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Q J Med 2000; 93: 767-781
© 2000 Association of Physicians

Annual General Meeting

The Association of Physicians of Great Britain and Ireland 2000

Ninety-fourth Annual General Meeting

The Ninety-fourth Annual General Meeting was held in London on Thursday and Friday 27 and 28 April. The attendance book was signed by 277 ordinary members and 50 senior members.

The President, Professor C.R.W. Edwards, took the chair.

The Minutes of the last Annual General Meeting, having been published in QJM (December 1999), were taken as read, confirmed and signed. The following Officers and Executive Officers were elected:

Executive Committee

President: Professor C.R.W. Edwards President-elect: Professor N.D.C. Finlayson Honorary Treasurer: Professor A.P. Weetman Honorary Secretary: Professor S.A. Amiel

Members for English and Wales

Professor J.M. Rhodes Professor M. Whyte Professor J.G.P. Sissons Professor M. Wiles Professor P.J. Vallance

Members for Scotland

Professor J. McKillop Professor B. Williams Professor J. Seckl

Members for Ireland

Professor A.A.J. Adgey Professor R.W. Stout Professor D. Powell

The following Honorary, Senior and Ordinary Members were elected:

Honorary Members

Dr D. Fearon Dr M.J. Whelton Dr T. Segal

Senior Members

Dr M. Allison Dr J.P. Miller Dr K.D. Bardham Dr I.M. Murray-Lyon Professor C.J. Bulpitt Professor M.C. Orme Dr D.L.W. Davidson Professor G.S. Panayi Professor A.I.F.W. Eddleston Professor A.B. Tattersfield    Eddleston Dr D.C. Evered Dr R.P.H. Thompson Dr R. Harvey Dr W.M.G. Tunbridge Dr G.R.V. Hughes Dr A.D.B. Webster Professor D.C. Mackie Professor D.G. Williams

Ordinary Members

Ballinger, Anne B, MD, MRCP. Senior Lecturer Honorary Consultant, Digestive Diseases Research Centre, St Bartholomew's & The Royal London School of Medicine, Turner Street, London E1 2AD

Bonthron, Professor David T, BM, ChB, MRCP, FRCP. Professor of Molecular Paediatrics, Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds LS0 7TF

Camici, Professor Paolo G, MD, FACC, FESC, FRCP. Professor of Cardiovascular Pathophysiology, MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN

Day, Christopher P, BA, MBChB, MA, MRCP, MD, PhD, FRCP. Senior Lecturer in Hepatology/Consultant Physician, Department of Medicine, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH

Eastell, Professor Richard, BSC, MD, FRCP, MBChB, MRCP, FRCP. Professor of Bone Metabolism/Director, Division of Clinical Sciences, University Division of Clinical Sciences Centre, Northern General Hospital, Sheffield S5 7AU

Field, Max, BSc, MD, FRCP. Senior Lecturer, University Department of Medicine, Queen Elizabeth Building, Royal Infirmary, Glasgow G31 2ER

Finlay, Professor Andrew Y, MBBS, MRCP, FRCP. Professor of Dermatology/Honorary Consultant Dermatologist, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN

Hattersley, Professor Andrew T, BA, BM, ChB, MRCP, MA, DM, FRCP. Professor in Molecular Medicine, Department of Diabetes and Vascular Medicine, University of Exeter, School of Postgraduate Medicine and Health Sciences, Barrack Road, Exeter, Devon EX2 5AX

Iredale, John R, BM, MRCP, DM, FRCP MRC. Senior Clinical Fellow, Division of Cell & Molecular Medicine, Mailpoint 811, Level D, South Block, Southampton General Hospital, Southampton SO16 6YD

Isenberg, Professor David A, MBBS, MRCP, MD, FRCP. Professor of Rheumatology, Center for Rheumatology, Middlesex Hospital, Arthur Stanley House, 40–50 Tottenham Street, London W1P 9PG

Johnston, Professor Sebastian L, MBBS, MRCP, PhD. Professor Fellow in Respiratory Medicine, Department of Respiratory Medicine, National Heart and Lung Institute of St Mary's, Imperial College School of Medicine, Norfolk Place, London W2 1PG

Krishna, Sanjeev, BA(Hons), BM BCh, MRCP DPhil. Honorary Senior Lecturer/Consultant Physician, Department of Infectious Diseases, St George's Hospital Medical School, Cranmer Terrace, Tooting, London SW17 0RE

Macdonald, Professor Thomas M, BSc, MBChB, MD, FRCP, LLD. Professor of Clinical Pharmacology and Pharmacoepidemiology, Department of Clinical Pharmacology and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY

Moore, Kevin P, BSc, MBBS, MRCP, FRCP. Senior Lecturer in Medicine, Department of Medicine, Royal Free Hospital, London NW3 2PF

Phillips, Aled O, BSc, MB, BCh, MRCP, MD. Senior Lecturer/Consultant Nephrologist, Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN

Reid, Professor David M, MBChB, MRCP, MD, FRCP. Professor of Rheumatology, Department of Medicine & Therapeutics, University of Aberdeen Medical School, Polwarth Building, Aberdeen AB25 2ZD

Seckl, Michael J, BSc, MBBS, MRCP, PhD. Lung Cancer Research Group, CRC Laboratories, Cyclotron Building, Hammersmith Hospital, Du Cane Road, London W12 0NN

Stevenson, Robert D, MBChB, MD, FRCP. Consultant Physician in Respiratory Medicine, Department of Respiratory Medicine, Royal Infirmary, Glasgow G4 0SF

Thursz, Mark, MBBS, MRCP, MD. Senior Lecturer in Medicine, Division of Medicine, Imperial College School of Medicine, St Mary's Campus, Norfolk Place, London W2 1NY

Trembath, Professor Richard C, BSc, MBBS, MRCP, FRCP. Professor of Medical Genetics/Head, Division of Medical Genetics/Honorary Consultant in Clinical Genetics, Department of Medicine and Genetics, University of Leicester, University Road, Leicester LE1 7RH

Unwin, Professor Robert J, BM, PhD, MRCP, FRCP. Professor of Physiology & Nephrology, Center for Nephrology, University College London, Bland-Sutton Building, Middlesex Hospital, Mortimer Street, London W1N 8AA

Williams, Graham R, BSc, MBBS, MRCP, PhD, FRCP. MRC Group Head (Associate)/Senior Lecturer/Honorary Consultant, Imperial College School of Medicine, Molecular Endocrinology Group, 5th Floor, MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN

Willison, Hugh J, MBBS, MRCP, PhD, FRCP. Reader in Neurology/Honorary Consultant, University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, South Glasgow University Hospitals NHS Trust, Glasgow G51 4TF

Woolf, Adrian S, MBBS, MA, MRCP, MD, FRCPCH. Head of Nephro-Urology Unit/Reader in Nephrology, Nephro-Urology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH

The new members were welcomed to the Association by the President. The President also thanked Doctors Michael Whelton and Michael Murphy for hosting the Association's last meeting in Cork.

The Honorary Treasurer, Professor A.P. Weetman, presented his report as Honorary Treasurer.

Professor Julian Hopkin, Executive Editor of QJM, reported that discussions of collaboration between the QJM and The Royal College of Physicians Journal had concluded that a combined journal would not meet the needs of the organizations involved, but after discussion with each of the Royal Colleges of Physicians including Edinburgh, Glasgow, London and Dublin, the QJM would be made available to their fellows and members at a reduced rate—the electronic journal £20 and the paper version £35. Professor Hopkin then announced his resignation after eight years in service.

Professor David Warrell reported that Professor Julian Hopkin was resigning as Executive Editor and had agreed to remain in post until a suitable replacement could be appointed. The post had been advertised in the QJM, and flyers describing the post and inviting submissions were also in the delegate packs for the present meeting.

Professor N.D.C. Finlayson, President-elect, invited the Association to its next meeting in Edinburgh, Scotland on 5 and 6 April, 2001.

Opening Reception and Annual Dinner

The welcome reception was held at the Science Museum in South Kensington. An excellent buffet was provided and the occasion was enjoyed by all. The History of Medicine lecture was presented by Professor Roy Porter and the Annual Dinner on the Friday night was held at the Royal College of Physicians of London.

Scientific Business

Thursday 27 April
2.00–3.00 p.m.

Professor John Collinge, Director of MRC Prion Unit, Head of Department of Neurogenetics, Imperial College of Medicine, London. The Osler Lecture—The human prion diseases: from the South Fore to South Kensington

3.00 p.m. (1)

J. C. Mason (introduced), E. Lidington (introduced), H. Yarwood (introduced), K. Davies, D.O. Haskard. Cardiovascular Medicine and Rheumatology Units, ICSM, Hammersmith Hospital, London. Induction of endothelial cell (EC) decay-accelerating factor (DAF) expression—a mechanism for cytoprotection against complement-mediated injury during inflammation and angiogenesis

Vascular endothelium, by virtue of its anatomical location, is directly exposed to autologous complement. This potential for local endothelial injury is increased in chronic inflammatory diseases such as rheumatoid arthritis, vasculitis and atherosclerosis by complement activation. We investigated the hypothesis that maintenance of vascular integrity during inflammation is dependent upon the induction of the complement regulatory proteins DAF, CD59 and membrane cofactor protein (MCP). All three proteins were identified on resting ECs, and no induction of CD59 or MCP expression was observed. In contrast, TNF, IFN and C5b-9 each increased DAF expression via a protein kinase C (PKC)-independent pathway. Furthermore, vascular endothelial growth factor (VEGF) and thrombin were identified as agonists for a distinct PKC-dependent pathway of DAF expression. Upregulation depended upon increased DAF mRNA and protein synthesis, and was maximal at 24 h (thrombin, C5b-9) and 48–72 h (TNF/IFN and VEGF). Pharmacological antagonists showed that whilst VEGF-induced expression required p38 MAPK activation, the effect of thrombin was inhibited by antagonists of both p38 and p42/44. Increased DAF expression was functionally relevant, since it reduced C3 deposition following complement activation by 60% (p<0.02), and this was inhibited by anti-DAF mAb 1H4 (p<0.02). Furthermore, 1H4 (but not control mAbs) also led to a significant increase in EC apoptosis in VEGF-stimulated cultures (p<0.05) and inhibited proliferation (p<0.02). These data provide evidence for distinct pathways for the regulation of complement activation during inflammation and angiogenesis, which may represent important mechanisms for the maintenance of vascular integrity during chronic inflammation. However, our data also suggest that DAF may have functions related to EC survival that are additional to complement regulation.

3.25 p.m. (2)

M. Gurnell (introduced)¹, I. Barroso (introduced)², V.E.F. Crowley (introduced)^1,3, A.J. Schafer (introduced)², S. O'Rahilly^1,3, V.K.K. Chatterjee¹. University of Cambridge, Departments of ¹Medicine and ³Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK. ²Incyte Genetics Ltd, Cambridge, UK. Dominant negative mutations in human PPAR are associated with severe insulin resistance, diabetes mellitus and hypertension

Thiazolidinediones represent a novel class of anti-diabetic agent. They improve insulin sensitivity and lower plasma glucose and blood pressure in subjects with type 2 diabetes. Although these agents are high-affinity ligands for the peroxisome proliferator-activated receptor gamma (PPAR), there is no direct evidence to conclusively implicate this nuclear receptor in mammalian glucose homeostasis. We have screened the human PPAR gene in a cohort of 84 unrelated subjects with severe insulin resistance, defined by the coexistence of extreme hyperinsulinaemia and the skin lesion acanthosis nigricans. Two different heterozygous missense mutations (P467L, V290M) were identified within the PPAR ligand-binding domain, in three subjects from two families, but not in unaffected members or control subjects. In addition to severe type 2 diabetes mellitus, all affected individuals developed early-onset marked hypertension unrelated to diabetic comorbidity.

In the PPAR crystal structure, the P467L and V290M mutations are predicted to destabilize helix 12 which is critical for transactivation by the receptor. Consonant with this, both receptor mutants exhibit impaired ligand-binding, coactivator recruitment and transcriptional activity. Moreover, they inhibit the action of coexpressed wild-type PPAR in a dominant negative manner. As in other mutant nuclear receptor contexts (acute promyelocytic leukaemia, resistance to thyroid hormone), this property correlates with their ability to silence basal gene transcription through aberrant corepressor (NCoR, SMRT) interaction. Our findings represent the first germline loss-of-function mutations in PPAR, and provide compelling genetic evidence that this receptor is important in controlling insulin sensitivity, glucose homeostasis and blood pressure in man.

4.15 p.m. (3)

D.A. Price (introduced), A. Oxenius (introduced), P.J. Easterbrook (introduced)¹, C.A. O'Callaghan (introduced), A.D. Kelleher (introduced), J.A. Whelan (introduced), G. Sontag (introduced)², A.K. Sewell (introduced), R.E. Phillips. Nuffield Department of Clinical Medicine and Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU; ¹Caldecot Centre, King's College Hospital, London SE5 9RS; ²St Stephen's Centre, Chelsea and Westminster Hospital, London SW10 9NH. Highly active antiretroviral therapy for primary HIV-1 infection preserves immune function of virus-specific T lymphocytes

Highly active antiretroviral therapy (HAART) has been strongly advocated for the management of primary human immunodeficiency virus (HIV) infection. However, the effects of early therapeutic intervention on host immunity, in particular the critical virus-specific T lymphocyte response, are unclear. We conducted a longitudinal analysis of HIV-specific T cell immunity in patients with strictly defined primary HIV-1 infection. HAART was initiated either at seroconversion or after a delay of at least 6 months. The impact of early versus delayed treatment on HIV-specific T lymphocyte responses was assessed functionally by direct ex vivo interferon (IFN) ELISPOT analysis, and physically by peptide-human leukocyte antigen (HLA) class I tetrameric complex quantification. Initiation of HAART at seroconversion preserved HIV-specific CD8⁺ cytotoxic T Lymphocyte function while treatment was maintained; this sustained CD8⁺ T lymphocyte activity correlated with measurable HIV-specific CD4⁺ T lymphocyte help. Further, even a limited course of HAART for 2 to 6 weeks during primary infection preserved HIV-specific T lymphocyte responses. In contrast, delayed initiation of HAART, when acute HIV infection had resolved, led to a progressive decay in both the number and function of HIV-specific CD8⁺ T lymphocytes; this was associated with absent HIV-specific CD4⁺ T lymphocyte help. These results demonstrate that unless HAART is initiated at seroconversion, HIV-specific T lymphocyte responses are compromised. The implications of this study in relation to the timing of therapeutic intervention in HIV-1-infected individuals are discussed.

4.40 p.m. (4)

C. Berry (introduced), Y. Alexander (introduced), M.J. Brosnan (introduced), C.A. Hamilton (introduced), J.J.V. McMurray, A.F. Dominiczak. University Department of Medicine and Therapeutics, Western Infirmary, University of Glasgow, Glasgow G11 6NT. Angiotensin-II-stimulated superoxide production in human blood vessels

Increased superoxide (O^-₂) production may contribute to reduced bioavailable nitric oxide and endothelial dysfunction in vascular disease states. We sought to investigate whether, and by what mechanisms, angiotensin II (AII) may increase O^-₂ production in human blood vessels. Internal mammary arteries (IMA) collected at the time of coronary revascularization surgery were incubated in the absence (control) or presence of 1 µmol/l AII, or 1 µmol/l norepinephrine (NE) for 4 hs. AII-incubated rings were also co-incubated in the presence or absence of an NADH oxidase inhibitor, diphenyleneiodonium (DPI, 1000 µmol/l) or a specific AII type 1 (AT₁) receptor antagonist, losartan (1 µmol/l). Superoxide production was measured by lucigenin-enhanced chemiluminescence. Immunocytochemical identification of NADH oxidase within the vessel wall was undertaken using specific monoclonal antibodies to the active subunits, p22 and p91 phox. AII increased O^-₂ production in IMA (control=978±117 pmol/min/mg, AII 1690±213 pmol/min/mg; n=27, p<0.0001) whereas NE, which was used as a positive control, did not (control 731±323 pmol/min/mg, NE 636±241; n=10, p=0.76). Losartan blocked the AII-mediated increase of O^-₂ production (losartan 947±245 pmol/min/mg, losartan+ AII 1037±231 pmol/min/mg tissue; n=11, p=0.15). Inhibition of NADH oxidase enzyme by co-incubation with DPI inhibited the AII-mediated increase in O^-₂ production (DPI 1124±338 pmol/min/mg. AII+DPI 1055±146 pmol/min/mg; n=8, p=0.9). P22 and p91 phox proteins were identified throughout the vascular wall. We report, for the first time in human arteries, that angiotensin II increases O^-₂ production by an AT₁-receptor-specific, NADH oxidase-dependent mechanism. These observations suggest a novel therapeutic role for AT₁ receptor antagonists in reducing oxidative stress in cardiovascular disease.

5.05 p.m. (5).

D.M. Forton^1,2 (introduced), H.C. Thomas², S.D. Taylor-Robinson^1,2 (introduced). ¹MR Unit, Hammersmith Hospital, ²Hepatology Section, Department of Medicine, St Mary's Hospital, Imperial College School of Medicine, London. Does hepatitis C affect the brain? A proton magnetic resonance spectroscopy (¹H-MRS) study

Patients with hepatitis C (HCV) often report symptoms of fatigue and depression, scoring lower on quality-of-life questionnaires than patients with hepatitis B (HBV) and equivalent hepatic inflammation. Negative-strand HCV RNA has been detected in monocytes and dendritic cells, indicating viral replication. HCV may be introduced from monocytes to microglia by a Trojan horse mechanism. We examined the hypothesis that cerebral metabolite abnormalities result from HCV infection of the brain.

Magnetic resonance spectra were acquired from voxels positioned in the basal ganglia (BG), white matter (WM) and occipital grey matter (GM) using a PRESS sequence (TE 135 ms, TR 1500 ms) at 1.5 T in three patient groups: (1) 27 patients with biopsy-proven mild HCV infection (mean age 44.7, 46% male, mean liver necro-inflammatory score 3.3/18, mean liver fibrosis score 1.6/6), of who 33% had a history of previous intravenous drug abuse (IVDA+ve) at least 6 months prior to the study; (2) 11 HbeAg+ve patients with HBV infection without cirrhosis, none IVDA-ve; (3) 20 healthy volunteers (mean age 42.0, 50% male), none IVDA+ve.

A significant elevation in BG choline/creatine was seen in the HCV group compared to the other groups [median Cho/Cr and (ISD): HCV: 1.12(0.15); HBV: 0.96(0.15)**; Vols: 1.05(0.13)*. **p<0.005, *p<0.02]. A similar non-significant trend was seen in WM. No difference was seen in the HCV group according to IVDA+ve status. This study demonstrates BG MRS abnormalities in HCV infection in the absence of cirrhosis. Similar abnormalities occur in cerebral HIV infection. The changes associated with hepatic encephalopathy are qualitatively different. Our finding that HBV patients (viraemic controls) have normal MRS suggests that the passage of systemic cytokines across the blood-brain barrier is unlikely to be the cause of the HCV abnormalities. This, together with the absence of a correlation with IVDA, raises the possibility of direct cerebral infection by HCV.

Friday 28 APRIL
9.00 a.m. (6).

P.J. McKeveney (introduced), V.M. Hodges (introduced), D.A. Simpson (introduced), T.R.J. Lappin (introduced), P.C. Winter (introduced), C.C. Doherty, A.P. Maxwell. Department of Haematology, The Queen's University of Belfast and Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB. ERICs—a novel family of erythropoietin-responsive genes involved in cell development

The polypeptide hormone erythropoietin (EPO) plays an integral role in erythropoiesis. Although widely used for treating renal anaemia, the genes regulated by EPO are not fully defined. We used differential display polymerase chain reactions to identify candidate EPO-responsive genes by comparing gene expression in murine splenic erythroblasts stimulated or deprived of EPO. We identified and cloned a novel cDNA tag whose expression, confirmed by ribonuclease protection assay, is stimulated 3-fold by EPO.

Database searching with the sequence of this gene, designated ERICI (erythropoietin-induced cDNA 1), permitted extension of the murine ERICI sequence, and revealed a series of humans EST homologues, indicating that there are three distinct human genes with homology to ERICI. The murine and human ERIC genes have been found, by reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blotting analyses, to be widely expressed both within the haematopoietic compartment and in non-haematopoietic tissues such as kidney, thymus, testis and spleen, suggesting a fundamental role in cell function. The complete 2.5 kb human ERICI coding sequence has now been cloned. This translates to a protein with tyrosine phosphorylation and coiled coil domains. Using a baculovirus expression system to produce human ERICI protein, we have generated specific antisera (confirmed by Western blotting) for subsequent functional and immunohistochemical studies. Human ERICI is phosphorylated in vitro and has a perinuclear localization in response to EPO stimulation, suggesting a role in signal transduction.

EPO stimulation of erythroid cells transiently upregulates ERICI with maximal gene expression between 12 and 18 h. The tissue distribution of human ERICI in vivo implies that this protein is not restricted to erythopoiesis but has a wider role in cell development.

9.25 a.m. (7).

S. Krishna (introduced) and C.J. Woodrow (introduced by G.E. Griffin). Department of Infectious Diseases, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE. Intraerythrocytic Plasmodium falciparum expresses a high-affinity glucose transporter: implications for the pathophysiology of hypoglycaemia in cerebral malaria

Asexual stages of Plasmodium falciparum cause severe malaria and are wholly dependent upon host glucose for energy. We have identified a hexose transporter in the membrane of P. falciparum (PfHT1) and studied its function and expression during parasite development in vitro. PfHT1 is a saturable, sodium-independent and stereospecific transporter that has a relatively high affinity for glucose (K_m=1 mM) when expressed in Xenopus laevis oocytes. Competition experiments with glucose analogues show that hydroxyl groups at positions C-1 and C-3 are important for ligand binding. mRNA levels for PfHT1, assessed quantitatively using PCR techniques, are highest during the small ring stages of infection and are tightly regulated during development. Confocal immunofluorescence microscopy localizes PfHT1 to the region of the parasite plasma membrane and not to host structures. PfHT1 can also transport fructose (K_m=11 mM), and fructose replaces glucose as an energy source for cultured parasites. Erythrocytes express GLUT1 (a glucose-specific) and GLUT5 (a fructose-specific) transporter. Extension of competition studies on PfHT1 from oocytes to cultured parasites confirm that in infected erythrocytes, glucose enters through GLUT1 and fructose through GLUT5, but that uptake into parasites is via a single transporter with the enzymic characteristics of PfHT1. The high affinity of glucose for PfHT1 has implications in the pathogenesis of cerebral malaria, in which microvascular obstruction of cerebral capillaries with parasitized red cells is characteristic. Modelling studies suggest that the relatively high affinity of PfHT1 increases the proportion (by up to 60%) of glucose taken up by parasites compared with that transported across the blood brain barrier when glucose delivery becomes rate-limiting for metabolism. These findings have implications for development of new drug targets in malaria as well as for understanding the pathophysiology of severe disease.

9.50 a.m. (8).

R.C. Trembath¹ (introduced), D. Lloyd¹ (introduced), S. Jackson¹ (introduced), S. O'Rahilly², S. Shackleton¹ (introduced). ¹Division of Medical Genetics, University of Leicester, ²Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge. Partial lipodystrophy (PLD) is caused by domain-specific mutations of the gene encoding the nuclear envelope protein lamin A/C

We have recently described the clinical and genetic features of partial lipodystrophy (Dunnigan-Köbberling type), a model of the metabolic syndrome X. In a genetic linkage study, we located the PLD gene at 1q11-q23 with evidence of a common founder haplotype. Fine regional mapping using a panel of nine markers typed in a further seven independent kindreds with PLD detected a number of disease specific haplotypes. Two chromosome recombination events were observed in two affected individuals, suggesting that the disease gene is located in a 3.9 cM interval between markers D1S2346 (centromeric boundary) and D1S2624 (telomeric boundary).

LMNA has been localized to 1q21.2 in an interval containing the markers D1S2624 and D1S2125 by radiation hybrid mapping. The A type lamins (lamins A and C) are two alternatively transcribed products of LMNA and are members of the intermediate filament (IF) family of proteins, forming components of the nuclear lamina, a fibrous proteinaceous meshwork underlying the inner nuclear membrane. Heterozygotes mutations of lamin A/C have recently been reported in the autosomal dominant type of Emery-Dreifuss muscular dystrophy, and in families presenting with dilated cardiomyopathy and conduction defects (CDM1). The molecular basis of the apparent tissue specificity is poorly understood. We searched for mutation of the LMNA gene in a cohort of 11 independently ascertained PLD families and observed highly-restricted and site-specific missense changes associated with a dystrophy process that appears to be predominant in a further cell type, namely the adipocyte. These disease states represent an important group of disorders associated with defects of the nuclear envelope.

10.15 a.m. (9).

A. Lalvani (introduced), A.A. Pathan (introduced), H. McShane (introduced), R.J. Wilkinson (introduced)*, M. Latif (introduced)*, C.P. Conlon (introduced), G. Pasvol* and A.V.S. Hill. Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU; *Wellcome Centre for Clinical Tropical Medicine, Imperial College School of Medicine, Northwick Park Hospital, London. Rapid detection of M. tuberculosis infection by enumeration of antigen-specific T cells

There is no reliable means of detecting latent M. tuberculosis infection and even in patients with active tuberculosis, confirmation of infection is often not possible. We hypothesized that the detection of M. tuberculosis antigen-specific T cells might accurately signal infection with this intracellular pathogen. Using a sensitive ex vivo enzyme-lined immunospot (ELISPOT) assay, we enumerated peripheral blood-derived interferon--secreting T lymphocytes responding to a panel of peptide epitopes from the early secreted antigenic target-6 (ESAT-6), an antigen that is highly specific for M. tuberculosis complex but absent from Bacille Calmette Guerin (BCG) 96% of tuberculosis patients (n=47) had circulating ESAT-6-specific T lymphocytes, compared with 8% of control patients with non-tuberculous illnesses (n=47), indicating that these T cells are an accurate marker of M. tuberculosis infection. By comparison, of the 26 tuberculosis patients who had a diagnostic tuberculin skin test, only 18 (69%) were positive (p=0.003). 85% of recently exposed household contacts (n=26) were identified as infected by our assay, while no unexposed BCG-vaccinated subjects responded (n=26). This antigen-specific T-cell-based approach enables accurate confirmation of M. tuberculosis infection in under 24 hs and successfully distinguishes between M. tuberculosis infection and BCG vaccination. This capability could facilitate global tuberculosis control by identifying latently infected individuals, and accelerating and improving diagnosis in patients with suspected tuberculosis.

11.10 a.m. (10).

I.S. Farooqi (introduced), G.S.H. Yeo (introduced), S. Aminian (introduced), J. Keogh (introduced), S. O'Rahilly. University Department of Medicine, Addenbrooke's Hospital, Cambridge. Mutations in the human melanocortin 4 receptor: the commonest monogenic form of human obesity

Recent studies of genetic syndromes of rodent obesity have provided novel insights into molecules involved in the control of energy homeostasis. Mice lacking the melanocortin-4 receptor (MC4R) are hyperphagic, severely obese, hyperinsulinaemic and exhibit increased linear growth; heterozygotes display an intermediate phenotype.

We sequenced the entire coding region of the MC4R gene in 243 subjects with severe, early-onset obesity (<10 years). We found two frameshift mutations (CTCT deletion in codon 211, GT insertion at codon 279) which segregated with obesity in the families in a dominant manner. We also identified six missense mutations, N62S, V103I (n=3), T112M, R165Q, I251L (n=7) and C271Y. V103I and I251L were also found in a control population. N62S was found in homozygous form in five children with severe obesity from a highly consanguineous pedigree; all four heterozygote parents were not obese. When the mutant receptors were co-transfected with a cyclic AMP-responsive reporter plasmid in HEK293 cells, no response to the addition of ligand (MSH) was seen with the CTCT deletion, whereas the N62S mutant showed an attenuated response (50% that of the wild-type receptor).

Several features of the phenotype, including hyperphagia, tendency to tall stature, hyperinsulinaemia and preserved reproductive function closely resemble those previously reported in MC4R knockout mice. Thus, mutations in MC4R represent the commonest monogenic form of human obesity described to date, and the mode of inheritance may reflect the degree of receptor signalling dysfunction resulting from specific mutations.

11.35 a.m. (11).

H.J. Lachmann (introduced), D.R. Booth (introduced), S.E. Booth (introduced), A. Bybee (introduced), J.D. Gillmore (introduced), P.N. Hawkins. National Amyloidosis Centre, Department of Medicine, Royal Free Hospital, London NW3 2PF. Hereditary systemic amyloidosis is unexpectedly frequent in Britain

Management of systemic monoclonal immunoglobulin AL amyloidosis includes high-dose chemotherapy. However, in contrast to reactive systemic AA amyloidosis, AL cannot be confirmed immunohistochemically in many cases. Diagnosis is based on clinical features and exclusion of other forms of amyloid, and although a monoclonal gammopathy supports the diagnosis it may be an incidental finding. Hereditary systemic amyloidosis is rare and is dominantly transmitted, and so has not been considered in the absence of a family history.

Recently we identified the fibrinogen -chain Glu526Val variant, a cause of hereditary amyloidosis not previously described in Britain, in a woman with end-stage hepatic and renal amyloidosis thought to be of AL type but who had survived unusually long. Plasma fibrinogen is produced in the liver, and she therefore received liver and kidney transplants. She is completely well 3 years later, and amyloid is longer seen on serum amyloid P component (SAP) scintigraphy. We have subsequently found this mutation in 12 of 80 British patients with non-AA amyloidosis but in none of 50 healthy controls. Four of these patients had received inappropriate chemotherapy. Hereditary fibrinogen amyloidosis usually present with renal dysfunction in middle age when there may also be amyloid in the liver, spleen and adrenal glands on SAP scintigraphy.

This mutation has previously been reported in only five kindreds worldwide but is evidently much more common and, importantly, has variable penetrance. Renal transplantation is appropriate for many patients, but liver transplantation is potentially curative and should be considered in severely affected younger individuals. Fibrinogen amyloidosis has a much better prognosis than AL type and the diagnosis has major implications for management and family support. DNA analysis is therefore mandatory in patients with systemic non-AA amyloidosis regardless of family history.

12.00 noon (12).

B. Gooptu (introduced), P.R. Elliott (introduced), J.T. Finch (introduced)*, R.L. Davis (introduced)**, A.E. Shrimpton (introduced)**, P. Holohan (introduced)**, R.W. Carrell (introduced), and D.A. Lomas. Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Hills Road, Cambridge, *Laboratory of Molecular Biology, MRC Centre, Cambridge, and **State University of New York Health Science Centre, Syracuse, USA. Familial dementia caused by polymerization of mutant neuroserpin

Substantial progress has been made towards understanding the pathophysiology of protein polymerization in the superfamily of serine protease inhibitors (serpins). We now describe a new disease, familial encephalopathy with neuroserpin inclusion bodies (FENIB), in a large pedigree of Irish-English descent. The disease is characterized by progressive dementia, perseveration and movement disorder. Post-mortem and ex vivo biopsies revealed characteristic PAS-positive, diastase-resistant inclusion bodies scattered through the cerebral cortex. The inclusions were unlike any seen previously and could not be characterized by a US reference laboratory. Biochemical analysis revealed the inclusions to be formed of the neurone-specific protein, neuroserpin. DNA analysis showed that all the affected individuals were heterozygotes for the 53SerPro Mutation in the neuroserpin gene. The onset of disease was within a narrow age range, with 5% of heterozygotes developing dementia under the age of 45, 42% by age 50, 70% by age, 53, and 83% by age 56; 95% of heterozygotes over 56 were affected. The location of the mutation at position 53 is identical to the Siiyama mutation of ₁-antitrypsin, associated with severe liver disease. We have previously shown that this deficiency is caused by intermolecular loopsheet insertions resulting in the formation of chains of ₁-antitrypsin polymers. Such polymers are poorly secreted, and accumulate in the endoplasmic reticulum in inclusion bodies that have similar characteristics to the neuroserpin inclusions described above. Examination of the inclusions from the brains of affected individuals showed that they were also formed by loopsheet polymers. Support for these findings comes from a second family with a similar phenotype and another neuroserpin mutation (53SerArg) that will also predictably favour the formation of polymers. Our findings provide a molecular mechanism for a familial dementia and suggest that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps more common neurodegenerative diseases.

12.25 p.m. (13).

G.T. McInnes, D.J. Hole (introduced), A.F. Lever, P.A. Meredith (introduced), L.S. Murray (introduced), J.L. Reid. Departments of Medicine and Therapeutics and Public Health, University of Glasgow, Western Infirmary, Glasgow G11 6NT. Outcome differences between hypertensive patients treated with ACE inhibitors and those treated with calcium channel blockers

The objective of this study was to compare the influences of mortality of ACE inhibitors (ACEIs) and calcium channel blockers (CCBs) in hypertensive patients. The Glasgow Blood Pressure Clinic holds a computerized data base of 11 000 hypertensive patients record-linked with the Registrar General Scotland for information of death and causes of death. Between 1 January 1980 and 31 December 1995, 5207 patients received prescriptions for antihypertensive drugs: ACEIs, n=1559; CCBs, n=2295. Compared with at-risk in-patients never treated with ACEIs or CCBs, all cause, CHD and vascular mortality was reduced in patients treated with ACEIs (but never CCBs) and increased in patients treated with CCBs (but never ACEIs). Patients exposed to both ACEIs and CCBs had intermediate levels of risk. Using Cox's proportional hazards model adjusted for age, sex and epoch (4 years) of first prescription, relative risk (RR) (compared with patients never receiving that class) for all-cause mortality (857 deaths) was 0.73 (p=0.009) in ACEI-treated patients and 1.35 (p=0.0002) in CCB-treated patients; RRs for all vascular mortality (514 deaths) were 0.77 (p=0.02) and 1.54 (p=0.0001), respectively, and RRs for CHD mortality (347 deaths) were 0.72 (p=0.03) and 1.72 (p=0.0001) respectively. Hypertensive patients treated with ACE inhibitors have a survival advantage. In contrast, treatment with CCBs is associated with a poorer outcome. Large numbers of well-documented fatal events and prolonged follow-up may have allowed the demonstration of morality differences not apparent in relatively short-term prospective trials.

3.00 p.m. (14).

A.S. Woolf (introduced), S.A. Feather (introduced), S. Malcolm (introduced), V. Wright (introduced), D. Blaydon (introduced), ¹C.J.D. Reid (introduced), ¹F.A. Flinter (introduced), ³W. Proesmans (introduced), ³K. Devriendi (introduced), ²P. Warwicker (introduced), ²J.A. Goodship (introduced) and ²T.H.J. Goodship. Nephro-Urology and Molecular Genetics Units, Institute of Child Health, University College London, ¹Division of Medical and Molecular Genetics, Guy's Hospital, London, ²Department of Medicine, University of Newcastle upon Tyne, Newcastle, UK and ³Centre for Human Genetics, Leuven, Belgium. Vesicoureteric reflux is genetically heterogenous with a major locus on chromosome 1

Primary vesicoureteric reflux (VUR) affects 1% of Caucasians, and associated reflux nephropathy (RN) causes 15% of chronic renal failure in children and adults. Genetics may play a role in the pathogenesis of VUR because of a 30–50-fold increased risk in immediate relatives of probands. We report the first genome-wide search of VUR and RN in seven European families with up to seven affecteds who have apparent dominant inheritance. We used 387 polymorphic markers spaced on average at 10 cM through the genome with affecteds-only parametric and non-parametric linkage analyses with the Genehunter programme.

The most positive locus spans 20 cM on chromosome 1 between markers GATA176C01 and D1S1653 with a non-parametric lod score (NPL) of 5.76 (p=0.0002) and a parametric lod score of 3.16. Saturation with markers at 1cM increased the NPL to 5.94 (p=0.00009). Hence, VUR maps to chromosome 1. This same region was significant in analyses for VUR alone or RN alone: thus lower-tract malformations and kidney disease may have identical genetic determinants. There was, however, evidence of genetic heterogeneity, and 12 additional loci were identified with p<0.05. Of note, no significant linkage was found to 6p, where a urinary tract malformation locus was previously reported, or to 10q where PAX2 mutations cause VUR in renal-coloboma syndrome. Our results support the hypotheses that VUR and RN are genetic disorders, and offer the prospect of genetic screening to replace invasive cystograms for diagnosis in selected kindreds.

3.25 p.m. (15).

J.C.S. Dean (introduced), S.J. Moore (introduced)*, A. Osborne (introduced), S. Joss (introduced), P.D. Turnpenny (introduced)**, N.E. Haites. Department of Medical Genetics, University of Aberdeen Medical School, Foresterhill, Aberdeen AB25 2ZD, *Newfoundland and Labrador Medical Genetics Program, Memorial University of Newfoundland, St John's, Newfoundland, Canada, **Clinical Genetics Service, Royal Devon and Exeter Hospital, Exeter. Adverse fetal effects of anti-epileptic drugs used in pregnancy are associated with mutation in the maternal MTHFR gene

Congenital malformations occur in 6–9% of children born to mothers taking anti-epileptic drugs (AED, anticonvulsants). The frequency of developmental delay is uncertain. Polypharmacy is associated with increased risk, but genetic factors may also play a role. Eighty-three affected children ascertained through the UK National Fetal Anticonvulsant Syndrome Association and clinical referral underwent a standardized clinical assessment. In 58 pregnancies, the mother took sodium valproate (valproate monotherapy in 40), in 24 carbamazepine (13 monotherapy) and in 10 phenytoin (five monotherapy). Thirty seven children (44%) had congenital malformations typical of AED exposure. Sixty (72%) showed delayed development, particularly affecting speech and language. Fifty-nine per cent had behaviour difficulties. Glue ear (28%), joint laxity (58%) and myopia (35%) were common. The fetal anticonvulsant syndromes as a group were associated with maternal homozygous 677CT mutation in MTHFR (methylene tetrahydrofolate reductase) (odds ratio 2.7, 95% CI 1.1–6.6). For fetal valproate syndrome, there was also an association with the child's genotype (²=6.47, p<0.04). The relative risk that the child of a mother homozygous for 677CT will suffer a fetal anticonvulsant syndrome is 2.05 (95% CI 1.16–3.6). This supports an aetiological role for the folic acid pathway in the fetal anticonvulsant syndromes. We suggest that where possible, epileptic mothers with homozygous MTHFR mutation should avoid valproate, carbamazepine and phenytoin. When these drugs cannot be avoided, the nature of the neurodevelopmental and other disorders seen suggests that folate supplements should be given throughout pregnancy and not just for the first trimester.

3.50 p.m. (16).

A.J. Simpson (introduced), J.-M. Sallenave (introduced) and C. Haslett. Rayne Laboratory, Medical School, Teviot Place, Edinburgh EH8 9AG. Genetic augmentation of elafin (elastase specific inhibitor) protects the lung against inflammatory injury

We are testing the hypothesis that genetic augmentation of epithelial production of the low-molecular-mass antiproteinase elafin will protect against inflammatory injury without deleterious consequences for antimicrobial host defences. Lung epithelial (A549) cells were transfected in vitro with replication-deficient adenovirus encoding elafin cDNA (Ad-elafin), with control virus (Ad-lacZ), or with medium alone prior to addition of neutrophil elastase (NE) or activated human neutrophils. Ad-elafin protected cells against NE-mediated injury morphologically, by reducing cell detachment (16% and 20% of detachment of untransfected and Ad-lacZ-treated cells, respectively, p<0.05), and by reducing release of ¹¹¹indium from radiolabelled cells. Protection was associated with inhibition of NE (2% of the NE activity in supernatants from untransfected and Ad-lacZ treated cells respectively, p<0.05). Ad-elafin also protected against morphological damage and ¹¹¹indium release induced by human neutrophils activated with PAF and fMLP. C57/B16 mice were then treated intratracheally with Ad-elafin, Ad-lacZ or phosphate-buffered saline (PBS), followed 5 days later by a dose of Pseudomonas aeruginosa known to induce lung injury. The following day bronchoalveolar lavage fluid (BALF) was retrieved. Ad-elafin treatment resulted in significantly less lung injury (median BALF protein 3.3 g/l in Ad-elafin mice, 5.4 in Ad-lacZ mice, 5.7 in PBS mice, p<0.05), and a trend towards reduced free neutrophil myeloperoxidiase in BALF. Thus augmented elafin production protects against neutrophil-mediated injury in vitro and against injury induced by bacteria in vivo. This approach may be applicable to the treatment of inflammatory lung disease, particularly where the lung is infected or at risk of serious secondary infections.

4.45 p.m. (17).

W.L.G. Oldfield (introduced), K.E. Shirley (introduced), B.M. Haselden (introduced), M. Larche (introduced), A.B. Kay. Department of Allergy and Clinical Immunology, Imperial College School of Medicine, National Heart and Lung Institute, London SW3 6LY. Attenuation of late-phase allergic reactions by MHC class II-restricted, allergen-derived T-cell peptide epitopes

Intradermal injection to T-cell peptide epitopes derived from a segment of chain 1 of Fel d 1 (the major cat allergen) elicited isolated late asthmatic reactions (LAR) in cat-allergic subjects of the appropriate MHC class II haplotype (Haselden BM et al., J Exp Med 1999; 189:1885). A single administration was followed by a period of hyporesponsiveness (‘anergy/tolerance’) which was maintained for up to 6 months. We have now synthesized multiple overlapping peptides (MOP) (16/17) which spanned the majority of both chains of Fel d 1 (and therefore presumably bind multiple HLA haplotypes) for use as a prototype therapeutic ‘vaccine’ for cat allergy. MOP did not release histamine in vitro from basophil-enriched peripheral blood mononuclear cells confirming the lack of IgE-binding/cross-linking. After administration to cat-allergic asthmatics, MOP provoked LARs (p=0.039). These reactions were dose-dependent in terms of the frequency and magnitude of the reactions (p=0.008). However, no further reactions were observed when peptides were readministered 2–18 weeks later (p=0.008). Furthermore, the cutaneous late-phase reaction to whole cat dander was markedly abrogated by a single intradermal injection of MOP (p=0.014). There was no change in the allergic early-phase reaction. Our data also suggest that incremental increases in MOP from low to high concentrations induced tolerance without LAR. Thus MHC class-II-restricted allergen-derived T-cell peptide epitopes may form the basis of a safe and effective desensitizing T cell-based vaccine for atopic allergic disease.

5.10 p.m.

Professor Roy Porter, Wellcome Institute for the History of Medicine. The History of Medicine Lecture—The public image of a physician in the eighteenth century

Table-top presentations

Digital imaging and PACS. D.J. Allison, N. Stickland. Department of Imaging, Division of Investigative Science, ICSM

The power of micro bubble imaging. D. Cosgrove, M. Blomley. Department of Imaging, Investigative Sciences Division, ICSM

Expression profiling of laser microdissected tissues by high density cDNA microarrays. T. Jurcevic, C. O'Meara, V. Efthasiou, Z. Leech. ICRF Molecular Oncology Unit, Department of Cancer Medicine, ICSM, Hammersmith Campus

Virtual reality objective assessment of psychomotor skills. A. Darzi¹, N. Taffinder¹, S. Smith¹, V. Datta¹, D. Kitney². ¹Division of Surgery, Anaesthetics and Intensive Care, ICSM, ²Biomedical Systems, Department of Electrical Engineering ICSTM

Small Area Health Statistics Unit-Rapid Inquiry Facility. P. Aylin, L. Jarup. Department of Epidemiology and Public Health, Division of Primary Care and Population Health Sciences, ICSM

Calcium regulation of cardiac contraction. A. Williams, S. Harding, K. Macleod, N. Severs, S. Marston. Department of Cardiac Medicine, NHLI Division, ICSM

Exhaled markers and mediators in exhaled breath condensate in patients with lung diseases. S.A. Kharitonov, T. Hanazawa, P. Montuschi, P.J. Barnes. Department of Thoracic Medicine, National Heart and Lung Institute, ICSM

Poster presentations

1. Investigations into the kinematics of rowing in elite oarsmen. A.H. McGregor^1,2, A.M.J. Bull², L. Anderton³, W.M.W. Gedroyc³. ¹Department of Orthopaedic & Trauma Surgery, ICSM, ²BioDynamic Group, ICSTM, ³IMR Unit, St Mary's Hospital
   
2. Stem cells: the future for tissue repair and replacement. J. Polak¹, L. Hench¹, L. Buttery¹, A. Bishop². ¹Tissue Engineering Centre, ICSM, ²Histochemistry, ICSM
   
3. Does hospital at home substitute for hospital care: Evidence from randomized controlled trials. S. Shepperd. Department of Primary Health Care and General Practice, Division of Primary Care and Population Health Sciences, ICSM
   
4. How effective and cost effective are community based Parkinson's disease nurse specialists? A large randomised controlled trial. B. Hurwitz, B. Jarman, A. Cook. Department of Primary Health Care and General Practice, Division of Primary Care and Population Health Sciences, ICSM
   
5. Northern Finland Birth Cohort Studies: Intrauterine and early life factors and adult health. M-R. Jarvelin¹, L. Lauren¹, P. Zitting², A-L. Hartikainen², P. Elliott¹. ¹Department of Epidemiology and Public Health, Division of Primary Care and Population Health Sciences, ICSM, ²Department of Public Health and General Practice, University of Oulu, Finland
   
6. On behalf of the INTERMAP Cooperative Research Group. INTERMAP Study: Design and Methods. P. Elliott, J. Diamond. Department of Epidemiology and Public Health, Division of Primary Care and Population Health Sciences, ICSM
   
7. Hepatitis C among injecting drug users. M. Hickman, A. Judd. Department of Social Science and Medicine, Division of Primary Care and Population Health Sciences, ICSM
   
8. Clinical trails of antihypertensive therapy for diabetic retinopathy: present and future. N. Chaturvedi¹, J. Fuller². ¹Department of Primary Health Care and General Practice, Division of Primary Care and Population Health Sciences, ICSM, ²Department of Epidemiology and Public Health, University College London
   
9. Rapid assessment and response: innovative public health technology. T. Rhodes, C. Fitch. Department of Social Science and Medicine, Division of Primary Care and Population Health Sciences, ICSM
   
10. Making sense of Wernicke's area. R. Wise¹, S. Scott², A. Leff¹, C. Blank¹. ¹Cyclotron Unit, MRC CSC, Division of Neuroscience and Psychological Medicine, ICSM, ²Institute of Cognitive Neurosciences, University College, London
    
11. Investigation of Novel Antidepressant Drug Action Using PET and [11C]WAY-100635: ß-blocker Binding to Human Brain 5-HT1A Receptors in vivo. E.A. Rabiner^1,2, R.N. Gunn¹, P.A. Sargent^1,2, M. Koepp¹, J. Meyer³, C.J. Bench¹, P.J. Cowen¹, P.M. Grasby¹. ¹Cyclotron Unit, Division of Neuroscience and Psychological Medicine, ICSM, ²Psychopharmacology Research Unit, Warneford Hospital, University of Oxford, ³The PET Centre, Clark Institute of Psychiatry, University of Toronto, Canada
    
12. Isolation of a progressive motor neuron dysfunction locus, Loa. S. Nicholson¹, A. Witherden¹, M. Hafezparast¹, J. Peters², S. Ball², J. Martin³, D. Rogers⁴, E. Fisher¹. ¹Department of Neurogenetics, Division of Neuroscience and Psychological Medicine, ICSM, ²MRC Mammalian Genetics Unit, Harwell, ³Royal London Hospital, Whitechapel, ⁴SmithKline Beecham
    
13. Identifying gene defects in motorneurone disease/amyotrophic lateral scierosis families that lack copper/zinc superoxide dismutase mutations. J. Mitchell, J. Habgood, R.W. Orell, N. Kaushik, A. Malaspina, I.M. Gardiner, J. Greenwood, J. deBelleroche. Department of Neuromuscular Diseases, Division of Neuroscience and Psychological Medicine, ICSM
    
14. Imaging the immune response to Alzheimer's and Parkinson's disease in vivo with PET. R. Banati, A. Cagnin, D. Brooks. Cyclotron Unit, MRC Clinical Sciences Centre, Department of Sensorimotor Systems, Division of Neuroscience and Psychological Medicine, ICSM
    
15. Suppression of pendular nystagmus by cannabis and alcohol in a patient with multiple sclerosis. A.L.M. Pambakian¹, T. Hodgson¹, P.E. Hart², F. Shon², C. Kennard¹. ¹Department of Sensorimotor Systems, Division of Neuroscience and Psychological Medicine, ICSM, ²Department of Neurology, Atkinson Morley Hospital, London
    
16. Novel ion channel targets for pain relief in injured human sensory neurons. K. Coward¹, S. Till¹, M. Boettger¹, P. Facer¹, R. Birch², C. Plumpton³, S. Tate³, C. Bountra³, P. Anand¹. ¹Peripheral Neuropathy Unit, Division of Neuroscience and Psychological Medicine, ICSM, ²Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, ³Molecular Pharmacology and Neurosciences Units, Glaxo Wellcome, Stevenage
    
17. Immune responses to dystrophin: implications for gene therapy of Duchenne muscular dystrophy. A. Ferrer, K.E. Wells, J. McMahon, D.J. Wells. Gene targeting Unit, Department of Neuromuscular Diseases, Division of Neuroscience and Psychological Medicine, ICSM
    
18. Mapping cerebral autonomic centres using functional neuroimaging in normal subjects and in autonomic failure. H. Critchley^1,2,3, R. Dolan², C.J. Mathias^1,3. ¹Autonomic Unit, National Hospital for Neurology & Neurosurgery/Institute of Neurology, University College London, ²Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London, ³Division of Neuroscience & Psychological Medicine, ICSM
    
19. Structural biology of prion replication. G.S. Jackson¹, L.L.P. Hosszul², A. Power¹, N.J. Baxter², J. Kenney³, H. Saibil³, J. Craven², J.P. Watho², A.R. Clarke¹, J. Collinge¹. ¹MRC Prion Unit and Department of Neurogenetics, ICSM, ²Krebs Institute for Molecular Biology and Biotechnology, University of Sheffield, ³Department of Crystallography, Birkbeck College, London, ⁴Department of Biochemistry, School of Medical Sciences, University of Bristol
    
20. The generation of transgenic animals by natural mating after transduction of spermatogonia. C. Readhead¹, Carlos Lois¹, Delyth Morgan², Robert Winston². ¹Department of Biology, California Institute of Technology, California 91125, USA, ²Department of Reproductive Science and Medicine, Division of Paediatrics, Obstetrics and Gynaecology, ICSM
    
21. Candidate genes in polycystic ovary syndrome. L. Haddad, N. Gharani, E. Cela, P. Saker, J. Evans, C. Robertson, K. Rush, M. McCarthy, S. Franks. ¹Department of Reproductive Science & Medicine, Division of Paediatrics, Obstetrics & Gynaecology, ICSM, ²Section of Endocrinology & Metabolic Medicine, Division of Medicine, ICSM
    
22. Laminopathies: a common cause of muscular dystrophy and isolated dilated cardiomyopathy. S. Brown, I. Naom, G. Camici, E. Mercuri, F. Muntoni, C.A. Sewry, I. Ugo. Dubowitz Neuromuscular Centre, Department of Paediatrics and Neonatal Medicine, Division of Paediatrics, Obstetrics & Gynaecology, ICSM
    
23. Maple syrup urine disease metabolites induce apoptosis in neural cells without cytochrome c release or changes in mitochondrial membrance potential. P. Jouvet¹, P. Rustin², U. Felderhoff¹, J. Pocock³, U. Joashi¹, N.D. Mazarakis¹, C. Sarraf⁴, A.D. Edwards¹, H. Mehmet¹. ¹Weston Laboratory, Division of Paediatrics, Obstetrics and Gynaecology, ICSM, ⁴Histopathology, ICSM, ²Unite de Recherche sur les Handicapes Genetiques de l'enfant, INSERM U393, Hopital Necker Enfants Malades, Paris, ³Department of Neurochemistry, Institute of Neurology, University of College London
    
24. Haemophilus genes in Neisseria: natural inter-generic chromosomal gene transfer between major human pathogens. S.J. Kroll, K.E. Wilks, J.L. Farrant, P.R. Langford. Division of Paediatrics, Obstetrics and Gynaecology, ICSM
    
25. Role of Cofactors for steroid hormone receptors in female reproduction. R. White¹, I. Rosewell¹, M.A. Jacobs¹, S. Milligan², M.G. Parker¹. ¹Division of Paediatrics, Obstetrics and Gynaecology, ICSM and Molecular Endocrinology Laboratory, ICRF, Lincoln's Inn Fields, ²King's College London, Guy's Campus
    
26. Neuropeptides in the new millenium: the cart before the horse. S. Taheri, S. Stanley, S. Russell, C. Small, K. Murphy, L. Seal, D. Morgan, D. Sunter, C. Abbott, C. Dakin, M. Ghatei, S. Bloom. Division of Investigative Sciences, ICSM
    
27. Enhanced susceptibility to sepsis due to SPEA-producing Streptococcus pyogenes in HLA transgenic mice. S. Sriskandan, M. Unnikrishnan, T. Kruasz, H. Dewchand, S. van Noorden, J. Cohen, D.M. Altmann. Departments of Infectious Diseases, Histopathology and transplantation Biology, MRC Clinical Sciences Centre, ICSM
    
28. The anti-Kaposl's sarcoma and anti-angiogenic activity of sulphated dextrins. M. Thornton, L. Barkley, J.C. Mason, S. Shaunak. Department of Infectious Diseases, Division of Investigative Science and Cardiovascular Medicine, NHLI Division, ICSM
    
29. Computer aided drug design in obesity. M. Barakat, P. Dean, S.R. Bloom. Department of Metabolic Medicine, Division of Investigative Science, ICSM
    
30. Molecular mechanism of action of glucocorticoids: effects on chromatin structure. K. Ito, P.J. Barnes, I.M. Adcock. Department of Thoracic Medicine, ICSM
    
31. Towards anti-inflammatory gene therapy for pulmonary and cardiovascular diseases. U. Griesenbach, P. Scheid, P.K. Jeffrey, J. Yap¹, N. Moat¹, D.M. Geddes, E.W.F.W. Alton. Department of Gene Therapy, National Heart and Lung Institute, and ¹Royal Brompton Hospital
    
32. Absolute myocardial blood flow to stunned myocardium is normal in patients with coronary artery disease. E. Barnes, D.P. Dutka, C.S.R. Baker, O. Rimoldi, P.G. Camici, R.J.C. Hall. Department of Cardiology and MRC Cyclotron Unit, Hammersmith Hospital
    
33. Washing powder asthma revisited. P. Cullinan, J.M. Harris, A.M. Hole, M. Jones, A.J. Newman Taylor. Department of Occupational and Respiratory Medicine, NHLI
    
34. Non-inflammatory phagocytosis of monosodium urate (MSU) crystals by macrophages: Implications for the control of joint inflammation in gout. C. Landis¹, D. Yagnik¹, P. Hillyer¹, D. Marshall¹, T. Krausz², D. Haskard¹. ¹BHF Cardiovascular Medicine Unit, NHLI, ICSM, ²Histopathology Department, Division of Investigative Science, ICSM
    
35. The electrophysiology of remodelling of gap-junctions in atrial fibrillation. P. Kanagaratnam, A. Chow, P. Patel, A. Cherian, D. O'Regan, R. Stanbridge, B. Glenville, R. Schilling, V. Markides, D. Davies, N. Severs, N. Peters. NHLI Division at St Mary's Hospital, ICSM
    
36. A small molecule antagonist of eosinophil chemokine receptors. I. Sabroe¹, VEL Stubbs¹, M.J. Peck², B. Jan Van Keulen², T.J. Williams¹, J.E. Pease¹. ¹Leukocyte Biology Section, Biomedical Sciences Division, Imperial College School of Medicine, ²UCB Pharma R & D, B-1420 Braine l’Alleud, Belgium
    
37. HHT at HHT: Patients, genes and models for an inherited vascular disease. G.M.F Wallace³, M.E. Begbie¹, P. Gupta², M. Chaudhary¹, C.I. Mordin¹, J. Curtis¹, J.M.B. Hughes¹, J.E. Jackson², J.J. Mullins³, C.L. Shovlin¹. ¹Respiratory Medicine, NHLI, ICSM, ²Department of Imaging, ICSM, ³University of Edinburgh
    
38. CD36 mutations and malaria susceptibility. T.J. Aitman¹, L.D. Cooper¹, P.J. Norsworthy¹, F.N. Wahid¹, B.R. Curtis², P.M. McKeigue³, D. Kwiatkowski⁴, B.M. Greenwood⁴, R.W. Snow⁵, K. Marsh⁵, A.V. Hill⁶, J. Scott¹. ¹Molecular Medicine Group, MRC CSC, ICSM, ²Blood Center of Southeastern Wisconsin, Medical College of Wisconsin, Milwaukee, USA, ³Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine, ⁴MRC Laboratories, Fajara, The Gambia, ⁵KEMRI Coastal Research Unit, Kilifi, Kenya, ⁶Wellcome Trust Centre for Human Genetics, University of Oxford
    
39. Fusogenic peptide mediate Triglyceride Capture by Microsomal Triglyceride Transfer Protein. J. Read¹, T.A. Anderson², P.J. Ritchie¹, B. Vanloo³, J. Amey¹, M. Rosseneu³, J. Scott^1,4, C.C. Shoulders¹. ¹MRC Molecular Medicine Group, MRC CSC, ICSM, ⁴NHLI Division, ICSM, ²Department of Biochemistry, University of Minnesota Medical School, Minneapolis, USA, ³Department of Biochemistry, University of Gent, Belgium
    
40. Targeted suicide gene therapy for breast and ovarian cancer: from the clinic to the future. I. McNeish, G. Vassaux, T. Tenev, V. Stoll, M. Marani, H. Hurst, N. Lemoine. ICRF Molecular Oncology Unit, Department of Cancer Medicine, ICSM, Hammersmith
    
41. TNF alpha regulates inflammatory cell traffic to the rheumatoid joint. P.C. Taylor¹, A.M. Peters², E. Paleolog¹, R.N. Maini¹. ¹Kennedy Institute of Rheumatology, ²Centre for Biological and Medical Systems, ICSTM
    
42. Application of microelectrodes to measure oxygen levels in arthritic joints. E. Paeolog¹, J. Miotla¹, S. Ballara¹, P. Taylor¹, P. Winlove², P. Etherington², R.N. Maini¹. ¹Kennedy Institute of Rheumatology, ²Centre for Biological and Medical Systems, ICSTM
    
43. Efficient adenoviral gene transfer reveals that NF B is a major regulator in rheumatoid arthritis. F. Brennan, B. Foxwell, J. Bondeson, M. Feldmann. Kennedy Institute of Rheumatology
    
44. Investigation of the effect of interleukin-1 on gene expression in articular cartilage by protein mass spectrometry. M. Bolton, M. Hermansson, R. Wait, J. Sakiatvaia. Kennedy Institute of Rheumatology
    
45. Costimulatory blockade by the induction of an endogenous xenospecific antibody response. N.J. Rogers, V. Mirenda, I. Jackson, A. Dorling, R.I. Lechler. Immunology Department, Division of Medicine, ICSM
    
46. Towards antigen-specific immunotherapy of leukaemia. I. Bellantuono¹, L. Gao¹, F. Dazzi², S. Marley², J.M. Goldman², H.J. Stauss¹. ¹Immunology Department, Division of Medicine, ICSM, ²Department of Haematology, Investigative Science Division, ICSM
    
47. Gene transfer to the corneal endothelium: modulation of graft rejection. A.J.T. George¹, W.J. King¹, R.M. Corner¹, C. Lebosse¹, D.F.P. Larkin². ¹Immunology Department, Division of Medicine, ICSM, ²Moorfields Eye Hospital, London
    
48. Phosphorylation of human estrogen receptor a at serine 118 is mediated by two distinct signal transduction pathways. D. Chen¹, E. Washbrook¹, T. Riedl², P.E. Pace¹, J. Taylor¹, D. Constantinidou¹, R.C. Coombes¹, J.M. Egly², S. Ali¹. ¹CRC Laboratories, Department of Cancer Medicine, Division of Medicine, ICSM, ²Institut de Genetique et de Biologie Moleculaire et Cellulaire, Universite Louis Pasteur, Strasbourg, France
    
49. Genetic factors influencing outcome of hepatitis B and C. M. Thursz¹, A. Hill², J. Bell², H.C. Thomas¹. ¹Hepatology Section, Division of Medicine, ICSM, ²Oxford
    
50. Does hepatitis C virus infect the brain? D. Forton, S. Taylor-Robinson, P. Karayiannis, H.C. Thomas. Hepatology Section, Division of Medicine, ICSM
    
51. Imaging of enzyme inactivation in vivo using PET. A. Salem, E. Aboagye, P. Price. Section of Cancer Therapeutics, Division of Medicine, ICSM
    
52. A novel duodenal apical membrane calcium transporter may explain disorders due to variations in calcium absorption. J.R. Walters, N. Barley. Gastroenterology Section, Division of Medicine, ICSM
    
53. The role of CDX-2 in the development of the gastrointestinal tract. R. Playford¹, J. Tucci³, K. Chawemgsaksophak³, N. Wright³, R.A. Goodlad², F. Beck⁴. ¹Gastroenterology Section, Division of Medicine, ICSM, ²Histopathology Unit, ICRF, ³Department of Histopathology, Investigative Science Division, ICSM, ⁴University of Leicester, ⁵The Howard Florey Institute, University of Melbourne, Australia
    
54. Nitric oxide and gastric somatostatin cells in health and H. Pylori infection. J. Calam, N. Arebi. Gastroenterology Section, Division of Medicine, ICSM
    
55. Towards defining the carbohydrate motifs involved in the adhesion of malaria-infected erythrocytes to the human placenta. W. Chai¹, J.G. Beeson², G.V. Brown², A.M. Lawson¹. ¹The Glycosciences Laboratory, Glycobiology Section, Division of Medicine, ICSM, ²The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    
56. New insights into the expression and regulation of the carbohydrate ligands for the lymphocyte homing receptor, L-selectin—relevance to anti-adhesion therapeutics. C. Galustian¹, M. Kiso², A. Lubineau³, A.M. Lawson¹, T. Feizi¹. ¹The Glycosciences Laboratory, Glycobiology Section, Division of Medicine, ICSM, ²Department of Applied Bioorganic Chemistry, Gifu University, Japan, ³Laboratoire de Chimie Organique Multifunctionelle, Universite du Paris Sud, Orsay, France
    
57. Effect of lamivudine on HTLV-I proviral load, anti-tax CTL frequency and T-cell phenotype in patients with HTLV-associated spastic paraparesis. G. Taylor¹, C.R.M. Bangham², P. Rudge³, J.N. Weber¹. ¹Department of GUM, Section of Infectious Diseases, Division of Medicine, ICSM, ²Section of Immunology, Division of Investigative Science, ICSM, ³National Hospital, Queen Square, London
    
58. Influence of polymorphisms in the gene for the IL-1 receptor antagonist and IL-1 beta on tuberculosis. R. Wilkinson¹, P. Patel¹, Z. Toossi², G. Pasvol¹. ¹Department of Tropical Medicine, Section of Infectious Diseases, Division of Medicine, ICSM, Northwick Park Hospital, ²Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio
    
59. Immune reconstitution on non-nucleoside-based HAART. B. Gazzard¹, A. Sullivan¹, F. Gotch². ¹HIV Research Unit, Section of Infectious Diseases, Division of Medicine, ICSM. Chelsea and Westminster Hospital, ²Department of Immunology, Division of Investigative Science, ICSM
    
60. The effects of diuretics and angiotensin converting enzyme inhibitors on renal function in the very elderly — results from the HYVET pilot trial. N.S. Beckett, J.D. Sadler, A.E. Fletcher, C.J. Bulpitt. Care of the Elderly Section, Division of Medicine, ICSM
    
61. Factors altering arterial compliance. C. Rajkumar¹, F. Dockery¹, O. Aziz¹, A.S. Agarwal², J.C. Chambers¹, J.S. Kooner¹, C.J. Bulpitt¹. ¹Care of the Elderly Section, Division of Medicine, ICSM ²Department of Urology, Hammersmith Hospital
    
62. Diagnostic mutations in establishing cancer aetiology and risk. A.R. Boobis, N.J. Gooderham, M. Yadollahi-Farsani, A.M. Lynch, D.S. Davies. Division of Medicine, ICSM
    
63. Sildenafil inhibits hypoxia-induced pulmonary hypertension. L. Zhao, N.A. Mason, N.W. Morrell, M.R. Wilkins. Division of Medicine, ICSM
    
64. Cell surface ADP-ribosylationtransferase attenuates PDGF-dependent proliferation of vascular myocytes. B. Saxty, S. Johnstone, M. Yadollahi-Farsani, J. MacDermot. Division of Medicine, ICSM
    
65. 2-Methoxyoestrone-3-O-sulphamate: a novel drug for cancer therapy. A. Purohit¹, H.A.M. Hejaz², L. MacCarthy-Morrogh¹, G. Packham³, B.V.L. Potter², M.J. Reed¹. ¹Endocrinology & Metabolic Medicine Section, Division of Medicine, ICSM, ²Department of Pharmacy and Pharmacology, University of Bath, ³Ludwig Institute for Cancer Research, ICSM
    
66. The production of glucose by the human placenta in vivo. C.H. Prendergast², D.G. Johnston¹, A. Burchell¹, K.H. Parker⁴, R. Gray¹, S. Venkatesan¹, P. Bannister¹, K.W. Murphy², R.W. Beard², L. Regan², S. Robinson¹, P. Steer³, D. Halliday¹. ¹Endocrinology & Metabolic Medicine Section, Division of Medicine, ICSM, ²Department of Obstetrics & Gynaecology, ICSM, ³Department of Maternal Fetal Medicine, ICSM, ⁴Biological & Medical Systems, ICSTM, ⁵Department of Obstetrics & Gynaecology, University of Dundee
    
67. Correlation between histology and outcome in ANCA-associated systemic vasculitis. G. Gaskin¹, H.T. Cook², F. Ahmed¹, D.J. Evans¹, C.D. Pusey¹. ¹Renal Section, Division of Medicine, ICSM, ²Histopathology Department, Division of Investigative Science, ICSM
    
68. Goodpasture's disease is associated with CD4⁺T cells reactive to human GBM and the autoantigen 3(IV)NC. A.D. Salama¹, A. Chaudhry¹, L. Lightstone¹, R.I. Lechler², C.D. Pusey¹. ¹Renal Section, Division of Medicine, ICSM, ²Immunology Department, Division of Medicine, ICSM
    
69. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo: a mechanism for protection against autoimmunity. P.R. Taylor¹, A. Carugati¹, V.A. Fadok², H.T. Cook³, M. Andrews⁴, M.C. Carroll⁵, J.S. Savill⁶, P.M. Henson², M. Botto¹, M.J. Walport¹. ¹Rheumatology section, Division of Medicine, ICSM, ³Department of Histopathology, Division of Investigative Science, ICSM, ²Department of Paediatrics, National Jewish Medical Research Centre, Denver, USA, ⁴Division of Renal & Inflammatory Disease, University hospital, Nottingham, ⁵Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, USA, ⁶Centre for Inflammation Research, University of Edinburgh Medical School
    
70. Nephrotoxic nephritis: increased disease in C1q-deficient mice. M.G. Robson¹, H.T. Cook², M. Botto¹, P.R. Taylor¹, C.D. Pusey³, M.J. Walport¹, K.A. Davies¹. ¹Rheumatology section, Division of Medicine, ICSM, ²Department of Histopathology, Division of Investigative Science, ICSM, ³Renal Section, Division of Medicine, ICSM
    
71. Genetic analysis of lupus-prone mouse strains. T.J. Vyse¹, M.E.K. Haywood¹, J.H. Slingsby¹, M.B. Hogarth¹, S. Izui², S.J. Rozzo³, B.L. Kotzin³, M.J. Walport¹, B.J. Morley¹. ¹Rheumatology section, Division of Medicine, ICSM, ²Department of Pathology, Centre Medical Universitaire, University of Geneva, ³Department of Clinical Immunology, UCHSC, Denver, USA
    
72. Challenges of haematopoietic stem-cell transplantation: opportunities for an integrated approach including both basic and clinical science, to GVH and GVL. E. Simpson¹, H. Stauss², G. Lombardi², R.I. Lechler², J. Goldman³, F. Dazzi³. ¹Transplantation Biology, MRC Clinical Sciences Centre, ICSM, ²Immunology Department, Division of Medicine, ICSM, ³Haematology Department, Division of Investigative Sciences, ICSM
    
73. Crystallization and structural analysis of active site-inhibited human coagulation factor Vila (Des-Gla). D.J.D. Johnson¹, P.J. Nugent¹, E.G.D. Tuddenham¹, K. Harlos¹, G. Kemball-Cook². ¹Haemostasis Research Group, MRC Clinical Sciences Centre, ICSM, ²Structural Biology Department, Wellcome Trust for Human Genetics, Oxford
    
74. Heterochromatin-mediated gene silencing and disease. C. Everett, A. Saveliev, S. Uribe Lewis, T. Sharpe, D. Kazazi, R. Festenstein. Gene Control mechanisms and Disease, Division of Medicine, ICSM
    
75. Diabetic nephropathy: key stages in the control of mesangial fibrosis in response to high glucose. N. Wahab, N. Yevdokimova, B. Weston, T. Roberts, R. Mason. Biomedical Sciences Division, ICSM.
    
76. Cellular and molecular mechanisms underlying Hermansky-Pudlak syndrome and related human disease affecting melanocytes and platelets. E. Mules¹, A. Hume¹, J. Ramalho¹, D. Barral¹, R. Swank², S. Kingsmore³, M. Seabra¹. ¹Molecular Genetics, Biomedical Sciences Division, ICSM, ²Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA, ³Molecular Staging Inc., USA
    

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