QJM Advance Access originally published online on October 9, 2006
QJM 2006 99(11):783-796; doi:10.1093/qjmed/hcl103
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Annual General Meeting |
The One-Hundredth Annual General Meeting of the Association of Physicians of Great Britain and Ireland 2006
The Centenary Annual General Meeting was held in Guy's Campus of King's College London on 6 and 7 April 2006. The attendance book was signed by Ordinary Members and Senior Members.The President, Professor R. Lechler, took the chair.
The Minutes of the last Annual General Meeting, having been published in the QJM (September 2005), were taken as read, confirmed and signed. The following Officers and Executive Officers were elected:
Executive Committee
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Ordinary Members
Bath, Phillip MW, BSc, MB, BS, MRCP, MD, FRCP. Professor of Stroke Medicine, Division of Stroke Medicine, University of Nottingham Queen's Medical Centre, Nottingham NH7 2UH.
Buchan, Alastair M, BA, MA, BM, BCh, MRCP, FRCPC, FRCP Ed. Professor of Clinical Geratology, Nuffield Dept of Medicine, John Radcliffe Hospital, Oxford OX3 9DU.
Dockrell, David H, MB, B Ch, BAO, BA, MRCPI, MD, DTM & H, FRCPI, FRCP. Senior Lecturer and Hon. Consultant in Infectious Diseases, Division of Genomic Medicine University of Sheffield Medical School, Sheffield S10 2RX.
Festenstein, Richard J, MBBS, MRCP, PhD. Professor of Molecular Medicine and Consultant in Neurogenetics, Gene Control Mechanisms and Disease Group, MRC Clinical Sciences Centre, Hammersmith Hospital, London W12 ONN.
Khakoo, Salim I, MD, MRCP, MBBS, BSc. Wellcome Senior Clinical Fellow and Consultant Hepatologist, Liver Research Group, Southampton University, Southampton General Hospital, Southampton SO16 6YD.
Knight, Julian C, DPhil, MRCP, MB ChB, BA. Wellcome Trust senior Research Fellow in Clinical Science/Honorary Consultant Physician, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosvelt Drive, Oxford OX3 7BN.
Korbonits, Marta, PhD, MD. Reader in Endocrine Research, Dept of Endocrinology, William Harvey Research Institute, Barts and the London Medical School, John Vane Science Centre, London EC1M 6BQ.
Kotecha, Sailish, BA, MB, BS, MA, MRCP, DCH, PhD, FRCPCH. Professor of Child Health and Head of Dept, Dept of Child Health, Cardiff University, Cardiff CG14 4XN.
Maini, Mala K, MBBS, DTM&H, MRCP, PhD. MRC Clinician Scientist/Senior Lecturer, Dept of Immunology and Molecular Pathology and Hon Consultant, Centre for Sexual Health and HIV Research, UCL, London WC1T 4JF.
Mufti, Ghulam J, MB, MRCPath, DM, FRCPath, FRCP. Professor of Haemato-oncology, Dept of Haematological Medicine, King's College London School of Medicine, King's College Hospital, London SE5 9PJ.
Owen, Mike, BSc, MB BS, PhD, FRCPsych, FMedSci. Professor of Psychological Medicine, Wales College of Medicine Biology, Life and Health Sciences, Cardiff University, Cardiff CF14 4XN.
Sattar, Naveed, MBChB, PhD, MRCPath. Professor of Metabolic Medicine, Vascular Biochemistry, QEB, Glasgow Royal Infirmary, Glasgow G31 2ER.
Singer, Mervyn, MB BS, MD, FRCP. Professor of Intensive Care Medicine, Bloomsbury Inst of Intensive Care Medicine UCL, 5th floor, Jules Thorn Building, Middlesex Hospital, Mortimer St, London W1T 3AA.
Screaton, Gavin R, BA, BM BCh, DPhil, FMedSci, FRCP. Professor of Medicine, Commonwealth Building, Hammersmith Hospital, Du Cane Road, London W12 ONN.
Starr, John M, MBBS, MA, FRCPEd, FRIPH. Consultant Physician and Senior Lecturer, General and Geriatric Medicine, Lothian Universities NHS Trust, Western General Hospital, Edinburgh EH4 2XU.
Taylor, Peter C, BA, BM, BCh, PhD, FRCP. Reader in Experimental Rheumatology, Kennedy Institute of Rheumatology Division, Imperial College, 1 Aspenlea Rd, Hammersmith, London W6 8LH.
Wilkinson, Robert J, MA, BM BCh, DTM&H, PhD, FRCP. Wellcome Trust Senior Fellow and Senior Lecturer, Current Address: Institute of Infectious Diseases and Molecular Medicine, Wernher and Beit Building South,University of Cape Town, Anzio Rd, Observatory 7925, South Africa.
The new members were welcomed to the Association by the President.
The President then invited the Honorary Treasurer, Professor J. Connell, and the Editor of the QJM, Dr C. Martyn, to report to the membership.
The Honorary Treasurer, Professor Connell, reported that the finances of the Association remained in good order. He presented income and expenditure for the 12 months to the end of December 2005. He reminded the members of the Association that the main strategy has been to maintain the overall balance of the accounts at a sum roughly four times the direct charitable expenditure incurred by the Association. As the balance has risen due to enhanced revenue, an increase in expenditure was justified.
Income from subscriptions was stable. Income from the Oxford University Press from the publication of the QJM has risen over the last few years, and is likely to remain at or above this level for the immediate future.
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.
At the end of December 2005, the overall fund balance was £483 592, compared with £399 600 at the end of December 2004. The balance at the end of 2005 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 the Association had increased the level of the award to £1000 in 2005. The Executive Committee had also recommended an increase in the expenditure in support of intercalated fees. After review of the scheme, Professor Connell proposed increasing the number of awards each year to eleven, and raising the value of each award to £6000. The response to the Links with Developing Countries Scheme suggested that a ceiling of expenditure of £30 000 was appropriate. Professor Connell also pointed out that the publication of the history of the Association would incur a cost of up to £20 000, spread over several years.
The members accepted the accounts and the proposals for expenditure.
The Editor of the QJM, Dr Martyn, reported a continuing improvement in several indicators of QJM's performance, including the number of unsolicited articles received, use of the electronic QJM and the number of institutions with access to the journal. The impact factor has reached 2.6. An electronic manuscript submission and tracking system was instituted in February 2005. All articles are now dealt with online. Although library subscriptions had continued to fall, this should not be seen as a cause for concern. Libraries now tend to purchase the QJM through consortia sales, which more than offsets any loss in revenue from individual subscriptions. The financial state of the journal is sound, and its profitability last year was greater than expected. A working party to consider strategic issues around the future of the QJM has been established under the chairmanship of Professor Edwin Gale.
The President-elect, Professor Martin Gale, gave a short introduction to the proposed meeting in Bristol on 29 and 30 March 2007.
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Opening Reception and Annual Dinner |
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 Top Opening Reception and Annual... Demonstrations |
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The welcome reception on Thursday evening was held at the Imperial War Museum. The Annual Dinner was held in the Great Hall at Lincolns Inn Fields. Members enjoyed an excellent dinner in superb surroundings, and the occasion was enjoyed by all. After dinner, members and guests were addressed by the Rt Hon. The Lord Owen.
Thursday 6 April 2006
2.00–3.00 pm
The Osler Lecture—Hedgehogs, Hox genes and Motor Neurons
Professor Andrew Lumsden, FRS, FMedSci, Director, the MRC Centre for Developmental Neurobiology, King's College London.
3.00 pm
(1) CD34+ cells, modified to express anticoagulants on differentiation, promote repair to a pre-injured state after endovascular injury
D. Chen (introduced) R.I. Lechler*, A. Dorling (introduced). Dept of Immunology, Imperial College London (*now King's College, London).
Arterial injury, followed by chronic intimal vascular smooth muscle cell (VSMC) hyperplasia and scarring, underpins the manifestations of diseases such as atherosclerosis and hypertension. Animal models have implicated tissue factor (TF) and thrombin in the evolution of these pathological changes, though the mechanisms by which they act remain ill-defined, especially in vivo. In some conditions, neointimal VSMC arise from bone-marrow (BM)-derived progenitors. This study aimed to determine how TF and thrombin influenced endovascular repair by these BM-derived cells. After wire-induced arterial injury, wild-type (WT) mice showed progressive neointimal hyperplasia, where most neointimal cells had an mixed phenotype, displaying both endothelial (EC) and VSMC markers. Injured vessels failed to regenerate a new endothelium. Two strains of transgenic (Tg) mice expressing the membrane-tethered anticoagulants tissue factor pathway inhibitor or hirudin as fusion proteins, driven by an 
smooth muscle actin promoter, were generated. Injury in these mice was followed by regeneration of a normal endothelium without neointimal expansion. This type of repair response was also seen when WT mice were reconstituted with BM from Tg mice or injected with Tg CD34+ progenitor cells at the time of injury. Conversely, Tg reconstituted with WT BM showed a WT-like response. Responses to injury were the same in both strains, indicating that thrombin generated by TF caused the changes seen in WT mice. This study confirms the important role of coagulation proteins in the pathology seen after endovascular injury. Most importantly, it illustrates, for the first time, that these proteins cause progressive disease by inhibiting repair by BM-derived progenitors, instead promoting accumulation of undifferentiated neointimal cells and inhibiting the development of normal EC. These findings enhance our understanding of neointimal hyperplasia, and suggest a novel avenue for therapeutic manipulation, using modified BM-derived progenitors, to promote repair back to a pre-injured state after endovascular injury, with implications for the treatment of vascular disease.
3.25 pm
(2) Molecular aetiology of the myeloproliferative disorders
P.J. Campbell1 (introduced), C.N. Harrison2 (introduced), and A.R. Green1. 1Dept of Haematology, Cambridge Institute for Medical Research; 2St Thomas’ Hospital, London. On behalf of the PT-1 study group.
An activating mutation in the tyrosine kinase JAK2 occurs in the majority of patients with a myeloproliferative disorder. The human myeloproliferative disorders represent a spectrum of clonal haematological malignancies, with three main members: polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF). For over quarter of a century, it has been realized that these diseases reflect transformation of a multipotent haematopoietic stem cell, but the identity of underlying target gene(s) has remained elusive.
In 2005, we and others demonstrated that a single acquired point mutation in JAK2 is present in virtually all patients with PV, and in approximately half those with either ET or IMF. The mutation increases kinase activity and confers cytokine independence in vitro together with erythrocytosis in vivo. In an example of scientific serendipity, these results coincided with our publication of the MRC PT-1 trial, the largest randomized study of any MPD yet performed. Analysis of prospective data from 776 ET patients demonstrated that JAK2 mutation status defines two biologically distinct subtypes of ET, with differences in presentation, outcome and response to therapy. Mutation-positive patients displayed multiple features resembling PV, and were more sensitive to treatment with hydroxyurea but not anagrelide. Our results suggest that mutation-positive ET and PV form a continuum, with the degree of erythrocytosis determined by physiological or genetic modifiers, with mutation-negative ET representing a distinct disorder. Our data lay the foundation for new approaches to the diagnosis, classification and therapy of the myeloproliferative disorders.
4.15 pm
(3) Scar-associated macrophages are the major source of collagenolytic MMP-13 in hepatic fibrosis
J.A. Fallowfield1, J.S. Duffield2, C.M. Constandinou1, R. Lang3, R.C. Benyon1 (all introduced) and J.P. Iredale1. 1Liver Research Group, Southampton; 2Renal Division, Harvard Institute of Medicine, Boston, USA; 3Dept of Ophthalmology, Children's Hospital Research Foundation, Cincinatti, Ohio, USA.
Remarkably, the identity and source of the rodent collagenase which mediates matrix remodelling in liver fibrosis remains elusive, despite the importance of this data to the interpretation of models designed to determine the pathogenesis of fibrosis and provide proof of concept of potential therapies.
We have previously shown that conditional ablation of scar-associated macrophages (SAM) early during resolution of fibrosis resulted in persistence of hepatic scarring (Duffield JS, et al., JCI 2005) and, therefore, sought to determine whether macrophages could represent the source of MMP-13, considered to be the key interstitial collagenase in rodents. Additionally, immunohistochemical analysis of human cirrhotic tissue demonstrated MMP-13 and MMP-1 (human interstitial collagenase) in large scar-associated phagocytes, suggesting that MMP-13 may additionally play a role in remodelling of human liver fibrosis.
Using rat carbon tetrachloride (CCl4) models of progressive fibrosis and spontaneous resolution, we found a striking relationship between MMP-13 expression and the population kinetics of ED-1 positive macrophages. Comparison between the 4- and 12-week CCl4 fibrosis models, which result in complete and partial resolution respectively, provided strong circumstantial evidence that the presence of SAM are a requirement for complete histological resolution. Indeed, peak expression of MMP-13 mRNA after 12 weeks CCl4 occurred at a time when the number of scar myofibroblasts were reduced, but macrophages were abundant and associated with scars. Furthermore, laser capture microdissection demonstrated that MMP-13 gene expression was restricted to tissue selected from regions of fibrosis rich in SAM. Dual immunostaining and in situ hybridization identified MMP-13 production within a population of large scar-associated phagocytes. Depletion of murine SAM after chronic CCl4 injury resulted in a 5-fold reduction in MMP-13 mRNA. Finally, MMP-13 gene deletion abrogated remodelling of experimental liver fibrosis in a murine knockout model.
We have determined that SAM are the major cellular source of MMP-13 in resolving liver fibrosis. Additionally, expression of this macrophage-derived collagenase may be a critical determinant of complete resolution of advanced fibrosis/cirrhosis.
4.40 pm
(4) Clinical and molecular genetic spectrum of human leptin receptor deficiency
I.S. Farooqi (introduced by S. O'Rahilly), G. Matarese, E. Lank, J. Keogh, J. Greenfield, I. Barroso, S. O'Rahilly. University Depts of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Cambridge.
While morbid obesity due to congenital deficiency of the adipocyte-derived hormone leptin has been reported in several human families, to date only one family has been reported whose obesity results from a loss of function mutation in the leptin receptor. In that family a truncated, secreted form of the extracellular domain resulted in very high circulating concentrations of bound leptin. We screened 300 patients with severe, early-onset obesity for mutations in the leptin receptor, and found 8 probands to be homozygous or compound heterozygous for nonsense and/or missense mutations. All of the missense mutations were impaired in their ability to phosphorylate Stat3 in response to leptin in transfected HEK293 cells and showed impaired ligand binding. Serum leptin levels were not elevated disproportionately to fat mass, even in those with homozygous null mutations. In addition to their obesity, affected subjects had hypogonadotropic hypogonadism and mild hypothalamic hypothyroidism. However the spectrum of leptin receptor deficiency appears to be milder than seen in congenital leptin deficiency. On average, when compared to leptin-deficient patients, leptin-receptor-deficient patients were less obese (mean BMI SDS 4.2 vs. 6.8), less hyperphagic (mean ad libitum energy intake at a test meal 115 vs. 245 kJ/kg lean mass) and had less severe impairment of T cell function. In summary, severe early-onset obesity due to leptin receptor deficiency occurs in multiple ethnic groups, and cannot be predicted by measurement of plasma leptin. The clinical spectrum is broader than that seen in congenital leptin deficiency. Whether that relates to the effects of genetic background, residual receptor activity or functions of leptin independent of the canonical receptor, remains to be established.
5.05 pm
(5) Corneal confocal microscopy: a rapid, non-invasive and reiterative examination technique to quantify diabetic neuropathy
R.A. Malik, M. Tavakoli, P. Kallinikos, A. Iqbal, N. Efron (all introduced), A.J.M. Boulton.
Depts of Medicine and Optometry, University of Manchester, Manchester.
There is an urgent need to develop surrogate markers to aid in the diagnosis and assessment of treatment efficacy in human diabetic neuropathy. We have no microalbuminuria equivalent of diabetic nephropathy for diabetic neuropathy, and depend on time-consuming (electrophysiology/quantitative sensory tests) or invasive (skin or sural nerve biopsy) methods to quantify neuropathy. We used in vivo corneal confocal microscopy (IVCCM), a rapid, non-invasive and reiterative method to visualize and quantify corneal nerves (fibre density (NFD) (no./mm2), branch density (no./mm2), (NBD), length (NFL) (µm) and tortuosity (NFT). Twenty-one control subjects and 116 diabetic patients were graded into those with no (n = 30), mild (n = 37), moderate (n = 25) and severe (n = 24) somatic neuropathy. With increasing severity of neuropathy there was a progressive reduction (mean ± SE) in NFD (48.1 ± 3.6 vs. 33.9 ± 2.4 vs. 30.1 ± 1.9 vs. 29.4 ± 3.0 vs. 17.6 ± 3.1, p = 0.003), NBD (35.2 ± 5.8 vs. 23 ± 2.9 vs. 18.1 ± 2.3 vs. 14.9 ± 2.3 vs. 11.8 ± 2.9, p = 0.001) NFL (11.4 ± 0.9 vs. 9.2 ± 0.8 vs. 6.7 ± 0.6 vs. 5.5 ± 0.5 vs. 4.3 ± 0.3, p = 0.001) and an increase in NFT (24.2 ± 2.1 vs. 25.7 ± 2.5 vs. 24.0 ± 1.7 vs. 28.9 ± 2.3 vs. 43.7 ± 2.8, p = 0.09). In 25 diabetic patients, we also assessed the benefits of intensive diabetes control (HbA1c 8.1 ± 0.3 to 7.5 ± 0.2, p = 0.08, cholesterol 4.9 ± 0.2 to 4.2 ± 0.2, p = 0.01, systolic 145.8 ± 4.9 to 135.9 ± 3.7, p = 0.09 and diastolic 77.8 ± 2.7 to 70.8 ± 2.5, p = 0.03 BP) over 24 ± 1.6 months, on corneal nerve morphology. At baseline there was a significant reduction in NFD (18.6 ± 2.1 vs. 44.5 ± 3.3, p = 0.001); NBD (7.2 ± 1.52 vs. 8.9 ± 0.2, p < 0.0001) and NFL (8.3 ± 0.5 vs. 13.5 ± 0.8, p < 0.0001). Over the follow-up period, NFD (23.5 ± 2.0, p = 0.03) and NBD (11.1 ± 1.3, p = 0.06) improved, with no change in NFL (8.4 ± 0.5, p = 0.67), and the improvement in NFD correlated significantly with the improvement in HbA1c (r = –0.52, p = 0.008). IVCCM represents a new non-invasive way of rapidly and accurately quantifying the severity of diabetic neuropathy and assessing therapeutic efficacy.
Friday 7 April 2006
9.00 am
(6) Mechanically-modulated signalling by titin kinase in muscle disease
S. Lange, E. Rostkova, J. Kristensen, G. Franzen, B. Brandmeier, E. Ehler, L. Larsson1, M. Gautel (all introduced by A.M. Shah). Muscle Cell Biology, Cardiovascular Division and Randall Division for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London; and 1Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden.
Heart and skeletal muscle constantly remodel to adapt to changes in mechanical load. Myogenic and pleiotropic transcription factors (e.g. MyoD, serum response factor [SRF], GATA) and their post-translational modification are essential components of this process. We found that the giant muscle protein titin, an elastic linker in the contractile machinery of muscle, contains a protein kinase domain (TK) that can respond to mechanical stress. A complex of several proteins links this domain to pathways controlling increased muscle gene expression, leading to muscle growth, and to others controlling their destruction, thus leading to muscle loss. The dynamic balance between growth and loss is influenced mainly by muscle mechanical activity. The zinc-finger protein nbr1 interacts in a conformation-dependent way via its PB1-domain with the regulatory domain of TK, and targets the kinase scaffolding, ubiquitin-associated p62/SQSTM1 to the sarcomere. p62 in turn interacts with MURF2, a muscle-specific ubiquitin ligase that can shuttle between the sarcomere and nucleus, where it interacts with the transactivation domain of SRF. Nuclear translocation of MURF2 is induced by mechanical inactivity, and causes reduction of nuclear SRF and repression of transcription. This novel pathway thus provides direct feedback from the mechanically active sarcomere to the transcriptional machinery, contributing to strain-adaptation of muscle gene expression. A human mutation in the TK domain causes hereditary muscle disease by disrupting this pathway. In acute quadriplegic myopathy (AQM), a common complication in ventilated and muscle-relaxed intensive care patients, the complete mechanical arrest leads to massive activation of MURF-mediated transcriptional repression, which is likely to be a key component in the pathomechanism.
9.25 am
(7) Muckle Wells syndrome—the paradigm of an IL-1ß-driven disease: insights from treatment
H.J. Lachmann1, T. Jung2, T.M. Wright2, K.S. Leslie3, M. Offer1, C.E. Grattan3 (all introduced), P.N. Hawkins1. 1National Amyloidosis Centre, Royal Free and University College Medical School, London; 2Novartis Pharma AG, Translational Medicine, Basel and Cambridge; 3Dept of Dermatology, Norfolk and Norwich Hospital.
IL-1, originally characterized as endogenous pyrogen, has a pivotal role in inflammation and host response to infection, along with wide-ranging regulation of cytokine expression generally. Studies with the first clinically available IL-1 inhibitor anakinra (recombinant IL-1 receptor antagonist) have however been disappointing in many disorders ranging from sepsis to rheumatoid arthritis. We report here studies in Muckle-Wells syndrome (MWS), an extremely rare auto-inflammatory disease that manifests as fever, rash, limb pain and deafness, which is associated with over-expression of IL-1. MWS is caused by mutations in the gene for NALP3/cryopyrin, a protein that has a major role within the inflammasome regulating activation of caspase 1 and secretion of IL-1. We discovered that the refractory multi-system inflammation in MWS remits completely following treatment with anakinra, and report here sustained remission of MWS in 15 patients, including resolution of nephrotic syndrome in the two individuals who had developed AA amyloidosis. Although the pharmacological half-life of anakinra in MWS greatly exceeds its very short plasma half-life, daily injections are nevertheless required to maintain remission. We proceeded to treat four patients with MWS with a novel human anti-IL-1ß monoclonal antibody (ACZ885), a single infusion of which produced total resolution of symptoms and acute-phase activity for a median of 181 days. These findings indicate that disease activity in MWS is mediated via IL-1ß rather than IL-1, and demonstrate the potential to dissect pathogenesis of disease with highly specific biological agents. The remarkable efficacy and duration with which ACZ885 inhibited IL-1ß in MWS supports re-investigation of the role of IL-1 in candidate diseases such as rheumatoid arthritis, osteoarthritis and psoriasis using long-acting IL-1 inhibitors that may achieve a greater and more sustained effect in joints and skin than anakinra can.
9.50 am
(8) IL-2 signalling pathway blockage restores steroid sensitivity in steroid resistant inflammatory disease
C.M. Dayan, T.J. Creed, S.D. Hearing, C.S.J. Probert, M.R. Norman, R. Lee (all introduced by S. Lightman). Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol.
Glucocorticoids are widely used to treat inflammatory disease, but consistently in diseases such as inflammatory bowel disease, asthma or rheumatoid arthritis, 20–30% of individuals respond poorly. We studied the maximal suppression of PHA stimulated lymphocyte proliferation by 10–6 M dexamethasone (‘Imax’) and found it to be relatively stable in healthy volunteers over time, independent of steroid responsiveness in other tissues (HPA axis, skin) and to correlate with the in vivo response to steroid therapy in patients with inflammatory bowel disease. This suggests that steroid resistance is an intrinsic property of an individual's immune system, independent of the presence of inflammatory disease. Interleukin-2 (IL-2) has been shown by ourselves and others to reduce the antiproliferative effect of steroids. We therefore hypothesized that blockade of the high affinity IL-2 receptor (CD25) would act as a steroid sensitizer.
In vitro, the humanized monoclonal anti-CD25 antibody, basiliximab, increased Imax to sensitive levels in all subjects studied (n = 32) despite basiliximab having relatively little effect on its own. Additional studies using flow cytometry suggest that steroid resistance is due to a subpopulation of lymphocytes that escape steroid inhibition and that CD25 blockade or inhibition of JAK/STAT signalling renders this population steroid-sensitive.
In vivo, a single infusion of basiliximab in combination with steroids given to 30 patients with steroid-resistant ulcerative colitis resulted in complete remission after 8 weeks in 70% of patients with moderate disease and 50% of severe cases. Higher rates of remission were seen after 6 months (75% and 50% respectively). CD25 blockade is particularly attractive as a steroid-sensitizing strategy, as CD25 is only expressed on activated T cells, and hence lacks the side-effects of generalized, long lasting immunosuppression. In addition, there is no amplification of steroid side-effects in non-lymphoid tissues.
10.15 am
(9) Targeting C-reactive protein for treatment of cardiovascular disease
M.B. Pepys1, P.N. Hawkins1, and the following (all introduced), G.M. Hirschfield2, G.A. Tennent1, J.R. Gallimore1, M.C. Kahan1, V. Bellotti1, R.M. Myers2, M.D. Smith2, A. Polara2, A.J.A. Cobb1, S.V. Ley2, J.A. Aquilina2, C.V. Robinson2, I. Sharif3, G.A. Gray3, C.A. Sabin1, M.C. Jenvey4, S.E. Kolstoe4, D. Thompson4, S.P. Wood4. 1Royal Free and University College Medical School; 2University of Cambridge, 3University of Edinburgh; 4University of Southampton.
Inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. We have identified C-reactive protein (CRP), the classical acute phase protein that activates complement, as an important mediator of this pathogenic inflammation. Human CRP activates both human and rat complement, whereas rat CRP does not activate complement. Administration of human CRP to rats therefore provides a good model for clinically relevant in vivo effects of human CRP, and we have shown that human CRP substantially increases infarct size in the heart or the brain after occlusion of the coronary or the middle cerebral artery, respectively. The mechanism involves binding of CRP to damaged cells, complement activation, and increased cell death through direct injury and exacerbation of inflammation. There is strong supportive evidence for operation of this mechanism in human disease. Here we report design and synthesis of palindromic bis-phosphocholines as the first specific small molecule inhibitors of CRP. The lead compound, 1,6-bis(phosphocholine)-hexane, forms complexes with five drug molecules cross-linking two pentameric CRP molecules so that the ligand binding B-face of CRP is occluded, thereby blocking its adverse effects. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction completely abrogated the greatly increased infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection and neuroprotection in acute myocardial infarction and stroke, respectively. There is also compelling evidence that high CRP concentrations may contribute to tissue damage in a wide range of other inflammatory disorders, for which CRP inhibitory drugs should therefore provide clinical benefit.
11.10 am
(10) The ‘window of opportunity’ for treating early rheumatoid arthritis
E.H.S. Choy, C.M. Smith, L. Chau, D. Walker, A. Hassell, V. Farewell (all introduced), D.L. Scott. Rheumatology Dept, Weston Education Centre, Kings College School of Medicine, London.
Rheumatoid arthritis (RA), the commonest chronic inflammatory disease in the UK, is poorly controlled by current conventional therapy in which disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX) are used sequentially. We tested the hypothesis that a ‘window of opportunity’ exists in early RA in which optimal conventional DMARD therapy can change course of the disease. Taking MTX as a base treatment, we evaluated the effects of added therapy targeted against two key pathogenic changes in early RA: synovial CD4+T cell infiltration, which can be inhibited by cyclosporin, and defects in the hypothalamic pituituary adrenal (HPA) stress response, which can be reversed by 6–9 months steroid therapy.
We evaluated combination therapy in a 2-year randomized controlled trial with a 2 x 2 design. Cyclosporin, prednisolone or both (triple therapy) were added to MTX in patients with active RA within 2 years of diagnosis. We randomized 467 eligible cases after screening 1391 patients at 42 specialist units in 2000–2. By 2 years, 247 (53%) cases were on their initial treatment, 132 (28%) had changed therapy and 88 (19%) were lost to follow-up. Patients were assessed 6-monthly; results were analysed on an intention to treat basis.
Structural damage assessed radiologically was reduced by adding cyclosporin or prednisolone to MTX; 50% less patients developed new erosions (p = 0.03 and 0.01, respectively); standardized X-ray scores (Larsen's method) were reduced by two units (p = 0.003 and 0.009). Triple therapy did not further reduce structural damage. Disability and quality of life improved significantly with by triple therapy compared to MTX alone, assessed using disease-specific (health assessment questionnaire), generic (SF-36) or economic (EuroQol) measures (p = 0.14 to 0.05). Triple therapy also significantly reduced synovitis (lower disease activity scores) and gave more remissions (p = 0.03 and 0.012). Adding cyclosporin or prednisolone alone to MTX did not give similar benefits. There were no more deaths or serious adverse effects with triple therapy.
Combination therapy is substantially better than MTX monotherapy, and it is becoming untenable to treat early RA with MTX monotherapy. A ‘window of opportunity’ exists in early RA when combinations reduce structural damage, give sustained improvements in quality of life and achieve more remissions.
11.35 am
(11) Features of epigenetic silencing in patients and mice with triplet-repeat expansions
R. Festenstein, N. Rothe, C. Everett, A. Saveliev, K. Hiragami (all introduced by G.R. Williams). MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London.
In order to determine the way DNA triplet-repeat expansions, that cause Myotonic Dystrophy and Friedreich's Ataxia (FRDA), induce gene silencing, we examined their effect on a reporter gene in transgenic mice. We found gene silencing which had features reminiscent of heterochromatin-mediated silencing previously observed in the fruit fly, Drosophila, and termed position effect variegation (PEV). PEV has allowed the nature of so-called epigenetic silencing to be dissected in vivo at the molecular level in fruit flies—our work has allowed us to pursue this phenomenon in mammals. Mutagenesis studies in Drosophila revealed over 100 modifiers of the proportion of cells that silence affected genes; many of these are components of chromatin or enzymes that modify chromatin. In PEV, once the decision to express is made, this is then ‘locked-in’ at the cellular level and importantly, the information to express appears to be encoded at the ‘epigenetic’ level by modifications in chromatin structure allowing daughter cells to inherit the gene expression decision of the parent cell. Using a combination of expression analysis at the RNA and protein level combined with analysis of the chromatin structure by nuclease accessibility and immunoprecipitation experiments we have shown differences in the histone modifications and DNA methylation status of affected genes in ‘transgene-expressing’ versus ‘non-expressing’ cells (which were otherwise identical). Moreover by crossing our transgenic mice to ‘PEV-modifier’ mice (that lack or over-express murine homologues of Drosophila modifier genes) we w able to modify the extent of triplet-repeat induced silencing. Variations in the extent of silencing between inbred strains of mice suggest that such ‘chromatin-modifiers’ may be disease-modifying loci. Thus, polymorphisms in the equivalent genes in the human population may be the cause of variability in disease severity in subjects with identical genetic defects. Thus, modulation of stochastic gene silencing may provide a potential therapeutic opportunity in patients with diseases caused by so-called ‘position effects’.
12 noon
(12) Functional characterization of the asthma gene, a disintegrin and metalloprotease (ADAM) 33
H.M. Haitchi, Y. Yang, Y.Y. Pang, R.M. Powell, D.E. Davies (all introduced), S.T. Holgate. Division of Infection, Inflammation and Repair, School of Medicine, University of Southampton, Southampton.
Polymorphic variation in ADAM33, the first asthma gene to be identified by positional cloning, is strongly associated with reduced lung function in children and adults, including COPD. Although ADAM proteins are multifunctional, nothing is known about the role of ADAM33 in airways. We postulated that abnormalities in ADAM33 expression or function play a role in asthma pathogenesis or progression.
Tissues were obtained after ethical approval and informed consent. ADAM33 expression was assessed using bisulphite sequencing, quantitative RT-PCR and immuno-methods. ADAM33 localization was analysed using GFP-tagged proteins with confocal microscopy and metalloprotease (MP) activity using PNA-FRET-peptide libraries.
The ADAM33 promoter contained a CpG island, which was unmethylated in fibroblasts, but hypermethylated in epithelial cells. Demethylation induced epithelial expression of ADAM33, suggesting that methylation controls its cell type-selective expression. In adult bronchi, ADAM33 mRNA and protein was expressed in smooth muscle and myofibroblasts, but in human developing lung, it was present in undifferentiated mesenchyme. Although several mRNA variants were detected, there was no difference in ADAM33 mRNA or protein between asthmatic or non-asthmatic subjects. However, transcripts encoding the MP domain were rare, suggesting tight regulation of catalytic activity. Recombinant MP domain was active, and several substrate sequences were identified. Although full-length ADAM33 was retained in the endoplasmatic reticulum (ER), chimeras of CD4 and the ADAM33 transmembrane and cytoplasmic tail trafficked beyond the ER, but four asthma-associated point mutations were without effect. However, a more commonly expressed variant lacking the MP and disintegrin domains gave a distinct vesicular localization, suggesting that the composition of the ADAM33 extracellular domain was able to influence trafficking.
Although simple up- or down-regulation of ADAM33 does not explain its contribution to asthma pathogenesis, its expression in embryonic and adult mesenchymal cells suggests it may be involved in airway wall ‘modelling’ as well as remodelling in chronic respiratory disease beyond asthma.
12.25 pm
(13) Oxyntomodulin both increases energy expenditure and reduces energy intake in obese humans—an effective double hit
K. Wynne*, A.J. Park*, C.J. Small, K. Meeran, M.A. Ghatei, G.S. Frost (all introduced) and S.R. Bloom. Dept of Metabolic Medicine, Imperial College, London W12 ONN. *Joint first authors.
Obesity is dramatically increasing worldwide. Dietary and lifestyle interventions have failed to abate an epidemic fuelled by low levels of physical activity and the easy availability of highly palatable, calorie-dense food. The satiety hormone oxyntomodulin has recently been found to greatly decrease body-weight in obese humans when administered over a 4-week period.
We investigated the effect of oxyntomodulin on energy expenditure in obese volunteers. Fifteen healthy obese participants self-administered oxyntomodulin or saline, pre-prandially, three times daily for four days, in a randomized controlled double-blind cross-over protocol. Volunteers were advised to maintain their normal dietary and exercise regimen. Energy expenditure was measured by indirect calorimetry and combined heart rate and movement monitoring in a ‘free-living’ environment. Energy intake was measured during a study meal.
Oxyntomodulin markedly increased activity-related energy expenditure by 143 ± 109 kcal/day or 26.2 ± 9.9% (p < 0.05); total energy expenditure by 9.4 ± 4.8% (p < 0.05) and physical activity level by 9.5 ± 4.6% (p < 0.05), without a change in resting energy expenditure. Oxyntomodulin administration also reduced energy intake at the study meal by 128 ± 29 kcal (p < 0.001) or 17.3 ± 5.5% (p < 0.01), with no change in perceived meal palatability. During even this short oxyntomodulin treatment period, body weight was reduced by 0.5 ± 0.2% (p < 0.05).
Oxyntomodulin is the first therapy demonstrated to result in appetite suppression combined with an increase in activity. Voluntary dietary restriction results in an adaptive decrease in energy expenditure that opposes weight loss. In contrast, oxyntomodulin reduces energy intake and increases energy expenditure, resulting in negative energy balance. Oxyntomodulin is a strong candidate for the basis of future anti-obesity therapies.
3.00 pm
(14) Slow conduction of the cardiac impulse and sudden cardiac death
A.A. Grace1,5, W.H. Colledge2, C.L.-H. Huang2, R.C. Saumarez3,4,5 (introduced by E.R. Chilvers4,5) Depts of 1Biochemistry, 2Physiology, 3Engineering and 4Medicine, University of Cambridge; 5Papworth Hospital, Cambridge.
The hypothesis is that the main determinants for arrhythmic risk and sudden cardiac death (SCD) reside within the heart. Brugada syndrome is characterized by familial ventricular fibrillation, and is due to loss-of-function mutations in the gene encoding cardiac voltage-gated sodium channels, SCN5A. Our pre-clinical programme uses genetically modified (GM) mice to explore how such genetic alterations, associated with SCD, relate to clinical arrhythmogenesis. Scn5a+/– GM mice have evidence of slow conduction, re-entrant excitation and ventricular arrhythmias along with sinus node dysfunction and atrioventricular block that recapitulate key aspects of corresponding disease phenotypes. Our clinical programme uses adaptations of the physiological techniques applied to mice, and this approach has now been tested prospectively in hypertrophic cardiomyopathy. The trial design was based on a positive predictive accuracy (PPA) of 0.4, a specificity of 0.8 and a SCD rate of 3% per year. 185 patients were studied, yielding 179 technically satisfactory studies. Test-positive patients had increased S1S2 coupling intervals at which electrogram duration started to increase and increased electrogram durations in response to extrastimuli indicative of slow conduction. The group of 23 test-positive patients had 9 VF events. The group of 156 test-negative patients had 3 VF events. The test-positive group had an annual mortality of 7.9% per year, while the mortality rate for the entire pooled patient group was 1.3% per year. The PPA for SCD is 0.39 (95%CI 0.19–0.59) and the negative predictive accuracy is >0.95. Accordingly, we have made quantitative measurements of the conduction of the cardiac impulse transferable between GM mice and patients, and have shown slow conduction to be a common component of the arrhythmogenic substrate. We propose that a detailed description of the electrophysiology of the human ventricle, to include measures of cardiac conduction, predicts the likelihood of SCD and provides a platform for treatment.
3.25 pm
(15) Axonal protection achieved by lamotrigine in a model of multiple sclerosis
D.A. Bechtold, R. Kapoor, D. Berry, K.J. Smith (all introduced by R.A.C. Hughes). Department of Clinical Neuroscience, King's College London.
Axonal degeneration is a major cause of permanent disability in multiple sclerosis (MS). We have recently shown that flecainide, a sodium channel-blocking agent, provides significant protection to axons in a model of MS, namely chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE) in rats. We have now assessed whether lamotrigine (LTG) is effective in this model, as this drug may be more suitable for clinical use. LTG administration from 7 days post-immunization to the end of the trial (28 days) significantly reduced the magnitude of the terminal neurological deficit (vehicle-treated controls: 3.5 ± 2.7; LTG: 2.6 ± 2.0, p < 0.05), and also preserved more functional axons in the spinal cord (measured as the mean compound action potential area arising from dorsal column axons; vehicle: 31.7 ± 23.0 µV.ms; LTG: 42.9 ± 27.4, p < 0.05). Histological examination (n=71) revealed that LTG treatment also protected axons from degeneration (vehicle: 33.5% ± 38.5, LTG: 10.4% ± 12.5 degeneration; p < 0.01). The beneficial effects of LTG were shown consistently in three separate trials. Blood samples established that the LTG concentration was within the therapeutic range for patients with epilepsy. We hypothesize that axons at sites of inflammation become loaded with sodium ions due to a combination of enhanced sodium entry (arising from impulse activity and the appearance of a persistent sodium current) and impaired sodium extrusion due to ATP insufficiency (arising from the inhibitory effects of inflammatory nitric oxide on mitochondria). Raised intra-axonal sodium can cause degeneration due to calcium entry via reverse action of the axolemmal Na+/Ca++ exchanger. LTG probably protects axons by reducing sodium loading, but the drug can also reduce central glutamate release and block voltage-gated calcium channels. We conclude that LTG may provide a novel avenue for axonal protection in MS, and report that these findings have resulted in an ongoing clinical trial of LTG therapy in secondary progressive MS at University and King's Colleges, funded by the MS Society of GB and NI.
3.50 pm
(16) Attenuation of insulin stimulated brain appetite and reward responses in insulin resistance contributes to failure of appetite control in humans
S.A. Amiel, (and the following, all introduced), L. Reed, K. Anthony, E. Bingham, J.T. Dunn, P.K. Marsden. Diabetes Research Group, Department of Neuropsychology and PET Imaging Centre, King's College London School of Medicine and Institute of Psychiatry, King's College London.
The rising world-wide prevalence of obesity, with its risks of cardiovascular disease and type 2 diabetes, is a major global health challenge. The key feature is metabolic syndrome, recently redefined with increased visceral adiposity (waist circumference) as essential, and associated with insulin resistance, dyslipidaemia, hypertension and glucose intolerance. Despite clear health benefits, the ability of people with metabolic syndrome to achieve and sustain weight loss is surprisingly limited, leading to the hypothesis that there is a primary abnormality in the metabolic response of brain regions that control appetite and reward in insulin resistance.
We measured global and regional brain insulin sensitivity in 14 men, 7 insulin-sensitive (HOMA-IR 1.3, 0.9–1.58) and 7 insulin-resistant (HOMA-IR 6.3, 2.94–9.5), using 18fluoro-deoxyglucose positron emission tomography, twice in random order. In all studies, endogenous insulin was suppressed by somatostatin infusion, started 90 min prior to scanning. In one, basal insulin was replaced by low-dose insulin infusion (0.3 mU/kg/min); the other was a saline-infused control. Global cerebral metabolic rate for glucose (CMRglc) rose in response to insulin replacement, less in the insulin-resistant (7% vs. 17.4%, p = 0.033). Insulin-stimulated change in CMRglc correlated inversely with fasting insulin (r = –0.5). The maximal insulin effect (p < 0.001) was in bilateral ventral striate and insular cortex, and in amygdala, orbitomedial frontal cortex and retrosplenium. Quantitative analysis in these regions confirmed reduced insulin effect in the insulin-resistant, e.g. ventral striate CMRglc 3.2 ± 3.9 vs. 7.7 ± 1.7, p = 0.017. This is the first demonstration of brain insulin resistance in people with systemic insulin resistance. Reduced insulin effect in brain regions concerned with food-seeking and reward behaviours may be important in the aetiology of metabolic syndrome, diminishing the link between adequate energy intake and control of eating and suggesting a primary central mechanism for the syndrome.
4.45 pm
(17) A functional genetic variant in MAL/TIRAP associates with protection against invasive pneumococcal disease, bacteraemia, malaria and tuberculosis in different human populations
S.J. Chapman, C.C. Khor (joint first authors), F.O. Vannberg, A. Dunne1, C. Murphy1, E.Y. Ling, O. Kyrieleis1, A. Khan1, C. Aucan, S. Segal, C. Lienhardt2, A. Scott3, P. Aaby2, O.Y. Sow2, T.N. Williams3, R.J.O. Davies, D.P. Kwiatkowski, N.P. Day, D.W. Crook, K. Marsh3, J.A. Berkley3, L.A. J. O'Neill1 (all introduced), A.V.S. Hill. Wellcome Trust Centre for Human Genetics and Oxford Tropical Network, University of Oxford; Trinity College, Dublin1; EU AFTBVAC Consortium2; KEMRI-Wellcome Programme, Kilifi, Kenya3.
Toll-like receptors and members of their signalling pathway play an important role in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein MAL/TIRAP mediates downstream signalling of Toll-like receptors (TLR) 2 and 4. Here we report a case-control genetic association study of 4510 individuals from the Gambia, Kenya, United Kingdom and Vietnam, with four major infectious diseases: invasive pneumococcal disease, bacteraemia, malaria and tuberculosis. Individuals were genotyped for 33 polymorphisms, including a variant that encodes a serine to leucine amino acid substitution at position 180 of the MAL/TIRAP protein. Heterozygous carriage of this variant was found to be significantly and independently associated with protection from all four infectious diseases in the different patient populations. Highly significant overall protection against infectious diseases was observed when the study groups were combined (n = 2032 controls vs. 2622 cases, Mantel-Haenszel 2 x 2 
2 = 21.63, p = 3.3 x 10–6, odds ratio= 0.49, 95%CI 0.36–0.67). In MAL/TIRAP knockout cells, signalling via TLR2 was restored by the wild-type 180-Ser but not by the 180-Leu variant. In a molecular model of MAL/TIRAP, position 180 mapped to a region that was predicted to be involved in the interaction between MAL/TIRAP and TLR2. Indeed, unlike wild-type MAL/TIRAP, the 180-Leu variant was found to be unable to interact with TLR2. This study demonstrates for the first time a strong effect of a single nucleotide change on multiple major infectious causes of mortality.
5.10 pm
History of Medicine Lecture—Fifty Years of Clinical Science in Psychiatry: Reflections on People, Ideas, Technology and Bureaucracy
Professor Sir Michael Rutter, MD, FRS, FMedSci. Institute of Psychiatry, King's College London.
Special Poster Presentation of research work sponsored through the ‘Links with Developing Countries’ Scheme—Economic costs of podoconiosis (endemic non-filarial elephantiasis) in Wolaita Zone, Ethiopia
F. Tekola, D.H. Mariam, G. Davey (introduced by M.J. Newport). Department of Community Health, Addis Ababa University, Addis Ababa, Ethiopia.
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- Measurement of the diaphragm electromyogram in chronic obstructive pulmonary disease. CJ Jolley, G Rafferty, J Steier, K Sylvester, G Harikumar, YM Luo and J Moxham. King's College London School of Medicine, King's College Hospital, London.
- Conformational change in the IgE-FcRI interaction as a target for inhibitor design. AJ Beavil, J Hunt, M Bracher, D Dombrowicz, HJ Gould and BJ Sutton. MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Guy's Hospital Campus, King's College London.
- Systemic glucocorticoid fails to inhibit the c-jun/c-jun kinase phosphorylation cascade in bronchial mucosal cells of glucocorticoid resistant asthmatics. CJ Corrigan, B O'Connor, J Ratoff, KH Mallett, TK Loke and TH Lee. MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Guy's Hospital Campus, King's College London.
- IgE switching and synthesis is regulated locally in the bronchial mucosa in atopic and non-atopic asthma. P Takhar, L Smurthwaite, CJ Corrigan, BJ O'Connor, TH Lee and HJ Gould. MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Guy's Hospital Campus, King's College London.
- Reversing the defective induction of interleukin-10 secreting T cells in glucocorticoid-resistant asthma patients. Emmanuel Xystrakis, S Boswell, P Lavender, E Peek, D Richards, Z Urry, *D Robinson, **A O'Garra, C Corrigan, T Lee and C Hawrylowicz. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Guy's Hospital Campus, King's College London and *Imperial College; **National Institute for Medical Research, Mill Hill, London.
- Contribution of a Nox2 NADPH oxidase to adverse cardiac remodelling following myocardial infarction. YH Looi, A Siva, S Walker, N Anilkumar, S Johar, AC Cave, DJ Grieve and AM Shah. Cardiovascular Division, Denmark Hill Campus, King's College London.
- Mechanically modulated signalling by titin kinase: implications for muscle pathology. S Lange*, E Rostkova*, J Kristensen*, G Franzen*, B Brandmeier*, E Ehler*, L Larsson+ and M Gautel*. *Muscle Cell Biology, Cardiovascular Division and Randall Division for Cell and Molecular Biophysics, King's College London; + Clinical Neurophysiology, Uppsala University Hospital, Sweden.
- Insulin-like growth factor binding protein-2 protects against the development of diet-induced obesity and insulin resistance. SB Wheatcroft1, VA Ezzat1, WP Cawthorn3, M Modo2, S Williams2, A Vidal-Puig3, J Miell1, JK Sethi3, AM Shah1, PA Crossey1 and MT Kearney1. 1Cardiovascular Division and the 2Institute of Psychiatry, King's College London; and 3The University of Cambridge.
- Signalling pathways regulating ICAM-1 expression by endothelin-1 (ET-1): comparison with interleukin-1beta (IL-1ß) in normal and scleroderma dermal fibroblasts. C Waters1,xShi-Wen2, CP Denton2, DJ Abraham2 and JD Pearson1. 1Cardiovascular Division, King's College London and 2Centre for Rheumatology, Royal Free & UCL Medical School, London.
- AHSP is a quantitative trait gene that modifies the phenotype of ß thalassemia. MI Lai1, J Jiang1, N Silver1, S Best1, S Menzel1, A Mijovic2, C Garner3,4, MJ Weiss5 and SL Thein1,2. 1Molecular Haematology, Division of Gene and Cell Based Therapy and 2Dept of Haematological Medicine, King's College London School of Medicine, Denmark Hill Campus; 3Epidemiology Division and 4Dept of Environmental Health, Science and Policy, University of California at Irvine, US; 5Children's Hospital of Philadelphia, University of Pennsylvania, US.
- Functional differences between the isoforms of Rho with respect to epithelial-mesenchymal transition in the kidney. N Hutchison, BM Hendry and CC Sharpe. Department of Renal Medicine, Division of Gene and Cell-Based Therapy, Denmark Hill campus, King's College London School of Medicine.
- Decreased immune-regulatory function of T-regs in autoimmune hepatitis is associated with a lower expression of FOXP3. MS Longhi, SK Arora, RR Mitry, DP Bogdanos, G Mieli-Vergani, D Vergani and Y Ma. Institute of Liver Studies, King's College Hospital, King's College London School of Medicine.
- Altered cortical activation in Amyotrophic Lateral Sclerosis (ALS) differs in motor and extra-motor regions. Stanton BR, Simmons A, Williams V, Blain C and Leigh PN. Department of Neurology, King's College London School of Medicine and Institute of Psychiatry, King's College London.
- Corticospinal tract damage in patients homozygous for the D90A SOD1 gene mutation compared to sporadic ALS: A diffusion tensor imaging study. Blain CRV, Williams VC, Turner MR, Stanton BR, Barker GJ, Williams SCR, Andersen PM, Leigh PN, Simmons A and Jones DK. Department of Neurology, King's College London School of Medicine and Institute of Psychiatry, King's College London.
- A novel locus on chromosome 9p for familial motor neurone disease and fronto-temporal dementia identified using microarray SNP genotyping. C Vance1, A Al-Chalabi1, BN Smith1,xHu1, J Sreedharan1, D Troost4, F Baas5, V De Jong6 and CE Shaw.1,2,3 1Department of Neurology, Institute of Psychiatry, and 2Departments of Neurology and 3Molecular and Medical Genetics, King's College London School of Medicine, London; Departments of 4Neuropathology, 5Neurogenetics and 6Neurology, Academic Medical Centre, Amsterdam, Netherlands.
- Adoptive cell therapy using in-vitro generated CD4+ CD25+ regulatory T cells with indirect allospecificity to promote donor-specific transplantation tolerance. S Jiang, D Golshayan, J Tsang, D Game, G Lombardi and RI Lechler. Department of Nephrology and Transplantation, Guy's Hospital, King's College London.
- Translational psoriasis research provides new insights into mechanisms and therapies of chronic inflammatory disorders. U Laggner, C Tonel, M Gilliet and FO Nestle. St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London School of Medicine.
- Oral creatinine improves muscle function in idiopathic inflammatory myositis. Y-L Chung, H Alexanderson, N Pipitone, J Bell, I Lundberg and DL Scott. Rheumatology Unit, King's College London School of Medicine; Karolinska Institute, Stockholm, Sweden; Malmo Univeristy Hospital, Sweden; MR Unit, Imperial College, London.
- The influence of donor C3 allotype on late renal transplant outcome. K Brown1, E Kondeatis1, R Vaughan1, Pin Khon2, C Farmer3, J Taylor1, C Horsfield4, S He5, S Sacks1 and N Sheerin1. Department of Nephrology and Transplantation, Guy's Hospital1 and King's College Hospital,2 King's College London; Kent & Canterbury Hospital3 (Canterbury); Department of Histopathology, St Thomas’ Hospital, London4; and St Bartholomew's and the Royal London School of Medicine and Dentistry5.
- Locally produced complement as key mediator of transplantation-associated ischemia reperfusion injury. CA Farrar, W Zhou, T Lin and SH Sacks. Department of Nephrology and Transplantation, Guy's Hospital, King's College London.
- Functional MRI of memory: translation of a neuroscience method into a clinical tool for epilepsy patients. M Richardson1, J Duncan, P Thompson, S Baxendale, B Strange and R Dolan. 1Institute of Psychiatry, King's College London; and University College London.
- Natural Resistance to HIV Infection: the Vif-APOBEC Conflict. MH Malim, King's College London.
- Applying optical proteomics to novel cancer biomarker discovery. M Kelleher, C Gillett, F Festy, P Thavasu and T Ng. Richard Dimbleby Dept of Cancer Research, King's College London.
- Pathway monitoring in tissue samples—EGFR activation status in Head and Neck Cancer. A Kong1, 2, P Leboucher4, R Leek3, V Calleja1, S Winter3, A Harris3, B Larijani1 and P Parker2,5. 1Cell Biophysics and 2Protein Phosphorylation Labs, Cancer Research UK, London; 3Weatherall Institute of Molecular Medicine, Cancer Research UK, University of Oxford; 4Laboratoire de Physiologie de la Pérception et de l’Action, College de France, Paris, France; and 5Cancer Division, King's College London, Guy's Campus, London.
- Blood-based biomarkers for Alzheimer's Disease. A Hye, S Lynham, M Thambisetty, J Cambell, F Rijsdijk, R Brown, P Sham, B Anderton, M Ward and Lovestone S. MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London.
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