QJM

QJM 2005 98(9):677-690; doi:10.1093/qjmed/hci107

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Published by Oxford University Press on behalf of the Association of Physicians 2005. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Annual General Meeting

The Ninety-Ninth Annual General Meeting of the Physicians of Great Britain and Ireland 2005

The Ninety-Ninth Annual General Meeting was held in Nottingham on Thursday 7 and Friday 8 April 2005. The attendance book was signed by ordinary members and senior members.

The President, Professor P. Rubin took the chair.

The Minutes of the last Annual General meeting, having been published in the QJM (September 2004) were taken as read, confirmed and signed. The following Officers and Executive Officers were elected:

Executive Committee President: Professor P.C. Rubin President-elect: Professor Sir G.R.D. Catto Honorary Treasurer: Professor J.M.C. Connell Honorary Secretary: Professor J.P. Iredale Members for England and Wales Professor C. Black Professor B. Casadei Professor C. Day Dr C. Gelder Professor A. Lever Professor D.A. Lomas Members for Scotland Professor A.D. Morris Professor N. Thomson Professor D.J. Webb Members for Ireland Dr C. Doherty Professor J. Kelleher Professor E. Trimble

The following honorary, senior and ordinary members were elected.

Honorary Members Professor H. Brady Professor P. Humphries Senior Members G.D. Bell R.F. Bing I. Bone J.E. Compston H.J. Dargie D. Donnai E.A.M. Gale I.M. Graham H.J.F. Hodgson C.M. Lockwood G.T. McInnes C.A. Seymour D.J. Shale J.G.P. Sissons J.F. Smyth H.C. Thomas J.O. Warner G.K. Wilcock T.J. Wilkin S.P. Wilkinson

Ordinary Members

Alcolado, John C, BM (Hons), DM, FRCP. Senior Lecturer and Reader in Medicine and Hon. Con. Physician, Dept of Endocrine and Diabetes Sciences, University Hospital of Wales, Cardiff University, Heath Park, Cardiff CF14 4XN.

Brown, Edwina A, BA, BM, BCh, DM, FRCP. Professor of Renal Medicine, Renal Unit, Charing Cross Hospital, Fulham Palace Road, London W6 8RF.

Brown, Roger, BA, BM, BCh, MRCP, PhD. Clinical Senior Lecturer in Medicine, University of Edinburgh, Lothian University Hospitals NHS Trust, Edinburgh.

Bruce, Ian N, MB, BCh, BAO. Senior Lecturer and Hon. Con. in Rheumatology, University of Manchester, Rheumatism Research Centre, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL.

Chinnery, Patrick F, MRCPath, PhD, MRCP, MBBS(Hons), BMedSci. Professor of Neurogenetics, Dept of Neurology, The Medical School, University of Newcastle upon Tyne, Newcastle Upon Tyne NE2 4HH.

Cockcroft, JR, BSc(Hons) Biochemistry, MB, ChB, MRCP (UK), FRCP. Professor of Cardiology, Wales Heart Research Institute, Heath Park, Cardiff CF14 4XN.

Crome, Peter, MBBS, MD, PhD. University Hospital of North Staffordshire, Keele University Medical School, Courtyard Annexe, Newcastle Road, Stoke-on-Trent, ST4 6QG.

Ehrenstein, Michael R, BSc, MBBS, PhD. Senior Lecturer/Consultant Rheumatologist, Dept of Rheumatology, Royal Free and University College London, Arthur Stanley House, London WIT 4NJ.

Evans, Tom, MB, BChir, PhD, MRCP, FRCP. Professor of Molecular Microbiology, Division of Immunology, Infection and Inflammation, University of Glasgow, Western Infirmary, Glasgow G11 6NT.

Gray, Christopher S, MBBS, MD. Professor of Clinical Geriatrics and Clinical Sub-Dean, University of Newcastle upon Tyne, Sunderland Royal Hospital, Kayll Road, Sunderland SR4 7TP.

Lang, Chim, BSc, MB, ChB, MRCP, MD, FRCP, FACC. Professor of Cardiology/Hon. Consultant Cardiologist, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY.

Lindsay, Robert, BSc, MB, ChB, MRCP, PhD. Senior Lecturer in Endocrinology and Metabolism, University of Glasgow, North Glasgow University Hospitals, 44 Church Street, Glasgow G11 6NT.

McShane, Helen, BSc, MBBS, MRCP, PhD. Wellcome Trust Clinician Scientist Fellow, The Centre for Clinical Vaccinology and Tropical Medicine, The Churchill Hospital, Oxford OX3 7LJ.

Morrison, Patrick, MB, BCh, BO(QUB), DCH, MD, DPH, FRCPCH, FFPHMI. Consultant in Clinical Genetics and Director of Regional Cancer Genetics Service, University of Ulster, Dept of Genetics, City Hospital, Belfast BT9 7AB.

McVeigh, Gary E, MD, PhD, FRCP. Consultant Physician and Reader in Clinical Pharmacology, Belfast City Hospital, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL.

Mutimer, David, MBBS, MD, FRACP, FRCP. Reader in Hepatology and Hon. Consultant Physician, Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH.

Phelps, Richard G, BA, MBBChir, MA, MRCP, PhD. Senior Lecturer in Nephrology and Hon. Consultant in Nephrology, Renal Autoimmunity Group, MRC Centre for Inflammation Research, University of Edinburgh, 2nd Floor Hugh Robson Building, 14 George Square, Edinburgh EH8 9XD.

Reeves, Helen, BMedSci, BMBS, MRCP, PhD. GSK Clinical Fellow, Senior Lecturer and Hon. Consultant Physician, School of Clinical Medical Sciences, University of Newcastle, 4th Floor, Leech Building, Newcastle upon Tyne NE2 4HH.

Simpson, John, BMedBiol(Hons), MBChB, MRCP, PhD, FRCPE. Senior Clinical Lecturer and Hon. Consultant in Respiratory Medicine, MRC Centre for Inflammation Research, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG.

Vestbo, Jorgen, DMedSci. Professor of Respiratory Medicine, University of Manchester, North West Lung Centre, South Manchester University Hospital, Southmoor Road, Manchester M23 9LT.

Walker, Mark, BMedSci, MBBS, MRCP, MD, FRCP. Professor of Molecular Diabetic Medicine, University of Newcastle Upon Tyne, SCMS Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH.

Watts, Richard A, BA, BMBCh, MA, MRCP, DM, FRCP. Consultant Rheumatologist, Ipswich Hospital NHS Trust, Heath Road, Ipswich IP4 5PD.

Wedderburn, Lucy R, BA, MBBS, MRCP, PhD, MRCPCH. Rheumatology Unit, CW Level 6, Institute of Child Health, University College of London, 30 Guilford Street, London WC1N 1EH.

Winstanley, Peter, MB ChB, MRCP, MD, DTM&H. Professor of Clinical Pharmacology, The Wellcome Trust Tropical Centre, University of Liverpool, L6 3GF.

The new members were welcomed to the Association by the President.

The President reminded members that the history of the Association that had been commissioned two years earlier was now being undertaken by an MSc student, and it was hoped this would be available to members published as a supplement in the QJM in the centenary year 2006/2007. Members were encouraged to note the dates of the centenary meeting to be held on the Guy's campus in London, under the presidency of Professor Sir Graham Cato, in their diaries.

The Honorary Treasurer, Professor John Connell, reported that the finances of the Association remained in good order, and thanked Professor A.P. Weetman (the previous Treasurer) for his stewardship of the accounts. He presented income and expenditure for the 12 months to the end of December 2004. He reminded the new members of the Association that over the last five years the main strategy has been to reduce the overall balance of the accounts to a sum roughly four times the direct charitable expenditure incurred by the Association. This expenditure is currently running at around £80 000 per year, making a balance of approximately £320 000 desirable.

Income from subscriptions was stable. Income from Oxford University Press from the publication of the QJM had also been maintained at a satisfactory level, while the Annual General Meeting in Dublin had returned a small surplus.

Direct charitable expenditure was accounted for by the schemes for links with developing countries, undergraduate summer electives and intercalated degrees. Expenditure on management and administration of the charity was essentially unchanged from previous years.

An important development was the positive gain on investment assets of £32 700. At the end of December 2004, therefore, the overall fund balance was £399 600 compared with £341 300 at the end of December 2003. The balance at the end of 2004 was therefore satisfactory.

In proposing future plans for the finances of the Association, Professor Connell indicated that he felt that a rise in charitable expenditure was appropriate. The studentships had proved very popular, and Professor Connell therefore proposed to increase the level of the award to £1000 in 2005. The response to the Links with Developing Countries Scheme suggested that the current level of expenditure of £20 000 was appropriate for another year. Professor Connell also pointed out that the publication of the history of the Association would incur a cost of up to £20 000; furthermore, members should anticipate a rise in expenditure on intercalated degree fees.

The members accepted the accounts and the proposals for expenditure.

Dr Christopher Martyn, the Editor, spoke on the affairs of the QJM. He reported that the rising trend in the number of unsolicited articles received by the QJM's editorial office has continued, with the number of submissions in 2004 more than double that for 2000. It is particularly encouraging that a greater proportion of unsolicited manuscripts are now coming from overseas. There has been an exponential increase in use of the electronic QJM over the last few years and the number of institutions with electronic access to the journal has also increased substantially. The QJM's impact factor is slowly improving and is currently 2.4.

Although library subscriptions continue to fall, this should not be seen as a cause for concern. More libraries are purchasing the QJM through consortia sales, which more than offsets any loss in revenue. The financial state of the journal is sound, and its profitability last year was greater than expected.

An electronic manuscript submission and tracking system was instituted earlier this year, and all articles are now dealt with online.

The QJM website is undergoing a re-design and the new version should be operational later this year.

The three volumes of minutes of the editorial board meetings of the QJM, dating back to the inception of the journal at the beginning of the last century, have been deposited in the archive of the Royal College of Physicians of London for safe keeping. No restrictions have been placed on access.

The President-Elect, Professor Sir Graham Cato, gave a short introduction to the proposed meeting on Guys campus on 6/7 April 2006.

	Opening Reception and Annual Dinner

Top Opening Reception and Annual... Scientific Business Demonstrations

 
The welcome reception on Thursday evening was held in the Long Gallery at Nottingham Castle. The Annual Dinner on Friday was held in Prestwold Hall, Nottingham. Members enjoyed an excellent dinner in fine surroundings. and the occasion was enjoyed by all.

	Scientific Business

Top Opening Reception and Annual... Scientific Business Demonstrations

 
Thursday 7 April 2005
    2.00–3.00 pm

Professor Peter Morris, Professor of Physics and Head of the MRI Centre, Nottingham University. The Osler Lecture—Reading Minds with Magnets

    3.00 pm (1)

A. Wheatley, C. Swan, N. Dourodier, A. Fenech (all introduced), I.P. Hall. Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham. Defining pharmacogenetic variability in major airway drug targets for asthma.

Responses of individuals with asthma to treatment vary both between individuals and between drugs. We systematically screened the major drug targets for genetic polymorphism in the Caucasian population, using DNA archives to estimate variability in these targets. The targets chosen were the ß2 adrenoceptor, the muscarinic M2 and M3 receptors, the histamine H1 receptor, the CysLTR1 receptor and the glucocorticoid receptor (/ß). At least 20 chromosomes were sequenced for all targets. A number of novel polymorphisms were identified in addition to known SNPs present on databases. Genetic variability between targets ranged from rates of 1/180 bases to 1/1600 bases. The highest polymorphic rate was present in the ß2 adrenoceptor: by contrast, the muscarinic M3 receptor contains only 1 SNP within the entire coding region.

Studies on the variants identified demonstrated functional differences in down-regulation and/or agonist efficacy profiles for the Arg/Gly16, Gln/Glu 27 and Thr/Ile164 polymorphisms in the ß2 adrenoceptor, and in reporter gene expression for alleles of a CA repeat in the core promoter for the muscarinic M2 receptor. For the latter, three low-expressing alleles were identified using luciferase constructs in transfection experiments in primary human airway smooth muscle, these being the (CA)1, (CA)3 and (CA)8 alleles. The allelic frequencies in a random Caucasian population (n = 175) were 44%, 15% and 17%, respectively. Initial data suggest a possible role for this polymorphism in increasing risk of asthma. In a Nottingham sib pair asthma family population (n = 62 families) significant over-transmission of low-expression alleles was seen in asthmatic offspring (global allelic TDT p = 0.008).

These data demonstrate that significant genetic variability exists in key airway drug targets, which may influence both treatment response and the risk of developing asthma.

    3.25 pm (2)

G.R. Small, P.W.F. Hadoke, I. Sharif, C.J. Kenyon, G.A. Gray (all introduced), B.R. Walker. Centre of Cardiovascular Science, University of Edinburgh, Edinburgh. Enhancing angiogenesis by preventing local generation of glucocorticoid.

Increasing angiogenesis is a therapeutic goal to improve tissue repair in ischaemia. Glucocorticoids (GCs) inhibit angiogenesis, but the potential of anti-GCs to enhance angiogenesis has not been explored. We confirmed that GCs inhibit new vessel formation in mouse aortae cultured in Matrigel, and in polyurethane sponges implanted subcutaneously in mice. Administering the GC-receptor antagonist RU486 enhanced angiogenesis in isolated aortae, in sc sponges, in healing surgical wounds, and in the infarcted myocardium following coronary artery ligation in mice. However, systemic GC antagonists are unlikely to be useful drugs because of adverse effects. How can the anti-GC action be targeted to the vessel wall?

Within vascular smooth muscle cells, the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11HSD1) regenerates active GCs (cortisol, or corticosterone in rodents) from inactive metabolites (cortisone or 11-dehydrocorticosterone, DHC). In isolated aortic rings, DHC inhibited angiogenesis by 54%; this effect was prevented by 11HSD1 inhibition with carbenoxolone, and was absent in vessels from 11HSD1 null (–/–) mice. Similar results were obtained in steroid-impregnated sc sponges implanted in wild type and –/– mice. Moreover, 31% more new vessel growth occurred into untreated sponges in –/– than wild type mice, suggesting that 11HSD1 tonically inhibits angiogenesis by regenerating GCs within the vessel wall.

Would loss of 11HSD1-mediated GC regeneration be useful to enhance angiogenesis in ischaemia? In 11HSD1 –/– mice, compared with wild type controls, angiogenesis was greater in surgical skin wounds and in infarcted myocardium 7 days after coronary artery ligation. The latter was associated with protection from left ventricular dysfunction (ejection fraction 66.0 ± 5.5% in sham-operated mice vs. 19.5 ± 1.4% in wild type infarction vs. 35.2 ± 4.7% in –/– infarction, p < 0.01).

We conclude that angiogenesis is tonically inhibited by endogenous glucocorticoids, including those generated locally by 11HSD1. 11HSD1 inhibition offers a novel approach to enhance angiogenesis and to promote beneficial remodelling following myocardial infarction.

    4.15 pm (3)

A.T. Hattersley, A.L. Gloyn, E.L. Edghill, F. Reimann, F.M. Gribble, P. Proks, F.M. Ashcroft (all introduced except A.T. Hattersley). Molecular Genetics, Peninsula Medical School Exeter, Dept of Biochemistry, Cambridge University and Dept of Physiology, Oxford University. Severity of diabetic phenotype and treatment response in patients with activating Kir6.2 mutations reflect the ATP sensitivity of the K_ATP channel.

Kir6.2 is in a tetramer structure with SUR1 in the pancreatic beta cell K_ATP channel. Insulin release can result from the closure of this channel in response to either (i) ATP generated through metabolism or (ii) binding by sulphonylureas drugs. We have recently shown that heterozygous gain-of-function mutations in Kir6.2 cause permanent neonatal diabetes (PNDM), which may be associated with neurological features. We assessed whether the ATP sensitivity of the mutation altered the clinical phenotype and the response to therapy, through additional genetic, clinical and functional studies.

Kir6.2 mutations account for approximately 45% of patients diagnosed with permanent diabetes <6 months and 87% are spontaneous ‘de novo’ mutations. There is a striking genotype phenotype relationship with the common mutations R201H (n = 13), and R201C (n = 6), being associated with isolated PNDM, while V59M (n = 11) is associated with moderate motor and educational developmental delay in addition to PNDM. Three mutations (Q52R, V59G and I296L) all resulted in a severe novel multi-system syndrome we have termed DEND syndrome, characterized by Developmental delay, Epilepsy and Neonatal Diabetes. Three other mutations (G53S, G53R and I182V) resulted in transient neonatal diabetes (TNDM).

Structural modelling showed that the mutations involved in isolated diabetes are located at ATP binding sites, while the neurological mutations affect the channel gating or the pore directly. We studied the functional consequences of the channel by expressing the mutated Kir6.2 channel with SUR1 in Xenopus oocytes. All mutations showed reduced channel closure in response to ATP, but this response was graded by clinical phenotype associated with the mutation: wild type > TNDM > PNDM > DEND syndrome.

Patients can discontinue insulin and show improved glycaemic control on high-dose sulphonylureas with possible neurological improvement, whereas DEND patients have not responded to sulphonylureas. We conclude that structural and functional attributes of Kir6.2 mutations determine the clinical syndrome and response to sulphonylurea therapy.

    4.40 pm (4)

N.C. Henderson, F. Poirier, C. Haslett, J.P. Iredale, K.J. Simpson, T. Sethi. MRC Centre for Inflammation Research, Edinburgh Medical School, Edinburgh. Galectin-3 regulates myofibroblast activation and tissue fibrosis.

Chronic inflammation leading to fibrosis, with loss of tissue architecture and subsequent organ failure, represents a massive healthcare burden worldwide. Central to fibrogenesis and the scarring of organs is the activation of fibroblasts into matrix secreting myofibroblasts. Here we show that disruption of the gene encoding Galectin-3 blocks the effective transdifferentiation of precursors to myofibroblasts, and markedly attenuates organ fibrosis in murine models of hepatic, renal and pulmonary fibrosis. Ex-vivo Galectin-3 knockout hepatic stellate cells (hepatic myofibroblast precursors) exhibit defective activation to the myofibroblast phenotype, and this abnormality is reversed by the addition of exogenous recombinant Galectin-3. Inhibition of Galectin-3 expression by siRNA in primary murine and human hepatic stellate cells significantly reduces myofibroblast activation and procollagen (I) expression. Furthermore, siRNA knockdown of Galectin-3 in vivo inhibits fibroblast activation to the myofibroblast phenotype following hepatic injury. These data suggest a fundamental pan-organ mechanistic role for Galectin-3 in the regulation of myofibroblast activation and consequent tissue fibrosis. Inhibition of Galectin-3 function may therefore provide a novel therapeutic approach to the treatment of fibrosis in a wide variety of organs and disease states.

    5.05 pm (5)

M.J. Newport, K. Butterworth, J. Howson, J. Stockton, H. Cordell, T. Goetghebuer, A. Marchant (all introduced). Department of Medicine, Brighton and Sussex Medical School, University of Sussex, WT/JDRF Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge and Faculty of Medicine, Universite Libre de Bruxelles, Belgium. Neonatal twin BCG vaccination: towards the identification of interferon- regulatory genes.

Interferon-gamma (IFN-) is essential for immunity to several important intracellular pathogens, including Mycobacterium tuberculosis. Dysregulation of this cytokine underlies common autoimmune disorders such as type I diabetes. Understanding the normal regulation of IFN- production is therefore of great importance to both health and disease. Infant M. bovis BCG vaccination is an excellent model in which to study the role of host genetic variation in the regulation of IFN- production: BCG represents a controlled antigenic challenge in which immunologically naive infants receive the same dose of a well-characterized infection, and immune responses are measured at the same interval post-vaccination in all infants.

Using a classical twin study design, we have shown that IFN- responses to neonatal BCG in Gambian infants are strongly genetically regulated. We have subsequently used the sibling pair method, exploiting the fact that dizygous twins are age-matched siblings who have also shared a common in-utero environment, to discover the specific genes involved. A genome-wide linkage scan conducted in 150 dizygous twin families identified three chromosomal regions harbouring genes that are significantly linked to IFN- responses. Further molecular studies are underway to determine the mechanisms involved in the regulation of IFN- responses.

These genes are potential targets for much needed novel therapeutic and prophylactic interventions for a range of immune-mediated diseases, both infectious and non-infectious.

Friday 8 April 2005
    9.00 am (6)

K. Moore, O. Boutaud, M. Wilson, B.T. Breeder, J.A. Oates, L. Jackson Roberts II. Dept of Medicine, Royal Free & University College Medical School, University College, London, Clinical Pharmacology Vanderbilt University, Nashville, USA and University of Essex. Paracetamol reduces ferryl myoglobin and prevents rhabdomyolysis-induced renal failure.

Rhabdomyolysis can be caused by a variety of insults that lead to muscle injury, and the release of myoglobin (Mb) into the circulation. Circulating myoglobin is deposited in the kidney, where it causes renal injury, and accounts for 7% of all cases of acute renal failure in the US. We have shown that this is caused by an oxidative injury to the kidney resulting from redox cycling between the ferric and ferryl heme moieties of myoglobin.

Using optical spectroscopy, we discovered that paracetamol potently reduces ferryl Mb to ferric Mb, and inhibits Mb-induced oxidation of arachidonic acid in vitro at an EC50 of 2.3 ± 0.6 µM, which is 40-fold below normal therapeutic plasma concentrations of paracetamol. We then explored whether paracetamol would protect against renal injury in a rat model of rhabdomyolysis. Visibly, kidneys from rhabdomyolysis animals were very discoloured, but appeared virtually normal in rhabdomyolysis animals treated with paracetamol. Plasma creatinine was significantly increased in rats with rhabdomyolysis (234 ± 43 µM) compared with controls (43 ± 2 µM) or rhabdomyolysis animals treated with paracetamol (81 ± 6 µM), p < 0.01. Creatinine clearance was markedly decreased by 76% in animals with rhabdomyolysis compared to controls (p > 0.001), but was not significantly different from controls in rhabdomyolytic animals treated with paracetamol. Plasma levels of F₂-isoprostanes, markers of oxidative injury, were significantly increased in rhabdomyolysis animals (145 ± 15 pg/ml vs. controls 74 ± 10 pg/ml, p < 0.01), and were significantly reduced in rhabdomyolysis animals treated with paracetamol (93 ± 20 pg/ml, p < 0.01).

These findings suggest that paracetamol may represent a novel, safe and effective treatment for the prevention of acute renal failure in patients with rhabdmyolysis, and may have a major impact on therapy or prevention of other forms of haemoglobinuric acute renal injury such as that secondary to malaria or other forms of intravascular haemolysis.

    9.25 am (7)

J.C. Knight (introduced by P.J. Ratcliffe). University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford. Functional characterization of non-coding DNA polymorphism regulating gene expression: insights into defining complex disease susceptibility.

Genetic diversity is postulated to be responsible for much of the variation observed between individuals in their susceptibility to multifactorial complex disease traits. There is increasing awareness that variation in non-coding DNA sequences that modulate the process of gene expression may be at least as important as that observed with non-synonymous coding DNA sequence variations that affect the phenotype of the translated protein. The evidence for such ‘regulatory’ non-coding DNA polymorphism is growing. Variation in gene expression shows heritability, and can be mapped as a quantitative trait. Allele-specific effects appear highly context-specific and of modest magnitude. Specific examples of functional regulatory polymorphisms underlying complex disease traits are reviewed to illustrate the difficulties inherent in such analysis.

A major road block in the field is the paucity of experimental tools to demonstrate effects of regulatory polymorphisms in vivo at the level of transcription. A novel method for detecting differential protein-DNA binding to specific haplotypes in living cells by chromatin immunoprecipitation (‘haploChIP’) is described. The approach uses primer extension with MALDI-TOF mass spectrometry to allow highly sensitive and accurate allele-specific quantification. HaploChIP defines allele-specific transcriptional activity by quantification of phosphorylated RNA polymerase II (Pol II) loading to allelic variants of a gene in vivo. At the human TNF/LTA locus, where cytokine polymorphisms have been associated with many infectious, inflammatory and autoimmune diseases, haplotype-specific differences in phosphorylated polymerase loading are found that correlate with differences in levels of transcript expression. Moreover, haploChIP allows specific molecular mechanisms to be resolved by analysis of haplotype-specific binding by candidate transcription factors. This is illustrated by activated B cell factor-1 recruitment at LTA, encoding lymphotoxin alpha. The haploChIP method has potential to allow genome-wide screening for common DNA polymorphisms that affect gene regulation in vivo.

    9.50 am (8)

L.D. Church, A. Coney, C. Ray, S.P. Young, J. Marshall (introduced), P.A. Bacon. Depts of Rheumatology and Physiology, University of Birmingham. Sphingomylinase as a link between inflammation and atherosclerosis.

Connective tissue disease provides an ideal opportunity to probe the ill-understood mechanisms whereby inflammation promotes atherosclerosis. We previously showed that systemic vasculitis (SV) is associated with diffuse endothelial cell dysfunction (ECD), the first step in the complex process of atherosclerosis. As blockade of the inflammatory cytokine TNF can reverse ECD, we tested the hypothesis that sphingolipid mediators may link inflammatory cytokines to the depression of endothelial NO synthase that underlies ECD.

In human T-cells exposed to TNF, aberrant Ca²⁺ signals after TCR activation are accompanied by sphingolipid release. Both are blocked in cells from sphingomyelinase knock-out mice. In rat aorta, the effect of SMase and C₂-ceramide on NO production to both adenosine and to bradykinin (BK) stimulation was examined ex vivo using a NO electrode. Endothelium-specific NO production was significantly inhibited. Similar inhibition following pre-treatment with SMase or C₂-ceramide was seen using cultured HUVECs in-vitro. eNOS activation is Ca²⁺ dependent, so intracellular calcium signalling ([Ca²⁺]_i) to BK or thrombin was examined in HUVEC using a single-cell imaging system. This revealed depressed [Ca²⁺]_i responses to both mediators. Analysis of the site of the signalling perturbation, using intracellular and transmembrane fluxes in response to the receptor-independent action of thapsigargin performed under Ca²⁺-free conditions, showed specific inhibition of Ca²⁺ influx across the plasma membrane. Finally the in vivo relevance of these findings was assessed in a well-documented model of blood-flow. SMase was infused into the femoral artery of male Wistar rats and endothelium-dependent NO-mediated flow responses to acetylcholine (ACh) were measured in both the local femoral and in the distal brachial artery. Vasodilatation was impaired both locally and distally within 10 min of SMase exposure. This depression was maintained for more than 1 h.

These data in T-cells and EC are consistent with the novel hypothesis that SMase activated by TNF can affect receptor-mediated Ca²⁺ signalling and depress NO responses. We propose a model in which high local cytokine concentrations from inflammation in blood vessels produces local EC activation, but also releases sphingolipid mediators that can induce downstream ECD and initiate atherogenesis.

    10.15 am (9)

S. Subramanian, C. Mpofu, S.W. Edwards, C.A. Hart, B.J. Campbell, L.G. Yu (all introduced), J.M. Rhodes. Schools of Clinical Sciences and Biological Sciences, University of Liverpool, Liverpool. Pathogenic roles for adherent and invasive E. coli in Crohn's disease and colon cancer: a synergistic effect of microbial mannan.

Escherichia coli are found beneath the colonic mucus in Crohn's disease (CD) and colon cancer (Gastroenterology 2004; 127:80–93). They are also found within CD tissue macrophages and within colon cancer cells. These E. coli adhere to and invade epithelial cancer cell lines and induce interleukin-8 (IL-8) release. We now show that this IL-8 release is mediated by ERK and p38 MAPkinase pathways. Mucosal E. coli isolates, 7 from CD and 14 from colon cancer, incubated with confluent HT29 colon cancer cells for 8 h caused median IL-8 release of 873 pg/ml (range 498–1760) and 230 pg/ml (range 115–1970) above control values, respectively (both p < 0.05). This was paralleled by ERK activation from 5 min. Pre-treatment with selective inhibition of ERK (U0126) and p38 (SB203580), both at 10 µM, caused median reductions in IL-8 release of 69% and 72% (both p < 0.001), respectively. Inhibition of NFB by pre-treatment with BAY11-7082 (10 µM) completely inhibited IL-8 release (p = 0.002).

Mucosal E. coli from CD survived 2 h incubation with adherent human monocytes better than non-invasive control E. coli (ATCC259222): 36% median survival (range 6–57) vs. 1% (0–4), p = 0.03. Knowing that about 60% CD patients have antibodies (ASCA) to yeast mannan, we tested the hypothesis that such mannans, also expressed by Mycobacterium paratuberculosis, might impair macrophage killing of mucosal E. coli. S. cerevesiae mannan (1 mg/ml) increased survival of CD-E. coli within monocyte-derived macrophages at 2 h by 268 ± 115% [mean ± SE]; n = 6, p = 0.001) and within adherent monocytes (2 h adherent) by 405 ± 218% (n = 10, p = 0.01).

These studies support a central role for adherent and invasive E. coli in both CD and colon cancer. Mannan-induced impairment of E. coli killing by macrophages may explain the pathogenesis of acquired CD, analogous to the genetic NOD2 defect present in a minority of patients. Intra-epithelial E. coli may promote colon cancer progression via NFB activation (Cell 2004; 118:285–96).

    11.10 am (10)

N.L. Mills, S.D. Robinson, T. Sandstrom, F.R. Cassee, K. Donaldson (all introduced), W. MacNee, N.A. Boon, D.E. Newby. Centre for Cardiovascular Science, Edinburgh University, Edinburgh. Combustion derived nanoparticulate impairs vascular function and endogenous fibrinolysis in man.

Although the mechanisms are unknown, air pollution is associated with an increase in cardiovascular morbidity and mortality. We have previously demonstrated vascular dysfunction in cigarette smokers. As combustion products and particulate matter are common to both air pollution and cigarette smoke, we hypothesized that air pollution would cause detrimental vascular effects. We investigated the effects of (a) dilute diesel exhaust and (b) ambient particle inhalation, on vascular and fibrinolytic function in man.

Studies used a double-blind randomized crossover design with: (a) 15 healthy men exposed to dilute diesel exhaust (DE, 300 µg/m³) or air for 1 h; and (b) 12 male patients with stable ischaemic heart disease and 12 age-matched volunteers exposed to concentrated ambient particles (CAPs) or air for 2 h. Six hours after all exposures, bilateral forearm blood flow and plasma fibrinolytic markers were measured before and during unilateral intra-brachial bradykinin, acetylcholine, and nitroprusside infusions.

(a) There was a dose-dependent increase in blood flow with each vasodilator (p < 0.001 for all) that was attenuated following exposure to DE: bradykinin (p = 0.006), acetylcholine (p = 0.07), and sodium nitroprusside (p < 0.001). Bradykinin caused a dose-dependent increase in plasma tissue plasminogen activator (t-PA) concentration (p < 0.001) that was suppressed following exposure to DE (p < 0.001; area under the curve decreased by 34%).

(b) The average CAPs exposure concentration was 190 ± 37.2 µg/m³. Chemical analysis of ambient particulate identified low levels of carbon. Although there was a dose-dependent increase in blood flow with each vasodilator and plasma t-PA release (p < 0.001), this was unaffected by CAPs or filtered air in either group.

Inhalation of diesel exhaust particulate markedly impairs the regulation of vascular tone and endogenous fibrinolysis in man. The equivalent mass of ambient particulate, low in combustion component, did not affect vascular function. These findings provide a potential mechanism that links combustion-derived air pollution to the pathogenesis of atherothrombosis and acute myocardial infarction.

    11.35 am (11)

L.R. Wedderburn (introduced), A. Patel, H. Varsani, I. de Kleer, W. de Jager, D. Pharoah, B. Prakken and P. Woo. Rheumatology Unit, Institute of Child Health, University College, London and University Medical Center, Utrecht, The Netherlands. CD4+25^bright T regulatory cells suppress inflammation in oligoarticular juvenile idiopathic arthritis (JIA) and are directly correlated with good clinical outcome.

Persistent oligoarticular Juvenile Idiopathic Arthritis (Pers-OA JIA) is a self-remitting disease with a benign clinical course, while extended oligoarticular (Ext-OA) JIA is a subtype with a much less favourable prognosis. One of the key players of immune regulation is the CD4+CD25^bright regulatory T-cell (Treg). Treg can be identified by their high expression of CD25, constitutive expression of CTLA4 and GITR, and expression of the transcription factor FoxP3.

In a study of a total of 94 patients with oligoarticular JIA, we compared number, phenotype and functionality of CD4+CD25^bright Treg and mRNA FoxP3 levels in patients with Pers-OA JIA, to those with Ext-OA JIA using flow cytometry, RT-PCR, and in vitro functional and suppression assays.

Patients with Pers-OA JIA had a significantly higher frequency of CD4+CD25^bright T cells, with concomitant higher levels of mRNA FoxP3 in the peripheral blood, than did Ext-OA JIA patients. In addition, Pers-OA JIA patients showed higher percentages of synovial fluid (SF) FoxP3-expressing CD4+CD25+ Tregs than Ext-OA JIA patients. The CD4+CD25^bright cells of both patient groups, and the CD4+CD25^int T cells of Pers-OA JIA patients were able to suppress responses of CD25-negative cells in vitro. A markedly higher expression of CTLA4, GITR and HLA-DR on SF CD4+CD25^bright Tregs compared to their peripheral counterparts, suggests that the CD4+CD25+ Tregs undergo maturation in the joint. In correlation with this matured phenotype the SF CD4+CD25^bright T cells showed an increased regulatory capacity in vitro, compared to PB CD4+CD25^bright T cells. We have previously shown high levels of inflammatory T cells in the joint, which express CCR5 and CXCR3 and migrate towards a chemokine gradient: we are now investigating whether Treg from these patients are also able to suppress T-cell migration or cytokine production.

    12 noon (12)

I. Sabroe, L.C. Parker, E.C. Jones, L.R. Prince, G.E. Morris, S.K. Dower (all introduced), M.K.B. Whyte. Academic Unit of Respiratory Medicine, University of Sheffield, Royal Hallamshire Hospital, Sheffield. Induction and maintenance of neutrophilic inflammation by TLR agonists.

Neutrophils provide a principal defence against microbial infection. Bacterial products can be detected by newly-discovered members of the IL-1R superfamily, the Toll-like receptors (TLRs). We have previously shown that neutrophils express TLR2 and TLR4, and that their agonists induce anti-microbial responses. In contrast, prolongation of neutrophil lifespan by TLR agonists is dependent upon signalling from other cells such as monocytes. Here, we show that induction of inflammation by TLR agonists can be mediated by synergistic interactions between monocytes and tissue cells such as airway smooth muscle. This synergy requires IL-1 generation, but also the generation of other, as yet unidentified, mediators facilitating cooperative responses. In contrast, we have previously shown that neutrophil survival induced by TLR agonists and PBMC is IL-1-independent, demonstrating compartmentalization in the mechanisms of monocyte-dependent neutrophil recruitment and survival. In the work presented here, we also show that neutrophil responses to TLR agonists can be regulated by induction of tolerance, observed at the level of MAPK signalling, and potentially mediated by down-regulation of TLR4 surface expression. Tolerized neutrophils do not show global functional paresis, remaining responsive to survival factors released from PBMC, and continuing to secrete IL-8, potentially facilitating further neutrophil recruitment. Induction of neutrophil tolerance appears to allow tailoring of the neutrophil response to its environment, reducing the likelihood of excessive inflammatory responses. These data point to a complex network of responses regulating neutrophil responses to microbes, coordinated at the level of the neutrophil and by other immune and tissue cells, and identify new pathways potentially amenable to pharmacological treatment of neutrophilic inflammation.

    12.25 pm (13)

K. Wynne, A.J. Park, C. Small, M. Patterson, S. Ellis, K. Murphy, A.M. Wren, G. Frost, K. Meeran, M. Ghatei (all introduced), S.R. Bloom. Department of Metabolic Medicine, Imperial College, London. Subcutaneous oxyntomodulin reduces body weight in overweight subjects.

Currently, there is no effective medical treatment for obesity. Oxyntomodulin is a gut hormone previously reported to reduce acute food intake in humans after intravenous administration. We aimed to determine whether longer-term subcutaneous administration of oxyntomodulin would reduce appetite and body weight.

Healthy overweight volunteers self-administered either saline or oxyntomodulin (400 nmol) subcutaneously for 4 weeks, three times daily, 30 min pre-prandially, in a randomized double-blind parallel-group protocol. The volunteers were asked to maintain their usual diet and level of physical exercise. Subjects’ energy intake, body weight and levels of adipose hormones were measured.

Body weight was reduced by 2.3 (±1.6) kg in the oxyntomodulin treatment group over the 4-week study period, compared to 0.5 (±1.7) kg in the control group (p = 0.0106). Thus, on average, the treatment group had an additional 0.45 kg weight loss per week. The treatment group also demonstrated a reduction in leptin and an increase in adiponectin levels. Energy intake within the treatment group was significantly reduced by 170 (±127) kcal (or 25 ± 18%) at an initial study meal (p = 0.0007) and by 250 (±220) kcal (or 35 ± 32%) at a final study meal (p = 0.0023), with no change in subjective food palatability.

Oxyntomodulin administration resulted in considerable weight loss in healthy overweight individuals, accompanied by changes in the levels of adipose hormones which were consistent with a loss of body fat. The substantial anorectic effect was well-maintained over the 4-week period. Oxyntomodulin may thus represent an important new therapy for obesity.

    3.00 pm (14)

B. Eksteen (introduced), A. Grant (introduced), D.H. Adams. Liver Laboratories, Institute of Biomedical Research, University of Birmingham, Birmingham. Aberrant expression of gut-specific adhesion molecules in the liver explains the association between primary sclerosing cholangitis and inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease characterized by progressive bile duct destruction, and often develops as an extra-intestinal complication of inflammatory bowel disease (IBD). However, liver and bowel inflammation are rarely concomitant, and PSC can develop in patients whose colons have been previously removed. Lymphocytes homing to the gut in IBD are controlled by restricted local expression of the chemokine CCL25 and the endothelial adhesion molecule MAdCAM-1, which selectively recruit mucosal lymphocytes expressing the respective receptors CCR9 and 4ß7. We proposed that aberrant hepatic expression of CCL25 and MADCAM-1 would result in the recruitment of mucosal T cells to the liver in PSC and mediate extra-intestinal inflammation in the absence of active IBD.

We demonstrated increased CCL25 and MAdCAM-1 expression on the endothelium of vessels in the liver of patients with PSC, whereas both were absent or detected at low levels in other liver diseases. Of lymphocytes isolated from human PSC liver tissue, 20% co-expressed CCR9 with 4ß7 and were thus of mucosal origin, compared with <5% of T cells in other diseases. The CCR9⁺ 4ß7⁺ population were memory T cells, as demonstrated by phenotype (CD11a^high) and interferon secretion. CCL25 triggered PSC lymphocyte migration and 4ß7-dependent adhesion to MAdCAM-1, thus confirming the ability of this chemokine to promote liver recruitment.

We show that PSC is associated with the recruitment of mucosal T-cells to the liver by aberrant expression of the gut-specific chemokine CCL25, which activates 4ß7 binding to MAdCAM-1 on hepatic endothelium. This is the first demonstration in humans that T cells activated in the gut can be recruited to an extra-intestinal site of disease, and provides a paradigm to explain the pathogenesis of extra-intestinal complications of IBD.

    3.25 pm (15)

K.M. Channon, L. Zhao (introduced), J. Khoo (introduced), M.R. Wilkins. Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford. Endothelial tetrahydrobiopterin regulates susceptibility to hypoxic pulmonary hypertension through nitric oxide synthase coupling.

Pulmonary hypertension is characterized by vasoconstriction and vascular remodelling. Loss of endothelial nitric oxide (NO) bioavailability is implicated in pulmonary hypertension pathogenesis. Recent evidence suggests that the co-factor tetrahydrobiopterin (BH4) is an important regulator of nitric oxide synthase (NOS) enzymatic function. We evaluated the effect of systemic BH4 deficiency in the hph-1 mouse, an ENU mutant with reduced expression of GTP-cyclohydrolase I (GCH), the rate-limiting enzyme in BH4 biosynthesis. BH4 deficiency resulted in pulmonary hypertension, RV hypertrophy (RVH) and vascular remodelling, even in normoxic conditions; susceptibility to hypoxia-induced pulmonary hypertension was greatly increased. In endothelial-targeted transgenic mice over-expressing GCH (GCH-Tg mice), lung BH4 levels were elevated 2–3-fold, and resulted in complete protection from hypoxia-induced pulmonary hypertension. Crossing GCH-Tg mice with hph-1 mice restored lung BH4 levels to normal, and rescued the pulmonary hypertension, RVH and vascular remodelling seen in hph-1 mice. Across all genotypes (wild type, hph-1, hph-1/GCH-Tg and GCH-Tg), lung BH4 availability controlled pulmonary vascular tone, right ventricular hypertrophy and vascular structural remodelling in a dose-dependent manner in both normoxia and hypoxia. Furthermore, BH4 availability had striking effects on the immediate vasoconstriction response to acute hypoxia, on NOS activity and on NOS-dependent superoxide synthesis. These findings suggest that endothelial BH4 availability is essential for maintaining pulmonary vascular homeostasis, is a critical mediator in the pathogenesis of pulmonary hypertension, and is a novel therapeutic target.

    3.50 pm (16)

J. Zou (introduced), A.N. Turner, R.G. Phelps (introduced). Renal Autoimmunity Group, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh. The major T cell epitopes in the Goodpasture antigen are destroyed at the initiation of endosomal processing.

It is a paradox that the epitopes recognized by T cells of patients with Goodpasture's disease have high affinity for HLA DR15 (the disease-associated class II molecule), but are presented to T cells at low abundance relative to other epitopes in the autoantigen, even epitopes with much lower affinity for DR15 (JASN 2003; 14:2801).

A possible explanation could be that the disease-associated epitopes are consistently destroyed during antigen processing. Such a mechanism has been suggested in experimental murine autoimmune encephalomyelitis, where the high affinity epitope recognized by the major autoreactive T cell populations is destroyed early during its processing by antigen-presenting cells (Nature Immunol 2003; 3:169). We investigated the potential of T cells that recognise 3(IV)NC1, the autoantigen of Goodpasture's disease, to similarly escape tolerance.

The course of fragmentation of r-3(IV)NC1 by human lysosomes was examined by MALDI TOF mass spectrometry and Edman micro-sequencing. After 5 min, four fragments could be detected, two generated by cuts within one, and two by cuts within a second, of the four epitopes recognized by T cells from most patients with Goodpasture's disease. By 1 h, 3(IV)NC1 fragments were detected that indicated destructive proteolysis of all four epitopes that we have shown to be recognized by patients’ T cells. Inhibitor and substrate specificity studies demonstrated that the rapid destruction of T cell epitopes was effected by an aspartyl protease, almost certainly cathepsin D.

Globular antigens must be ‘unlocked’ by critical proteolytic events before their processing may proceed to generate the short peptides recognized by CD4 T cells. Our results echo those in a murine model of autoimmunity, and suggest that antigen unlocking can be so constant a feature of antigen processing that tolerance is shaped around the ‘unlocked self’, exposing potential for autoimmunity targeted against the epitopes destroyed in the unlocking.

    4.45 pm (17)

G. Devereux, R.N. Barker, S. Martindale, G. McNeill, A. Seaton (introduced), A.J. Rees. Departments of Environmental and Occupational Medicine, Medicine and Therapeutics, University of Aberdeen, Aberdeen. Antioxidant intake in pregnancy in relation to wheeze and eczema in the first two years of life.

We have hypothesized that the recent increases in asthma, eczema and hay fever may be a consequence of pregnant women consuming less dietary antioxidants. We recruited 2000 pregnant women at 12 weeks gestation, and characterized dietary antioxidant intake. The 1924 singleton births were followed up by questionnaires at 6, 12 and 24 months, with response rates of 85.1%, 78.6% and 71.4%, respectively. For 223 neonates, cord blood mononuclear cell (CBMC) cytokine and proliferative responses after stimulation with allergens were measured. CBMC proliferative responses were negatively associated with maternal dietary vitamin E intake. CBMC proliferative and cytokine responses at birth were positively associated with wheezing (p = 0.007), GP-diagnosed asthma (p = 0.039) and atopic sensitization (p = 0.001–0.029) in the second year of life. Furthermore, in the second year of life ‘wheeze in the absence of a cold’ (p = 0.009) and atopic eczema in children with atopic mothers (p = 0.016) were negatively associated with maternal dietary vitamin E intake. Maternal vitamin C intake was positively associated with wheeze (p = 0.01) and atopic eczema (p = 0.048) in the second year of life. These adverse associations with maternal vitamin C are likely to be a consequence of residual confounding by factors associated with socio-economic status and a healthy lifestyle, although a genuine adverse effect is possible. This is the first report of beneficial associations between maternal dietary vitamin E intake during pregnancy and wheeze and atopic eczema in children. The immunological associations suggest a causative association and a likely mechanism. The prevention of atopic disease by manipulating the diets of pregnant women remains a possibility.

    5.10 pm

Dr Peter Toghill, Retired Consultant Physician, Nottingham. History of Medicine Lecture—Clinical Apprentices in Nottingham.

	Demonstrations

Top Opening Reception and Annual... Scientific Business Demonstrations

 

1. Differential expression and responsiveness by normal and ulcerative colitis colonic myofibroblasts to isoforms of platelet-derived growth factor. K Hughes, R Seth, YR Mahida. Institute of Infection, Immunity & Inflammation and Divisions of Gastroenterology & Pathology, University Hospital, Queen's Medical Centre, Nottingham.
   
2. An ionic organic polymer and anti-toxin antibody protect against Clostridium difficile toxin-induced loss of epithelial barrier function. P Sutton, S Li, J Webb, K Solomon, YR Mahida. Institute of Infection, Immunity & Inflammation and Division of Gastroenterology, University Hospital, Queen's Medical Centre, Nottingham.
   
3. The effect of nutritional restriction in mid and late gestation on uncoupling protein-2 mRNA abundance in the ovine neonatal and adolescent lung. MG Gnanalingham, A Mostyn, GS Gopalakrishnan, J Dandrea, ME Symonds, T Stephenson. Centre for Reproduction and Early Life, Institute of Clinical Research, University of Nottingham, Nottingham.
   
4. Does concurrent prescription of antidepressants and NSAIDS substantially increase the risk of upper gastrointestinal bleeding? LJ Tata¹, PJ Fortun², RB Hubbard ¹, L Smeeth³, CJ Hawkey², CJP Smith⁴, HJ Whitaker⁵, CP Farrington⁵, TR Card¹, J West¹. ¹Departments of Epidemiology and Public Health, ²Wolfson Digestive Diseases Centre, and ⁴Respiratory Medicine, University of Nottingham, ³Dept of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, ⁵Dept of Statistics, The Open University.
   
5. Fertility and pregnancy-related events in women with coeliac disease: a population based cohort study. LJ Tata¹, T Card¹, R Logan¹, R Hubbard¹, C Smith², J West¹. ¹Division of Epidemiology and Public Health, University of Nottingham, ²Respiratory Medicine, Nottingham City Hospital, Nottingham.
   
6. The most common drug causes of preventable hospital admissions: a systematic review. S Slavenburg¹, R Howard², S Royal³, A Avery³. ¹University of Nijmegen, ²University of Nottingham and NPCRP, ³University of Nottingham.
   
7. The influence of parasite infection on the prevalence of asthma: A systemic review of observational studies. J Leonardi-Bee, J Britton, and the Parasites in Asthma Collaboration. Department of Epidemiology and Public Health, University of Nottingham, Nottingham.
   
8. Malignancy and mortality in people with coeliac disease: a general population based cohort study. J West, RFA Logan, C Smith, R Hubbard, TR Card. Division of Epidemiology and Public Health, University of Nottingham.
   
9. Investigation of human bronchial epithelial cell proteome following allergenic exposure. R Furmonaviciene¹, A Knox², F Shakib¹. ¹Division of Immunology, ²Division of Respiratory Medicine, University of Nottingham.
   
10. Acute effect of Naproxen on the inflammatory cell infiltrate in H. pylori-infected volunteers. MW James, AM Zaitoun, CT Atherton, CJ Hawkey, JC Atherton. Wolfson Digestive Diseases Centre, University Hospital, Nottingham.
    
11. H. pylori reduces biopsy-induced mucosal damage with acute Naproxen in healthy volunteers. MW James, CT Atherton, AM Zaitoun, CJ Hawkey, JC Atherton. Wolfson Digestive Diseases Centre, University Hospital, Nottingham.
    
12. Indomethacin alters Helicobacter pylori CagA-dependent signalling in gastric epithelial cells in vitro. MW James, RH Argent, CJ Hawkey, JC Atherton. Wolfson Digestive Diseases Centre, University Hospital, Nottingham.
    
13. Hepatic tissue carbon dioxide and the Pringle manoeuvre. JS Hammond, A Brooks, I Ahmed, K Girling, W Doherty, D Lobo, IJ Beckingham. Dept of Medicine and Surgery, University of Nottingham.
    
14. Immunotherapy of cancer using ex vivo generated dendritic cells (DCs) pulsed with peptides of human telomerase reverse transcriptase. A McKechnie, A Robins, C Verma, J Hannoe, A Takhar, J Eremin, F Farzaneh, N Habib, O Eremin. Dept of Surgery, University of Nottingham.
    
15. Prognostic value of MICA expression in colorectal carcinoma. NFS Watson^1,2, JH Scholefield², Z Madjd¹, A Green³, R Moss¹, I Spendlove¹, IO Ellis³, LG Durrant¹. ¹Cancer Research UK Academic Unit of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, ²Division of Gastrointestinal Surgery, University Hospital, Queen's Medical Centre, Nottingham, ³Dept of Histopathology, University of Nottingham, City Hospital, Nottingham.
    
16. Interactions between the epidermal growth factor receptor (EGFR) and tethered transforming growth factor alpha (TGF) in a co-culture model. AS Takhar, AJ McKenzie, PA Clarke, SA Watson. Academic Unit of Cancer Studies, University of Nottingham, Nottingham.
    
17. Antibacterial prophylaxis for pancreatic necrosis: Does the choice of agent make a difference? E Villatoro¹, R Hall², M Larvin¹. ¹Wolfson Digestive Diseases Centre, University of Nottingham, ²Derby Hospitals NHS Trust, Derby, for the Cochrane Collaboration Upper GI & Pancreatic Diseases Group.
    
18. Evidence for endotoxin tolerance in patients with obstructive jaundice. RE Bullock¹, GP Aithal², A Samaraweera¹, N Irshad¹, BJ Rowlands¹, C Fiuza¹. Divisions of ¹Surgery and ²Gastroenterology, Queen's Medical Centre University Hospital, Nottingham.
    
19. Defining the functional phenotype of CD8+ T lymphocytes in COPD. RA Urbanowicz, J Saunders, J Corne, L Fairclough. Division of Immunology, School of Molecular Medical Sciences, Nottingham.
    
20. Apoptotic pathways of detachment-induced cell death in isolated human enterocytes. I Daniels, RG Long. David Evans Medical Research Centre/Dept of Gastroenterology, City Hospital, Nottingham.
    
21. Nitric oxide synthase activity in coeliac disease. I Daniels, I Murray, RG Long. David Evans Medical Research Centre/Dept of Gastroenterology, City Hospital, Nottingham.
    
22. Reduced matrix metalloproteinase activity in COPD: evidence that MMP9 is not the major airway metalloproteinase. G Lowry¹, N Henderson², J Blakey², JM Corne¹, Johnson SR². ¹Respiratory Medicine, Queen's Medical Centre, Nottingham. ²Division of Therapeutics and Molecular Medicine, University of Nottingham.
    
23. Mechanisms of angiogenesis: vascular endothelial growth factor induction by PGE₂ in human airway smooth muscle cells is mediated by EP2/EP4 receptors and Sp-1. D Bradbury, J Stocks, L Corbett, D Clarke, AJ Knox. Centre for Respiratory Research, City Hospital, Nottingham.
    
24. Beta-adrenoceptor agonists and glucocorticoids repress eotaxin gene transcription in human airway smooth muscle cells by selective inhibition of histone H4 acetylation: relevance for asthma therapy. M Nie, L Corbett, AJ Knox, LH Pang. Centre for Respiratory Research, City Hospital, Nottingham.
    
25. IL-1 differentially regulates ₂ adrenoceptor and PGE₂-mediated cAMP accumulation and chloride efflux from Calu-3 bronchial epithelial cells: relevance for mucosal inflammatory diseases. A Clayton, E Holland, L Pang, A Knox. Centre for Respiratory Research, City Hospital, Nottingham.
    
26. The conservation and expression of lecA in isolates of P. aeruginosa from the cystic fibrosis lung. S Crusz, S Diggle, A Smyth, M Camara, R Finch, A Knox, P Williams. Institute of Infection, Inflammation and Immunity, University of Nottingham.
    
27. Asthma, adrenal insufficiency and inhaled corticosteroid use. KJ Mortimer¹, LJ Tata², CJP Smith², Y Tang³, K Wu³, G Hochhaus³, RB Hubbard², TW Harrison¹, AE Tattersfield¹. ¹Division of Respiratory Medicine, University of Nottingham, ²Division of Epidemiology and Public Health, Nottingham University, ³Department of Pharmaceutics, University of Florida, USA.
    
28. Comparison of levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases in abdominal aortic aneurysm specimens from patients on versus not on statins preoperatively. WRW Wilson², J Evans¹, PRF Bell¹, MM Thompson². ¹Dept of Surgery, Leicester University, Leicester, ²Dept of Vascular Surgery, St George's Hospital Medical School, London.
    

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