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Q J Med 2002; 95: 621-634
© 2002 Association of Physicians

Annual General Meeting

The Association of Physicians of Great Britain and Ireland 2002

Ninety-Sixth Annual General Meeting

The Ninety-Sixth Annual General Meeting was held in Cardiff on Thursday and Friday 18 and 19 April 2002. The attendance book was signed by ordinary members and senior members.

The President, Professor S. Tomlinson, took the chair.

The Minutes of the last Annual General meeting, having been published in the QJM (November 2001), were taken as read, confirmed and signed. The following Officers and Executive Officers were elected:

Executive Committee

President: Professor S. Tomlinson President-elect: Professor D. Barker Honorary Treasurer: Professor A.P. Weetman Honorary Secretary: Professor J.M.C. Connell

Members for England and Wales

Professor E. Childers Professor C.O. Savage Professor A.V.S. Hill Professor H. Watkins Professor J. Iredale Professor C.M. Wiles

Members for Scotland

Professor R. Jung Professor B. Walker Professor J.H. McKillop

Members for Ireland

Professor A.B. Atkinson Professor G.H. Tomkin Professor J. Donohoe

The following Honorary, Senior and Ordinary Members were elected:

Honorary Members

Professor D. Porteous Professor Sir G. Catto

Senior Members

Dr A.D. Beattie Dr R.H. Jones Professor S.R. Bloom Professor W.A. Littler Professor C.R.W. Edwards Dr T.J. McKenna Dr D.T. Fearon Dr H.C. Miller Dr M. Green Dr B. Rajagopala Professor R.A.C. Hughes Professor R.W. Stout

Ordinary Members

Ordinary Members

Bhattacharya, Shoumo, MB BS, MD, MRCP, MSc. Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN

Caulfield, Mark J, MB BS, MD, FRCP. Department of Clinical Pharmacology, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ

Ebers, George Cornell, MD, FRCP(C). Department of Clinical Neurology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE

Fitzgerald C, MA Cantab, MB.BChir, MD, MRCP. Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge CB2 2XZ

Gelder, Colin Malcolm, BSc, MB BS, PhD, MRCP. Section of Infection and Immunity, University of Wales College of Medicine, Tenovus Building, University Hospital of Wales, Heath Park, Cardiff CF4 2XX

Ghosh, Subrata, MB BS, MD, FRCP. Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN

Green, Anthony Richard, MB BS, PhD, FRCP, FRCPath, FMedSci. University of Cambridge Department of Haematology, Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 2XY

Griffiths, Christopher EM, BSc, MB BS, MD, MRCPath, FRCP. Dermatology Centre, Irving Building, Hope Hospital, Manchester M6 8HD

Holyoake, Tessa L, MB, ChB, PhD, FRCP, MRCPath. Academic Transfusion Medicine Unit, Department of Medicine, University of Glasgow, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER

Kopelman, Peter, MB BS, MD, FRCP. Barts and the London Queen Mary's School of Medicine and Denistry, Turner Street, London E1 2AD

McInnes, Iain, MB ChB, MRCP. Centre for Rheumatic Diseases, Department of Medicine, Royal Infirmary, Queen Elizabeth Building, Level 3, 10 Alexandra Parade, Glasgow G31 2ER

Maxwell, Patrick, BA, MB BS, MRCP, DPhil. Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN

Morgan, Bryan Paul, BSc, Dip Miol Methods, PhD, MRCP, MRCPath, FRCPath, FmedSci. Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN

Neubauer, Stefan, MD. Department of Cardiovascular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU

Neyses, Ludwig, MD. Manchester Heart Centre, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL

O'Brien, Timothy, MB BCh, PhD, MRCPI, MD, FACP, FRCPI, FRCP. Department of Medicine, University College Hospital, Galway, Ireland

Passmore, Anthony Peter, BSc, MB BCh, BAO, MD, FRCP (London), FRCP (Glasgow). Department of Geriatric Medicine, The Queen's University of Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL

Phillips, David, MA, MB BCh, PhD, FRCP. MRC Environmental Epidemiology Unit, Southampton General Hospital, Southampton SO16 6YD

Read, Robert C, MB ChB, MD, FRCP. Academic Unit of Infection and Immunity, Division of Genomic medicine, F Floor, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX

Sampson, Julian R, BMedSci, BMBS, MSc, DM, FRCP. Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XN

Shields, Michael David, MB ChB, MD, FRCP, FRCPCH. Department of Child Health, Institute of Clinical Science, Grosvenor Road, Belfast BT12 6BJ

Smith, Kenneth GC, BM BS, PhD, FRACP, FRCP. Department of Medicine, University of Cambridge Clinical School, Cambridge, Institute for Medical Research Box 139, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY

Taylor-Robinson, Simon David, MB BS, MD, MRCP (UK). Hepatology Section, Department of Medicine A, Faculty of Medicine, St Mary's Hospital Campus, Imperial College of Science, Technology and Medicine, Praed Street, London W2 1NY

Tinker, Andrew, BA, MB BS, PhD, MRCP. Room F2, 4th Floor, Rayne Institute, Centre for Clinical Pharmacology, UCL, Department of Medicine, 5 University Street, London WC1E 6JJ

Wordsworth, Bryan Paul, MB BS, FRCP. Seddon Ward, Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX3 7LD

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 the income and expenditure for the 12 months to 31 December 2001. Income from the Oxford University Press, arising from the publication of the QJM, had risen further in 2001, but next year's income was likely to be some £40–50 000, the surplus in 2001 being due to money set aside for the development of the journal not being fully used. Subscriptions continued at the same level, and Professor Weetman informed the AGM that he had now reconciled the bank statements with the list of members and found a number of anomalies. He will be writing to members who were not paying the correct subscription in the coming months.

The Executive Committee had decided to keep subscriptions at the same level this year and next year, but a rise in subscriptions would almost certainly occur in 2004, and the Executive Committee had also agreed to review subscriptions every 3 years, rather than every 5 years as at present. For the second consecutive time, a loss rather than a surplus had been incurred on the Annual General Meeting, held in Edinburgh 2001, although the losses were not as great as those for the London meeting in the preceding year. Together these losses offset previous surpluses, but Professor Weetman had reminded both the present local secretary and the future local secretary that meetings were expected to break even. Expenditure on printing and stationery, postage and administration remained approximately the same as previous years.

With regard to direct charitable expenditure, the Links with Developing Countries scheme had proven popular once again, with 21 submissions, seven of which were chosen for funding. In line with the agreement at the previous AGM, the sum of £42 116 was set aside for successful links, and more specific aims would be established for the next round of the scheme. The intercalated fees continued to prove popular, and as an overall result the Association's expenditure almost balanced its income, with a small deficit of £2216. Unfortunately, world events in the autumn of 2001 had led to a fall in the value of the investment assets of £59 610, and Professor Weetman had approached Towry Law to review the investments. Overall, the fund balances now totalled £340 765, compared with £400 376 in 2000. Professor Weetman reminded the AGM that the overall strategy for expenditure was to maintain a balance of approximately four times the size of the direct charitable expenditure in order to maintain the Association's charitable status. Several factors made the financial situation in 2002 difficult to predict accurately. The likely income from Oxford University Press was not known, subscriptions might change, and there might be further losses on investments. He therefore proposed that the Intercalated Studentships Scheme continued as before, while the Links with Developing Countries Scheme awards would be £25 000 in the forthcoming year. This would approximately total £80 000 in direct charitable expenditure, giving a target fund balance of around £320 000, and this seemed a realistic figure to aim for at the end of the 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. The financial state of the QJM was currently sound despite the continuing fall in library subscriptions. He was trying to develop other sources of revenue for the journal and, through Oxford University Press, was negotiating a 5-year agreement with Bell and Howell to allow the QJM to be included in their on-line and CD-ROM services. The cover of the QJM had been redesigned to give the journal a greater visual impact. The first issue with the new look had appeared in January 2002. The number of submissions of articles to the QJM had increased in 2001 compared with previous years. There were plans to link to the Manuscript Central system that enables on-line submission and peer review of papers in 2002. He was keen to refresh the membership of the editorial board, because he felt that many current members were too committed elsewhere to be able to devote much time to the journal. The executive committee had agreed that it would be useful to recruit new editorial board members. These might include younger physicians who were not yet members of the Association, a medical statistician, and people from countries outside the UK. It was also suggested that editorial board members might serve for a limited period, say 3 years, to ensure a flow of new ideas into the journal's development.

Professor D. Barker, President-elect, invited the Association to its next meeting in Southampton, on 3 and 4 April 2003.

Opening Reception and Annual Dinner
The welcome reception on Thursday evening was held in the National Museum and Gallery of Wales, and the Annual Dinner on the Friday night was held in Cardiff City Hall. An excellent dinner was provided and the occasion was enjoyed by all.

Scientific Business

Thursday, 18 April 2002
2.00–3.00 p.m.

Professor Peter S. Harper, CBE, DM, FRCP, Professor of Medical Genetics, University of Wales College of Medicine, Cardiff. The Osler Lecture—New insights from inherited neurological diseases

3.00 p.m. (1)

C.M. Gelder, O.M. Williams (introduced), L.K. Borysiewicz. Infection and Immunity, University of Wales College of Medicine, UK, Imperial College of Science, Technology and Medicine, London, UK. New insights into the pathogenesis of recurrent respiratory papillomatosis

Recurrent Respiratory Papillomatosis (RRP) is a rare disease (USA incidence 1/100 000) characterized by the presence of multiple benign tumours in the larynx and other sites within the upper aerodigestive tract. Left untreated, these lesions enlarge and endanger the airway. Though a variety of medical treatments have been tried for this condition, repeated surgical ablation remains the mainstay of therapy, and it is not unusual for patients to require more than 100 surgical procedures. RRP is therefore associated with considerable morbidity, and high annual treatment costs (in USA $100 million). RRP is caused by Human Papillomavirus (HPV) infection, usually by HPV types -6 and -11. However, as HPV infection is common and RRP rare, there are likely to be host and/or viral factors in disease pathogenesis.

In an attempt to identify such factors, we have investigated 50 patients. The hunt for viral factors included HPV typing, determination of HPV load, viral sequencing and a search for co-factor viruses. Studies on the host included an immune screen, HLA typing, T-cell proliferative studies using HPV-11 L1 virus-like particles (VLPs), and epitope mapping using short-term CD4⁺ T-cell lines and L1-specific peptides.

The most striking finding was an HLA class II association with disease susceptibility (HLA-DRB1*0301, p=0.0001, Fisher's exact test). In addition, the strength of a patient's T-cell proliferative response to HPV-11 L-1 VLPs was inversely related to their clinical status. Patients with RRP who mounted a CD4⁺ T-cell response to the HPV-11 VLPs recognized the same regions of the L-1 molecule as did HLA-matched normal donors, and this response was associated with an identical pattern of cytokine production. Failure to respond to the VLPs was not due to mutations in the immunodominant CD4⁺ T-cell epitopes within L-1.

We conclude that there is a host immune deficit in patients with severe RRP.

3.25 p.m. (2)

N. French (introduced), K. Grimwade (introduced), M. Dedicoat (introduced), C.F. Gilks. Liverpool School of Tropical Medicine, Liverpool L3 5QA, Hlabisa District Hospital, Kwazulu-Natal, South Africa. HIV-infection in adults increases rates of severe and fatal falciparum malaria in regions of unstable transmission

HIV infection and malaria are leading public health problems in sub-Saharan Africa. The interaction between these two conditions is poorly understood and difficult to unravel in immune populations where parasitaemia and HIV-associated fever commonly co-exist. We took the opportunity to investigate the relationship between HIV and falciparum malaria in a non-immune population in Hlabisa district, Kwazulu-Natal during an epidemic of malaria between January and April 2000. Systematic case-finding of malaria was undertaken at Hlabisa hospital and four community clinics at the epicentre of the outbreak. All acute fever cases were assessed with a rapid malaria slide test, with positive tests subsequently confirmed by microscopy along with anonymized HIV-testing of a blood spot collected on filter paper. HIV seroprevalence was 29% in the 613 adult malaria cases. Overall case-fatality was 4.6%. HIV was disproportionately represented in the severe cases (defined according to WHO criteria). In a logistic regression model, the ORs for HIV associated with hospital admission, severe disease and death were 1.0 (95% CI 0.7–1.4), 2.1 (1.3–3.5) and 7.5 (2.2–25.6), respectively. HIV was the most important risk factor for severe disease in this non-immune adult population, followed by age over 60. Increased emphasis on prevention of malaria is necessary in populations with a high prevalence of HIV. In addition investigation of HIV/P. falciparum co-infection may offer new insights into the anti-parasite/anti-toxic immune response.

4.15 p.m. (3)

B. Casadei, C.E. Sears, E.A. Ashley, S.M. Bryant (all introduced). University Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford. A cardiac ‘neuronal’ nitric oxide synthase isoform regulates contraction and calcium fluxes: a novel mechanism involved in the autocrine control of cardiac function

In the heart, calcium (Ca) modulates myocardial contraction and excitability. Our previous work has shown that nitric oxide (NO) released by nitrovasodilators can directly regulate cardiac pacemaker activity and the amplitude of Ca transients in sinoatrial node cells.

Here we show that both targeted gene disruption and specific pharmacological inhibition of a recently identified ‘neuronal-type’ NO synthase (nNOS) in the cardiac sarcoplasmic reticulum (SR) enhance Ca current (I_Ca) density (at 0 mV -11.4±0.5 vs. -9.1±0.5 pA/pF in LV myocytes from nNOS^-/- and control mice, respectively, p<0.01) and delay I_Ca inactivation (37.3±21.5 vs. 26.9±1.6 ms, p<0.05) resulting in greater Ca influx. Furthermore, SR Ca content is significantly greater in nNOS^-/- myocytes (0.78±0.04 vs. 0.64±0.03 pC/pF, p<0.05) and in control myocytes after nNOS inhibition with 100 µM L-VNIO (0.71±0.05 pC/pF vs. 0.54±0.05 pC/pF, p<0.05). Myofilament Ca sensitivity did not differ between nNOS^-/- mice and controls. Consistent with these changes, both basal and ß-adrenergic-stimulated myocyte contraction was enhanced in nNOS^-/- myocytes or after L-VNIO. In basal conditions, nNOS^-/- myocytes exhibited greater fractional shortening (%) when field-stimulated at 1, 3 or 6 Hz (e.g. at 6 Hz, 10.7±0.92 vs. 7.21±0.8, p<0.05). Similarly, myocyte contraction in response to 2 nM isoproterenol was enhanced in the presence of nNOS inhibition/gene disruption, e.g. at 6 Hz the % increased contraction was 25.2±10.8 in control mice; 68.2±11.2 in the nNOS^-/-, and 65.1±13.2 in controls treated with L-VNIO (p<0.05). There was no added effect of L-VNIO on contraction in nNOS^-/- myocytes.

These findings demonstrate that nNOS-derived NO plays a previously unrecognized role in the autocrine regulation of myocardial function. Since increases in intracellular Ca stimulate nNOS synthesis of NO, which in turn acts to inhibit Ca fluxes, our data suggest that cardiac nNOS may provide a ‘negative feedback’ mechanism that protects the myocardium against Ca overload.

4.40 p.m. (4)

E.P. Reeves, H. Lu, H.L. Jacobs, C.G.M. Messina, S. Bolsover, G. Gabella, E.O. Potma, A. Warley, J. Roes (all introduced), A.W. SEGAL. Departments of Medicine, Anatomy, Physiology and Windeyer Institute of Medical Sciences, University College London, Institut de Biologie Structurale, Grenoble, Ultrafast Laser and Spectroscopy Laboratory, Materials Science Centre, University of Groningen, and Rayne Institute, St Thomas' Hospital. Role of oxygen free radicals in phagocytes: directly microbicidal or activators of proteases by potassium flux?

According to the hitherto accepted view, neutrophils kill ingested micro-organisms by subjecting them to high concentrations of highly toxic reactive oxygen species (ROS) and myeloperoxidase-catalysed halogenation. We show here that this simple scheme, which for many years has served as a satisfactory working hypothesis, is inadequate. We find that mice made deficient in the neutrophil granule proteases, elastase and cathepsin G, but normal in respect of superoxide production and iodinating capacity, are unable to resist staphylococcal and candidal infections. We have shown, further, that activation of the NADPH oxidase, provokes the influx of an enormous concentration of ROS into the endocytic vacuole. The resulting accumulation of anionic charge is compensated by a surge of potassium ions which cross the membrane in a pH-dependent manner. The consequent rise in ionic strength engenders the release of cationic granule proteins, including elastase and cathepsin G, from the anionic sulphated proteoglycan matrix. It is the proteases, thus activated, that are primarily responsible for the destruction of the bacteria. The supposed killing of microbes by ROS in neutrophils provided the basis for the wide implication of the direct involvement of reactive oxygen in the pathogenesis of many aspects of human disease. These theories now deserve re-evaluation.

5.05 p.m. (5)

R.S. Jackson*¹ (introduced), I.S. Farooqi*¹ (introduced), J.W. Creemers², J.C. Hutton², G. Dockray³, J. Holst⁴, M.T. Dattani⁵ (introduced), S. Middeton¹, K.J. Lindley⁵, S. O'Rahilly¹ (*equal contributors). ¹University Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, ²Laboratory for Molecular Oncology, University of Leuven, Belgium, ³Physiological Laboratory, University of Liverpool, ⁴Department of Endocrinology, University of Copenhagen, Denmark, ⁵Institute of Child Health, London. A syndrome of intractable neonatal diarrhoea and hypoglycaemia resulting from congenital deficiency of prohormone convertase 1

A Caucasian female presented in the neonatal period with a complex, ultimately fatal illness characterized by severe uncontrollable diarrhoea, recurrent hypoglycaemia and obesity. The diarrhoea was malabsorptive in type with high levels of unabsorbed faecal sugars. She had reduced concentrations of circulating insulin and ACTH despite very elevated levels of their precursors. She was found to be a compound heterozygote for a nonsense and a missense mutation in the gene encoding the neuroendocrine-specific enzyme prohormone convertase 1 (PC1). When expressed ex vivo, the missense mutant showed severe impairment of catalytic activity, while the nonsense mutation was predicted to result in a protein truncated within the catalytic domain. We examined gastrointestinal function in the only previously reported case of PC1 deficiency, an adult female, and found evidence for malabsorption, including steatorrhea, low serum B12 not correctable by intrinsic factor, low red-cell folate and serum 25-hydroxy cholecalciferol, and markedly impaired bile salt resorption. Pancreatic exocrine function appeared normal. Examination of the circulating levels of precursors for gut-derived hormones revealed elevated levels of unprocessed proglucagon and progastrin gut-derived pro-hormones including proglucagon and progastrin. These subjects provide genetic evidence that the maintenance of normal human intestinal absorptive function is critically dependent on an intact gut neuroendocrine system. PC1 deficiency represents the first example of a genetic disorder affecting gut neuroendocrine cells that can present with malabsorptive diarrhoea.

Friday, 19 April 2002
9.00 a.m. (6)

S.D. Bamforth, J. Braganca, J.J. Eloranta, F. Marques, K. Kranc, J.N. Murdoch, H. Farza, D.J. Henderson, H.C. Hurst, S. Bhattacharya (all introduced). Department of Cardiovascular Medicine, University of Oxford, ICRF Molecular Oncology Unit, Hammersmith Hospital, London, and Neural Development Unit, Institute of Child Health, London. A new transcriptional mechanism that controls cardiac, adrenal and neural development

CBP and p300 are homologous nuclear proteins that interact with DNA-binding transcription factors, and acetylate histones, thus facilitating (‘co-activating’) gene transcription. Mutations in CBP result in Rubinstein-Taybi Syndrome. This is characterized by dominantly inherited cardiac malformations, skeletal defects and mental retardation. We identified and cloned Cited2, which encodes a protein that binds tightly to CBP/p300, and have generated knockout mice. Mice lacking Cited2 die with severe cardiac malformations, adrenal agenesis, abnormal cranial ganglia, open neural tubes, and neural crest defects. The spectrum of cardiac malformations includes atrial and ventricular septal defects, overriding aorta, double-outlet right ventricle, persistent truncus arteriosus, right-sided aortic arches, and anomalous subclavian artery (dysphagia lusoria). We have established that Cited2 functions as a co-activator for the transcription factor AP-2 (TFAP2, which is required for cardiac, neural crest and neural tube development). Abnormal embryogenesis in mice lacking Cited2, results, at least in part, from defective TFAP2 function. Importantly, mutations in TFAP2B cause Char Syndrome, which is characterized by dominantly inherited cardiac and cranio-facial defects. These studies have identified a new transcriptional mechanism that links Cited2, p300/CBP and TFAP2, and is critical for normal cardiac, adrenal, neural crest and neural tube development. This mechanism is defective in at least two human congenital heart disease syndromes, and is likely to be affected in others.

9.25 a.m. (7)

J.M. Hopkin, P.-S. Gao (introduced), E. Bottini (introduced), T. Shirakawa (introduced), D. Sun (introduced). Experimental Medicine, University of Wales Swansea, UK, Statistics and Biometrics, University of Rome Medical School, Italy, Public Health, Kyoto University Graduate Medical School, Japan, Department of Parasitology, Shanghai University Medical School, China. Genetic variation in Th-2 immune signalling and the burden of worm parasitization

Th-2 immune signalling, by the cytokine IL-13, mediated by transducer-transactivating molecule STAT6, promotes mucosal eosinophila, mucus hyper-secretion and smooth muscle hyper-activity. These phenomena are of pathological importance in bronchial asthma, and are protective against infestation with parasitic worms. We have identified common genetic variants of Th-2 immune signalling that predict asthma, and reasoned that their commonness suggests some balancing evolutionary advantage—perhaps enhanced Th-2 immune responses against parasitic worms. We conducted an epidemiological investigation of genetic variation within Th-2 and Th-1 immune signalling pathways in relation to asthma and the burden of Ascaris lumbricoides infection in two Oriental populations (500 Japanese from Osaka City, where asthma is common and ascaris infection absent, and 600 Chinese from Shanghai Province, where asthma is rare and ascaris infection endemic). Asthma was investigated as a categorical variable, and ascaris burden (assayed by faecal egg count) in centiles, using discriminant and regression statistical analysis. Discriminant analysis pointed to a major genetic effect on high (upper quartile) ascaris burden. The major effect in limiting high ascaris burden was attributable to a common (0.5) variant in the 3' untranslated region of STAT6. This variant independently contributed 13.89, and 7.65 (through interaction with a variant of IFN-), to the total ² of 34.77 in the regression analysis (p=0.0002 and 0.006). In addition there was a lesser independent limitation on high ascaris burden from a variant of IL-13 (p=0.04). Homozygosity for the 3'UTR variant of STAT6 protected against high ascaris burden (OR 0.34, 95% CI 0.17-0.69) in the Chinese. Homozygosity for this STAT6 variant predicted asthma in the Japanese (OR 2.52, 95% CI 1.16–5.36). One element of the genetic risk for asthma derives from common variants in Th-2 immune signalling (notably of STAT6 in this example) which provide evolutionary advantage against worm infestation.

9.50 a.m. (8)

T.L. Stewart¹ (introduced), P. Roschger² (introduced), B. Grabner² (introduced), P. Fratzl³ (introduced), V. Mann¹ (introduced), R.M. Aspden¹ (introduced), K. Klaushofer² (introduced), S.H. Ralston¹. ¹Bone Research Group, University of Aberdeen, UK, ²Ludwig Boltzman Institute of Osteology, Vienna, and ³Erich Schmid Institute of Material Science, Leoben, Austria. COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fractures by altering collagen production and impairing bone mineralization

A polymorphic Sp1 binding site has been identified in the COL1A1 gene that predicts the risk of osteoporotic fractures, independent of differences in bone mineral density. We examined the functional mechanisms responsible for this association. Ex vivo mechanical testing of bone cores from patients of different genotype showed reduced yield strength (adjusted for bone density) in G/T heterozygotes (n=7) when compared with G/G homozygotes (n=10) (mean±SD=4.60±0.3 vs. 3.55±0.2 Mpa; p=0.03). Analysis using quantitative backscatter electron imaging showed reduced mineralization of bone in G/T heterozygotes (n=7) when compared with G/G homozygotes (n=6) (21.5±0.5% vs. 20.2±0.7%, p=0.04) and increased heterogeneity of mineralization, as reflected by broadening of the bone mineral density distribution peak (4.5±0.5% vs. 3.5±0.5%, p=0.04). Osteoblasts from G/T heterozygotes produced a abnormal ratio of collagen alpha I (1) chains, relative to alpha I (2) when compared with G/G homozygotes (2.3 : 1.0 vs. 1.99 : 1.0, p=0.007), even though cell growth, total protein and alkaline phosphatase were similar in the two groups. Cultures from G/T heterozygotes also had an impaired ability to form mineralized bone in vitro when compared with G/G homozygotes, as reflected by Alizarin Red S staining of ß-glycerol phosphate supplemented cultures (1.64±0.1 vs. 0.6±0.1 mM Alizarin/10⁵ cells, p<0.0001). Our data indicate that the COLIA1 ‘T’ allele influences the ratio, but not total amount, of collagen type I alpha chains produced by bone cells, leading to abnormal mineralization of bone both in vivo and in vitro and reduced bone strength. The studies define a novel genetic mechanisms of osteoporosis which predisposes to fracture by affecting bone quality rather than bone quantity.

10.15 a.m. (9)

B. Göttgens, M.J. Sanchez, A.R. Green (introduced by M.R. Bennett). University of Cambridge Department of Haematology, Cambridge Institute for Medical Research, Cambridge CB2 2XY. Haematopoietic stem cells: playing with their potential

One of the central issues of metazoan biology concerns the mechanisms whereby a multipotent stem cell gives rise to distinct mature cell types and there has been considerable interest in the clinical applications of manipulating stem cell plasticity. Haematopoiesis is the best characterized stem cell system, and a close link has long been recognized between the development of blood and endothelium. The Stem Cell Leukaemia (SCL) gene encodes a bHLH transcription factor with a pivotal role in the formation of blood and endothelium. Loss-of-function and gain-of-function studies by our laboratory and others have demonstrated that SCL is essential for establishing the transcriptional programme responsible for the formation of haematopoietic stem cells and have focused attention on the regulation of SCL itself.

We have therefore systematically characterized the transcriptional regulation of the murine SCL gene using a combination of long-range genomic sequence comparisons, chromatin studies and transgenic analysis of reporter constructs. Our results have defined a chromosomal domain sufficient for normal SCL transcription, and revealed a panel of spatially distinct enhancers, each of which directs expression to a sub-domain of the normal SCL expression pattern. Of particular note, a SCL 3' enhancer specifically targets expression to haematopoietic stem cells, progenitors and endothelial cells throughout ontogeny, suggesting that this enhancer functions at a nodal point for signals that establish the transcriptional programme for blood and endothelium. Molecular characterization of this enhancer is illuminating the mechanisms that control formation of haematopoietic stem cells and is providing novel tools for stem cell manipulation.

11.10 a.m. (10)

S. Kumar (introduced), G. Valsamakis (introduced), P.G. McTernan (introduced), A.H. Barnett. Division of Medical Sciences, University of Birmingham B15 2TL. Resistin: the link between central obesity and diabetes?

Obesity increases the risk of type 2 diabetes and cardiovascular disease, but the precise mechanisms responsible for this association are unclear. Furthermore, the risk of diabetes is greater with central rather than gluteo-femoral obesity. Adipocyte secreted factors may determine the risk of developing diabetes in obese individuals. Resistin is a protein shown in mice to produce insulin resistance and glucose intolerance, but its relevance to human diabetes not known. We examined resistin expression and secretion by human adipose tissue. Quantitative PCR analysis of human adipose tissue samples (n=32 in total) confirmed expression of resistin mRNA. There was a depot-specific difference in resistin mRNA expression, in that both the subcutaneous and omental abdominal depots showed four-fold higher resistin mRNA expression, compared to thigh fat (p=0.038). The regulation of resistin protein secretion by adipocytes in vitro by insulin and rosiglitazone (an insulin action enhancer) was also examined. ELISA was used to measure resistin secretion in vitro by abdominal subcutaneous adipocytes (Scad; n=12) treated with insulin and/or rosiglitazone (an insulin action enhancer). The addition of rosiglitazone was associated with a reduction in resistin secretion in vitro, compared to insulin alone (1 nM Ins 1.42±0.88 ng/ml vs. 1 nM Ins+RSG: 0.97±0.03 ng/ml, p<0.0002; 10 nM Ins: 1.44±0.08 ng/ml vs. 10 nM Ins±RSG: 0.99±0.3 ng/ml, p=0.0002, 100 nM Ins: 1.62±0.11 ng/ml vs. 100 nM Ins±RSG: 1.01±0.05 ng/ml, p=0.0001). Finally, serum concentrations of resistin were significantly increased in 10 diabetic patients compared to 16 non-diabetic subjects (18.2±1.2 vs. 12.7±0.8 ng/ml respectively, p=0.0004). Resistin levels also correlated with increasing obesity in the non-diabetic subjects (p=0.043). Taken together, these studies indicate that human adipose tissue is an important source of circulating resistin and could potentially link obesity and diabetes. Further studies are required to clarify its role in the natural history of human diabetes, particularly as its secretion may be reduced by rosiglitazone.

11.35 a.m. (11)

J.C. Mason (introduced), Z. Ahmed (introduced), D.O. Haskard. Cardiovascular Medicine Unit, Faculty of Medicine, Imperial College, Hammersmith Hospital, London. Complement-mediated vascular endothelial injury is inhibited by statins through upregulation of expression of complement inhibitory proteins

Complement-mediated vascular injury is implicated in the pathophysiology of atherosclerosis, a cause of early mortality in systemic rheumatic diseases. As HMG CoA reductase inhibitors have a beneficial effect on endothelial cell (EC) function above and beyond their lipid-lowering actions, we explored the hypothesis that statins modulate vascular EC resistance to complement through upregulation of complement-inhibitory proteins.

Human umbilical vein EC (HUVEC) and aortic EC were incubated with atorvastatin or simvastatin and expression of decay-accelerating factor (DAF), membrane cofactor protein (MCP) and CD59 was measured by flow-cytometry. An increase in DAF expression of up to 4-fold was seen 24–48 h post-stimulation. CD59 expression was increased by 50% while MCP was unchanged. Statin-induced DAF upregulation required increased steady-state mRNA and de novo protein synthesis. Inclusion of L-mevalonate, or geranylgeranyl pyrophosphate, reversed the effect on DAF expression, confirming the role of HMGCoA reductase inhibition, and suggesting that DAF expression is negatively regulated by geranylgeranyl synthesis. Neither farnesyl pyrophosphate nor squalene had any effect suggesting that DAF regulation is independent of cholesterol lowering. Statin-induced DAF expression is mediated by a protein kinase C-, NF-B-dependent pathway and is independent of PI-3 kinase, nitric oxide and RhoA. Upregulation of DAF is functionally relevant, resulting in a reduction in C3 deposition and complement-mediated EC lysis, inhibitable by anti-DAF mAb 1H4.

These observations suggest a novel action of the statins on vascular endothelium, resulting in enhanced protection against complement-mediated injury. Modulation of complement regulatory protein expression by statins might have direct therapeutic effects in systemic rheumatic diseases involving complement, such as SLE, and may represent a strategy by which the risk of premature atherosclerosis can be reduced.

12.00 noon (12)

R. Mahadeva (introduced), T.R. Dafforn (introduced), R.W. Carrell (introduced), D.A. Lomas. Respiratory Medicine Unit, Department of Medicine and Department of Haematology, University of Cambridge, Cambridge. Design of a six-mer peptide that selectively anneals to Z ₁-antitrypsin and blocks polymerization: implications for the prevention of Z ₁-antitrypsin-related cirrhosis

Conformational diseases such as amyloidosis, Alzheimer's disease, prion diseases, and the serpinopathies are all caused by structural rearrangements within a protein that transform it into a pathological species. These diseases are typified by the Z variant of ₁-antitrypsin (E342K), which causes the retention of protein within hepatocytes as inclusion bodies that are associated with neonatal hepatitis, juvenile cirrhosis and hepatocellular carcinoma. The inclusion bodies result from the Z mutation perturbing the conformation of the protein which facilitates a sequential interaction between the reactive centre loop of one molecule and the ß-sheet A of a second. Therapies to prevent liver disease must block this reactive loop–ß-sheet polymerization without interfering with other proteins of similar tertiary structure. We have used reactive loop peptides to explore the differences between the pathogenic Z and normal M ₁-antitrypsin. The results show that the reactive loop must be partially inserted into ß-sheet A in Z ₁-antitrypsin. This conformational difference was exploited with a 6-mer reactive loop peptide (FLEAIG) that selectively and stably bound Z ₁-antitrypsin. The importance of this finding is that the peptide prevented the polymerization of Z ₁-antitrypsin, and did not significantly anneal to other proteins (such as antithrombin, ₁-antichymotrypsin and plasminogen activator inhibitor-1) with a similar tertiary structure. These findings provide a lead compound for the development of small-molecule inhibitors that can be used to treat patients with Z ₁-antitrypsin deficiency. Moreover, they demonstrate how a conformational disease process can be selectively inhibited with a short peptide.

12.25 p.m. (13)

M.A. Saleem (introduced), R. Coward (introduced), C. Xing (introduced), L. Ni (introduced), P.W. Mathieson. Academic Renal Unit, University of Bristol, Southmead Hospital, Bristol BS10 5NB. Podocytes: key cells in glomerular physiology and pathology

Podocytes are key cells in the mammalian kidney, but human podocytes have been difficult to study in vitro, because of a lack of representative cell lines. We transfected human podocytes with a temperature-sensitive transgene to obtain conditionally immortalized cell lines: at non-permissive temperature (37 °C) the transgene is silenced and cells develop a mature phenotype, expressing key podocyte-specific proteins nephrin and podocin. We have normal cells and a series of human ‘knockout’ cell lines derived from patients with single gene defects causing congenital nephrotic syndrome (including nephrin and podocin mutants). The mature podocytes produce in vitro unique components of type IV collagen and laminin which characterize glomerular basement membrane (GBM). The podocytes express glucocorticoid receptors, and are profoundly affected by therapeutic concentrations of dexamethasone with enhanced proliferation and survival (without any effect on apoptosis), down-regulation of cyclin kinase inhibitor p21, up-regulation of structural proteins such as tubulin-, and alteration of key proteins influencing permeability with down-regulation of vascular endothelial growth factor and up-regulation of nephrin. There is recent evidence that podocyte injury is an early feature of diabetic nephropathy: we have found that podocytes express the insulin-sensitive GLUT4 pathway, previously thought to be confined to muscle cells and adipocytes. Podocytes incubated with glucose and insulin translocate GLUT4 to the cell surface along with other key proteins mediating insulin-sensitive glucose uptake. GBM production is altered by high-glucose medium.

Thus we have used our novel cell lines to add to evidence for the key role of podocytes in glomerular physiology and pathology, including novel evidence that podocytes may be important in the therapeutic efficacy of corticosteroids in glomerular disease and that these cells are insulin-sensitive. Our conditionally-transformed human podocytes will be valuable tools for study of podocyte biology in health and disease.

3.00 p.m. (14)

G.C. Jayson*, J. Zweit, A. Jackson, C. Mulatero, M. Ranson, P. Julyan, J. Wagstaff, L. Hakannson, G. Groenewegen, D. Hastings, J. Lawrance, T. Ward, A. McGown, T. Tang, D. Levitt, S. Merreaud, F. Lehmann, M. Herold, H. Zwierzina (*introduced by Professor N. Thatcher). CRC Department of Medical Oncology, Christie Hospital NHS Trust, Withington, Manchester M20 4BX. Molecular and biological evaluation of the anti-VEGF antibody HuMV833

Angiogenesis is central to the pathogenesis of cancer. The process is controlled by a number of cytokines, of which the most potent is Vascular Endothelial Growth Factor (VEGF). Thus the development of neutralizing anti-VEGF antibodies could be of therapeutic benefit to large numbers of patients. However, the optimum dose and schedule of this class of agent remain to be established.

We have performed the first positron emission tomographic (PET) pharmacokinetic study of an anti-angiogenic agent by labelling the anti-VEGF antibody HuMV833 with ¹²⁴I. PET studies were performed 24 and 48 h after drug administration, and revealed profound heterogeneity of tumour drug distribution and clearance in relation to normal organs, which cleared the drug in a homogeneous fashion.

Dynamic, contrast-enhanced magnetic resonance (MR) evaluation of tumour vascular permeability, a phenotype regulated by VEGF, revealed marked heterogeneity within the tumours and a significant reduction in permeability following administration of the antibody. Forty-eight hours after the administration of HuMV833, all tumours had shown a median reduction in permeability of 44% (range 5–91%), indicating that the antibody inhibited the biological activity of VEGF in the tumours.

These data have revealed striking heterogeneity in drug uptake, drug clearance, biology and biological response suggesting that the traditional incremental, cohort-based, phase I clinical trial design is not capable of identifying the optimum biologically-active dose of cytostatic anti-angiogenic agents. A supplementary cohort of patients who are treated with an intra-patient dose escalation strategy may be required to control for the significant inter-tumoural variation in drug pharmacokinetics and biology.

3.25 p.m. (15)

G.C. Ebers and the Canadian Collaborative Study Group (introduced by R. Thakker). Department of Clinical Neurology, Radcliffe Infirmary, Oxford OX2 6HE. Collaborative twin study on multiple sclerosis: final report

Although twin studies historically have been useful in identifying genetic components to disease, there have always been reservations in using data from these studies to model the inheritance of susceptibility. This has much to do with problems in ascertainment. It has taken some two decades to collect the population of twins in Canada in which one or both has multiple sclerosis. These data now approach complete ascertainment, and the length of follow-up is such that the risk of development of the disease in presently unaffected twins approaches zero. The distribution of gender, zygosity and phenotype all indicate that the usual ascertainment biases are absent. The study now includes some 438 pairs and permits the subdivision of twin groups into cohorts retaining statistical meaning. In addition, it allows the calculation of proband-wise concordance rates under conditions of near complete ascertainment.

A highly significant increase in concordance of monozygotic vs. dizygotic twins was found as expected and as has been previously shown in this cohort. The size of the cohort now allows comparison of dizygotic twin rate to that in gender-matched sibling controls and indicates a highly significant excess of concordance of dizygotic twins. In the context of other studies of adoptees, half-siblings and conjugal pairs, these results indicate that the increase in risk for dizygotic twins is likely to be related to a timing-related factor and draws attention to the maternal-foetal relationship, a relatively unexplored area of environmental interaction in adult onset disease.

3.50 p.m. (16)

C.D. Ellson, A.M. Condliffe, K.A. Cadwallader, K.E. Anderson, P.T. Hawkins, L.R. Stephens, E.R. Chilvers (all introduced). Department of Medicine, University of Cambridge, Addenbrooke's and Papworth Hospitals, Cambridge, The Inositides Laboratory, Babraham Institute, Babraham, Cambridge. Regulation of the neutrophil NADPH oxidase complex by the phospho-inositide 3-kinase signalling pathway

Neutrophil-mediated lung damage has been implicated in the pathogenesis of a variety of lung diseases including ARDS and bronchiectasis. Activation of the NADPH oxidase complex in neutrophils results in the production of superoxide anions (O₂^-) that are highly toxic to tissues. The generation of O₂^- by neutrophils is also dramatically increased if neutrophils are initially primed by agents such as TNF or LPS. However, the molecular mechanisms underlying O₂^- generation remain unknown. Having demonstrated that activation of the phosphoinositide 3-kinase (PI3K) signalling pathway is essential for O₂^- formation, we sought to define how the lipid products of PI3K stimulate O₂^- generation, and to identify the PI3K isoform(s) involved. We employed a cell-free system containing the purified NADPH oxidase components p47^phox, p67^phox, p40^phox, GTPS-Rac and cytochrome b. Contrary to expectation, O₂^- generation was only supported by phosphatidylinositol 3-phosphate (PtdIns(3)P), the product of type III PI3K, which hitherto had no recognized function in mammalian cells; PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂, the products of type I and II PI3K activity, had no effect on O₂^- formation. This effect required the p40^phox NADPH oxidase component and was dependent on the binding of PtdIns(3)P to the novel PX lipid binding domain of p40^phox. Subsequent digital fluorescent imaging of RAW 264.7 cells transfected with chimeric fluorescent PtdIns(3)P binding proteins demonstrated dramatic accumulation of PtdIns(3)P at the phagosome membrane following zymosan particle ingestion. Finally, measurement of PtdIns(3,4,5)P₃, the initial product of the conventional type I PI3K, revealed that neutrophil priming enhanced agonist-stimulated PtdIns(3,4,5)P₃ accumulation and caused selective activation of PI3K. These data reveal for the first time the molecular basis of NADPH oxidase activation in neutrophils and the ability of priming agents to up-regulate PI3K activity. Since neutrophils are the only cells to express PI3K, both p40^phox and PI3Koffer novel therapeutic targets to control O₂^- formation.

4.45 p.m. (17)

S. Hood, J. Cannon¹, R. Foo, M. Scanlon², C.C.M. Brown, K. Jamieson, H. Sharaf, S. Monteith, J. Fatibene (all introduced), M.J. brown. ¹Clinical Pharmacology Unit, University of Cambridge, Ixworth Practice and ²St Mary's Hospital, London. High prevalence of aldosterone-sensitive hypertension in unselected patients

Studies in hospital clinics have suggested that primary hyperaldosteronism (PHA) is commoner than previously suspected. The aims of the Prevalence of Primary Hyperaldosteronism detected by Aldosterone/Renin ratio and Spironolactone Testing (PHARST) study were to determine the prevalence of PHA in unselected patients, using both biochemical and pharmacological criteria, and to assess confounding effects on diagnosis of antihypertensive drug treatment. 835 patients, aged 21–79 years, on primary-care hypertension registers, attended for measurement of plasma electrolytes, renin activity (pmol/ml/h) and aldosterone (pmol/l). Patients with aldosterone/renin ratios >400 had a 1-month trial of spironolactone 50 mg/day, added to existing treatment, and a spiral CT scans of the adrenals. The pre-specified measure of a positive response to spironolactone was a fall in systolic BP of 20 mmHg. Blood DNA was used to seek novel genetic variants in the melanocortin 5 (MC5) and SGK genes, putative mediators, respectively, of increased aldosterone secretion or response.

Some 12.3% of patients had aldosterone/renin ratios >800, of whom 70.1% were spironolactone responders. The prevalence of PHA is thus 9.2% (95% CI 7.7, 11.8). However, few patients had high absolute levels of plasma aldosterone or adenomas on CT, and most of these had bilateral aldosterone secretion on adrenal vein sampling. The mean plasma Na⁺, K⁺ and HCO₃^- in both PHA and other patients were 140, 4.0 and 28.0 meq/L. The PHA patients had higher BP (154/93 mmHg) on more drugs than the rest (144/88 mmHg). Based on spironolactone responses, ACE inhibitors and ß-blockers reduced, respectively, specificity or sensitivity of the aldosterone/renin ratio, whereas CCBs and diuretics did not confound. A C627G variant, creating a PheLeu substitution in the MC5 receptor expressed in zona glomerulosa, was found in 33% of PHA patients, and 23% of 210 non-PHA controls (p<0.05); no coding variants were found in SGK.

Aldosterone-sensitive hypertension is a common but probably polygenic condition, which may embrace a spectrum between increased aldosterone secretion and sensitivity. Resistance to conventional treatment is more useful than plasma electrolytes as a clue to the diagnosis.

5.10 p.m.

Dr Deirder Hine, DBE, FFPHM, FRCP, Chair Commission Health Improvement, President Royal Society of Medicine, Retired Chief Medical Officer, Welsh Office. The History of Medicine Lecture—The shoulders of giants

Demonstrations

1. High dose oral folic acutely improves endothelial function in patients with coronary artery disease unrelated to plasma homocysteine. S.J. Moat, S.N. Doshi, M.J. Lewis, I.F.W. McDowell, J. Goodfellow. Departments of Pharmacology, Therapeutics and Toxicology, Medical Biochemistry and Cardiology, Wales Heart Research Institute, UWCM, Cardiff.
   
2. Self-discontinuation of antiepileptic medication in pregnancy: detection by hair analysis. J. Williams¹, V. Myson², S. Steward², G. Jones², J. Wilson¹, M. Kerr^2,4, P.E.M. Smith^2,3. 1. Department of Clinical Pharmacology, UWCM, Cardiff; 2. Epilepsy Unit, UHW, Cardiff; 3. Department of Neurology, UHW, Cardiff; 4. Department of Psychological Medicine, UWCM, Cardiff.
   
3. Complement C3A stimulates pituitary prolactin, growth hormone and ACTH release. K. Francis, B.M. Lewis, P. Monk, M.F. Scanlon, J. Ham, P. Gasque. Departments of Medicine and Medical Biochemistry, UWCM, Cardiff.
   
4. Scrum caps and the prevention of soft tissue injuries to the head. S.J. Jones¹, R.A. Lyons¹, R. Evans², R.G. Newcombe¹, S.R. Palmer¹. 1. Department of Epidemiology, Statistics and Public Health, UWCM, Cardiff; 2. Emergency Unit, UHW, Cardiff.
   
5. Postpartum thyroiditis in South Wales. L.D.K.E. Premawardhana¹, B. Harris², R. John³, C. Darke⁴, A.B. Parkes¹, J.H. Lazarus¹. 1. Department of Medicine, UWCM; 2. Psychological Medicine, UWCM; 3. Medical Biochemistry, UHW; 4. Welsh Blood Service, Llantrisant, Mid Glamorgan.
   
6. Antigen presentation by dendritic cells is NFKB dependent. J. Bondeson, S. Yoshimura, M. Feldmann. Department of Medicine (Rheumatology), UWCM, Cardiff and Kennedy Institute, London.
   
7. Physiotherapy in chronic multiple sclerosis. T.P. Pickersgill¹, C. Lawthom¹, K.J. Fuller¹, R. van Deursen², R.G. Newcombe³, C.M. Wiles¹. 1. Departments of Medicine (Neurology), UWCM, Cardiff; 2. Physiotherapy Education, UWCM, Cardiff; 3. Department of Epidemiology, Statistics and Public Health, UWCM, Cardiff.
   
8. Bulbar and respiratory factors in motor neuron disease. S. Hadjikoutis, C.M. Wiles. Department of Medicine (Neurology), UWCM, Cardiff.
   
9. Cervical auscultation for aspiration: effect of clinical information. A.E. Stroud, R.G. Newcombe, C.M. Wiles. Departments of Medicine (Neurology) and Epidemiology, Statistics and Public Health, UWCM, Cardiff.
   
10. Place of residence and risk of fracture in older people: a population based study of over 65-year-olds in Cardiff. J. Saunders^1,2, A. Johansen^1,2, J. Butler¹, M. Stone^1,2, P. Richmond³, S. Jones², R.A. Lyons². 1. Bone Research Unit; 2. Collaboration for Accident Prevention and Injury Control; 3. Accident and Emergency Department. UWCM, Cardiff.
    
11. Using a surveillance system in A&E to monitor falls incidence in Cardiff. I.R.G. Collings¹, J. Saunders^1,2, L.D. Davies¹, A. Johansen^1,2, K. Wareham¹, C.G. Murugasu¹, M. Stone^1,2, S. Jones², R.A. Lyons², P. Richmond³. 1. Bone Research Unit; 2. Collaboration for Accident Prevention and Injury Control; 3. Accident and Emergency Department, UWCM, Cardiff.
    
12. Socioeconomic deprivation and the risk of fracture. A. Johansen^1,2, M. Stone^1,2, S. Jones², J. Saunders^1,2, R.A. Lyons². 1. Bone Research Unit; 2. Collaboration for Accident Prevention and Injury Control, UWCM, Cardiff.
    
13. Fracture epidemiology during snowfall. J. Saunders^1,2, K. Wareham¹, A. Johansen^1,2, M. Stone^1,2, S. Jones², R.A. Lyons², J. Gallacher, P. Richmond³. 1. Bone Research Unit; 2. Collaboration for Accident Prevention and Injury Control; 3. Accident and Emergency Department, UWCM, Cardiff.
    
14. The effect of socioeconomic deprivation on likelihood of referral for bone densitometry. J. Saunders^1,2, A. Johansen^1,2, M. Stone^1,2, W. Evans³, R. Pettit³, S. Jones², R.A. Lyons². 1. Bone Research Unit; 2. Collaboration for Accident Prevention and Injury Control; 3. Medical Physics Department, UWCM, Cardiff.
    
15. Neural transplantation for Huntingtons' disease: a UK safety study. A.E. Rosser on behalf of the NEST-UK consortium. Department of Medicine (Neurology), UWCM, Cardiff and School of Biosciences, Cardiff University.
    
16. Evolving anti-complement therapeutics. C.L. Harris, D.A. Fraser, B.P. Morgan. Department of Medical Biochemistry, UWCM, Cardiff.
    
17. Hypertension superimposed on Type II diabetes induces progressive nephropathy. U. Janssen, S.G. Riley, A. Vassiliadou, J. Floege, A.O. Phillips. Department of Medicine, Institute of Nephrology, UWCM, Cardiff.
    
18. Interaction between the TGFb₁ II receptor (Smad) pathway and bcatenin during TGFb₁ mediated adherens junction disassembly. V.C. Tean, A.O. Phillips. Department of Medicine, Institute of Nephrology, UWCM, Cardiff.
    
19. Haemodynamic effects of the prone position for spinal surgery in TIVA versus inhalational anaesthesia. P.S. Sudheer, B. Ateleanu, S.W. Logan, C. McBeth, J.E. Hall. Department of Anaesthetics and Intensive Care, UHW, Cardiff.
    
20. The effect of cardiopulmonary bypass on saccadic eye movements. S. Karthikeyan, R. Abel, S. Pugh, J.E. Hall. Department of Anaesthetics and Intensive Care, UHW, Cardiff.
    
21. Only 1% of adult HFE C282Y homozygotes in South Wales have a clinical diagnosis of iron overload. A. McCune¹, L.N. Al-Jader², A. May¹, S.L. Hayes³, H.A. Jackson¹, M. Worwood¹. 1. Department of Haematology, UWCM, Cardiff; 2. Department of Epidemiology and Public Health, UWCM, Cardiff; 3. Department of Public Health, Iechyd Morgannwg Health.
    
22. Assessment of digital stereoscopic optic disc images using a Z screen. J.E. Morgan¹, N.J.L. Sheen², R. Goyal¹, J.M. Wild², R.V. North². 1. Department of Medicine (Ophthalmology), UWCM, Cardiff; 2. Department of Optometry and Vision Sciences, Cardiff University.
    
23. A diabetic retinopathy screening service: one years experience. R. Gibbins, P. Webb, D.R. Owens. Department of Medicine (Endocrinology, Diabetes & Metabolism) UWCM, Cardiff.
    
24. The role of post-prandial lipaemia in the pathogenesis of coronary heart disease in patients with Type 2 diabetes. M. Evans, A.W. Thomas, R.A. Anderson, A. Rees. Department of Medicine (Endocrinology, Diabetes & Metabolism), UWCM, Cardiff.
    
25. Adenosine: regulated cell proliferation in pituitary endocrine and follicullostellate cells—differential roles for the A₁ and A_2B adenosine receptors. A. Rees, M.D. Lewis, B.M. Lewis, M.F. Scanlon, J. Ham. Department of Medicine (Endocrinology, Diabetes & Metabolism), UWCM, Cardiff.
    
26. Embryo transfer studies in diabetes. J.C. Alcolado, D. Adams, B.M. Lewis, R.J. Gill-Randall. Department of Medicine (Endocrinology, Diabetes & Metabolism), UWCM, Cardiff.
    
27. Dissecting the molecular causes of hypothyroidism. N. Jordan, N. Williams, M. Owens, C. Evans, M. Ludgate. Department of Medicine (Endocrinology, Diabetes & Metabolism), UWCM, Cardiff.
    
28. The role of the TPAR gamma in thyroid eye disease: possible contraindication for Thiazolidenedione therapy. K. Starkey, A. Heufelder, G. Baker, M. Evans, J.S. Davies, M. Ludgate. Department of Medicine (Endocrinology, Diabetes & Metabolism), UWCM, Cardiff.
    
29. A multicentre randomised trial comparing policies of pausing or continuing chemotherapy for advanced colorectal cancer. T.S. Maughan, R.D. James, D. Kerr, J.A. Ledermann, M.T. Seymour, C. Topham, D. Cain, and R.J. Stephens on behalf of the MRC Colorectal Cancer Group. Clinical Trials Unit, Velindre Hospital NHS Trust, Cardiff.
    
30. The Wales Cancer Trials Network: the first three years. T.S. Maughan, M.D. Mason, N. Stuart, L. Branston. Department of Medicine (Oncology), Velindre Hospital NHS Trust, Cardiff.
    
31. The role of CD44 and Ezrin in the adhesion and invasiveness of prostate cancer cells during endothelium interactions. G.M. Harrison, W.G. Jiang, M.D. Mason. Departments of Medicine (Oncology) and Surgery, Metastasis Research Group, UWCM Cardiff.
    
32. The generation of human T-lymphocytes using individual thymic stromal culture systems. R.H. Evans^1,2, K.E. Hartman², S.A. Kalams², D.T. Scadden². 1. Department of Medicine, UWCM, Cardiff; 2. Partners AIDS Research Centre, Massachusetts, Harvard Medical School, Boston, USA.
    
33. Nitric oxide and nonlinear control of vascular tone. D. Parthimos, D.H. Edwards, T.M. Griffith. Department of Diagnostic Radiology, Wales Heart Research Institute, UWCM, Cardiff.
    
34. Role of gap junctions in the mediation of endothelium-dependent relaxation. A.T. Chaytor, D.H. Edwards, T.M. Griffith. Department of Diagnostic Radiology, Wales Heart Research Institute, UWCM, Cardiff.
    
35. Deletion of the gene encoding CD59 in mice increases disease severity in a murine model of rheumatoid arthritis. A.S. Williams¹, D. Holt², P.J. Richards¹, R.M. Goodfellow¹, B.D. Williams¹, B.P. Morgan². 1. Department of Medicine (Rheumatology); 2. Complement Biology Group, Department of Medical Biochemistry, UWCM, Cardiff.
    
36. n-3 Fatty acids; modulation of pathological mediators in arthritic synovial tissue. A.S. Williams¹, S. Rees², P.J. Richards¹, N. Amos¹, J.L. Harwood², C. Dent³, B. Caterson², B.D. Williams¹. 1. Department of Medicine (Rheumatology), UWCM, Cardiff; 2. Connective Tissue Biology Laboratory, University of Wales College Cardiff; 3. Department of Trauma and Orthopaedic Surgery, UWCM, Cardiff.
    
37. Loss of e-cadherin from prostate cancer cells is mediated by matrilysin, a novel mechanism in HFFISF-induced cellular scattering. G. Davies, W.G. Jiang, M.D. Mason. Departments of Surgery and Medicine (Oncology), UWCM, Cardiff.
    
38. Cancer and the telomere clock. Kipling D. Department of Pathology, UWCM, Cardiff.
    
39. Maths: a new sydrome caused by lactose intolerance. S.B. Matthews, A.K. Campbell. Department of Medical Biochemistry, Cardiff and Vale NHS Trust, and UWCM, Cardiff.
    
40. Mutational analysis of British families with pseudoxanthoma elasticum. F.M. Pope, C. Elford, M. Campbell, C.S. Smith, F. McDonald, D. Germain. Division of Life Sciences, Kings College, London; Department of Child Health, UHW; Department of Clinical Genetics, Birmingham Womens Hospital; Hopital European Georges Pompidou, Paris.
    
41. Use of a portfolio in a final GP attachment: inter-rater reliability, student evaluation and tutors' comments. A. Grant. Department of General Practice, UWCM, Cardiff.
    
42. The contribution of Epstein-Barr virus Latent-Membrane Protein-1 to the pathogenesis of Hodgkin's Disease. M. Rowe¹, C. Fielding¹, A. Mehl¹, P. Brennan¹, S. Hoe Park². 1. Department of Pathology (Infection & Immunity), UWCM, Cardiff; 2. National University of Medicine, Seoul, Korea.
    
43. Pacing the left ventricle via the coronary sinus in heart failure acutely improves diastolic filling by relieving diastolic ventricular interaction. R.A. Bleasdale¹, M.S. Turner¹, C.E. Mumford¹, G. Middleton², V. Paul³, J.A. Morris-Thurgood¹, M.P. Frenneaux¹. 1. Department of Cardiology, UWCM, Cardiff; 2. Department of Medical Physicis, UHW, Cardiff; 3. Department of Cardiology, St. Peter's Hospital, Chertsey.
    
44. Effectiveness of pulmonary rehabilitation: analysis of numbers needed to treat. P.J. Turner Lawlor, T.L. Griffiths. Department of Medicine (Respiratory Medicine), UWCM, Llandough Hospital, Penarth.
    
45. Bone mineral density in patients with COPD and low body mass. K. Shiels, E. Jones, R. Pettit, T.L. Griffiths. Department of Medicine (Respiratory Medicine) UWCM, Llandough Hospital and Department of Medical Physics, Cardiff and Vale NHS Trust.
    
46. Role if IL-6 and its soluble receptors in the control of acute inflammation. N. Topley¹, T. Wilkinson¹, S. Hurst¹, R. McLoughlin¹, J.D. Williams¹, S. Jones². 1. Department of Medicine (Institute of Nephrology), UWCM, Cardiff; 2. School of Biosciences, UCC, Cardiff.
    
47. Differentiation to a myofibroblast phenotype is associated with structural changes in cell surface proteoglycans. G. Thomas, M. Davies, R. Steadman. Department of Medicine (Institute of Nephrology) UWCM, Cardiff.
    
48. The expression of hyaluronan synthase isoforms and the rate of wound healing of human peritoneal mesothelial cells in a high throughput in vitro model. T. Bowen, L.W. Morgan, S. Yung, J. Martin, A. Calabro, V.C. Hasuall, N. Topley, M. Davies, J.D. Williams. Department of Medicine (Institute of Nephrology), UWCM, Cardiff.
    
49. Altered body composition in chronic respiratory disease. A.A. Ionescu, W.D. Evans, L.S. Nixon, K. Chatham, P.A. Routledge, D.J. Shale. Department of Medicine (Respiratory Medicine), UWCM Llandough Hospital, Penarth.
    
50. Admissions to Cardiff Poisons Treatment Unit involving drugs of abuse, between 1989 to 2000. R.A. Spears, J.P. Thompson, P.A. Routledge, A. Hutchings. Therapeutics and Toxicology, Academic Centre, UWCM Llandough Hospital, Penarth.
    
51. The psychosocial impact of the All Wales Cancer Genetics Service. C. Wilkinson, J. Turner, R Tudor-Edwards. Department of General Practice, UWCM, Cardiff.
    
52. Archie Cochrane, man of vision with feet of clay! His work and ‘The Collaboration’. Professor P.C. Elwood. MRC Unit, UWCM Llandough Hospital, Penarth.
    
53. Gene array for defining prognosis in acute myeloid leukaemia. K.I. Mills and A.K. Burnett. Department of Haematology, University of Wales College of Medicine, Cardiff.
    

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