QJM vol. 97 no. 9 © Association of Physicians 2004; all rights reserved.
Annual General Meeting |
The Ninety-Eighth Annual General Meeting of the Association of Physicians of Great Britain and Ireland 2004
The Ninety-Eighth Annual General Meeting was held in Dublin on Thursday 25 and Friday 26 March 2004. The attendance book was signed by ordinary members and senior members.The President, Professor G. Tomkin, took the chair.
The Minutes of the last Annual General meeting, having been published in the QJM (November 2003), 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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Overseas Ordinary Member
Lai Kar Neng, MBBS, MRCP, MD, FRCPE, MRCPath, FRCP, FRACP, FRCPG, FACP, DSc, FRCPath, Chair Professor and Chief of Medicine, Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong.
Ordinary Members
Atherton, John, BA, MA, BM BCh, MD, FRCP, MRCP, Professor of Gastroenterology, Wolfson Digestive Diseases Centre, C Floor, South Block, University Hospital, Nottingham NG7 2UH.
Bateman, David Nicholas, BSc, MBBS, MRCP, MD, FRCP, FRCPE, Consultant Clinical Toxicologist and Director, Scottish Poisons Information Bureau, Royal Infirmary of Edinburgh.
Black, Graeme Charles Mackinlay, BA (Hons), BM BCh, DPhil, FRCOphth, CCST, Wellcome Trust Senior Research Fellow in Clinical Science, Academic Units of Clinical Genetics and Opthalmology, School of Medicine, University of Manchester, St Mary's Hospital, Hathersage Road, Manchester, M13 OJH.
Bushby, Kate, MB ChB, MSc, MD, FRCP, Action Research Professor of Neuromuscular Genetics, Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ.
Cope, Andrew, BSc, MBBS, ECFMGS, MRCP, PhD, Wellcome Senior Fellow in Clinical Science, Senior Lecturer in Rheumatology and Honorary Consultant Rheumatologist, Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College, London, W6 8LH.
Danesh, John, MB ChB, MSc, DPhil, Professor of Epidemiology & Medicine and Head of Department of Public Health & Primary Care, Institute of Public Health, University of Cambridge, Strangeways Site, Wort's Causeway, Cambridge CB1 8RN.
Denton, Christopher Paul, BSc, MBBS, PhD, MRCP, FRCP, Senior Lecturer in Rheumatology and Honorary Consultant, Centre for Rheumatology, Royal Free Campus, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2QG.
Donnelly, Richard, MB ChB (Hons), PhD, MD, MRCP/FRCP, FRACP, Professor of Vascular Medicine and Associate Dean Faculty of Medicine & Health Sciences, The Medical School, University of Nottingham, Derby City General Hospital, Derby DE22 3DT.
Donnelly, Seamus, MB BCh BAO, MRCPI, MD, FRCPI, Head of Department of Medicine & Therapeutics, University College of Dublin and St Vincent's University Hospital, Elm Park, Dublin 4.
Fisher, Barrie Miles, MB ChB, MRCP, MD, FRCP, Consultant Physician, Department of Diabetes & Endocrinology, Glasgow Royal Infirmary, Glasgow G4 OSF.
Fogarty, Damian Gerard, BSc, MB BCh BAO, MRCP, MD, Senior Lecturer in Renal Medicine/Consultant Nephrologist, Regional Nephrology Unit, Belfast City Hospital, Faculty of Medicine, Queen's University Belfast, Lisburn Road, Belfast BT9 7AB.
Ford, Gary Ashley, BA, MB BChir, MA (Cantab), MRCP, FRCP, Professor of Pharmacology of Old Age, Wolfson Unit of Clinical Pharmacology, Claremont Place, University of Newcastle upon Tyne, NE1 7RU.
Godfrey, Keith, BM, MRCP, PhD, Tenured MRC Clinical Scientist and Honorary Senior Lecturer, MRC Environmental Epidemiology Unit, Southampton General Hospital, Southampton SO16 6YD.
Gregory, John, MD, FRCP, FRCPCH, DCH, MB ChB, T(M) (Paed), Reader in Paediatric Endocrinology & Diabetes, Department of Child Health, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN.
Hingorani, Aroon Dinesh, BA, MBBS, MRCP, MA, PhD, Senior Lecturer and Honorary Consultant, Centre for Clinical Pharmacology, Department of Medicine, UCL, Rayne Building, London WC1E 6JJ.
Howarth, Peter Hugo, BSc, MBBS, MRCP, DM, FRCP, Senior Lecturer in Medicine and Honorary Consultant Physician, Respiratory Cell and Molecular Biology, Infection, Inflammation and Repair Research Division, Southampton General Hospital, Southampton SO16 6YD.
Hudson, Mark, MB ChB, FRCP(E), FRCP, Consultant Physician and Honorary Senior Lecturer, Liver Unit, Freeman Hospital, Freeman Road, High Heaton, Newcastle upon Tyne, NE7 7DN.
Innes, Alastair, BSc, MB ChB, PhD, FRCPE, Consultant Physician, Respiratory Unit, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU.
Johnson, Margaret Anne, MBBS, MD, FRCP, Consultant Physician in General Medicine, HIV/AIDS, Thoracic Medicine and Honorary Senior Lecturer, Department of Thoracic Medicine, Royal Free Hospital NHS Trust, Pond Street, London, NW3 2QG.
Jones, Paul, BSc, MBBS, PhD, MRCP, FRCP, Professor of Respiratory Medicine, St George's Hospital Medical School, Cranmer Terrace, London, SW17 ORE.
Keavney, Bernard, BSc (Hons), BM BCh, MRCP, DM, Senior Lecturer in Cardiology, Freeman Hospital, High Heaton, Newcastle Upon Tyne, NE7 7DN.
Khan, Michael BSc, MBBS, MRCP, PhD, FRCP, Head of Molecular Medicine, Biomedical Research Institute, Biological Sciences, University of Warwick, Coventry, CV4 7AL.
Lane, Stephen, MB BCh BAO, MRCPI, PhD, FRCPI, FRCP, Consultant Physician in General and Respiratory Medicine, Department of Respiratory Medicine, Adelaide and Meath Hospital, Dublin 24.
Lehner, Paul, BSc, MBBS, MRCP, PhD, FRCP, Wellcome Trust Senior Clinical Fellow and Honorary Consultant Physician, Cambridge Institute for Medical Research, Wellcome Trust /MRC Building, Hills Road, Cambridge, CB2 2XY.
McMullin, Mary Frances, MB BCh BAO, MRCP, MD, MRCPath, Reader and Consultant Haematologist, Department of Haematology, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB.
Mahadeva, Ravi, MBBS, MRCP, MD, Consultant Physician, Respiratory Medicine Unit, Department of Medicine, Cambridge Institute for Medical Research, Wellcome Trust /MRC Building, Hills Road, Cambridge, CB2 2XY.
Mahida, YR, MB ChB, MD, FRCP, Professor in Medicine, University Hospital, Queen's Medical Centre, Nottingham, NG7 2UH.
Mason, Malcolm David, MBBS, MRCP, FRCR, MD, FRCP, Professor of Clinical Oncology, Section of Clinical Oncology & Palliative Medicine, Velindre Hospital, Whitchurch, Cardiff, CF14 2TL.
Mehta, Anil, MBBS, MRCP, MSc, FRCPCH, FRCP, Senior Lecturer and Honorary Consultant Paediatrician, Tayside Institute of Child Health, Ninewells Hospital and Medical School, Dundee, DD1 9SY.
Morris, Andrew David, MB ChB, MRCP MSc, MD, FRCP (Edinburgh and Glasgow), Professor of Diabetic Medicine, Division of Medicine & Therapeutics, Ninewells Hospital, Dundee, DD1 9SY.
Munro, Colin Scott, MA, MB BChir, MRCP, MD, FRCP, Honorary Professor of Dermatology, Department of Dermatology, Southern General Hospital, Glasgow G51 4TF.
Newport, Melanie, MBBS, MRCP, PhD, MRCPCH, Wellcome Trust Advanced Clinical Fellow and Honorary Consultant in Infectious Diseases, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY.
Ng, Leong Loke, MB, MRCP, MD, FRCP, Professor of Medicine & Therapeutics, Department of Cardiovascular Sciences, Leicester Royal Infirmary, Level 4, Clinical Sciences Building, Leicester, LE2 7LX.
Nolan, John, BSc, MB BCh BAO, ACGME, Associate Professor of Endocrinology & Biochemistry, Department of Endocrinology, Hospital Five, St James’ Hospital, Dublin 8.
Ong, Albert, BA, BmBCh, MA, DM, MRCP, FRCP, Senior Lecturer in Nephrology, Academic Nephrology Group, University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield, S5 7AU.
Pavord, Ian, MRCP, FRCP, DM, Consultant Respiratory Physician and Honorary Senior Lecturer, Respiratory Medicine, Glenfield Hospital, Groby Road, Leicester, LE3 9QP.
Pearce, Simon, MBBS, MRCP, RCP, MD, Senior Lecturer in Endocrinology and Honorary Consultant Physician, Institute of Human Genetics, Newcastle University, Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ.
Pitzalis, Constantino, MRCP, PhD, JCHMT, FRCP, Professor of Experimental Rheumatology and Honorary Consultant, Academic Department of Rheumatology, Guy's Hospital, St Thomas’ Street, London, SE1 9RT.
Powis, Stephen Huw, BSc, BM BCh, MRCP, PhD, FRCP, Professor of Renal Medicine & Director, Centre for Nephrology, Royal Free and University College Medical School, Royal Free Campus, University College London, Rowland Hill Street, London, NW3 2PF.
Robinson, Douglas Stewart, MA, MB BChir, MD, FRCP, Reader and Honorary Consultant Physician, Allergy and Clinical Immunology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Dovehouse Street, London, SW3 6LY.
Rosser, Anne, BA PhD, MB BChir, MRCP, Professor of Clinical Neuroscience, Department of Neurology, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN.
Sabroe, Ian, BSc, MBBS, MRCP, PhD, MRC Clinician Scientist Fellow and Reader in Respiratory Medicine, Academic Unit of Respiratory Medicine, Division of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital, Sheffield, S10 2JF.
Spiller, RC, MB BChir Cantab, MSc, MD, Professor of Gastroeneterology, Wolfson Digestive Disease Centre, University Hospital, Nottingham, NG7 2UH.
Stewart, Gordon, BSc, MB ChB, MRCP, MD, Senior Lecturer in Medicine, Department of Medicine, University College London, Rayne Institute, University Street, London, WC1E 6JJ.
Trump, Dorothy, BA (Hons), MD, CCST, Professor of Human Molecular Genetics, St Mary's Hospital, Heathersage Road, Manchester, M13 OJH.
Vyse Timothy James, BA, MBBS, MRCP, PhD, Senior Lecturer and Honorary Consultant, Rheumatology Section, Eric Bywaters Centre, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 ONN.
Williams, Hywel Charles, BSc, MBBS, MRCP, MSc, PhD, FRCP, Foundation Professor of Dermato-Epidemiology, University of Nottingham, Centre of Evidence-Based Dermatology, Queen's Medical Centre, Nottingham, NG7 2UH.
Zumla, Alimuddin, BSc, MB ChB, MSc, MRCP, PhD, FRCP London and Edinburgh, Professor of Infectious Diseases and International Health, Royal Free and University College London Medical School, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London, W1P 6DB.
The new members were welcomed to the Association by the President.
The Honorary Secretary, Professor J.M.C. Connell, confirmed that Professor John Iredale would take over the responsibility as Honorary Secretary for the Association following the Dublin meeting. Professor Connell reminded members that a History of the Association had been commissioned, and anticipated that this would be available for members during the Centenary Year 2006/2007. He reminded members that the meeting in 2005 would be held in Nottingham, and that the Centenary Meeting would be held in London in 2006. He encouraged members to note these dates in their diaries.
The Honorary Treasurer, Professor A.P. Weetman, reported that the accounts of the Association remained in good order. He presented income and expenditure for the 12 months to the end of December 2003. He reminded the new members of the Association that over the last five years, the main strategy has been to reduce the overall balance of the accounts to a sum roughly four times the direct charitable expenditure incurred by the Association. This expenditure is currently running at around £80 000 per year, making a balance of approximately £320 000 desirable.
Income from subscriptions had fallen slightly, as a result of further reconciliation of the membership list with bank payments, when a further set of anomalies had been identified. Members were asked to check their subscriptions were in order. Income from the Oxford University Press from the publication of the QJM had risen by over £10 000, despite a sum of £4000 being made available for promotion. Dr Martyn, Editor of the QJM, had asked the Executive Committee for a sum of up to £10 000 to be set aside for further promotion of the Journal during the forthcoming year and this had been approved. In addition it was likely that the income from QJM sales would fall in the future, not least due to some difficulties the publisher had had with their distributor in the US.
Direct charitable expenditure had risen slightly on Undergraduate Studentships and Intercalated fees, as new Medical Schools came into the annual round. Expenditure on management and administration of the charity had increased slightly in certain areas, but decreased in others.
The most noteworthy figure in this regard, however, was the deficit on the AGM held in Winchester, which unfortunately was £11 036. Professor Weetman reminded the members that the AGM was normally expected to break even, but this meeting had proved more expensive than previous meetings. Both he and Professor Connell had emphasized to organizers of future meetings that deficits should be avoided wherever possible, and the estimates for the present meeting in Dublin looked likely to achieve this outcome.
Another important development was the positive gain on investment assets of £18 653, which contrasted with the loss of £33 437 in the same period in the previous year. At the end of December 2003, therefore, the overall fund balance was £341 332, compared with £316 904 at the end of December 2002. The balance at the end of 2003 was therefore satisfactory and close to the target figure.
In proposing future plans for the finances of the Association, Professor Weetman indicated that he saw no virtue at the present time in raising subscription rates, although the membership had been advised that this might prove necessary at the last AGM. Income from the stock market was difficult to predict, as was income from the OUP, but failure to incur a deficit at the Dublin meeting would help the financial situation. With regard to expenditure, the studentships and intercalated fees continued to prove very popular and Professor Weetman therefore proposed to continue these at the same level for the current cycle. In addition, the response to the Links with Developing Countries Scheme suggested that the current level of expenditure of £20 000 was appropriate for another year. This would bring the charitable expenditure to approximately £85 000 a year, which would be one quarter of the final balance of the accounts at year end. Professor Weetman also pointed out that this was his last year as Treasurer and, by maintaining the status quo, there would be sufficient flexibility for his successor, Professor Connell, to vary both expenditure and subscriptions in the forthcoming years, during which time there would also be the extra expense of researching and publishing the History of the Association.
The members accepted the accounts and the proposals for expenditure.
Dr Christopher Martyn, the Editor, spoke on the affairs of the QJM. He reported that the number of submissions of articles continued to increase. Some 236 unsolicited original papers, commentaries and reviews had been received in 2003, which compared favourably with the 96 articles that had been received in 2000. Use of the QJM website had also increased substantially. There had been about 196 000 web downloads in 2003, which represented a more than doubling of use over the previous year. The QJM's impact factor remained fairly steady at 2.4. Less satisfactory, however, was the falling subscription rate. Currently, there are only 711 institutional subscribers and a negligible number of private subscriptions. Although there has been a corresponding fall in revenue, this has been offset by consortia sales, and the QJM continues to be profitable. Even so, he suggested that it was time to take active measures to promote the journal. This had been discussed at the executive committee meeting of the Association earlier in the year. The committee had agreed that money could be spent to promote the journal at conferences and to offer free trial subscriptions to physicians in other countries. They also agreed that the editorial budget should be increased to allow the Editor to commission more articles for the journal and to purchase pictures and photographs for the cover.
A history of the Association of Physicians had been commissioned, and it was hoped that this would be completed during the Centenary Year of the Association 2006/2007. It is planned that one issue of the QJM in 2006/2007 will be devoted to its publication.
Opening Reception and Annual Dinner
The welcome reception and buffet supper on Thursday evening was held at the House of Lords, College Green, by permission of the Governors of The Bank of Ireland. The Annual Dinner on the Friday was preceded by a reception hosted by the Minister of Health at the Royal College of Surgeons in Ireland. An excellent dinner was provided and the occasion was enjoyed by all.
Scientific Business
Thursday 25th March 2004
2.00–3.00 pm
Professor Peter Humphries, Department of Genetics, Trinity College, Dublin. The Osler Lecture—From the discovery of a gene to understanding the biochemistry of retinitis pigmentosa
3.00 pm (1)
K. Mullan C. Phillips, D. Owens, G.H. Tomkin. Department of Diabetes, Trinity College Dublin and The Adelaide And Meath Hospital, Dublin. Microsomal triglyceride transfer protein and triglyceride-rich lipoprotein metabolism in type 2 diabetes.
The increased atherosclerosis of type 2 diabetes may be due to disturbed postprandial triglyceride-rich lipoprotein metabolism. Microsomal triglyceride transfer protein (MTP) is central to chylomicron and very low density lipoprotein (VLDL) assembly. The present study investigated the role of MTP in type 2 diabetes. Eighty-two type 2 diabetic patients were examined for the common heterozygous –493 MTP G/ T promotor polymorphism. Following a high-fat meal, apo B48, apo B100, cholesterol and triglyceride were measured. Fourteen type 2 diabetic patients from the above group, and 19 controls who were undergoing routine gastroscopy had D2 biopsies and a fat meal 1 week later. Ethics committee approval was obtained and subjects gave informed consent. MTP genotyping was performed by PCR-RFLP. Chylomicron and VLDL Apo B48 and B100 were measured by gradient gel electrophoresis. MTP mRNA was determined using the Rnase protection assay. Thirty-three subjects were heterozygous for the G/ T substitution. LDL cholesterol was significantly lower in these subjects (3.0 ± 0.2 vs. 3.5 ± 0.1 mmol/l, p < 0.02). Apo B48 was significantly higher in the VLDL fraction postprandially (7.0 ± 1.4 vs. 2.9 ± 0.4 µg /ml plasma p < 0.002) with significantly less cholesterol (100 ± 9 vs. 143 ± 16 µg/ml plasma, p < 0.005). Intestinal MTP was significantly greater in diabetic patients compared to controls (p < 0.03) and there was a significant positive correlation between MTP mRNA and chylomicron Apo B48/cholesterol (r = 0.76, p < 0.01) and apo B100/cholesterol (r = 0.5, p < 0.05). This study suggests that MTP plays an important role in the dyslipidaemia of diabetes. The results of the polymorphism study suggest that the common G/ T polymorphism, which has been shown not to effect lipoproteins in non-diabetic subjects, may be anti-atherogenic in diabetic subjects, through its effect on LDL via the production of smaller, cholesterol-poor, apo B48 and B100-containing particles. The increase in MTP mRNA in the diabetic subjects, and the positive correlation with apo B48/cholesterol and apo B100/cholesterol suggests value in searching for an intestinal MTP inhibitor.
3.25 pm (2)
D.J.B. Marks1, M. Harbord1, M. Joshi1, B. Al-Lazikani2, M. Novelli3, S. Bloom1 (all introduced), A.W. Segal1. 1Dept of Medicine, University College London, London, 2Inpharmatica, London, 3Dept of Histopathology, University College London, London. Failure of acute inflammation in Crohn's disease.
Crohn's disease is a chronic inflammatory disorder, thought to result from over-activation of the immune response. Instead, we show that the primary lesion is a failure of acute inflammation.
We investigated the inflammatory response in vivo using skin windows. Cytokine production (IL-8 and IL-1ß) and neutrophil accumulation was reduced in Crohn's patients, although the early mediators of inflammation, including histamine and eicosanoids, were normal. Using a novel serial rectal biopsy technique, neutrophil accumulation and IL-8 production were found to be similarly impaired in the bowel.
We subsequently modelled this situation in vitro, by stimulating macrophages with wound fluid taken from sites of acute surgical trauma and rich in the early inflammatory mediators. When applied to cells from healthy controls, this resulted in IL-8 production. This response was reduced in cells from Crohn's patients.
Next we investigated the influence of polymorphisms in the gene for CARD15, known to increase susceptibility to Crohn's disease. These did not underlie the basal defect in inflammation, but impaired the ability to compensate for a poor response. Application of MDP, the proposed CARD15 ligand, in vivo to skin windows and in vitro to macrophages augmented IL-8, IL-1ß and other pro-inflammatory cytokine production, except in patients carrying the polymorphisms. Importantly, it corrected neutrophil recruitment in skin windows to normal levels only in patients carrying wild-type alleles.
We propose that the underlying defect in Crohn's disease is a weak response to acute tissue trauma. Part of the normal compensation for such impairment involves the CARD15 pathway, which is also defective in some patients. Persistence of undigested matter in the bowel wall consequent to impaired immune clearance probably underlies granuloma formation, and chronic inflammation develops as a secondary phenomenon. This novel theory may be applicable to other granulomatous disorders.
4.15 pm (3)
J. Danesh, J.G. Wheeler, G.M. Hirschfield, S. Eda, G. Eiriksdottir, A. Rumley, G.D.O. Lowe, M.B. Pepys, V. Gudnason. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease.
We report data from the largest prospective study so far of C-reactive protein and other circulating inflammatory markers, as well as updated meta-analyses, to help evaluate their relevance to the prediction of coronary heart disease (CHD).
Measurements were made in the baseline samples of up to 2459 incident cases of non-fatal myocardial infarction or death from CHD and of up to 3969 controls ‘nested’ within the Reykjavik prospective study of 18 569 participants. Paired measurements of inflammatory markers were made, on average, 12 years apart in 379 of these individuals to quantify within-individual fluctuations.
The long-term stability of C-reactive protein values (within-individual correlation coefficient: 0.59 [0.52–0.66]) was comparable to those of blood pressure and total serum cholesterol. After adjustment for baseline values of established risk factors, the odds ratio for CHD was 1.45 (95%CI 1.25–1.68) in a comparison of individuals in the top third vs. those in the bottom third of baseline C-reactive protein values, with similar overall findings in an updated meta-analysis involving a total of 7068 CHD cases. By comparison, the odds ratios for CHD in the present study were probably weaker for ESR (1.30 [1.13–1.51]) and von Willebrand factor (1.11 [0.97–1.27]), but generally stronger for established risk factors such as total cholesterol concentration (2.35 [2.03–2.74]) and cigarette smoking (1.87 [1.62–2.16]).
C-reactive protein is a comparatively moderate predictor of CHD, only about half as strong as that suspected recently. Recommendations on its use in CHD prediction may need to be reviewed.
4.40 pm (4)
A.O.M. Wilkie, A. Goriely, G.A.T. McVean, R.M.S. Hansen, M. Röjmyr, B. Ingemarsson, A.M.M. van Pelt, D.G. de Rooij (all introduced). NDCLS, Weatherall Institute of Molecular Medicine, University of Oxford; Department of Statistics, University of Oxford; Pyrosequencing AB, Uppsala, Sweden; Department of Cell Biology, University of Utrecht, The Netherlands. Paradoxical positive selection of a harmful FGFR2 mutation in the male germline.
Mutation is fundamental to the genetic basis of phenotypic variation and disease, but the processes driving mutation are poorly understood. Work on Apert syndrome, an autosomal dominant congenital malformation characterized by craniosynostosis and syndactyly, has revealed evidence for a new mechanism influencing mutation: paradoxical selective advantage acting in the male germline.
Previously we demonstrated that 
98% of cases of Apert syndrome (birth prevalence 1:70 000) are caused by specific de novo nucleotide transversions, 755C 
G or 758C G, in the gene encoding fibroblast growth factor receptor type 2 (FGFR2). These mutations always (75/75 cases) arise from the unaffected father and are associated with increased paternal age.
Using Pyrosequencing technology, we have now developed a robust method to measure the level of one of these mutations, 755C G, in samples of sperm from normal male donors. We find that most men produce this mutation at measurable levels (maximum of 1:6250); the average level increases with donor age, closely matching epidemiological data on Apert syndrome births.
Moreover, we provide evidence, from analysis of the distribution of mutations on the two FGFR2 alleles in heterozygotes for a nearby single nucleotide polymorphism, that these mutations are rare events that are enriched by clonal expansion in mutated spermatogonial stem cells. This result has implications for diverse fields, including clinical genetics, oncology, stem cell biology and evolution, and could probably only have been discovered from studies of human genetic disease.
5.05 pm (5)
D.G. Parr (introduced), P.J. Guest (introduced), R.A. Stockley. Lung Investigation Unit, University Hospital, Birmingham, UK. Standardized CT densitometry is a valid measure of emphysema progression in COPD.
Emphysema has long been considered an irreversible condition that can only be diagnosed and quantified pathologically. With the development of novel therapies, there is a real potential to repair emphysematous change, but outcome assessment is problematic. Computed tomography identifies low attenuation areas that match pathological areas of emphysema, but quantification to assess progress/resolution requires an accuracy not employed routinely, and there remain concerns regarding the interpretation of radiological data. We have demonstrated that individual scanners generate different data and that body mass influences CT densitometry. We have shown calibration methodology to be critically important in longitudinal and comparative multi-centre studies, and have developed an internal calibration method using air densitometry to overcome these technical difficulties. CT measurements of emphysema relate to the CO2 debt (r = –0.53, p < 0.001), validating the radiological method further against a physiological measure that correlates well with the pathological extent of emphysema (Burrows 1965). Subsequent studies in 119 subjects with 
1-antitrypsin deficiency have shown that the classic description of predominantly basal disease is only a feature in 60%, and that regional differences in the quantity and distribution of emphysema account for physiological differences between patients. Pairs analysis, matching for total emphysema index and age, demonstrated greater FEV1 impairment (% predicted) in basal disease (mean difference 9.94, 95%CI 3.85–16.03, p = 0.002) and greater impairment of KCO (% predicted) (mean difference 6.15, 95%CI 0.17–12.12, p = 0.03) and PaO2 (kPa) (mean difference 0.50, 95%CI 0.03–0.98, p = 0.04) with upper lung involvement, regardless of emphysema severity.
Emphysema distribution was associated with discordance between FEV1 and KCO (r = 0.43, p < 0.001). Notwithstanding this variable relationship, the progression of emphysema on CT scan over 3 years in 39 patients relates to the decline of FEV1 (r = –0.424, p = 0.007) although the sensitivity of different densitometric parameters to progression is variably influenced by disease stage. Our findings have shown the critical importance of air calibration for standardization of cross-sectional and longitudinal CT densitometry studies of emphysema. The data provide compelling evidence of physiological variability between lung regions and validate CT densitometry for measuring emphysema progression and the effects of treatment.
9.00 am (6)
S.R. Walmsley, C. Print, R.S. Johnson, T. Cramer, A.M. Condliffe (all introduced), E.R. Chilvers. Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, CB2 2QQ, Department of Pathology, University of Cambridge and Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA. Hypoxia inhibits neutrophil apoptosis via hypoxia inducible factor (HIF)-1-dependent regulation of NF-
B.
Neutrophils are key effector cells of the innate immune response, and are required to migrate and function within highly adverse micro-environmental conditions. These sites are characterized by low levels of oxygen and glucose and high levels of reductive metabolites. In contrast to its effect in other cell types, we have shown that hypoxia causes a profound inhibition of neutrophil apoptosis, a process that is vital for the efficient resolution of granulocytic inflammation. We sought to establish the cellular basis for this survival effect in particular, to determine the oxygen-sensing mechanism employed, the role of the transcriptional regulator HIF-1 and the target genes involved.
Neutrophils were obtained from human peripheral blood or the bone marrow of myeloid targeted HIF-1 knockout (–/–) or wt mice and cultured under normoxic (19 kPa), hypoxic (3 kPa) or anoxic conditions. Apoptosis was assessed by cell morphology and FACS analysis of AnnexinV/Pi staining. RNA integrity was confirmed by Agilent and samples run on ‘in-house’ apoptosis gene array filters (988 cDNAs). Array findings were confirmed by TaqMan PCR. Immunoprecipitation and SDS-PAGE were employed for protein analysis and ELISA for NF-B activity.
Neutrophils displayed stabilization of HIF-1 under hypoxic/anoxic conditions and following inhibition of the oxygen-sensing prolyl-hydroxylase-domain-containing enzymes (PHDs) with dimethyloxaloylglycine (1 mM). In murine BM neutrophils, HIF-1 protected against cell death following hypoxic challenge with markedly decreased survival in HIF –/– cells. After 6 h culture, human neutrophils showed a significant (p < 0.005) increase in gene expression of GAPDH, MIF and NF-B at reduced oxygen tensions, which was associated with increased NF-B expression and activity. Moreover, the hypoxic survival effect was abrogated by the NF-B inhibitor gliotoxin. In conclusion, hypoxia causes a profound inhibition of neutrophil apoptosis. This is mediated via a PHD/HIF-1-dependent pathway which in turn regulates NF-B expression and activity.
9.25 am (7)
A. Siva1, F. Baker1, D. Picton1, S. Blackwood1, S. Dyas1, M. Erskine1, T.D. Spector2 (all introduced), M.J. Brown1. 1Clinical Pharmacology Unit, University of Cambridge; 2Twin Research Unit, St Thomas’ Hospital. Homocysteine and coronary artery disease: genetic and clinical studies.
Homocysteine (hcy) is an important risk factor for coronary artery disease (CAD), but it is unknown whether hcy itself causes vascular damage or is a marker for other factors. We have investigated this question in two ways. Firstly, we used a classic twin study to estimate the genetic contribution to plasma hcy. Secondly, we undertook a limited outcome trial of hcy reduction in patients with CAD. We measured hcy (HPLC), B12 and folate (RIA) in blood from 1015 female Caucasian twin pairs, 242 monozygotic (MZ) and 773 dizygotic (DZ), aged 18–80 years, from the St Thomas’ Registry. Heritability (h2) was calculated as 2 x (rMZ–rDZ), where r was the correlation coefficient for the residual of hcy regressed upon other relevant variables. h2 was 0.43 for raw data, and 0.57 after correcting for folate, B12 and smoking. In a randomized, double-blind placebo-controlled trial, 1882 patients were enrolled either at the time of a positive coronary angiogram, or during admission to a CCU with an acute coronary syndrome. They were randomly assigned to folic acid 5 mg or placebo for up to 2 years. The composite endpoint was non-fatal myocardial infarction, cardiovascular death, or unplanned revascularization. In two out of four centres, blood was drawn for hcy, folate and B12. Overall, 942 patients on folate and 940 on placebo completed 3181 patient-years (median 1.7 years), and suffered 187 primary endpoints. In a Cox hazard regression analysis, the only predictors of outcome were plasma hcy (RR 1.038, 95%CI 1.015–1.062) and age. Folic acid reduced hcy from 11.2 ± 6.9 to 9.7 ± 5.3 µmol/l, but there was no difference in composite outcome (RR 0.97, 95%CI 0.72–1.29) (p = 0.28 for log-rank test on Kaplan-Meier analysis). There was a two-fold difference in non-fatal myocardial infarction (folate 23, placebo 12, p = 0.05), but no difference in deaths or revascularization. The heritability of hcy is greater than for other major risk factors measured previously in the same twins (blood pressure, LDL), suggesting that hcy is more likely to be a primary cause of CAD than a silent marker of other risks. Our negative finding with folic acid could be due to undesirable inhibition of BH4 synthesis (co-factor for NO synthase), and counsels against use of pharmacological rather than physiological sources of folic acid pending larger outcome trials.
9.50 am (8)
S. George, I. Barroso, J. Rochford, C. Wolfrum, S. Gray, M. Soos, J. Wilson, R. Williams, M. Umpleby, S. Schinner, H. Alban- Davies, D. Barford, M. Stoffel (all introduced), S. O’Rahilly. Departments of Medicine, Clinical Biochemistry and Paediatrics, University of Cambridge, Cambridge, UK; The Wellcome Trust Sanger Institute, Cambridge, UK; The Rockefeller University, New York, NY 10021, USA; Department of Diabetes, Endocrinology and Medicine, St Thomas’ Hospital, London, UK; Darrent Valley Hospital, Dartford, UK; Section of Structural Biology, Institute of Cancer Research, London, UK. Autosomal dominant human insulin resistance and diabetes mellitus due to a missense mutation in AKT2.
Inherited post-receptor defects in insulin signalling have long been suggested to contribute to the development of human insulin resistance and type 2 diabetes mellitus. To date, however, there has been no definitive evidence for this phenomenon. We describe a three-generation family with autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Genotyping revealed a heterozygous missense mutation in the catalytic domain of AKT2. This was present in all affected individuals in the pedigree but in none of the unaffected family members tested or in 1500 control subjects.
This mutation of a very highly conserved residue results in a catalytically inactive kinase that is unable to mediate insulin signalling to metabolic end-points. It also interferes in a dominant-negative fashion with insulin signalling through co-expressed wild-type AKT kinases. These findings establish AKT signalling as essential for the maintenance of insulin sensitivity in humans, and provide the first example of a form of insulin-resistant diabetes mellitus resulting from an inherited defect of post-receptor insulin signal transduction.
10.15 am (9)
M.R. Thursz1, W. Khamri1 (introduced), M. Worku1 (introduced), Q.N. Karim1 (introduced), M.M. Walker1 (introduced), A. Moran2 (introduced), K. Reid3 (introduced), H. Clark3 (introduced). 1Faculty of Medicine, Imperial College, London W2 1NY, 2University of Ireland, Galway, 3Department of Biochemistry, Oxford University. Helicobacter varies LPS antigenic structure to evade surfactant protein D.
Helicobacter pylori, a Gram –ve bacterium, causes chronic gastritis, gastric carcinoma and peptic ulcers. H. pylori infection is invariably persistent, implying that the organism has mechanisms to evade immunological responses. Surfactant protein D (SPD) is a collagenous lectin, a component of innate immune defence. SPD is a pathogen associated microbial pattern receptor, which adheres to carbohydrate structures on the surface of bacteria, viruses and fungi. In Gram –ve organisms, SPD recognizes LPS.
SPD was originally described in the lung, but we have demonstrated its presence in gastric mucosa by RT-PCR and immunohistochemistry. These studies indicate that H. pylori infection is associated with increased levels of SPD expression. SPD was found to bind H. pylori in a lectin-specific manner, leading to agglutination and inhibition of motility.
Binding studies demonstrated wide variation in SPD binding affinity between strains and even between organisms of the same strain. Using the reference laboratory strain J178, an SPD ‘escape variant’ J178v was isolated using several cycles of SPD agglutination, filtration and culture. SPD has a high affinity for J178, but is unable to bind or agglutinate J178v. LPS extracted from J178 and J178v were analysed in a competitive inhibitory ELISA assay: the IC50 for J178 was 5.34 µg/ml compared to 76.4 µg/ml for J178v. Structural analysis using both NMR and a panel of monoclonal antibodies revealed changes in the terminal Lewis X and the degree of fuoscylation in the O chain of the LPS. Sequencing of the LPS biosynthesis genes identified a cytosine insertion in a poly-C tract of the fucosyl transferase I gene leading to a premature stop codon.
Susceptibility to low-dose infection by Helicobacter was increased in SPD –/– mice. Clinical isolates of H. pylori from gastric mucus have higher affinity for SPD than isolates from gastric tissue. It therefore seems likely that SPD susceptible organisms become trapped in mucus and removed by physical clearance.
Therefore this mechanism may protect against low dose infection, but is overwhelmed by larger doses containing a number of SPD ‘escape variants.’ Kinetic studies indicate that the SPD susceptible variants have a counterbalancing advantage in growth rate.
11.10 am (10)
R.S. Drummond, M.J. Brosnan, A. Kirk, C.A. Hamilton (all introduced), J.M.C. Connell, A.F. Dominiczak. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, G11 6NT. Single nucleotide polymorphisms (SNPs) within oxidative stress genes affect arterial compliance in patients with coronary artery disease (CAD): gene-function relationships.
Background: A common NOS3 SNP (894G T) which encodes a Glu298®Asp amino acid substitution in the endothelial NO synthase protein has been associated with cardiovascular disorders in which NO bioactivity is impaired.
The gene coding for p22phox, a critical component of the NADH/NAD(P)H oxidase enzyme system, a major source of vascular SO, is CYBA. Among the allelic polymorphisms reported in CYBA is C242T, associated with progression of coronary atherosclerosis. Consistent characteristic changes in the pressure pulse wave shape have been associated with ageing, risk factors for cardiovascular disease and impaired NO bioactivity. Therefore radial applanation tonometry with pulse waveform analysis (PWA) can be used to quantify arterial compliance as well as dynamic changes in NO bioactivity. We hypothesize that the two SNPs within oxidative stress genes influence vascular compliance in patients with CAD.
Methods: We recruited 100 patients with angiographically documented coronary artery disease. Genotypes were determined with polymerase chain reaction and restriction digestion. Radial artery pressure waveforms were recorded using a calibrated tonometer. Windkessel-based diastolic pressure decay analysis was then used to generate large (C1) and small (C2) artery compliance values. Differences between genotype groups were analysed using unequal variance unpaired Student's t tests.
Results: The distribution of the genotypes in either gene did not differ significantly from that expected under Hardy Weinberg equilibrium. Homozygosity for a common NOS3 polymorphism (894 G T) was associated with decreased small artery 
compliance but not with large artery compliance or blood pressure. In contrast, the CYBA 242T allele was associated with decreased large artery compliance and increased systolic and pulse pressure.
We confirmed our hypothesis that SNPs in the NOS3 and CYBA genes contribute to vascular compliance, thus implicating the PWA as a cardiovascular intermediate phenotype.
11.35 am (11)
M.J. Leandro (introduced), M.R. Ehrenstein (introduced), J.C.W. Edwards (introduced), J. Manson (introduced), G. Cambridge (introduced), D.A. Isenberg. Centre for Rheumatology, University College London, London, United Kingdom. Treatment of refractory lupus nephritis with B lymphocyte depletion.
Purpose: To use full-dose rituximab to treat active refractory renal SLE patients.
Methods: Six F patients were treated. They had failed conventional immunosuppression including IV cyclophosphamide (CYC). Median age was 31 years (17–48). Mean disease duration was 9 years (4–15). All patients had renal involvement (5 WHO class IV, 1 class V), one (patient 2) had severe thrombocytopaenia and haemolytic anaemia. Patients were treated with two doses of 1 g rituximab and two doses of 750 mg IV CYC given 2 weeks apart. Other immunosuppressives were stopped. Prednisolone and hydroxychloroquine were continued.
Patients were assessed for disease activity by the BILAG index. Mean follow-up is currently 9.5 months (range 4–22 months).
Results: All patients improved, with four patients (67%) showing a major improvement. Baseline BILAG global scores were 25, 24, 16, 14, 12 and 20 (mean 19). BILAG global scores at 3 months were 3, 7, 4, 5, 8, and 6 (mean 6), respectively. BILAG global scores at 6 months for patients 1 to 3 were 5, 10, and 3 (mean 6). Creatinine decreased by a mean of 23% at 3 months (range 12%–56%) and a mean of 14% at 6 months (range 0%–28%). Albumin increased by a mean of 30% at 3 months (range 2%–94%) and a mean of 18% at 6 months (range 7%–34%). Urine protein/creatinine decreased by a mean of 63% at 3 months (range 27%–94%) and of 58% at 6 months (range 0%–91%). B cell repopulation of the PB occurred between 4 and 8 months in patients 1–4 (mean 6 months). C3 levels increased by 56% at 3 months (range 11%–106%) and of 29% at 6 months (range 0%–78%). In four patients, C3 serum levels normalized. Anti-dsDNA antibodies decreased by a mean of 66% at 3 months (range 10%–100%) and of 74% at 6 months (range 43%–100%). Treatment was well tolerated: mild neutropenia with fever (1 patient), pyelonephritis (2 patients), low IgM (3 patients), low IgG (1 patient) were noted.
Conclusions: B cell depletion should be considered in active refractory patients, particularly with renal and haematological involvement, although the optimal rituximab dose remains to be established.
12 noon (12)
H. McShane (introduced), A. Pathan (introduced), A.V.S. Hill. Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ. MVA85A, a new vaccine against tuberculosis: Phase I studies.
Tuberculosis (TB) kills about three million people annually and one third of the world are latently infected with Mycobacterium tuberculosis (M. tb). Co-infection with M. tb and HIV and multi-drug-resistant strains of M. tb present major new challenges. The currently available vaccine, M. bovis BCG, is largely ineffective at protecting against adult pulmonary disease in endemic areas, and a more effective TB vaccine is a major global public health priority. However, as BCG does confer worthwhile protection against TB meningitis and leprosy, it may be unethical and impractical to test and deploy a vaccine strategy that does not include BCG. Protective immunity against M. tb is dependent on an intact cellular immune system.
Both Class-II-restricted CD4+ and Class-I-restricted CD8+ T lymphocytes are necessary for protection. Although several vaccine delivery systems are capable of inducing T cells, when used alone these delivery systems induce only low-level responses. Heterologous prime-boost immunization strategies involve immunizing with two different vaccines, each expressing the same antigen, several weeks apart. These strategies induce higher levels of CD4+ and CD8+ T cells than homologous boosting strategies. We have evaluated a prime-boost strategy, using BCG as a priming immunization and recombinant modified vaccinia virus Ankara expressing antigen 85A (MVA85A) as a boost. MVA is an attenuated vaccinia virus that does not replicate in human cells. Antigen 85A is an immunodominant antigen, conserved amongst all mycobacterial species. This BCG prime-MVA85A boost is immunogenic and protective in the mouse, guinea pig and macaque model of TB.
We are evaluating the safety and immunogenicity of MVA85A in a series of small Phase I studies in healthy volunteers. Currently, this is the only candidate TB vaccine in clinical trials anywhere. We find that MVA85A is safe and induces remarkably high levels of specific effector T cell responses. Vaccinees who received BCG prime-MVA85A boost show even higher levels of antigen specific T cells than those immunized with MVA85A alone. These strategies are currently being evaluated further in a TB endemic area in West Africa.
12.25 pm (13)
R.D.G Leslie, C.-D. Agardh (introduced), C.M. Cilio, Å. Lethagen, K. Lynch, M. Palmér, R.A. Harris, J. Robertson, Å. Lernmark (all introduced). St Bartholomew's Hospital, London, UK; University Hospital MAS, Malmö; St Görans Hospital, Stockholm; Karolinska Hospital, Stockholm; Diamyd Therapeutics AB, Stockholm, Sweden. Alum-formulated human recombinant GAD65 can improve insulin secretion in autoimmune diabetes.
Type 1 diabetes mellitus (T1DM) is due to destruction of insulin-secreting pancreatic cells by an abnormal immune response. At clinical onset, 90% of patients with T1DM have serum autoantibodies, including glutamic acid decarboxylase (GAD) autoantibodies. Such GAD autoantibodies can predict the disease and identify adults with non-insulin-requiring diabetes as the most prevalent form of autoimmune diabetes. Studies of animal models of autoimmune diabetes suggest that GAD autoreactivity is critical. To determine if immunomodulation by administration of alum-formulated human recombinant GAD65 is safe, and to identify a dose for further clinical development we studied non-insulin-requiring diabetic adults with GAD autoantibodies.
The study was a randomized, double-blind, placebo-controlled, group-comparison, dose-escalation study in 47 patients. Patients were allocated into one of four dose groups receiving either placebo or 4, 20, 100 or 500 µg alum-formulated recombinant human GAD65 (Diamyd) administered subcutaneously at intervals and with follow-up over 6 months. There were no relevant adverse events. Using 20 µg, fasting C-peptide increased at 6 months, both when compared to placebo (p = 0.0011) and compared to the initial fasting (36%, p = 0.008) and stimulated (19%, p = 0.016) C-peptide. An effect on T cells was indicated in this group by an increase in the CD4+CD25+/CD4+CD25-ratio (p < 0.05) and, overall, by a correlation in this ‘regulatory’ T cell ratio increase with the increase in fasting C-peptide (r = 0.55; p < 0.001).
The study demonstrates the clinical safety of alum-formulated recombinant human GAD65 (Diamyd) and supports the potential of antigen-specific therapy to prevent autoimmune diabetes.
3.00 pm (14)
B.R. Conway1, A.-J. McKnight1, D.A. Savage1, D.G. Fogarty1, H.R. Brady2, A.P. Maxwell1. 1Nephrology Research Group, Queen's University, Belfast, 2Dept of Medicine and Therapeutics, University College Dublin, the Conway Institute and the Dublin Molecular Medicine Centre. The genetics of diabetic nephropathy: pooling approaches to identify disease susceptibility genes.
A genetic susceptibility to diabetic nephropathy exists, prompting a search for the causal gene variants. Identification of such genes would permit detection of patients with diabetes who are at risk of nephropathy and enable targeting of therapy. We have combined two approaches to find disease susceptibility genes.
Firstly, genome-wide screening with a large number of markers, dispersed across the genome, has been used to detect chromosomal regions that may contain disease susceptibility genes. To undertake such a screen, we combined equal quantities of genomic DNA from Irish type 1 diabetic patients, with and without nephropathy, to generate separate case (n = 200) and control (n = 200) DNA pools, respectively. In collaboration with the MRC Geneservice, Hinxton, each pool was typed for 6000 microsatellite markers distributed at an average density of 0.7 cM throughout the genome. Provisional evidence of association with nephropathy was found in over 100 genomic regions.
A second strategy, suppression subtractive hybridization, was used to identify novel candidate genes. Over 200 genes were differentially expressed in human mesangial cells exposed to high extracellular glucose compared to normal glucose concentrations. Prominent amongst the up-regulated genes was a group coding for proteins that control the actin cytoskeleton, which is disrupted in the diabetic glomerulus.
We searched for genes up-regulated by high extracellular glucose that lie in genomic regions associated with diabetic nephropathy. One such up-regulated cytoskeletal gene, caldesmon, lies at 7q35, a region linked to nephropathy. This gene was comprehensively screened for common DNA polymorphisms by denaturing HPLC and sequencing. A 579A G variant in the promoter region of the gene was associated with type 1 diabetic nephropathy in an Irish case-control study (n = 606). The synergistic approach of genome wide screening and expression studies has generated over 30 novel candidate susceptibility genes.
3.25 pm (15)
A. Dorling (introduced), D. Chen (introduced), R.I. Lechler. Dept. of Immunology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN. Targeted expression of anticoagulants on EC membranes is very effective at inhibiting intravascular thrombosis in systemic endotoxaemia.
Anticoagulants significantly impact the development of pathology in experimental systemic endotoxaemia. However, recent trials of anticoagulants in human sepsis yielded disappointing results and were associated with significant bleeding. We hypothesized that targeted expression of anticoagulants on endothelial cells (EC) should be an efficient and relatively safe way of inhibiting intravascular thrombosis without associated haemorrhagic side effects. Two novel strains of transgenic mice, expressing membrane-tethered human tissue factor pathway inhibitor or hirudin under the control of a modified CD31 promoter, were generated. A short sequence encoding a region of the cytoplasmic domain of P-selectin was incorporated to limit expression to activated membranes. The mice had a normal phenotype. Cell surface expression of the transgenic fusion proteins was confirmed on activated but not resting EC, platelets and leukocytes.
After injection of lipopolysaccharide (LPS), parental strain mice and negative littermates showed markedly prolonged bleeding times, severe depletion of plasma fibrinogen, a profound thrombocytopenia and elevated thrombin-anti-thrombin complex levels, indicative of widespread, uncontrolled, intravascular thrombosis. In contrast, transgenic mice were significantly protected from these changes. Bone marrow reconstitution experiments using lethally irradiated recipients allowed the generation of mice expressing the proteins only on EC or only on platelets and leukocytes. The former remained significantly protected from the profound coagulopathy induced by LPS, whereas the latter showed only minimal protection. Antibody inhibition experiments confirmed a genuine qualitative advantage to expressing the anticoagulants on EC compared to platelets and leukocytes. These results are consistent with our hypothesis. We propose that targeting soluble reagents to activated EC using, for instance, hirudin conjugated to anti-E-selectin antibodies, holds real promise for safe and extremely effective therapy in systemic sepsis.
3.50 pm (16)
F.M. Swords1, A.H. Baig1, M.O. Thorner2 (all introduced), A.J.L. Clark1. 1Department of Endocrinology, St Bartholomew's Hospital, London; 2Department of Medicine, University of Virginia, Charlottesville, VA, USA. Constitutive activity of the ACTH receptor: a novel cause of adrenal hyperplasia and two novel mechanisms of constitutive activity.
Adrenal pathology is increasingly recognized as a cause of hypertension. However, the pathophysiology of non-pituitary-dependant adrenal hyperplasia remains poorly understood, and the search for a definitive adrenal mitogen continues. We have characterized the first two naturally occurring mutations of the ACTH receptor (MC2R) causing constitutive activation, derived from one patient with ACTH-independent adrenal hyperplasia and a second with sub-clinical ACTH hypersensitivity.
Furthermore, we propose two novel mechanisms to underlie this activation. The first mutation results in single amino acid substitution:F278C. Stable Y6 cell lines expressing F278C had a three-fold increase in basal cAMP accumulation compared to those expressing the wild type (WT) MC2R (p < 0.005). F278C continues to bind ACTH with similar IC50 for displacement to the WT, and continues to respond to ACTH with a similar EC50 but with an upward shift in its dose response curve. However, receptor desensitization and internalization were dramatically impaired compared to WT (p < 0.001). This pattern could be partially replicated by pharmacological inhibition of PKA in WT cells, disruption of two serine residues close to the mutation, or the putative PKA phosphorylation site, and suggests that impairing the ability to ‘switch off’ signalling is as damaging as inappropriate ‘switching on’ of a G-protein-coupled receptor. In the second patient two residues, C21R and S247G, were substituted.
In expression studies, either mutation alone led to a loss of ligand binding and responsiveness; however, the presence of both mutations produced a constitutively active receptor (basal activity increased two-fold, p < 0.005) with no response to, or binding of ligand. We propose that both residues are involved in maintaining receptor configuration—presumably tethering of the third extracellular loop with the N-terminal tail. Either mutation alone causes loss of ligand binding and responsiveness. However, in the presence of both mutations, the unconstrained activated conformation is adopted and constitutive activation occurs.
4.45 pm (17)
A.I. Russell1, D.S. Cunninghame Graham1, R.J. Powell2, D.A. Isenberg3, M.J. Walport1, T.J. Vyse1 (introduced). 1Rheumatology Section, Imperial College Faculty of Medicine, Hammersmith Hospital, London W12 0NN, UK, 2Clinical Immunology Unit, Queen's Medical Centre, Nottingham NG7 2UH, 3The Middlesex Hospital, University College London, Arthur Stanley House, Tottenham Street, London W1T 4NJ. Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus.
Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus. The C-reactive protein (CRP) response is defective in patients with acute flares of disease, and mice with targeted deletions of the serum amyloid P component gene (Sap) develop a lupus-like illness. In humans, the genes for CRP (CRP) and SAP (APCS) map to 1q23.2 within an interval linked with SLE. We have investigated the candidate genes CRP and APCS in two cohorts totalling 586 UK simplex SLE families. The inheritance of an intronic dinucleotide repeat and seven single nucleotide polymorphisms in the CRP and APCS genes were examined by application of family-based tests of association and linkage. Basal levels of CRP were influenced independently by two polymorphisms at the CRP locus, CRP 2 and CRP 4. Furthermore, the latter polymorphism was linked/associated with SLE and antinuclear autoantibody production. Thus, the polymorphism associated with reduced basal CRP was also associated with the development of SLE.
These data support the hypothesis that defective disposal of potentially immunogenic material is a contributory factor in lupus pathogenesis. The identification of polymorphisms that determine basal CRP levels have implications in ischaemic heart disease, where CRP level is an important predictor of risk.
5.10 pm
Professor David Powell, Department of Diabetes and Endocrinology, The Mater Hospital, Dublin. History of Medicine Lecture—The history of the Dublin teaching hospitals.
Demonstrations
- Loss of glucose responsiveness in pancreatic beta cells. O’Driscoll L, Gammell P, Clynes M. National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
- Endothelial dysfunction in obese and early onset Type 2 diabetes subjects. McQuaid S, O’Gorman DJ, Cosgrove J, Yeow TP, Mulvihill N, Nolan JJ. Metabolic Research Unit, Dept. of Endocrinology, St. James's Hospital, Dublin.
- The effect of acute and chronic exercise on glucose disposal and PI3-K activity in obese and Type 2 diabetes patients. O’Gorman DJ. McQuaid S, Yousif O, Karlsson H, Gasparro D, Chibalin A, Zierath JR, Nolan JJ. Metabolic Research Unit, St. James's Hospital, Dublin, Ireland; Department of Surgical Sciences, Karolinska Institutet, Stockholm, Sweden.
- Specificity and clinical utility of methods for the detection of macroprolactin. Smith TP, Gibney J, Kavanagh L, Fahie-Wilson MN, McKenna TJ. Department of Investigative Endocrinology, St. Vincent's University Hospital, Dublin, Ireland, and Department of Clinical Chemistry, Southend Hospital, Essex, United Kingdom.
- Routine screening for macroprolactin. Gibney J, Smith TP, McKenna TJ. Department of Endocrinology and Department of Medicine, St. Vincent's University Hospital, Elm Park and The Conway Institute of Biomolecular and Biomedical Research, University College, Dublin.
- Macroprolactinaemic patients exhibit increased levels of peripheral blood CD5 positive B lymphocytes. Kavanagh L, Smith TP, Gibney J, McKenna TJ. Department of Investigative Endocrinology, St. Vincent's University Hospital, Dublin.
- Consequences of gene promotor hypermethylation in colorectal cancer. Fox EJP, Leahy DT, Lennon AM, Geraghty R, Keegan D, White A, Mulcahy HE, Hyland JM, Fennelly D, O’Donoghue DP, Sheahan K. Department Of Pathology, Conway Institute Of Biomolecular And Biomedical Research, University College Dublin And Centre For Colorectal Diseases, St Vincents Hospital Dublin.
- Distinguishing UC patients with dysplasia/cancer from those without it using measurements of genomic instability. O'sullivan J, Rabinovitch P, Sheahan K, Bronner M, Mulcahy H, O’Farrelly C, O’Riain C, Hyland J, O’Donoghue DP. Brentnall D. Centre for Colorectal Disease, St Vincent's University Hospital, Dublin. Department of Medicine, Pathology, University of Washington, Seattle, WA. Department of Pathology, Cleveland Clinic, Ohio.
- A novel role for serum amyloid-a (a-saa) in adhesion molecule expression through nfkb-dependent signal transduction pathway. Mullan R, Mason LG, Markham T, O’Hara R, Fitzgerald O, Bresnihan B, Veale DJ, Fearon U. University College Dublin Ireland and Department of Rheumatology, St Vincents Hospital, Dublin.
- Anti-TNF therapy in psoriasis and psoriatic arthritis: clinical and angiogenic responses. Markham T, Fearon U, Mullan R, Rogers S, Golden-Mason L, Bresnihan B, Fitzgerald O, Veale DJ, Department Of Rheumatology and Department of Dermatology, St Vincent's University Hospital, Dublin.
- Oral bisphosphonates may reverse the decline in bone mineral density in adults with cystic fibrosis. Cawood TJ, Smith D, Wen YC, Gibney J, Au-Yeoung ML, Dodd JD, McKenna M, Fitzgerald O, Gallagher C, O'shea D. Departments of Endocrinology, Bone Densitometry, Radiology and Respiratory Medicine, St Vincents Hospital Dublin.
- The effect of body mass index on duration of intensive care stay and in-hospital mortality after cardiac surgery in an Irish centre. Cawood TJ, O'shea D, Dowd N, McGovern E, Tolan M, Young V, O’Connell M, Lyons FM. Department of Endocrinology St Columcilles Hospital, Loughlinstown, and Department of Anaesthesia and Cardiac Surgery, St James Hospital, Dublin.
- Compositional abnormalities of low density lipoprotein in type 2 diabetes: An explanation for increased atherogenicity? Phillips C, Owens D, Collins P, Tomkin GH. Department of Diabetes and Endocrinology, Trinity College, The Adelaide and Meath Hospital Dublin and Department of Biochemistry, The Royal College of Surgeons in Ireland, Dublin.
- Downward resetting of the osmotic threshold for thirst in patients with syndrome of inappropriate antidiuretic hormone. Smith D, Moore K, Tormey W, Baylis PH, Thompson CJ. Department Of Endocrinology, Beaumont Hospital, Dublin.
- The development of a sputum induction assay in normal and asthmatic subjects. Jatoi JA, Jatoi MN, Cullen JP, Lane SJ. Adelaide & Meath Hospital, Dublin. Maree A, Curtin R, Dooley M, Shields D, Fitzgerald DJ. Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Departments of Cardiology, St. James's Hospital and Beaumont Hospital, Dublin.
- Aspirin resistance in cardiovascular disease: Sub-optimal treatment of heavier patients. Maree A, Curtin R, Dooley M, Shields D, Fitzgerald DJ. Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Departments of Cardiology, St. James's Hospital and Beaumont Hospital, Dublin.
- Variation in COX-1 may influence platelet sensitivity to aspirin. Maree A, Curtin R, Dooley M, Shields D, Fitzgerald DJ. Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Departments of Cardiology, St. James's Hospital and Beaumont Hospital Dublin.
- Aldosterone to rennin ratio is better related to aortic than peripheral blood pressure and predicts response to aldosterone antagonism in hypertension. Mahmud A, Feely J. Department of Therapeutics, Trinity Centre for Health Sciences, St James Hospital, Dublin.
- Glucosamine and razoxane reverse basic calcium phosphate crystal-induced mitogenesis, Il-1ß, TNF and COX-2 mRNA expression in human fibroblasts. Whelan LC, Trevis M, Park M, Nolan K, McCarthy GM. Departments of Clinical Pharmacology and Chemistry, Royal College of Surgeons in Ireland, Mater Misericordiae Hospital, Dublin.
- Basic calcium phosphate (BCP) crystals upregulate microsomal prostaglandin E2 synthase 1 (mPGES1) and peroxisome proliferator-activated receptor g (PPARg) mRNA in human fibroblasts. Molloy ES, Morgan MP, Whelan LC, Fitzgerald DJ, Crofford LJ, McCarthy GM. Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, University of Michigan, Ann Arbor, MI, USA.
- Sequential rifabutin and furazolidone-based eradication therapy after failure of standard first- and second-line eradication attempts in Helicobacter pylori infected patients. Qasim A, Sebastian S, McLoughlin R, McDonald S, Buckley M, O’Connor H, O’Morain CA. Department of Gastroenterology, Adelaide and Meath Hospital Dublin.
- Gastric polyps: types, frequency and associations. Sebastian S, Maguire A, Qasim A, O’Connor H, Buckley M, O’Morain C. Department of Gastroenterology, Adelaide and Meath Hospital, Dublin.
- The CCR5-D32 mutation affects hepatitis C viral clearance and tends towards less severe inflammation amongst individuals chronically infected with HCV from a single source. Goulding C, McManus R, Murphy A, Mc Kiernan S, Barrett S, Crowe J, Kelleher D. Dept of Clinical Medicine and Dublin Molecular Medicine Centre, Trinity Centre for Health Sciences, St. James Hospital, Dublin and Centre for Liver Diseases, Mater Misericordiae Hospital, Dublin.
- Low pH results in co-ordinate regulation of gene expression in oesophageal cells. Duggan S, Abdel-Latif M, Fox E, Gallagher W, Reynolds JR, Kelleher D. Dublin Molecular Medicine Centre, Trinity College Dublin and Conway Institute, University College Dublin.
- Lipotoxins: Potential pro-resolution, anti-fibrotic roles in renal inflammation. Maderna P, Mitchell DM, McMahon B, Rodgers K, Reville K, Cummins E, Kieran NE, Godson C. Department of Medicine and Therapeutics, Conway Institute and Mater Misericordiae University Hospital, University College Dublin and Dublin Molecular Medicine Centre.
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