TY - BOOK T1 - Muscle Biopsy: A practical approach 3rd edition A1 - Dubowitz V A1 - Sewry CA Y1 - 2007/// VL - 3 PB - Saunders/Elsevier SN - 1 4160 2593 6 N2 - - ER - TY - BOOK T1 - Atlas of Tropical Medicine and Parasitology A1 - Wallace Peters A1 - Geoffrey Pasvol Y1 - 2007/// VL - 6th PB - Elsevier CY - Philadelphia SP - 1 EP - 429 N2 - - ER - TY - BOOK T1 - Oxford Handbook of Dialysis A1 - J Levy A1 - J Morgan A1 - E Brown Y1 - 2005/06// PB - Oxford University Press SN - 0-19-852954-6 N2 - - ER - TY - BOOK T1 - Viral Hepatitis A1 - Thomas HC, A1 - Lemon.S A1 - Zuckerman A ED - Thomas HC, Lemon S; and Zuckerman A Y1 - 2005/// VL - Third Edition PB - Blackwell Publishing CY - Oxford, UK SN - 1-4051-3005-9 SP - 3 EP - 876 N2 - - ER - TY - BOOK T1 - Viral Hepatitis A1 - Thomas HC A1 - Lemon S A1 - Zuckerman AJ ED - Thomas HC; Lemon S; Zuckerman AJ Y1 - 2005/// VL - Third Edition PB - Blackwell Publishing CY - Oxford; UK SP - 1 EP - 876 N2 - - ER - TY - BOOK T1 - A Guide to the MRCP Part 2 Written Paper A1 - Warrens, A N A1 - Persey, M A1 - Fertleman, M A1 - Powis, S H A1 - Zumla, A Y1 - 2005/// VL - Second Edition PB - Hodder Arnold CY - London SN - 0-340-80658-3 N2 - - ER - TY - BOOK T1 - Oxford handbook of tropical medicine A1 - Eddleston M A1 - Davidson RN A1 - Wilkinson RJ A1 - Pierini S Y1 - 2004/// VL - 2 PB - Oxford University Press SN - 0-1985-2509-5 SP - 1 EP - 712 N2 - - ER - TY - BOOK T1 - Malaria A hematological perspective A1 - Pasvol G ED - Abdalla SH; Pasvol G Y1 - 2004/// PB - Imperial College Press SN - 1-86094-357-8 N2 - - ER - TY - BOOK T1 - Gastroenterology Update A1 - Ghosh S A1 - Watts D A1 - Kinnear M ED - Mayberry J Y1 - 2004/// PB - Radcliffe Publishing Ltd CY - Oxon OX14 1AA SN - 1 85775 631 2 SP - 75 EP - 100 N2 - - ER - TY - BOOK T1 - Supportive Care for the Renal Patient A1 - Brown EA ED - Chambers EJ; Germain M; Brown E Y1 - 2004/// PB - Oxford University Press SN - 0-19-851616-9 N2 - - ER - TY - BOOK T1 - Child Public Health A1 - Blair M A1 - Waterston T A1 - Stewart Brown S A1 - Crowther R Y1 - 2003/11// IS - 1 PB - Oxford University Press SN - 0-19-263192-6 SP - 1 EP - 256 N2 - - UR - http://www.oup.com ER - TY - BOOK T1 - ILSI Europe Concise Monograph Series A1 - Warner, JO ED - Warner, JO Y1 - 2003/// PB - Food Allergy SP - 1 EP - 40 N2 - - ER - TY - BOOK T1 - Infection and Immunity A1 - Lightstone EB ED - Friedland JS; Lightstone EB Y1 - 2003/// PB - Martin Dunitz CY - 11 New Fetter Lane, London EC4P 4EE SN - 1 84184 373 3 N2 - - UR - http://www.dunitz.co.uk ER - TY - BOOK T1 - Mosby's Colour Atlas and Text of Gastroenterology and Liver Disease A1 - Aspinall RJ A1 - Taylor-Robinson SD Y1 - 2002/// SN - 0-7234-3103-5 N2 - - ER - TY - BOOK T1 - WHO-UNAIDS Guidelines for Standard HIV Isolation and Characterisation Procedures A1 - Weber JN A1 - Fenyo EM Y1 - 2002/// SN - 9-2415-9021-1 N2 - - ER - TY - BOOK T1 - Pass Finals A1 - Geoff Smith A1 - Elizabeth Carty A1 - Louise Langmead Y1 - 2002/// VL - 1 PB - Elsevier CY - Edinburgh UK N2 - - ER - TY - BOOK T1 - Tropical medicine and parasitology A1 - Peters W A1 - Pasvol G Y1 - 2002/// SN - 0-7234-3191-4 N2 - - ER - TY - BOOK T1 - Preventing kidney disease: the ethnic challenge in Brent A1 - Lightstone L A1 - Woolnough L Y1 - 2002/// PB - National Kidney Research Fund SN - 1-9042-2704-X N2 - - ER - TY - BOOK T1 - Preventing kidney disease: the ethnic challenge A1 - Lightstone E Y1 - 2001/// PB - National Kidney Research Fund CY - Peterborough, England SN - 1-9042-2700-7 N2 - - ER - TY - BOOK T1 - Textbook of Pediatric Asthma: An international perspective. A1 - Warner, JO ED - Naspitz CK; Szefler SJ; Tinkelman DG; Warner JO. Y1 - 2001/// PB - Martin Dunnitz, London SP - 1 EP - 410 N2 - - ER - TY - BOOK T1 - The Complement Factsbook A1 - Morley, B J ED - Morley, B J and Walport, M J Y1 - 2000/// PB - Academic Press N2 - - ER - TY - BOOK T1 - Diagnostic and Therapeutic Antibodies A1 - George AJT A1 - Urch CE Y1 - 2000/// PB - Humana Press CY - Totowa, New Jersey SN - 0-89603-798-3 SP - 1 EP - 477 N2 - - ER - TY - BOOK T1 - HLA in Health and Disease A1 - Warrens AN ED - Lechler RI ; Warrens AN Y1 - 2000/// PB - Academic Press CY - London SN - 0-12-440315-8 N2 - - ER - TY - BOOK T1 - Hypertension and the Elderly A1 - Bulpitt, C A1 - Rajkumar, C A1 - Beckett, N Y1 - 1999/// VL - First PB - Science Press CY - London SN - 1-85873-301-4 N2 - - ER - TY - BOOK T1 - Diagnosis in color Neonatology A1 - Markiewicz M ED - Mosby Y1 - 1999/// SN - 0-7234-3011-x N2 - - ER - TY - BOOK T1 - Complications of long term dialysis A1 - Brown EA ED - Brown EA; Parfrey P Y1 - 1998/// PB - Oxford University Press CY - Oxford N2 - - ER - TY - BOOK T1 - Meningitis: A Guide for Families A1 - Kroll, JS A1 - Pollard, AJ A1 - Habibi, P Y1 - 1997/// PB - Publishing Solutions CY - London SN - 1-901336-00-X SP - 5 EP - 112 N2 - - ER - TY - BOOK T1 - New diagnostic techniques in paediatric respiratory medicine. A1 - Warner, JO ED - Warner JO; Zach M; Carson K-H; Sennhauser FH. Y1 - 1997/// IS - 2 PB - European Respiratory Monograph 5 N2 - - ER - TY - BOOK T1 - Meningitis - A Guide for Families A1 - Kroll S A1 - Pollard A A1 - Habibi P Y1 - 1997/// PB - Publishing Solutions (UK) Ltd N2 - - ER - TY - CHAP T1 - Susceptibility to infectious diseases A1 - Walley, A A1 - Hill, A ED - Alan Wright and Nick Hastie T2 - Genes and Common Diseases: Genetics in Modern Medicine Y1 - 2007/08// VL - First PB - Cambridge University Press SN - 052154100X N2 - - ER - TY - CHAP T1 - Renal and Urological Disease A1 - Hobson, HJ ED - Palmer KT, Cox RAF, Brown I T2 - Fitness for Work Y1 - 2007/// VL - 4th PB - Oxford University Press CY - Oxford, UK SP - 429 EP - 444 N2 - - ER - TY - CHAP T1 - Sex-specific aspects of dyslipidaemia and atherosclerosis A1 - Godsland, I F ED - Packard, C J T2 - The Year in Lipid Disorders Y1 - 2007/// M2 - 1 PB - Clinical Publishing CY - Oxford N2 - - ER - TY - CHAP T1 - Infectious diseases: Gene therapy A1 - S Fidler ED - Thomson Scientific T2 - Encyclopdeia of Genetics Y1 - 2007/// VL - second M2 - 1 PB - thomson scientific CY - UK N2 - - ER - TY - CHAP T1 - Familial amyotrophic lateral sclerosis A1 - Shaw, CE A1 - Arechavala-Gomeza, V A1 - Al-Chalabi, A ED - Andrew Eisen,Pamela J. Shaw, T2 - Motor Neuron Disorders and Related Diseases, Handbook of Clinical Neurology Series Y1 - 2006/12// PB - Elsevier SN - 0444518940 N2 - - ER - TY - CHAP T1 - Endemic Burkitt's Lymphoma A1 - Griffin BE A1 - Rochford R ED - ES Robertson T2 - Epstein-Barr Virus Y1 - 2006/// PB - Caister Academic Press CY - UK SP - 113 EP - 137 N2 - - ER - TY - CHAP T1 - Host Genetics and Susceptibility to infection A1 - Wilkinson RJ A1 - Levin M ED - Guerrant R.L, Walker, D.H. and Weller, P.F. T2 - Tropical Infectious Diseases: Principles, pathogens and practice Y1 - 2006/// VL - 2 M2 - 1 PB - Churchill Livingstone CY - Philadelphia SN - 0-443-06668-X SP - 53 EP - 67 N2 - - ER - TY - CHAP T1 - Handbook “Disorders of iron homeostasis, erythrocytes, erythropoiesis A1 - Maxwell PH A1 - Pugh CW ED - Beaumont C. Beuzard Y. Beris P. & Brugnara C. T2 - Regulation of oxygen sensing and erythropoietin production. Y1 - 2006/// VL - First PB - European School of Haematology CY - Paris, France SP - 13 EP - 36 N2 - - ER - TY - CHAP T1 - Hypertension in the Elderly A1 - Beckett, N A1 - Peters, R T2 - Encyclopaedia of Ageing Y1 - 2006/// M2 - 1 PB - Springer Publishing Company SP - 559 EP - 562 N2 - - ER - TY - CHAP T1 - Hypoxia Inducible Factor-1 and oxygen sensing. A1 - P. Maxwell. T2 - In Actualities Nephrologiques Jean Hamburger Hospital Necker 2006 Y1 - 2006/// SN - 2257108213 N2 - - ER - TY - CHAP T1 - Mycobacterium avium paratuberculosis in Crohn's Disease: Player or spectator? A1 - Geoff Smith A1 - Fergus Shanahan ED - Peter Irving David Rampton Fergus Shanahan T2 - Clinical Dilemmas in Inflammatory Bowel Disease Y1 - 2006/// VL - 1 PB - Blackwell Publishing CY - London SN - 1-4051-3377-5 N2 - - ER - TY - CHAP T1 - Transplantation and Rejection A1 - Lechler, RI A1 - George, AJT ED - Male D., Brostoff J., Roth D.B. and Roitt I. T2 - Immunology Y1 - 2006/// VL - 7th PB - Mosby Elsevier CY - Philadelphia SN - 0-323-03399-7 SP - 383 EP - 399 N2 - - ER - TY - CHAP T1 - Skin Manifestations of Meningogoccal Infection. A1 - Faust SN, Habibi P, Heyderman R A1 - Faust N A1 - Habibi p A1 - Hederman n ED - Ed. John Harper, Arnold Orange, Neil Prose. T2 - Text Book of Paediatric Dermatology Y1 - 2006/// VL - 2nd Ed M2 - Volume 1 PB - Blackwell Publishing Ltd. CY - Oxford SP - 471 EP - 485 N2 - - ER - TY - CHAP T1 - Immunosuppressive drugs in renal transplantation - 2006 A1 - Warrens, A N ED - Haskard, D O T2 - Horizons in Medicine - 17 Y1 - 2006/// PB - Royal College of Physicians of London SN - 1-86016-253-3 SP - 71 EP - 77 N2 - - ER - TY - CHAP T1 - Recent advances in retroviral replication: Cellular machines and novel anti-viral defense mechanisms. A1 - Engelman, A A1 - Cherepanov, P ED - Hefferon, K L T2 - Recent Advances in RNA Virus Replication Y1 - 2006/// PB - Transworld Research Network CY - Kerala, India SN - 81-7895-214-9 SP - 91 EP - 129 N2 - - ER - TY - CHAP T1 - Screening for type 2 diabetes A1 - Johnston, DG A1 - Alberti, KGMM A1 - Godsland, IF A1 - Pierce, M A1 - Shepperd, S ED - Marmot M, Elliott P T2 - Coronary Heart Disease Epidemiology: from aetiology to public health Y1 - 2005/// VL - 2nd PB - Oxford University Press CY - Oxford SN - 0-19-852573-7 N2 - - ER - TY - CHAP T1 - Hepatitis B surface antigen (HBsAg) variants. A1 - Carman WF A1 - Jazayeri M A1 - Basune A A1 - Thomas HC A1 - Karayiannis P ED - Thomas HC; Lemon S; Zuckerman AJ T2 - Viral Hepatitis Y1 - 2005/// PB - Blackwell Publishing SN - 1-4051-30059 SP - 225 EP - 241 N2 - - ER - TY - CHAP T1 - Gastrointestinal Diseases A1 - Chaudhary R A1 - Ghosh S ED - Lakhani m, Charlton R T2 - Recent Advances in Primary Care Y1 - 2005/// PB - Royal College of General Practitioners CY - London SP - 197 EP - 222 N2 - - ER - TY - CHAP T1 - “Intracellular Models of M.tuberculosis Infection” A1 - Chan, John A1 - Silver, Richard A1 - Kampmann, Beate A1 - Wallis, Robert ED - Stuart Cole et al, T2 - “ Tuberculosis” Y1 - 2005/// PB - ASM Press, Washington (2005) N2 - - ER - TY - CHAP T1 - Hepatitis in HIV infected persons A1 - Main J A1 - McCarron B ED - Thomas H; Lemon S; Zuckerman A T2 - Viral Hepatitis Y1 - 2005/// PB - Blackwell N2 - - ER - TY - CHAP T1 - IN VITRO ASSAYS FOR IMMUNE-MONITORING IN TRANSPLANTATION A1 - Hernandez-Fuentes M ED - Hornick PI, Rose ML. T2 - Transplant Immunology Y1 - 2005/// PB - Humana Press CY - New Jersey N2 - - ER - TY - CHAP T1 - New Concepts in Irritable Bowel Syndrome-Visceral Hypersensitivity, Inflammation and New Therapeutic Targets A1 - Ghosh, S A1 - Akbar, A ED - Dr S.B. Gupta T2 - The Association Of Physicians Of India Medicine Update 2005 Y1 - 2005/01// M2 - 15 PB - Urvi Compugraphics CY - Mumbai SN - 81-901048-4-5 SP - 396 EP - 405 N2 - - ER - TY - CHAP T1 - Hepatitis C Virus: Structure and Molecular Virology A1 - McGarvey MJ A1 - Houghton M ED - Howard C Thomas, Stanley Lemon, Arie J Zuckerman T2 - Viral Hepatitis Y1 - 2005/// M2 - Third Edition PB - Blackwell Publishing Inc. CY - Malden, Massachusetts SP - 381 EP - 406 N2 - - ER - TY - CHAP T1 - Estrogen deprivation and hormone replacement therapy: effects on glucose and insulin metabolism and the metabolic syndrome A1 - Godsland, IF ED - Lauritzen C, Studd J T2 - Current Management of the Menopause Y1 - 2005/// VL - 1st PB - Dunitz CY - London SN - 1-84184-232-X N2 - - ER - TY - CHAP T1 - Peritoneal Dialysis A1 - Brown E ED - Levy J T2 - The Year in Renal Medicine Y1 - 2005/// PB - Clinical Publishing CY - Oxford SN - 1 904392 39 3 SP - 23 EP - 41 N2 - - ER - TY - CHAP T1 - Screening for Type 2 diabetes A1 - Johnston DG A1 - Alberti KGMM A1 - Godsland IF A1 - Pierce M A1 - Shepperd S ED - Marmot M, Elliott P T2 - Coronary Heart Disease Epidemiology Y1 - 2005/// VL - 2nd Edition PB - OUP CY - Oxford SP - 714 EP - 750 N2 - - ER - TY - CHAP T1 - Haematology A1 - Irene A G Roberts A1 - Neil A Murray ED - Janet M Rennie T2 - Roberton's Textbook of Neonatology Y1 - 2005/// VL - Fourth edition PB - Elsevier Churchill Livingstone SN - 0 443 07355 4 SP - 739 EP - 772 N2 - - UR - http://www.elsevierhealth.com ER - TY - CHAP T1 - Monoclonal antibody therapy A1 - George AJT ED - Kaufmann SHE; Steward MW T2 - Topley & Wilson's Microbiology and Microbial Infections: Immunology. 10th Edition Y1 - 2005/// PB - Hodder Arnold CY - London SN - 0 340 88569 6 SP - 353 EP - 374 N2 - - ER - TY - CHAP T1 - Pneumococcal vaccination A1 - Mcintosh EDG ED - Prof Mark Wilcox T2 - The Year in Infection Y1 - 2005/// M2 - 2 PB - Clinical Publishing CY - Oxford SP - 105 EP - 122 N2 - - ER - TY - CHAP T1 - Molecular variations in the core promoter, precore and core regions of hepatitis B virus, and their clinical significance. A1 - Karayiannis P A1 - Carman WF A1 - Thomas HC ED - Thomas HC; Lemon S; Zuckerman AJ T2 - Viral Hepatitis Y1 - 2005/// PB - Blackwell Publishing SN - 1-4051-30059 SP - 242 EP - 262 N2 - - ER - TY - CHAP T1 - Chapter 20: Dose finding in paediatrics A1 - Mcintosh EDG T2 - Paediatric Clinical Research Manual Y1 - 2005/// SP - 20.1 EP - 20.19 N2 - - ER - TY - CHAP T1 - Treatment of chronic hepatitis C A1 - Heathcote J A1 - Main J ED - Thomas H; Lemon S; Zuckerman A T2 - Viral Hepatitis Y1 - 2005/// PB - Blackwell N2 - - ER - TY - CHAP T1 - Malaria A1 - Pasvol G ED - Eddlestone m, Davidson R, Wilkinson R, Pierini S T2 - Oxford handbook of tropical Medicine Y1 - 2005/// M2 - 2nd Edition PB - Oxford University Press SN - 0 19 852509 5 SP - 9 EP - 37 N2 - - ER - TY - CHAP T1 - Nuclear magnetic resonance spectroscopy of in the study of human liver. A1 - Lim AK A1 - Khan SA A1 - Cox IJ A1 - Taylor-Robinson SD ED - Tosi R, Tugnoli V T2 - Nuclear Magnetic Resonance Spectroscopy in the Study of Neoplastic Tissue. Y1 - 2005/// VL - 1 PB - Nova Science CY - Hauppauge, New York SN - 1-59454-258-9 SP - 295 EP - 311 N2 - - ER - TY - CHAP T1 - How to manage renal disease in pregnancy A1 - Lightstone L ED - Jayne Franklyn T2 - Horizons in Medicine 16 Updates on major clinical advances Y1 - 2004/08// PB - Royal College of Physicians of London CY - London SN - 1 86016 233 9 SP - 261 EP - 270 N2 - - ER - TY - CHAP T1 - The Human T Cell Lymphotropic Viruses A1 - Taylor GP ED - Zuckerman, AJ, Banatvala JE, Pattison JR, Griffiths PD, Schoub BD T2 - Principles and Practice of Clinical Virology 5th Ed Y1 - 2004/05// PB - John Wiley & Sons SN - 0-470-84338-1 SP - 759 EP - 777 N2 - - ER - TY - CHAP T1 - Malaria A1 - Pasvol G ED - Cohen, J and Powderly, WG T2 - Infectious Diseases Y1 - 2004/// PB - Mosby CY - London SP - 1579 EP - 1591 N2 - - ER - TY - CHAP T1 - The von Hippel-Lindau Protein: a key player in oxygen homeostasis and matrix assembly. A1 - Esteban M A1 - Mandriota S A1 - Maxwell P ED - Matsuzawa Y, Kita T, Nagai R & Teramoto T. T2 - Atherosclerosis XIII. Y1 - 2004/// VL - First Edition SN - 0444514481 SP - 450 EP - 453 N2 - - ER - TY - CHAP T1 - Novel Vaccines Against Tuberculosis A1 - Wilkinson RJ ED - Myron M. Levine, James B. Kaper, Rino Rappuoli, Margaret Liu, and Michael F. Good T2 - New Generation Vaccines Y1 - 2004/// VL - 3 PB - Marcel Dekker CY - New York SP - 519 EP - 535 N2 - - ER - TY - CHAP T1 - "Glenn" (Interview with me about oral history research) A1 - Riordan, M T2 - An Unauthorised Biography of the World: Oral history on the front lines Y1 - 2004/// PB - BTL Books CY - Toronto, Canada SN - 1-896357-93-8 SP - 245 EP - 263 N2 - - ER - TY - CHAP T1 - “ Acute Respiratory Infections” A1 - Kampmann, Beate ED - Eddleston M, Pierini S, Davidson RN and Wikinson RJ (eds) T2 - Oxford Handbook of Tropical Medicine Y1 - 2004/// VL - 2nd edition. CY - Oxford N2 - - ER - TY - CHAP T1 - The utility of self-propagating hepatitis C virus RNAs in the stidy of molecular biology and of antiviral agents A1 - Karayiannis P ED - Hadziyannis S T2 - Hepatitis B and C 2004 Y1 - 2004/// SP - 43 EP - 55 N2 - - ER - TY - CHAP T1 - Biological Therapies in Inflammatory Bowel Disease A1 - Ghosh S ED - Bianchi Porro G, Ardizzone S, Colombo E T2 - IBD Year Book 2004 Y1 - 2004/// PB - Nomos Edizioni CY - Milano SP - 107 EP - 127 N2 - - ER - TY - CHAP T1 - Pathogenesis of anemai of malaria A1 - Abdalla SH A1 - Pasvol G ED - Abdalla SH and Pasvol G T2 - Malaria A hematological perspective Y1 - 2004/// PB - Imperial College Press SN - 1-86094-357-8 N2 - - ER - TY - CHAP T1 - Glycosylation and Muscular Dystrophy A1 - Brown SC A1 - Muntoni F ED - Winder SJ T2 - Molecular Mechanisms in Muscular Dystrophy Y1 - 2004/// PB - Landes Bioscience N2 - - ER - TY - CHAP T1 - Muscle Physiology A1 - Lopez-Rivero J-L A1 - Piercy RJ ED - Hinchcliff KW, Kaneps AJ & Gore RJ T2 - Equine Sports MEdicine and Surgery Y1 - 2004/// PB - Elsevier CY - London N2 - - ER - TY - CHAP T1 - Muscle disorders of Equine Athletes A1 - Piercy RJ A1 - Lopez Rivero JL ED - Hinchcliff KW, Kaneps AJ & Gore RJ T2 - Equine Sports Medicine and Surgery Y1 - 2004/// PB - Elsevier CY - London N2 - - ER - TY - CHAP T1 - Definition, epidemiology, diagnosis and management of anemia of malaria A1 - Pasvol G A1 - Abdalla SH ED - Abdalla SH and Pasvol G T2 - Malaria A hematological perspective Y1 - 2004/// PB - Imperial College Press SN - 1-86094-357-8 N2 - - ER - TY - CHAP T1 - Confusion and coma A1 - Pasvol G ED - Cohen, J and Powderly, WG T2 - Infectious Diseases Y1 - 2004/// PB - Mosby CY - London SP - 1459 EP - 1465 N2 - - ER - TY - CHAP T1 - Actinobacillus. A1 - Bossé, J T A1 - MacInnes, J I ED - Gyles, C L, Prescott, J F, Songer, J G, and Thoen, C O T2 - Pathogenesis of bacterial infections of animals. Y1 - 2004/// VL - Third PB - Blackwell Publishing CY - Ames, Iowa SN - 0-8138-2939-9 SP - 225 EP - 241 N2 - - ER - TY - CHAP T1 - The Road to Transplantation Tolerance A1 - Salama AD A1 - MH Sayegh ED - M Weir T2 - Medical management of Kidney Transplantation Y1 - 2004/// PB - Lippincott, Williams and Wilkins N2 - - ER - TY - CHAP T1 - ). Probing cellular function with bioluminescence imaging. A1 - Rutter GA A1 - da Silva Xavier G A1 - Tsuboi T A1 - Mitchell K A1 - Hanrahan JW ED - John Wiley and Sons T2 - Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics. Y1 - 2003/// PB - John Wiley and Sons N2 - - ER - TY - CHAP T1 - Anti-glomerular basement membrane disease A1 - Levy J A1 - Pusey CD ED - Warrell DA; Cox TM; Firth JD T2 - Oxford Textbook of Medicine, 4th Edition Y1 - 2003/// PB - Oxford University Press CY - Oxford SN - 0-19-852789-6 SP - 335 EP - 339 N2 - - ER - TY - CHAP T1 - Intensive Care A1 - Modi N ED - Greenough A, Milner A, Roberton NRC T2 - Neonatal Respiratory Disorders 2nd Edition Y1 - 2003/// PB - Arnold CY - London SP - 205 EP - 215 N2 - - ER - TY - CHAP T1 - Crescentic glomerulonephritis A1 - Levy JB A1 - Pusey CD ED - Brady HR, Wilcox CS T2 - Therapy in Nephrology and Hypertension, 2nd Edition Y1 - 2003/// PB - WB Saunders CY - Philadelphia SP - 177 EP - 188 N2 - - ER - TY - CHAP T1 - The hapatitis B virus: Genotypes, genome organisation and replication A1 - Karayiannis P ED - S.J. Hadziyannis T2 - Hepatitis B and C Y1 - 2003/// PB - Paschalides CY - Athens SN - 960-399-139-2 SP - 20 EP - 34 N2 - - ER - TY - CHAP T1 - Hepatitis A1 - Main J A1 - Thomas HC ED - Finch RG, Greenwood D, Norrby SR, Whitley RJ T2 - Antibiotic and Chemotherapy Y1 - 2003/// N2 - - ER - TY - CHAP T1 - Mechanisms of allorecognition A1 - Dupont, P J A1 - Herbert, P E A1 - Warrens, A N ED - Lesavre, P Drueke, T Legendre, C Niaudet, P T2 - Actualites Nephrologiques Jean Hamburger: Hopital Necker Y1 - 2003/// PB - Flammarion Medicine-Sciences CY - Paris SN - 2-257-10815-9 N2 - - ER - TY - CHAP T1 - Principles and Purpose for Child Health Informatics A1 - Blair M ED - Rigby M T2 - Vision and Value in Health Information Y1 - 2003/// PB - Radcliffe N2 - - ER - TY - CHAP T1 - The role of ascorbate in gastric juice and the impact of helicobacter infection. A1 - MJG Farthing A1 - GV Smith A1 - ZW Zhang ED - Hunt Tytgat T2 - Helicobacter pylori Basic mechanisms to clinical cure 2002 Y1 - 2003/// PB - Kluwer Academic Publishers CY - Dordrecht SP - 195 EP - 204 N2 - - ER - TY - CHAP T1 - Mechanisms of allorecognition A1 - Dupont PJ A1 - Herbert PE A1 - Warrens AN ED - Lesavre P, Drueke T, Legendre C and Niaudet P T2 - Actualites Nephrologiques Jean Hamburger Y1 - 2003/// PB - Flammarion SN - 2-257-10815-9 SP - 285 EP - 298 N2 - - ER - TY - CHAP T1 - Plasma exchange A1 - Levy J A1 - Pusey CD ED - Johnson RJ, Feehally J T2 - Comprehensive Clinical Nephrology, 2nd Edition Y1 - 2003/// PB - Harcourt Publishers SN - 07234-31175 SP - 1035 EP - 1042 N2 - - ER - TY - CHAP T1 - Malaria. A1 - Maitland K A1 - Newton C ED - Robert E Rakel T2 - Conns Current Therapy Y1 - 2003/// PB - WB Saunders CY - Houston, TX SP - 96 EP - 104 N2 - - ER - TY - CHAP T1 - Selection of Dialysis Modality A1 - EA Brown ED - J Weber T2 - Horizons in Medicine Y1 - 2003/// PB - Royal College of Physicians N2 - - ER - TY - CHAP T1 - Neoglycolipids: identification of functional carbohydrate epitopes A1 - Feizi T A1 - Lawson AM A1 - Chai W ED - Wong C.-H T2 - Carbohydrate-based drug discovery Y1 - 2003/// PB - Wiley-VCH CY - Weinheim SP - 747 EP - 760 N2 - - ER - TY - CHAP T1 - Hepatitis C in HIV infection A1 - Main J ED - Bassendine M, Foster GR, Miles A T2 - The effective management of hepatitis C infection Y1 - 2003/// PB - Aesulapius Medical Press SN - 1 903044 33 2 N2 - - ER - TY - CHAP T1 - Hepatitis C virus: Protein translation, IRES function and DNA immunisation. A1 - Karayiannis P ED - S.J. Hadziyannis T2 - Hepatitis B and C Y1 - 2003/// PB - Paschalides CY - Athens SN - 960-399-139-2 SP - 277 EP - 288 N2 - - ER - TY - CHAP T1 - Child Health Indicators of Life and Development- Report to the European Commission Health Monitoring Programme A1 - Blair M A1 - Kohler L A1 - Rigby M A1 - Mechtler R A1 - et al ED - Rigby MJ, Kohler L T2 - C Y1 - 2002/09// PB - EU N2 - - ER - TY - CHAP T1 - Calcium, phosphate and magnesium disturbances A1 - Dorling A T2 - Acute renal failure in practice Y1 - 2002/// SN - 1-8609-4216-4 SP - 174 EP - 183 N2 - - ER - TY - CHAP T1 - Gene therapy for AIDS and other ifnectious diseases A1 - john Frater A1 - Sarah Fidler ED - Gavin Brooks T2 - Gene Therapy; The use of DNA as a drug Y1 - 2002/// VL - 1 M2 - 1 PB - Pharmaceutical press CY - London UK SN - 0853694559 SP - 189 EP - 215 N2 - - ER - TY - CHAP T1 - Steroid sulfatase A1 - Newman SP A1 - Purohit A A1 - Reed MJ A1 - Potter BVL T2 - Wiley encyclopedia of molecular medicine Y1 - 2002/// SN - 0-4712-0306-8 SP - 3012 EP - 3013 N2 - - ER - TY - CHAP T1 - Thyroid disease and osteoporosis A1 - Williams GR T2 - Oxford textbook of endocrinology and diabetes Y1 - 2002/// SN - 0-1926-3045-8 SP - 677 EP - 683 N2 - - ER - TY - CHAP T1 - Changes in metabolic, inflammatory and endothelial indices of cardiovascular risk A1 - Godsland I T2 - Textbook of men's health Y1 - 2002/// SN - 1-8421-4011-6 SP - 317 EP - 335 N2 - - ER - TY - CHAP T1 - The Renal Transplant Recipient A1 - Warrens AN ED - Glynne P, Allen A and Pusey C T2 - Acute Renal Failure in Practice Y1 - 2002/// PB - Imperial College Press SN - 1-86094-287-3 SP - 453 EP - 464 N2 - - ER - TY - CHAP T1 - Rapidly progressive glomerulonephritis A1 - Gaskin G T2 - Acute renal failure in practice Y1 - 2002/// SN - 1-8609-4287-3 SP - 341 EP - 355 N2 - - ER - TY - CHAP T1 - HY antigen A1 - Simpson E T2 - Wiley encyclopedia of molecular medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 1684 EP - 1686 N2 - - ER - TY - CHAP T1 - Acute Peritoneal Dialysis A1 - EA Brown ED - Glynne P, Allen A, Pusey C ( T2 - Acute renal failure in practice Y1 - 2002/// PB - Imperial College Press N2 - - ER - TY - CHAP T1 - An analysis of CPR decision-making by elderly patients A1 - Sayers GM A1 - Schofield I A1 - Aziz M ED - Fulford KWM, Dickenson D, Murray TH T2 - Healthcare Ethics and Human Values: An Introductory Text with Readings and Case Studies Y1 - 2002/// PB - Blackwell Publishers Inc CY - Oxford N2 - - ER - TY - CHAP T1 - The molecular biology of hepatitis B virus A1 - Karayiannis P ED - N.Tassopoulos T2 - Hepatitis B: 21st Century Y1 - 2002/// SN - 9-6086-8980-5 SP - 41 EP - 54 N2 - - ER - TY - CHAP T1 - Androgenic modulation of the immune response A1 - Reed MJ A1 - Purohit A A1 - Singh A T2 - Menopause: the state of the art Y1 - 2002/// SN - 1-8421-4160-0 SP - 23 EP - 27 N2 - - ER - TY - CHAP T1 - Laser and focused ultrasound ablation of primary and secondary liver tumours A1 - Dick EA A1 - Taylor-Robinson SD A1 - Gedroyc WM T2 - Multi-treatment modalities of liver tumours Y1 - 2002/// SN - 0-3064-6746-1 SP - 197 EP - 210 N2 - - ER - TY - CHAP T1 - HIV infection in children A1 - Tudor-Williams G A1 - Southall D T2 - International child health care:a practical manual for hospitals worldwide Y1 - 2002/// SN - 0-7279-1476-6 SP - 446 EP - 450 N2 - - UR - NULL ER - TY - CHAP T1 - Pulmonary renal syndrome A1 - Allen AR A1 - Pusey CD ED - Davison AM T2 - Nephrology Y1 - 2002/// PB - McGraw Hill SN - 0-0770-9525-1 SP - 205 EP - 211 N2 - - ER - TY - CHAP T1 - Pituitary adenomas A1 - Kearney T A1 - Johnston DG T2 - Endocrinology: specialist handbook Y1 - 2002/// SN - 1-8418-4158-7 SP - 1 EP - 19 N2 - - ER - TY - CHAP T1 - Xenotransplantation: will pigs fly? A1 - George, AJT A1 - Lechler RI T2 - Future Strategies for Tissue and Organ Replacement Y1 - 2002/// SN - 1-8609-4311-X SP - 215 EP - 236 N2 - - ER - TY - CHAP T1 - Human DNA tumour viruses A1 - Griffin BE A1 - Caparros-Wanderley W T2 - The cancer handbook Y1 - 2002/// SN - 0-3337-7659-3 SP - 49 EP - 73 N2 - - UR - NULL ER - TY - CHAP T1 - HUS and TTP A1 - Salama AD ED - Glynne, Allen and Pusey T2 - Acute Renal Failure Y1 - 2002/// PB - Imperial College Press N2 - - ER - TY - CHAP T1 - When to treat hypertension/ When the benefits outweigh the risks A1 - Beckett, N ED - Rai, G. Mulley, G T2 - Elderly Medicine A Training Guide Y1 - 2002/// VL - First PB - Martin Dunitz CY - UK SN - 90-5823-234-4 SP - 183 EP - 186 N2 - - ER - TY - CHAP T1 - Hypopituitarism in adults A1 - Johnston DG A1 - Al Mrayat M A1 - Kearney T T2 - Conn's current therapy Y1 - 2002/// SN - 0-7216-8744-X SP - 637 EP - 643 N2 - - ER - TY - CHAP T1 - Calcium, phosphate and magnesium disturbances A1 - Dorling A T2 - Acute renal failure in practice Y1 - 2002/// SN - 1-8609-4216-4 SP - 174 EP - 183 N2 - - ER - TY - CHAP T1 - Thrombocytopenia in the newborn A1 - Roberts IAG A1 - Murray NA T2 - Platelets Y1 - 2002/// SN - 0-1249-3951-1 SP - 635 EP - 658 N2 - - UR - http://NULL ER - TY - CHAP T1 - Anemia, aplastic (pure red cell aplasia) A1 - Piercy RJ ED - Brown CM, Bertone JJ T2 - 5 Minute Veterinary Consult Y1 - 2002/// PB - Lippincott Williams & Wilkins CY - Baltimore N2 - - ER - TY - CHAP T1 - Vasculitis A1 - Gaskin G A1 - Pusey CD Y1 - 2001/// M2 - 4th SN - 0-6833-0488-7 SP - 792 EP - 804 N2 - - ER - TY - CHAP T1 - Plasmapheresis and immunoadsorption A1 - Griffin SV A1 - Lockwood CM A1 - Pusey CD Y1 - 2001/// M2 - 2nd SN - 0-6320-4359-8 SP - 597 EP - 611 N2 - - ER - TY - CHAP T1 - The molecular and cellular biology of muscle A1 - Brown SC A1 - Walsh FS A1 - Dickson G ED - Karparti G; Hilton-Jones D; Griggs RC T2 - Disorders of Voluntary Muscle Y1 - 2001/// M2 - 7th PB - Cambridge University Press SN - 0-5216-5062-3 SP - 42 EP - 49 N2 - - ER - TY - CHAP T1 - Training of primary care workers in child protection A1 - Blair M ED - Carter Y, Bannon M T2 - Child Protection in Primary Care Y1 - 2001/// PB - Radcliffe SN - 1-8577-5224-4 N2 - - ER - TY - CHAP T1 - Tubulointerstitial Nephritis in Rheumatologic Disease A1 - Salama AD A1 - Pusey CD ED - Adu, Madaio and Emery T2 - Rheumatology and the Kidney Y1 - 2001/// PB - Oxford University Press N2 - - ER - TY - CHAP T1 - Genetics and molecular medicine A1 - Vyse TJ Y1 - 2001/// SN - 0-6320-5859-5 SP - 3 EP - 24 N2 - - ER - TY - CHAP T1 - A promoter probe plasmid based on green fluorescent protein: a strategy for studying meningococcal gene expression A1 - Webb SAR A1 - Langford PR A1 - Kroll JS Y1 - 2001/// M2 - 39 SN - 0-8960-3849-1 SP - 663 EP - 677 N2 - - ER - TY - CHAP T1 - Is parental 'Informed Consent' always necessary for research involving newborn infants? A1 - Modi N Y1 - 2001/// SN - 0-7546-1301-1 SP - 237 EP - 247 N2 - - ER - TY - CHAP T1 - The European Working Party on High Blood Pressure in the Elderly (EWPHE) Trial A1 - Fagard RH A1 - Bulpitt CJ A1 - Staessen JA A1 - Thijs L Y1 - 2001/// SN - 0-8247-0270-0 SP - 159 EP - 175 N2 - - ER - TY - CHAP T1 - Congenital muscular dystrophies A1 - Mercuri E A1 - Muntoni F Y1 - 2001/// SN - 0-1926-3291-4 SP - 10 EP - 38 N2 - - ER - TY - CHAP T1 - Peptic Ulcer Disease A1 - Kinnear M A1 - Ghosh S ED - R Walker, C Edwards T2 - Clinical Pharmacy and Therapeutics Y1 - 2001/// PB - Churchill Livingstone CY - Edinburgh SP - 135 N2 - - ER - TY - CHAP T1 - Vasculitis A1 - Gaskin G A1 - Pusey CD ED - Massry SG, Glassock RJ T2 - Massry and Glassock's Textbook of Nephrology, 4th Edition Y1 - 2001/// PB - Lippincott Williams and Wilkins CY - New York SN - 0-683-30488-7 SP - 792 EP - 804 N2 - - ER - TY - CHAP T1 - Is obtaining informed consent to neonatal randomized controlled trials an elaborate ritual? Interviews with parents and clinicians A1 - Mason S A1 - Allmark P A1 - Megone C A1 - Bratlid D A1 - Dalla-Vorgia P A1 - Gill A A1 - Morrogh P A1 - Reiter-Theil S A1 - Fellman V A1 - Greisen G A1 - Hellstrom-Westas L A1 - Latini G A1 - LeRoux N A1 - Modi N A1 - Moya M A1 - Nelson N A1 - Petmezaki S A1 - Phillips A A1 - Rissell G A1 - Ryan C A1 - Saliba E A1 - Weindling A Y1 - 2001/// SN - 0-7546-1301-1 SP - 209 EP - 235 N2 - - ER - TY - CHAP T1 - Genetics of Duchenne muscular dystrophy A1 - Brown SC A1 - Dickson G ED - Reeve E T2 - Encyclopedia of Genetics Y1 - 2001/// PB - Fitzroy Dearborn SN - 1-8849-6434-6 SP - 467 EP - 473 N2 - - ER - TY - CHAP T1 - Rheumatologic diseases associated with interstitial nephritis A1 - Salama AD A1 - Pusey CD Y1 - 2001/// SN - 0-1926-3178-0 SP - 465 EP - 484 N2 - - ER - TY - CHAP T1 - Diabetic acidosis, hypersmolar coma, and lactic acidosis A1 - Alberti KG Y1 - 2001/// M2 - 3rd SN - 0-7817-1750-7 SP - 1438 EP - 1451 N2 - - UR - NULL ER - TY - CHAP T1 - Xenotransplantation A1 - Dorling A A1 - Lechler RI Y1 - 2001/// SN - 0-632-03676-1 SP - 136 EP - 176 N2 - - ER - TY - CHAP T1 - Anemia A1 - Pasvol G A1 - Abdalla SH ED - Guerrant R, Walker DH and Weller PF T2 - Essentials of Tropical Infectious Disease Y1 - 2001/// PB - Churchill Livingstone International CY - New York SN - 0-4430-7909-9 SP - 93 EP - 98 N2 - - ER - TY - CHAP T1 - Pathology of vascular disease A1 - Cook HT A1 - Pusey CD Y1 - 2001/// SN - 0-8493-1335-X SP - 3 EP - 21 N2 - - ER - TY - CHAP T1 - Diabetes mellitus A1 - Alberti KG A1 - Tattersall RB Y1 - 2001/// SN - 0-1926-2950-6 SP - 235 EP - 236 N2 - - UR - NULL ER - TY - CHAP T1 - Generation of human type 1- and type 2-polarized dendritic cells from peripheral blood. A1 - Kalinski, P A1 - Vieira, PL A1 - Schiutemaker, JHN A1 - Cai, Q A1 - Kapsenberg, ML ED - D. Korholz, Humana Press T2 - Methods in Molecular Medicine – Cytokines and Colony Stimulating Factors Y1 - 2001/// N2 - - ER - TY - CHAP T1 - Goodpasture's syndrome and other anti-GBM disease A1 - Pusey CD Y1 - 2001/// M2 - 3rd SN - 0-1229-9100-1 SP - 172 EP - 175 N2 - - ER - TY - CHAP T1 - Fetal pain and stress A1 - Modi N A1 - Glover V ED - Anand KJS, Stevens BJ, McGrath PJ T2 - Pain in Neonates. 2nd ed Y1 - 2000/// PB - Elsevier SP - 217 EP - 227 N2 - - ER - TY - CHAP T1 - Factor I A1 - Morley, B J ED - Morley, B J and Walport M J T2 - The Complement Factsbook Y1 - 2000/// PB - Academic Press SP - 83 EP - 86 N2 - - ER - TY - CHAP T1 - The antibody molecule A1 - George AJT ED - George AJT and Urch CE T2 - Diagnostic and Therapeutic Antibodies Y1 - 2000/// PB - Humana Press CY - Totowa, NJ SP - 1 EP - 21 N2 - - ER - TY - CHAP T1 - Use of biosensors to measure the kinetics of antibody-antigen interactions A1 - George AJT ED - George AJT and Urch CE T2 - Diagnostic and Therapeutic Antibodies Y1 - 2000/// PB - Humana Press CY - Totowa NJ SP - 363 EP - 372 N2 - - ER - TY - CHAP T1 - The analysis of genetic susceptibility A1 - Vyse, T J A1 - Morley, B J ED - Lechler, R and Warrens, A T2 - HLA in health and disease Y1 - 2000/// VL - 2nd PB - Academic press SP - 107 EP - 128 N2 - - ER - TY - CHAP T1 - Neurologic Questions A1 - Reed S A1 - Piercy RJ A1 - Perris EE ED - Savage CJ T2 - Equine Medicine Secrets Y1 - 1999/// PB - Hanley and Belfus CY - Philadelphia N2 - - ER - TY - CHAP T1 - ‘Reflections on a Journey: Geographical perspectives on disability’ A1 - Smith, R.G ED - Jones, M and Basser Marks, L.A T2 - Disability, Divers-ability and Legal Change: International studies on human rights. Y1 - 1999/// PB - Kluwer Law International CY - The Hague, Netherlands SP - 49 EP - 65 N2 - - ER - TY - CHAP T1 - Fluid and Electrolyte Balance A1 - Modi N ED - Roberton NRC, Rennie J, T2 - Textbook of Neonatology Y1 - 1999/// M2 - 3rd edition, PB - Churchill Livingstone SP - 1009 EP - 1037 N2 - - ER - TY - CHAP T1 - Genetics of Asthma A1 - Walley AJ A1 - Cookson WOCM ED - R.A. Stockley T2 - Molecular Biology Of The Lung Volume II: Asthma and Cancer Y1 - 1999/// PB - Birkhaüser Verlag CY - Basel, Switzerland SN - 0-8176-5968-4 SP - 23 EP - 39 N2 - - ER - TY - CHAP T1 - Jaundice A1 - Modi N ED - Levitt GA, Harvey D, Cooke RWI T2 - Practical Perinatal Care – The Baby under 1000g Y1 - 1999/// PB - Butterworth Heinemann SP - 101 EP - 112 N2 - - ER - TY - CHAP T1 - Stabilization and transport of critically ill children A1 - Britto J A1 - Habibi P ED - David TJ T2 - Recent Advances in Paediatrics Y1 - 1999/// PB - Churchill Livingstone SP - 85 EP - 113 N2 - - ER - TY - CHAP T1 - Gene Therapy for ifnectious diseases A1 - S Fidler ED - N R Lemoine T2 - Understanding Gene therapy Y1 - 1999/// VL - 1 M2 - 1 PB - BIOS Scientific publishers Ltd CY - Oxford UK SN - 1-85996-180-0 SP - 99 EP - 125 N2 - - ER - TY - CHAP T1 - Skin Manifestations of Meningogoccal Infection A1 - Heyderman R A1 - Habibi P ED - John Harper, Arnold Orange, Neil Prose T2 - Text Book of Paediatric Dermatology Y1 - 1999/// M2 - 1 PB - Blackwell Publishing Ltd CY - Oxford SP - 384 EP - 394 N2 - - ER - TY - CHAP T1 - Collapse A1 - Piercy RJ ED - Marr C T2 - Cardiology of the Horse Y1 - 1999/// VL - 1st PB - W. B. Saunders Co. Ltd CY - London N2 - - ER - TY - CHAP T1 - Enhancing outcome after extremely preterm birth. A1 - Modi N ED - Fox NA, Leavitt LA, Warhol JG, eds. The T2 - Role of early experience in infant development Y1 - 1999/// M2 - Pediatric Round Table Series PB - Johnson & Johnson Pediatric Institute SP - 267 EP - 282 N2 - - ER - TY - CHAP T1 - Tempe (fermented soybeans) isoflavonoids & tempe extract down regulate the angiogenesis and invasion-related stromal Ets 1transcription factor in cultured human endothelial cells and fibroblasts A1 - Kiriakidis S A1 - Starcke S A1 - Jha HC A1 - Wernert N ED - George G. Skouteris and Garth L. Nicolson T2 - Intermolecular Cross-Talk in Tumor Metastasis.NATO Science Series A: Life Sciences Y1 - 1999/// PB - IOS Press CY - Netherlands SP - 176 EP - 184 N2 - - ER - TY - CHAP T1 - Renal Function A1 - Modi N A1 - Coulthard M ED - Levitt G, Harvey D, Cooke RWI, T2 - Practical Perinatal Care – The Baby under 1000 g Y1 - 1999/// PB - Butterworth Heinemann SP - 199 EP - 211 N2 - - ER - TY - CHAP T1 - Management of postnatal disorders of fluid balance A1 - Modi N ED - Brace RA, Hanson MA, Rodeck CH, T2 - Fetus and Neonate Body Fluids and Kidney Function Y1 - 1998/// M2 - Volume IV PB - Cambridge University Press SP - 299 EP - 322 N2 - - ER - TY - CHAP T1 - Renal failure A1 - Warrens, A N ED - Hornick, P Lumley, J Grace, P T2 - Case presentations for the MRCS and AFRCS Y1 - 1997/// M2 - 2 PB - Butterworth Heinemann CY - London SN - 0-7506-3258-5 SP - 4 EP - 9 N2 - - ER - TY - CHAP T1 - Renal failure A1 - Warrens, A N ED - Hornick, P Lumley, J Grace, P T2 - Case presentations for the MRCS and AFRCS Y1 - 1997/// M2 - 1 PB - Butterworth Heinemann CY - London SN - 0-7506-3257-7 SP - 6 EP - 10 N2 - - ER - TY - CHAP T1 - Adhesion molecules in xenotransplantation A1 - Simon, A R A1 - Warrens, A N ED - Steinhoff, G T2 - Adhesion molecules in organ transplantation Y1 - 1997/// PB - Springer Verlag N2 - - ER - TY - CHAP T1 - Antioxidative Constituents of Tempe A1 - Jha HC A1 - Kiriakidis S A1 - Hoppe M A1 - Egge H T2 - Reinventing the Hidden Miracle of Tempe Y1 - 1997/// PB - Indonesian Tempe Foundation CY - Jakarta N2 - - ER - TY - CONF T1 - Helium-oxygen gas mixtures in paediatric respiratory diseases (Invited Lecture) A1 - Chowdhury, M M M U1 - 29th Meeting of the Scandinavian Society of Anaesthesia and Intensive Care (SSAI) AD - Göteborg, Sweden Y1 - 2007/09/07/ Y2 - 2007/09/05/ N2 - - ER - TY - CONF T1 - The role of membrane lipid composition and tail structure in virus host cell association, entry, and infection. A1 - Ewers, H A1 - Bacia, K A1 - Chai, W A1 - Schwarzmann, G A1 - Feizi, T A1 - Schwille, P A1 - Smith, AE A1 - Helenius, A U1 - 61st Annual Meeting of the Society-of-General-Physiologists Y1 - 2007/07// Y2 - // VL - 130 SP - 3A EP - 3A N2 - - ER - TY - CONF T1 - Vaccination strategies for breaking induced tolerance to HY antigens A1 - Chai JG A1 - Coe D A1 - Cerundolo V A1 - Stevenson F A1 - Simpson E A1 - Scott D A1 - Dyson J U1 - Keystone Symposia AD - Banff, Canada Y1 - 2007/03/28/ Y2 - 2007/03/28/ PB - Keystone sympoisa N2 - - ER - TY - CONF T1 - Improving CPAP delivery using helium-oxygen mixtures A1 - Chowdhury M M M A1 - Dixon P A1 - Habibi P U1 - Europaediatrics AD - Barcelona, Spain J1 - European Journal of Paediatrics Y1 - 2006/// Y2 - 2006/09/07/ N2 - - ER - TY - CONF T1 - Central nervous system involvement in hepatitis C virus infection: what to measure? A1 - Forton, DM A1 - Allsop, J A1 - Thomas, HC A1 - Taylor-Robinson, SD U1 - 12th International Symposium on Hepatic Encephalopathy and Nitrogen Metabolism Y1 - 2006/// Y2 - // SP - 284 EP - 290 N2 - - ER - TY - CONF T1 - Urinary proteomic profiles are able to discriminate between active and inactive lupus nephritis A1 - Karen Mosley A1 - Liz Lightstone A1 - Robert Edwards A1 - Jo Crozier A1 - Charles Pusey U1 - The American Society of Nephrology AD - Philadelphia J1 - J Am Soc Nephrol Y1 - 2005/10// Y2 - 2005/11// VL - 16 SP - TH-FC035 N2 - - ER - TY - CONF T1 - European ALS Consortium (EALSC): Second annual Research Workshop, a summary report A1 - Swash, M A1 - Rowland, L P A2 - MICHAEL SWASH & LEWIS P. ROWLAND U1 - European ALS Consortium (EALSC): Second annual Research AD - Nice J1 - Amyotrophic Lateral Sclerosis. 2005; 6: 125–128 Y1 - 2005/06// Y2 - 2004/05/14/ VL - Volume 6, Number 2 / PB - Taylor & Francis Health Sciences, part of the Taylor & Francis Group CY - Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders SN - 1466-0822 SP - 125 EP - 128 N2 - - UR - http://taylorandfrancis.metapress.com/(w0sph445bzvnfj55cvc5nzn2)/app/home/contribution.asp?referrer=parent&backto=issue,10,10;journal,6,35;linkingpublicationresults,1:105857,1 ER - TY - CONF T1 - Postcards from the Edge: An Oral History of the Treatments of Homesexuality in Britain since the 1950s A1 - Smith, R.G U1 - Oral History Association 36th Annual Meeting AD - San Diego, United States of America J1 - Britsh Medical Journal - see journal publications Y1 - 2004/// Y2 - 2002/10// N2 - - ER - TY - CONF T1 - Killer cell immunoglobulin-like receptor (KIR) mRNA expression in natural killer (NK) cells A1 - Brooks, CR A1 - Rosenberg, WM A1 - Khakoo, SI U1 - Annual Meeting of the British-Association-for-the-Study-of-the-Liver Y1 - 2003/05// Y2 - // VL - 52 SP - U17 EP - U17 N2 - - ER - TY - CONF T1 - Natural killer (NK) cell receptor genotypes in hepatitis C virus infection A1 - Khakoo, SI A1 - Brooks, CR A1 - Howell, M A1 - Alexander, GJ A1 - Rosenberg, WM U1 - Annual Meeting of the British-Association-for-the-Study-of-the-Liver Y1 - 2003/05// Y2 - // VL - 52 SP - U26 EP - U26 N2 - - ER - TY - CONF T1 - Reduced pallidal magnetisation transfer ratios are associated with fatigue in pre-cirrhotic patients with primary biliary cirrhosis A1 - Forton, DM A1 - Prince, M A1 - Allsop, J A1 - Patel, N A1 - Goldblatt, J A1 - Thomas, HC A1 - Bassendine, M A1 - Jones, DEJ A1 - Taylor-Robinson, SD U1 - 11th International Symposium on Hepatic Encephalopathy and Nitrogen Metabolism Y1 - 2003/// Y2 - // SP - 173 EP - 174 N2 - - ER - TY - CONF T1 - Murine CD4+CD25+ Tregs: towards the identification of molecular markers A1 - F Rovis A1 - BC Lee A1 - RI Lechler A1 - OA Garden U1 - British Society of Immunology AD - Harrogate, UK Y1 - 2003/// Y2 - 2003/12// PB - Immunology SP - 119 N2 - - ER - TY - CONF T1 - MRL/Mp CD4+CD25- T cells resist suppression by CD25+ Tregs in vitro: a defect of effector T cells in lupus? A1 - CR Monk A1 - M Spachidou A1 - F Rovis A1 - RI Lechler A1 - OA Garden U1 - British Society of Immunology AD - Harrogate, UK Y1 - 2003/// Y2 - 2003/12// PB - Immunology SP - 81 N2 - - ER - TY - CONF T1 - Preventing Renal Disease: The NKRF ABLE project A1 - Lightstone L U1 - Ethnicity and Renal Failure: disparity or diversity? AD - British Library Y1 - 2003/// Y2 - 2003/10// PB - SouthWest Thames Renal Research Institute CY - St Helier Hospital, Carshalton, Surrey N2 - - ER - TY - CONF T1 - Androgenic modulation of the immune response A1 - Reed, MJ A1 - Purohit, A A1 - Singh, A A1 - Chander, SK U1 - 10th World Congress on the Menopause Y1 - 2003/// Y2 - // SP - 23 EP - 27 N2 - - ER - TY - CONF T1 - Urinary monocyte chemoattractant protein-1 is more useful than PDGF-BB or INF-? for monitoring activity of lupus nephritis A1 - Barhamein MY A1 - Tam FWK A1 - Lai P A1 - Chaudhry A A1 - Thompson M A1 - Pusey CD A1 - Lightstone L U1 - American Society of Nephrology 36th Meeting AD - San Diego Y1 - 2003/// Y2 - 2003/// VL - 14 PB - J Am Soc Nephrol N2 - - ER - TY - CONF T1 - Urinary levels of monocyte chemoattractant protein-1 (MCP-1) as a disease marker of disease activity in ANCA associated vasculitis A1 - Hammad TM A1 - Tam FWK A1 - Pusey CD A1 - Levy JB U1 - American Society of Nephrology 36th Meeting AD - San Diego Y1 - 2003/// Y2 - 2003/// VL - 14 PB - J Am Soc Nephrol N2 - - ER - TY - CONF T1 - Natural killer (NK) cell receptor genotypes in hepatitis C virus infection. A1 - Khakoo, SI A1 - Brooks, CL A1 - Alexander, G A1 - Howell, M A1 - Rosenberg, W U1 - 53rd Annual Meeting of the Association-for-the-Study-of-Liver-Diseases (AASLD) Y1 - 2002/10// Y2 - // VL - 36 SP - 275A EP - 275A N2 - - ER - TY - CONF T1 - Use of ultrasound contrast agents in hepatology A1 - Lim, AKP A1 - Harvey, CJ A1 - Taylor-Robinson, SD A1 - Blomley, MJK A1 - Cosgrove, DO U1 - Falk Symposium on Medical Imaging in Gastroenterology and Hepatology Y1 - 2002/// Y2 - // VL - 124 SP - 132 EP - 139 N2 - - ER - TY - CONF T1 - Regulation of aromatase in normal and malignant breast tissues: The role of the immune system A1 - Singh, A A1 - Purohit, A A1 - Ghilchik, MW A1 - Reed, MJ U1 - 3rd International Symposium on Hormonal Carcinogenesis Y1 - 2001/// Y2 - // SP - 277 EP - 284 N2 - - ER - TY - CONF T1 - Clinical experience with preimplantation genetic diagnosis at Hammersmith 1989-1998 A1 - Lavery, SA A1 - Winston, RML U1 - 11th World Congress on In Vitro Fertilization and Human Reproductive Genetics Y1 - 1999/// Y2 - // SP - 397 EP - 404 N2 - - ER - TY - CONF T1 - Hormone replacement therapy in diabetes A1 - Stevenson, JC A1 - Godsland, IF U1 - 8th International Congress on the Menopause Y1 - 1997/// Y2 - // SP - 315 EP - 322 N2 - - ER - TY - JFULL T1 - Eroding the resistance of Duffy negativity to invasion by Plasmodium vivax? A1 - Pasvol, G J1 - Trans R Soc Trop Med Hyg Y1 - 2007/10// VL - 101 SN - 0035-9203 SP - 953 EP - 954 N2 - Individuals possessing red cells negative for the Duffy blood group antigen are said to possess absolute resistance to infection by the malarial parasite Plasmodium vivax. Now in this issue of Transactions, initial evidence is presented from the Brazilian Amazon to suggest that P. vivax is being transmitted amongst Duffy-negative individuals. This supports data from East Africa where the same phenomenon has been observed. Thus the emerging picture is that P. vivax in both South America and in Africa is now evolving pathways other than Duffy to enter red cells. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17658565&query_hl=1 ER - TY - JFULL T1 - Replicative Competence of the T131I, K141E, and G145R Surface Variants of Hepatitis B Virus. A1 - Jammeh, S A1 - Thomas, HC A1 - Karayiannis, P J1 - J Infect Dis Y1 - 2007/10/01/ VL - 196 SN - 0022-1899 SP - 1010 EP - 1013 N2 - Variants of hepatitis B surface antigen have been described in different clinical settings, but their replicative capacity in vitro has remained unexplored. Point mutations leading to sT131I, sK141E, and sG145R amino-acid substitutions were engineered by site-directed mutagenesis into an infectious plasmid clone of the virus. The mutated constructs were transfected into Huh7 cells, and their replication capacity was documented by LightCycler (Roche Diagnostics) measurements of virion-associated hepatitis B virus (HBV) DNA, intracellular relaxed circular double-stranded DNA, and pregenomic RNA. The sT131I and sG145R variants replicated with efficiency equal to that of the wild type, whereas the sK141E variant was replication impaired. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17763322&query_hl=1 ER - TY - JFULL T1 - ENPP1 K121Q polymorphism and obesity, hyperglycaemia and type 2 diabetes in the prospective DESIR Study. A1 - Meyre, D A1 - Bouatia-Naji, N A1 - Vatin, V A1 - Veslot, J A1 - Samson, C A1 - Tichet, J A1 - Marre, M A1 - Balkau, B A1 - Froguel, P J1 - Diabetologia Y1 - 2007/10// VL - 50 SN - 0012-186X SP - 2090 EP - 2096 N2 - AIMS/HYPOTHESIS: We assessed the predictive value of ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1) SNPs with regard to the risk of developing obesity and/or type 2 diabetes in a large French general population. METHODS: We genotyped the ENPP1 SNPs K121Q (rs1044498), IVS20delT-11 (rs1799774) and A/G+1044TGA (rs7754561) in 5,153 middle-aged participants of the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. RESULTS: At baseline, the K121Q polymorphism was not associated either with BMI (p = 0.98) or with class I obesity (odds ratio [OR] 0.99, p = 0.81), but showed a borderline association with class II obesity (OR 1.65, p = 0.02). The K121Q variant was not associated with any trait during the 9-year follow-up. Pooled analyses both at baseline and at follow-up failed to show any association with hyperglycaemia (OR 1.08, p = 0.28) or type 2 diabetes (OR 1.15, p = 0.38). However, we did show an association of the Q121 allele with the risk of hyperglycaemia (OR 1.45, p = 0.001; n = 265) and type 2 diabetes (OR 1.65, p = 0.01; n = 103) in participants reporting a family history of type 2 diabetes. These results did not remain significant after a Bonferroni correction. The IVS20delT-11 and A/G+1044TGA polymorphisms and the three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA [QdelTG]) were not associated with any trait, either at baseline or at follow-up. CONCLUSIONS/INTERPRETATION: In a general French population we did not find an association of the QdelTG risk haplotype with adult obesity and type 2 diabetes. We detected nominal evidence of association between the K121Q polymorphism and both severe adult obesity at baseline and the risk of hyperglycaemia or type 2 diabetes in participants with a family history of type 2 diabetes in pooled analyses both at baseline and follow-up. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17704904&query_hl=1 ER - TY - JFULL T1 - 3,17-Disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol Derivatives: Synthesis, In Vitro and In Vivo Anticancer Activity. A1 - Bubert, C A1 - Leese, MP A1 - Mahon, MF A1 - Ferrandis, E A1 - Regis-Lydi, S A1 - Kasprzyk, PG A1 - Newman, SP A1 - Ho, YT A1 - Purohit, A A1 - Reed, MJ A1 - Potter, BV J1 - J Med Chem Y1 - 2007/09/06/ VL - 50 SN - 0022-2623 SP - 4431 EP - 4443 N2 - Estradiol-3,17-O,O-bis-sulfamates inhibit steroid sulfatase (STS), carbonic anhydrase (CA), and, when substituted at C-2, cancer cell proliferation and angiogenesis. C-2 Substitution and 17-sulfamate replacement of the estradiol-3,17-O,O-bis-sulfamates were explored with efficient and practical syntheses developed. Evaluation against human cancer cell lines revealed the 2-methyl derivative 27 (DU145 GI50 = 0.38 muM) as the most active novel bis-sulfamate, while 2-ethyl-17-carbamate derivative 52 (GI50 = 0.22 muM) proved most active of its series (cf. 2-ethylestradiol-3,17-O,O-bis-sulfamate 4 GI50 = 0.21 muM). Larger C-2 substituents were deleterious to activity. 2-Methoxy-17-carbamate 50 was studied by X-ray crystallography and was surprisingly 13-fold weaker as an STS inhibitor compared to parent bis-sulfamate 3. The potential of 4 as an orally dosed anti-tumor agent is confirmed using breast and prostate cancer xenografts. In the MDA-MB-231 model, dramatic reduction in tumor growth or regression was observed, with effects sustained after cessation of treatment. 3-O-Sulfamoylated 2-alkylestradiol-17-O-carbamates and sulfamates have considerable potential as anticancer agents. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17696419&query_hl=1 ER - TY - JFULL T1 - Platelet-Derived Growth Factor Reorganizes the Actin Cytoskeleton through 3-Phosphoinositide-Dependent and 3-Phosphoinositide-Independent Mechanisms in Human Mesangial Cells. A1 - Harper, L A1 - Kashiwagi, Y A1 - Pusey, CD A1 - Hendry, BM A1 - Domin, J J1 - Nephron Physiol Y1 - 2007/09/05/ VL - 107 SN - 1660-2137 SP - p45 EP - p56 N2 - Background: Platelet-derived growth factor (PDGF) is a potent activator of mesangial cell proliferation and migration. Although phosphoinositide 3-kinase (PI3K) enzymes are important downstream targets of the PDGF receptor, the contribution made by their 3-phosphoinositide products in the reorganization of actin cytoskeleton and focal adhesions has been questioned. Methods and Results: Pharmacological inhibition of the PI3K activity blocks PDGF-induced migration of human primary mesangial cells using an in vitro scrape wound healing assay. Acute (<10 min) inhibition of the PI3K activity did not alter the effect of PDGF on either stress fibre dissolution or reorganization of focal adhesions. However, at later times (>30 min), PDGF-stimulated responses were inhibited. In contrast, PDGF-stimulated membrane ruffling remained insensitive to PI3K inhibitors throughout. Inhibition of protein kinase C and Erk also attenuated PDGF-stimulated mesangial cell migration; however, neither signaling pathway was responsible for the initial effects on filamentous actin and focal adhesions. Conclusions: We propose that following PDGF stimulation of mesangial cells, reorganization of the actin cytoskeleton occurs in a biphasic manner. The mechanism responsible for mesangial cell migration that occurs immediately following PDGF stimulation may serve to 'prime' for the subsequent 3-phosphoinositide-, protein-kinase-C-, and Erk-dependent migration. Copyright (c) 2007 S. Karger AG, Basel. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17804914&query_hl=1 ER - TY - JFULL T1 - Comparative Analysis of Antisense Oligonucleotide Sequences for Targeted Skipping of Exon 51 During Dystrophin Pre-mRNA Splicing in Human Muscle. A1 - Arechavala-Gomeza, V A1 - Graham, IR A1 - Popplewell, LJ A1 - Adams, AM A1 - Aartsma-Rus, A A1 - Kinali, M A1 - Morgan, JE A1 - Van Deutekom, JC A1 - Wilton, SD A1 - Dickson, G A1 - Muntoni, F J1 - Hum Gene Ther Y1 - 2007/09/03/ SN - 1043-0342 N2 - Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in the absence of functional protein. In the majority of cases these are out-of-frame deletions that disrupt the reading frame. Several attempts have been made to restore the dystrophin mRNA reading frame by modulation of pre-mRNA splicing with antisense oligonucleotides (AOs), demonstrating success in cultured cells, muscle explants, and animal models. We are preparing for a phase I/IIa clinical trial aimed at assessing the safety and effect of locally administered AOs designed to inhibit inclusion of exon 51 into the mature mRNA by the splicing machinery, a process known as exon skipping. Here, we describe a series of systematic experiments to validate the sequence and chemistry of the exon 51 AO reagent selected to go forward into the clinical trial planned in the United Kingdom. Eight specific AO sequences targeting exon 51 were tested in two different chemical forms and in three different preclinical models: cultured human muscle cells and explants (wild type and DMD), and local in vivo administration in transgenic mice harboring the entire human DMD locus. Data have been validated independently in the different model systems used, and the studies describe a rational collaborative path for the preclinical selection of AOs for evaluation in future clinical trials. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17767400&query_hl=1 ER - TY - JFULL T1 - Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. A1 - Lee-Kirsch, MA A1 - Gong, M A1 - Chowdhury, D A1 - Senenko, L A1 - Engel, K A1 - Lee, YA A1 - de Silva, U A1 - Bailey, SL A1 - Witte, T A1 - Vyse, TJ A1 - Kere, J A1 - Pfeiffer, C A1 - Harvey, S A1 - Wong, A A1 - Koskenmies, S A1 - Hummel, O A1 - Rohde, K A1 - Schmidt, RE A1 - Dominiczak, AF A1 - Gahr, M A1 - Hollis, T A1 - Perrino, FW A1 - Lieberman, J A1 - Hübner, N J1 - Nat Genet Y1 - 2007/09// VL - 39 SN - 1061-4036 SP - 1065 EP - 1067 N2 - TREX1 acts in concert with the SET complex in granzyme A-mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutières syndrome and familial chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3' UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 x 10(-7)). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17660818&query_hl=1 ER - TY - JFULL T1 - Synergistic inhibition of HIV-1 infection by combinations of soluble polyanions with other potential microbicides. A1 - Gantlett, KE A1 - Weber, JN A1 - Sattentau, QJ J1 - Antiviral Res Y1 - 2007/09// VL - 75 SN - 0166-3542 SP - 188 EP - 197 N2 - Several polyanionic compounds with potential for use as topically applied microbicides to prevent HIV-1 sexual transmission, such as PRO 2000, are currently in phase III clinical efficacy trials. Microbicidal formulations may well comprise combinations of inhibitors to increase potency, reduce dose and minimize problems of HIV-1 resistance. We have therefore evaluated in vitro, the anti-HIV-1 activity of two leading polyanionic microbicides combined with other antiretroviral agents with microbicidal potential. Dextran sulfate (DS) and PRO 2000 were combined with the neutralizing antibody IgG1b12, the peptide-based fusion inhibitor T20, the CCR5 antagonist TAK779 and the cyanobacterial protein cyanovirin-N. Anti-HIV-1 activity was assessed in a single cycle replication assay using pseudoviruses carrying a luciferase reporter gene and the envelope glycoproteins from HIV-1 isolates JR-FL (R5) and HxB2 (X4), against both immortalized and primary CD4+ cell targets. The data were analyzed for synergy using Calcusyntrade mark software. Results indicate that PRO 2000 and DS can act synergistically with most inhibitors tested, although the degree of synergy depends on inhibitor concentration and combination. These data provide a rational basis for testing of microbicide combinations in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17408760&query_hl=1 ER - TY - JFULL T1 - New approaches to the treatment of dense deposit disease. A1 - Smith, RJ A1 - Alexander, J A1 - Barlow, PN A1 - Botto, M A1 - Cassavant, TL A1 - Cook, HT A1 - de Córdoba, SR A1 - Hageman, GS A1 - Jokiranta, TS A1 - Kimberling, WJ A1 - Lambris, JD A1 - Lanning, LD A1 - Levidiotis, V A1 - Licht, C A1 - Lutz, HU A1 - Meri, S A1 - Pickering, MC A1 - Quigg, RJ A1 - Rops, AL A1 - Salant, DJ A1 - Sethi, S A1 - Thurman, JM A1 - Tully, HF A1 - Tully, SP A1 - van der Vlag, J A1 - Walker, PD A1 - Würzner, R A1 - Zipfel, PF A1 - Dense Deposit Disease Focus Group J1 - J Am Soc Nephrol Y1 - 2007/09// VL - 18 SN - 1046-6673 SP - 2447 EP - 2456 N2 - The development of clinical treatment protocols usually relies on evidence-based guidelines that focus on randomized, controlled trials. For rare renal diseases, such stringent requirements can represent a significant challenge. Dense deposit disease (DDD; also known as membranoproliferative glomerulonephritis type II) is a prototypical rare disease. It affects only two to three people per million and leads to renal failure within 10 yr in 50% of affected children. On the basis of pathophysiology, this article presents a diagnostic and treatment algorithm for patients with DDD. Diagnostic tests should assess the alternative pathway of complement for abnormalities. Treatment options include aggressive BP control and reduction of proteinuria, and on the basis of pathophysiology, animal data, and human studies, plasma infusion or exchange, rituximab, sulodexide, and eculizumab are additional options. Criteria for treatment success should be prevention of progression as determined by maintenance or improvement in renal function. A secondary criterion should be normalization of activity levels of the alternative complement pathway as measured by C3/C3d ratios and C3NeF levels. Outcomes should be reported to a central repository that is now accessible to all clinicians. As the understanding of DDD increases, novel therapies should be integrated into existing protocols for DDD and evaluated using an open-label Bayesian study design. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17675665&query_hl=1 ER - TY - JFULL T1 - The pathogenesis of vascular inflammation by anti-neutrophil cytoplasm antibodies A1 - Pusey, C J1 - PEDIATR NEPHROL Y1 - 2007/09// VL - 22 SN - 0931-041X SP - 1427 EP - 1427 ER - TY - JFULL T1 - Monocytosis in BXSB mice is due to epistasis between Yaa and the telomeric region of Chromosome 1 but does not drive the disease process. A1 - Rogers, NJ A1 - Gabriel, L A1 - Nunes, CT A1 - Rose, SJ A1 - Thiruudaian, V A1 - Boyle, J A1 - Morley, BJ J1 - Genes Immun Y1 - 2007/08/30/ SN - 1466-4879 N2 - The BXSB murine model of systemic lupus erythematosus is differentiated from other murine models of lupus by a severe monocytosis. The recently identified Y-linked autoimmune accelerator locus, Yaa, which is fundamental to accelerated disease in male BXSB mice, is required for the monocytic phenotype in BXSB. It has also recently been shown to induce monocytosis in combination with the Nba2 locus from NZB. To dissect the genetic basis and associated pathogenicity of BXSB-related monocytosis, a panel of existing congenic mice were studied and a novel sub-congenic mouse B10.Y(BXSB).BXSB-Bxs3 was generated. Monocytosis was found to be caused by an epistatic interaction between Yaa and the telomeric region of chromosome 1, an area of approximately 30 cM. Bxs3 and Yaa together were sufficient to generate monocytosis equivalent to that of BXSB. In contrast to the NZB model, however, where monocytosis tightly correlated with autoantibody production and lethal lupus nephritis, this was not the case in BXSB. While Yaa(+) mice bearing the Bxs3 locus drive monocytosis, glomerulonephritis and autoantibody production, both autoantibody production and nephritis are discreet events that occur in the absence of the Bxs3 locus. Yaa is a pre-requisite for monocytosis, demonstrating a novel synergistic interaction between Yaa and Bxs3.Genes and Immunity advance online publication, 30 August 2007; doi:10.1038/sj.gene.6364424. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17728791&query_hl=1 ER - TY - JFULL T1 - Regulation of Fibroblast Growth Factor Receptor-1 by Thyroid Hormone: Identification of a Thyroid Hormone Response Element in the Murine Fgfr1 Promoter. A1 - O'shea, PJ A1 - Guigon, CJ A1 - Williams, GR A1 - Cheng, SY J1 - Endocrinology Y1 - 2007/08/30/ SN - 0013-7227 N2 - Thyroid hormone (T3) is essential for normal skeletal development, acting mainly via the TRalpha1 nuclear receptor. Nevertheless, the mechanisms of T3 action in bone are poorly defined. Fibroblast growth factor receptor-1 (FGFR1) is also essential for bone formation. Fgfr1 expression and activity are positively regulated by T3 in osteoblasts and, in mice that harbor a dominant negative PV mutation targeted to TRalpha1 or TRbeta, Fgfr1 expression is sensitive to skeletal thyroid status. To investigate mechanisms underlying T3 regulation of FGFR1, we obtained primary calvarial osteoblasts from wild-type and TRbeta(PV/PV) littermate mice. T3 treatment increased Fgfr1 expression 2-fold in wild-type cells but 8-fold in TRbeta(PV/PV) osteoblasts. The 4-fold increased T3-sensitivity of TRbeta(PV/PV) osteoblasts was associated with a markedly increased ratio of TRalpha1:TRbeta1 expression that resulted from reduced TRbeta1 expression in TRbeta(PV/PV) osteoblasts compared to wild-type. Bio-informatic and gel shift studies, and mutational analysis, identified a specific TR binding site 279-264 nucleotides upstream of the murine Fgfr1 promoter transcription start site. Transient transfection analysis of a series of Fgfr1 promoter 5'-deletion constructs, of a mutant reporter construct, and a series of heterologous promoter constructs, confirmed that this region of the promoter mediates a TR-dependent transcriptional response to T3. Thus, in addition to indirect regulation of FGFR1 expression by T3 reported previously, T3 also activates the Fgfr1 promoter directly via a thyroid hormone response element located at positions -279/-264. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17761769&query_hl=1 ER - TY - JFULL T1 - Identification of the PIP(2)-binding site on Kir6.2 by molecular modelling and functional analysis. A1 - Haider, S A1 - Tarasov, AI A1 - Craig, TJ A1 - Sansom, MS A1 - Ashcroft, FM J1 - EMBO J Y1 - 2007/08/22/ VL - 26 SN - 0261-4189 SP - 3749 EP - 3759 N2 - ATP-sensitive potassium (K(ATP)) channels couple cell metabolism to electrical activity by regulating K(+) fluxes across the plasma membrane. Channel closure is facilitated by ATP, which binds to the pore-forming subunit (Kir6.2). Conversely, channel opening is potentiated by phosphoinositol bisphosphate (PIP(2)), which binds to Kir6.2 and reduces channel inhibition by ATP. Here, we use homology modelling and ligand docking to identify the PIP(2)-binding site on Kir6.2. The model is consistent with a large amount of functional data and was further tested by mutagenesis. The fatty acyl tails of PIP(2) lie within the membrane and the head group extends downwards to interact with residues in the N terminus (K39, N41, R54), transmembrane domains (K67) and C terminus (R176, R177, E179, R301) of Kir6.2. Our model suggests how PIP(2) increases channel opening and decreases ATP binding and channel inhibition. It is likely to be applicable to the PIP(2)-binding site of other Kir channels, as the residues identified are conserved and influence PIP(2) sensitivity in other Kir channel family members. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17673911&query_hl=1 ER - TY - JFULL T1 - Immunotherapy with Antibody-Targeted HLA Class I Complexes: Results of in vivo Tumour Cell Killing and Therapeutic Vaccination. A1 - Savage, P A1 - Dyson, J A1 - Milrain, M A1 - Mathews, D A1 - King, B A1 - Chan, HT A1 - Barber, L A1 - Epenetos, A A1 - Ogg, G A1 - McMichael, A A1 - Glennie, MJ A1 - French, RR J1 - Tumour Biol Y1 - 2007/08/20/ VL - 28 SN - 1010-4283 SP - 205 EP - 211 N2 - Background: The delivery of antibody-targeted major histocompatibility complex (MHC) class I complexes containing immunogenic peptides to the surface of tumour cells allows cytotoxic T lymphocytes (CTLs) of non-tumour specificity to recognise and kill the tumour cell. Previous studies have demonstrated the activity of this system in vitro and in a simple pre-clinical model. This system has also been shown to be an effective method of expanding antigen-specific CTLs in vitro when used to target MHC class I complexes to the surface of B cells. Methods: Mice were immunised with ovalbumin and the survival of EL4Hu20 lymphoma cells targeted with H2-D(b)/Ova complexes and control MHC complexes was compared by FACS analysis. A tumour protection assay was performed where immunised mice were injected B16Hu20 melanoma cells targeted with H2-K(b)/Ova or control complexes. T cell expansion in vivo was examined by administering B cells targeted with MHC class I/peptide complexes and assessing T cell expansion by tetramer analysis. Results: In vivo killing of H2-D(b)/Ova-targeted lymphoma cells in the immunised mice was demonstrated with these cells present at only 12% of the level of the control cells. In contrast, in non-immunised mice the survival of H2-D(b)/Ova-targeted and control cells was comparable. In the tumour protection assay, injection of melanoma cells targeted with H2-K(b)/Ova complexes resulted in the development of only a solitary metastasis in each mouse. This compared to an average of 130 metastases in the control mice injected with B16Hu20 cells targeted with a control MHC peptide complex. In vivo CTL expansion was demonstrated after a single intravenous administration of Daudi B cells coated with H2-D(b)/Uty complexes produced an increase in the proportion of Uty-reactive CTLs from 3.3 to 21.5%. Conclusion: This study supports the development of antibody-delivered MHC complexes as a method of producing CTL-mediated lysis of cancer cells in vivo. As a therapeutic vaccine, the system may provide an effective approach for expanding oligoclonal T cell responses in vivo in the treatment of malignancy and infectious diseases. Copyright (c) 2007 S. Karger AG, Basel. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17709989&query_hl=1 ER - TY - JFULL T1 - Positive replication and linkage disequilibrium mapping of the chromosome 21q22.1 malaria susceptibility locus. A1 - Khor, CC A1 - Vannberg, FO A1 - Chapman, SJ A1 - Walley, A A1 - Aucan, C A1 - Loke, H A1 - White, NJ A1 - Peto, T A1 - Khor, LK A1 - Kwiatkowski, D A1 - Day, N A1 - Scott, A A1 - Berkley, JA A1 - Marsh, K A1 - Peshu, N A1 - Maitland, K A1 - Williams, TN A1 - Hill, AV J1 - Genes Immun Y1 - 2007/08/16/ SN - 1466-4879 N2 - Four cytokine receptor genes are located on Chr21q22.11, encoding the alpha and beta subunits of the interferon-alpha receptor (IFNAR1 and IFNAR2), the beta subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-gamma receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44 kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/12 controls). Within the IFNAR1 gene, a newly studied C --> G single-nucleotide polymorphism (IFNAR1 272354c-g) at position -576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case-control studies. When all three studies were combined, using the Mantel-Haenszel test, the presence of IFNAR1 -576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95% CI: 1.17-1.64; P=1.7 x 10(-4)). This study builds on previous work to further highlight the importance of the type-I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations.Genes and Immunity advance online publication, 16 August 2007; doi:10.1038/sj.gene.6364417. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17703179&query_hl=1 ER - TY - JFULL T1 - Increased rates of preterm delivery are associated with the initiation of highly active antiretrovial therapy during pregnancy: a single-center cohort study. A1 - Martin, F A1 - Taylor, GP J1 - J Infect Dis Y1 - 2007/08/15/ VL - 196 SN - 0022-1899 SP - 558 EP - 561 N2 - It remains controversial whether in human immunodeficiency virus (HIV)-positive pregnant women an increased rate of preterm delivery is associated with highly active antiretroviral therapy (HAART). Since 1995 the management and outcome of all HIV-infected pregnant women delivering at St. Mary's Hospital London have been prospectively documented. The prevalence of preterm delivery and the correlation between gestational age and type of antiretroviral therapy were sought: preterm delivery occurred in 14.2% of the 211 deliveries. Initiation of HAART during pregnancy was associated with an increased risk of preterm delivery. This was independent of maternal health and class of antiretroviral therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17624841&query_hl=1 ER - TY - JFULL T1 - Genetic Study of the Melanin-Concentrating Hormone Receptor 2 (MCHR2) in Childhood and Adulthood Severe Obesity. A1 - Ghoussaini, M A1 - Vatin, V A1 - Lecoeur, C A1 - Abkevich, V A1 - Younus, A A1 - Samson, C A1 - Wachter, C A1 - Heude, B A1 - Tauber, M A1 - Tounian, P A1 - Hercberg, S A1 - Weill, J A1 - Levy-Marchal, C A1 - Le Stunff, C A1 - Bougnères, P A1 - Froguel, P A1 - Meyre, D J1 - J Clin Endocrinol Metab Y1 - 2007/08/14/ SN - 0021-972X N2 - Context: The Melanin Concentrating Hormone Receptor 2 (MCHR2) is a G protein-coupled receptor for MCH, a neuropeptide that plays important role in feeding behaviors. MCHR2 maps on chromosome 6q16.3, in a susceptibility locus for childhood obesity. Objective: The aim of this study was to investigate the association between MCHR2 variation and human obesity. Design: Case control and family-based studies were performed. Participants: 141 obese children and 24 non-obese adult subjects were sequenced and case-control analyses were conducted using 628 severely obese children and 1,401 controls. Results: Eleven Single Nucleotide Polymorphisms (SNPs) were identified. We showed nominal association between -38,245 ATG A/G SNP (p=0.03, 95%CI=[1.02-1.34], OR=1.17), A76A T/C SNP (p=0.03, 95%CI=[0.58-0.97], OR=0.75) and childhood obesity. Analysis of 645 trios with childhood obesity supported further the A76A T/C association, showing an over-transmission to obese children of the at risk T allele (59.0%, p=0.01), especially in children with most severe forms of obesity (Zscore of BMI>4) (67.0%, p=0.003). The A76A at risk T allele was also associated with overeating during meal (p=0.02) in an additional group of 102 non-obese children. None of MCHR2 variants, including the A76A SNP, showed association with adult severe obesity, although a trend for association of the T allele of this variant with food disinhibition (p=0.06) and higher hunger (p=0.09) was found. This variant was not associated with childhood obesity in an independent case-control study including 1,573 subjects (p=0.98). Moreover, the A76A SNP did not explain the linkage on the 6q locus. Conclusions: Our results altogether suggest that MCHR2 is not a major contributor to polygenic obesity and support a modest effect of the A76A SNP on food intake abnormalities in childhood. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17698913&query_hl=1 ER - TY - JFULL T1 - Anti-androgens increase N-terminal pro-BNP levels in men with prostate cancer. A1 - Dockery, F A1 - Bulpitt, CJ A1 - Agarwal, S A1 - Vernon, C A1 - Nihoyannopoulos, P A1 - Kemp, M A1 - Hooper, J A1 - Rajkumar, C J1 - Clin Endocrinol (Oxf) Y1 - 2007/08/13/ SN - 0300-0664 N2 - Objective The aim of this study was to determine the effects of anti-androgens on left ventricular (LV) function and levels of N-terminal proB-type natriuretic peptide (NT-proBNP), a sensitive cardiac risk marker, in men with prostate cancer as these are widely used drugs in this condition, and evidence suggests that endogenous androgens are cardioprotective in men. Design and patients Forty-three men (mean age 70.7 +/- 6.2 years) with prostate cancer were randomized to goserelin (an LH-releasing hormone analogue) or bicalutamide (an androgen-receptor blocker) for 6 months; 20 men with a history of prostate cancer on no treatment were studied in parallel. Results Mean changes in testosterone and oestradiol, respectively, from baseline to 6 months were -88% and -46% with goserelin, +50% and +44% with bicalutamide, and -1% and -9% for the 'no-treatment' group. Bicalutamide significantly increased NT-proBNP from baseline to 3 and 6 months (median value at baseline, 3 and 6 months: 55, 101 and 118 ng/l, respectively). Goserelin caused a significant increase from baseline to 3 months but not to 6 months (median value at baseline, 3 and 6 months: 66, 87 and 72 ng/l, respectively). No significant changes occurred in the 'no-treatment' cohort (median value at baseline 3 and 6 months: 60, 53 and 60 ng/l, respectively). No significant changes in LV function, blood pressure (BP), body mass index or waist-hip ratio occurred to account for the changes in NT-proBNP. Conclusion Androgen receptor blockade and, to a lesser extent, androgen suppression cause an increase in NT-pro-BNP in men with prostate cancer. The significance is not clear but could imply an adverse effect on cardiovascular risk following hormonal manipulation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17692108&query_hl=1 ER - TY - JFULL T1 - The relationship between p38 mitogen-activated protein kinase and AMP-activated protein kinase during myocardial ischemia. A1 - Jacquet, S A1 - Zarrinpashneh, E A1 - Chavey, A A1 - Ginion, A A1 - Leclerc, I A1 - Viollet, B A1 - Rutter, GA A1 - Bertrand, L A1 - Marber, MS J1 - Cardiovasc Res Y1 - 2007/08/08/ SN - 0008-6363 N2 - OBJECTIVE: p38 mitogen-activated protein kinase (p38 MAPK) and AMP-activated protein kinase (AMPK) are activated by, and influence sensitivity to, myocardial ischemia. Recently a number of studies have suggested that AMPK may participate in the activation of p38 MAPK. We therefore examined whether AMPK may be the principal "ischemia sensor" responsible for p38 MAPK activation during myocardial ischemia. METHODS: We used a variety of approaches to alter AMPK activity during ischemia and studied the repercussions on p38 MAPK activation. RESULTS: The activities of AMPK and p38 MAPK were temporally related in adult rat ventricular myocytes (ARVM) subjected to simulated ischemia and in isolated mouse hearts subjected to no-flow ischemia. However p38 MAPK activation was unaltered in mouse hearts lacking the predominant or minor myocardial isoforms, AMPKalpha2 or AMPKalpha1 respectively. Likewise, in ARVM, adenoviral-driven expression of the minor myocardial isoform AMPKalpha1, in a constitutively active or dominant negative form reducing AMPK activity, did not alter p38 MAPK activation under basal conditions or during simulated ischemia. Finally, pharmacological inhibition of AMPK during ischemia with compound C did not attenuate the coincident activation of p38 MAPK. CONCLUSIONS: Although AMPK and p38 MAPK are both activated during myocardial ischemia, the activation of p38 MAPK occurs independently of AMPK. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17765884&query_hl=1 ER - TY - JFULL T1 - Structural basis for binding of plasmodium falciparum erythrocyte membrane protein 1 to chondroitin sulfate and placental tissue and the influence of protein polymorphisms on binding specificity. A1 - Beeson, JG A1 - Andrews, KT A1 - Boyle, M A1 - Duffy, MF A1 - Choong, EK A1 - Byrne, TJ A1 - Chesson, JM A1 - Lawson, AM A1 - Chai, W J1 - J Biol Chem Y1 - 2007/08/03/ VL - 282 SN - 0021-9258 SP - 22426 EP - 22436 N2 - Chondroitin sulfate (CS) A is a key receptor for adhesion of Plasmodium falciparum-infected erythrocytes (IEs) in the placenta and can also mediate adhesion to microvascular endothelial cells. IEs that adhere to CSA express var2csa-type genes, which encode specific variants of the IE surface antigen P. falciparum erythrocyte membrane protein 1 (PfEMP1). We report direct binding of native PfEMP1, isolated from IEs and encoded by var2csa, to immobilized CSA. Binding of PfEMP1 was dependent on 4-O-sulfated disaccharides and glucuronic acid rather than iduronic acid, consistent with the specificity of intact IEs. Using immobilized CS oligosaccharides as neoglycolipid probes, the minimum chain length for direct binding of PfEMP1 was eight monosaccharide units. Similarly for IE adhesion to placental tissue there was a requirement for 4-O-sulfated GalNAc and glucuronic acid mixed with non-sulfated disaccharides; 6-O-sulfation interfered with the interaction between placental CSA and IEs. The minimum chain length for maximal inhibition of adhesion was 10 monosaccharide residues. Partially 4-O-sulfated CS oligosaccharides (45-55% sulfation) were highly effective inhibitors of placental adhesion (IC(50), 0.15 microg/ml) and may have potential for therapeutic development. We used defined P. falciparum isolates expressing different variants of var2csa in adhesion assays and found that there were isolate-specific differences in the preferred structural motifs for adhesion to CSA that correlated with polymorphisms in PfEMP1 encoded by var2csa-type genes. This may influence sites of IE sequestration or parasite virulence. These findings have significant implications for understanding the pathogenesis and biology of malaria, particularly during pregnancy, and the development of targeted interventions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17562715&query_hl=1 ER - TY - JFULL T1 - Thyroid status during skeletal development determines adult bone structure and mineralization. A1 - Bassett, JH A1 - Nordström, K A1 - Boyde, A A1 - Howell, PG A1 - Kelly, S A1 - Vennström, B A1 - Williams, GR J1 - Mol Endocrinol Y1 - 2007/08// VL - 21 SN - 0888-8809 SP - 1893 EP - 1904 N2 - Childhood hypothyroidism delays ossification and bone mineralization, whereas adult thyrotoxicosis causes osteoporosis. To determine how effects of thyroid hormone (T3) during development manifest in adult bone, we characterized TRalpha1(+/m)beta(+/-) mice, which express a mutant T3 receptor (TR) alpha1 with dominant-negative properties due to reduced ligand-binding affinity. Remarkably, adult TRalpha1(+/m)beta(+/-) mice had osteosclerosis with increased bone mineralization even though juveniles had delayed ossification. This phenotype was partially normalized by transient T3 treatment of juveniles and fully reversed in compound TRalpha1(+/m)beta(-/-) mutant mice due to 10-fold elevated hormone levels that allow the mutant TRalpha1 to bind T3. By contrast, deletion of TRbeta in TRalpha1(+/+)beta(-/ -) mice, which causes a 3-fold increase of hormone levels, led to osteoporosis in adults but advanced ossification in juveniles. T3-target gene analysis revealed skeletal hypothyroidism in TRalpha1(m/+)beta(+/-) mice, thyrotoxicosis in TRalpha1(+/+)beta(-/-) mice, and euthyroidism in TRalpha1(+/)beta(-/-) double mutants. Thus, TRalpha1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17488972&query_hl=1 ER - TY - JFULL T1 - Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies. A1 - Zhou, H A1 - Jungbluth, H A1 - Sewry, CA A1 - Feng, L A1 - Bertini, E A1 - Bushby, K A1 - Straub, V A1 - Roper, H A1 - Rose, MR A1 - Brockington, M A1 - Kinali, M A1 - Manzur, A A1 - Robb, S A1 - Appleton, R A1 - Messina, S A1 - D'Amico, A A1 - Quinlivan, R A1 - Swash, M A1 - Müller, CR A1 - Brown, S A1 - Treves, S A1 - Muntoni, F J1 - Brain Y1 - 2007/08// VL - 130 SN - 1460-2156 SP - 2024 EP - 2036 N2 - Dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYR1 mutations have been described in few congenital myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive RYR1 mutations exists, in most cases with recessive mutations the pattern of muscle weakness is remarkably different from that observed in dominant CCD. In order to characterize the spectrum of congenital myopathies associated with RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYR1 involvement. We have identified 25 RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive RYR1 mutations were distributed evenly along the entire RYR1 gene and were associated with a wide range of clinico-pathological phenotypes. Protein expression studies in nine cases suggested a correlation between specific mutations, RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyR1 expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyR1 protein. The phenomenon of protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients. Our data represent the most extensive study of RYR1-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyR1 calcium release channel. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17483490&query_hl=1 ER - TY - JFULL T1 - In vivo evidence for apoptosis in the bone marrow in systemic lupus erythematosus. A1 - Hepburn, AL A1 - Lampert, IA A1 - Boyle, JJ A1 - Horncastle, D A1 - Ng, WF A1 - Layton, M A1 - Vyse, TJ A1 - Botto, M A1 - Mason, JC J1 - Ann Rheum Dis Y1 - 2007/08// VL - 66 SN - 0003-4967 SP - 1106 EP - 1109 N2 - An increase in leucocyte apoptosis and impaired clearance of apoptotic cells has been observed in patients with systemic lupus erythematosus (SLE). Apoptotic cells are likely to be a key source of autoantigens in SLE as they express many of the nuclear autoantigens (in surface blebs and apoptotic bodies) that are relevant to this disease. The clearance of apoptotic cells is usually a rapid process, such that few cells are usually seen in the extracellular environment in vivo. We report a case in which multiple apoptotic bodies were observed in the bone marrow of a patient with SLE that was complicated by an immune-mediated pancytopenia. We have subsequently examined the frequency of apoptotic cells, identified morphologically, and by caspase-3 staining in bone-marrow trephine samples taken from patients with SLE over a 10-year period of follow-up. A high proportion of bone marrows contained apoptotic debris. The novel demonstration of apoptotic bodies in vivo in patients with SLE is unusual and supports the notion that the marrow may be a target organ in the disease. Their abundance is also consistent with the hypothesis that normal clearance mechanisms are defective and/or overwhelmed in SLE. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17277002&query_hl=1 ER - TY - JFULL T1 - Human muscle precursor cells give rise to functional satellite cells in vivo. A1 - Ehrhardt, J A1 - Brimah, K A1 - Adkin, C A1 - Partridge, T A1 - Morgan, J J1 - Neuromuscul Disord Y1 - 2007/08// VL - 17 SN - 0960-8966 SP - 631 EP - 638 N2 - Mouse satellite cells have been shown to be functional muscle stem cells, in that they are able to regenerate skeletal muscle and to reconstitute the satellite cell pool. Although human muscle precursor cells are able to contribute to skeletal muscle regeneration following transplantation into host mouse muscles, it is uncertain whether they also give rise to functional satellite cells. Here, we transplant human fetal muscle precursor cells into cryodamaged muscles in C(5)-/gamma-chain-/Rag2-host mice. The donor cells gave rise to muscle fibres that persisted for up to 6 months after grafting. Isolated muscle fibres, bearing satellite cells, were prepared from muscles 4 weeks after grafting. When placed in culture, a small proportion of these fibres gave rise to muscle precursor cells of human origin, indicating that the originally grafted cells had formed satellite cells as well as regenerated muscle fibres. These satellite cell-derived human muscle precursor cells were expanded in culture and formed muscle following their transplantation into a second series of host mice. This provides evidence that human, as well as mouse, muscle precursor cells, are capable of forming functional satellite cells in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17588754&query_hl=1 ER - TY - JFULL T1 - The Diagnostic Assessment of Suspected Pulmonary Embolism on the Acute Medical Take: An evidence based guide A1 - Proudfoot, A A1 - Bell, D J1 - Acute Medicine Y1 - 2007/08// VL - 6 PB - Rila Publications SP - 20 EP - 26 ER - TY - JFULL T1 - Implication of the satellite cell in dystrophic muscle fibrosis: a self-perpetuating mechanism of collagen overproduction. A1 - Alexakis, C A1 - Partridge, T A1 - Bou-Gharios, G J1 - Am J Physiol Cell Physiol Y1 - 2007/08// VL - 293 SN - 0363-6143 SP - C661 EP - C669 N2 - Because of its mechanical function, skeletal muscle is heavily influenced by the composition of its extracellular matrix (ECM). Fibrosis generated by chronic damage, such as occurs in muscular dystrophies, is thus particularly disastrous in this tissue. Here, we examined the interrelationship between the muscle satellite cell and the production of collagen type I, a major component of fibrotic ECM, by using both C2C12, a satellite cell-derived cell line, and primary muscle satellite cells. In C2C12 cells, we found that expression of collagen type I mRNA decreases substantially during skeletal muscle differentiation. On a single-cell level, collagen type I and myogenin became mutually exclusive after 3 days in differentiation medium, whereas addition of collagen markedly suppressed differentiation of C2C12 cells. Primary cultures of satellite cells associated with isolated single fibers of the young (4 wk old) mdx dystrophic mouse and of C57BL/10ScSn wild-type controls expressed collagen type I and type III mRNA and protein. This pattern persisted in wild-type mice at all ages. But, curiously, in older (18-mo-old) mdx mice, although the myogenic cells continued to express type III collagen, type I expression became restricted to nonmyogenic cells. These cells typically constituted part of a cellular sheet surrounding the old mdx fibers. This combination of features strongly suggests that the progression to fibrosis in dystrophic muscle involves changes in the mechanisms controlling matrix production, which generates positive feedback that results in a reprogramming of myoblasts to a profibrotic function. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17475662&query_hl=1 ER - TY - JFULL T1 - Bone marrow cells in the liver: diverse cells, diverse effects. A1 - Russo, FP A1 - Kallis, YN A1 - Alison, MR A1 - Forbes, SJ J1 - Hepatology Y1 - 2007/08// VL - 46 SN - 0270-9139 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17661406&query_hl=1 ER - TY - JFULL T1 - Long-term follow-up of the hepatitis C HENCORE cohort: response to therapy and occurrence of liver-related complications. A1 - Pradat, P A1 - Tillmann, HL A1 - Sauleda, S A1 - Braconier, JH A1 - Saracco, G A1 - Thursz, M A1 - Goldin, R A1 - Winkler, R A1 - Alberti, A A1 - Esteban, JI A1 - Hadziyannis, S A1 - Rizzetto, M A1 - Thomas, H A1 - Manns, MP A1 - Trepo, C A1 - HENCORE Group J1 - J Viral Hepat Y1 - 2007/08// VL - 14 SN - 1352-0504 SP - 556 EP - 563 N2 - The aims of the study were to verify the long-term effect of time on viral clearance in hepatitis C virus (HCV) patients and to find out factors possibly associated with disease progression. A total of 1641 patients recruited from eight European centres in 1996-1997 were re-analysed 5-7 years after inclusion. The occurrence of decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation was analysed in relation to different host and viral factors. Ninety-three per cent of the HCV patients who had cleared the virus (spontaneously or after antiviral therapy) remained HCV-RNA-negative during follow up and may be considered as 'cured'. Among patients who were sustained responders at inclusion, 2.3% developed liver complications during follow up, and 31% of non-responders did. Advanced age at infection and presence of the human leucocyte antigen (HLA) DRB1*1201-3 allele were possibly associated with a higher rate of progression to decompensated cirrhosis or HCC. Decompensated cirrhosis might be further associated with male gender, non-response to previous therapy, and lack of HLA DRB1*1301 allele, whereas HCC seems to be associated with the presence of the HLA DQ02 allele. Long-term follow up of HCV patients indicates that virological response persists over time and is associated with a very low incidence of liver complications. Advanced age at inclusion, advanced age at infection, viral genotype 1, non-response to previous therapy and possibly some specific HLA alleles are factors independently associated with a faster rate of progression towards liver complications. The large proportion of patients lost to follow up stresses the need for a strengthened and optimized management of HCV patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17650289&query_hl=1 ER - TY - JFULL T1 - Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. A1 - Stutzmann, F A1 - Vatin, V A1 - Cauchi, S A1 - Morandi, A A1 - Jouret, B A1 - Landt, O A1 - Tounian, P A1 - Levy-Marchal, C A1 - Buzzetti, R A1 - Pinelli, L A1 - Balkau, B A1 - Horber, F A1 - Bougnères, P A1 - Froguel, P A1 - Meyre, D J1 - Hum Mol Genet Y1 - 2007/08/01/ VL - 16 SN - 0964-6906 SP - 1837 EP - 1844 N2 - The melanocortin-4 receptor (MC4R) gene pathogenic mutations are the most prevalent forms of monogenic obesity, responsible for approximately 2% of obesity cases, but its role in common obesity is still elusive. We analyzed the contribution of non-synonymous mutations V103I (rs2229616, c.307G > A) and I251L (no rs, c.751A > C) to obesity in 16 797 individuals of European origin from nine independent case-control, population-based and familial cohorts. We observed a consistent negative association of I251L variant (prevalence ranging 0.41-1.21%) with both childhood and adult class III obesity [odds ratio (OR) ranging from 0.25 to 0.76, 0.001 < P-value < 0.05] and with modulation of body mass index (BMI) in general populations, in eight out of nine studies, whereas only one study showed an association between V103I and BMI. Meta-analyses of previous published data with the current ones provided strong evidence of the protective effect of I251L toward obesity (OR = 0.52, P = 3.58 10-5), together with a modest negative association between V103I and obesity (OR = 0.80, P = 0.002). Taken together, gain-of-function mutations I251L and V103I may be responsible for a preventive fraction of obesity of 2%, which mirrors the prevalence of monogenic obesity due to MC4R haploinsufficiency. These results also emphasize the importance of the MC4R signalling tonus to prevent obesity, even in the context of our current obesogenic environment. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17519222&query_hl=1 ER - TY - JFULL T1 - Rate of change and instability in body mass index, insulin resistance and lipid metabolism as predictors of atherosclerotic vascular disease. A1 - Christen, A A1 - Efstathiadou, Z A1 - Laspa, E A1 - Johnston, DG A1 - Godsland, IF J1 - J Clin Endocrinol Metab Y1 - 2007/07/31/ SN - 0021-972X N2 - Context: By definition, levels of metabolic risk factors predict atherosclerotic vascular disease (AVD), but the effects of long-term adverse change and instability remain under-researched. Objective: To quantify long-term rates of change and instability in risk factors and relate these measures to clinical AVD outcomes. Design: Prospective cohort study with unmatched and age- and follow-up-matched control analyses. Setting: Teaching hospital day ward. Participants: Four-hundred and sixty-five predominantly healthy white males in an occupational cohort, who had undergone repeated metabolic risk factor measurements (mean observation period 11.6 years, range 2-28), 62 of whom developed clinical AVD. Main outcome measures: Rate of change and instability in metabolic risk factor levels were quantified in each individual by linear regression with time and evaluated as predictors of AVD and coronary and cerebrovascular disease separately. Results: As expected, baseline and/or mean follow-up measures of established risk-factors relating to blood pressure, lipid metabolism and sub-clinical inflammation were significant predictors. Predictors independent of baseline and mean follow-up levels, confirmed in matched and unmatched analyses, were: i) AVD: instability in weight (cases vs controls:2.9% vs +2.5%); ii) coronary heart disease: instability in body mass index (3.0% vs +2.3%), a decline (-0.041 vs -0.011 per decade) and instability (19.1% v 14.6%) in the HDL / non-HDL cholesterol ratio, declining ESR and increasing uric acid; iii) cerebrovascular disease: a decline in insulin sensitivity (-0.394 vs 0.324 per decade). Conclusions: Within an individual, long-term change in metabolic risk factors, as well as their absolute levels, can be important in AVD. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17666474&query_hl=1 ER - TY - JFULL T1 - C1q deficiency promotes the production of transgenic-derived IgM and IgG3 autoantibodies in anti-DNA knock-in transgenic mice. A1 - Fossati-Jimack, L A1 - Cortes-Hernandez, J A1 - Norsworthy, PJ A1 - Walport, MJ A1 - Cook, HT A1 - Botto, M J1 - Mol Immunol Y1 - 2007/07/31/ SN - 0161-5890 N2 - C1q-deficient mice have been shown to develop a lupus-like disease and to display an impaired clearance of apoptotic cells that are enriched in lupus autoantigens. However, the role of C1q in the regulation of autoreactive B cells remains debatable. To explore this we crossed MRL/Mp C1q-deficient mice with knock-in transgenic (Tg) mice expressing an anti-ssDNA antibody (V(H)3H9R and V(H)3H9R/V(L)kappa8R). Analysis of the V(H)3H9R mice showed that in the absence of C1q higher titres of Tg-derived IgM and IgG(3) anti-ssDNA antibodies were detectable. In contrast, in the V(H)3H9R/V(L)kappa8R C1q-deficient animals no increase in Tg antibody levels was observed. In both models the lack of C1q induced a marked reduction of marginal zone B cells and this was paralleled by a significant increase in the percentage of plasmocytes. Thus, one could postulate that in the absence of C1q the failure to clear efficiently dying cells provides an additional stimulus to the autoreactive Tg B cells resulting in their emigration from the marginal zone B cell compartment with subsequent increase in plasmocytes. However, the lack of C1q led to an increased production of Tg IgM and IgG(3) antibodies only in V(H)3H9R mice indicating that additional genetic susceptibility factors are required to break self-tolerance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17675234&query_hl=1 ER - TY - JFULL T1 - Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases. A1 - Smith, AJ A1 - Tsalenko, A A1 - Sampas, N A1 - Scheffer, A A1 - Yamada, NA A1 - Tsang, P A1 - Ben-Dor, A A1 - Yakhini, Z A1 - Ellis, RJ A1 - Bruhn, L A1 - Laderman, S A1 - Froguel, P A1 - Blakemore, AI J1 - Hum Mol Genet Y1 - 2007/07/31/ SN - 0964-6906 N2 - The discovery of copy number variation in healthy individuals is far from complete, and due to the resolution of detection systems used, the majority of loci reported so far are relatively large ( approximately 65% > 10kb). Applying a two-stage high-resolution array CGH approach to analyse 50 healthy Caucasian males from northern France, we discovered 2208 copy number variants (CNVs) detected by more than one consecutive probe. These clustered into 1469 copy number variant regions (CNVRs), of which 721 are thought to be novel. The majority of these are small (median size 4.4kb) and most have common boundaries, with a coefficient of variation less than 0.1 for 83% of end-points in those observed in multiple samples. Only 6% of the CNVRs analysed showed evidence of both copy number losses and gains at the same site. A further 6089 variants were detected by single probes: 48% of these were observed in more than one individual. In total, 2570 genes were seen to intersect variants: 1284 in novel loci. Genes involved in differentiation and development were significantly overrepresented, and approximately half the genes identified feature in the OMIM database. The biological importance of many of the genes affected, along with the well-conserved nature of the majority of the copy number variants, suggests they could have important implications for phenotype and, thus, be useful for association studies of complex diseases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17666407&query_hl=1 ER - TY - JFULL T1 - A patient with suspected miscarriage is found to have hypertension, renal failure, and thrombocytopenia: case outcome. A1 - Laing, CM A1 - Roberts, R A1 - Lightstone, L A1 - Graham, A A1 - Cook, TH A1 - Summers, S A1 - Pusey, CD J1 - BMJ Y1 - 2007/07/28/ VL - 335 SN - 1468-5833 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17656546&query_hl=1 ER - TY - JFULL T1 - Dual aromatase-steroid sulfatase inhibitors. A1 - Woo, LW A1 - Bubert, C A1 - Sutcliffe, OB A1 - Smith, A A1 - Chander, SK A1 - Mahon, MF A1 - Purohit, A A1 - Reed, MJ A1 - Potter, BV J1 - J Med Chem Y1 - 2007/07/26/ VL - 50 SN - 0022-2623 SP - 3540 EP - 3560 N2 - By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17580845&query_hl=1 ER - TY - JFULL T1 - Falling into TRAPS - receptor misfolding in the TNF receptor 1-associated periodic fever syndrome. A1 - Kimberley, FC A1 - Lobito, AA A1 - Siegel, RM A1 - Screaton, GR J1 - Arthritis Res Ther Y1 - 2007/07/23/ VL - 9 SN - 1478-6362 SP - 217 EP - 217 N2 - ABSTRACT: TNF receptor-associated periodic syndrome (TRAPS) is a dominantly inherited disease caused by missense mutations in the TNF receptor 1 (TNFR1) gene. Patients suffer from periodic bouts of severe abdominal pain, localised inflammation, migratory rashes, and fever. More than 40 individual mutations have been identified, all of which occur in the extracellular domain of TNFR1. In the present review we discuss new findings describing aberrant trafficking and function of TNFR1 harbouring TRAPS mutations, challenging the hypothesis that TRAPS pathology is driven by defective receptor shedding, and we suggest that TNFR1 might acquire novel functions in the endoplasmic reticulum, distinct from its role as a cell surface receptor. We also describe the clinical manifestations of TRAPS, current treatment regimens, and the widening array of patient mutations. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17666110&query_hl=1 ER - TY - JFULL T1 - CTLs target Th cells that acquire bystander MHC class I-peptide complex from APCs. A1 - Cox, JH A1 - McMichael, AJ A1 - Screaton, GR A1 - Xu, XN J1 - J Immunol Y1 - 2007/07/15/ VL - 179 SN - 0022-1767 SP - 830 EP - 836 N2 - CTLs can acquire MHC class I-peptide complexes from their target cells, whereas CD4(+) T cells obtain MHC class II-peptide complexes from APCs in a TCR-specific manner. As a consequence, Ag-specific CTL can kill each other (fratricide) or CD4(+) T cells become APCs themselves. The purpose of the acquisition is not fully understood and may be either inhibition or prolongation of an immunological response. In this study, we demonstrate that human CD4(+) Th cells are able to capture membrane fragments from APC during the process of immunological synapse formation. The fragments contain not only MHC class II-peptide complexes but also MHC class I-peptide complexes, rendering these cells susceptible to CTL killing in an Ag-specific manner. The control of CD4(+) Th cells by Ag-specific CTL, therefore, maybe another mechanism to regulate CD4(+) T cell expansion in normal immune responses or cause immunopathology during the course of viral infections such as HIV. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17617573&query_hl=1 ER - TY - JFULL T1 - LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. A1 - Shun, MC A1 - Raghavendra, NK A1 - Vandegraaff, N A1 - Daigle, JE A1 - Hughes, S A1 - Kellam, P A1 - Cherepanov, P A1 - Engelman, A J1 - Genes Dev Y1 - 2007/07/15/ VL - 21 SN - 0890-9369 SP - 1767 EP - 1778 N2 - LEDGF/p75 directly interacts with lentiviral integrase proteins and can modulate their enzymatic activities and chromosomal association. A novel genetic knockout model was established that allowed us for the first time to analyze HIV-1 integration in the absence of LEDGF/p75 protein. Supporting a crucial role for the cofactor in viral replication, HIV-1 vector integration and reporter gene expression were significantly reduced in LEDGF-null cells. Yet, integrase processed the viral cDNA termini normally and maintained its local target DNA sequence preference during integration. Preintegration complexes extracted from knockout cells moreover supported normal levels of DNA strand transfer activity in vitro. In contrast, HIV-1 lost its strong bias toward integrating into transcription units, displaying instead increased affinity for promoter regions and CpG islands. Our results reveal LEDGF/p75 as a critical targeting factor, commandeering lentiviruses from promoter- and/or CpG island-proximal pathways that are favored by other members of Retroviridae. Akin to yeast retrotransposons, disrupting the lentiviral targeting mechanism significantly perturbs overall integration. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17639082&query_hl=1 ER - TY - JFULL T1 - Alpha1,3-galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here? A1 - Cooper, DK A1 - Dorling, A A1 - Pierson, RN A1 - Rees, M A1 - Seebach, J A1 - Yazer, M A1 - Ohdan, H A1 - Awwad, M A1 - Ayares, D J1 - Transplantation Y1 - 2007/07/15/ VL - 84 SN - 0041-1337 SP - 1 EP - 7 N2 - The ability to genetically engineer pigs that no longer express the Galalpha1,3Gal (Gal) oligosaccharide has been a significant step toward the clinical applicability of xenotransplantation. Using a chronic immunosuppressive regimen based on costimulatory blockade, hearts from these pigs have survived from 2 to 6 months in baboons. Graft failure was predominantly from the development of a thrombotic microangiopathy. Potential contributing factors include the presence of preformed anti-nonGal antibodies or the development of low levels of elicited antibodies to nonGal antigens, natural killer (NK) cell or macrophage activity, and inherent coagulation dysregulation between pigs and primates. The breeding of pigs transgenic for an "anticoagulant" gene, such as human tissue factor pathway inhibitor, hirudin, or CD39, or lacking the gene for the prothrombinase, fibrinogen-like protein-2, is anticipated to inhibit the change in the endothelium to a procoagulant state that takes place in the pig organ after transplantation. The identification of the targets for anti-nonGal antibodies and/or human macrophages might allow further genetic modification of the pig, and xenogeneic NK cell recognition and activation may be inhibited by the transgenic expression of human leukocyte antigen molecules and/or by blocking the function of activating NK receptors. The ultimate goal of induction of T-cell tolerance may be possible only if these hurdles in the coagulation system and innate immunity can be overcome. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17627227&query_hl=1 ER - TY - JFULL T1 - IkappaB genetic polymorphisms and invasive pneumococcal disease. A1 - Chapman, SJ A1 - Khor, CC A1 - Vannberg, FO A1 - Frodsham, A A1 - Walley, A A1 - Maskell, NA A1 - Davies, CW A1 - Segal, S A1 - Moore, CE A1 - Gillespie, SH A1 - Denny, P A1 - Day, NP A1 - Crook, DW A1 - Davies, RJ A1 - Hill, AV J1 - Am J Respir Crit Care Med Y1 - 2007/07/15/ VL - 176 SN - 1073-449X SP - 181 EP - 187 N2 - RATIONALE: Increasing evidence supports a key role for the transcription factor nuclear factor (NF)-kappaB in the host response to pneumococcal infection. Control of NF-kappaB activity is achieved through interactions with the IkappaB family of inhibitors, encoded by the genes NFKBIA, NFKBIB, and NFKBIE. Rare NFKBIA mutations cause immunodeficiency with severe bacterial infection, raising the possibility that common IkappaB gene polymorphisms confer susceptibility to common bacterial disease. OBJECTIVES: To determine whether polymorphisms in NFKBIA, NFKBIB, and NFKBIE associate with susceptibility to invasive pneumococcal disease (IPD) and thoracic empyema. METHODS: We studied the frequencies of 62 single-nucleotide polymorphisms (SNPs) across NFKBIA, NFKBIB, and NFKBIE in individuals with IPD and control subjects (n=1,060). Significantly associated SNPs were then studied in a group of individuals with thoracic empyema and a second control group (n=632). MEASUREMENTS AND MAIN RESULTS: Two SNPs in the NFKBIA promoter region were associated with protection from IPD in both the initial study group and the pneumococcal empyema subgroup. Significant protection from IPD was observed for carriage of mutant alleles at these two loci on combining the groups (SNP rs3138053: Mantel-Haenszel 2x2 chi2=13.030, p=0.0003; odds ratio [OR], 0.60; 95% confidence interval [CI], 0.45-0.79; rs2233406: Mantel-Haenszel 2x2 chi2=18.927, p=0.00001; OR, 0.55; 95% CI, 0.42-0.72). An NFKBIE SNP associated with susceptibility to IPD but not pneumococcal empyema. None of the NFKBIB SNPs associated with IPD susceptibility. CONCLUSIONS: NFKBIA polymorphisms associate with susceptibility to IPD. Genetic variation in an inhibitor of NF-kappaB therefore not only causes a very rare immunodeficiency state but may also influence the development of common infectious disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17463416&query_hl=1 ER - TY - JFULL T1 - A single dose of vitamin D enhances immunity to mycobacteria. A1 - Martineau, AR A1 - Wilkinson, RJ A1 - Wilkinson, KA A1 - Newton, SM A1 - Kampmann, B A1 - Hall, BM A1 - Packe, GE A1 - Davidson, RN A1 - Eldridge, SM A1 - Maunsell, ZJ A1 - Rainbow, SJ A1 - Berry, JL A1 - Griffiths, CJ J1 - Am J Respir Crit Care Med Y1 - 2007/07/15/ VL - 176 SN - 1073-449X SP - 208 EP - 213 N2 - RATIONALE: Vitamin D was used to treat tuberculosis (TB) in the preantibiotic era. Prospective studies to evaluate the effect of vitamin D supplementation on antimycobacterial immunity have not previously been performed. OBJECTIVES: To determine the effect of vitamin D supplementation on antimycobacterial immunity and vitamin D status. METHODS: A double-blind randomized controlled trial was conducted in 192 healthy adult TB contacts in London, United Kingdom. Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was assessed with a functional whole blood assay (BCG-lux assay), which measures the ability of whole blood to restrict luminescence, and thus growth, of recombinant reporter mycobacteria in vitro; the readout is expressed as a luminescence ratio (luminescence postinfection/baseline luminescence). IFN-gamma responses to the Mycobacterium tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay. Vitamin D supplementation significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro compared with placebo (mean luminescence ratio at follow-up, 0.57, vs. 0.71, respectively; 95% confidence interval for difference, 0.01-0.25; p=0.03) but did not affect antigen-stimulated IFN-gamma secretion. CONCLUSIONS: A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses. Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent TB infection. Clinical trial registered with www.clinicaltrials.gov (NCT 00157066). L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17463418&query_hl=1 ER - TY - JFULL T1 - Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. A1 - Hickson, M A1 - D'Souza, AL A1 - Muthu, N A1 - Rogers, TR A1 - Want, S A1 - Rajkumar, C A1 - Bulpitt, CJ J1 - BMJ Y1 - 2007/07/14/ VL - 335 SN - 1468-5833 SP - 80 EP - 80 N2 - OBJECTIVE: To determine the efficacy of a probiotic drink containing Lactobacillus for the prevention of any diarrhoea associated with antibiotic use and that caused by Clostridium difficile. DESIGN: Randomised double blind placebo controlled study. PARTICIPANTS: 135 hospital patients (mean age 74) taking antibiotics. Exclusions included diarrhoea on admission, bowel pathology that could result in diarrhoea, antibiotic use in the previous four weeks, severe illness, immunosuppression, bowel surgery, artificial heart valves, and history of rheumatic heart disease or infective endocarditis. INTERVENTION: Consumption of a 100 g (97 ml) drink containing Lactobacillus casei, L bulgaricus, and Streptococcus thermophilus twice a day during a course of antibiotics and for one week after the course finished. The placebo group received a longlife sterile milkshake. MAIN OUTCOME MEASURES: Primary outcome: occurrence of antibiotic associated diarrhoea. Secondary outcome: presence of C difficile toxin and diarrhoea. RESULTS: 7/57 (12%) of the probiotic group developed diarrhoea associated with antibiotic use compared with 19/56 (34%) in the placebo group (P=0.007). Logistic regression to control for other factors gave an odds ratio 0.25 (95% confidence interval 0.07 to 0.85) for use of the probiotic, with low albumin and sodium also increasing the risk of diarrhoea. The absolute risk reduction was 21.6% (6.6% to 36.6%), and the number needed to treat was 5 (3 to 15). No one in the probiotic group and 9/53 (17%) in the placebo group had diarrhoea caused by C difficile (P=0.001). The absolute risk reduction was 17% (7% to 27%), and the number needed to treat was 6 (4 to 14). CONCLUSION: Consumption of a probiotic drink containing L casei, L bulgaricus, and S thermophilus can reduce the incidence of antibiotic associated diarrhoea and C difficile associated diarrhoea. This has the potential to decrease morbidity, healthcare costs, and mortality if used routinely in patients aged over 50. TRIAL REGISTRATION: National Research Register N0016106821. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17604300&query_hl=1 ER - TY - JFULL T1 - Nanopipet delivery of individual molecules to cellular compartments for single molecule fluorescence tracking. A1 - Bruckbauer, A A1 - James, P A1 - Zhou, D A1 - Yoon, JW A1 - Excell, D A1 - Korchev, Y A1 - Jones, R A1 - Klenerman, D J1 - Biophys J Y1 - 2007/07/13/ SN - 0006-3495 N2 - We have developed a new method, using a nanopipet, for controlled voltage-driven delivery of individual fluorescently labeled probe molecules to the plasma membrane which we used for single molecule fluorescence tracking (SMT). The advantages of the method are: application of the probe to predefined regions on the membrane; release of only one or a few molecules onto the cell surface; combined with total internal reflection fluorescence (TIRF) microscopy there is very low background due to unbound molecules; the experiment can first be optimized and then repeated on the same cell. We validated the method by performing a SMT study of the diffusion of individual membrane glycoproteins labeled with Atto 647-wheat germ agglutin (WGA) in different surface domains of boar spermatozoa. We found little deviation from Brownian diffusion with a mean diffusion coefficient of 0.79 +/- 0.04 microm(2)/s in the acrosomal region and 0.10 +/- 0.02 microm(2)/s in the postacrosomal region; this difference probably reflects different membrane structure. We also showed that we can analyze diffusional properties of different sub-regions of the cell membrane and probe for the presence of diffusion barriers. This new method should be straightforward to extend to other probes and cells and can be used as a new tool to investigate the cell membrane. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17631532&query_hl=1 ER - TY - JFULL T1 - Response to Mallet et al., 'Nodular regenerative hyperplasia is a new cause of chronic liver disease in HIV-infected patients'. A1 - Garvey, LJ A1 - Thomson, EC A1 - Lloyd, J A1 - Cooke, GS A1 - Goldin, RD A1 - Main, J J1 - AIDS Y1 - 2007/07/11/ VL - 21 SN - 0269-9370 SP - 1494 EP - 1495 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17589202&query_hl=1 ER - TY - JFULL T1 - Increased duration of viral suppression is associated with lower viral rebound rates in patients with previous treatment failures. A1 - Benzie, AA A1 - Bansi, LK A1 - Sabin, CA A1 - Portsmouth, S A1 - Hill, T A1 - Johnson, M A1 - Gilson, R A1 - Easterbrook, P A1 - Gazzard, B A1 - Fisher, M A1 - Orkin, C A1 - Dunn, D A1 - Delpech, V A1 - Taylor, GP A1 - Walsh, JC A1 - Phillips, AN A1 - United Kingdom Collaborative HIV Cohort (CHIC) Study Group J1 - AIDS Y1 - 2007/07/11/ VL - 21 SN - 0269-9370 SP - 1423 EP - 1430 N2 - OBJECTIVE: We investigated whether the rate of viral rebound decreases with increasing duration of viral suppression and, if so, whether rebound rates in patients previously failing antiretroviral regimens ultimately decline to levels as low as those seen in patients who have never experienced virological failure. METHODS: All patients from the UK CHIC Study (n = 21 256) who achieved a viral load (VL) of < or = 50 copies/ml while receiving HAART were followed until viral rebound (two consecutive VL > 400 copies/ml). Patients could re-enter the analysis if they experienced a subsequent VL < or = 50 copies/ml. Rebound rates were calculated according to the number of regimens previously failed and duration of viral suppression. RESULTS: Of 12 648 patients on HAART 10 237 (80.9%) achieved a VL < or = 50 copies/ml. During 26 494 person-years (PY) of follow-up, 1853 (18.1%) patients experienced at least one viral rebound 'event', with 2460 events in total [rebound rate, 9.3 (range, 8.9-9.7)/100 PY). Within the first year of viral suppression, the rate of viral rebound was 8.3 (7.5-9.1)/100 PY in patients who had not previously failed treatment, increasing to 32.7 (27.6-37.8)/100 PY in patients who had failed more than four regimens. Irrespective of previous treatment failure, rebound rates in those who remained suppressed for > 4 years were similar to those in patients who had at no time experienced treatment failure. CONCLUSION: After around 4 years of viral suppression rebound rates in individuals with multiple prior treatment failures approach those of individuals with no prior treatment failure. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17589188&query_hl=1 ER - TY - JFULL T1 - Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance. A1 - Boffito, M A1 - Winston, A A1 - Jackson, A A1 - Fletcher, C A1 - Pozniak, A A1 - Nelson, M A1 - Moyle, G A1 - Tolowinska, I A1 - Hoetelmans, R A1 - Miralles, D A1 - Gazzard, B J1 - AIDS Y1 - 2007/07/11/ VL - 21 SN - 0269-9370 SP - 1449 EP - 1455 N2 - BACKGROUND: Cumulative antiretroviral exposure can result in multiclass HIV drug resistance. Experimental antiretroviral agents offer limited therapeutic benefit as resistance quickly develops after their introduction as a sole new agent. OBJECTIVE: To assess the pharmacokinetic profile, safety and virological response of two novel investigational antiretroviral agents when used in combination in HIV-1-infected subjects with multidrug-resistant virus. METHODS: HIV-1-infected subjects, with current virological failure on a stable antiretroviral regimen with no viable treatment options were assigned to a regimen comprising two new investigational agents, etravirine, a novel nonnucleoside reverse transcriptase inhibitor, and darunavir, a novel protease inhibitor, plus nucleoside reverse transcriptase inhibitors (and enfuvirtide in selected patients) for 24 weeks. Virological, immunological and safety parameters were collected. Detailed pharmacokinetic assessments of darunavir and etravirine were determined on days 7 and 28. RESULTS: Follow up of 24 weeks was achieved by 10/12 patients. Median reduction in HIV RNA was 2.7 log10 copies/ml (range, 2.3-3.9) and increase in CD4 lymphocytes was 113 cells/microl (range, 41-268). HIV RNA was < 40 copies/ml in nine. No serious adverse events were recorded. Plasma exposure to darunavir was similar to historic control data and exposure to etravirine similar to historic data when etravirine was administered with a boosted protease inhibitor. CONCLUSION: This first study to assess the use of etravirine and darunavir in HIV-1-infected subjects with no treatment options showed highly effective virological and immunological responses over 24 weeks of therapy with no new safety concerns or unexpected pharmacokinetic interactions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17589191&query_hl=1 ER - TY - JFULL T1 - A patient with suspected miscarriage is found to have hypertension, renal failure, and thrombocytopenia: case progression. A1 - Laing, CM A1 - Roberts, R A1 - Lightstone, L A1 - Graham, A A1 - Cook, TH A1 - Summers, S A1 - Pusey, CD J1 - BMJ Y1 - 2007/07/07/ VL - 335 SN - 1468-5833 SP - 44 N2 - L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17615226&query_hl=1 ER - TY - JFULL T1 - International perspectives, progress, and future challenges of paediatric HIV infection A1 - Prendergast, A A1 - Tudor-Williams, G A1 - Jeena, P A1 - Burchett, S A1 - Goulder, P J1 - LANCET Y1 - 2007/07/07/ VL - 370 SN - 0140-6736 SP - 68 EP - 80 N2 - Paediatric HIV infection is a growing health challenge worldwide, with an estimated 1500 new infections every day. in developed countries, well established prevention programmes keep mother-to-child transmission rates at less than 2%. However, in developing countries, where transmission rates are 25-40%, interventions are available to only 5-10% of women. Children with untreated natural infection progress rapidly to disease, especially in resource-poor settings where mortality is greater than 50% by 2 years of age. As in adult infection, antiretroviral therapy has the potential to rewrite the natural history of HIV, but is accessible only to a small number of children needing therapy. We focus on the clinical and immunological features of HIV that are specific to paediatric infection, and the formidable challenges ahead to ensure that all children worldwide have access to interventions that have proved successful in developed countries. ER - TY - JFULL T1 - MicroRNA-124a regulates Foxa2 expression and intracellular signaling in pancreatic beta-cell lines. A1 - Baroukh, N A1 - Ravier, MA A1 - Loder, MK A1 - Hill, EV A1 - Bounacer, A A1 - Scharfmann, R A1 - Rutter, GA A1 - Van Obberghen, E J1 - J Biol Chem Y1 - 2007/07/06/ VL - 282 SN - 0021-9258 SP - 19575 EP - 19588 N2 - MicroRNAs (miRNAs) are short non-coding RNAs that have been implicated in fine-tuning gene regulation, although the precise roles of many are still unknown. Pancreatic development is characterized by the complex sequential expression of a gamut of transcription factors. We have performed miRNA expression profiling at two key stages of mouse embryonic pancreas development, e14.5 and e18.5. miR-124a2 expression was strikingly increased at e18.5 compared with e14.5, suggesting a possible role in differentiated beta-cells. Among the potential miR-124a gene targets identified by biocomputation, Foxa2 is known to play a role in beta-cell differentiation. To evaluate the impact of miR-124a2 on gene expression, we overexpressed or down-regulated miR-124a2 in MIN6 beta-cells. As predicted, miR-124a2 regulated Foxa2 gene expression, and that of its downstream target, pancreatic duodenum homeobox-1 (Pdx-1). Foxa2 has been described as a master regulator of pancreatic development and also of genes involved in glucose metabolism and insulin secretion, including the ATP-sensitive K(+) (K(ATP)) channel subunits, Kir6.2 and Sur-1. Correspondingly, miR-124a2 overexpression decreased, and anti-miR-124a2 increased Kir6.2 and Sur-1 mRNA levels. Moreover, miR-124a2 modified basal and glucose- or KCl-stimulated intracellular free Ca(2+) concentrations in single MIN6 and INS-1 (832/13) beta-cells, without affecting the secretion of insulin or co-transfected human growth hormone, consistent with an altered sensitivity of the beta-cell exocytotic machinery to Ca(2+). In conclusion, whereas the precise role of microRNA-124a2 in pancreatic development remains to be deciphered, we identify it as a regulator of a key transcriptional protein network in beta-cells responsible for modulating intracellular signaling. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17462994&query_hl=1 ER - TY - JFULL T1 - TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. A1 - Cauchi, S A1 - El Achhab, Y A1 - Choquet, H A1 - Dina, C A1 - Krempler, F A1 - Weitgasser, R A1 - Nejjari, C A1 - Patsch, W A1 - Chikri, M A1 - Meyre, D A1 - Froguel, P J1 - J Mol Med Y1 - 2007/07// VL - 85 SN - 0946-2716 SP - 777 EP - 782 N2 - TCF7L2 variants have been consistently associated with type 2 diabetes (T2D) in populations of different ethnic descent. Among them, the rs7903146 T allele is probably the best proxy to evaluate the effect of this gene on T2D risk in additional ethnic groups. In the present study, we investigated the association between the TCF7L2 rs7903146 polymorphism and T2D in Moroccans (406 normoglycemic individuals and 504 T2D subjects) and in white Austrians (1,075 normoglycemic individuals and 486 T2D subjects). Then, we systematically reviewed the association of this single nucleotide polymorphism (SNP) with T2D risk in a meta-analysis, combining our data with data from previous studies. The allelic odds ratios (ORs) for T2D were 1.56 [1.29-1.89] (p = 2.9 x 10(-6)) and 1.52 [1.29-1.78] (p = 3.0 x 10(-7)) in Moroccans and Austrians, respectively. No heterogeneity was found between these two different populations by Woolf test (chi (2) = 0.04, df = 1, p = 0.84). We found 28 original published association studies dealing with the TCF7L2 rs7903146 polymorphism in T2D. A meta-analysis was then performed on 29,195 control subjects and 17,202 cases. No heterogeneity in genotypic distribution was found (Woolf test: chi (2) = 31.5, df = 26, p = 0.21; Higgins statistic: I2 = 14.1%). A Mantel-Haenszel procedure was then performed to provide a pooled odds ratio (OR) of 1.46 [1.42-1.51] (p = 5.4 x 10(-140)). No publication bias was detected, using the conservative Egger's regression asymmetry test (t = -1.6, df = 25, p = 0.11). Compared to any other gene variants previously confirmed by meta-analysis, TCF7L2 can be distinguished by its tremendous reproducibility of association with T2D and its OR twice as high. In the near future, large-scale genome-wide association studies will fully extend the genome coverage, potentially delivering other common diabetes-susceptibility genes like TCF7L2. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17476472&query_hl=1 ER - TY - JFULL T1 - Cytotoxic killing and immune evasion by repair A1 - Chan, C A1 - George, AJT A1 - Stark, J J1 - J STAT PHYS Y1 - 2007/07// VL - 128 SN - 0022-4715 SP - 393 EP - 411 N2 - The interaction between the immune system and pathogens is a complex one, with pathogens constantly developing new ways of evading destruction by the immune system. The immune system's task is made even harder when the pathogen in question is an intra-cellular one (such as a virus or certain bacteria) and it is necessary to kill the infected host cell in order to eliminate the pathogen. This causes damage to the host, and such killing therefore needs to be carefully controlled, particularly in tissues with poor regenerative potential, or those involved in the immune response itself. Host cells therefore possess repair mechanisms which can counteract killing by immune cells. These in turn can be subverted by pathogens which up-regulate the resistance of infected cells to killing. In this paper, we explore the hypothesis that this repair process plays an important role in determining the efficacy of evasion and escape from immune control. We model a situation where cytotoxic T lymphocytes (CTL) and natural killer (NK) cells kill pathogen-infected and turnout cells by directed secretion of preformed granules containing perforin and granzymes. Resistance to such killing can be conferred by the expression of serine protease inhibitors (serpins). These are utilized by several vitally infected and tumour cells, as well as playing a role in the protection of host bystander, immune and immune-privileged cells. We build a simple stochastic model of cytotoxic killing, where serpins can neutralize granzymes stoichiometrically by forming an irreversible complex, and the survival of the cell is determined by the balance between serpin depletion and replenishment, which in its simplest form is equivalent to the well known shot noise process. We use existing analytical results for this process, and additional simulations to analyse the effects of repair on cytotoxic killing. We then extend the model to the case of a replicating target cell population, which gives a branching process coupled to shot noise. We show how the process of repair can have a major impact on the dynamics of pathogen evasion and escape of tumour cells from immune surveillance. ER - TY - JFULL T1 - Anti-LFA-1 monotherapy prevents neointimal formation in a murine model of transplant intimal hyperplasia. A1 - Soleimani, B A1 - Wieczorek, G A1 - Katopodis, A A1 - Zenke, G A1 - George, AJ A1 - Hornick, PI A1 - Weitz-Schmidt, G J1 - J Heart Lung Transplant Y1 - 2007/07// VL - 26 SN - 1557-3117 SP - 724 EP - 731 N2 - BACKGROUND: Cardiac allograft vasculopathy (CAV) is the pre-eminent cause of late cardiac allograft failure. It is characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). To date, blockade of the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) has been shown to be effective in preventing TIH in experimental models of transplantation, but only when combined with other immunosuppressants. In this study we explored the impact of monotherapy against LFA-1 in a carotid artery allograft model of TIH. METHODS: B10A(2R) (H-2(h2)) mice were used as donors and C57BL/6 (H-2(b)) mice used as recipients. The recipients were treated with a monoclonal antibody against LFA-1alpha (M17/4) or isotype-matched control immunoglobulin. Grafts were harvested after 35 days and analyzed by histomorphometry and immunohistochemistry. Blood samples were taken and analyzed by differential cell count and alloantibody levels. RESULTS: We found that treatment with M17/4 resulted in a significant reduction in TIH compared with controls. Immunostaining revealed that LFA-1alpha blockade inhibited CD45+ leukocyte infiltration, prevented intimal smooth muscle cell (SMC) proliferation, and preserved the medial SMC population. Finally, we demonstrated a reduction in the serum alloantibody titer in the group treated with anti-LFA-1alpha when compared with controls. CONCLUSIONS: We have demonstrated for the first time that LFA-1alpha blockade on its own can prevent development of TIH in an experimental model. The concept of modulating LFA-1alpha-mediated leukocyte migration and T-cell activation may therefore be of relevance to clinical cardiac transplantation and, as such, represents a potential target for therapeutic intervention against clinical CAV. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17613404&query_hl=1 ER - TY - JFULL T1 - Leptin predicts the development of diabetes in Mauritian men, but not women: a population-based study. A1 - Söderberg, S A1 - Zimmet, P A1 - Tuomilehto, J A1 - Chitson, P A1 - Gareeboo, H A1 - Alberti, KG A1 - Shaw, JE J1 - Int J Obes (Lond) Y1 - 2007/07// VL - 31 SN - 0307-0565 SP - 1126 EP - 1133 N2 - OBJECTIVE: To determine if levels of the adipocyte-derived hormone, leptin, predict the development of type 2 diabetes. METHODS: Population-based surveys were undertaken in the multiethnic nation of Mauritius in 1987, 1992 and 1998. Questionnaires, anthropometric measurements, and a 2-h 75-g oral glucose tolerance test were included. A cohort of 2330 participants who were free of diabetes, aged 25-79 years in 1987, and who were followed-up in 1992 and 1998 was studied. Serum leptin was measured in baseline samples. Glucose tolerance was classified according to WHO (World Health Organization) 1999 criteria. RESULTS: In total, 456 subjects developed diabetes over 11 years with similar incidences in all ethnic groups (P=0.2). Baseline leptin correlated positively with anthropometric measurements, fasting and postload insulin and homeostasis model assessment indices (all P<0.001), and inversely with subsequent weight increase. Participants with incident diabetes had higher serum levels of leptin at baseline than those remaining nondiabetic (P<0.001). After adjustment for confounders, high leptin levels and high leptin/body mass index ratio were independently associated with incident diabetes over 11 years in men (odds ratio for top versus bottom quartile of leptin 2.18; 95% CI: 1.09-4.35), but not in women. CONCLUSION: We conclude that high leptin levels are associated with the future development of diabetes, and the association is independent of other factors in men, but not in women. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17325688&query_hl=1 ER - TY - JFULL T1 - Mechanisms of disease: lessons from ethnicity in the role of triglyceride metabolism in ischemic heart disease. A1 - Godsland, IF A1 - Johnston, DG A1 - Chaturvedi, N J1 - Nat Clin Pract Endocrinol Metab Y1 - 2007/07// VL - 3 SN - 1745-8374 SP - 530 EP - 538 N2 - Mean risk factor levels in various ethnic groups illustrate the potential importance of triglyceride metabolism in the risk for ischemic heart disease (IHD). Serum triglyceride concentrations are a surrogate for a range of potentially atherogenic disturbances in lipoprotein species, including increased concentrations of remnants of VLDL and chylomicron metabolism, increased small, dense LDL concentrations and reduced HDL concentrations. Differences between at-risk groups in lipoprotein profiles reflect alterations in the metabolism of triglycerides that might be greater than differences observed when only circulating triglyceride concentrations are measured. This atherogenic lipoprotein profile is typically found in association with increased visceral fat, insulin resistance and type 2 diabetes and might be a characteristic of Asian Indian ethnicity. By contrast, despite being relatively insulin resistant, Afro-Caribbean men in the UK have a low risk of IHD and lack the adverse lipoprotein profile. This could result from secretion of relatively large proportions of their VLDL as small, triglyceride-poor particles, levels of which are not augmented in response to loss of insulin action. These considerations re-endorse the potential importance of triglyceride metabolism in IHD and present opportunities for identifying useful areas in which drug targets for reducing IHD risk can be sought. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17581622&query_hl=1 ER - TY - JFULL T1 - Measurement of estrone sulfate in postmenopausal women: comparison of direct RIA and GC-MS/MS methods for monitoring response to endocrine therapy in women with breast cancer. A1 - Stanway, SJ A1 - Purohit, A A1 - Reed, MJ J1 - Anticancer Res Y1 - 2007/07// VL - 27 SN - 0250-7005 SP - 2765 EP - 2767 N2 - BACKGROUND: High concentrations of estrone sulfate (EIS) are present in serum of pre- and postmenopausal women. Most assays for this estrogen conjugate involve enzyme hydrolysis and chromatographic purification prior to RIA. We have compared concentrations of serum EIS in postmenopausal women measured by direct RIA or GC-MS/MS methods. PATIENTS AND METHODS: We analysed serum EIS concentrations using a direct 'ultrasensitive' RIA. Serum EIS concentrations were also measured by GC-MS/MS in which estrone conjugates are isolated using a solid-phase technique after which enzyme hydrolysis is employed to liberate estrone prior to GC-MS/MS analysis. RESULTS: We analysed 32 serum samples collected from 8 postmenopausal women participating in a Phase I trial of the steroid sulfatase inhibitor 667 COUMA TE. Concentrations of E1S were 998+/-86 pmol/l (mean +/- sem) and 912+/-114 pmol/l as measured by direct RIA and GC-MS/MS methods respectively. There was a highly significant correlation (r=0.96, p<0.001) between concentrations of EIS measured by the different methods. CONCLUSION: We conclude that the direct 'ultrasensitive' RIA for the measurement of serum EIS provides a reliable method for assaying serum concentrations of this estrogen conjugate and should be useful in monitoring the response to endocrine therapy in postmenopausal women with hormone-dependent breast cancer. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17695445&query_hl=1 ER - TY - JFULL T1 - Neoglycolipid Probes Prepared via Oxime Ligation for Microarray Analysis of Oligosaccharide-Protein Interactions. A1 - Liu, Y A1 - Feizi, T A1 - Campanero-Rhodes, MA A1 - Childs, RA A1 - Zhang, Y A1 - Mulloy, B A1 - Evans, PG A1 - Osborn, HM A1 - Otto, D A1 - Crocker, PR A1 - Chai, W J1 - Chem Biol Y1 - 2007/07// VL - 14 SN - 1074-5521 SP - 847 EP - 859 N2 - Neoglycolipid technology is the basis of a microarray platform for assigning oligosaccharide ligands for carbohydrate-binding proteins. The strategy for generating the neoglycolipid probes by reductive amination results in ring opening of the core monosaccharides. This often limits applicability to short-chain saccharides, although the majority of recognition motifs are satisfactorily presented with neoglycolipids of longer oligosaccharides. Here, we describe neoglycolipids prepared by oxime ligation. We provide evidence from NMR studies that a significant proportion of the oxime-linked core monosaccharide is in the ring-closed form, and this form selectively interacts with a carbohydrate-binding protein. By microarray analyses we demonstrate the effective presentation with oxime-linked neoglycolipids of (1) Lewis(x) trisaccharide to antibodies to Lewis(x), (2) sialyllactose analogs to the sialic acid-binding receptors, siglecs, and (3) N-glycans to a plant lectin that requires an intact N-acetylglucosamine core. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17656321&query_hl=1 ER - TY - JFULL T1 - Gene expression profiling of fibroblasts in response to applied bio-mechanical force A1 - Eastwood, M A1 - Shiwen, X A1 - Bou-Gharios, G A1 - Black, C A1 - Abraham, D J1 - TISSUE ENG Y1 - 2007/07// VL - 13 SN - 1076-3279 SP - 1699 EP - 1699 ER - TY - JFULL T1 - Neutrophil-mediated innate immune resistance to mycobacteria. A1 - Martineau, AR A1 - Newton, SM A1 - Wilkinson, KA A1 - Kampmann, B A1 - Hall, BM A1 - Nawroly, N A1 - Packe, GE A1 - Davidson, RN A1 - Griffiths, CJ A1 - Wilkinson, RJ J1 - J Clin Invest Y1 - 2007/07// VL - 117 SN - 0021-9738 SP - 1988 EP - 1994 N2 - Neutrophils contain antimicrobial peptides with antituberculous activity, but their contribution to immune resistance to tuberculosis (TB) infection has not been previously investigated to our knowledge. We determined differential white cell counts in peripheral blood of 189 adults who had come into contact with patients diagnosed with active TB in London, United Kingdom, and evaluated them for evidence of TB infection and capacity to restrict mycobacterial growth in whole-blood assays. Risk of TB infection was inversely and independently associated with peripheral blood neutrophil count in contacts of patients diagnosed with pulmonary TB. The ability of whole blood to restrict growth of Mycobacterium bovis bacille Calmette Guérin and Mycobacterium tuberculosis was impaired 7.3- and 3.1-fold, respectively, by neutrophil depletion. In microbiological media, human neutrophil peptides (HNPs) 1-3 killed M. tuberculosis. The neutrophil peptides cathelicidin LL-37 and lipocalin 2 restricted growth of the organism, the latter in an iron-dependent manner. Black African participants had lower neutrophil counts and lower circulating concentrations of HNP1-3 and lipocalin 2 than south Asian and white participants. Neutrophils contribute substantially to innate resistance to TB infection, an activity associated with their antimicrobial peptides. Elucidation of the regulation of neutrophil antimicrobial peptides could facilitate prevention and treatment of TB. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17607367&query_hl=1 ER - TY - JFULL T1 - Enhanced ex vivo stimulation of Mycobacterium tuberculosis-specific T cells in human immunodeficiency virus-infected persons via antigen delivery by the Bordetella pertussis adenylate cyclase vector. A1 - Connell, TG A1 - Shey, MS A1 - Seldon, R A1 - Rangaka, MX A1 - van Cutsem, G A1 - Simsova, M A1 - Marcekova, Z A1 - Sebo, P A1 - Curtis, N A1 - Diwakar, L A1 - Meintjes, GA A1 - Leclerc, C A1 - Wilkinson, RJ A1 - Wilkinson, KA J1 - Clin Vaccine Immunol Y1 - 2007/07// VL - 14 SN - 1556-6811 SP - 847 EP - 854 N2 - The genetically detoxified Bordetella pertussis adenylate cyclase is a promising delivery system for immunodominant tuberculosis antigens in gamma interferon release assays. This system has not been evaluated in human immunodeficiency virus (HIV)-infected persons in high tuberculosis prevalence areas. A whole-blood gamma interferon release assay with Mycobacterium tuberculosis antigens (early-secreted antigenic target 6, culture filtrate protein 10, alpha-crystallin 2, and TB10.3) delivered by adenylate cyclase in addition to native tuberculosis antigens (without adenylate cyclase delivery) was evaluated in 119 adults in Khayelitsha Township, Cape Town, South Africa. Results were compared to tuberculin skin test results of 41 HIV-positive and 42 HIV-negative asymptomatic persons, in addition to 36 HIV-positive persons with recently diagnosed smear- or culture-positive pulmonary tuberculosis. Delivery of tuberculosis antigens by adenylate cyclase decreased by 10-fold the amount of antigen required to restimulate T cells. Furthermore, the responses of HIV-positive persons with a low response to native tuberculosis antigens were enhanced when these antigens were delivered by adenylate cyclase. When gamma interferon responses to the tuberculosis antigens (with or without delivery by adenylate cyclase) were combined, a significantly higher number of patients were scored positive than by tuberculin skin testing. Ex vivo responses to tuberculosis antigens delivered by adenylate cyclase are maintained in the context of HIV infection. Our findings suggest that the majority of those in this population are infected with tuberculosis, which is of significant public health importance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17522328&query_hl=1 ER - TY - JFULL T1 - The role of membrane lipid composition and tail structure in virus host cell association, entry, and infection. A1 - Ewers, H A1 - Bacia, K A1 - Chai, W A1 - Schwarzmann, G A1 - Feizi, T A1 - Schwille, P A1 - Smith, AE A1 - Helenius, A J1 - J GEN PHYSIOL Y1 - 2007/07// VL - 130 SN - 0022-1295 SP - 3A EP - 3A ER - TY - JFULL T1 - Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. A1 - Jayne, DR A1 - Gaskin, G A1 - Rasmussen, N A1 - Abramowicz, D A1 - Ferrario, F A1 - Guillevin, L A1 - Mirapeix, E A1 - Savage, CO A1 - Sinico, RA A1 - Stegeman, CA A1 - Westman, KW A1 - van der Woude, FJ A1 - de Lind van Wijngaarden, RA A1 - Pusey, CD A1 - European Vasculitis Study Group J1 - J Am Soc Nephrol Y1 - 2007/07// VL - 18 SN - 1046-6673 SP - 2180 EP - 2188 N2 - Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17582159&query_hl=1 ER - TY - JFULL T1 - Frequency of and risk factors for Hiv dementia in an Hiv clinic in sub-Saharan Africa A1 - McGrath, NM A1 - Cooke, GS J1 - Neurology Y1 - 2007/07// VL - 69 SP - 411 EP - 412 ER - TY - JFULL T1 - Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane. A1 - Olofsson, CS A1 - Collins, S A1 - Bengtsson, M A1 - Eliasson, L A1 - Salehi, A A1 - Shimomura, K A1 - Tarasov, A A1 - Holm, C A1 - Ashcroft, F A1 - Rorsman, P J1 - Diabetes Y1 - 2007/07// VL - 56 SN - 0012-1797 SP - 1888 EP - 1897 N2 - Mouse beta-cells cultured at 15 mmol/l glucose for 72 h had reduced ATP-sensitive K+ (K(ATP)) channel activity (-30%), increased voltage-gated Ca2+ currents, higher intracellular free Ca2+ concentration ([Ca2+]i; +160%), more exocytosis (monitored by capacitance measurements, +100%), and greater insulin content (+230%) than those cultured at 4.5 mmol/l glucose. However, they released 20% less insulin when challenged with 20 mmol/l glucose. Glucose-induced (20 mmol/l) insulin secretion was reduced by 60-90% in islets cocultured at 4.5 or 15 mmol/l glucose and either oleate or palmitate (0.5 mmol/l). Free fatty acid (FFA)-induced inhibition of secretion was not associated with any major changes in [Ca2+]i or islet ATP content. Palmitate stimulated exocytosis by twofold or more but reduced K+-induced secretion by up to 60%. Basal (1 mmol/l glucose) K(ATP) channel activity was 40% lower in islets cultured at 4.5 mmol/l glucose plus palmitate and 60% lower in islets cultured at 15 mmol/l glucose plus either of the FFAs. Insulin content decreased by 75% in islets exposed to FFAs in the presence of high (15 mmol/l), but not low (4.5 mmol/l), glucose concentrations, but the number of secretory granules was unchanged. FFA-induced inhibition of insulin secretion was not associated with increased transcript levels of the apoptosis markers Bax (BclII-associated X protein) and caspase-3. We conclude that glucose and FFAs reduce insulin secretion by interference with the exit of insulin via the fusion pore. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17456851&query_hl=1 ER - TY - JFULL T1 - A patient with suspected miscarriage is found to have hypertension, renal failure, and thrombocytopenia: case presentation. A1 - Laing, CM A1 - Roberts, R A1 - Lightstone, L A1 - Graham, A A1 - Cook, TH A1 - Summers, S A1 - Pusey, CD J1 - BMJ Y1 - 2007/06/30/ VL - 334 SN - 1468-5833 SP - 1372 N2 - L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17600028&query_hl=1 ER - TY - JFULL T1 - Assisted peritoneal dialysis--an evolving dialysis modality. A1 - Brown, EA A1 - Dratwa, M A1 - Povlsen, JV J1 - Nephrol Dial Transplant Y1 - 2007/06/25/ SN - 0931-0509 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17595188&query_hl=1 ER - TY - JFULL T1 - Slower CD4 cell decline following cessation of a 3 month course of HAART in primary HIV infection: findings from an observational cohort. A1 - Fidler, S A1 - Fox, J A1 - Touloumi, G A1 - Pantazis, N A1 - Porter, K A1 - Babiker, A A1 - Weber, J J1 - AIDS Y1 - 2007/06/19/ VL - 21 SN - 0269-9370 SP - 1283 EP - 1291 N2 - OBJECTIVE: To investigate the effect of a short course of HAART during primary HIV infection (PHI) on rate of CD4 cell and viral load change. METHODS: Data following HAART cessation from 89 individuals (seroconverting 1999-2003) who chose to take a 3 month course of HAART at PHI were compared with 179 untreated controls in CASCADE, using linear and nonlinear random effects models. Participants were non-randomized but frequency matched for age, sex, risk factor, year of seroconversion and presentation within the first 6 months of seroconversion. Time to CD4 cell count < 350 cells/microl and initiation of clinically indicated antiretroviral therapy (ART) were also compared as competing risks. RESULTS: The rate of CD4 cell decline following therapy cessation appeared significantly slower among treated participants than untreated controls: losses of 51 cells/microl [95% confidence interval (CI), 32-69] and 77 cells/microl (95% CI, 65-89), respectively, 3 years after seroconversion (P = 0.011). Based on extrapolated data, viral loads also differed significantly at this point (4.09 and 4.53 copies/ml, respectively). At 2 years, there was no significant difference in mean viral load levels: 4.31 copies/ml (95% CI, 4.14-4.48) and 4.47 copies/ml (95% CI, 4.28-4.66), respectively. CASCADE seroconverters were more likely to reach CD4 cell count < 350 cells/microl or initiate clinically indicated ART (hazard ratio, 1.45; 95% CI, 1.02-2.05; P = 0.039). CONCLUSION: A short course of ART at PHI may delay CD4 cell decline. Confirmation of this requires a randomized clinical trial powered to address definitively the role of ART intervention in PHI (currently underway through SPARTAC). L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17545704&query_hl=1 ER - TY - JFULL T1 - High frequency of rapid immunological progression in African infants infected in the era of perinatal HIV prophylaxis. A1 - Mphatswe, W A1 - Blanckenberg, N A1 - Tudor-Williams, G A1 - Prendergast, A A1 - Thobakgale, C A1 - Mkhwanazi, N A1 - McCarthy, N A1 - Walker, BD A1 - Kiepiela, P A1 - Goulder, P J1 - AIDS Y1 - 2007/06/19/ VL - 21 SN - 0269-9370 SP - 1253 EP - 1261 N2 - OBJECTIVES: To determine the natural history of HIV infection following peripartum single-dose nevirapine (sd-NVP) prophylaxis in a resource-limited country, and to assess implications for antiretroviral therapy (ART) roll-out programmes. METHODS: Infants of HIV-infected mothers in KwaZulu-Natal, South Africa, were tested on days 1 and 28 to detect intrauterine (IU) and intrapartum (IP) infection. Infant follow-up included monthly viral load and CD4 cell measurement. ART was initiated at infant CD4 cell% < or = 20%. RESULTS: In 740 infants born to 719 HIV-infected women, mother-to-child transmission (MTCT) was 10.3% (69% IU, 31% IP). Median viral load was higher in mothers of infants infected IP than IU (279 000 versus 86 600 copies/ml; P = 0.039) and lower in mothers of uninfected infants (median 26 750 copies/ml; P < 0.001). Peak viraemia was higher in infants infected IP than IU (5 160 000 versus 984 000 copies/ml; P < 0.001). Median viral load at birth in IU-infected infants (155 000 copies/ml) fell 1.4 log to 6510 copies/ml by day 5 and was beneath the detection limit using dried blood spot analysis in 38% of infants. CD4 cell% declined rapidly, to < or = 20% in 70% and < or = 25% in 85% [current World Health Organization (WHO) criteria for initiating ART] of infants by 6 months. CONCLUSIONS: MTCT was reduced by sd-NVP through an effect on IP transmission. Where MTCT occurred despite NVP, two-thirds of transmissions arose IU; IP-infected babies were born to mothers with very high viral load. Disease progression was particularly rapid, 85% infants meeting WHO criteria for ART within 6 months. These findings argue for more effective MTCT-prevention programmes in resource-limited countries. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17545701&query_hl=1 ER - TY - JFULL T1 - IgM and IgA anti-erythrocyte autoantibodies induce anemia in a mouse model through multivalency-dependent hemagglutination but not through complement activation. A1 - Baudino, L A1 - Fossati-Jimack, L A1 - Chevalley, C A1 - Martinez-Soria, E A1 - Shulman, MJ A1 - Izui, S J1 - Blood Y1 - 2007/06/15/ VL - 109 SN - 0006-4971 SP - 5355 EP - 5362 N2 - By generating IgM and IgA switch variants of the 34-3C IgG2a anti-red blood cell (RBC) autoantibody, we evaluated the pathogenic activity of these 2 isotypes in view of the Fc-associated effector functions (ie, complement activation and polyvalency-dependent agglutination). We found that polymeric forms of 34-3C IgM and IgA anti-RBC autoantibody were as pathogenic as IgG2a, which was the most pathogenic among 4 different IgG subclasses, whereas their monomeric variants completely lacked pathogenic effects. Histological examination showed that 34-3C IgM and IgA autoantibodies caused anemia as a result of multivalency-dependent hemaggultination and subsequent sequestration of RBC in the spleen, in contrast to Fc receptor- and complement receptor-mediated erythrophagocytosis by Kupffer cells with IgG isotypes. In addition, the development of anemia induced by IgM and IgA isotypes of 34-3C antibody and by 2 additional IgM anti-RBC monoclonal autoantibodies was not inhibited at all in C3-deficient mice, indicating the lack of involvement of complement activation in the pathogenesis of IgM- and IgA-induced anemia. Our data demonstrate a remarkably high pathogenic potential of polymeric forms of IgM and IgA anti-RBC autoantibodies due to their ability to induce hemagglutination but completely independent of complement activation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17317854&query_hl=1 ER - TY - JFULL T1 - Clinical, immunological, and epidemiological importance of antituberculosis T cell responses in HIV-infected Africans A1 - Rangaka, MX A1 - Diwakar, L A1 - Seldon, R A1 - van Cutsem, G A1 - Meintjes, GA A1 - Morroni, C A1 - Mouton, P A1 - Shey, MS A1 - Maartens, G A1 - Wilkinson, KA A1 - Wilkinson, RJ J1 - CLIN INFECT DIS Y1 - 2007/06/15/ VL - 44 SN - 1058-4838 SP - 1639 EP - 1646 N2 - Background. Human immunodeficiency virus (HIV)-associated tuberculosis is a major cause of mortality in Africa. The assay of T cell interferon-gamma released in response to antigens of greater specificity than purified protein derivative is a useful improvement over the Mantoux tuberculin skin test, but few studies have evaluated interferon gamma secretion in HIV-infected individuals.Methods. Mycobacterium tuberculosis antigen-specific interferon-gamma secretion was assessed by whole blood assay and enzyme-linked immunospot, which were compared with the Mantoux tuberculin skin test in HIV-infected and HIV-uninfected individuals without active tuberculosis and HIV-infected patients with pulmonary tuberculosis in Khayelitsha, South Africa.Results. The skin test and whole blood assay responses to purified protein derivative in HIV-positive subjects were decreased, compared with responses in HIV-negative subjects (P < .001). By contrast, the responses to M. tuberculosis antigens (early secreted antigenic target 6, culture filtrate protein 10, TB10.3, and alpha-crystallin 2) were less affected, indicating a high prevalence of latent tuberculosis (similar to 80%) in both HIV-negative and HIV-positive subject groups. Whole blood assay responses did not differ between the HIV-positive subjects without tuberculosis and HIV-positive subjects with tuberculosis, but the enzyme-linked immunospot method response to early secreted antigenic target 6 and culture filtrate protein 10 was higher in the group of HIV-infected subjects with tuberculosis (P <= .04), although this group had lower CD4(+) cell counts. A ratio of the combined enzyme-linked immunospot method response divided by the CD4(+) cell count of 11.0 had 88% sensitivity and 80% specificity for active pulmonary tuberculosis in HIV-infected individuals.Conclusions. Interferon-gamma release appears to be less impaired than skin testing by HIV coinfection. The novel potential to relate the enzyme-linked immunospot method and CD4(+) cell count to assist diagnosis of active tuberculosis in patients with HIV infection is important and deserves further evaluation. ER - TY - JFULL T1 - Results of endoscopic surgery and intralesional steroid therapy for airway compromise due to tracheobronchial Wegener's Granulomatosis. A1 - Nouraei, SA A1 - Obholzer, R A1 - Ind, PW A1 - Salama, AD A1 - Pusey, CD A1 - Porter, F A1 - Howard, DJ A1 - Sandhu, GS J1 - Thorax Y1 - 2007/06/15/ SN - 0040-6376 N2 - BACKGROUND: Upper airway compromise due to tracheobronchial stenosis commonly occurs in patients with Wegener's Granulomatosis (WG). There is at present no consensus on the optimal management of this life-threatening condition. OBJECTIVE: To assess the results of laryngo-tracheo-bronchoscopy, intralesional steroid therapy, laser surgery and dilatation in managing obstructive tracheobronchial WG. Methods Records of eighteen previously-untreated stridulous patients with obstructive tracheobronchial WG, treated between 2004 and 2006 were prospectively recorded on an airway database and retrospectively reviewed. Information about patient and lesion characteristics and treatment details were recorded. Treatment progress was illustrated using a timeline plot, and intervention-free intervals were calculated with actuarial analysis. RESULTS: There were nine males and the average age at presentation was 40 (16) years [range 13-74]. There were thirteen patients with tracheal, and five patients with tracheal and bronchial lesions. The average tracheal lesion height was 8 (3) mm, located 23 (9) mm below the glottis. There were 1, 10 and 7 Myer-Cotton grade I, II and III lesions respectively. Mean intervention-free interval following minimally-invasive treatment was 26 (2.8) months. Following endobronchial therapy the median intervention-free interval was 22 months (p>0.8 vs. tracheal lesions). No patient required a tracheostomy or endoluminal stenting. CONCLUSIONS: Intralesional steroid therapy and conservative endoluminal surgery is an effective strategy for treating airway compromise due to active tracheal and bronchial WG. It obviates the need for airway bypass or stenting. We recommend the combination of endotracheal dilatation, conservative laser surgery and steroid therapy as the standard of care for treating airway compromise due to obstructive tracheobronchial WG. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17573443&query_hl=1 ER - TY - JFULL T1 - Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. A1 - Pickering, MC A1 - de Jorge, EG A1 - Martinez-Barricarte, R A1 - Recalde, S A1 - Garcia-Layana, A A1 - Rose, KL A1 - Moss, J A1 - Walport, MJ A1 - Cook, HT A1 - de Córdoba, SR A1 - Botto, M J1 - J Exp Med Y1 - 2007/06/11/ VL - 204 SN - 0022-1007 SP - 1249 EP - 1256 N2 - Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype-phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17517971&query_hl=1 ER - TY - JFULL T1 - RESOLVE-ing sepsis in children - not yet! A1 - Nadel, S J1 - Crit Care Y1 - 2007/06/08/ VL - 11 SN - 1466-609X SP - 138 EP - 138 N2 - ABSTRACT: The Researching Severe Sepsis and Organ Dysfunction in Children: A Global Perspective study of drotrecogin alfa activated versus placebo was the largest study of adjunctive therapy ever performed in children with severe sepsis. Despite this, the study failed to show any significant differences in outcome between the treatment and placebo groups. The results raise questions about how we should perform meaningful clinical trials in relatively rare conditions such as paediatric sepsis, where the easily measurable endpoints (such as death) are infrequent. A radical rethink of the design of such studies is urgently needed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17561989&query_hl=1 ER - TY - JFULL T1 - Atomic resolution insight into host cell recognition by Toxoplasma gondii. A1 - Blumenschein, TM A1 - Friedrich, N A1 - Childs, RA A1 - Saouros, S A1 - Carpenter, EP A1 - Campanero-Rhodes, MA A1 - Simpson, P A1 - Chai, W A1 - Koutroukides, T A1 - Blackman, MJ A1 - Feizi, T A1 - Soldati-Favre, D A1 - Matthews, S J1 - EMBO J Y1 - 2007/06/06/ VL - 26 SN - 0261-4189 SP - 2808 EP - 2820 N2 - The obligate intracellular parasite Toxoplasma gondii, a member of the phylum Apicomplexa that includes Plasmodium spp., is one of the most widespread parasites and the causative agent of toxoplasmosis. Micronemal proteins (MICs) are released onto the parasite surface just before invasion of host cells and play important roles in host cell recognition, attachment and penetration. Here, we report the atomic structure for a key MIC, TgMIC1, and reveal a novel cell-binding motif called the microneme adhesive repeat (MAR). Using glycoarray analyses, we identified a novel interaction with sialylated oligosaccharides that resolves several prevailing misconceptions concerning TgMIC1. Structural studies of various complexes between TgMIC1 and sialylated oligosaccharides provide high-resolution insights into the recognition of sialylated oligosaccharides by a parasite surface protein. We observe that MAR domains exist in tandem repeats, which provide a highly specialized structure for glycan discrimination. Our work uncovers new features of parasite-receptor interactions at the early stages of host cell invasion, which will assist the design of new therapeutic strategies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17491595&query_hl=1 ER - TY - JFULL T1 - Multiple mitochondrial DNA deletions in monozygotic twins with OPMD. A1 - Muqit, MM A1 - Larner, AJ A1 - Sweeney, MG A1 - Sewry, C A1 - Stinton, VJ A1 - Davis, MB A1 - Healy, DG A1 - Payne, SJ A1 - Chotai, K A1 - Wood, NW A1 - Lane, RJ J1 - J Neurol Neurosurg Psychiatry Y1 - 2007/06/05/ SN - 1468-330X N2 - BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is caused by expansions of the poly (A) binding protein 2 (PABP2) gene. Previous histological analyses have revealed mitochondrial abnormalities in the muscle of OPMD patients but their significance remains uncertain. OBJECTIVE: We had the rare opportunity to study monozygotic twins with identical expansions of the PABP2 gene but markedly different severity of OPMD. Both had histological features of mitochondrial myopathy. We determined whether mitochondrial DNA abnormalities underlay these changes. METHODS: Clinical information was obtained by history and examination. Muscle biopsies were obtained from each subject and genetic analysis was performed using long range PCR and Southern blotting. RESULTS: We demonstrate for the first time the presence of mitochondrial DNA (mtDNA) deletions by Southern blotting in individuals with OPMD. This correlates with the presence of mitochondrial myopathy in both twins. Moreover, both twins had different mtDNA deletions that may explain their phenotypic differences. CONCLUSION: We hypothesise that mitochondrial dysfunction may occur as a consequence of PABP2 gene mutations, and that this dysfunction may affect the phenotypic manifestations of OPMD. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17550990&query_hl=1 ER - TY - JFULL T1 - Genes expressed by both mesangial cells and bone marrow-derived cells underlie genetic susceptibility to crescentic glomerulonephritis in the rat. A1 - Smith, J A1 - Lai, PC A1 - Behmoaras, J A1 - Roufosse, C A1 - Bhangal, G A1 - McDaid, JP A1 - Aitman, T A1 - Tam, FW A1 - Pusey, CD A1 - Cook, HT J1 - J Am Soc Nephrol Y1 - 2007/06// VL - 18 SN - 1046-6673 SP - 1816 EP - 1823 N2 - The Wistar-Kyoto (WKY) rat shows marked susceptibility to crescentic glomerulonephritis. In the model of nephrotoxic nephritis (NTN) that is induced by a small dose of nephrotoxic globulin, WKY rats developed crescents in 80 +/- 2% of glomeruli at day 10, whereas no crescents were seen in Lewis rats. This was associated with marked increase in monocyte chemoattractant protein-1 synthesis in WKY glomeruli. It was posited whether susceptibility depended on circulating cells or intrinsic renal cells. Bone marrow (BM) isografts from WKY to WKY or Lewis to Lewis did not affect susceptibility to NTN. When BM was transferred from WKY to Lewis rats, crescents developed in 35 +/- 9% of glomeruli 10 d after induction of NTN, indicating that susceptibility could be transferred by BM cells. However, crescents were also seen in WKY rats that were given Lewis marrow. For assessment of the contribution of intrinsic renal cells, kidneys from WKY or Lewis rats were transplanted into F1 animals. In NTN, the ratio of crescents in the transplanted kidney to the native kidney was significantly higher for WKY-to-F1 than for Lewis-to-F1 transplants, demonstrating that the kidney itself also influences susceptibility. Mesangial cell responses were then examined in the two strains. Mesangial cells that were derived from WKY rats synthesized significantly more monocyte chemoattractant protein-1 basally and after stimulation with heat-aggregated rabbit IgG or TNF-alpha. These results show that susceptibility to NTN in the WKY rat depends on both circulating and intrinsic renal cells and that there are genetic differences between the strains in mesangial responses to inflammatory stimuli. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17475818&query_hl=1 ER - TY - JFULL T1 - Borrelia burgdorferi binding of host complement regulator factor H is not required for efficient mammalian infection. A1 - Woodman, ME A1 - Cooley, AE A1 - Miller, JC A1 - Lazarus, JJ A1 - Tucker, K A1 - Bykowski, T A1 - Botto, M A1 - Hellwage, J A1 - Wooten, RM A1 - Stevenson, B J1 - Infect Immun Y1 - 2007/06// VL - 75 SN - 0019-9567 SP - 3131 EP - 3139 N2 - The causative agent of Lyme disease, Borrelia burgdorferi, is naturally resistant to its host's alternative pathway of complement-mediated killing. Several different borrelial outer surface proteins have been identified as being able to bind host factor H, a regulator of the alternative pathway, leading to a hypothesis that such binding is important for borrelial resistance to complement. To test this hypothesis, the development of B. burgdorferi infection was compared between factor H-deficient and wild-type mice. Factor B- and C3-deficient mice were also studied to determine the relative roles of the alternative and classical/lectin pathways in B. burgdorferi survival during mammalian infection. While it was predicted that B. burgdorferi should be impaired in its ability to infect factor H-deficient animals, quantitative analyses of bacterial loads indicated that those mice were infected at levels similar to those of wild-type and factor B- and C3-deficient mice. Ticks fed on infected factor H-deficient or wild-type mice all acquired similar numbers of bacteria. Indirect immunofluorescence analysis of B. burgdorferi acquired by feeding ticks from the blood of infected mice indicated that none of the bacteria had detectable levels of factor H on their outer surfaces, even though such bacteria express high levels of surface proteins capable of binding factor H. These findings demonstrate that the acquisition of host factor H is not essential for mammalian infection by B. burgdorferi and indicate that additional mechanisms are employed by the Lyme disease spirochete to evade complement-mediated killing. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17420242&query_hl=1 ER - TY - JFULL T1 - Avoiding hypernatraemic dehydration in healthy term infants. A1 - Modi, N J1 - Arch Dis Child Y1 - 2007/06// VL - 92 SN - 1468-2044 SP - 474 EP - 475 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17515616&query_hl=1 ER - TY - JFULL T1 - Pulmonary Embolism in the Critically Ill A1 - Proudfoot , A A1 - Cocburn , E A1 - Bell, D J1 - Care of the Critically Ill Y1 - 2007/06// VL - 23.3 PB - Theta Press SP - 79 EP - 86 ER - TY - JFULL T1 - Issues in SMA clinical trial design. The International Coordinating Committee (ICC) for SMA Subcommittee on SMA Clinical Trial Design. A1 - Kaufmann, P A1 - Muntoni, F A1 - International Coordinating Committee for SMA Subcommittee on SMA Clinical Trial Design J1 - Neuromuscul Disord Y1 - 2007/06// VL - 17 SN - 0960-8966 SP - 499 EP - 505 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17300938&query_hl=1 ER - TY - JFULL T1 - Risk of HIV transmission in discordant partners. A1 - Fox, J A1 - Fidler, S J1 - J HIV Ther Y1 - 2007/06// VL - 12 SN - 1462-0308 SP - 48 EP - 53 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17641573&query_hl=1 ER - TY - JFULL T1 - A personalised genetic treatment for DMD A1 - Fletcher, S A1 - Adams, AM A1 - Harding, PL A1 - McClorey, G A1 - Muntoni, F A1 - Iversen, PL A1 - Wilton, SD J1 - J GENE MED Y1 - 2007/06// VL - 9 SN - 1099-498X SP - 529 EP - 529 ER - TY - JFULL T1 - Prospective study of sputum induction, gastric washing, and bronchoalveolar lavage for the diagnosis of pulmonary tuberculosis in patients who are unable to expectorate. A1 - Brown, M A1 - Varia, H A1 - Bassett, P A1 - Davidson, RN A1 - Wall, R A1 - Pasvol, G J1 - Clin Infect Dis Y1 - 2007/06/01/ VL - 44 SN - 1537-6591 SP - 1415 EP - 1420 N2 - BACKGROUND: Many adults with pulmonary tuberculosis are unable to expectorate. Gastric washing, sputum induction using nebulized hypertonic saline, and bronchoscopy with bronchoalveolar lavage have all been used to obtain specimens for diagnosis, but to our knowledge, the timing and volume of induced sputum have not been well studied, and these 3 methods have not been compared. METHODS: The study recruited consecutive adult inpatients with chest radiography findings suggestive of tuberculosis who were unable to expectorate. Subjects provided 3 induced sputum samples for culture on day 1 and additional samples on days 2 and 3. In addition, gastric washing specimens were collected on days 1, 2, and 3. A proportion of subjects with negative smear results underwent bronchoalveolar lavage. RESULTS: The study recruited 140 subjects. Among 107 subjects who provided 3 gastric washing specimens and at least 3 induced sputum specimens, 43% had cultures positive for Mycobacterium tuberculosis. Use of 3 induced sputum samples detected more cases than did use of 3 gastric washings (39% vs. 30%; P=.03). Among 79 subjects with culture results for all 5 induced sputum specimens, there was no difference in yield between samples obtained by induced sputum induction performed in a single day or that performed over 3 days (34% vs. 37%; P=.63). There was no association between sputum volume and positive culture results. No additional cases were diagnosed in the 21 patients who underwent bronchoscopy. CONCLUSIONS: Use of 3 induced sputum samples was more sensitive than use of 3 gastric washings for diagnosis of tuberculosis in patients who could not expectorate spontaneously. Use of bronchoscopy with bronchoalveolar lavage did not increase diagnostic sensitivity. Samples could be collected in 1 day, allowing for faster diagnosis, faster initiation of treatment, and shorter hospital stay. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17479935&query_hl=1 ER - TY - JFULL T1 - TLR9 polymorphisms determine murine lymphocyte responses to Helicobacter: results from a genome-wide scan. A1 - Anderson, AE A1 - Worku, ML A1 - Khamri, W A1 - Bamford, KB A1 - Walker, MM A1 - Thursz, MR J1 - Eur J Immunol Y1 - 2007/06// VL - 37 SN - 0014-2980 SP - 1548 EP - 1561 N2 - Immune responses to microorganisms in the gastrointestinal tract must be carefully controlled to avoid disease. Helicobacter are Gram-negative bacteria which cause persistent infection and, in a minority of hosts, peptic ulceration or gastric cancer. Lymphocyte responses are important determinants of the outcome of infection. Therefore, it is important to identify the genetic determinants of lymphocyte responses to this mucosal pathogen. Using a (C57BL/6xBALB/c) F2 mouse model of Helicobacter infection, we mapped a region of linkage for lymphoproliferation to chromosome 9. Analysis of candidate genes in this region revealed variation of DNA sequence and gene expression in the TLR9 gene between C57BL/6 and BALB/c mouse strains. Reporter assays demonstrated higher levels of TLR9 transcriptional activity and increased NF-kappaB activation associated with the C57BL/6 TLR9 promoter and coding sequences. The importance of TLR9 in the control of lymphocyte responses was confirmed by demonstrating that lymphoproliferation and IFN-gamma secretion was diminished in the TLR9-/- mouse. Furthermore, neutrophil infiltration of the gastric epithelium is reduced in the absence of TLR9. Regulation of TLR9 expression and signalling therefore appears to play an important role in the control of lymphocyte responses to Helicobacter and potentially other luminal microorganisms. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17474149&query_hl=1 ER - TY - JFULL T1 - The relationship between P38-MAPK and AMPK during myocardial ischaernia A1 - Jacquet, S A1 - Zarrinpashneh, E A1 - Chavey, A A1 - Leclerc, I A1 - Rutter, GA A1 - Bertrand, L A1 - Marber, MS J1 - J MOL CELL CARDIOL Y1 - 2007/06// VL - 42 SN - 0022-2828 SP - S52 EP - S52 ER - TY - JFULL T1 - Evidence for boosting Mycobacterium tuberculosis-specific IFN-gamma responses at 6 weeks following tuberculin skin testing A1 - Naseer, A A1 - Naqvi, S A1 - Kampmann, B J1 - EUR RESPIR J Y1 - 2007/06// VL - 29 SN - 0903-1936 SP - 1282 EP - 1283 ER - TY - JFULL T1 - Mesangial immune complex glomerulonephritis due to complement factor D deficiency A1 - Abrera-Abeleda, MA A1 - Xu, Y A1 - Pickering, MC A1 - Smith, RJH A1 - Sethi, S J1 - KIDNEY INT Y1 - 2007/06// VL - 71 SN - 0085-2538 SP - 1142 EP - 1147 N2 - Complement factor D is a serine protease essential for the activation of the alternative pathway and is expressed in the kidney, adipocytes, and macrophages. Factor D is found at relatively high levels in glomeruli suggesting that this component of the complement cascade could influence renal pathophysiology. In this study, we utilize mice with a targeted deletion of the activating complement factor D gene and compare these results to mice with targeted deletion of the inhibitory complement factor H gene. Eight-month-old mice with a deleted factor D gene spontaneously develop albuminuria and have reduced creatinine clearance due to mesangial immune complex glomerulonephritis. These mesangial deposits contain C3 and IgM. In contrast to the mesangial location of the immune deposits in the factor D-deficient mice, age-matched factor H-deficient mice develop immune deposits along the glomerular capillary wall. Our observations suggest that complement factor D or alternative pathway activation is needed to prevent spontaneous accumulation of C3 and IgM deposits within the mesangium. Our studies show that the complement factor D gene knockout mice are a novel model of spontaneous mesangial immune complex glomerulonephritis. ER - TY - JFULL T1 - IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37. A1 - Martineau, AR A1 - Wilkinson, KA A1 - Newton, SM A1 - Floto, RA A1 - Norman, AW A1 - Skolimowska, K A1 - Davidson, RN A1 - Sørensen, OE A1 - Kampmann, B A1 - Griffiths, CJ A1 - Wilkinson, RJ J1 - J Immunol Y1 - 2007/06/01/ VL - 178 SN - 0022-1767 SP - 7190 EP - 7198 N2 - Vitamin D deficiency is associated with susceptibility to tuberculosis, and its biologically active metabolite, 1alpha,25 dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), has pleiotropic immune effects. The mechanisms by which 1alpha,25(OH)(2)D(3) protects against tuberculosis are incompletely understood. 1alpha,25(OH)(2)D(3) reduced the growth of mycobacteria in infected human PBMC cultures in a dose-dependent fashion. Coculture with agonists or antagonists of the membrane or nuclear vitamin D receptors indicated that these effects were primarily mediated by the nuclear vitamin D receptors. 1alpha,25(OH)(2)D(3) reduced transcription and secretion of protective IFN-gamma, IL-12p40, and TNF in infected PBMC and macrophages, indicating that 1alpha,25(OH)(2)D(3) does not mediate protection via these cytokines. Although NOS2A was up-regulated by 1alpha,25(OH)(2)D(3), inhibition of NO formation marginally affected the suppressive effect of 1alpha,25(OH)(2)D(3) on bacillus Calmette Guérin in infected cells. By contrast, 1alpha,25(OH)(2)D(3) strongly up-regulated the cathelicidin hCAP-18 gene, and some hCAP-18 polypeptide colocalized with CD14 in 1alpha,25(OH)(2)D(3) stimulated PBMC, although no detectable LL-37 peptide was found in supernatants from similar 1alpha,25(OH)(2)D(3)-stimulated PBMC cultures. A total of 200 mug/ml of the active peptide LL-37, in turn, reduced the growth of Mycobacterium tuberculosis in culture by 75.7%. These findings suggest that vitamin D contributes to protection against TB by "nonclassical" mechanisms that include the induction of antimicrobial peptides. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17513768&query_hl=1 ER - TY - JFULL T1 - Allergy - still a Cinderella subject A1 - Warner, JO J1 - PEDIATR ALLERGY IMMU Y1 - 2007/06// VL - 18 SN - 0905-6157 SP - 273 EP - 273 ER - TY - JFULL T1 - New ABCC8 mutations in relapsing neonatal diabetes and clinical features. A1 - Vaxillaire, M A1 - Dechaume, A A1 - Busiah, K A1 - Cavé, H A1 - Pereira, S A1 - Scharfmann, R A1 - de Nanclares, GP A1 - Castano, L A1 - Froguel, P A1 - Polak, M A1 - SUR1-Neonatal Diabetes Study Group J1 - Diabetes Y1 - 2007/06// VL - 56 SN - 0012-1797 SP - 1737 EP - 1741 N2 - Activating mutations in the ABCC8 gene that encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the pancreatic islet ATP-sensitive K(+) channel (K(ATP) channel) cause both permanent and transient neonatal diabetes. Recently, we have described the novel mechanism where basal Mg-nucleotide-dependent stimulatory action of SUR1 on the Kir6.2 pore is increased. In our present study, we identified six new heterozygous ABCC8 mutations, mainly in patients presenting the transient form of neonatal diabetes (six of eight), with a median duration of initial insulin therapy of 17 months (range 0.5-38.0). Most of these mutations map to key functional domains of SUR1. Whereas Kir6.2 mutations are a common cause of permanent neonatal diabetes and in a few cases associate with the DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome, SUR1 mutations are more frequent in transient (52%) compared with permanent (14%) neonatal diabetes cases screened for ABCC8 in our series. Although ketoacidosis is frequent at presentation, SUR1 mutations associate mainly with transient hyperglycemia, with possible recurrence later in life. One-half of the SUR1 neonatal diabetic patients presented with de novo mutations. In some familial cases, diabetes is not always present in the adult carriers of SUR1 mutations, supporting variability in their clinical expressivity that remains to be fully explained. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17389331&query_hl=1 ER - TY - JFULL T1 - In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. A1 - Zhang, Y A1 - Wallace, DL A1 - de Lara, CM A1 - Ghattas, H A1 - Asquith, B A1 - Worth, A A1 - Griffin, GE A1 - Taylor, GP A1 - Tough, DF A1 - Beverley, PC A1 - Macallan, DC J1 - Immunology Y1 - 2007/06// VL - 121 SN - 0019-2805 SP - 258 EP - 265 N2 - Human natural killer (NK) cells form a circulating population in a state of dynamic homeostasis. We investigated NK cell homeostasis by labelling dividing cells in vivo using deuterium-enriched glucose in young and elderly healthy subjects and patients with viral infection. Following a 24-hr intravenous infusion of 6,6-D(2)-glucose, CD3(-) CD16(+) NK cells sorted from peripheral blood mononuclear cells (PBMC) by fluorescence-activated cell sorter (FACS) were analysed for DNA deuterium content by gas chromatography mass spectrometry to yield minimum estimates for proliferation rate (p). In healthy young adults (n=5), deuterium enrichment was maximal approximately 10 days after labelling, consistent with postmitotic maturation preceding circulation. The mean (+/- standard deviation) proliferation rate was 4 x 3 +/- 2 x 4%/day (equivalent to a doubling time of 16 days) and the total production rate was 15 +/- (7 x 6) x 10(6) cells/l/day. Labelled cells disappeared from the circulation at a similar rate [6 x 9 +/- 4 x 0%/day; half-life (T((1/2))) < 10 days]. Healthy elderly subjects (n=8) had lower proliferation and production rates (P=2 x 5 +/- 1 x 0%/day and 7 x 3 +/- (3 x 7) x 10(6) cells/l/day, respectively; P=0 x 04). Similar rates were seen in patients chronically infected with human T-cell lymphotropic virus type I (HTLV-I) (P=3 x 2 +/- 1 x 9%/day). In acute infectious mononucleosis (n=5), NK cell numbers were increased but kinetics were unaffected (P=2 x 8 +/- 1 x 0%/day) a mean of 12 days after symptom onset. Human NK cells have a turnover time in blood of about 2 weeks. Proliferation rates appear to fall with ageing, remain unperturbed by chronic HTLV-I infection and normalize rapidly following acute Epstein-Barr virus infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17346281&query_hl=1 ER - TY - JFULL T1 - Tef712 regulates glucose-stimulated insulin secretion and insulin gene expression in min6 beta-cells. A1 - Xavier, GDS A1 - Rutter, GA J1 - DIABETES Y1 - 2007/06// VL - 56 SN - 0012-1797 SP - A437 EP - A437 ER - TY - JFULL T1 - Low intensity transplantat regimens facilitate recruitment of donor apecific regulatory T cell which promote heamatopoietic engraftment A1 - Weng, L A1 - Dyson, J A1 - Dazzi, F J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 379 EP - 379 ER - TY - JFULL T1 - FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. A1 - Fanciulli, M A1 - Norsworthy, PJ A1 - Petretto, E A1 - Dong, R A1 - Harper, L A1 - Kamesh, L A1 - Heward, JM A1 - Gough, SC A1 - de Smith, A A1 - Blakemore, AI A1 - Froguel, P A1 - Owen, CJ A1 - Pearce, SH A1 - Teixeira, L A1 - Guillevin, L A1 - Graham, DS A1 - Pusey, CD A1 - Cook, HT A1 - Vyse, TJ A1 - Aitman, TJ J1 - Nat Genet Y1 - 2007/06// VL - 39 SN - 1061-4036 SP - 721 EP - 723 N2 - Naturally occurring variation in gene copy number is increasingly recognized as a heritable source of susceptibility to genetically complex diseases. Here we report strong association between FCGR3B copy number and risk of systemic lupus erythematosus (P = 2.7 x 10(-8)), microscopic polyangiitis (P = 2.9 x 10(-4)) and Wegener's granulomatosis in two independent cohorts from the UK (P = 3 x 10(-3)) and France (P = 1.1 x 10(-4)). We did not observe this association in the organ-specific Graves' disease or Addison's disease. Our findings suggest that low FCGR3B copy number, and in particular complete FCGR3B deficiency, has a key role in the development of systemic autoimmunity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17529978&query_hl=1 ER - TY - JFULL T1 - The safety, efficacy, and pharmacokinetic profile of a switch in antiretroviral therapy to saquinavir, ritonavir, and atazanavir alone for 48 weeks and a switch in the saquinavir formulation. A1 - Winston, A A1 - Mallon, PW A1 - Satchell, C A1 - MacRae, K A1 - Williams, KM A1 - Schutz, M A1 - Law, M A1 - Cooper, DA A1 - Emery, S J1 - Clin Infect Dis Y1 - 2007/06/01/ VL - 44 SN - 1537-6591 SP - 1475 EP - 1483 N2 - BACKGROUND: Toxicities observed with current combination antiretroviral therapy (CART) warrant a search for novel options, such as class-sparing regimens. Ritonavir-boosted double-protease inhibitor (PI)-only regimens are such an option but are prone to pharmacokinetic interactions. METHODS: This 48-week randomized study examined the safety and efficacy of a switch in CART to a once-daily regimen of saquinavir (SQV), ritonavir (RTV), and atazanavir (ATV) that did not include nucleoside reverse-transcriptase inhibitors (NRTIs). The study also assessed the pharmacokinetic profile of a change in the SQV formulation, from 200 mg to 500 mg, in 2 regimens (SQV-RTV twice per day plus NRTIs [arm 1] and SQV-RTV-ATV once per day without NRTIs [arm 2]) in human immunodeficiency virus type 1-infected subjects (plasma human immunodeficiency virus RNA level, <50 copies/mL). Patients underwent an initial SQV formulation change or a CART change to SQV-RTV-ATV with intense pharmacokinetic sampling. All patients were subsequently assigned to receive SQV-RTV-ATV (1500, 100, and 300 mg once per day, respectively) without NRTIs for 48 weeks. The primary end point was the percentage of patients who experienced virologic failure. RESULTS: Of 25 subjects enrolled, scleral icterus was the most common adverse event (3 patients [12.5%]). Three subjects (12.5%) experienced virologic failure; and mean (+/- standard error of the mean) increase in the CD4(+) lymphocyte count was 63 +/- 36 cells/ mu L over 48 weeks (P=.012). The SQV geometric mean area under the time curve parameters were not significantly altered for the 2 SQV formulations (arm 1, 23.32 vs. 18.76 ngxh/mL [geometric mean ratio, 0.80] for the 200-mg vs. 500-mg formulations, respectively; arm 2, 50.31 vs. 44.79 ngxh/mL [geometric mean ratio, 0.88], for the 200-mg vs. 500-mg formulations, respectively). CONCLUSIONS: A CART regimen of SQV-RTV-ATV alone demonstrated sustained virologic efficacy and was associated with significant increases in the CD4(+) lymphocyte count. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17479946&query_hl=1 ER - TY - JFULL T1 - Lack of endothelial cell survivin causes embryonic defects in angiogenesis, cardiogenesis, and neural tube closure A1 - Zwerts, F A1 - Lupu, F A1 - De Vriese, A A1 - Pollefeyt, S A1 - Moons, L A1 - Altura, RA A1 - Jiang, YY A1 - Maxwell, PH A1 - Hill, P A1 - Oh, H A1 - Rieker, C A1 - Collen, D A1 - Conway, SJ A1 - Conway, EM J1 - BLOOD Y1 - 2007/06/01/ VL - 109 SN - 0006-4971 SP - 4742 EP - 4752 N2 - We explored the physiologic role of endothelial cell apoptosis during development by generating mouse embryos lacking the inhibitor of apoptosis protein (IAP) survivin in endothellum. This was accomplished by intercrossing survivin(lox/lox) mice with mice expressing cre recombinase under the control of the endothelial cell specific tiel promoter (tiel-cre mice). Lack of endothelial cell survivin resulted in embryonic lethality. Mutant embryos had prominent and diffuse hemorrhages from embryonic day 9.5 (E9.5) and died before E13.5. Heart development was strikingly abnormal. Survivin-null endocardial lineage cells could not support normal epithelial-mesenchymal transformation (EMT), resulting in hypoplastic endocardial cushions and in utero heart failure. In addition, 30% of mutant embryos had neural tube closure defects (NTDs) that were not caused by bleeding or growth retardation, but were likely due to alterations in the release of soluble factors from endothelial cells that otherwise support neural stem cell proliferation and neurulation. Thus, regulation of endothelial cell survival, and maintenance of vascular integrity by survivin are crucial for normal embryonic angiogenesis, cardiogenesis, and neurogenesis. ER - TY - JFULL T1 - Examining the candidacy of ghrelin as a gene responsible for variation in adult stature in a United Kingdom population with type 2 diabetes. A1 - Gueorguiev, M A1 - Wiltshire, S A1 - Garcia, EA A1 - Mein, C A1 - Lecoeur, C A1 - Kristen, B A1 - Allotey, R A1 - Hattersley, AT A1 - Walker, M A1 - O'rahilly, S A1 - Froguel, P A1 - Grossman, AB A1 - McCarthy, MI A1 - Hitman, GA A1 - Korbonits, M J1 - J Clin Endocrinol Metab Y1 - 2007/06// VL - 92 SN - 0021-972X SP - 2201 EP - 2204 N2 - CONTEXT: Recently, a quantitative trait locus for stature was reported on chromosome 3p26 in patients with type 2 diabetes. OBJECTIVE: Given that ghrelin is a peptide involved in GH release and located on 3p26, we hypothesized that variation within its gene (GHRL) may be responsible for the quantitative trait locus on 3p26. DESIGN: The evidence for linkage around GHRL was refined with the genotyping of an additional four microsatellites (D3S4545, D3S1537, D3S1597, and D3S3611), giving a total of 27 markers, followed by multipoint variance components linkage analysis. Probands from the linkage families were typed for five common single nucleotide polymorphisms (SNPs) within GHRL and tested for association with adult stature using haplotype trend regression. RESULTS: The maximum multipoint evidence for linkage between adult stature and the 27 microsatellites yielded an LOD score of 2.58 (P = 0.0003) between D3S1297 and D3S1304. Five common (frequency of > or =5%) SNPs were typed in the probands [two promoter SNPs (rs27647 and rs26802), two exonic (rs696217 and rs4684677), and one intronic (rs35683)] capturing 80% of the total common variation in GHRL. No association was found between any SNP (or haplotypes thereof) and adult stature. CONCLUSION: Common genetic variation within GHRL is not responsible for variation in adult stature in this population. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17389697&query_hl=1 ER - TY - JFULL T1 - Fatal hypertrophic cardiornyopathy and nemaline myopathy associated with ACTA1 K336E mutation A1 - Marston, S A1 - Bertini, E A1 - Porfirio, A A1 - Graziano, C A1 - Petrini, S A1 - D'Amico, A A1 - Santorelli, FM A1 - Pacileo, G A1 - Sewry, C J1 - J MOL CELL CARDIOL Y1 - 2007/06// VL - 42 SN - 0022-2828 SP - S73 EP - S73 ER - TY - JFULL T1 - Bayesian network analysis of resistance pathways against HIV-1 protease inhibitors. A1 - Deforche, K A1 - Camacho, R A1 - Grossman, Z A1 - Silander, T A1 - Soares, MA A1 - Moreau, Y A1 - Shafer, RW A1 - Van Laethem, K A1 - Carvalho, AP A1 - Wynhoven, B A1 - Cane, P A1 - Snoeck, J A1 - Clarke, J A1 - Sirivichayakul, S A1 - Ariyoshi, K A1 - Holguin, A A1 - Rudich, H A1 - Rodrigues, R A1 - Bouzas, MB A1 - Cahn, P A1 - Brigido, LF A1 - Soriano, V A1 - Sugiura, W A1 - Phanuphak, P A1 - Morris, L A1 - Weber, J A1 - Pillay, D A1 - Tanuri, A A1 - Harrigan, PR A1 - Shapiro, JM A1 - Katzenstein, DA A1 - Kantor, R A1 - Vandamme, AM J1 - Infect Genet Evol Y1 - 2007/06// VL - 7 SN - 1567-1348 SP - 382 EP - 390 N2 - Interpretation of Human Immunodeficiency Virus 1 (HIV-1) genotypic drug resistance is still a major challenge in the follow-up of antiviral therapy in infected patients. Because of the high degree of HIV-1 natural variation, complex interactions and stochastic behaviour of evolution, the role of resistance mutations is in many cases not well understood. Using Bayesian network learning of HIV-1 sequence data from diverse subtypes (A, B, C, F and G), we could determine the specific role of many resistance mutations against the protease inhibitors (PIs) nelfinavir (NFV), indinavir (IDV), and saquinavir (SQV). Such networks visualize relationships between treatment, selection of resistance mutations and presence of polymorphisms in a graphical way. The analysis identified 30N, 88S, and 90M for nelfinavir, 90M for saquinavir, and 82A/T and 46I/L for indinavir as most probable major resistance mutations. Moreover we found striking similarities for the role of many mutations against all of these drugs. For example, for all three inhibitors, we found that the novel mutation 89I was minor and associated with mutations at positions 90 and 71. Bayesian network learning provides an autonomous method to gain insight in the role of resistance mutations and the influence of HIV-1 natural variation. We successfully applied the method to three protease inhibitors. The analysis shows differences with current knowledge especially concerning resistance development in several non-B subtypes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17127103&query_hl=1 ER - TY - JFULL T1 - Distal myopathy caused by homozygous missense mutations in the nebulin gene. A1 - Wallgren-Pettersson, C A1 - Lehtokari, VL A1 - Kalimo, H A1 - Paetau, A A1 - Nuutinen, E A1 - Hackman, P A1 - Sewry, C A1 - Pelin, K A1 - Udd, B J1 - Brain Y1 - 2007/06// VL - 130 SN - 1460-2156 SP - 1465 EP - 1476 N2 - We describe a novel, recessively inherited distal myopathy caused by homozygous missense mutations in the nebulin gene (NEB), in which other combinations of mutations are known to cause nemaline (rod) myopathy (NM). Two different missense mutations were identified in homozygous form in seven Finnish patients from four unrelated families with childhood or adult-onset foot drop. Both mutations, when combined in compound heterozygous form with more disruptive mutations in NEB, are known to cause NM. Hitherto, no patients with NM have been found to have two missense mutations in NEB. Muscle weakness predominantly affected ankle dorsiflexors, finger extensors and neck flexors, a distribution different both from the patterns of weakness seen in NM caused by NEB mutations, and those of the known recessively inherited distal myopathies. Singleton cases need to be distinguished from the Laing type of distal myopathy. Histologically, this myopathy differs from NM in that nemaline bodies were not detectable with routine light microscopy, and they were inconspicuous or absent even with electron microscopy. Rimmed vacuoles, commonly seen in other distal myopathies, were not a feature. We conclude that homozygous missense mutations in NEB cause a novel distal myopathy, predominantly involving lower leg extensor muscles, finger extensors and neck flexors. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17525139&query_hl=1 ER - TY - JFULL T1 - Basolateral P2X4-like receptors regulate the extracellular ATP-stimulated epithelial Na+ channel activity in renal epithelia. A1 - Zhang, Y A1 - Sanchez, D A1 - Gorelik, J A1 - Klenerman, D A1 - Lab, M A1 - Edwards, C A1 - Korchev, Y J1 - Am J Physiol Renal Physiol Y1 - 2007/06// VL - 292 SN - 0363-6127 SP - F1734 EP - F1740 N2 - Extracellular ATP initiates potent effects on sodium transport across renal epithelia through membrane-associated purinergic receptors. Dependent on the location of these receptors, ATP either inhibits or stimulates sodium reabsorption. Using A6 cells, transepithelial electrical resistance measurements, and scanning ion conductance microscopy, we have identified the purinergic receptors involved in the stimulatory action on the epithelial cell basolateral plasma membrane. Addition of the potent P2X(4) receptor agonist 2-methylthio-ATP (2MeSATP) to the basolateral side of the A6 monolayer stimulated amiloride-sensitive sodium conductance and produced similar cell morphological changes to those found with ATPgammaS, aldosterone, or hypotonic stress. The agonist potency order determined by sodium conductance changes of the monolayer was: 2MeSATP >or= ATPgammaS > CTP, a similar agonist potency profile to that of cloned P2X(4) receptors but with higher sensitivity for beta, gamma-methylene-ATP and alpha,beta-methylene-ATP. We further demonstrated that the ATP effect on sodium transport was potentiated by ivermectin, not blocked by suramin and PPADS, enhanced by Zn(2+) but not by Cu(2+), and significantly reduced but not totally inhibited by brilliant blue G. These results led us to conclude that basolateral P2X(4)-like receptors were involved. We suggest that there is a reciprocal purinergic system acting both at a basolateral and apical location for control of Na(+) transport. This requires a mechanism within the cell that leads to either basolateral or apical ATP release to regulate renal tubular function. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17356127&query_hl=1 ER - TY - JFULL T1 - Predictors of progression of coronary artery calcium in type 2 diabetes: The predict study A1 - Elkeles, RS A1 - Rubens, M A1 - Godsland, IF A1 - Nugara, F A1 - Richmond, W A1 - Flather, MD J1 - ATHEROSCLEROSIS SUPP Y1 - 2007/06// VL - 8 SN - 1567-5688 SP - 8 EP - 8 ER - TY - JFULL T1 - Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families. A1 - Graham, DS A1 - Akil, M A1 - Vyse, TJ J1 - Rheumatology (Oxford) Y1 - 2007/06// VL - 46 SN - 1462-0324 SP - 927 EP - 930 N2 - OBJECTIVES: This is a family-based association study to investigate the genetic contribution of tyrosine kinase 2 (TYK2 ) to disease susceptibility in 380 UK systemic lupus erythematosus (SLE) families, consisting of parents and affected offspring. METHODS: Genotyping was performed using the Sequenom platform on DNA from affected individuals and their parents. Haplotypes were constructed using Haploview from the founders, and family-based association was conducted using GENEHUNTER-TDT and Family-Based Association Test. RESULTS: There are two associated haplotypes across TYK2, both carrying alleles with distorted inheritance. One SNP shows individual association to SLE. This is the under-transmitted rare A allele of TYK2 SNP 6 (P = 0.004), which tags the under-transmitted haplotype 2 (P = 0.055). A second SNP shows a trend for association. This is the A allele of TYK2 SNP 13, which is unique to the over-transmitted haplotype 1 (P = 0.014). We defined a 2.8 kb core association region in TYK2, between these two variants, which narrows down the 5.7 kb gap in the study by Sigurdsson et al. (Sigurdsson S, Nordmark G, Goring HH et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005;76:528-37). CONCLUSIONS: We have shown association to SLE from individual SNPs and haplotypes in TYK2. The strongest individual association, which is carried on the associated haplotype, is from TYK2 SNP 6. The variant is located close to an intron/exon boundary, suggesting a role for mis-splicing events in molecular pathogenesis. The associated haplotype also carries a missense mutation at TYK2. Therefore it is likely that the allelic contribution of TYK2 to SLE is complex, our data confirm previous findings and provide additional resolution regarding the causal polymorphisms in this gene. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17384181&query_hl=1 ER - TY - JFULL T1 - Hypogonadal bone loss: sex steroids or gonadotropins? A1 - Williams, GR J1 - Endocrinology Y1 - 2007/06// VL - 148 SN - 0013-7227 SP - 2610 EP - 2612 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17507579&query_hl=1 ER - TY - JFULL T1 - Coexistence in the same family of both focal and diffuse forms of hyperinsulinism A1 - Valayannopoulos, V A1 - Vaxillaire, M A1 - Aigrain, Y A1 - Jaubert, F A1 - Bellanne-Chantelot, C A1 - Ribeiro, MJ A1 - Brunelle, F A1 - Froguel, P A1 - Robert, JJ A1 - Polak, M A1 - Nihoul-Fekete, C A1 - de Lonlay, P J1 - DIABETES CARE Y1 - 2007/06// VL - 30 SN - 0149-5992 SP - 1590 EP - 1592 ER - TY - JFULL T1 - Variation in FTO contributes to childhood obesity and severe adult obesity. A1 - Dina, C A1 - Meyre, D A1 - Gallina, S A1 - Durand, E A1 - Körner, A A1 - Jacobson, P A1 - Carlsson, LM A1 - Kiess, W A1 - Vatin, V A1 - Lecoeur, C A1 - Delplanque, J A1 - Vaillant, E A1 - Pattou, F A1 - Ruiz, J A1 - Weill, J A1 - Levy-Marchal, C A1 - Horber, F A1 - Potoczna, N A1 - Hercberg, S A1 - Le Stunff, C A1 - Bougnères, P A1 - Kovacs, P A1 - Marre, M A1 - Balkau, B A1 - Cauchi, S A1 - Chèvre, JC A1 - Froguel, P J1 - Nat Genet Y1 - 2007/06// VL - 39 SN - 1061-4036 SP - 724 EP - 726 N2 - We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17496892&query_hl=1 ER - TY - JFULL T1 - Burden, features, and outcome of neurological involvement in acute falciparum malaria in Kenyan children. A1 - Idro, R A1 - Ndiritu, M A1 - Ogutu, B A1 - Mithwani, S A1 - Maitland, K A1 - Berkley, J A1 - Crawley, J A1 - Fegan, G A1 - Bauni, E A1 - Peshu, N A1 - Marsh, K A1 - Neville, B A1 - Newton, C J1 - JAMA Y1 - 2007/05/23/ VL - 297 SN - 1538-3598 SP - 2232 EP - 2240 N2 - CONTEXT: Plasmodium falciparum appears to have a particular propensity to involve the brain but the burden, risk factors, and full extent of neurological involvement have not been systematically described. OBJECTIVES: To determine the incidence and describe the clinical phenotypes and outcomes of neurological involvement in African children with acute falciparum malaria. DESIGN, SETTING, AND PATIENTS: A review of records of all children younger than 14 years admitted to a Kenyan district hospital with malaria from January 1992 through December 2004. Neurological involvement was defined as convulsive seizures, agitation, prostration, or impaired consciousness or coma. MAIN OUTCOME MEASURES: The incidence, pattern, and outcome of neurological involvement. RESULTS: Of 58,239 children admitted, 19,560 (33.6%) had malaria as the primary clinical diagnosis. Neurological involvement was observed in 9313 children (47.6%) and manifested as seizures (6563/17,517 [37.5%]), agitation (316/11,193 [2.8%]), prostration (3223/15,643 [20.6%]), and impaired consciousness or coma (2129/16,080 [13.2%]). In children younger than 5 years, the mean annual incidence of admissions with malaria was 2694 per 100,000 persons and the incidence of malaria with neurological involvement was 1156 per 100,000 persons. However, readmissions may have led to a 10% overestimate in incidence. Children with neurological involvement were older (median, 26 [interquartile range {IQR}, 15-41] vs 21 [IQR, 10-40] months; P<.001), had a shorter duration of illness (median, 2 [IQR, 1-3] vs 3 [IQR, 2-3] days; P<.001), and a higher geometric mean parasite density (42.0 [95% confidence interval {CI}, 40.0-44.1] vs 30.4 [95% CI, 29.0-31.8] x 10(3)/microL; P<.001). Factors independently associated with neurological involvement included past history of seizures (adjusted odds ratio [AOR], 3.50; 95% CI, 2.78-4.42), fever lasting 2 days or less (AOR, 2.02; 95% CI, 1.64-2.49), delayed capillary refill time (AOR, 3.66; 95% CI, 2.40-5.56), metabolic acidosis (AOR, 1.55; 95% CI, 1.29-1.87), and hypoglycemia (AOR, 2.11; 95% CI, 1.31-3.37). Mortality was higher in patients with neurological involvement (4.4% [95% CI, 4.2%-5.1%] vs 1.3% [95% CI, 1.1%-1.5%]; P<.001). At discharge, 159 (2.2%) of 7281 patients had neurological deficits. CONCLUSIONS: Neurological involvement is common in children in Kenya with acute falciparum malaria, and is associated with metabolic derangements, impaired perfusion, parasitemia, and increased mortality and neurological sequelae. This study suggests that falciparum malaria exposes many African children to brain insults. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17519413&query_hl=1 ER - TY - JFULL T1 - Glucose is necessary for embryonic pancreatic endocrine cell differentiation. A1 - Guillemain, G A1 - Filhoulaud, G A1 - Da Silva-Xavier, G A1 - Rutter, GA A1 - Scharfmann, R J1 - J Biol Chem Y1 - 2007/05/18/ VL - 282 SN - 0021-9258 SP - 15228 EP - 15237 N2 - Mature pancreatic cells develop during embryonic life from endodermal progenitors, and this developmental process depends on activation of a hierarchy of transcription factors. While information is available on mesodermal signals controlling pancreas development, little is known about environmental factors, such as the levels of nutrients including glucose, that may control this process. Here, we studied the effects of glucose on pancreatic cells development. We used an in vitro model where both endocrine and acinar cells develop from early pancreatic and duodenal homeobox-1 (PDX1)-positive embryonic pancreatic progenitors. We first showed that glucose does not have a major effect on global pancreatic cell proliferation, survival, and acinar cell development. On the other hand, glucose controlled both alpha and beta cell development. Specifically, the surface occupied by insulin-positive cells was 20-fold higher in pancreases cultured in presence than in absence of glucose, and this effect was dose-dependent over the range 0.5-10 mm. Glucose did not appear to control beta cell development by activating the proliferation of early progenitors or beta cells themselves but instead tightly regulated cell differentiation. Thus, glucose did not modify the pattern of expression of Neurogenin3, the earliest marker of endocrine progenitor cells, but was necessary for the expression of the transcription factor NeuroD, a direct target of Neurogenin3 known to be important for proper pancreatic endocrine cell development. We conclude that glucose interferes with the pancreatic endocrine cells development by regulating the transition between Ngn3 and upstream NeuroD. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17376780&query_hl=1 ER - TY - JFULL T1 - A comparison of the behavior of C57BL/6 and C57BL/10 mice A1 - Deacon, RMJ A1 - Thomas, CL A1 - Rawlins, JNP A1 - Morley, BJ J1 - BEHAV BRAIN RES Y1 - 2007/05/16/ VL - 179 SN - 0166-4328 SP - 239 EP - 247 N2 - Selection of an appropriate animal model is a crucial first step in many research programs. The C57BL/6 (B6) mouse is the most widely used inbred mouse strain in biomedical research; this is particularly so in behavioral studies. However, there are several C57BL substrains, all derived from common ancestors. C57BL/10 (B10) mice are superficially almost identical to B6 mice in appearance and behavior and widely used in inflammation and immunology research, yet rarely in behavioral studies. The present study assessed the comparability of behavioral results from these two strains, to determine whether they could be used interchangeably in future behavioral experiments. The results showed that the behavior of B6 mice clearly differed from that of B10 mice: in tests of cognition, species-typical behaviors, and motor coordination the B6 strain performed better. Consequently, B6 mice will probably remain the preferred choice for behavioral studies. Interpretation of results derived from the B10 strain should take into account its particular behavioral characteristics. (c) 2007 Elsevier B.V. All rights reserved. ER - TY - JFULL T1 - Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment. A1 - Weng, L A1 - Dyson, J A1 - Dazzi, F J1 - Proc Natl Acad Sci U S A Y1 - 2007/05/15/ VL - 104 SN - 0027-8424 SP - 8415 EP - 8420 N2 - Low- or reduced-intensity conditioning regimens for allogeneic hemopoietic stem cell transplantation are effective at establishing donor hematopoietic engraftment and host-vs.-graft (HvG) tolerance. We investigated the mechanisms of HvG tolerance induction and maintenance in an animal model in which transplantation of sublethally irradiated female recipients with bone marrow (BM) from syngeneic male donors produces mixed chimerism. Splenocytes from chimeric mice inhibited HY-specific CD8(+) T cell responses both in vitro and in vivo, and their adoptive transfer facilitated donor hematopoietic engraftment. These properties were contained within the CD4(+)CD25(+) population. The conditioning protocol alone led to a proportional expansion of regulatory T cells (T(regs)), but the inhibitory activity was induced only if male BM was infused. The administration of anti-CD25-depleting antibodies to conditioned recipients at time of BM transplantation prevented donor-recipient chimerism but did not affect engraftment if performed after the establishment of chimerism, thus indicating that recipient T(regs) are required for the generation but not the maintenance of HvG tolerance. We conclude that donor-specific T(regs) of recipient origin are recruited when the donor antigens are present during reduced-intensity conditioning-induced T(reg) expansion. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17494756&query_hl=1 ER - TY - JFULL T1 - TCRzetadim lymphocytes define populations of circulating effector cells that migrate to inflamed tissues. A1 - Zhang, Z A1 - Gorman, CL A1 - Vermi, AC A1 - Monaco, C A1 - Foey, A A1 - Owen, S A1 - Amjadi, P A1 - Vallance, A A1 - McClinton, C A1 - Marelli-Berg, F A1 - Isomäki, P A1 - Russell, A A1 - Dazzi, F A1 - Vyse, TJ A1 - Brennan, FM A1 - Cope, AP J1 - Blood Y1 - 2007/05/15/ VL - 109 SN - 0006-4971 SP - 4328 EP - 4335 N2 - The T-cell receptor zeta (TCRzeta) chain is a master sensor and regulator of lymphocyte responses. Loss of TCRzeta expression has been documented in infectious, inflammatory, and malignant diseases, suggesting that it may serve to limit T-cell reactivity and effector responses at sites of tissue damage. These observations prompted us to explore the relationship between TCRzeta expression and effector function in T cells. We report here that TCRzeta(dim) lymphocytes are enriched for antigen-experienced cells refractory to TCR-induced proliferation. Compared to their TCRzeta(bright) counterparts, TCRzeta(dim) cells share characteristics of differentiated effector T cells but use accessory pathways for transducing signals for inflammatory cytokine gene expression and cell contact-dependent pathways to activate monocytes. TCRzeta(dim) T cells accumulate in inflamed tissues in vivo and have intrinsic migratory activity in vitro. Whilst blocking leukocyte trafficking with anti-TNF therapy in vivo is associated with the accumulation of TCRzeta(dim) T cells in peripheral blood, this T-cell subset retains the capacity to migrate in vitro. Taken together, the functional properties of TCRzeta(dim) T cells make them promising cellular targets for the treatment of chronic inflammatory disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17255353&query_hl=1 ER - TY - JFULL T1 - Dichotomous effects of C-C chemokines in HIV-1 pathogenesis. A1 - Ansari, AW A1 - Heiken, H A1 - Moenkemeyer, M A1 - Schmidt, RE J1 - Immunol Lett Y1 - 2007/05/15/ VL - 110 SN - 0165-2478 SP - 1 EP - 5 N2 - Chemokines play a critical role in shaping innate and adaptive immunity. These molecules also participate in maintaining the immune balance in the body. Apart from their regulatory role, these mediators are involved in several inflammatory and autoimmune diseases including viral infection such as HIV-1/AIDS. Chemokine co-receptor CCR5 and CXCR4 and their ligands significantly contribute to HIV-1 disease progression. C-C chemokines such CCL3, CCL4 and CCL5 have been shown to possess antiviral effects by binding to HIV-1 co-receptors. CCL2, a member of the C-C chemokine family, displays a different feature instead. It is a potential enhancer rather than inhibitor of viral replication, a property exhibited by most of the C-C chemokine members. In addition, the role of CCL2 is well established in forming a Th2 type of response by directing differentiation of Th0 cells towards Th2 type, a unique feature of HIV-1 disease. We propose a hypothesis in which the chemotactic nature of CCL2 drives recruitment of target cells to the site of infection as one of the mechanisms operating in vivo that favours viral replication and eventually a high viral load in infected individuals. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17434211&query_hl=1 ER - TY - JFULL T1 - The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita A1 - Mihai, S A1 - Chiriac, MT A1 - Takahashi, K A1 - Thurman, JM A1 - Holers, VM A1 - Zillikens, D A1 - Botto, M A1 - Sitaru, C J1 - J IMMUNOL Y1 - 2007/05/15/ VL - 178 SN - 0022-1767 SP - 6514 EP - 6521 N2 - Epidermolysis bullosa acquisita is a subepidermal blistering disease associated with tissue-bound and circulating autoantibodies against type VII collagen, a major constituent of the dermal-epidermal junction. The passive transfer of Abs against type VII collagen into mice induces a subepidermal blistering disease dependent upon activation of terminal complement components. To further dissect the role of the different complement activation pathways in this model, we injected C1qdeficient, mannan-binding lectin-deficient, and factor B-deficient mice with rabbit Abs against murine type VII collagen. The development and evolution of blistering had a similar pattern in mannan-binding lectin-deficient and control mice and was initially only marginally less extensive in Clq-deficient mice compared with controls. Importantly, factor B-deficient mice developed a delayed and significantly less severe blistering disease compared with factor B-sufficient mice. A significantly lower neutrophilic infiltration was observed in factor B-deficient mice compared with controls and local reconstitution with granulocytes restored the blistering disease in factor B-deficient mice. Our study provides the first direct evidence for the involvement of the alternative Pathway in an autoantibody-induced blistering disease and should facilitate the development of new therapeutic strategies for epidermolysis bullosa acquisita and related autoimmune diseases. The Journal of Immunology, 2007, 178: 6514-6521. ER - TY - JFULL T1 - Preadipocyte response and impairment of differentiation in an inflammatory environment. A1 - Poulain-Godefroy, O A1 - Froguel, P J1 - Biochem Biophys Res Commun Y1 - 2007/05/11/ VL - 356 SN - 0006-291X SP - 662 EP - 667 N2 - Recent reports suggest the potential role of toll-like receptor 4 (TLR4) in initiation of inflammatory responses and fatty acid-induced insulin resistance. We describe here the synthesis of pro-inflammatory products in 3T3-L1 preadipocyte cell line after stimulation with lipopolysaccharide (LPS), a TLR4 agonist. Expression profiles of mRNA coding for IL6, CCL2, CCL5, CCL11, NOS2, and PTGS2 demonstrated a higher responsiveness to LPS of these transcripts in preadipocytes than in fully differentiated adipocytes, confirming inflammatory features of preadipocytes. IL6, CCL2, CCL5 and CCL11 were secreted in 3T3-L1 supernatants within 4 h after LPS stimulation. In addition, continuous exposure to LPS during adipocyte differentiation impaired this process as was demonstrated by analysis of mRNA profiles of lipogenesis enzymes (FABP4, GPD1, LPL), adipokines (adiponectin, resistin, visfatin, leptin), and of the transcription factor PPARgamma. This suggests that toll-like receptor mediated activation could regulate maintenance of preadipocyte status, and inflammatory environment encountered in inflamed white adipose tissue. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17383612&query_hl=1 ER - TY - JFULL T1 - In vivo T lymphocyte dynamics in humans and the impact of human T-lymphotropic virus 1 infection. A1 - Asquith, B A1 - Zhang, Y A1 - Mosley, AJ A1 - de Lara, CM A1 - Wallace, DL A1 - Worth, A A1 - Kaftantzi, L A1 - Meekings, K A1 - Griffin, GE A1 - Tanaka, Y A1 - Tough, DF A1 - Beverley, PC A1 - Taylor, GP A1 - Macallan, DC A1 - Bangham, CR J1 - Proc Natl Acad Sci U S A Y1 - 2007/05/08/ VL - 104 SN - 0027-8424 SP - 8035 EP - 8040 N2 - Human T-lymphotropic virus type 1 (HTLV-1) is a persistent CD4+ T-lymphotropic retrovirus. Most HTLV-1-infected individuals remain asymptomatic, but a proportion develop adult T cell leukemia or inflammatory disease. It is not fully understood how HTLV-1 persists despite a strong immune response or what determines the risk of HTLV-1-associated diseases. Until recently, it has been difficult to quantify lymphocyte kinetics in humans in vivo. Here, we used deuterated glucose labeling to quantify in vivo lymphocyte dynamics in HTLV-1-infected individuals. We then used these results to address four questions. (i) What is the impact of HTLV-1 infection on lymphocyte dynamics? (ii) How does HTLV-1 persist? (iii) What is the extent of HTLV-1 expression in vivo? (iv) What features of lymphocyte kinetics are associated with HTLV-1-associated myelopathy/tropical spastic paraparesis? We found that CD4+CD45RO+ and CD8+CD45RO+ T lymphocyte proliferation was elevated in HTLV-1-infected subjects compared with controls, with an extra 10(12) lymphocytes produced per year in an HTLV-1-infected subject. The in vivo proliferation rate of CD4+CD45RO+ cells also correlated with ex vivo viral expression. Finally, the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis was associated with significantly increased CD4+CD45RO+ cell proliferation. We suggest that there is persistent viral gene expression in vivo, which is necessary for the maintenance of the proviral load and determines HTLV-1-associated myelopathy/tropical spastic paraparesis risk. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17483473&query_hl=1 ER - TY - JFULL T1 - In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol. A1 - Chander, SK A1 - Foster, PA A1 - Leese, MP A1 - Newman, SP A1 - Potter, BV A1 - Purohit, A A1 - Reed, MJ J1 - Br J Cancer Y1 - 2007/05/07/ VL - 96 SN - 0007-0920 SP - 1368 EP - 1376 N2 - Drugs that inhibit growth of tumours and their blood supply could have considerable therapeutic potential. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE) has been shown to inhibit the proliferation of MCF-7 (ER+) breast cancer cells and angiogenesis in vitro. 2-MeOE2bisMATE and its analogue, 17-Cym-2-MeOE2MATE, were investigated for their ability to inhibit in vivo angiogenesis and tumour growth. The mouse Matrigel plug assay for angiogenesis was used to investigate the effect of compounds on neovascularisation and was quantified using a FITC-dextran injection technique. Nude mice bearing tumours derived from MCF-7 cells were used to assess efficacy on tumour growth. Tumour sections were stained for VEGFR-2 and Ki67 to assess tumour angiogenesis and cell proliferation respectively. Matrigel plugs supplemented with basic fibroblast growth factor resulted in increased neovascularisation over 7 days. Oral administration of 2-MeOE2bisMATE for 7 days at 10 or 50 mg kg(-1) significantly reduced neovascularisation to or below control levels respectively. 17-Cym-2-MeOE2MATE at 20 mg kg(-1) was equally effective. 2-MeOE2bisMATE, dosed daily for 21 days, caused a 52% reduction in tumour growth at 5 mg kg(-1) and 38% regression at 20 mg kg(-1). 17-Cym-2-MeOE2MATE (20 mg kg(-1)) reduced tumour growth by 92%. Immunohistochemistry revealed a reduction in angiogenesis and proliferation. Matrigel plug and tumour imaging after FITC-dextran injection indicated that 2-MeOE2bisMATE caused a marked disruption of vasculature. These sulphamoylated oestrogen derivatives have been shown to be potent inhibitors of angiogenesis in vivo. This, together with their ability to inhibit tumour growth, indicates the potential of this new class of drugs for further development for cancer therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17426705&query_hl=1 ER - TY - JFULL T1 - Cytokines in human breast cyst fluid. A1 - Parish, DC A1 - Ghilchik, MW A1 - Day, JM A1 - Eaton, J A1 - Purohit, A A1 - Reed, MJ J1 - J Steroid Biochem Mol Biol Y1 - 2007/05// VL - 104 SN - 0960-0760 SP - 241 EP - 245 N2 - Gross cystic breast disease is a common benign disorder in which palpable cysts occur in the breast and are normally treated by aspiration of the contents. The cysts are classified as either Type 1, containing a high level of potassium ions and a low level of sodium ions, or as Type 2, with low potassium and high sodium ion concentrations. Steroid sulphatase activity in MDA-MB-231 and MCF-7 cell lines is regulated by exogenous breast cyst fluid (BCF), possibly because of cytokines in the BCF. A screening method was used to determine the range of cytokines in eight BCFs, four of each type. This was an array system, which uses antibodies immobilised on a membrane to qualitatively detect 79 different cytokines or growth factors. Nine cytokines were detected well above background levels: all were found in both types of BCF, but only epidermal growth factor (EGF) was higher in Type 1. All the other factors were higher in Type 2 BCF. Two of these cytokines, IL-6 and EGF, have previously been suggested to affect steroid sulphatase expression and several (MIP-1beta, IL-8, NAP-2) are known to affect MCF-7 cell chemotaxis. In addition two cytokines were measured by ELISA in 57 BCFs, and both IL-1beta and IL-13 were found in BCF, with significantly higher amounts of IL-1beta in Type 1 than Type 2 BCF (35.5+/-4.4 pg/ml versus 9.9+/-2.9 pg/ml). L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17467271&query_hl=1 ER - TY - JFULL T1 - Humidity control as a strategy for lattice optimization applied to crystals of HLA-A*1101 complexed with variant peptides from dengue virus. A1 - Chotiyarnwong, P A1 - Stewart-Jones, GB A1 - Tarry, MJ A1 - Dejnirattisai, W A1 - Siebold, C A1 - Koch, M A1 - Stuart, DI A1 - Harlos, K A1 - Malasit, P A1 - Screaton, G A1 - Mongkolsapaya, J A1 - Jones, EY J1 - Acta Crystallogr Sect F Struct Biol Cryst Commun Y1 - 2007/05/01/ VL - 63 SN - 1744-3091 SP - 386 EP - 392 N2 - T-cell recognition of the antigenic peptides presented by MHC class I molecules normally triggers protective immune responses, but can result in immune enhancement of disease. Cross-reactive T-cell responses may underlie immunopathology in dengue haemorrhagic fever. To analyze these effects at the molecular level, the functional MHC class I molecule HLA-A*1101 was crystallized bound to six naturally occurring peptide variants from the dengue virus NS3 protein. The crystals contained high levels of solvent and required optimization of the cryoprotectant and dehydration protocols for each complex to yield well ordered diffraction, a process that was facilitated by the use of a free-mounting system. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17565177&query_hl=1 ER - TY - JFULL T1 - Peritonitis, peritoneal inflammation and membrane permeability: a longitudinal study of dialysate and serum MCP-1 in stable patients on peritoneal dialysis. A1 - Malik, AR A1 - Little, MA A1 - Henriksson, M A1 - Tam, FW A1 - Brown, EA J1 - J Nephrol Y1 - 2007/05// VL - 20 SN - 1121-8428 SP - 340 EP - 349 N2 - BACKGROUND: Increase in peritoneal membrane permeability (D/P) correlates with systemic and peritoneal markers of inflammation and neoangiogenesis. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is a potent chemoattractant and activator of monocytes/macrophages. We measured the serum (sMCP-1) and dialysate MCP-1 (dMCP-1) concentrations of stable peritoneal dialysis (PD) patients and studied various factors affecting MCP-1 production. We also looked at the correlation of dMCP-1 concentrations with change in D/P over 12 months. METHODS: Forty-five stable prevalent and 6 new PD patients (22 CAPD, 29 APD) were studied. Median PD duration was 21 months (range 1-114). D/P was measured by standardized peritoneal equilibration test (PET). Patients with recent peritonitis within 3 months of the start of study were excluded. MCP-1 concentrations were measured in serum, overnight dialysate and post-PET dialysate, both at baseline and at 12 months by ELISA. RESULTS: On univariate analysis, post-PET dMCP-1 concentrations positively correlated with sMCP-1 (p=0.0002), duration of PD (p=0.02), dialysate volume (p=0.001), peritoneal creatinine clearance (p=0.0002) and D/P (p=0.001). There was a negative correlation with residual renal function (p=0.001). dMCP-1 concentrations were higher in patients with past peritonitis (p=0.001). On multivariate analysis, factors independently associated with dMCP-1 were sMCP-1 (p=0.003) and past peritonitis (p=0.001). Thirty patients completed this study, and D/P rose by > 0.1 in 20% patients. dMCP-1 concentrations were higher in baseline and 12-month samples in patients with change in D/P >0.1. CONCLUSIONS: We conclude that dMCP-1 concentrations are related to past peritonitis and serum MCP-1. It is difficult to interpret the relationship of dMCP-1 with change in D/P over time due to the small number of patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17557268&query_hl=1 ER - TY - JFULL T1 - Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation. A1 - Rowbotham, NJ A1 - Hager-Theodorides, AL A1 - Cebecauer, M A1 - Shah, DK A1 - Drakopoulou, E A1 - Dyson, J A1 - Outram, SV A1 - Crompton, T J1 - Blood Y1 - 2007/05/01/ VL - 109 SN - 0006-4971 SP - 3757 EP - 3766 N2 - TCR signal strength is involved in many cell fate decisions in the T-cell lineage. Here, we show that transcriptional events induced by Hedgehog (Hh) signaling reduced TCR signal strength in mice. Activation of Hh signaling in thymocytes in vivo by expression of a transgenic transcriptional-activator form of Gli2 (Gli2DeltaN(2)) changed the outcome of TCR ligation at many stages of thymocyte development, allowing self-reactive cells to escape clonal deletion; reducing transgenic TCR-mediated positive selection; reducing the ratio of CD4/CD8 single-positive (SP) cells; and reducing cell surface CD5 expression. In contrast, in the Shh(-/-) thymus the ratio of CD4/CD8 cells and both positive and negative selection of a transgenic TCR were increased, demonstrating that Shh does indeed influence TCR repertoire selection and the transition from double-positive (DP) to SP cell in a physiological situation. In peripheral T cells, Gli2DeltaN(2) expression attenuated T-cell activation and proliferation, by a mechanism upstream of ERK phosphorylation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17227833&query_hl=1 ER - TY - JFULL T1 - Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3. A1 - Villegas-Mendez, A A1 - Montes, R A1 - Ambrose, LR A1 - Warrens, AN A1 - Laffan, M A1 - Lane, DA J1 - J Thromb Haemost Y1 - 2007/05// VL - 5 SN - 1538-7933 SP - 980 EP - 988 N2 - BACKGROUND: The endothelial cell protein C receptor (EPCR) presents protein C to the thrombin:thrombomodulin complex on the endothelium of large vessels, and enhances the generation of activated protein C (APC) and activation of protease-activated receptor-1. A previous report has demonstrated binding of soluble (s) EPCR to activated neutrophils via surface proteinase 3 (PR3). METHODS: We now report further characterization of this interaction. Activated neutrophils and purified PR3 both decrease endothelial cell (EC) surface EPCR, suggestive of its proteolysis. RESULTS: When added to purified recombinant sEPCR, PR3 produced multiple cleavages, with early products including 20 kDa N-terminal and C-terminal (after Lys(176)) fragments. The binding of active site blocked PR3 to sEPCR was studied by surface plasmon resonance. Estimates of the K(D) of 18.5-102 nM were obtained with heterogeneous binding, suggestive of more than a single interaction site. CONCLUSIONS: This work demonstrates PR3 binding to and proteolysis of EPCR and suggests a mechanism by which anticoagulant and cell protective pathways can be down-regulated during inflammation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17459006&query_hl=1 ER - TY - JFULL T1 - Tibolone and its delta-4, 7alpha-methyl norethisterone metabolite are reversible inhibitors of human aromatase. A1 - Raobaikady, B A1 - Parsons, MF A1 - Reed, MJ A1 - Purohit, A J1 - J Steroid Biochem Mol Biol Y1 - 2007/05// VL - 104 SN - 0960-0760 SP - 154 EP - 160 N2 - Tibolone is used for the treatment of climacteric symptoms and osteoporosis in menopausal women. After ingestion, it is rapidly converted to a number of metabolites including 3alpha- and 3beta-hydroxy derivatives and the delta-4, 7alpha-methylnorethisterone (7alpha-MeNET) metabolite, which is rapidly cleared from circulation. Tibolone and some of its metabolites act in a tissue-selective manner to inhibit steroid sulphatase (STS) and 17beta-hydroxysteroid dehydrogenase Type 1 (17beta-HSD1) activities but also stimulate steroid sulphotransferase and 17beta-HSD2 activities. In the present study we have examined whether the ability of tibolone and its 7alpha-MeNET metabolites to regulate the activities of enzymes involved in oestrogen formation or inactivation extends to another key enzyme involved in oestrogen synthesis, the aromatase, which converts androstenedione to oestrone. Using JEG-3 choriocarcinoma cells, which have a high level of aromatase activity, tibolone and 7alpha-MeNET, but not the 3alpha- or 3beta-hydroxy metabolites, were found to inhibit aromatase activity in intact cells and also lysates prepared from these cells (up to 61% inhibition at 10muM). An investigation into the nature of aromatase inhibition by these compounds revealed that they inhibit aromatase activity by a reversible mechanism. Tibolone and 7alpha-MeNET also inhibited aromatase activity in MCF-7 breast cancer cells, which have a much lower level of aromatase activity than JEG-3 cells. It is concluded that, in addition to inhibiting STS and 17beta-HSD1, tibolone and 7alpha-MeNET may exert some of their tissue-selective effects in regulating oestrogen synthesis by also inhibiting aromatase activity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17467267&query_hl=1 ER - TY - JFULL T1 - Monitoring peripheral blood regulatory T cells on clinically defined groups of kidney transplant recipients. A1 - Sagoo, P A1 - Sawitzki, B A1 - Hernandez-Fuentes, M A1 - Perucha, E A1 - Craciun, L A1 - Brouard, S A1 - Chaprnan, S A1 - Bradeau, C A1 - Peters, B A1 - Roberts, I A1 - Janssen, U A1 - Soulillou, JP A1 - Warrens, AN A1 - Wood, K A1 - Goldman, M A1 - Volk, HD A1 - Lechler, RI J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 340 EP - 340 ER - TY - JFULL T1 - Identification of tolerant patients based on a combinational analysis of foxp3 and aMannosidase transcription. A1 - Sawitzki, BS A1 - Hernandez-Fuentes, M A1 - Sagoo, P A1 - Perucha, E A1 - Lemoine, A A1 - Brouard, S A1 - Chapman, S A1 - Peters, B A1 - Roberts, I A1 - Janssen, U A1 - Soulillou, JP A1 - Warrens, A A1 - Wood, K A1 - Goldman, M A1 - Lechler, R A1 - Volk, HD J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 488 EP - 488 ER - TY - JFULL T1 - Neutrophils as antigen-presenting cells: Bridging innate and adaptive immunity. A1 - Ambrose, LR A1 - Smith, LM A1 - Little, MAP A1 - Dupont, PJ A1 - Warrens, AN J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 412 EP - 412 ER - TY - JFULL T1 - Biomarkers of tolerance in kidney transplants. A1 - Hernandez-Fuentes, MP A1 - Sawitzki, B A1 - Sagoo, P A1 - Craciun, L A1 - Brouard, S A1 - Perucha, E A1 - Chapman, S A1 - Bradeau, C A1 - Peters, B A1 - Roberts, I A1 - Sergeant, R A1 - Janssen, U A1 - Warrens, A A1 - Wood, K A1 - Soulillou, JP A1 - Goldman, M A1 - Volk, HD A1 - Lechler, RI J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 337 EP - 337 ER - TY - JFULL T1 - International Diabetes Federation: a consensus on Type 2 diabetes prevention. A1 - Alberti, KG A1 - Zimmet, P A1 - Shaw, J J1 - Diabet Med Y1 - 2007/05// VL - 24 SN - 0742-3071 SP - 451 EP - 463 N2 - AIMS: Early intervention and avoidance or delay of progression to Type 2 diabetes is of enormous benefit to patients in terms of increasing life expectancy and quality of life, and potentially in economic terms for society and health-care payers. To address the growing impact of Type 2 diabetes the International Diabetes Federation (IDF) Taskforce on Prevention and Epidemiology convened a consensus workshop in 2006. The primary goal of the workshop and this document was the prevention of Type 2 diabetes in both the developed and developing world. A second aim was to reduce the risk of cardiovascular disease in people who are identified as being at a higher risk of Type 2 diabetes. The IDF plan for prevention of Type 2 diabetes is based on controlling modifiable risk factors and can be divided into two target groups: People at high risk of developing Type 2 diabetes. The entire population. CONCLUSIONS: In planning national measures for the prevention of Type 2 diabetes, both groups should be targeted simultaneously with lifestyle modification the primary goal through a stepwise approach. In addition, it is important that all activities are tailored to the specific local situation. Further information on the prevention of diabetes can be found on the IDF website: http://www.idf.org/prevention. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17470191&query_hl=1 ER - TY - JFULL T1 - Flow-PRA characterisarion of de novo Anti-HLA class I donor specific antibodies in patients with apparent 'transplant accommodation'. A1 - Dorling, A A1 - Hingley, S A1 - Clarke, HM J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 345 EP - 345 ER - TY - JFULL T1 - Modification of dendritic cells for the induction of tolerance. A1 - Khan, AH A1 - Harper, JE A1 - Beutelspacher, SC A1 - Lombardi, G A1 - McClure, MO A1 - George, AJT J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 487 EP - 487 ER - TY - JFULL T1 - Mucosal and systemic immune responses in patients with diarrhea due to CS6-expressing enterotoxigenic Escherichia coli. A1 - Qadri, F A1 - Ahmed, T A1 - Ahmed, F A1 - Bhuiyan, MS A1 - Mostofa, MG A1 - Cassels, FJ A1 - Helander, A A1 - Svennerholm, AM J1 - Infect Immun Y1 - 2007/05// VL - 75 SN - 0019-9567 SP - 2269 EP - 2274 N2 - Colonization factor CS6 expressed by enterotoxigenic Escherichia coli (ETEC) is a nonfimbrial polymeric protein. A substantial proportion of ETEC strains isolated from patients in endemic settings and in people who travel to regions where ETEC is endemic are ETEC strains expressing CS6, either alone or in combination with fimbrial colonization factor CS5 or CS4. However, relatively little is known about the natural immune responses elicited against CS6 expressed by ETEC strains causing disease. We studied patients who were hospitalized with diarrhea (n = 46) caused by CS6-expressing ETEC (ETEC expressing CS6 or CS5 plus CS6) and had a disease spectrum ranging from severe dehydration (27%) to moderate or mild dehydration (73%). Using recombinant CS6 antigen, we found that more than 90% of the patients had mucosal immune responses to CS6 expressed as immunoglobulin (IgA) antibody-secreting cells (ASC) or antibody in lymphocyte supernatant (ALS) and that about 57% responded with CS6-specific IgA antibodies in feces. More than 80% of the patients showed IgA seroconversion to CS6. Significant increases in the levels of anti-CS6 antibodies of the IgG isotype were also observed in assays for ASC (75%), ALS (100%), and serum (70%). These studies demonstrated that patients hospitalized with the noninvasive enteric pathogen CS6-expressing ETEC responded with both mucosal and systemic antibodies against CS6. Studies are needed to determine if the anti-CS6 responses protect against reinfection and if protective levels of CS6 immunity are induced by vaccination. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17296752&query_hl=1 ER - TY - JFULL T1 - Advanced diagnostic imaging options in horses with neurological disease that localises to the head A1 - Jose-Cunilleras, E A1 - Piercy, RJ J1 - EQUINE VET EDUC Y1 - 2007/05// VL - 19 SN - 0957-7734 SP - 179 EP - 181 ER - TY - JFULL T1 - Mechanisms of action of TRAIL in inhibiting immune response to alogeneic tissue. A1 - Kumar, R A1 - Herbert, PE A1 - Warrens, AN J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 148 EP - 148 ER - TY - JFULL T1 - Reversal of refractory c4d chronic allograft nephropathy with ritximab. A1 - Galliford, J A1 - Cook, T A1 - Brookes, P A1 - Chan, K A1 - Taube, D A1 - Dorling, A J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 526 EP - 526 ER - TY - JFULL T1 - Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism. A1 - Bassett, JH A1 - O'Shea, PJ A1 - Sriskantharajah, S A1 - Rabier, B A1 - Boyde, A A1 - Howell, PG A1 - Weiss, RE A1 - Roux, JP A1 - Malaval, L A1 - Clement-Lacroix, P A1 - Samarut, J A1 - Chassande, O A1 - Williams, GR J1 - Mol Endocrinol Y1 - 2007/05// VL - 21 SN - 0888-8809 SP - 1095 EP - 1107 N2 - Thyrotoxicosis is an important but under recognized cause of osteoporosis. Recently, TSH deficiency, rather than thyroid hormone excess, has been suggested as the underlying cause. To investigate the molecular mechanism of osteoporosis in thyroid disease, we characterized the skeleton in mice lacking either thyroid hormone receptor alpha or beta (TRalpha(0/0), TRbeta-/-). Remarkably, in the presence of normal circulating thyroid hormone and TSH concentrations, adult TRalpha(0/0) mice had osteosclerosis accompanied by reduced osteoclastic bone resorption, whereas juveniles had delayed endochondral ossification with reduced bone mineral deposition. By contrast, adult TRbeta-/- mice with elevated TSH and thyroid hormone levels were osteoporotic with evidence of increased bone resorption, whereas juveniles had advanced ossification with increased bone mineral deposition. Analysis of T3 target gene expression revealed skeletal hypothyroidism in TRalpha(0/0) mice, but skeletal thyrotoxicosis in TRbeta-/- mice. These studies demonstrate that bone loss in thyrotoxicosis is independent of circulating TSH levels and mediated predominantly by TRalpha, thus identifying TRalpha as a novel drug target in the prevention and treatment of osteoporosis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17327419&query_hl=1 ER - TY - JFULL T1 - Negative pressure ventilation in pediatric critical care setting. A1 - Deep, A A1 - De Munter, C A1 - Desai, A J1 - Indian J Pediatr Y1 - 2007/05// VL - 74 SN - 0973-1679 SP - 483 EP - 488 N2 - Invasive ventilation is associated with both pulmonary and non-pulmonary complications. There has been a renewed interest in the use of negative pressure ventilation (NPV) for various medical conditions to minimise the complications associated with positive pressure ventilation. The routine use of NPV in an ICU setting still requires further studies and research. In this article, the authors review the clinical applications of NPV together with associated risks and limitations. Case reports of patients with cardiac, neuromuscular and respiratory diseases managed with NPV on our unit are described. NPV improved the clinical condition in each of these patients and decreased the requirement for invasive therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17526961&query_hl=1 ER - TY - JFULL T1 - Modulation of dendritic cell function by tissue factor and coagulation proteases. A1 - Shrivastava, S A1 - Dorling, A J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 414 EP - 414 ER - TY - JFULL T1 - Burden of paediatric invasive pneumococcal disease in Europe, 2005. A1 - McIntosh, ED A1 - Fritzell, B A1 - Fletcher, MA J1 - Epidemiol Infect Y1 - 2007/05// VL - 135 SN - 0950-2688 SP - 644 EP - 656 N2 - Within the European Union (EU), documenting the burden of invasive pneumococcal disease (IPD) in infants and children is important for coordinating effective pneumococcal immunization policies. Our objective was to document the burden of IPD in countries of the EU plus Switzerland and Norway. European affiliates of Wyeth Vaccines made available recent epidemiological data on IPD from local disease surveillance programmes, including unpublished sources. Recent literature and websites were also searched to provide as wide a representation as possible. This included OVID and abstracts from a number of international meetings, dating from the year 2000. The reported rates of paediatric IPD per 100000 (age) ranged from a low of 1.7 (<2 years) to 4.2 (2-15 years) in Sweden to a high of 93.5 to 174 (<2 years) to 56.2 (<5 years) in Spain. The percentage of circulating serotypes causing IPD that are covered by 7-valent pneumococcal conjugate vaccine (PCV) IPD serotype coverage ranged from 60% to 80% for European children aged <2 years. Under reporting, differences in reporting methods, antibiotic prescribing and disparities in blood-culturing practices may explain the differences in reported disease incidence. Because of the excellent clinical efficacy of the PCV against IPD, national pneumococcal vaccination programmes in Europe have the potential to prevent much morbidity and mortality. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16959054&query_hl=1 ER - TY - JFULL T1 - Predictive factors for the development of scoliosis in Duchenne muscular dystrophy. A1 - Kinali, M A1 - Main, M A1 - Eliahoo, J A1 - Messina, S A1 - Knight, RK A1 - Lehovsky, J A1 - Edge, G A1 - Mercuri, E A1 - Manzur, AY A1 - Muntoni, F J1 - Eur J Paediatr Neurol Y1 - 2007/05// VL - 11 SN - 1090-3798 SP - 160 EP - 166 N2 - OBJECTIVE: Scoliosis is a frequent complication (68-90%) of Duchenne muscular dystrophy (DMD). Prevention of limb deformities, rehabilitation in knee-ankle-foot-orthoses (KAFOs) and glucocorticoids prolong walking and standing, and might reduce scoliosis. We evaluated possible predictive factors for scoliosis development in a large DMD population. METHODS: Case notes of 123 DMD boys, > or = 17 years, followed at our centre between 1992 and 2002 were reviewed. Univariate analysis was used to relate two outcome measures (age at onset of scoliosis and severity at 17 years) with (i) glucocorticoids treatment; (ii) ages at (a) loss of independent ambulation, (b) rehabilitation into KAFOs, (c) loss of standing, (iii) forced vital capacity (FVC) (%) between 11 and 12 years and (iv) lower limb contractures. RESULTS: In total, 37/123 boys (30%) received intermittent prednisolone (0.75 mg/kg/day, 10 day/month) for a median 1-year (2 months-9 years), starting between 7.7 and 12.4 years (mean 9.5). About 96/123 (78%) were rehabilitated into KAFOs at 10.2+/-1.6 years. Age at loss of ambulation in KAFOs was 12.3+/-1.9 years and at loss of standing 12.8+/-2.1 years. About 95/123 (77%) boys developed scoliosis (Cobb angle >30 degrees ). Mean age+/-S.D. at scoliosis onset was 12.7+/-1.6 years. Forty-three boys (35%) had scoliosis surgery by 15+/-1.2 years. Later age at loss of ambulation (p<0.0001) and longer duration of prednisolone treatment (p=0.01) related to later scoliosis onset. Ages at loss of ambulation and standing were inversely related to scoliosis severity at 17 years (p<0.005). Hip asymmetry and %FVC at 11-12 years were directly related to scoliosis severity (p=0.02). CONCLUSIONS: Our data indicate a significant association between prolonged ambulation and a reduced risk of scoliosis development. Glucocorticoid administration, in our series, appear to be associated with a later onset of scoliosis, but did not alter the severity at 17 years, probably reflecting the shorter overall glucocorticoid exposure in this population. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17257866&query_hl=1 ER - TY - JFULL T1 - Gastrostomy placement in paediatric patients with neuromuscular disorders: indications and outcome. A1 - Ramelli, GP A1 - Aloysius, A A1 - King, C A1 - Davis, T A1 - Muntoni, F J1 - Dev Med Child Neurol Y1 - 2007/05// VL - 49 SN - 0012-1622 SP - 367 EP - 371 N2 - Studies of children with neurodevelopmental disorders have shown that receiving nutrition through a gastrostomy can improve clinical outcomes and quality of life. However, there is little information on gastrostomy and its effect in patients with neuromuscular disorders. A retrospective casenote review of all patients with a gastrostomy, followed-up at the Hammersmith Hospital, London, was undertaken to assess the indications for, and outcomes of, gastrostomy placement. Notes for 32 patients (17 males, 15 females) were reviewed (age range 32mo-31y; median age 12y 5mo). We found three main groups of diagnoses: congenital muscular dystrophy (n=15), structural congenital myopathies (n=11), and other neuromuscular disorders (n=6). Two main patterns of feeding problems were identified before gastrostomy: swallowing difficulties, and nutrition and growth problems. The follow-up period after gastrostomy was from 12 months to 19 years (mean 5y). Weight faltering was reversed in 17 out of 22 patients, and height faltering in 9 out of 14, where data were available. Twenty-six patients had a reduced frequency of chest infections. No significant complication of gastrostomy placement was documented. Twenty-eight patients or theirਠ