
Gilks, Charles F, MBBS, D Phil, FRCP. Professor in Tropical Medicine, Head, Division of Tropical Medicine, Liverpool School of Tropical Medicine, Liverpool L3 5QA
Groves, Richard William, MB BS, FRCP. Sr Lecturer in Dermatology, Centre for Dermatology, University College London, Jules Thorn Institute, 7th Floor, Middlesex Hospital, Mortimer Street, London W1T 3AA
Hall, Alistair Scott, MB ChB, MRCP, PhD. Professor of Clinical Cardiology, Academic Unit of Cardiovascular Medicine, Yorkshire Heart Centre, G Floor, Jubilee Building, Leeds General Infirmary, Leeds LS1 3EX
Hawkey, Christopher John, BM BCh, DM, FRCP. Professor of Gastroenterology, Division of Gastroenterology, University Hospital, Nottingham NG7 2UH
Hillhouse, Edward, PhD, MB BS, FRCP. Professor of Medicine, The Sir Quinton Hazell Molecular Medicine Research Centre, Department of Biological Sciences, University of Warwick, Coventry CV4 7AL
Hughes, Jeremy, MB BS, MRCP, PhD. Wellcome Trust Sr Research Fellow & Hon Consultant Nephrologist, University of Edinburgh/MRC Centre for Inflammation Research, Department of Clinical & Surgical Sciences (Internal Medicine) Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW
Isaacs, John D, BSc, MB BS, PhD. Sr Lecturer/Hon Consultant in Rheumatology, Molecular Medicine Unit, Clinical Sciences Building, St James University Hospital, Leeds LS9 7TF
Jardine, Alan George, MB ChB, MD, FRCP. Sr lecturer in Medicine & Nephrology, Department of Medicine & Therapeutics, Western Infirmary, Glasgow G11 6NT
Jodrell, Duncan Ian. ICRF Medical Oncology Unit, University Department of Oncology, MRC Building, Western General Hospital, Edinburgh EH4 2XU
Jones, David EJ, BM BCh, MRCP, PhD. Sr Lecturer/Hon Consultant Physician, Centre for Liver Research, SCMS, Medical School, University of Newcastle, Framlington Place, Newcastle upon Tyne NE2 4HH
Monson, John Patrick, MB BS, MD, FRCP. Professor of Clinical Endocrinology, Department of Endocrinology, St Bartholomew's Hospital, London EC1A 7BE
Price, Pat, MB BChir, FRCR, MD, FRCP. Ralston Paterson Professor of Radiation Oncology, Manchester University & Christie Hospital, Wilmslow Road, Withington, Manchester M20 4BX
Pugh, Christopher William. MRC Sr.Clinical Fellow/Hon Consultant Physician, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Headington, Oxford, OX3 7QF
Ray, David William, MB ChB, MRCP, PhD. Glaxo Wellcome Fellow and Honorary Consultant Endocrinologist, Endocrine Sciences Research Group, Department of Medicine, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT
Santis, George, MB ChB, MD, MRCP. Department of Respiratory Medicine & Allergy, 5th Floor Thomas Guy House, GKT School of Medicine, Guy's Hospital, London SE1 9RT
Satsangi Jack, MBBS, MRCP, DPhil. Professor of Gastroenterology, Gastrointestinal Unit, Medical Sciences, Edinburgh University, Western General Hospital, Edinburgh EH4 2XU
Scott, David GI, MB ChB, MD, FRCP. Consultant Rheumatologist/Hon Professor, Department of Rheumatology, Norfolk & Norwich Health Care NHS Trust, Brunswick Road, Norwich NR1 3SR
Scott, David L, MB ChB, MD, FRCP. Professor of Clinical Rheumatology, Department of Rheumatology, Dulwich Hospital, Dulwich, London SE22 8PT
Vickers, Mark Adrian, BM BCh, MRCP, DM, MRCPath. Sr Lecturer in Haematology, Department of Medicine & Therapeutics, University of Aberdeen Medical School, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD
Wardlaw, Andrew, MBBChir, PhD, FRCP. Professor of Respiratory Medicine/Hon Consultant Physician, Department of Respiratory Medicine, Glenfield Hospital, Groby Road, Leicester LR3 9QP
The new members were welcomed to the Association by the President.
The Honorary Treasurer, Professor A.P. Weetman, reported that the accounts of the Association continued to be in good order. He presented income and expenditure for the 12 months to 31 December 2000. Income from the Oxford University Press, arising from the publication of QJM, had risen by £20 000 following the renegotiation of the contract in 2000. Income from this source was unlikely to be of the same level next year, as some of the surplus which had been negotiated would be reinvested in improving the Journal. Nonetheless, this was a welcome increase in income which could be used to further the direct charitable expenditure of the Association. The income from subscriptions had remained static. Interest from investments also remained static. For the first time in a number of years no surplus on the Annual General Meeting, held in London in 2000, had accrued. In fact, this meeting made a loss of £9720 owing to the high costs of staging the meeting in London. This loss to some extent had offset the surpluses which had accumulated, but future meetings would continue to be run as near to break-even as possible. Expenditure on items such as printing and stationery, postage, telephone and bank charges remained approximately similar to previous years. Administration costs had risen, as an electronic version of the membership list had been produced, and there was a carry over of administration charges from 1999. Unrealized losses on investment assets had occurred during 2000, and Professor Weetman would discuss these with the accountants.
Professor Weetman reminded the AGM of his proposals to reduce the fund balance to a figure of around four times the annual direct charitable expenditure, and had originally set a target of £300 000 for the fund balance by 2002. This was important to maintain the charitable status of the Association. The large surplus which had accumulated previously had been reduced during 1999, and the expenditure during 2000 of £77 000 was close to the figure that had previously been suggested. However, the Links with Developing Countries Scheme had proved to be very popular, with only five applications being funded from 17 high-quality applications. In view of this, the Executive Committee had agreed that it was worthwhile to increase expenditure, raising the amount from £25 000 to £40 000 per year. If this was done, then together with the intercalated fees, the annual expenditure of the Association would be around £90 000 per year, which would mean that it was appropriate to maintain a fund balance of around £360 000. In view of the uncertainties over the income from Oxford University Press next year, and in the light of possible deficits on future meetings, Professor Weetman felt that the present fund balance would be appropriate, provided the situation was monitored again next year. The members accepted the accounts and the proposals for expenditure.
Dr C.N. Martyn then presented the Annual Report to the Association of Physicians on the affairs of the QJM. After eight years as executive editor, Professor Julian Hopkin had stepped down and Dr Martyn had taken over. Professor David Warrell continued as senior editor. Tribute was paid to Professor Hopkin for the work he had done in editing the journal over this long period.
Dr Martyn informed the Association that, although the QJM was currently in a sound financial state, the revenue from library subscriptions had been falling by more than 5% each year for some time. The falling rate of library subscriptions is affecting almost all established medical journals and it is likely that the trend will continue. He was having discussions with the publishers, Oxford University Press, about ways to grow new sources of revenue. Other developments included plans to implement online submission and peer review of manuscripts and a re-design of the cover.
He reminded the Association that the impact factor of the QJM was high (2.25) and that time from acceptance of a manuscript to its publication was short. He hoped that members would continue to submit both reviews and papers reporting original research.
Professor S. Tomlinson, President-elect, invited the Association to its next meeting in Cardiff, Wales on 18 and 19 April 2002.
Opening Reception and Annual Dinner
The welcome reception on Thursday evening was held in the National Gallery of Scotland, and the Annual Dinner on the Friday night was held in the Royal Museum of Scotland. An excellent dinner was provided and the occasion was enjoyed by all.
Scientific Business
2.00–3.00 p.m.
Professor David Porteous, CBiol, FIBiol, FMedSci, Professor of Human Molecular Genetics and Medicine, Head of Medical Genetics, University of Edinburgh, Molecular Medicine, Centre and Director, Genetics Core, Wellcome Trust Millennial Clinical, Research Facility. Western General Hospital Campus, Edinburgh. The Osler Lecture—Cystic fibrosis: delivering the right message
3.00 p.m. (1)
J. Hughes, J. Wesson1 (introduced), A. Beshensky1 (introduced), C. Giachelli2 (introduced) and R.J. Johnson2 (introduced). MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, 1Medical College of WI and VAMC, Milwaukee, USA and 2University of Washington, Seattle, USA. Osteopontin is a critical inhibitor of renal deposition of calcium oxalate
Calcium oxalate (CaOx) renal calculi are a common clinical problem. The multifunctional protein osteopontin (OPN) is expressed in the kidney and is present in rodent and human urine. In vitro evidence suggests a potential role for OPN as an inhibitor of renal CaOx deposition, with the presence of OPN favouring formation of CaOx dihydrate (COD) rather than more adhesive CaOx monohydrate (COM) crystals. We used mice with a targeted deletion of the OPN gene to test the hypothesis that OPN actively inhibits renal CaOx deposition in vivo.
Hyperoxaluria was induced in OPN knockout (ko) and wild-type (wt) mice by the administration of 1% ethylene glycol (an oxalate precursor) in the drinking water for 4 weeks. Baseline levels of urine oxalate, calcium and citrate were comparable between groups. Ethylene glycol induced a 3-fold increase in urinary oxalate levels, and CaOx crystalluria. At 4 weeks, OPN ko mice exhibited marked intratubular deposition of CaOx. Interestingly, wt mice did not develop disease and exhibited significant protective up-regulation of renal OPN expression by immunocytochemistry. Polarized light microscopy and x-ray diffraction analysis indicated that the deposited renal crystals in OPN ko mice were exclusively COM with no evidence of COD, despite COD crystalluria in OPN ko mice.
This study supports a crucial role for OPN as an inhibitor of renal CaOx deposition in vivo, and suggests that OPN-directed modulation of CaOx crystal structure to favour COD is renoprotective. These results hold future therapeutic promise for patients with renal stone disease.
3.25 p.m. (2)
P. Vallance, J. Leiper (introduced), L. Tran (introduced), J. Murray-Rust1 (introduced), N. McDonald1 (introduced), G. Whitley2 (introduced). Centre for Clinical Pharmacology, University College London, WC1E 6JJ. 1Department of Structural Biology, Birkbeck College. 2Department of Biochemistry, St George's hospital Medical School. DDAH—insights into the dysregulation of nitric oxide generation in vascular disease
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. It is synthesized by methylation of arginine residues in proteins, and degraded to citrulline by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Plasma levels of ADMA are increased in a variety of cardiovascular and neurological disorders, and this would be expected to decrease nitric oxide generation and thereby disrupt important cell–cell signalling. Studies in cells suggest that reduced metabolism of ADMA by DDAH is the mechanism by which ADMA accumulates. We have recently identified two human DDAH isoforms, and localized the genes to chromosomes 1p22 and 6p21.3. DDAH-1 and 2 have different specific tissue distributions, and these show that DDAH-1 is the major isoform in the nervous system, whereas DDAH-2 is the cardiovascular isoform. We are interested in how disease may affect DDAH-2 activity or expression, and whether DDAH might be a target for novel drug therapies. Two approaches have been taken. In the first, we explored transcriptional regulation of DDAH isoforms. Retinoic acid has emerged as an inducer of DDAH expression, and this induction is associated with enhanced nitric oxide generation. We have solved the crystal structure of a bacterial DDAH. This reveals a critical cysteine residue in the active site that is susceptible to modulation by oxidative stress or by nitric oxide itself. This finding may help explain how oxidative stress affects vascular function.
4.15 p.m. (3)
M.R. Thursz, L. Zhang, U. Dumpis, J. Bell, H.C. Thomas, A.V.S. Hill. Division of Medicine, Imperial College, London. Nuffield Department of Medicine, Oxford. Identification of a gene for chronic HBV infection by genome-wide linkage analysis and family-based association studies
Background: 300 million people worldwide are chronically infected with hepatitis B virus (HBV). In most populations, over 80% of subjects rapidly clear the infection, whereas the remainder become persistent carriers. Data from a twin study and HLA association studies indicate a significant genetic component to the variable outcome of HBV infection. Identification of non-HLA genetic susceptibility factors provides an important new route to understanding the key pathophysiological pathways affecting this infection.
Methods: Genetic factors were sought in a large cohort of affected sibling pairs from West Africa with chronic HBV infection. A genome-wide linkage analysis was performed with over 300 polymorphic microsatellite markers; single-point lod scores and probabilities were calculated using the SIBPAIR-ANALYZE software package.
Results: Evidence of linkage (LOD score=3.55, p=0.000026) was found on the long arm of chromosome 21. This region contains a cluster of cytokine receptor II genes in a 180-kb segment of DNA. The Gambian families used for the genome scan, and a further set of Italian families with cases of chronic HBV, were investigated in family-based association studies based on polymorphisms identified within this region. Both populations have a highly significant (p<0.001) association with a polymorphism in the IL-10 receptor II gene.
Conclusions: Our genome-wide linkage study found a single peak of significant linkage on the long arm of chromosome 21. Very similar levels of allelic association in the Gambian and Italian families suggest that this is an important locus in Europeans as well as Africans.
4.40 p.m. (4)
C.W. Pugh (introduced), A.C.R. Epstein (introduced), P.H. Maxwell (introduced), C. Willam (introduced) and P.J. Ratcliffe. The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Headington, Oxford OX3 7QF. Peptide inhibition of hypoxia-inducible factor-1 
subunit degradation
Oxygen homeostasis is of fundamental importance in multicellular organisms. Hypoxia-inducible factor-1 (HIF) is a heterodimeric transcription factor which underlies the major gene regulatory homeostatic mechanism, leading to hypoxic up-regulation of expression of genes involved in such diverse processes as energy metabolism, angiogenesis, vasomotor control, matrix metabolism and apoptosis. The dominant mode of regulation of HIF is by the normoxic destruction by the 26S proteosome of ubiquitylated HIF subunits. We have identified the critical regions responsible for degradation within the HIF subunits, and shown that the process is saturable.
We have shown that HIF ubiquitylation is mediated by an E3 ubiquitin ligase, in which the von Hippel Lindau disease tumour suppressor protein (pVHL) acts as the recognition component. These phenomena are conserved in multicellular organisms from C. elegans to man. In the absence of wild-type pVHL, HIF subunits are consequently stabilized, leading to constitutive expression of a hypoxic phenotype. This process provides an explanation for the angiogenic phenotype of the lesions in von Hippel Lindau disease.
Understanding of the fundamental mechanisms involved has allowed us to design peptides to block normoxic degradation of HIF chains. Peptides have been isolated that are capable of stabilizing HIF subunits, leading to up-regulation of downstream gene expression in normoxia, and augmentation of hypoxic expression of these genes. These results allow assessment of the key regulatory modifications necessary for interaction between HIF chains and pVHL. Furthermore, since HIF activation leads to up-regulation of genes that should benefit ischaemic tissues by allowing collateral growth and metabolic adaptation, this may form a basis for future therapies in vascular disease.
5.05 p.m. (5)
N.A. Mabbott1 (introduced), M.E. Bruce1 (introduced), M. Botto2, M.J. Walport2, M.B. Pepys3. 1Institute for Animal Health, Edinburgh EH9 3JF. 2Division of Medicine, Hammersmith ICSM, London W12 0NN. 3Department of Medicine, Royal Free and University College Medical School, London NW3 2PF. Complement contributes to pathogenesis of transmissible spongiform encephalopathy
The transmissible spongiform encephalopathies (TSEs), or ‘prion’ diseases, are neurodegenerative disorders which include Creutzfeldt-Jakob disease (CJD) and kuru in humans, bovine spongiform encephalopathy, transmissible mink encephalopathy, and scrapie in sheep and goats. Following peripheral exposure, prion infectivity usually accumulates in lymphoid tissues before neuroinvasion. This accumulation is dependent on mature follicular dendritic cells (FDCs) which express the host prion protein, PrPc. The mechanisms by which the TSE agent initially localizes to lymphoid follicles, and interacts with FDCs, are not known. Here we show for the first time that complement component C3 co-localizes with PrP and FDCs in the spleen, and is more abundant after TSE infection. Furthermore, temporary depletion of C3, or genetic deficiency of C1q, significantly delayed the onset of disease following peripheral infection, and reduced the early accumulation of the disease-specific isomer of the prion protein, PrPSc, in the spleen. In combined genetic deficiency of C2 and factor B, most individuals also showed prolonged incubation periods, but in a few disease started earlier than usual, perhaps reflecting direct involvement of C1q and/or C4 with cellular receptors in the absence of later components. Nevertheless, during the early stages of infection, C3 (and perhaps also C1q) clearly contributes to the localization of TSE infectivity in lymphoid tissue, and is thus a potential therapeutic target in peripherally transmitted TSE diseases such as variant CJD. Interestingly, glycosaminoglycans and other polyanions that reduce susceptibility to TSE when administered around the time of peripheral infection, also inhibit binding of C1q to classical pathway activators and potentiate C1 inhibitor.
Friday 6 April 2001
9.00 a.m. (6)
J.R. Petrie1, C. Perry1,2, C.J.G. Kelly2, V. Nicolson2,3, I.P. Salt2,3, A. Spiers2, S.J.C. Cleland2, G.W. Gould3 (all introduced) and J.M.C. Connell2. 1University Departments of Medicine, 2Medicine and Therapeutics, and 3Institute of Biomedical and Life Sciences, University of Glasgow. Does insulin resistance result in impaired insulin-mediated vascular relaxation in humans?
We have previously shown that insulin is a nitric oxide (NO)-dependent vasodilator in man, and that this vascular action is related to whole-body insulin sensitivity. We have now examined: (i) the molecular mechanisms of insulin action with respect to NO production in cultured human aortic endothelial cells (HAECs); (ii) whether insulin-mediated vascular relaxation (IMVR) ex vivo is impaired in polycystic ovarian syndrome (PCOS), a state of insulin resistance; and (iii) the effect of induced insulin resistance; (low-dose dexamethasone, DXM) on IMVR ex vivo in healthy males. Insulin stimulation of HAECs resulted in rapid, dose-dependent recruitment of PI3K to both IRS-1 and IRS-2 with a rapid, sustained, dose-dependent stimulation of PKB activity (sensitive to wortmannin). NO production (Sievers 280A NO meter) was up-regulated within 5 min. In the artery studies, contractile responses to norepinephrine (NE) were assessed in arteries with <300 µm internal diameter (from gluteal biopsies) at baseline, after 30-min incubation with insulin (100 pM), and after a further incubation with both insulin and L-NMMA (an inhibitor of NO synthase). In women with PCOS, ED50 for NE dose-contraction responses was reduced in control vessels by insulin (p<0.05) but not in vessels from cases, while in men, DXM resulted in a 30% decrease in insulin sensitivity with no change in IMVR (PD20). The signalling cascade for insulin's action on endothelial cells is similar to that for its conventional target tissues (e.g. adipose tissue, muscle). Although there is evidence of vascular insulin resistance in women with PCOS, this is not the case for glucocorticoid-induced insulin resistance.
9.25 a.m. (7)
K.G.C. Smith (introduced), A.J. Cutler (introduced), B.J. Morley1 (introduced) and N.R. Pritchard (introduced). Department of Medicine and the Wellcome Trust Centre for the Molecular Mechanisms of Disease, University of Cambridge, CB2 2XY and 1Rheumatology Section, Division of Medicine, Imperial College School of Medicine. Failure of Fc receptor-mediated negative regulation as a cause of autoimmune disease
Systemic lupus erythematosus (SLE) is a polygenic autoimmune disease characterized by autoantibody production. Fc
RIIb (CD32) is a receptor for the Fc portion of IgG, and negatively regulates activation of cells including B cells and macrophages. It has been suspected of playing a role in the pathogenesis of SLE, as Fcgr2 is contained in genetic susceptibility intervals in the (NZBxNZW) F1 and BXSB mouse models of SLE, and FcRIIb-deficient mice develop autoimmune disease. FcRIIB is in a major susceptibility locus in human SLE.
We sequenced Fcgr2 and identified a haplotype defined by mutations in the Fcgr2 promoter present in all SLE-prone mouse strains (NZB, BXSB, SB/le, MRL) and in non-obese diabetic (NOD) mice, but absent in six control strains. This haplotype was associated with reduced expression of FcRII on macrophages and activated B cells, and with macrophage hyperactivity.
All of the major mouse models of SLE and diabetes share a Fcgr2 promoter haplotype associated with reduced expression and function of FcRII, strongly suggesting that the FcRII defect is important in the development of autoimmune disease. A model will be proposed explaining how this single genetic defect, by dysregulating a number of cell types involved in inflammation, could result in an amplification of autoimmunity. Studies on the incidence of this haplotype in the wild mouse population have also provided insight into the evolution of the pro-inflammatory genome.
9.50 a.m. (8)
M. Vickers1, E. McLeod1, T.D. Spector2, I.J. Wilson (introduced by A.J. Rees). 1Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD. 2St Thomas's Hospital, London. The mechanisms of acquired skewed X-inactivation: a twin study
Only one unmethylated X-chromosome is active in female human cells. X-inactivation is random during embryogenesis, so most females have both X-chromosomes active in approximately equal amounts. The demonstration that a sample of cells has mainly one X-chromosome active is commonly used as an assay for monoclonality. However, it has recently become clear that X-chromosome usage in the blood of most normal elderly females becomes skewed. It has been suggested that this may represent the development of premalignant clones. Alternatively, it may represent the selection of one X-chromosome over the other, or a stochastic effect. To investigate the mechanisms underlying this phenomenon, X-inactivation profiles in 33 monozygotic and 22 dizygotic elderly twin pairs were studied. Differential methylation-sensitive restriction enzyme cutting at a hypervariable locus in the human androgen receptor gene (HUMARA) was studied on purified granulocytes using T-cells as controls. A large genetic effect on skewed granulocytic X-inactivation was found (p<0.05); heritability was estimated to be 0.68. A further contributor to acquired skewing is stochastic asymmetric stem-cell division, which we model, and show is unlikely to account for a substantial part of variance. We also demonstrate this phenomenon using a red-cell mutation flow cytometric assay. Two monozygotic twin pairs had X-inactivation ratios skewed markedly in opposite directions, evidence for a further stochastic mechanism, suggestive of single over-represented clones. In conclusion, all three suggested mechanisms contribute to acquired X-inactivation, but the dominant mechanism is genetic selection. The observed proportion of putatively clonal haematopoiesis is similar to the lifetime incidence of haematopoietic stem-cell malignancy, consistent with the concept that clonal haematopoiesis precedes stem-cell malignancy. The selection of the ‘fittest’ X-chromosome may help to explain females’ slower rates of ageing.
10.15 a.m. (9)
D.W. Ray (introduced), F.R.A. Stevens (introduced), A.M. Heagerty. Department of Medicine, Stopford Building, University of Manchester, Manchester M13 9PT. Selective targeting of glucocorticoid action for treatment of inflammatory disease
Glucocorticoids are the most potent anti-inflammatory agents known, but their utility is compromised by a wide range of significant side-effects, for example osteoporosis and glucose intolerance. Glucocorticoid anti-inflammation is principally mediated by opposing the action of the NF
B transcription factor. NFB is activated by pro-inflammatory cytokines, including interleukin 1 and tumour necrosis factor. In addition, glucocorticoids activate numerous other genes which are not required for anti-inflammation, but which may lead to side-effects. Understanding how the glucocorticoid receptor (GR) responds to ligands by initiating these two divergent pathways is essential if more selective glucocorticoid analogues are to be developed.
Ligand binding to the GR induces protein folding and recruitment of other proteins. One group of proteins, termed co-activators, mediates activation of target genes, an activity not required for anti-inflammatory activity. Such gene transactivation may lead to side-effects.
We identified a tyrosine residue at amino acid 735 as a key steroid contact using a computer model of the GR. Substitution of this tyrosine resulted in a panel of molecules with altered ligand-dependent activity. We were able to generate mutant GR with retained affinity for ligand, but loss of co-activator recruitment, and transactivation. These activation deficient, mutant GRs retained anti-NFB activity. Furthermore, we were able to generate mutant GR which inappropriately recruited co-activators in response to binding an antagonist ligand, RU486, in contrast to the wild-type GR which showed no such recruitment.
We have thus identified the ‘switch’ which allows glucocorticoids to fully activate the GR, recruit co-activators and activate target genes. We show that this can be disrupted without losing high-affinity ligand binding or the therapeutically useful anti-NFB activity.
11.10 a.m. (10)
E.A. Warburton, J.H.F. Rudd, T.D. Fryer1, H.A. Jones, J.C.C. Clark1, N.A. Antoun1, P. Johnstrom, A.P. Davenport, P.J. Kirkpatrick1, J.D. Pickard1 (all introduced), P.L. Weissberg. Department of Medicine and the 1Wolfson Brain Imaging Centre, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ. Atherosclerotic plaque inflammation imaged with (18F) flurodeoxyglucose positron emission tomography (18FDG-PET)
Rupture of atherosclerotic plaques and subsequent events such as myocardial infarction and stroke are causally related to the activity of plaque inflammatory cells. We have used the glucose analogue 18FDG with PET imaging to demonstrate inflammatory cell activity non-invasively in patients with transient ischaemic attacks and carotid artery stenosis. Six patients with symptomatic carotid stenosis awaiting carotid endarterectomy were imaged using 18FDG-PET. Helical CT was performed for anatomical co-registration. Detailed histology of excised carotid plaques followed each patient's operation. In a series of separate experiments, excised carotid plaques were incubated with 18FDG in vitro. Phosphor imaging and histological analysis was used to assess the nature of the cellular plaque uptake of 18FDG. Symptomatic carotid plaques were clearly detected by 18FDG-PET at 180–200 min post injection. In one patient with bilateral disease, there were significant differences in the accumulation of 18FDG between the asymptomatic and symptomatic carotid lesions. Histology revealed heavy macrophage infiltration of all plaque specimens. In the in vitro experiments, phosphor imaging showed uptake of 18FDG into excised plaque, predominantly in regions of macrophage infiltration. There was no uptake in plaque specimens devoid of inflammatory cells. This study provides strong evidence that 18FDG-PET imaging can identify unstable carotid atherosclerotic lesions, and may have a role in identifying patients at high risk for stroke. It also demonstrates a novel approach to atheroma imaging in general, based on the cellular pathology of the disease process rather than its anatomical consequences.
11.35 a.m. (11)
E.M. EL-Omar1, K.E.L. McColl2, W.-H. Chow3, J. Fraumeni Jr3, C. Rabkin3. 1Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, 2Department of Medicine and Therapeutics, University of Glasgow, Glasgow, 3Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA. Cytokine gene polymorphisms and increased risk of gastric cancer
Helicobacter-pylori-induced gastritis is an essential early step in the multi-stage pathway to gastric cancer (GC). The distribution and severity of this gastritis determines the clinical outcome. The pro-inflammatory cytokines IL-1ß and TNF are both inhibitors of acid secretion and key mediators of the host's response to the infection. We examined whether genetic polymorphisms in the IL-1 and TNFA genes influence risk of GC and its presumptive precursors hypochlorhydria and gastric atrophy (HC/ATR). We genotyped four IL-1 loci (IL-1B-511, IL-1B-31, IL-1B+3954, and IL-1RN), and one TNFA locus (TNFA-308) in (1) H.-pylori-infected GC relatives (GCR) with HC/ATR (n=45) vs. those without (n=58), and (2) GC patients (n=366) vs. population controls (n=429). The IL-1ß-enhancing genotypes IL-1B-511/-31T+ and IL-RN*2/*2 were associated with greatly increased risk of HC/ATR, with age-adjusted odds ratios (OR) of 8.1 (95% CI 1.8–37) and 4.5 (95% CI 1.5–14), respectively. The same genotypes also increased the risk of GC with ORs of 1.9 (95% CI 1.5–2.6) and 3.7 (95% CI 2.4–5.7), respectively. The TNFA-308 locus had a similar but weaker effect, with the pro-inflammatory allele 2 increasing the OR for HC/ATR and GC (OR for HC/ATR=3.2, 95% CI 1.3–8.0; OR for GC=1.6, 95% CI 1.2–2.1). The combined population attributable fraction of GC due to the pro-inflammatory IL-1 and TNFA genotypes was 52%.
We have demonstrated at least two susceptibility loci in the IL-1 gene cluster and one in the TNFA gene for GC and its precursors. These loci influence an early stage of the disease process, and require the presence of H. pylori infection. Our demonstration of genetic variation in risk validates the most widely-accepted multi-stage aetiology proposed for GC, and provides clear evidence of multi-locus genetic interaction in causing this disorder.
12.00 noon (12)
N.W. Morrell (introduced), P.D. Upton (introduced), X. Yang (introduced), K.B. Jourdan (introduced), S. Stewart (introduced), C. Atkinson (introduced), R.C. Trembath1. Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, and 1Department of Medical Genetics, University of Leicester. Role of TGF-ß superfamily receptors in the pathogenesis of primary pulmonary hypertension
Primary pulmonary hypertension (PPH) is a devastating condition resulting from obliteration of small pulmonary arteries. We (RCT) have recently demonstrated that heterozygous germline mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-ß (TGF-ß) superfamily, underlie familial and sporadic (
26%) cases of PPH (Nat Genetics 2000; 26:81–4). Since the cellular localization of BMPR-II in the lung is unknown, we studied the expression of BMPR-II, and type I and II receptors for TGF-ß (TGF-ßRI and TGF-ßRII) by immunohistochemistry and in situ hybridization. BMPR-II, TGF-ßRI and TGF-ßRII were mainly localized to endothelial cells in the normal pulmonary vasculature, with weaker focal staining of the tunica media. However, in PPH cases, BMPR-II expression was also prominent within plexiform lesions and on myofibroblasts comprising concentric intimal lesions in small pulmonary arteries. The expression profile of TGF-ß superfamily receptors was further characterized by RT-PCR in primary cultures of pulmonary-artery smooth-muscle cells (PASMCs), revealing mRNA transcripts for type I (TGF-ßRI, ActRI, Alk-1, BMPR-IB) and type II (TGF-ßRII, BMPR-II, ActRII, ActRIIB) receptors. The presence of TGF-ß superfamily signalling pathways in these cells was confirmed by demonstration of ligand-stimulated activation of signalling Smad proteins, using confocal microscopy. In addition, we determined that PASMCs isolated from patients with PPH, some of which harbour BMPR-II mutations, exhibit abnormal growth responses to TGF-ß1 and BMPs 2, 4 and 7, compared with cells from normal subjects or patients with secondary pulmonary hypertension. The cellular localization of BMPR-II to key cell types within vascular lesions in PPH supports the suggestion from genetic studies that mutations in this receptor play a causal role in PPH. In addition, the abnormal growth responses to TGF-ß1 and BMPs suggest that altered integration of TGF-ß superfamily growth signals may underlie the pathogenesis of PPH.
12.25 p.m. (13)
K. Raza, A. Filer, D. Carruthers, J. Gardner-Medwin, J. Townend (introduced), P.A. Bacon. Departments of Rheumatology and Cardiology, University of Birmingham, Birmingham B15 2TT. Endothelial dysfunction in primary vasculitis—a model for atherosclerosis?
We previously hypothesized that vasculitis was a major factor in the increased CVS mortality of RA. Our recent studies of vascular responses in primary systemic vasculitis (1°SNV), using endothelial-dependant vasodilatation, suggest that widespread endothelial cell dysfunction (ECD) provides a mechanism for initiation of atherosclerosis.
A preliminary cross-sectional study of brachial artery responses showed that ECD similar to that in established atheromatous heart disease occurs in 1°SNV (Raza et al. Circulation 2000; 102:1470–2). In classic PAN, this might be explained by direct inflammatory vasculitis in the muscular arteries. However, a similar degree of significantly depressed ECD (p=0.0001 vs. controls) was seen in Wegener's granulomatosis (WG). A prospective study of ANCA-associated vasculitis (AA.SV), largely affecting small blood vessels, showed that ECD occurs diffusely, distant from active inflammation, and led to two further studies. The first examined endothelial responses in small forearm skin vessels, and again found significantly depressed results in both PAN and AA.SV. The second examined the relationship of ECD to disease activity in a serial study of 12 SNV patients with disease flare, when repeat scans after remission showed significant normalization. Thus, ECD does not always represent fixed damage, although it does persist in stable disease.
Endothelial injury, or dysfunction, is regarded as the initial event in atheroma, leaving the endothelium susceptible to further insult from inflammation or classical risk factors. The diffuse ECD documented here in 1°SNV could be the initiating event in the accelerated CVS events in RA. In support of this, we find similar ECD in both RA and SLE. These results further predict that atheroma will be common in 1°SNV, a hypothesis we are currently testing. Thus SNV provides a model to study the early development of atheroma, where the initiating event is normally hidden in the mists of time.
3.00 p.m. (14)
G.F. Hoyne and J.R. Lamb (introduced by C. Haslett). Immunobiology Group, Respiratory Medicine Unit, MRC Centre for Inflammation Research, University of Edinburgh Medical School, Edinburgh EH8 9AG. Notch signalling facilitates the development of peripheral T cell tolerance
The induction of tolerance is essential for the maintenance of tissue homeostasis; a breakdown in the normal regulatory mechanisms that operate in the periphery can lead to the development of allergic and autoimmune diseases. Regulatory CD4+ T (Tr) cells play an important role in both the induction and maintenance of tolerance to self and foreign antigens, but little is known about the signals that direct naïve T cells to become Tr cells. Notch, which functions as a transmembrane receptor, can bind to distinct ligands Delta and Serrate. Notch signalling is important in regulating cell fate decisions during embryogenesis. We have now shown that peripheral T cells are also sensitive to the effects of Notch signalling. The presentation of antigen by APCs expressing Notch ligand can induce naïve CD4+ T cells to differentiated as TR cells, and this leads to the development of long-lived antigen-specific tolerance. Expression of Notch ligand on T cells also leads to tolerance to both soluble proteins and allogeneic transplantation antigens. Further, in a murine model of respiratory mucosal tolerance, the induction of tolerance was preceded by a transient activation of CD4+ T cells that gives rise to the development of CD4+ T cells. The induction of tolerance coincides with the secretion of the immunoregulatory cytokine IL-10 by T cells and the ability of the cells to signal through the Notch pathway. Moreover, naturally-occurring CD4+ Tr cell populations constitutively express transcripts for IL-10 and Notch ligands. Thus, it appears that a combination of signals including ligation of the TCR and IL-10 receptors enables activated T cells to signal through Notch, and it is this combination of signals that is required for Tr cell differentiation. Further dissection of the Notch signalling pathway in T cells is likely to provide novel therapeutic targets for the treatment of a diverse range of diseases, including allergy, autoimmunity and transplant rejection.
3.25 p.m. (15)
I.B. McInnes (introduced), J.A. Gracie (introduced), B.P. Leung (introduced), X.-Q. Wei (introduced), F.Y. Liew (introduced), R.D. Sturrock. Centre for Rheumatic Diseases and Department of Immunology, University of Glasgow, Glasgow. IL-18—a novel pro-inflammatory cytokine in rheumatoid arthritis (RA)
Identification of mechanisms that promote TNF production in RA synovial membrane will be of crucial importance in identifying new therapeutic targets. IL-18 is a novel cytokine that can promote T-cell and macrophage activation. We have explored the hypothesis that IL-18 promotes synovial inflammation, particularly through TNF production.
IL-18 in both pro- and active forms, and IL-18 receptor, were present in RA synovial. IL-18-induced TNF production in RA synovial cultures that was enhanced by addition of IL-12 and IL-15. Cell-subset analysis revealed that IL-18 promoted TNF production either directly through IL-18R on synovial macrophages or indirectly, through synergistically enhancing cognate interactions between T cells/macrophages. IL-18 administration to DBA/1 mice immunized with type II collagen (CII) in incomplete Freund's adjuvant (FA) promoted development of erosive inflammatory arthritis, comparable in severity to that in CII/complete FA-immunized controls. This was associated ex vivo with high levels of TNF production and development of a Th1 response. To determine the effect of IL-18 deficiency, we generated ‘IL-18-knockout’ DBA/1 mice, which developed CIA of significantly reduced incidence/severity compared with heterozygote or wt littermates. CII-specific immune responses ex vivo were suppressed in both T-cell and humoral compartments. CIA could be reinstated by administration of IL-18 in vivo, with complete restoration of CII-specific immune responses.
Together these data indicate that IL-18 is expressed and mediates pro-inflammatory functions in vitro in human synovial tissues and in vivo in the CIA model. In particular, it can effectively promote TNF production. As such, IL-18 represents an exciting novel therapeutic target in RA.
3.50 p.m. (16)
W.J.H. Griffiths (introduced), W.S. Sly1 (introduced) and T.M. Cox, Department of Medicine, University of Cambridge, Cambridge CB2 2QQ. 1St Louis University School of Medicine, MO 63104, USA. Functional and molecular studies of the intestinal iron transport defect in haemochromatosis
Hereditary haemochromatosis is caused by increased absorption of iron, and is linked to disabling mutations in the HFE gene, homozygosity for which occurs in 0.4% of Europeans. To examine potential interactions between HFE and proteins of iron transport, we raised antibodies to peptide sequences within HFE, and to the divalent metal transporter DMT1. Using human CaCo-2 cells with a small intestinal phenotype, we found by fluorescent laser confocal microscopy that endogenous DMT1 and HFE molecules localize to distinct endosomal compartments, but that HFE protein interacts with vesicles containing a transferrin receptor sub-class. HFE may signal requirements for epithelial uptake by DMT1, whose cognate mRNA harbours an iron-response element that regulates its translation. To investigate the functional effects of reduced HFE expression, we determined unidirectional iron uptake by small intestinal mucosa from wild-type and age- and sex-matched HFE-knockout mice that develop iron storage. Uptake of ferrous iron was enhanced at all six concentrations (3.5–450 µM). Apparent Vmax was 29.8±4.6 (compared with 13.0±1.0 pg atom/min/mg, n=6, p<0.001) in HFE-KO mice, but was reduced by DMT1 antibody: pre-treatment of HFE mucosa with antibody reduced uptake to below the rates of wild-type mucosa pre-treated with avian control IgG (p<0.02). Uptake at low concentrations of ferric iron was increased in HFE-KO mice, and studies with the Fe (II)-specific chelator ferrozine showed that mucosal ferrireductase activity, which was saturated at low iron concentrations, reduced Fe (III) to Fe (II) for uptake via DMT1. Uptake at higher concentrations of ferric iron appeared not to involve DMT1, and was independent of HFE genotype. Increased expression of DMT1 carriers suggested by the kinetic studies was confirmed by a two-fold increase in immunoreactive DMT1 protein in mucosal extracts from HFE-KO mice compared with wild type, by competitive ELISA (p<0.01). Disruption of the HFE gene up-regulates intestinal DMT1 transporters and enhances uptake of ferrous iron by this mechanism; DMT1 also mediates increased uptake after reduction of ferric iron presented at physiological concentrations.
4.45 p.m. (17)
A.D. Struthers, C. Farquharson (introduced), K.M. Yee (introduced), G. Lyles (introduced), S.D. Pringle (introduced). Department of Clinical Pharmacology and Therapeutics and Department Cardiology, Ninewells Hospital, Dundee. Aldosterone-induced vasculopathy: a new entity to explain why spironolactone reduces deaths in heart failure
In the RALES trial, aldosterone blockade reduced mortality by 30% in patients with chronic heart failure (CHF). If we can understand the mechanisms behind this effect, then we will be able to see whether aldosterone blockade is likely to produce similar benefits in other cardiovascular diseases.
In our first study, aldosterone produced endothelial dysfunction even in normal individuals. In tissue culture, aldosterone also reduces NO produced by vascular cells. Correspondingly, spironolactone improved vascular endothelial dysfunction (177% vs. 95% p<0.001) and NO bioactivity (-35% vs. 18% p<0.05) in patients with chronic heart failure (CHF).
One of the questions which arises is whether these beneficial vascular effects of spironolactone are really due to aldosterone blockade, or whether they are due to K/Mg retention within the body. To establish this, we did an analogous study with amiloride. Despite increasing serum K by the same amount as spironolactone, amiloride had no significant effects on endothelial function or NO bioactivity.
Beneficial vascular effects often also translate into beneficial autonomic effects. We found this to be the case in two studies. Firstly, aldosterone clearly blunted the normal baroreflex response to phenylephrine in man. Secondly, spironolactone improved heart rate variability in patients with CCF.
In conclusion, aldosterone produces its own vasculopathy, adversely affecting endothelial nitric oxide. This effect even leads to abnormal baroreflex sensitivity and worse sympathovagal balance. These mechanisms are very likely to underlie the benefits seen in the RALES study, and suggest that similar benefits on mortality may well be seen after aldosterone blockade in a wide range of other cardiovascular diseases. A HOPE-type trial using aldosterone blockade is now warranted to see if aldosterone blockade produces the same benefits in vascular patients as ramipril did in HOPE.
5.10 p.m.
Dr Martin Eastwood, Retired Consultant Gastroenterologist, Western General Hospital, Edinburgh, and retired Reader, University of Edinburgh. The History of Medicine Lecture—Edinburgh medicine: the most recent 350 years
Demonstrations
- TOXBASE—clinical management of poisoning on-line: the first years experience. DN Bateman, AM Good, CA Kelley, WH Laing. Scottish Poisons Bureau, Royal Infirmary of Edinburgh.
- Designing drugs to inhibit verotoxin: receptor interactions. G Browne, S Flitsch, M Walkinshaw, AN Turner. Renal Unit, Royal Infirmary of Edinburgh and Institute of Cell, Animal and Population Biology, University of Edinburgh.
- Regulation of the transcription factors AP-1 and NF-kB in human lung in smoking related diseases. A Crowther, I Rahman, W Macnee. Respiratory Medicine, ELEGI Colt Research Labs, Department of Medical and Radiological Sciences, University of Edinburgh.
- Management of Graves' disease in pregnancy. A Don-Wauchope, O Herlihy, GJ Beckett, AD Toft. Endocrine Clinic and University Department of Clinical Biochemistry, Royal Infirmary of Edinburgh.
- Clearance of apoptotic cells regulates macrophage killing of leucocytes and resident glomerular cells. J Duffield, S Brown, J Savill. Inflammation Repair Group, University of Edinburgh/MRC for Inflammation Research.
- Randomized controlled study of MRS vs CPAP therapy for the sleep apnea/hypopnea syndrome. HM Engleman, D Graham, J McDonald, G Lello, NJ Douglas. Scottish National Sleep Centre, University of Edinburgh, Royal Infirmary of Edinburgh.
- Randomized placebo controlled trial of CPAP on blood pressure in the sleep apnea/hypopnea syndrome. JF Faccenda, TW Mackay, NA Boon, NJ Douglas. Scottish National Sleep Centre, University of Edinburgh, Royal Infirmary of Edinburgh.
- Cognitive and structural abnormalities of the brain in young patients with type 1 diabetes: effects of severe hypoglycaemia and microvascular disease. SC Ferguson, RJ McCrimmon, A Blane, J Wardlaw, P Perros, JJK Best, IJ Deary, BM Frier. Department of Diabetes, Royal Infirmary of Edinburgh.
- Glucocorticoid potentiation of macrophage clearance of cells dying by apoptosis. J Gilmour, G Thomas, S Brown, KE Chapman, JR Seckl, J Savill. Inflammation Repair Group, University of Edinburgh/MRC Centre for Inflammation Research and Molecular Medicine Centre, University of Edinburgh.
- Dose response and time course characteristics of the cutaneous response to ultraviolet radiation in relation to the melanocortin 1 receptor mutation. T Ha, N Flanagan, JL Rees. University of Edinburgh and University of Newcastle.
- Factors modulating cell death and proliferation in tubulointerstitial renal disease. J Hughes, V Ophascharoensuk, M Mazzali, R Krofft, S Shankland, RJ Johnson. Inflammation Repair Group, University of Edinburgh/MRC Centre for Inflammation Research and University of Washington, Seattle.
- Exercising with severe lung disease: physiological adaptations in cystic fibrosis. JA Innes, AP Greening, J Lenney. Respiratory Medicine Unit, Western General Hospital and University of Edinburgh.
- A ten year audit of secondary prevention in coronary bypass patients: identifying a forgotten population. J Irving, H Oram, J Boyd, P Rutledge, F McRae, P Bloomfield. Department of Cardiology, Royal Infirmary of Edinburgh.
- Tissue-specific autoantigens are expressed in human thymus. M King, D Wong, RG Phelps, AN Turner. Autoimmunity Group, University of Edinburgh/MRC Centre for Inflammation Research.
- Integrin suppression by a novel RAS mediated pathway. Y Lad, T Sethi. Lung Inflammation Group, University of Edinburgh/MRC Centre for Inflammation Research.
- The effects of acute insulin-induced hypoglycaemia on attention and intelligence in humans. V McAulay, SC Ferguson, IJ Deary, BM Frier. Department of Diabetes, Royal Infirmary of Edinburgh.
- Tissue factor induction in a whole blood model: potencies of different bacterial lipopoly-saccharides. JM McIlroy, D Stirling, IR Poston. Haemophilia and Thrombosis Centre, Department of Haematology, Royal Infirmary of Edinburgh.
- Assessment of endothelial function in remodelled atherosclerotic coronary arteries. AL McLeod, DE Newby, DB Northridge, KAA Fox, NG Uren. Department of Cardiology, Royal Infirmary of Edinburgh.
- Impaired endogenous fibrinolysis: explanation for the smoker's paradox. DE Newby, AL McLeod, NG Uren, LL Flint, CA Ludlum, KAA Fox, DJ Webb, NA Boon. Department of Cardiology, Royal Infirmary of Edinburgh.
- Acute liver failure serum reduces hepatocyte-matrix adhesion by a cell-death independent mechanism. PN Newsome, J Tsiaoussis, LKJ Nelson, I Ansell, JA Ross, T Sethi, PC Hayes, JN Plevris. Liver Unit, Royal Infirmary of Edinburgh.
- Twenty year comparison of a Bjork-Shiley mechanical heart valve with porcine bioprostheses. H Oxenham, P Bloomfield, DJ Wheatley, RJ Lee, J Cunningham, RJ Prescott, HC Miller. Departments of Cardiology and Cardiac Surgery, Royal Infirmary of Edinburgh and the Medical Statistics Unit, University of Edinburgh.
- Linkage disequilibrium mapping and SNP analysis of the human melanocortin 1 receptor. AJ Ray, RM Harding, JL Rees. University of Newcastle, University of Oxford and University of Edinburgh.
- Differential regulation of inflammatory cell apoptosis and augmented non-phlogistic removal of apoptotic cells by phagocytes as a potential therapeutic target. AG Rossi, C Ward, J Murray, MC Martin, S Fujihara, KM Giles, J Sarma, L Murray, E Taylor, I Dransfield, C Haslett. Lung Inflammation Group, University of Edinburgh/MRC Centre for Inflammation Research.
- Dysfunctional signal transduction and abnormal nitric oxide production in the pathogenesis of psoriasis. E Sabin, M Jackson, R Weller, SEM Howie, RC Mackenzie. Departments of Medical and Radiological Sciences and Pathology, University of Edinburgh.
- A novel gamma chain mutation in a symptomatic family with hypodysfibrinogenaemia. A Sefcick, D Stirling, CA Ludlum. Department of Haematology, Royal Infirmary of Edinburgh.
- Stem cell factor attentuates liver injury induced by paracetamol but not Fas ligation. KJ Simpson, CM Hogeboam, DJ Harrison, C Bone-Larsen, SL Kunkel, NW Lukacs. Division of Clinical and Surgical Sciences, University of Edinburgh, Department of Pathology, University of Michigan, USA and Cell Injury and Apoptosis Group, University of Edinburgh/MRC Centre for Inflammation Research.
- Vascular endothelial cells are a major source of factor VIII mRNA expression. D Stirling, H Pearson, CA Ludlum. Haemophilia and Thrombosis Centre, Department of Haematology, Royal Infirmary of Edinburgh.
- The notch ligand delta-1 regulates CD4+T cell proliferation and survival. K Tan, J Lamb, G Hoyne. Immunobiology Group, University of Edinburgh/MRC Centre for Inflammation Research.
- Haemodynamic effects of acute and chronic administration of low dose carvedilol, a vasodilating betablocker in patients with cirrhosis and portal hypertension. D Tripathi, G Therapondos, HF Lui, AJ Stanley, PC Hayes. Liver Unit, Royal Infirmary of Edinburgh.
- Proteolysis inducing factor contributes to the inflammatory response by regulating monocyte gene expression via NF-kB. T Watchorn, I Waddell, JA Ross. Molecular Immunology Group, Department of Clinical and Surgical Sciences, University of Edinburgh and CV and GI Discovery Department, Astra Zeneca, Macclesfield.
- Insulin does not mediate the effects of fat or carbohydrate consumption on post-prandial haemodynamics or fibrinolysis. F Witherow, AHM Reid, AD Flapan. Department of Cardiology, Royal Infirmary of Edinburgh.
- Peripheral and systemic vascular effects of bradykinin in healthy volunteers and patients with heart failure: influence of angiotensin coverting enzyme inhibition. FN Witherow, DE Newby, DJ Webb, KAA Fox. Department of Cardiology, Royal Infirmary of Edinburgh.
- Cystic fibrosis: the value of non-invasive monitoring of airways inflammation by markers in exhaled breath and breath condensate. F Wood, M Davis, D Porteous, JA Innes, AP Greening. Respiratory Medicine Unit, Western General Hospital and Gene Therapy Group, University of Edinburgh/MRC Centre for Inflammation Research.
- Unravelling antigen processing. J Zhou, AN Turner, RG Phelps. Autoimmunity Group, University of Edinburgh/MRC Centre for Inflammation Research.
- Mechanotransduction pathways in chondrocytes are altered in osteoarthritis. SJ Millward-Sadler, MO Wright, G Nuki, DM Salter. Departments of Pathology, Biomedical Sciences and Medical Sciences, University of Edinburgh and the Cell Injury and Apoptosis Group, University of Edinburgh/MRC Centre for Inflammation Research.
- Vasculitis assessment for European studies. R Luqmani, P Bacon, D Jayne, K Westman, N Rasmussen. Rheumatology Unit, Department of Medical Sciences, Western General Hospital.
- Altered metabolism of glucocorticoids within the blood vessel wall provides a new explanation for endothelial dysfunction in hypertension. PWF Hadoke, C Christy, CJ Kenyon, JJ Mullins, JR Seckl, BR Walker. Department of Molecular Endocrinology, Molecular Medical Centre, Western General Hospital, Edinburgh.
- Tissue-specific changes in 11b-hydroxysteroid dehydrogenase type 1 in obesity offer a novel therapeutic target for lowering intra-adipose cortisol concentrations. R Andrew, DEW Livingstone, N Morton, JJ Mullins, JR Seckl, BR Walker. Department of Molecular Endocrinology, Molecular Medicine Centre, Western General Hospital, Edinburgh.
- Glucocorticoid receptor expression is programmed by events in early life: an explanation for the association between low birthweight and adult cardiovascular risk. MJ Nyirenda, ME Cleasby, RM Reynolds, L Welberg, P McKeiguye, H Lithell, BR Walker, JR Seckl. Department of Molecular Endocrinology, Molecular Medicine Centre, Western General Hospital, Edinburgh.
- Expression profiling of endothelial cells reacting on oxidized LDL mediated injury. PA Henriksen, C Haslett, DJ Webb, JM Sallenave, Y Kotelevtsev. Department of Medical & Radiological Sciences, University of Edinburgh.
- Identification of genes participating in the renal response to chronic aldosterone excess: novel candidate genes involved in blood pressure control. HJL Pearson, G Graham, RW Brown. Department of Molecular Endocrinology, Department of Medical Sciences, Western General Hospital.
- Classification of arterial plaque by analysis of Radiofrequency Intravascular Ultrasound data. RJ Watson, F Davidson, KAA Fox, WN McDicken. Cardiovascular Research Unit, Department of Cardiology, Royal Infirmary of Edinburgh and Medical Physics, University of Edinburgh.
- Is uric acid an independent risk factor in cardiovascular disease? WS Waring, DJ Webb, SRJ Maxwell. Clinical Pharmacology Unit Department of Medical Sciences, Western General Hospital, Edinburgh.
- Investigation of the role of the endothelin system in the regulation of vascular tone and regional haemodynamics by conditional knockout of the mouse endothelin B receptor. A Bagnall, DJ Webb, Y Kotelevtsev. Wellcome Trust CVRI, Department of Medical Sciences, Western General Hospital.
- p53 and pRb deficiency in hepatocytes: Cre-Lox technology and adenovirus-mediated deletion of the retinoblastoma gene. S Prost, S Sheahan, M Vooijs, A Berns, DJ Harrison. Department of Pathology, University of Edinburgh.
- Are systematic reviews ‘good science' or ‘just dirty secondary research’? Evidence from the Cochrane Stroke Group. P Sandercock, H Fraser, B Thomas, A McInnes, J Kwan, G Counsell. Department of Clinical Neurosciences, Western General Hospital, Edinburgh.
- Novel ruthenium (RuII) organo-metallic complexes: in vitro cytotoxicity in wild type and ‘drug resistant’ human cancer cell lines. DI Jodrell, J Cummings, RE Aird, R Hayward, R Morris, H Chen, P del Socorro Murdoch, PJ Sadler, JF Smith. ICRF Oncology Unit, Western General Hospital, Edinburgh.
- Venous occlusion plethysmography: a pharmacodynamic measure in the clinical development of the novel anti-cancer agent, antagonist G, a broad spectrum neuropeptide growth factor antagonist. S Clive, D J Webb, A MacLellan, J Smith, DI Jodrell. ICRF Oncology Unit and Clinical Pharmacology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh.
- Peripheral vascular tone in patients with cirrhosis: Role of the renin-angiotensin and endothelin systems. A Helmy, DE Newby, R Jalan, PC Hayes, DJ Webb. Liver Unit, Department of Medicine, Royal Infirmary of Edinburgh and Clinical Pharmacology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh.
- Prions and the gut. AN Shmakov, J Bode, S Ghosh. Gastroenterology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh.
- Intestinal epithelial cell culture. M Aldhous, S Ghosh. Gastroenterology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh.
- Genetics of inflammatory bowel disease: progress and perspectives. J Satsangi. Gastroenterology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh.
- Physiological characterization of cardiac hypertrophy development and regression in transgenic hypertensive rats. A Ryding, M Denvir, JJ Mullins. Molecular Physiology, Wellcome Trust CVRI, University of Edinburgh.
- Studies of recombinant prorenin uptake in the coronary vasculature of rats. A Ryding, J Paterson, JJ Mullins. Molecular Physiology, Wellcome Trust CVRI, University of Edinburgh.
- Malignant vascular injury in transgenic rats. T Colledge, S Fleming, J Savill, JJ Mullins. Molecular Physiology, Wellcome Trust CVRI, University of Edinburgh.
- CSF tau protein in dementia. A Green. CJD Surveillance Unit, University of Edinburgh, Western General Hospital.
- Raised CSF concentrations of brain-specific proteins in patients with sporadic and variant Creutzfeldt-Jacob disease. A Green, EJ Thompson, M Zeidler, G Stewart, MA Macleod, RSG Knight, RG Will. CJD Surveillance Unit, University of Edinburgh, Western General Hospital and National Hospital, Queen Square, London.
- Prion protein isoform analysis in sporadic and variant Creutzfeldt-Jacob disease. MW Head, T Bunn, JW Ironside. CJD Surveillance Unit, University of Edinburgh, Western General Hospital.
- Predicting outcome after stroke: its roles in patient management, clinical governance and randomized trials. M Dennis. Department of Clinical Neurosciences, University of Edinburgh.
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