TY - BOOK T1 - Methods in Molecular Biology - Comparative Genomics - WebACT: An Online Genome Comparison Suite A1 - Abbott, JC A1 - Aanensen, DM A1 - Bentley, SD ED - Bergman, Nicholas H. Y1 - 2007/07// IS - 1 PB - Humana Press SN - 1-58829-693-8 N2 - - ER - TY - BOOK T1 - “Protein Crystallization Strategies for Structural Genomics” A1 - Naomi E. Chayen ed. ED - Naomi E. Chayen Y1 - 2007/06// VL - 1st PB - International University Line, USA, CY - California USA N2 - - ER - TY - BOOK T1 - Weight-of-evidence for forensic DNA profiles A1 - Balding DJ Y1 - 2005/01// PB - Wiley CY - Chichester UK SN - 0-470-86764-7 N2 - - ER - TY - BOOK T1 - Handbook of Statistical Genetics, 2nd edition A1 - n. ED - Balding DJ; Bishop M; Cannings C Y1 - 2003/// PB - Wiley CY - Chichester SN - 0-470-84829-4 N2 - - ER - TY - BOOK T1 - Genetics of Apoptosis A1 - Grimm SW ED - Grimm S Y1 - 2002/// PB - BIOS Scientific Publishers CY - Oxford UK N2 - - ER - TY - BOOK T1 - The year in rheumatic disorders 2002: special issue: rheumatoid arthritis A1 - Cope AP Y1 - 2002/// SN - 0-9537-3399-8 N2 - - ER - TY - BOOK T1 - Handbook of statistical genetics, 1st edition A1 - n. ED - Balding DJ; Bishop M; Cannings C Y1 - 2001/// PB - Wiley CY - Chichester UK SN - 0-4718-6094-8 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 - CHAP T1 - Automation of non-conventional crystallization techinques for screening and optimization A1 - Naomi E. Chayen ED - Mark R. Sanderson and Jane V. Skelly T2 - Macromolecular Crystallography conventional and high throughput methods Y1 - 2007/08// VL - 1st PB - Oxford university Press CY - UK SP - 45 EP - 58 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 - High throughput optimisation techniques A1 - Chayen N.E. ED - Chayen N.E. T2 - protein Crystallization Strategies for Structural Genomics Y1 - 2007/06// VL - 1st PB - IUL Press CY - Cal USA N2 - - ER - TY - CHAP T1 - Microbulles ciblees pour I'imagerie ultrasonore A1 - Sennoga, CA A1 - Yeh, JS A1 - Seddon, JM A1 - Nourshargh, S A1 - Eckersley, RJ A1 - Haskard, DO A1 - Cosgrove , DO A1 - Nihoyannopoulos, P ED - Tranquart F, Correreas J-M, Bouakaz A T2 - Echographie de Contraste Y1 - 2007/// PB - Springer CY - Paris SP - 321 EP - 328 N2 - - ER - TY - CHAP T1 - Mapping lymphocyte plasma membrane proteins: A proteomic approach A1 - Peirce M J A1 - Saklatvala J A1 - Cope A P A1 - Wait R ED - AP Cope T2 - Arthritis Research: Y1 - 2007/// M2 - 136 PB - Humana Press 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 - Eotaxins A1 - Sabroe, I A1 - Williams, T.J A1 - Pease, J.E ED - Laurent, G. and Shapiro, S. T2 - Encyclopedia of Respiratory Medicine. Y1 - 2006/// PB - Elsevier SN - 0-12-438360-2 N2 - - ER - TY - CHAP T1 - The application of in vivo MRI and MRS in phenomic studies of murine models of disease A1 - Bell, JD ED - G. Webb T2 - Modern Magnetic Resonance Y1 - 2006/// M2 - 2 PB - Springer CY - UK 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 - Gestational trophoblastic disease A1 - Fisher RA A1 - Sebire NJ ED - Moffett A, Loke C, McClaren A T2 - Biology and Pathology of Trophoblast Y1 - 2005/// PB - Cambridge University Press N2 - - ER - TY - CHAP T1 - Non-viral vectors for gene therapy A1 - Davies JC A1 - Alton EWFW ED - Huang L, Hung MC and Wagner E T2 - Airway gene therapy. Y1 - 2005/// VL - 2 M2 - 2 SP - 291 EP - 314 N2 - - ER - TY - CHAP T1 - Quantitative Profiling of Protein-DNA Binding on Microarrays A1 - Ragoussis J A1 - Field S A1 - Udalova IA ED - Bina M T2 - Methods in Molecular Biology, vol. 338: Gene Mapping, Discovery, and Expression: Methods and Protocols Y1 - 2005/// PB - Humana Press Inc CY - USA N2 - - ER - TY - CHAP T1 - Pharmacogenetic issues A1 - Walker MC A1 - Johnson MR A1 - Patsalos PN ED - Majkowski J, Bougeois BFD, Patsalos PN and Mattson RH T2 - Antiepileptic drugs: Combination therapy and interactions Y1 - 2005/// PB - University Press N2 - - ER - TY - CHAP T1 - Protein Crystallization: Automation, Robotization and Miniaturization A1 - Chayen, N.E. ED - Sundstrum, M.; Norin, M.; Edwards, A. T2 - Structural Genomics and High Throughput Structural Biology Y1 - 2005/// PB - CRC Press Taylor and Francis SP - 29 EP - 48 N2 - - ER - TY - CHAP T1 - Molecular basis of hemophilia A A1 - Kemball-Cook, G A1 - Tuddenham, EGD ED - Lee, CA; Berntorp, EE; Hoots, WK T2 - Textbook of Hemophilia Y1 - 2005/// PB - Blackwell CY - Oxford SN - 1 405 12769 4 SP - 19 EP - 26 N2 - - ER - TY - CHAP T1 - Recombination hotspots as a point process. A1 - De Iorio M A1 - de Silva E A1 - Stumpf MPH T2 - Philosophical Transactions of the Royal Society B: Genetic Variation and Human Health Y1 - 2005/// N2 - - 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 - Host recognition by fungal pathogens A1 - Bignell, E. A1 - Rogers, T. ED - Giaconda Sans-Blas and Richard A. Calderone T2 - Pathogenic fungi: Host interactions and emerging strategies for control Y1 - 2004/// PB - Caister Academic Press CY - Norfolk SN - 0-9542464-8-9 SP - 3 EP - 48 N2 - - ER - TY - CHAP T1 - The hypothalamo-pituitary-adrenal axis A1 - John CD A1 - Theogaraj E A1 - Buckingham JC ED - Evers E & Maze M T2 - Anaesthetic Pharmacology: Physiologic Principles and Clinical Practice Y1 - 2004/// PB - Harcourt Health Sciences CY - St Louis, Missouri, USA N2 - - ER - TY - CHAP T1 - Normal Haemostasis A1 - Kemball-Cook, G A1 - Tuddenham, EGD A1 - McVey, JH ED - Hoffbrand, Tuddenham and Catovsky T2 - Postgraduate Haematology Y1 - 2004/// VL - 5th PB - Blackwell CY - Oxford SN - 1 405 10821 5 SP - 783 EP - 807 N2 - - ER - TY - CHAP T1 - Genetic origin and diagnosis of gestational trophoblastic disease A1 - Fisher RA ED - Hancock BW, Newlands ES, Berkowitz RS, Cole L T2 - Gestational Trophoblastic Disease Y1 - 2003/// VL - 2nd PB - http://www.isstd.org SP - 6 EP - 38 N2 - - ER - TY - CHAP T1 - Crystallisation of Membrane Proteins in Oils - Chapter 8 A1 - Chayen, N.E. ED - Iwata, S T2 - Methods and Results in Crystallization of Membrane Proteins Y1 - 2003/// PB - International University Line CY - USA SP - 131 EP - 139 N2 - - ER - TY - CHAP T1 - Regulation of Eosinophil Trafficking in Asthma and Allergy A1 - Pease, J. E. A1 - Weller, C.L. A1 - Williams, T.J. ED - Murphy, P.M. and Horuk, R. T2 - Chemokine Roles in Immunoregulation and Disease. Y1 - 2003/// VL - Chapter 7 PB - Springer SN - 3-540-40221-7 N2 - - ER - TY - CHAP T1 - ANOVA DDP Models: A Review A1 - De Iorio M A1 - Müller P A1 - Rosner GL A1 - MacEachern SN ED - D. Denison, M. Hansen, C. Holmes, B. Yu T2 - Nonlinear estimation and classifications Y1 - 2003/// PB - Springer – Verlag N2 - - ER - TY - CHAP T1 - The pathogenesis of Atherosclerosis A1 - Naoumova RP A1 - Scott J ED - Warrell D, Cox T, Firth J T2 - Oxford Textbook of Medicine 4th Edition Y1 - 2003/// PB - Oxford University Press SP - 797 EP - 801 N2 - - ER - TY - CHAP T1 - Prenatal/perinatal stress and its impact on psychosocial child development A1 - Glover V ED - Tremblay RE, Barr RG, Peters RDeV T2 - Encyclopedia on early childhood development (online) Y1 - 2003/// PB - Centre of Excellence for Early Childhood Development, Montreal, Canada SP - 1 EP - 5 N2 - - UR - http://www.excellence-jeunesenfants.ca/documents/GloverANGxp.pdf ER - TY - CHAP T1 - The role of NF-kappaB in inflammatory diseases. A1 - Andreakos E A1 - Udalova IA A1 - Sacre S ED - Beyaert R T2 - Nuclear Factor kappaB. Regulation and Role in Disease. Y1 - 2003/// PB - Kluwer Academic Publishers CY - Netherlands SP - 297 EP - 325 N2 - - ER - TY - CHAP T1 - Chemokines A1 - Pease, J. E. A1 - Williams, T.J. ED - Barnes, P.J. et al T2 - Asthma and COPD Y1 - 2002/// VL - First PB - Academic Press SN - 0-12-079028-9 N2 - - ER - TY - CHAP T1 - Lymphocyte biology A1 - Cope A T2 - The Year in Rheumatic Disorders 2002: special issue: rheumatoid arthritis Y1 - 2002/// SN - 0-9537-3399-8 SP - 81 EP - 106 N2 - - ER - TY - CHAP T1 - Imaging A1 - Taylor P T2 - The year in rheumatic disorders 2002: special issue: rheumatoid arthritis Y1 - 2002/// SN - 0-9537-3399-8 SP - 159 EP - 177 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 - Coalescent theory and modelling A1 - Balding DJ ED - Pagel M T2 - Encyclopedia of evolution Y1 - 2002/// SN - 0-1951-4864-9 SP - 170 EP - 175 N2 - - ER - TY - CHAP T1 - Genetics and pathogenesis of cystic fibrosis A1 - Griesenbach U A1 - Geddes DM A1 - Alton EW T2 - Textbook of respiratory cell and molecular biology Y1 - 2002/// SN - 9-0582 3178-X SP - 403 EP - 418 N2 - - ER - TY - CHAP T1 - Human fetal and maternal stress responses A1 - Gitau R A1 - Fisk NM A1 - Glover V T2 - Stress:Neural, endorcrine and molecular studies Y1 - 2002/// SN - 0-4152-7220-3 SP - 215 EP - 217 N2 - - ER - TY - CHAP T1 - Annexin 1 (Lipocortin 1) A1 - Solito E A1 - Mulla A A1 - Flower RJ A1 - Buckingham JC T2 - Wiley Encyclopaedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7496-2 SP - 1943 EP - 1947 N2 - - ER - TY - CHAP T1 - Cell culture systems in apoptosis A1 - Grimm S ED - Grimm, S T2 - Genetics of Apoptosis Y1 - 2002/// PB - BIOS Scientific Publishers CY - Oxford, UK N2 - - ER - TY - CHAP T1 - Angiogenesis A1 - Paleolog EM T2 - The year in rheumatic disorders 2002: special issue: rheumatoid arthritis Y1 - 2002/// SN - 0-9537-3399-8 SP - 63 EP - 80 N2 - - ER - TY - CHAP T1 - Fluid Physics and Macromolecular Growth in Microgravity - Chapter 14 A1 - Helliwell, J.R., A1 - Snell, E.H. A1 - Chayen, N.E., A1 - Judge, R.A., A1 - Boggon, T.J. A1 - Pusey, M.L. ED - Monti, S. ed (Taylor and Francis) T2 - Physics of Fluids in Microgravity Y1 - 2002/// SP - 489 EP - 514 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 - Fetal somatic gene therapy - a preventive approach to the treatment of genetic disease: the case for A1 - Coutelle C A1 - Themis M A1 - Schneider H A1 - Cook HT Y1 - 2001/// SN - 3-5406-7701-1 SP - 99 EP - 114 N2 - - ER - TY - CHAP T1 - Glucocorticoids and the HPA axis A1 - Cowell AM A1 - Buckingham JC Y1 - 2001/// SN - 3-7643-6059-3 SP - 129 EP - 146 N2 - - ER - TY - CHAP T1 - Exploring the pathogenesis of rheumatoid arthritis in transgenic and mutant mice A1 - Cope AP Y1 - 2001/// SN - 3-8055-7120-8 SP - 64 EP - 93 N2 - - ER - TY - CHAP T1 - Characterisation of the CRX gene: identification of alternatively spliced 5' exons and 3' sequence A1 - Hodges MJ A1 - Gregory-Evans CY Y1 - 2001/// SN - 0-3064-6679-1 SP - 71 EP - 86 N2 - - ER - TY - CHAP T1 - Lipocortin 1 A1 - Mulla A A1 - Flower RJ A1 - Buckingham JC ED - Fink G T2 - The Encyclopaedia of Stress Y1 - 2000/// PB - Academic Press CY - New York SP - 623 EP - 628 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 - The pathogenesis of atherosclerosis A1 - Naoumova RP A1 - Scott J ED - Weatherall DJ, Lendingham JG, Warrell DA T2 - Concise Oxford Textbook of Medicine Y1 - 2000/// PB - Oxford University Press SP - 48 EP - 50 N2 - - ER - TY - CHAP T1 - Glucocorticoids: Role in stress A1 - Buckingham JC ED - Fink G T2 - The Encyclopaedia of Stress Y1 - 2000/// PB - Academic Press CY - New York SP - 261 EP - 279 N2 - - ER - TY - CHAP T1 - Glucocorticoids: Effects of stress on A1 - Buckingham JC ED - Fink G T2 - The Encyclopaedia of Stress Y1 - 2000/// PB - Academic Press CY - New York SP - 229 EP - 243 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 - Chemokines and Eosinophils A1 - Hartnell, A. A1 - Pease, J. E. A1 - Conroy, D.M., A1 - Williams, T.J. ED - Holgate S & Busse W. T2 - Asthma & Rhinitis Y1 - 2000/// VL - Second Edition SN - 0-632-04175-7 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 - Oils for Crystals A1 - Chayen, N.E. ED - Bergfors, T. T2 - Crystallisation of Proteins: Techniques, Strategies and Tips Y1 - 1999/// PB - International University Line CY - USA SP - 163 EP - 179 N2 - - ER - TY - CHAP T1 - Insights Into the Nucleation and Growth of Protein Crystals A1 - Chayen, N.E T2 - Recent Research Developments in Crystal Growth Y1 - 1999/// PB - Trans World Research Network SP - 217 EP - 225 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 - Front Cover and sections on crystallisation of proteins A1 - Chayen, N.E. ED - Cressy, G. and Mercer, I.E. T2 - Crystals Y1 - 1999/// PB - Natural History Museum CY - London N2 - - ER - TY - CHAP T1 - The role of protein phosphatases in cell signalling by the high affinity receptor for immunoglobulin E A1 - Peirce M J ED - Ehud Razin and Juan Rivera T2 - Signal transduction in mast cells and basophils Y1 - 1999/// PB - Springer-Verlag CY - New York SN - 0-387-98625-1 SP - 134 EP - 151 N2 - - ER - TY - CHAP T1 - Automation, Microgravity and other topics on protein crystallisation A1 - Chayen, N.E. ED - Bergfors, T T2 - Crystallisation of Proteins: Techniques, Strategies and Tips Y1 - 1999/// PB - International University Line CY - USA SP - 219-220; 222 224,226,230-233, N2 - - ER - TY - CHAP T1 - The Molecular Defect in Hemophilia A A1 - Kemball-Cook, G A1 - Tuddenham, EGD ED - Forbes, CD; Aledort, L; Madhok, R T2 - Hemophilia Y1 - 1997/// PB - Chapman & Hall CY - London SN - 0 412 63820 7 SP - 21 EP - 33 N2 - - ER - TY - CHAP T1 - Genetics of gestational trophoblastic disease A1 - Fisher RA ED - Hancock BW, Newlands ES, Berkowitz RS T2 - Gestational Trophoblastic Disease Y1 - 1997/// PB - Chapman and Hall Medical, London SP - 5 EP - 26 N2 - - ER - TY - CONF T1 - Genetic mutations in the ras/raf/mapkinase pathway results in cherubism A1 - Idowu, BD A1 - Mangion, J A1 - Gale, RE A1 - Flanagan, AM U1 - Annual Meeting of the Bone-Research-Society Y1 - 2007/07// Y2 - // VL - 22 SP - 1124 EP - 1124 N2 - - ER - TY - CONF T1 - The interplay between recombination and selection can confound their inference from population data - But suggests a novel genome-wide method for detecting selection A1 - O'Reilly, P A1 - Birney, E A1 - Balding, D U1 - 35th European Mathematical Genetics Meeting Y1 - 2007/07// Y2 - // VL - 71 SP - 551 EP - 552 N2 - - ER - TY - CONF T1 - Bayesian shrinkage priors for detecting multiple causal variants from genome-wide association studies A1 - Hoggart, C A1 - De Iorio, M A1 - Whittakker, J A1 - Balding, D U1 - 35th European Mathematical Genetics Meeting Y1 - 2007/07// Y2 - // VL - 71 SP - 557 EP - 557 N2 - - ER - TY - CONF T1 - Turbo Genomic Control A1 - Astle, W A1 - Holmes, C A1 - Balding, D U1 - 35th European Mathematical Genetics Meeting Y1 - 2007/07// Y2 - // VL - 71 SP - 553 EP - 554 N2 - - ER - TY - CONF T1 - High prevalence and persistence of the Streptococcus pneumoniae Taiwan19F-14 clone among children in Greece A1 - A. Mavroidi A1 - I. Paraskakis A1 - A. Pangalis A1 - E. Kirikou A1 - A. Charisiadou A1 - T. Athanasiou A1 - P. Tassios A1 - L. Tzouvelekis U1 - 17th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)& 25th International Congress of Chemotherapy (ICC) AD - Munich, Germany Y1 - 2007/04/01/ Y2 - 2007/03/31/ N2 - - ER - TY - CONF T1 - HOX genes are a major target for epigenetic mis-regulation in adult and childhood leukaemia A1 - Strathdee, G A1 - Holyoake, TL A1 - Sim, A A1 - Parker, A A1 - Oscier, DG A1 - Melo, JV A1 - Meyer, S A1 - Eden, T A1 - Dickinson, AM A1 - Soutar, R A1 - Brown, R Y1 - 2007/04// Y2 - // VL - 137 SN - 0007-1048 SP - 81 EP - 81 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 - Using Text Mining for Understanding Insulin Signalling A1 - Ghanem M A1 - Ratcliffe J A1 - Curcin V A1 - Li X A1 - Tattoud R A1 - Scott J A1 - Guo YK U1 - 4th UK e-Science All Hands Meeting 2005\r\n Y1 - 2005/09// N2 - - UR - http://pubs.doc.ic.ac.uk/text-mining-insulin 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 - Wavelet Analysis of Gene Expression (WAGE) A1 - Turkheimer, FE A1 - Duke, DC A1 - Moran, LB A1 - Graeber, MB U1 - 2nd IEEE International Symposium on Biomedical Imaging Y1 - 2004/// Y2 - // SP - 1183 EP - 1186 N2 - - ER - TY - CONF T1 - Wavelet variance components in image space for spatio-temporal neuroimaging data A1 - Aston, J A1 - Turkheimer, F A1 - Cunningham, V A1 - Gunn, R U1 - Wavelets - Applications in Signal and Image Processing X Conference Y1 - 2003/// Y2 - // VL - 5207 SP - 849 EP - 857 N2 - - ER - TY - CONF T1 - Risk of leukaemia and related malignancies following radiation exposure: estimates for the UK population (Technical Report) A1 - Little MP U1 - Report of an Advisory Group on Ionising Radiation Y1 - 2003/// Y2 - 2003/// PB - Docs NRPB SP - 1 EP - 119 N2 - - ER - TY - CONF T1 - Human fetal and maternal stress responses A1 - Gitau, R A1 - Fisk, N A1 - Glover, V U1 - 7th Symposium on Catecholamines and Other Neurotransmitters in Stress Y1 - 2002/// Y2 - // SP - 215 EP - 217 N2 - - ER - TY - CONF T1 - Parents occupationally exposed to radiation prior to the conception of their children. A review of the evidence concerning the incidence of cancer in their children (Technical Report) A1 - Little MP U1 - Committee on Medical Aspects of Radiation in the Environment (COMARE) AD - Chilton Y1 - 2002/// Y2 - 2002/// PB - NRPB N2 - - ER - TY - CONF T1 - Risk of second cancer in therapeutically irradiated populations. Comparison with cancer risks in the Japanese atomic bomb survivors and in other exposed groups (Technical Report) A1 - Little MP U1 - Report of an Advisory Group on Ionising Radiation Y1 - 2000/// Y2 - 2000/// PB - Docs NRPB SP - 1 EP - 105 N2 - - ER - TY - CONF T1 - Non-Gaussian spectra and the search for cosmic strings. A1 - Magueijo J A1 - Lewin A U1 - Topological defects and CMB AD - Rome Y1 - 1997/// Y2 - 1997/// N2 - - UR - http://arxiv.org/abs/astro-ph/9702131 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 - Atopic sensitization and the international variation of asthma symptom prevalence in children. A1 - Weinmayr, G A1 - Weiland, SK A1 - Björkstén, B A1 - Brunekreef, B A1 - Büchele, G A1 - Cookson, WO A1 - Garcia-Marcos, L A1 - Gotua, M A1 - Gratziou, C A1 - van Hage, M A1 - von Mutius, E A1 - Riikjärv, MA A1 - Rzehak, P A1 - Stein, RT A1 - Strachan, DP A1 - Tsanakas, J A1 - Wickens, K A1 - Wong, GW A1 - and the ISAAC Phase Two Study Group J1 - Am J Respir Crit Care Med Y1 - 2007/09/15/ VL - 176 SN - 1073-449X SP - 565 EP - 574 N2 - Rationale: Atopic sensitization has long been known to be related to asthma in children, but its role in determining asthma prevalence remains to be elucidated further. Objectives: To investigate the role of atopic sensitization in the large international variation in the prevalence of childhood asthma. Methods: Cross-sectional studies of random samples of 8- to 12-year-old children (n = 1,000 per center) were performed according to the standardized methodology of Phase Two of the International Study of Asthma and Allergy in Childhood (ISAAC). Thirty study centers in 22 countries worldwide participated and reflect a wide range of living conditions, from rural Africa to urban Europe. Data were collected by parental questionnaires (n = 54,439), skin prick tests (n = 31,759), and measurements of allergen-specific IgE levels in serum (n = 8,951). Economic development was assessed by gross national income per capita (GNI). Measurements and Main Results: The prevalence of current wheeze (i.e., during the past year) ranged from 0.8% in Pichincha (Ecuador) to 25.6% in Uruguaiana (Brazil). The fraction of current wheeze attributable to atopic sensitization ranged from 0% in Ankara (Turkey) to 93.8% in Guangzhou (China). There were no correlations between prevalence rates of current wheeze and atopic sensitization, and only weak correlations of both with GNI. However, the fractions and prevalence rates of wheeze attributable to skin test reactivity correlated strongly with GNI (Spearman rank-order coefficient rho = 0.50, P = 0.006, and rho = 0.74, P < 0.0001, respectively). In addition, the strength of the association between current wheeze and skin test reactivity, assessed by odds ratios, increased with GNI (rho = 0.47, P = 0.01). Conclusions: The link between atopic sensitization and asthma symptoms in children differs strongly between populations and increases with economic development. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17575099&query_hl=1 ER - TY - JFULL T1 - TGF-beta1 Variants in Chronic Beryllium Disease and Sarcoidosis. A1 - Jonth, AC A1 - Silveira, L A1 - Fingerlin, TE A1 - Sato, H A1 - Luby, JC A1 - Welsh, KI A1 - Rose, CS A1 - Newman, LS A1 - du Bois, RM A1 - Maier, LA A1 - The ACCESS Group J1 - J Immunol Y1 - 2007/09/15/ VL - 179 SN - 0022-1767 SP - 4255 EP - 4262 N2 - Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-beta1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-beta1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-beta1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-beta1 variants or haplotypes. The -509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the -509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the -509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the -509C and codon 10T, implicated in lower levels of TGF-beta1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-beta1, although future studies will be needed to correlate TGF-beta1 protein levels with known TGF-beta1 genotypes and assess whether there is a shared mechanisms for TGF-beta1 in these two granulomatous diseases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17785866&query_hl=1 ER - TY - JFULL T1 - JAM-A mediates neutrophil transmigration in a stimulus-specific manner in vivo: evidence for sequential roles for JAM-A and PECAM-1 in neutrophil transmigration. A1 - Woodfin, A A1 - Reichel, CA A1 - Khandoga, A A1 - Corada, M A1 - Voisin, MB A1 - Scheiermann, C A1 - Haskard, DO A1 - Dejana, E A1 - Krombach, F A1 - Nourshargh, S J1 - Blood Y1 - 2007/09/15/ VL - 110 SN - 0006-4971 SP - 1848 EP - 1856 N2 - Junctional adhesion molecule-A (JAM-A) is a transmembrane protein expressed at tight junctions of endothelial and epithelial cells and on the surface of platelets and leukocytes. The role of JAM-A in leukocyte transmigration in vivo was directly investigated by intravital microscopy using both a JAM-A-neutralizing monoclonal antibody (mAb) (BV-11) and JAM-A-deficient (knockout [KO]) mice. Leukocyte transmigration (but not adhesion) through mouse cremasteric venules as stimulated by interleukin 1beta (IL-1beta) or ischemia/reperfusion (I/R) injury was significantly reduced in wild-type mice treated with BV-11 and in JAM-A KO animals. In contrast, JAM-A blockade/genetic deletion had no effect on responses elicited by leukotriene B(4) (LTB(4)) or platelet-activating factor (PAF). Furthermore, using a leukocyte transfer method and mice deficient in endothelial-cell JAM-A, evidence was obtained for the involvement of endothelial-cell JAM-A in leukocyte transmigration mediated by IL-1beta. Investigation of the functional relationship between JAM-A and PECAM-1 (CD31) determined that dual blockade/deletion of these proteins does not lead to an inhibitory effect greater than that seen with blockade/deletion of either molecule alone. The latter appeared to be due to the fact that JAM-A and PECAM-1 can act sequentially to mediate leukocyte migration through venular walls in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17505016&query_hl=1 ER - TY - JFULL T1 - Change in Salt Intake Affects Blood Pressure of Chimpanzees. Implications for Human Populations. A1 - Elliott, P A1 - Walker, LL A1 - Little, MP A1 - Blair-West, JR A1 - Shade, RE A1 - Lee, DR A1 - Rouquet, P A1 - Leroy, E A1 - Jeunemaitre, X A1 - Ardaillou, R A1 - Paillard, F A1 - Meneton, P A1 - Denton, DA J1 - Circulation Y1 - 2007/09/04/ SN - 1524-4539 N2 - BACKGROUND: -Addition of up to 15.0 g/d salt to the diet of chimpanzees caused large rises in blood pressure, which reversed when the added salt was removed. Effects of more modest alterations to sodium intakes in chimpanzees, akin to current efforts to lower sodium intakes in the human population, are unknown. Methods and Results-Sodium intakes were altered among 17 chimpanzees in Franceville, Gabon, and 110 chimpanzees in Bastrop, Tex. In Gabon, chimpanzees had a biscuit diet of constant nutrient composition except that the sodium content was changed episodically over 3 years from 75 to 35 to 120 mmol/d. In Bastrop, animals were divided into 2 groups; 1 group continued on the standard diet of 250 mmol/d sodium for 2 years, and sodium intake was halved for the other group. Lower sodium intake was associated with lower systolic, diastolic, and mean arterial blood pressures in Gabon (2-tailed P<0.001, unadjusted and adjusted for age, sex, and baseline weight) and Bastrop (P<0.01, unadjusted; P=0.08 to 0.10, adjusted), with no threshold down to 35 mmol/d sodium. For systolic pressure, estimates were -12.7 mm Hg (95% confidence interval, -16.9 to -8.5, adjusted) per 100 mmol/d lower sodium in Gabon and -10.9 mm Hg (95% confidence interval, -18.9 to -2.9, unadjusted) and -5.7 mm Hg (95% confidence interval, -12.2 to 0.7, adjusted) for sodium intake lower by 122 mmol/d in Bastrop. Baseline systolic pressures higher by 10 mm Hg were associated with larger falls in systolic pressure by 4.3/2.9 mm Hg in Gabon/Bastrop per 100 mmol/d lower sodium. Conclusions-These findings from an essentially single-variable experiment in the species closest to Homo sapiens with high intakes of calcium and potassium support intensified public health efforts to lower sodium intake in the human population. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17785625&query_hl=1 ER - TY - JFULL T1 - Functional constraint and small insertions and deletions in the ENCODE regions of the human genome. A1 - Clark, TG A1 - Andrew, T A1 - Cooper, GM A1 - Marguiles, EH A1 - Mullikin, JC A1 - Balding, DJ J1 - Genome Biol Y1 - 2007/09/04/ VL - 8 SN - 1465-6914 SP - R180 EP - R180 N2 - ABSTRACT: BACKGROUND: We describe the distribution of indels in the 44 ENCODE regions (~1% of the human genome) to evaluate the potential contribution of small insertion and deletion polymorphisms (indels) to human genetic variation [1]. We relate indels to known genomic annotation features and measures of evolutionary constraint. RESULTS: Indel rates are observed to be reduced approximately twenty-fold in exonic regions, five-fold in sequence that exhibits high evolutionary constraint in mammals and up to two-fold in some classes of regulatory elements (e.g. Formaldehyde Assisted Isolation of Regulatory Elements or FAIRE and hypersensitive sites). In addition, some non-coding transcription (start sites and 3UTR) and other chromatin-mediated regulatory sites also appear to have reduced indel rates. Overall indel rates for these data are estimated to be smaller than single nucleotide polymorphism (SNP) rates by a factor of approximately two, with both rates measured as base pairs (bp) per 100kb to facilitate comparison. CONCLUSION: Indel rates show a broadly similar distribution across genomic features compared to SNP density rates, with a reduction in rates in coding transcription and evolutionary constrained sequence. However, unlike indels, SNP rates do not appear to be reduced in some non-coding functional sequences such as pseudo-exons, FAIRE and hypersensitive sites. We conclude that indel rates are greatly reduced in transcribed and evolutionary constrained DNA and discuss why indel (but not SNP) rates appear to be constrained at some regulatory sites. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17784950&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 - Targeting of adenovirus serotype 5 (Ad5) and 5/47 pseudotyped vectors in vivo: fundamental involvement of coagulation factors and redundancy of CAR binding by Ad5. A1 - Waddington, SN A1 - Parker, AL A1 - Havenga, M A1 - Nicklin, SA A1 - Buckley, SM A1 - McVey, JH A1 - Baker, AH J1 - J Virol Y1 - 2007/09// VL - 81 SN - 0022-538X SP - 9568 EP - 9571 N2 - Vitamin K-dependent coagulation factors can promote adenoviral cell transduction in vitro. In vivo, warfarin pretreatment ablates liver targeting of an adenovirus serotype 5 (Ad5) vector deleted of CAR binding capability. Here, we assess in vivo transduction and biodistribution of Ad5 vectors with nonmodified fibers (Ad5) and a serotype 47 fiber-pseudotyped Ad5 (Ad5/47; subgroup D) virus following intravascular injection. Warfarin reduced liver transduction by both viruses. However, no impact on early liver virus accumulation was observed, suggesting no effect on Kupffer cell interactions. Hence, coagulation factors play a pivotal role in selectively mediating liver hepatocyte transduction of Ad5 and Ad5/47 vectors. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17553882&query_hl=1 ER - TY - JFULL T1 - Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis. A1 - Spagnolo, P A1 - Sato, H A1 - Grutters, JC A1 - Renzoni, EA A1 - Marshall, SE A1 - Ruven, HJ A1 - Wells, AU A1 - Tzouvelekis, A A1 - van Moorsel, CH A1 - van den Bosch, JM A1 - du Bois, RM A1 - Welsh, KI J1 - Tissue Antigens Y1 - 2007/09// VL - 70 SN - 0001-2815 SP - 219 EP - 227 N2 - Sarcoidosis is a heterogeneous disorder, both phenotypically and genetically. Two independent studies have recently shown that a functional polymorphism within butyrophilin-like 2 (BTNL2) gene predisposes to sarcoidosis independently of the human leukocyte antigen (HLA)-DRB1 alleles. However, in both studies, data analysis was not stratified by Löfgren's syndrome, a clinically and genetically distinct sarcoidosis subset. BTNL2, potentially encoding an immune coreceptor, is adjacent and in linkage disequilibrium (LD) with HLA-DRB1. We investigated six BTNL2 variants, including the functional rs2076530 (G > A), as well as HLA-DRB1 alleles, by sequence-specific primers-polymerase chain reaction, in 288 patients and 446 controls from two European countries. In the patient group as a whole, the HLA-DRB1*14 [odds ratio (OR) = 3.1, P(c) = 0.0003], DRB1*12 (OR = 2.5, P(c) = 0.003), and BTNL2 rs2076530 A allele (OR = 1.49, P(c) = 0.002) were all associated with disease susceptibility. However, after exclusion of patients presenting with Löfgren's syndrome and after adjusting for HLA-DRB1 alleles, the association between BTNL2 rs2076530 A and disease disappeared (P = 0.23). By contrast, both HLA-DRB1*14 and DRB1*12 remained strongly significant (OR = 3.60, P < 0.0001 and OR = 3.03, P = 0.003, respectively). BTNL2 haplotype 4, tagged by the rs2076530 G allele, also remained associated with non-Löfgren sarcoidosis after adjusting for HLA-DRB1 alleles (OR 0.37, P = 0.016). In summary, HLA-DRB1*14, DRB1*12, and BTNL2 haplotype 4--but not rs2076530 A--are associated with non-Löfgren sarcoidosis. However, the tight LD across the HLA complex makes it difficult to identify the precise location of the susceptibility locus/i. Larger sample sets from different ethnic groups, finer mapping, and more robust LD analyses across the HLA region are needed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17661910&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 - Predicted functions and linkage specificities of the products of the Streptococcus pneumoniae capsular biosynthetic loci. A1 - Aanensen, DM A1 - Mavroidi, A A1 - Bentley, SD A1 - Reeves, PR A1 - Spratt, BG J1 - J Bacteriol Y1 - 2007/08/31/ SN - 0021-9193 N2 - The sequences of the capsular biosynthetic (cps) loci of 90 serotypes of Streptococcus pneumoniae have recently been determined. Bioinformatic procedures were used to predict the general functions of 1973 of the 1999 gene products and to identify proteins within the same homology group, Pfam family and CAZy glycosyltransferase family. Correlating cps gene content with the 54 known capsular polysaccharide (CPS) structures provided tentative assignments of the specific functions of the different homology groups of each functional class (regulatory proteins, enzymes for synthesis of CPS constituents, polymerases, flippases, initial sugar transferases, glycosytransferases, phosphotransferases, acetyltransferases and pyruvyltransferases). Assignment of the glycosidic linkages catalyzed by the 342 glycosyltransferases (GTs) (92 homology groups) is problematic, but tentative assignments could be made by using this large set of cps loci and CPS structures to correlate the presence of particular GTs with specific glycosidic linkages, by correlating inverting or retaining linkages in CPS repeat units with the inverting or retaining mechanisms of the GTs predicted from their CAZy family membership, and by comparing the CPS structures of serotypes that have very similar cps gene content. These large scale comparisons between structure and gene content assigned the linkages catalyzed by 72% of the GTs and all linkages were assigned in 32 of the serotypes with known repeat unit structures. Clear examples where very similar initial sugar transferases or glycosyltransferases catalyze different linkages in different serotypes were also identified. These assignments should provide a stimulus for biochemical studies to evaluate the reactions that are proposed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17766420&query_hl=1 ER - TY - JFULL T1 - Genetic relatedness of the Streptococcus pneumoniae capsular biosynthetic loci. A1 - Mavroidi, A A1 - Aanensen, DM A1 - Godoy, D A1 - Skovsted, IC A1 - Kaltoft, MS A1 - Reeves, PR A1 - Bentley, SD A1 - Spratt, BG J1 - J Bacteriol Y1 - 2007/08/31/ SN - 0021-9193 N2 - Streptococcus pneumoniae (pneumococci) produce one of 91 capsular polysaccharides (CPS) that define the serotype. The cps loci of 88 pneumococcal serotypes whose CPS is synthesized by the Wzy-dependent pathway were compared with each other, and with additional streptococcal polysaccharide biosynthetic loci, and were clustered, according to the proportion of shared homology groups (HGs), weighted for the sequence similarities between the genes encoding the shared HGs. The cps loci of the 88 pneumococcal serotypes were distributed into eight major clusters and 21 sub-clusters. All serotypes within the same serogroup fell into the same major cluster but, in six cases, serotypes within the same serogroup were in different sub-clusters and, conversely, nine sub-clusters included completely different serotypes. The closely-related cps loci within a sub-cluster were compared to the known CPS structures to relate gene content to structure. The S. oralis and S. mitis polysaccharide biosynthetic loci clustered within the pneumococcal cps loci and were in a sub-cluster that also included the cps locus of pneumococcal serotype 21, whereas the S. agalactiae cps loci formed a single cluster that was not closely related to any of the pneumococcal cps clusters. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17766424&query_hl=1 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 - The PhenoGen Informatics website: tools for analyses of complex traits. A1 - Bhave, SV A1 - Hornbaker, C A1 - Phang, TL A1 - Saba, L A1 - Lapadat, R A1 - Kechris, K A1 - Gaydos, J A1 - McGoldrick, D A1 - Dolbey, A A1 - Leach, S A1 - Soriano, B A1 - Ellington, A A1 - Ellington, E A1 - Jones, K A1 - Mangion, J A1 - Belknap, JK A1 - Williams, RW A1 - Hunter, LE A1 - Hoffman, PL A1 - Tabakoff, B J1 - BMC Genet Y1 - 2007/08/30/ VL - 8 SN - 1471-2156 SP - 59 EP - 59 N2 - ABSTRACT: BACKGROUND: With the advent of "omics" (e.g. genomics, transcriptomics, proteomics and phenomics), studies can produce enormous amounts of data. Managing this diverse data and integrating with other biological data are major challenges for the bioinformatics community. Comprehensive new tools are needed to store, integrate and analyze the data efficiently. Description: The PhenoGen Informatics website (http://phenogen.uchsc.edu) is a comprehensive toolbox for storing, analyzing and integrating microarray data and related genotype and phenotype data. The site is particularly suited for combining QTL and microarray data to search for "candidate" genes contributing to complex traits. In addition, the site allows, if desired by the investigators, sharing of the data. Investigators can conduct "in-silico" microarray experiments using their own and/or "shared" data. CONCLUSION: The PhenoGen website provides access to tools that can be used for high-throughput data storage, analyses and interpretation of the results. Some of the advantages of the architecture of the website are that, in the future, the present set of tools can be adapted for the analyses of any type of high-throughput "omics" data, and that access to new tools, available in the public domain or developed at PhenoGen, can be easily provided. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17760997&query_hl=1 ER - TY - JFULL T1 - Lung Delivery Studies Using siRNA Conjugated to TAT(48-60) and Penetratin Reveal Peptide Induced Reduction in Gene Expression and Induction of Innate Immunity. A1 - Moschos, SA A1 - Jones, SW A1 - Perry, MM A1 - Williams, AE A1 - Erjefalt, JS A1 - Turner, JJ A1 - Barnes, PJ A1 - Sproat, BS A1 - Gait, MJ A1 - Lindsay, MA J1 - Bioconjug Chem Y1 - 2007/08/21/ SN - 1043-1802 N2 - The therapeutic application of siRNA shows promise as an alternative approach to small-molecule inhibitors for the treatment of human disease. However, the major obstacle to its use has been the difficulty in delivering these large anionic molecules in vivo. In this study, we have investigated whether siRNA-mediated knockdown of p38 MAP kinase mRNA in mouse lung is influenced by conjugation to the nonviral delivery vector cholesterol and the cell penetrating peptides (CPP) TAT(48-60) and penetratin. Initial studies in the mouse fibroblast L929 cell line showed that siRNA conjugated to cholesterol, TAT(48-60), and penetratin, but not siRNA alone, achieved a limited reduction of p38 MAP kinase mRNA expression. Intratracheal administration of siRNA resulted in localization within macrophages and scattered epithelial cells and produced a 30-45% knockdown of p38 MAP kinase mRNA at 6 h. As with increasing doses of siRNA, conjugation to cholesterol improved upon the duration but not the magnitude of mRNA knockdown, while penetratin and TAT(48-60) had no effect. Importantly, administration of the penetratin or TAT(48-60) peptides alone caused significant reduction in p38 MAP kinase mRNA expression, while the penetratin-siRNA conjugate activated the innate immune response. Overall, these studies suggest that conjugation to cholesterol may extend but not increase siRNA-mediated p38 MAP kinase mRNA knockdown in the lung. Furthermore, the use of CPP may be limited due to as yet uncharacterized effects upon gene expression and a potential for immune activation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17711319&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 - 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 - A down to-earth- approach A1 - Helliwell, John R. A1 - Naomi E. Chayen J1 - Nature Y1 - 2007/08/09/ VL - 448 SP - 658 EP - 659 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 - Arterial carboxyhemoglobin level and outcome in critically ill patients. A1 - Melley, DD A1 - Finney, SJ A1 - Elia, A A1 - Lagan, AL A1 - Quinlan, GJ A1 - Evans, TW J1 - Crit Care Med Y1 - 2007/08// VL - 35 SN - 0090-3493 SP - 1882 EP - 1887 N2 - OBJECTIVE:: Arterial carboxyhemoglobin is elevated in patients with critical illness. It is an indicator of the endogenous production of carbon monoxide by the enzyme heme oxygenase, which modulates the response to oxidant stress. The objective was to explore the hypothesis that arterial carboxyhemoglobin level is associated with inflammation and survival in patients requiring cardiothoracic intensive care. DESIGN:: Prospective, observational study. SETTING:: A cardiothoracic intensive care unit. PATIENTS:: All patients admitted over a 15-month period. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: Arterial carboxyhemoglobin, bilirubin, and standard biochemical, hematologic, and physiologic markers of inflammation were measured in 1,267 patients. Associations were sought between levels of arterial carboxyhemoglobin, markers of the inflammatory response, and clinical outcome. Intensive care unit mortality was associated with lower minimum and greater maximal carboxyhemoglobin levels (p < .0001 and p < .001, respectively). After adjustment for age, gender, illness severity, and other relevant variables, a lower minimum arterial carboxyhemoglobin was associated with an increased risk of death from all causes (odds risk of death, 0.391; 95% confidence interval, 0.190-0.807; p = .011). Arterial carboxyhemoglobin correlated with markers of the inflammatory response. CONCLUSIONS:: Both low minimum and high maximum levels of arterial carboxyhemoglobin were associated with increased intensive care mortality. Although the heme oxygenase system is protective, excessive induction may be deleterious. This suggests that there may be an optimal range for heme oxygenase-1 induction. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17568332&query_hl=1 ER - TY - JFULL T1 - Taxonomic and diagnostic markers for identification of Coccidioides immitis and Coccidioides posadasii. A1 - Tintelnot, K A1 - De Hoog, GS A1 - Antweiler, E A1 - Losert, H A1 - Seibold, M A1 - Brandt, MA A1 - Van Den Ende, AH A1 - Fisher, MC J1 - Med Mycol Y1 - 2007/08// VL - 45 SN - 1369-3786 SP - 385 EP - 393 N2 - The ribosomal Internal Transcribed Spacer (ITS) regions of the two recognized species of Coccidioides were studied using a reference set of strains that had been previously identified with species defining microsatellite polymorphisms. Unambiguous identification of the two species proved to be possible by amplifying and sequencing the ITS region. PCR-reactions are sensitive to amplification conditions requiring their careful optimization. Stable amplification and sequencing was achieved with primers ITS3 and 4, enabling species diagnosis. Alternatively, Restriction Fragment Length Polymorphism (RFLP) of the entire ITS region using an annealing temperature of 52 degrees C with the restriction enzymes BsrI and XcmI can also distinguish the species. Three strains typifying the species, Glenospora meteuropaea, G. metamericana and Geotrichum louisianoideum, were analyzed and found to be conspecific with C. posadasii. Although these species have nomenclatural priority over C. posadasii, the latter will be proposed for conservation as it has been included in the US select agent list. In addition, Coccidioides immitis is neotypified in this report. Results of antifungal susceptibility testing did not reveal differences between the two species. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17654264&query_hl=1 ER - TY - JFULL T1 - AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. A1 - Claret, M A1 - Smith, MA A1 - Batterham, RL A1 - Selman, C A1 - Choudhury, AI A1 - Fryer, LG A1 - Clements, M A1 - Al-Qassab, H A1 - Heffron, H A1 - Xu, AW A1 - Speakman, JR A1 - Barsh, GS A1 - Viollet, B A1 - Vaulont, S A1 - Ashford, ML A1 - Carling, D A1 - Withers, DJ J1 - J Clin Invest Y1 - 2007/08// VL - 117 SN - 0021-9738 SP - 2325 EP - 2336 N2 - Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRP alpha 2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK alpha2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMC alpha 2KO and AgRP alpha 2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17671657&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 - Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. A1 - Van Mil, SW A1 - Milona, A A1 - Dixon, PH A1 - Mullenbach, R A1 - Geenes, VL A1 - Chambers, J A1 - Shevchuk, V A1 - Moore, GE A1 - Lammert, F A1 - Glantz, AG A1 - Mattsson, LA A1 - Whittaker, J A1 - Parker, MG A1 - White, R A1 - Williamson, C J1 - Gastroenterology Y1 - 2007/08// VL - 133 SN - 0016-5085 SP - 507 EP - 516 N2 - BACKGROUND AND AIMS: Intrahepatic cholestasis of pregnancy (ICP) is characterized by liver impairment, pruritus, and elevated maternal serum bile acids. It can cause premature delivery and intrauterine death. Bile acid synthesis, metabolism, and transport are regulated by the bile acid sensor FXR, and we hypothesized that genetic variation in FXR confers susceptibility to ICP. METHODS: The coding regions and intron/exon boundaries of FXR were sequenced in 92 British ICP cases of mixed ethnicity. Subsequently, a case-control study of allele frequencies of these variants in 2 independent cohorts of Caucasian ICP patients and controls was performed. Variants were cloned into an FXR expression plasmid and tested in functional assays. RESULTS: We identified 4 novel heterozygous FXR variants (-1g>t, M1V, W80R, M173T) in ICP. W80R was not present in Caucasians and M1V was detected uniquely in 1 British case. M173T and -1g>t occur both in Caucasian cases and controls, and we found a significant association of M173T with ICP (OR, 3.2; 95% confidence interval, 1.1-11.2; P = .02) when the allele frequencies of both Caucasian cohorts were analyzed together. We demonstrate functional defects in either translation efficiency or activity for 3 of the 4 variants (-1g>t, M1V, M173T). CONCLUSIONS: This is the first report of functional variants in FXR. We propose that these variants may predispose to ICP, and because FXR has a central role in regulating bile and lipid homeostasis they may be associated with other cholestatic and dyslipidemic disorders. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17681172&query_hl=1 ER - TY - JFULL T1 - Unravelling the mechanisms underpinning chemokine receptor activation and blockade by small molecules: a fine line between agonism and antagonism? A1 - Wise, E A1 - Pease, JE J1 - Biochem Soc Trans Y1 - 2007/08// VL - 35 SN - 0300-5127 SP - 755 EP - 759 N2 - Chemokines are a family of small basic proteins which induce the directed migration of cells, notably leucocytes, by binding to specific GPCRs (G-protein-coupled receptors). Both chemokines and their receptors have been implicated in a host of clinically important diseases, leading to the notion that antagonism of the chemokine-chemokine receptor network may be therapeutically advantageous. Consequently, considerable effort has been put into the development of small-molecule antagonists of chemokine receptors and several such compounds have been described in the literature. One curious by-product of this activity has been the description of several small-molecule agonists of the receptors, which are typically discovered following the optimization of lead antagonists. In this review we discuss these findings and conclude that these small-molecule agonists might be exploited to further our understanding of the molecular mechanisms by which chemokine receptors are activated. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17635141&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 - Cell-penetrating-peptide-mediated siRNA lung delivery. A1 - Moschos, SA A1 - Williams, AE A1 - Lindsay, MA J1 - Biochem Soc Trans Y1 - 2007/08// VL - 35 SN - 0300-5127 SP - 807 EP - 810 N2 - The therapeutic application of siRNA (short interfering RNA) shows promise as an alternative approach to small-molecule inhibitors for the treatment of human disease. However, the major obstacle to its use has been the difficulty in delivering these large anionic molecules in vivo. A potential approach to solving this problem is the chemical conjugation of siRNA to the cationic CPPs (cell-penetrating peptides), Tat-(48-60) (transactivator of transcription) and penetratin, which have been shown previously to mediate protein and peptide delivery in a host of animal models. In this transaction, we review recent studies on the utility of siRNA for the investigation of protein function in the airways/lung. We show that, despite previous studies showing the utility of cationic CPPs in vitro, conjugation of siRNA to Tat-(48-60) and penetratin failed to increase residual siRNA-mediated knockdown of p38 MAPK (mitogen-activated protein kinase) (MAPK14) mRNA in mouse lung in vivo. Significantly, we will also discuss potential non-specific actions and the induction of immunological responses by CPPs and their conjugates and how this might limit their application for siRNA-mediated delivery in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17635153&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 - 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 - Pre- and post-synaptic sympathetic function in human hibernating myocardium. A1 - John, AS A1 - Mongillo, M A1 - Depre, C A1 - Khan, MT A1 - Rimoldi, OE A1 - Pepper, JR A1 - Dreyfus, GD A1 - Pennell, DJ A1 - Camici, PG J1 - Eur J Nucl Med Mol Imaging Y1 - 2007/07/28/ SN - 1619-7070 N2 - PURPOSE: Impaired pre-synaptic noradrenaline uptake-1 mechanism has been reported in a swine model of hibernating myocardium (HM). To ascertain whether adrenergic neuroeffector abnormalities are present in human HM, we combined functional measurements in vivo using cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) to assess pre- and post-synaptic sympathetic function. METHODS: Twelve patients with coronary artery disease and chronic left ventricular (LV) dysfunction underwent CMR at baseline and 6 months after bypass for assessment of regional and global LV function and identification of segments with reversible dysfunction. Before surgery, myocardial noradrenaline uptake-1 ([(11)C]meta-hydroxy-ephedrine; HED) and beta-adrenoceptor (beta-AR) density ([(11)C]CGP-12177) were measured with PET. Patient PET data were compared with those in 18 healthy controls. RESULTS: The volume of distribution (V(d)) of HED in HM (47.95+/-28.05 ml/g) and infarcted myocardium (42.69+/-25.76 ml/g) was significantly reduced compared with controls (66.09+/-14.48 ml/g). The V(d) of HED in normal myocardium (49.93+/-20.48 ml/g) of patients was also lower than that in controls and the difference was close to statistical significance (p=0.06). Myocardial beta-AR density was significantly lower in HM (5.49+/-2.35 pmol/g), infarcted (4.82+/-2.61 pmol/g) and normal (5.86+/-1.81 pmol/g) segments of patients compared with healthy controls (8.61+/-1.32 pmol/g). CONCLUSION: Noradrenaline uptake-1 mechanism and beta-AR density are reduced in the myocardium of patients with chronic LV dysfunction and evidence of HM. The increased sympathetic activity to the heart in these patients is a generalised rather than regional phenomenon which is likely to contribute to the remodelling process of the whole LV rather than playing a causative role in HM. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17661029&query_hl=1 ER - TY - JFULL T1 - SNP genome scanning localises oto-dental syndrome to chromosome 11q13 and microdeletions at this locus implicate FGF3 in dental and inner ear disease and FADD in ocular coloboma. A1 - Gregory-Evans, CY A1 - Moosajee, M A1 - Hodges, MD A1 - Mackay, DS A1 - Game, L A1 - Vargesson, N A1 - Bloch-Zupan, A A1 - Rüschendorf, F A1 - Santos-Pinto, L A1 - Wackens, G A1 - Gregory-Evans, K J1 - Hum Mol Genet Y1 - 2007/07/25/ SN - 0964-6906 N2 - We ascertained three different families affected with oto-dental syndrome, a rare but severe autosomal dominant craniofacial anomaly. All affected patients had the unique phenotype of grossly enlarged molar teeth (globodontia) segregating with a high frequency sensorineural hearing loss. In addition, ocular coloboma segregated with disease in one family (oculo-oto-dental syndrome). A genome-wide scan was performed using the Affymetrix GeneChip10K 2.0 Array. Parametric linkage analysis gave a single LOD score peak of 3.9 identifying linkage to chromosome 11q13. Haplotype analysis revealed three obligatory recombination events defining a 4.8 Mb linked interval between D11S1889 and SNP rs2077955. Higher resolution mapping and Southern blot analysis in each family identified overlapping hemizygous microdeletions. SNP expression analysis and real-time qRT-PCR in patient lymphoblast cell lines excluded a position effect on the flanking genes ORAOV1, PPFIA1 and CTTN. The smallest 43 kb deletion resulted in the loss of only one gene, FGF3, which was also deleted in all other otodental families. These data suggest that FGF3 haploinsufficiency is likely to be the cause of otodental syndrome. In addition, the Fas-associated death domain gene (FADD) was also deleted in the one family segregating ocular coloboma. Spatiotemporal in situ hybridisation in zebrafish embryos established for the first time that fadd is expressed during eye development. We therefore propose that FADD haploinsufficiency is likely to be responsible for ocular coloboma in this family. This study therefore implicates FGF3 and FADD in human craniofacial disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17656375&query_hl=1 ER - TY - JFULL T1 - Balancing bias, reliability, noise properties and the need for parametric maps in quantitative ligand PET: [(11)C]diprenorphine test-retest data. A1 - Hammers, A A1 - Asselin, MC A1 - Turkheimer, FE A1 - Hinz, R A1 - Osman, S A1 - Hotton, G A1 - Brooks, DJ A1 - Duncan, JS A1 - Koepp, MJ J1 - Neuroimage Y1 - 2007/07/24/ SN - 1053-8119 N2 - [(11)C]diprenorphine (DPN) is a non-subtype selective opioid receptor PET ligand with slow kinetics and no region devoid of specific binding. Parametric maps are desirable but have to overcome high noise at the voxel level. We obtained parameter values, parametric map image quality, test-retest reproducibility and reliability (using intraclass correlation coefficients (ICCs)) for conventional spectral analysis and a derived method (rank shaping), compared them with values obtained through sampling of volumes of interest (VOIs) on the dynamic data sets and tested whether smaller amounts of radioactivity injected maintained reliability. Ten subjects were injected twice with either approximately 185 MBq or approximately 135 MBq of [(11)C]DPN, followed by dynamic PET for 90 min. Data were movement corrected with a frame-to-frame co-registration method. Arterial plasma input functions corrected for radiolabelled metabolites were created. There was no overall effect of movement correction except for one subject with substantial movement whose test-retest differences decreased by approximately 50%. Actual parametric values depended heavily on the cutoff for slow frequencies (between 0.0008 s(-1) and 0.00063 s(-1)). Image quality was satisfactory for restricted base ranges when using conventional spectral analysis. The rank shaping method allowed maximising of this range but had similar bias. VOI-based methods had the widest dynamic range between regions. Average percentage test-retest differences were smallest for the parametric maps with restricted base ranges; similarly ICCs were highest for these (up to 0.86) but unacceptably low for VOI-derived VD estimates at the low doses of injected radioactivity (0.24/0.04). Our data can inform the choice of methodology for a given biological problem. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17764977&query_hl=1 ER - TY - JFULL T1 - Impact of protein acetylation in inflammatory lung diseases. A1 - Ito, K A1 - Charron, CE A1 - Adcock, IM J1 - Pharmacol Ther Y1 - 2007/07/24/ SN - 0163-7258 N2 - Chronic inflammatory lung diseases are characterized by increased expression of multiple inflammatory genes following activation by proinflammatory transcription factors, such as nuclear factor kappaB (NF-kappaB) and AP-1. Gene expression is, at least in part, regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein (CBP), which have intrinsic histone acetyltransferase (HAT) activity. Conversely gene repression is mediated via a combination of histone deacetylases (HDAC) and other corepressors. In asthma, the level of HAT activity is elevated in bronchial biopsies, whereas HDAC activity levels are only partially reduced and inhaled corticosteroids are able to reduce the increased HAT activity back to those seen in normal subjects. In contrast, in chronic obstructive pulmonary disease (COPD), there is a greater reduction in HDAC activity and HDAC2 expression but no difference in HAT activity. HAT and HDAC are also reported to modify a large and expanding number of nonhistone proteins, including nuclear import proteins, chaperones, cytoskeletal proteins, and other transcriptional factors, such as NF-kappaB and signal transducer and activation of transcription (STAT). Acetylation regulates several aspects of protein function and stability leading to differing effects on inflammatory gene expression and cell recruitment involved in the pathogenesis of inflammatory diseases. This review will examine the impact of acetylation on the function of key proteins involved in airway inflammatory disease and the effects of current therapies on acetylation status of key proteins. Further appreciation of the role of these changes may lead to the development of novel therapeutic approaches to inflammatory lung diseases that are currently difficult to treat. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17720252&query_hl=1 ER - TY - JFULL T1 - Amniotic fluid testosterone: relationship with cortisol and gestational age. A1 - Sarkar, P A1 - Bergman, K A1 - Fisk, NM A1 - O'connor, TG A1 - Glover, V J1 - Clin Endocrinol (Oxf) Y1 - 2007/07/18/ SN - 0300-0664 N2 - Introduction Foetal exposure to testosterone is increasingly implicated in the programming of future reproductive and nonreproductive behaviour. Some outcomes associated with prenatal exposure to testosterone may be predicted from exposure to prenatal stress, suggesting a link between them. The peak serum levels of testosterone in the foetus are thought to be around 14-18 weeks' gestation, and we explored testosterone levels at different gestations. Although best investigated in foetal plasma, this is now difficult because of the decline in frequency of foetal blood sampling; in this study, we used amniotic fluid as a biomarker to investigate foetal exposure. Aims To investigate the relationship between amniotic fluid testosterone, amniotic fluid cortisol, foetal gender, and gestational age. Methods Paired amniotic fluid and maternal plasma samples were collected from 264 pregnant women undergoing amniocentesis between 15 and 37 weeks' gestation (median 17 weeks [119 days]). Total testosterone and cortisol in amniotic fluid, and total plasma testosterone (maternal) were measured by radioimmunoassay. Results Amniotic fluid testosterone levels were higher in male than in female foetuses, with a median (interquartile range) of 0.85 nmol/l (0.60-1.17 nmol/l) and 0.28 nmol/l (0.175-0.45 nmol/l), respectively. No relationship between amniotic fluid testosterone and gestational age was detected in either sex. Amniotic fluid testosterone correlated positively with amniotic fluid cortisol in both sexes (r = 0.30 male foetuses, r = 0.33 female foetuses, P < 0.001 for both), and remained significant in multivariate analysis. Conclusion Testosterone in amniotic fluid did not change with gestation in the second and third trimester, raising questions about the timing of the reported early peak in the male foetus. The positive correlation between cortisol and testosterone in amniotic fluid suggests that increased foetal exposure to cortisol may also be associated with increased exposure to testosterone. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17634075&query_hl=1 ER - TY - JFULL T1 - Are cancer risks associated with exposures to ionising radiation from internal emitters greater than those in the Japanese A-bomb survivors? A1 - Little, MP A1 - Hall, P A1 - Charles, MW J1 - Radiat Environ Biophys Y1 - 2007/07/17/ SN - 0301-634X N2 - After ingestion or inhalation of radionuclides, internal organs of the human body will be exposed to ionising radiation. Current risk estimates of radiation-associated cancer from internal emitters are largely based on extrapolation of risk from high-dose externally exposed groups. Concerns have been expressed that extrapolated risk estimates from internal emitters are greatly underestimated, by factors of ten or more, thus implying a severe underestimation of the true risks. Therefore, data on cancer mortality and incidence in a number of groups who received exposure predominantly from internal emitters are examined and excess relative risks per Sv are compared with comparable (age at exposure, time since exposure, gender) matched subsets of the Japanese atomic bomb survivor cohort. Risks are examined separately for low LET and high LET internal emitters. There are eight studies informative for the effects of internal low LET radiation exposure and 12 studies informative for the effects of internal high LET radiation. For 11 of the 20 cancer endpoints (subgroups of particular study cohorts) examined in the low LET internal emitter studies, the best estimate of the excess relative risk is greater than the corresponding estimate in the Japanese atomic bomb survivors and for the other nine it is less. For four of these 20 studies, the relative risk is significantly (2-sided P < 0.05) different from that in the Japanese atomic bomb survivors, in three cases greater than the atomic bomb survivor relative risk and in one case less. Considering only those six low LET studies/endpoints with 100 or more deaths or cases, for four out of six studies/endpoints the internal emitter risk is greater than that in the Japanese atomic bomb survivors. For seven of the 24 cancer endpoints examined in the high LET internal emitter studies the best estimate of the ERR in the internal emitter study is greater than the corresponding estimate in the Japanese atomic bomb survivors and for the other 17 it is less. For six studies, the relative risk is significantly (2-sided P < 0.05) different from that in the Japanese atomic bomb survivors, in one case greater than the atomic bomb survivor relative risk and in five cases less. Considering only those eight high LET studies/endpoints with 100 or more deaths or cases, for five out of eight studies/endpoints the internal emitter risk is greater than that in the Japanese atomic bomb survivors. These results suggest that excess relative risks in the internal emitter studies do not appreciably differ from those in the Japanese atomic bomb survivors. However, there are substantial uncertainties in estimates of risks in the internal emitter studies, particularly in relation to lung cancer associated with radon daughter (alpha particle) exposure, so a measure of caution should be exercised in these conclusions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17639450&query_hl=1 ER - TY - JFULL T1 - Small molecule receptor agonists and antagonists of CCR3 provide insight into mechanisms of chemokine receptor activation. A1 - Wise, EL A1 - Duchesnes, C A1 - da Fonseca, PC A1 - Allen, RA A1 - Williams, TJ A1 - Pease, JE J1 - J Biol Chem Y1 - 2007/07/16/ SN - 0021-9258 N2 - Chemokine receptor CCR3 is highly expressed by eosinophils and signals in response to binding of the eotaxin family of chemokines, which are upregulated in allergic disorders. Consequently, CCR3 blockade is of interest as a possible therapeutic approach for the treatment of allergic disease. We have described previously a bi-specific antagonist of CCR1 and CCR3 named UCB35625, which was proposed to interact with the transmembrane residues Y41, Y113 and E287 of CCR1, all of which are conserved in CCR3. Here, we show that cells expressing the CCR3 constructs Y113A and E287Q are insensitive to antagonism by UCB35625 and also exhibit impaired chemotaxis in response to CCL11/Eotaxin suggesting that these residues are important for antagonist binding and also receptor activation. Furthermore, mutation of the residue Y113 to alanine was found to turn the antagonist UCB35625 into a CCR3 agonist. Screens of small molecule libraries identified a novel specific agonist of CCR3 named CH0076989. This was able to activate eosinophils and transfectants expressing both wild-type CCR3 and a CCR1:CCR3 chimaeric receptor lacking the CCR3 amino-terminus, indicating that this region of CCR3 is not required for CH0076989 binding. A direct interaction with the transmembrane helices of CCR3 was supported by mutation of the residues Y41, Y113 and E287 which resulted in complete loss of CH0076989 activity, suggesting that the compound mimics activation by CCL11. We conclude that both agonists and antagonists of CCR3 appear to occupy overlapping sites within the transmembrane helical bundle, suggesting a fine line between agonism and antagonism of chemokine receptors. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17635911&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 - Fluorescence lifetime tomography of live cells expressing enhanced green fluorescent protein embedded in a scattering medium exhibiting background autofluorescence. A1 - Soloviev, VY A1 - McGinty, J A1 - Tahir, KB A1 - Neil, MA A1 - Sardini, A A1 - Hajnal, JV A1 - Arridge, SR A1 - French, PM J1 - Opt Lett Y1 - 2007/07/15/ VL - 32 SN - 0146-9592 SP - 2034 EP - 2036 N2 - We present a novel fluorescence lifetime tomography system applied to a highly scattering autofluorescent phantom containing live cells expressing the fluorophore enhanced green fluorescent protein (EGFP). The fluorescence signal was excited using a fiber-laser-pumped supercontinuum source and detected using wide-field time gating imaging. To facilitate rapid 3D reconstruction of the fluorescence lifetime distribution, the time-resolved data were Fourier-transformed in time to give complex functions that formed a data set for the Fourier domain reconstruction. Initially the presence of an unspecified background autofluorescence signal impeded reconstruction of the lifetime distribution, but we show that this problem can be addressed using a simple iterative technique. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17632634&query_hl=1 ER - TY - JFULL T1 - Variation in estimated recombination rates across human populations. A1 - Graffelman, J A1 - Balding, DJ A1 - Gonzalez-Neira, A A1 - Bertranpetit, J J1 - Hum Genet Y1 - 2007/07/03/ SN - 0340-6717 N2 - Recently it has been reported that recombination hotspots appear to be highly variable between humans and chimpanzees, and there is evidence for between-person variability in hotspots, and evolutionary transience. To understand the nature of variation in human recombination rates, it is important to describe patterns of variability across populations. Direct measurement of recombination rates remains infeasible on a large scale, and population-genetic approaches can be imprecise, and are affected by demographic history. Reports to date have suggested broad similarity in recombination rates at large genomic scales and across human populations. Here, we examine recombination rate estimates at a finer population and genomic scale: 28 worldwide populations and 107 SNPs in a 1 Mb stretch of chromosome 22q. We employ analysis of variance of recombination rate estimates, corrected for differences in effective population size using genome-wide microsatellite mutation rate estimates. We find substantial variation in fine-scale rates between populations, but reduced variation within continental groups. All effects examined (SNP-pair, region, population and interactions) were highly significant. Adjustment for effective population size made little difference to the conclusions. Observed hotspots tended to be conserved across populations, albeit at varying intensities. This holds particularly for populations from the same region, and also to a considerable degree across geographical regions. However, some hotspots appear to be population-specific. Several results from studies on the population history of humans are in accordance with our analysis. Our results suggest that between-population variation in DNA sequences may underly recombination rate variation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17609980&query_hl=1 ER - TY - JFULL T1 - Apoptosis and chemo-resistance in colorectal cancer. A1 - Prabhudesai, SG A1 - Rekhraj, S A1 - Roberts, G A1 - Darzi, AW A1 - Ziprin, P J1 - J Surg Oncol Y1 - 2007/07/01/ VL - 96 SN - 0022-4790 SP - 77 EP - 88 N2 - Systemic chemotherapy plays an integral part in treating advanced colorectal cancer. However 50% of patients respond poorly or have disease progression due to resistance to chemotherapeutic agents. This article reviews the pathways that regulate apoptosis, apoptotic mechanisms through which chemotherapeutic agents mediate their effect and how deregulation of apoptotic proteins may contribute to chemo-resistance. Also discussed are potential therapeutic strategies designed to target these proteins and thereby improve response rates to chemotherapy in colorectal cancer. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17443738&query_hl=1 ER - TY - JFULL T1 - Economic factors affecting head and neck reconstructive microsurgery: the surgeons' and hospital's perspective. A1 - Deleyiannis, FW A1 - Porter, AC J1 - Plast Reconstr Surg Y1 - 2007/07// VL - 120 SN - 1529-4242 SP - 157 EP - 165 N2 - BACKGROUND: The purpose of this study was to determine the relative financial value of providing the service of free-tissue transfer for head and neck reconstruction from the surgeons' and hospital's perspective. METHODS: Medical and hospital accounting records of 58 consecutive patients undergoing head and neck resections and simultaneous free-flap reconstruction were reviewed. Software from the Center for Medicare and Medicaid Services was used to calculate anticipated Medicare payments to the surgeon based on current procedural terminology codes and to the hospital based on diagnosis-related group codes. RESULTS: The mean actual payment to the surgeon for a free flap was $2300.60. This payment was 91.6 percent ($2300 out of $2510) of the calculated payment if all payments had been reimbursed by Medicare. Total charges and total payment to the hospital for the 58 patients were $19,148,852 and $2,765,552, respectively. After covering direct costs, total hospital revenue (i.e., margin) was $1,056,886. The mostly commonly assigned diagnosis-related group code was 482 (n = 35). According to the fee schedule for that code, if Medicare had been the insurance plan for these 35 patients, the mean payment to the hospital would have been $45,840. The actual mean hospital payment was $44,133. This actual hospital payment represents 96 percent of the calculated Medicare hospital payment ($44,133 of $45,840). CONCLUSIONS: Free-flap reconstruction of the head and neck generates substantial revenue for the hospital. For their mutual benefit, hospitals should join with physicians in contract negotiations of physician reimbursement with insurance companies. Bolstered reimbursement figures would better attract and retain skilled surgeons dedicated to microvascular reconstruction. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17572558&query_hl=1 ER - TY - JFULL T1 - Bayesian shrinkage priors for detecting multiple causal variants from genome-wide association studies A1 - Hoggart, C A1 - De Iorio, M A1 - Whittakker, J A1 - Balding, D J1 - ANN HUM GENET Y1 - 2007/07// VL - 71 SN - 0003-4800 SP - 557 EP - 557 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 - Prenatal mood disturbance predicts sleep problems in infancy and toddlerhood. A1 - O'Connor, TG A1 - Caprariello, P A1 - Blackmore, ER A1 - Gregory, AM A1 - Glover, V A1 - Fleming, P A1 - ALSPAC Study Team J1 - Early Hum Dev Y1 - 2007/07// VL - 83 SN - 0378-3782 SP - 451 EP - 458 N2 - BACKGROUND: Experimental animal data link prenatal stress with sleep disturbance in offspring, but the link in humans is unclear. AIMS: To investigate the link between prenatal maternal anxiety and depression and infant sleep disturbance from 6 to 30 months of age. STUDY DESIGN: Longitudinal prospective study of a large birth cohort from pregnancy to 30 months. Questionnaire measures of anxiety and depression were completed by mothers at 18 and 32 weeks gestation and at 8 weeks and 8 months postpartum. SUBJECTS: The ALSPAC cohort, a prospective community study of women in the UK who have been followed since pregnancy. OUTCOME MEASURES: Measures of total sleep time, number of awakenings, and broadly defined sleep problems were available on children at ages 6, 18, and 30 months. RESULTS: Reliable measures of total sleep time, nighttime awakenings, and sleep problems were identified at 6, 18, and 30 months. Higher levels of prenatal maternal anxiety and depression predicted more sleep problems at 18 and 30 months, after controlling for postnatal mood and obstetric and psychosocial covariates; the association was not restricted to clinical extremes. No link with total sleep time was observed. CONCLUSIONS: Mood disturbance in pregnancy has persisting effects on sleep problems in the child, a finding that is consistent with experimental animal research. The findings add to a growing literature showing that maternal prenatal stress, anxiety, and depression may have lasting effects on child development. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17008033&query_hl=1 ER - TY - JFULL T1 - Disentangling HLA associations: Multivariate association study using Bayesian logistic regression A1 - Vignal, C A1 - Bansal, A A1 - Balding, D J1 - GENET EPIDEMIOL Y1 - 2007/07// VL - 31 SN - 0741-0395 SP - 502 EP - 502 ER - TY - JFULL T1 - The interplay between recombination and selection can confound their inference from population data - But suggests a novel genome-wide method for detecting selection A1 - O'Reilly, P A1 - Birney, E A1 - Balding, D J1 - ANN HUM GENET Y1 - 2007/07// VL - 71 SN - 0003-4800 SP - 551 EP - 552 ER - TY - JFULL T1 - The cost effectiveness of opportunistic chlamydia screening in England. A1 - Adams, EJ A1 - Turner, KM A1 - Edmunds, WJ J1 - Sex Transm Infect Y1 - 2007/07// VL - 83 SN - 1368-4973 N2 - BACKGROUND/AIM: The National Chlamydia Screening Programme (NCSP) is being implemented in England. This study aims to estimate the cost effectiveness of (a) the NCSP strategy (annual screening offer to men and women aged under 25 years) and (b) alternative screening strategies. METHODS: A stochastic, individual based, dynamic sexual network model was combined with a cost effectiveness model to estimate the complications and associated costs of chlamydial infection. The model was constructed and parameterised from the perspective of the National Health Service (NHS) (England), including the direct costs of infection, complications and screening. Unit costs were derived from standard data sources and published studies. The average and incremental cost effectiveness ratio (cost per major outcome averted or quality adjusted life year (QALY) gained) of chlamydia screening strategies targeting women and/or men of different age groups was estimated. Sensitivity analyses were done to explore model uncertainty. RESULTS: All screening strategies modelled are likely to cost the NHS money and improve health. If pelvic inflammatory disease (PID) progression is less than 10% then screening at any level is unlikely to be cost effective. However, if PID progression is 10% or higher the NCSP strategy compared to no screening appears to be cost effective. The incremental cost effectiveness analysis suggests that screening men and women aged under 20 years is the most beneficial strategy that falls below accepted thresholds. There is a high degree of uncertainty in the findings. CONCLUSIONS: Offering an annual screening test to men and women aged under 20 years may be the most cost effective strategy (that is, under accepted thresholds) if PID progression is 10% or higher. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17475686&query_hl=1 ER - TY - JFULL T1 - Management and outcome of healthy women with a persistently elevated beta-hCG. A1 - Palmieri, C A1 - Dhillon, T A1 - Fisher, RA A1 - Young, AM A1 - Short, D A1 - Mitchell, H A1 - Aghajanian, C A1 - Savage, PM A1 - Newlands, ES A1 - Hancock, BW A1 - Seckl, MJ J1 - Gynecol Oncol Y1 - 2007/07// VL - 106 SN - 0090-8258 SP - 35 EP - 43 N2 - PURPOSE: Raised serum beta human chorionic gonadotrophin (beta-hCG) not due to pregnancy can occur as a consequence of (1) gestational trophoblastic neoplasia (GTN), (2) non-gestational trophoblastic tumours, (3) a false-positive beta-hCG, (4) the menopause or (5) a high normal level. Accurate differentiation between these causes is vital to avoid potentially inappropriate investigations and therapies, which may induce infertility or other serious adverse events. Here we report the United Kingdom experience of patients with an elevated beta-hCG of initial uncertain cause and provide a clinical algorithm for the management of such cases. METHOD: The Charing Cross and Weston Park Hospital GTN databases were screened to identify patients referred with an elevated beta-hCG who were not pregnant and had no previous diagnosis of GTN. RESULTS: Between 1981 and 2004 fourteen women presented with persistently raised serum beta-hCG resulting in diagnostic problems. False-positive beta-hCG was excluded in all. Three patients developed gestational choriocarcinoma after 9-29 months. However, in 11 women no cause for the persistently elevated beta-hCG was found. One of these achieved chemotherapy-induced normalisation of serum beta-hCG, but the remaining 10 underwent surgery and/or chemotherapy without benefit. Thus, 71% (10/14) of patients remain well with unexplained elevated beta-hCG levels. CONCLUSION: Elevated serum and urinary beta-hCG levels in healthy women should be investigated systematically to exclude an underlying malignant process and to avoid inappropriate surgical and medical intervention. Long-term follow-up is required as tumours may not become apparent for many months or years. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17482245&query_hl=1 ER - TY - JFULL T1 - Turbo Genomic Control A1 - Astle, W A1 - Holmes, C A1 - Balding, D J1 - ANN HUM GENET Y1 - 2007/07// VL - 71 SN - 0003-4800 SP - 553 EP - 554 ER - TY - JFULL T1 - Association between heat shock protein 70/Hom genetic polymorphisms and uveitis in patients with sarcoidosis. A1 - Spagnolo, P A1 - Sato, H A1 - Marshall, SE A1 - Antoniou, KM A1 - Ahmad, T A1 - Wells, AU A1 - Ahad, MA A1 - Lightman, S A1 - du Bois, RM A1 - Welsh, KI J1 - Invest Ophthalmol Vis Sci Y1 - 2007/07// VL - 48 SN - 0146-0404 SP - 3019 EP - 3025 N2 - PURPOSE: The predisposition to sarcoidosis, a systemic granulomatous disorder of unknown etiology, is genetically determined, and genetics appears also to drive the disease down distinct phenotypic pathways. This study was undertaken to test the hypothesis that sarcoidosis-related uveitis represents a genetically distinct disease subset, by investigating single nucleotide polymorphisms (SNPs) in the HSP-70/1 and HSP-70/Hom genes. HSP70 molecules play a key role in the immune response by functioning both as chaperones and as inducers of proinflammatory cytokine secretion. METHODS: By sequence-specific primers-polymerase chain reaction (SSP-PCR) five SNPs were evaluated in 270 white patients with sarcoidosis, including 88 with sarcoid-related uveitis, and in 347 matched control subjects. One hundred twenty-five patients with idiopathic anterior uveitis (IAU) and 56 with idiopathic intermediate uveitis (IIU) were also included in the study as disease control subjects. RESULTS: The HSP-70/Hom rs2075800 G allele frequency was higher in the sarcoid-uveitis group than in both the sarcoid-non-uveitis and control groups (83% vs. 71%, OR = 2.00, P(c) = 0.01; and 83% vs. 66%, OR = 2.45, P(c) = 0.00005, respectively). Similar results were observed when considering the carriage frequency of the associated haplotype (HSP-70 haplotype 2) across the three study groups (47% vs. 29%, OR = 2.17, P(c) = 0.03; and 47% vs. 21%, OR = 3.26, P(c) = 0.0003, respectively). In addition, the carriage frequency of the HSP-70 haplotype 2 discriminated among sarcoid-related uveitis, IAU, and IIU (47% vs. 19%, OR = 3.26, P(c) = 0.001; and 47% vs. 23%, OR = 2.81, P(c) = 0.04, respectively). CONCLUSIONS: A strong association was found between HSP-70/Hom rs2075800 G and uveitis in patients with sarcoidosis. Further studies are needed to understand the molecular mechanisms underlying this association. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17591867&query_hl=1 ER - TY - JFULL T1 - Effect of arylamine acetyltransferase Nat3 gene knockout on N-acetylation in the mouse. A1 - Sugamori, KS A1 - Brenneman, D A1 - Wong, S A1 - Gaedigk, A A1 - Yu, V A1 - Abramovici, H A1 - Rozmahel, R A1 - Grant, DM J1 - Drug Metab Dispos Y1 - 2007/07// VL - 35 SN - 0090-9556 SP - 1064 EP - 1070 N2 - Arylamine N-acetyltransferases (NAT) catalyze the biotransformation of many important arylamine drugs and procarcinogens. NAT can either detoxify or activate procarcinogens, complicating the manner in which these enzymes may participate in enhancing or preventing toxic responses to particular agents. Mice possess three NAT isoenzymes: Nat1, Nat2, and Nat3. Whereas Nat1 and Nat2 can efficiently acetylate many arylamines, few substrates appear to be appreciably metabolized by Nat3. We generated a Nat3 knockout mouse strain and used it along with our double Nat1/2(-/-) knockout strain to further investigate the functional role of Nat3. Nat3(-/-) mice showed normal viability and reproductive capacity. Nat3 expression was very low in wild-type animals and completely undetectable in Nat3(-/-) mice. In contrast, greatly elevated expression of Nat3 transcript was observed in Nat1/2(-/-) mice. We used a transcribed marker polymorphism approach to establish that the increased expression of Nat3 in Nat1/2(-/-) mice is a positional artifact of insertion of the phosphoglycerate kinase-neomycin resistance cassette in place of the Nat1/Nat2 gene region and upstream of the intact Nat3 gene, rather than a biological compensatory mechanism. Despite the increase in Nat3 transcript, the N-acetylation of p-aminosalicylate, sulfamethazine, 2-aminofluorene, and 4-aminobiphenyl was undetectable either in vivo or in vitro in Nat1/2(-/-) animals. In parallel, no difference was observed in the in vivo clearance or in vitro metabolism of any of these substrates between wild-type and Nat3(-/-) mice. Thus, Nat3 is unlikely to play a significant role in the N-acetylation of arylamines either in wild-type mice or in mice lacking Nat1 and Nat2 activities. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17403913&query_hl=1 ER - TY - JFULL T1 - Filaggrin mutations in children with severe atopic dermatitis. A1 - Morar, N A1 - Cookson, WO A1 - Harper, JI A1 - Moffatt, MF J1 - J Invest Dermatol Y1 - 2007/07// VL - 127 SN - 1523-1747 SP - 1667 EP - 1672 N2 - Atopic dermatitis (AD) results from strong genetic and environmental interactions. AD shows genetic linkage to Chromosome 1q21. This region contains the epidermal differentiation complex (EDC), which consists of genes that form essential components of epidermal surfaces. Filaggrin (FLG) is one of these. Mutations in FLG/(R501X and 2282del4) are reported to be strongly associated with AD and to influence asthma accompanying AD. We investigated these effects in families recruited through a child with severe AD. We genotyped two panels of families, totalling 426, containing 990 affected and unaffected children. We found significant associations with AD (P=0.0001), asthma (P=0.006), and atopy (P=0.002). The FLG mutations were present in 26.7% of patients with AD, but were also present in 14.4% of children without AD. They were weakly associated with disease severity. The variants were not independently associated with asthma. The overall LOD score for genetic linkage of markers to the region was 3.57. This fell to 2.03 after accounting for the FLG mutations, indicating the presence of other genetic variants influencing AD at this locus. Our results provide further confirmation of the importance of mutations in FLG and the skin barrier in AD pathogenesis. The results indicate that investigations of other genes within the EDC should be undertaken. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17301831&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 - Mycobacterium tuberculosis Antigen 85A Induces Th-1 Immune Responses in Systemic Sarcoidosis. A1 - Hajizadeh, R A1 - Sato, H A1 - Carlisle, J A1 - Nadaf, MT A1 - Evans, W A1 - Shepherd, BE A1 - Miller, RF A1 - Kalams, SA A1 - Drake, WP J1 - J Clin Immunol Y1 - 2007/07// VL - 27 SN - 0271-9142 SP - 445 EP - 454 N2 - Sarcoidosis is a granulomatous disease of unknown etiology, characterized by a Th-1 immunophenotype. Although humoral immune responses by sarcoidosis subjects to mycobacterial proteins have been detected, mycobacterial antigens capable of inducing cellular immune responses in sarcoidosis subjects have not been reported. We used the enzyme-linked immunospot assay to assess for recognition of the Mycobacterium tuberculosis mycolyl transferase, Antigen 85A, by peripheral blood mononuclear cells from 25 sarcoidosis subjects, 22 PPD- (purified protein derivative) healthy volunteers, and 16 PPD+ healthy subjects. Reactivity to Ag85A whole protein was observed in 15 of 25 sarcoidosis subjects compared to 2 of 22 PPD- subjects (p=0.0006, Fisher's exact test) and to 14 of 16 PPD+ subjects (p=0.084, Fisher's exact test). Monoclonal antibody against HLA-DR inhibited recognition. In addition to immune recognition of Ag85A whole protein, peptide-mapping studies identified four immunogenic Ag85A peptides, which induced Th-1 immune responses in individual sarcoidosis subjects, suggesting that multiple epitopes from a mycobacterial protein may have a role in sarcoidosis immunopathogenesis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17357846&query_hl=1 ER - TY - JFULL T1 - Genetic mutations in the ras/raf/mapkinase pathway results in cherubism A1 - Idowu, BD A1 - Mangion, J A1 - Gale, RE A1 - Flanagan, AM J1 - J BONE MINER RES Y1 - 2007/07// VL - 22 SN - 0884-0431 SP - 1124 EP - 1124 ER - TY - JFULL T1 - The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia. A1 - Mohty, M A1 - Yong, AS A1 - Szydlo, RM A1 - Apperley, JF A1 - Melo, JV J1 - Blood Y1 - 2007/07/01/ VL - 110 SN - 0006-4971 SP - 380 EP - 383 N2 - Because the polycomb group gene BMI1 regulates the proliferation of both normal and leukemic stem cells, we examined whether BMI1 expression was associated with disease progression in chronic myeloid leukemia (CML). Levels of BMI1 RNA were significantly higher in patients with advanced-phase than in patients with chronic-phase CML in both CD34(+) cells (P = .006) and total peripheral-blood mononuclear cells (P < .001). E2F1, a transcription factor regulating BMI1, was up-regulated in CML compared with controls (P = .001). In a cohort of 64 CML patients, the level of BMI1 at diagnosis correlated with time to transformation to blast crisis, and the combination of low BMI1 and high proteinase-3 expression was associated in multivariate analysis with an improved overall survival (P = .001). We conclude that BMI1 may be a biomarker for the intrinsic heterogeneity of CML, and its measurement at diagnosis can help predict overall survival and thus contribute to better therapeutic decisions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17360938&query_hl=1 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 - Sendai virus-mediated CFTR gene transfer to the airway epithelium. A1 - Ferrari, S A1 - Griesenbach, U A1 - Iida, A A1 - Farley, R A1 - Wright, AM A1 - Zhu, J A1 - Munkonge, FM A1 - Smith, SN A1 - You, J A1 - Ban, H A1 - Inoue, M A1 - Chan, M A1 - Singh, C A1 - Verdon, B A1 - Argent, BE A1 - Wainwright, B A1 - Jeffery, PK A1 - Geddes, DM A1 - Porteous, DJ A1 - Hyde, SC A1 - Gray, MA A1 - Hasegawa, M A1 - Alton, EW J1 - Gene Ther Y1 - 2007/06/28/ SN - 0969-7128 N2 - The potential for gene therapy to be an effective treatment for cystic fibrosis has been hampered by the limited gene transfer efficiency of current vectors. We have shown that recombinant Sendai virus (SeV) is highly efficient in mediating gene transfer to differentiated airway epithelial cells, because of its capacity to overcome the intra- and extracellular barriers known to limit gene delivery. Here, we have identified a novel method to allow the cystic fibrosis transmembrane conductance regulator (CFTR) cDNA sequence to be inserted within SeV (SeV-CFTR). Following in vitro transduction with SeV-CFTR, a chloride-selective current was observed using whole-cell and single-channel patch-clamp techniques. SeV-CFTR administration to the nasal epithelium of cystic fibrosis (CF) mice (Cftr(G551D) and Cftr(tm1Unc)TgN(FABPCFTR)#Jaw mice) led to partial correction of the CF chloride transport defect. In addition, when compared to a SeV control vector, a higher degree of inflammation and epithelial damage was found in the nasal epithelium of mice treated with SeV-CFTR. Second-generation transmission-incompetent F-deleted SeV-CFTR led to similar correction of the CF chloride transport defect in vivo as first-generation transmission-competent vectors. Further modifications to the vector or the host may make it easier to translate these studies into clinical trials of cystic fibrosis.Gene Therapy advance online publication, 28 June 2007; doi:10.1038/sj.gt.3302991. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17597790&query_hl=1 ER - TY - JFULL T1 - [(11)C]Flumazenil PET in temporal lobe epilepsy: do we need an arterial input function or kinetic modeling? A1 - Hammers, A A1 - Panagoda, P A1 - Heckemann, RA A1 - Kelsch, W A1 - Turkheimer, FE A1 - Brooks, DJ A1 - Duncan, JS A1 - Koepp, MJ J1 - J Cereb Blood Flow Metab Y1 - 2007/06/20/ SN - 0271-678X N2 - Reduced signal on [(11)C]]flumazenil (FMZ) positron emission tomography (PET) is associated with epileptogenic foci. Linear correlations within individuals between parametric and nonparametric images of FMZ binding have been shown, and various methods have been used, without comparison of diagnostic usefulness. Using hippocampal sclerosis (HS) as a test case, we formally compare the diagnostic yield of parametric images obtained either with a parent tracer arterial plasma input function and spectral analysis (yielding volume-of-distribution (VD) images), or with an image-based input function and the simplified reference tissue model (binding potential images, BP-SRTM) with the diagnostic yield of semiquantitative-integrated (ADD) images from 10 to 20 or 20 to 40 mins (ADD1020 and ADD2040). Dynamic 90-min [(11)C]FMZ PET datasets and arterial plasma input functions were available for 15 patients with medically refractory medial temporal lobe epilepsy (TLE) and histologically verified unilateral HS and for 13 control subjects. SPM2 was used for analysis. ADD1020 and ADD2040 images showed decreased FMZ uptake ipsilateral to the epileptogenic hippocampus in 13/15 cases; 6/13 had bilateral decreases in the ADD1020 analysis and 5/13 in the ADD2040 analysis. BP-SRTM images detected ipsilateral decreases in 12/15 cases, with bilateral decreases in three. In contrast, VD images showed ipsilateral hippocampal decreases in all 15 patients, with bilateral decreases in three patients. Bilateral decreases in the ADD images tended to be more symmetrical and in one case were more marked contralaterally. Full quantification with an image-independent input should ideally be used in the evaluation of FMZ PET; at least in TLE, intrasubject correlations do not predict equivalent clinical usefulness.Journal of Cerebral Blood Flow & Metabolism advance online publication, 20 June 2007; doi:10.1038/sj.jcbfm.9600515. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17579659&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 - Laminar shear stress acts as a switch to regulate divergent functions of NF-{kappa}B in endothelial cells. A1 - Partridge, J A1 - Carlsen, H A1 - Enesa, K A1 - Chaudhury, H A1 - Zakkar, M A1 - Luong, L A1 - Kinderlerer, A A1 - Johns, M A1 - Blomhoff, R A1 - Mason, JC A1 - Haskard, DO A1 - Evans, PC J1 - FASEB J Y1 - 2007/06/08/ SN - 1530-6860 N2 - Regions of the arterial tree exposed to laminar flow, which exerts high shear stress, are protected from inflammation, endothelial cell (EC) death and atherosclerosis. TNFalpha activates NF-kappaB transcription factors, which potentially exert dual functions by inducing both proinflammatory and cytoprotective transcripts. We assessed whether laminar shear stress protects EC by modulating NF-kappaB function. Human umbilical vein EC (HUVEC) were cultured under shear stress (12 dynes/cm(2) for 16 h) using a parallel-plate flow chamber or were maintained in static conditions. Comparative real-time PCR revealed that preshearing significantly alters transcriptional responses to TNFalpha by enhancing the expression of cytoprotective molecules (Bcl-2, MnSOD, GADD45beta, A1) and suppressing proinflammatory transcripts (E-selectin, VCAM-1, IL-8). We demonstrated using assays of nuclear localization, NF-kappaB subunit phosphorylation, DNA-binding, and transcriptional activity that NF-kappaB is activated by TNFalpha in presheared HUVEC. Furthermore, a specific inhibitor revealed that NF-kappaB is essential for the induction of cytoprotective transcripts in presheared EC. Finally, we observed that NF-kappaB can be activated in vascular endothelium exposed to laminar shear stress in NF-kappaB-luciferase reporter mice, thus validating our cell culture experiments. We conclude that shear stress primes EC for enhanced NF-kappaB-dependent cytoprotective responsiveness while attenuating proinflammatory activation. Thus modulation of NF-kappaB function may underlie the atheroprotective effects of laminar shear stress.--Partridge, J., Carlsen, H., Enesa, K., Chaudhury, H., Zakkar, M., Luong, L., Kinderlerer, A., Johns, M., Blomhoff, R., Mason, J. C., Haskard, D. O., Evans, P. C. Laminar shear stress acts as a switch to regulate divergent functions of NF-kappaB in endothelial cells. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17557931&query_hl=1 ER - TY - JFULL T1 - ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. A1 - Leschziner, GD A1 - Andrew, T A1 - Pirmohamed, M A1 - Johnson, MR J1 - Pharmacogenomics J Y1 - 2007/06// VL - 7 SN - 1470-269X SP - 154 EP - 179 N2 - The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16969364&query_hl=1 ER - TY - JFULL T1 - Evaluation of molecular typing methods in characterizing a European collection of epidemic methicillin-resistant Staphylococcus aureus strains: the HARMONY collection. A1 - Cookson, BD A1 - Robinson, DA A1 - Monk, AB A1 - Murchan, S A1 - Deplano, A A1 - de Ryck, R A1 - Struelens, MJ A1 - Scheel, C A1 - Fussing, V A1 - Salmenlinna, S A1 - Vuopio-Varkila, J A1 - Cuny, C A1 - Witte, W A1 - Tassios, PT A1 - Legakis, NJ A1 - van Leeuwen, W A1 - van Belkum, A A1 - Vindel, A A1 - Garaizar, J A1 - Haeggman, S A1 - Olsson-Liljequist, B A1 - Ransjo, U A1 - Muller-Premru, M A1 - Hryniewicz, W A1 - Rossney, A A1 - O'Connell, B A1 - Short, BD A1 - Thomas, J A1 - O'Hanlon, S A1 - Enright, MC J1 - J Clin Microbiol Y1 - 2007/06// VL - 45 SN - 0095-1137 SP - 1830 EP - 1837 N2 - We analyzed a representative sample of methicillin-resistant Staphylococcus aureus (MRSA) from 11 European countries (referred to as the HARMONY collection) using three molecular typing methods used within the HARMONY group to examine their usefulness for large, multicenter MRSA surveillance networks that use these different laboratory methodologies. MRSA isolates were collected based on their prevalence in each center and their genetic diversity, assessed by pulsed-field gel electrophoresis (PFGE). PFGE groupings (< or = 3 bands difference between patterns) were compared to those made by sequencing of the variable repeats in the protein A gene spa and clonal designations based on multilocus sequence typing (MLST), combined with PCR analysis of the staphylococcal chromosome cassette containing the mec genes involved in methicillin resistance (SCCmec). A high level of discrimination was achieved using each of the three methodologies, with discriminatory indices between 89.5% and 91.9% with overlapping 95% confidence intervals. There was also a high level of concordance of groupings made using each method. MLST/SCCmec typing distinguished 10 groups containing at least two isolates, and these correspond to the majority of nosocomial MRSA clones described in the literature. PFGE and spa typing resolved 34 and 31 subtypes, respectively, within these 10 MRSA clones, with each subtype differing only slightly from the most common pattern using each method. The HARMONY group has found that the methods used in this study differ in their availability and affordability to European centers involved in MRSA surveillance. Here, we demonstrate that the integration of such technologies is achievable, although common protocols (such as we have developed for PFGE) may also be important, as is the use of centralized Internet sites to facilitate data analysis. PFGE and spa-typing data from analysis of MRSA isolates from the many centers that have access to the relevant equipment can be compared to reference patterns/sequences, and clonal designations can be made. In the majority of cases, these will correspond to those made by the (more expensive) method of choice-MLST/SCCmec typing-and these alternative methods can therefore be used as frontline typing systems for multicenter surveillance of MRSA. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17428929&query_hl=1 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 - 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 - S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase A1 - Aguilar, V A1 - Alliouachene, S A1 - Sotiropoulos, A A1 - Sobering, A A1 - Athea, Y A1 - Djouadi, F A1 - Miraux, S A1 - Thiaudiere, E A1 - Foretz, M A1 - Viollet, B A1 - Diolez, P A1 - Bastin, J A1 - Benit, P A1 - Rustin, P A1 - Carling, D A1 - Sandri, M A1 - Ventuar-Clapier, R A1 - Pende, M J1 - CELL METAB Y1 - 2007/06// VL - 5 SN - 1550-4131 SP - 476 EP - 487 N2 - S6 kinase (S6K) deletion in metazoans causes small cell size, insulin hypersensitivity, and metabolic adaptations; however, the underlying molecular mechanisms are unclear. Here we show that S6K-deficient skeletal muscle cells have increased AMP and inorganic phosphate levels relative to ATP and phosphocreatine, causing AMP-activated protein kinase (AMPK) upregulation. Energy stress and muscle cell atrophy are specifically triggered by the S6K1 deletion, independent of S6K2 activity. Two known AMPK-dependent functions, mitochondrial biogenesis and fatty acid beta-oxidation, are upregulated in S6K-deficient muscle cells, leading to a sharp depletion of lipid content, while glycogen stores are spared. Strikingly, AMPK inhibition in S6K-deficient cells restores cell growth and sensitivity to nutrient signals. These data indicate that S6K1 controls the energy state of the cell and the AMPK-dependent metabolic program, providing a mechanism for cell mass accumulation under high-calorie diet. ER - TY - JFULL T1 - Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized control trial. A1 - Kinross, J A1 - Warren, O A1 - Silk, D A1 - Darzi, A J1 - Ann Surg Y1 - 2007/06// VL - 245 SN - 0003-4932 SP - 1000 EP - 1000 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17522529&query_hl=1 ER - TY - JFULL T1 - A new pathologic scoring system for renal calcineurin-inhibitor toxicity correlates with future graft function. A1 - Cook, T J1 - Nat Clin Pract Nephrol Y1 - 2007/06// VL - 3 SN - 1745-8331 SP - 316 EP - 317 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17471278&query_hl=1 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 - Multiple molecular mechanism may account for resistanceto imatinib in resistant cell lines A1 - Pane, F A1 - Esposito, N A1 - Izzo, B A1 - Quarantelli, F A1 - Colavita, I A1 - Buonomo, T A1 - Roberti, V A1 - Soverini, S A1 - Melo, JV A1 - Martinelli, G A1 - Martinelli, R A1 - Ruoppolo, M A1 - Pane, F J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 418 EP - 418 ER - TY - JFULL T1 - Novel pathway in BCR-ABL signal transduction involves Akt-independent activation of PLC-gamma/mTOR/P70-S6 kinase A1 - Markova, B A1 - Breitenbuecher, F A1 - Melo, JV A1 - Duyster, J A1 - Huber, C A1 - Fischer, T J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 338 EP - 338 ER - TY - JFULL T1 - A high density genome-wide association study identifies novel susceptibility genes for type 2 diabetes mellitus and reveals new mechanisms for glucose intolerance A1 - Sladek, R A1 - Rocheleau, G A1 - Rung, J A1 - Dina, C A1 - Shen, LS A1 - Serre, D A1 - Boutin, P A1 - Prentki, M A1 - Posner, BI A1 - Balding, DJ A1 - Meyre, D A1 - Polychronakos, C A1 - Froguel, P J1 - DIABETES Y1 - 2007/06// VL - 56 SN - 0012-1797 SP - A94 EP - A94 ER - TY - JFULL T1 - SH3BP2, PTPN11 and NF1 mutations resulting in the cherubism phenotype A1 - Idowu, BD A1 - Mangion, J A1 - Gale, RE A1 - Flanagan, AM J1 - BONE Y1 - 2007/06// VL - 40 SN - 8756-3282 SP - S160 EP - S161 ER - TY - JFULL T1 - Analysis of 'candidate genes' for alcohol consumption in HXB/BXH rats A1 - Bhave, SV A1 - Saba, L A1 - Printz, M A1 - Flodman, R A1 - Gaydos, J A1 - Mangion, J A1 - Hubner, N A1 - Hoffman, PL A1 - Tabakoff, B J1 - ALCOHOL CLIN EXP RES Y1 - 2007/06// VL - 31 SN - 0145-6008 SP - 135A EP - 135A ER - TY - JFULL T1 - The Colorado INIA informatics weibsite - Analysis of 'candidate genes' for complextraits A1 - Bhave, SV A1 - Hornbaker, C A1 - Phang, T A1 - Saba, L A1 - Lapadat, R A1 - Kechris, K A1 - Gaydos, J A1 - McGoldrick, D A1 - Dolbey, A A1 - Soriano, B A1 - Ellington, A A1 - Ellington, E A1 - Jones, K A1 - Mangion, J A1 - Belknap, J A1 - Williams, RW A1 - Hunter, LE A1 - Hoffman, PL A1 - Talbakoff, B J1 - ALCOHOL CLIN EXP RES Y1 - 2007/06// VL - 31 SN - 0145-6008 SP - 134A EP - 134A ER - TY - JFULL T1 - A conserved sequence immediately N-terminal to the Bateman domains in AMP-activated protein kinase gamma subunits is required for the interaction with the beta subunits A1 - Viana, R A1 - Towler, MC A1 - Pan, DA A1 - Carling, D A1 - Viollet, B A1 - Hardie, DG A1 - Sanz, P J1 - J BIOL CHEM Y1 - 2007/06/01/ VL - 282 SN - 0021-9258 SP - 16117 EP - 16125 N2 - Mammalian AMP-activated protein kinase is a serine/threonine protein kinase that acts as a sensor of cellular energy status. AMP-activated protein kinase is a heterotrimer of three different subunits, i.e. alpha, beta and gamma, with alpha being the catalytic subunit and beta and gamma having regulatory roles. Although several studies have defined different domains in alpha and beta involved in the interaction with the other subunits of the complex, little is known about the regions of the gamma subunits involved in these interactions. To study this, we have made sequential deletions from the N termini of the gamma subunit isoforms and studied the interactions with alpha and beta subunits, both by two-hybrid analysis and by co-immunoprecipitation. Our results suggest that a conserved region of 20-25 amino acids in gamma 1, gamma 2, and gamma 3, immediately N-terminal to the Bateman domains, is required for the formation of a functional, active alpha beta gamma complex. This region is required for the interaction with the beta subunits. The interaction between the beta and gamma subunits does not require this region and occurs instead within the Bateman domains of the gamma subunit, although the beta-gamma interaction does appear to stabilize the beta-gamma interaction. In addition, sequential deletions from the C termini of the gamma subunits indicate that deletion of any of the CBS (cystathionine beta-synthase) motifs prevents the formation of a functional complex with the alpha and beta subunits. ER - TY - JFULL T1 - Functional characterization of point mutations in the LDLR gene found in Portuguese patients with clinical diagnosis of familial hypercholesterolaemia. A1 - Silva, S A1 - Patel, D A1 - Bourbon, M A1 - Soutar, AK J1 - ATHEROSCLEROSIS SUPP Y1 - 2007/06// VL - 8 SN - 1567-5688 SP - 213 EP - 213 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 - The use of isobaric tag peptide labeling (iTRAQ) and mass spectrometry to examine rare, primitive hematopoietic cells from patients with chronic myeloid leukemia A1 - Griffiths, SD A1 - Burthem, J A1 - Unwin, RD A1 - Holyoake, TL A1 - Melo, JV A1 - Lucas, GS A1 - Whetton, AD J1 - MOL BIOTECHNOL Y1 - 2007/06// VL - 36 SN - 1073-6085 SP - 81 EP - 89 N2 - Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell disease, associated with a t(9, 22) chromosomal translocation leading to formation of the BCR/ABL chimeric protein, which has an intrinsic tyrosine kinase activity. Recently, the BCR/ABL tyrosine kinase inhibitor imatinib mesylate (imatinib) has been successfully used clinically, although, disease relapse can still occur. The precise detail of the mechanism by which CML cells respond to imatinib is still unclear. We therefore systematically examined the effects of imatinib on the primitive CML cell proteome, having first established that the drug inhibits proliferation and induces increased apoptosis and differentiation. To define imatinib-induced effects on the CML proteome, we employed isobaric tag peptide labeling (iTRAQ) coupled to two-dimensional liquid chromatography/tandem mass spectrometry. Given the limited clinical material available, the isobaric tag approach identified a large population of proteins and provided relative quantification on four samples at once. Novel consequences of the action of imatinib were identified using this mass spectrometric approach. DEAD-box protein 3, heat shock protein 105 kDa, and peroxiredoxin-3 were identified as potential protein markers for response to imatinib. 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 - Heparin-bonded circuits versus nonheparin-bonded circuits: an evaluation of their effect on clinical outcomes. A1 - Mangoush, O A1 - Purkayastha, S A1 - Haj-Yahia, S A1 - Kinross, J A1 - Hayward, M A1 - Bartolozzi, F A1 - Darzi, A A1 - Athanasiou, T J1 - Eur J Cardiothorac Surg Y1 - 2007/06// VL - 31 SN - 1010-7940 SP - 1058 EP - 1069 N2 - Heparinization of the blood contact surface in cardiopulmonary bypass circuits has been promoted as an important step in the development of open heart surgery. As it decreases the inflammatory response resulting from the extracorporeal circulation, it may have a positive effect on clinical outcomes. This meta-analysis was carried out to examine if heparin-bonded circuits (HBCs) reduce the need for blood products and improve overall clinical outcome. A systematic literature search was performed to identify randomized controlled trials reporting outcomes of HBCs compared with non-HBCs. Primary outcomes assessed were postoperative blood/blood-product transfusion and blood loss. Secondary outcomes included all-cause mortality, acute postoperative myocardial infarction, stroke, re-sternotomy for postoperative bleeding, wound infection, atrial fibrillation, duration of ventilation, intensive care unit (ICU) and hospital-length of stay (LOS). Random effects meta-analytical techniques were applied to identify differences in outcomes between the two groups. Quality of the included studies and heterogeneity were assessed. From an initial review of 762-published studies, 41-randomized trials fulfilled the inclusion criteria, leaving 3434-patients' data for analysis. HBCs significantly decreased the incidence of blood transfusion required (OR=0.8; 95% CI=0.6:0.9, P=0.004). It also significantly decreased re-sternotomy (OR=0.6; 95% CI=0.4:0.8, P=0.002), duration of ventilation (WMD= -1.3h; 95% CI= -1.9:-0.6, P<0.001), ICU-LOS (WMD= -9.3h; 95% CI=-14.7:-3.9, P<0.001) and hospital-LOS (WMD= -0.5 day; 95% CI= -0.9:-0.1, P=0.02). HBCs had no effect on other adverse events evaluated. Although HBCs showed a positive effect on some of the clinical outcomes, we identified only marginal differences for other outcomes. Further evaluation of the cost-effectiveness of this technology is required. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17306555&query_hl=1 ER - TY - JFULL T1 - The polycomb group BMI-1 gene is a molecular marker for predicting prognosis of chronic myeloid leukaemia A1 - Mohty, M A1 - Yong, ASM A1 - Szydlo, RM A1 - Apperley, JF A1 - Melo, JV J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 196 EP - 197 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 - Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide through glutathione-depletion in imatinib-resistant cells A1 - Konig, H A1 - Hartel, N A1 - Schultheis, B A1 - Schatz, M A1 - Lorentz, C A1 - Melo, JV A1 - Hehlmann, R A1 - Hochhaus, A A1 - La Rosee, P J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 838 EP - 841 N2 - The development of resistance to imatinib mesylate may partly depend on high Bc-Abl-expression levels. Arsenic trioxide (ATO) has Bcr-Abl suppressing activity in vitro. Here we investigated means to improve ATO activity in CML by modulating cellular glutathione (GSH), a key regulator of ATO-activity in malignant disease. Our studies demonstrate that depletion of cellular glutathione using dl-buthionine-[S,R]-sulfoximine (BSO) enhances ATO activity against CML cells. GSH-depletion promotes enhanced Bcr-Abl specific activity of ATO through avid repression of Bcr-Abl protein levels and total cellular Bcr-Abl activity. These data provide a rationale for the clinical development of optimized ATO-based regimens through incorporation of GSH-modulators in CML treatment. ER - TY - JFULL T1 - Foxs and Ets in the transcriptional regulation of endothelial cell differentiation and angiogenesis. A1 - Dejana, E A1 - Taddei, A A1 - Randi, AM J1 - Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Y1 - 2007/06// IS - Issue 2 VL - Volume 1775 PB - Elsevier B.V. SP - 298 EP - 312 ER - TY - JFULL T1 - Chronic myeloid leukaemia as a model of disease evolution in human cancer. A1 - Melo, JV A1 - Barnes, DJ J1 - Nat Rev Cancer Y1 - 2007/06// VL - 7 SN - 1474-175X SP - 441 EP - 453 N2 - Chronic myeloid leukaemia (CML) can be considered as a paradigm for neoplasias that evolve through a multi-step process. CML is also one of the best examples of a disease that can be targeted by molecular therapy; however, the success of new 'designer drugs' is largely restricted to the chronic phase of the disease. If not cured at this stage, CML invariably progresses and transforms into an acute-type leukaemia undergoing a 'blast crisis'. The causes of this transformation are still poorly understood. What mechanisms underlie this progression, and are they shared by other common cancers? L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17522713&query_hl=1 ER - TY - JFULL T1 - When is a double Philadelphia not a double Philadelphia A1 - Brazma, D A1 - Grace, C A1 - Virgili, A A1 - Howard, J A1 - Chanalaris, A A1 - Melo, JV A1 - Apperley, JF A1 - Nacheva, EP J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 202 EP - 202 ER - TY - JFULL T1 - Nondestructive mechanical release of ordered polymer microfiber arrays from porous templates. A1 - Grimm, S A1 - Schwirn, K A1 - Göring, P A1 - Knoll, H A1 - Miclea, PT A1 - Greiner, A A1 - Wendorff, JH A1 - Wehrspohn, RB A1 - Gösele, U A1 - Steinhart, M J1 - Small Y1 - 2007/06// VL - 3 SN - 1613-6829 SP - 993 EP - 1000 N2 - The fabrication of one-dimensional (1D) nanostructures and microstructures inside the pores of porous templates is intensively investigated. The release of these structures is commonly accomplished by etching and destroying the templates. The 1D nanostructures and microstructures tend to condense because of the occurrence of capillary forces during drying of the specimens. It is shown that highly ordered arrays of polymer microfibers can be easily detached from silanized porous templates by mechanical lift-off. This procedure leaves the templates intact, thus allowing their recycling, and does not involve the use of solutions or solvents, thus circumventing condensation. Therefore, mechanical lift-off may enable the up-scaling of template-based approaches to the fabrication of highly ordered assemblies of 1D nanostructures and microstructures. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17352430&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 - Quality, size, and composition of pediatric endobronchial biopsies in cystic fibrosis. A1 - Regamey, N A1 - Hilliard, TN A1 - Saglani, S A1 - Zhu, J A1 - Scallan, M A1 - Balfour-Lynn, IM A1 - Rosenthal, M A1 - Jeffery, PK A1 - Alton, EW A1 - Bush, A A1 - Davies, JC J1 - Chest Y1 - 2007/06// VL - 131 SN - 0012-3692 SP - 1710 EP - 1717 N2 - BACKGROUND: Studies on airway remodeling in children with cystic fibrosis (CF) may be hampered by difficulty in obtaining evaluable endobronchial biopsy specimens because of large amounts of mucus and inflammation in the CF airway. We prospectively assessed how the quality of biopsy specimens obtained from children with CF compare with those from children with other airway diseases. METHODS: Fiberoptic bronchoscopy with endobronchial biopsy was performed in 67 CF children (age range, 0.2 to 16.8 years), 34 children with wheeze/asthma (W/A), and 64 control children with chronic respiratory symptoms. Up to three biopsy specimens were taken and stained with hematoxylin and eosin. Biopsy specimen size and structural composition were quantified using stereology. RESULTS: At least one evaluable biopsy specimen was obtained in 72% of CF children, in 79% of children with W/A, and in 72% of control subjects (difference was not significant). The use of large biopsy forceps (2.0 mm) rather than small biopsy forceps (1.0 mm) [odds ratio (OR), 5.8; 95% confidence interval (CI), 1.1 to 29.8; p = 0.037] and the number of biopsy specimens taken (odds ratio, 2.6; 95% confidence interval, 1.3 to 5.2; p = 0.006) significantly contributed to the success rate. Biopsy size and composition were similar between groups, except that CF children and those patients with W/A had a higher percentage of the biopsy specimen composed of muscle than did control subjects (median 6.2% and 9.7% vs 0.9%, respectively; p = 0.002). CONCLUSIONS: Biopsy size and quality are adequate for the study of airway remodeling in CF children as young as 2 months of age. Researchers should use large forceps when possible and take at least two biopsy specimens per patient. An increased airway smooth muscle content of the airway mucosa may contribute to the pathophysiology of CF lung disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17317731&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 - Integrated genetic linkage analysis and expression profiling in the rat heart to identify primary drivers of cardiac hypertrophy A1 - Sarwar, R A1 - Petretto, E A1 - Lu, H A1 - Kumaran, M A1 - Schroen, B A1 - Fischer, J A1 - Hubner, N A1 - Mangion, J A1 - Pinto, Y A1 - Pravenec, M A1 - Aitman, T A1 - Cook, S J1 - HEART Y1 - 2007/06// VL - 93 SN - 1355-6037 SP - A6 EP - A6 ER - TY - JFULL T1 - Airway remodelling in children with cystic fibrosis. A1 - Hilliard, TN A1 - Regamey, N A1 - Shute, J A1 - Nicholson, A A1 - Alton, EW A1 - Bush, A A1 - Davies, JC J1 - Thorax Y1 - 2007/05/25/ SN - 0040-6376 N2 - BACKGROUND: The relationship between airway structural changes and inflammation is unclear in early cystic fibrosis (CF) lung disease. OBJECTIVE: To determine changes of airway remodelling in children with CF, compared with appropriate disease and healthy controls. METHODS: Bronchoalveolar lavage and endobronchial biopsy were performed in a cross-sectional study of 43 children with CF (aged 0.3 to 16.8 years), 7 children with primary ciliary dyskinesia (PCD), 26 children with chronic respiratory symptoms (CRS) investigated for recurrent infection and/or cough, and 7 control children with no lower airway symptoms. Inflammatory cells, cytokines, proteases and matrix constituents were measured in bronchoalveolar lavage fluid (BALF). Reticular basement membrane (RBM) thickness was measured on biopsies using light microscopy. RESULTS: Increased concentrations of elastin, glycosaminoglycans and collagen were found in CF BALF compared to the CRS group and controls, and each correlated with elastase activity, MMP-9 and neutrophil concentration. Levels of inflammatory markers and matrix components were similar in the PCD and CF groups. In the CF group, both elastin concentration and MMP-9:TIMP-1 ratio, correlated negatively with FEV1 (r=-0.45, p<0.05 and r=-0.47, p<0.05 respectively). Median RBM thickness was greater in the CF group (5.9 mm) than controls (4.0 mm, p<0.01), and correlated with transforming growth factor-beta1 (TGF-beta1) concentration (r=0.53, p=0.01); however, there was no correlation with pulmonary function. CONCLUSIONS: This study provides evidence for two forms of airway remodelling in children with CF: firstly, matrix breakdown which correlates with proteases and pulmonary function, and secondly RBM thickening, related to TGF-beta1 concentration. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17526676&query_hl=1 ER - TY - JFULL T1 - The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas. A1 - Takaya, S A1 - Hashikawa, K A1 - Turkheimer, FE A1 - Mottram, N A1 - Deprez, M A1 - Ishizu, K A1 - Kawashima, H A1 - Akiyama, H A1 - Fukuyama, H A1 - Banati, RB A1 - Roncaroli, F J1 - J Neurooncol Y1 - 2007/05/23/ SN - 0167-594X N2 - The peripheral benzodiazepine receptor (PBR) is a 18 kDa molecule mainly involved in cholesterol transport through the mitochondrial membrane. In microglia, PBR is expressed from the earliest stages of activation and appears to exert a pro-inflammatory function. This molecule is commonly up-regulated in inflammatory, degenerative, infective and ischaemic lesions of the central nervous system but it has never been reported in glioma-infiltrating microglia. We examined two anaplastic astrocytomas showing minimal contrast-enhancement and therefore little damage of the blood brain barrier to minimise the presence of blood borne macrophages within tumour tissue. The two lesions were studied in vivo using positron emission tomography (PET) with the specific PBR ligand [(11)C](R)-PK11195 and the corresponding tumour tissue was investigated with an anti-PBR antibody. Glioma-infiltrating microglia were characterised for molecules involved in antigen presentation and cytotoxic activity. As comparison, PBR was investigated in three brains with multiple sclerosis (MS) and three with Parkinson's disease (PD). The expression profile of four anaplastic astrocytomas was also exploited and results were compared to the profile of eleven samples of normal temporal lobe and nine cases of PD. PET studies showed that [(11)C](R)-PK11195 binding was markedly lower in tumours than in the contralateral grey matter. Pathological investigation revealed that glioma-infiltrating microglia failed to express PBR and cytotoxic molecules although some cells still expressed antigen presenting molecules. PBR and cytotoxic molecules were highly represented in MS and PD. Evaluation of microarray datasets confirmed these differences. Our results demonstrated PBR suppression in glioma-infiltrating microglia and suggested that PBR may have a relevant role in modulating the anti-tumour inflammatory response in astrocytic tumours. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17520179&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 - 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 - 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 - 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 - A systematic comparison of kinetic modelling methods generating parametric maps for [(11)C]-(R)-PK11195. A1 - Anderson, AN A1 - Pavese, N A1 - Edison, P A1 - Tai, YF A1 - Hammers, A A1 - Gerhard, A A1 - Brooks, DJ A1 - Turkheimer, FE J1 - Neuroimage Y1 - 2007/05/15/ VL - 36 SN - 1053-8119 SP - 28 EP - 37 N2 - [(11)C]-(R)-PK11195 is presently the most widely used radiotracer for the monitoring of microglia activity in the central nervous system (CNS). Microglia, the resident immune cells of the brain, play a critical role in acute and chronic diseases of the central nervous system and in host defence against neoplasia. The purpose of this investigation was to evaluate the reliability and sensitivity of five kinetic modelling methods for the formation of parametric maps from dynamic [(11)C]-(R)-PK11195 studies. The methods we tested were the simplified reference tissue model (SRTM), basis pursuit, a simple target-to-reference ratio, the Logan plot and a wavelet based Logan plot. For the reliability assessment, the test-retest data consisted of four Alzheimer's patients that were scanned twice at approximately a six-week interval. For the sensitivity assessment, comparison of [(11)C]-(R)-PK11195 binding in Huntington's disease (HD) patients and normal subjects was performed using a group contrast to localize significant increases in mean pixel volume of distribution (VD) in HD. In all instances, a reference region kinetic extracted by a supervised clustering technique was used as input function. Reliability was assessed by use of the intra-class correlation coefficient (ICC) across a wide set of anatomical regions and it was found that the wavelet-based Logan plot, basis pursuit and SRTM gave the highest ICC values on average. The same methods produced the highest z-scores resulting from increases in mean striatal VD in HD patients compared with controls. The reference-to-target ratio and the Logan graphical approach were significantly less reliable and less sensitive. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17398120&query_hl=1 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 - Resistance to imatinib mesylate in chronic myeloid leukaemia. A1 - Melo, JV A1 - Chuah, C J1 - Cancer Lett Y1 - 2007/05/08/ VL - 249 SN - 0304-3835 SP - 121 EP - 132 N2 - Despite the remarkable results achieved with imatinib for the treatment of chronic myeloid leukaemia, the emergence of resistance to this tyrosine kinase inhibitor has become a significant problem. Much progress has been recently made in elucidating the mechanisms which underlie imatinib resistance. The most common cause of such drug resistance is the selection of leukaemic clones with point mutations in the Abl kinase domain leading to amino acid substitutions which prevent the appropriate binding of the drug. Other mechanisms include genomic amplification of BCR-ABL and modulation of drug efflux or influx transporters. There is a pressing need, therefore, to develop and test novel drugs and strategies. Two such compounds are now being explored in clinical trials. This review will describe the molecular basis of imatinib-resistance and strategies to overcome resistance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16949736&query_hl=1 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 - 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 - T lymphocyte rolling and recruitment into peripheral lymph nodes is regulated by a saturable density of L-selectin (CD62L). A1 - Galkina, E A1 - Florey, O A1 - Zarbock, A A1 - Smith, BR A1 - Preece, G A1 - Lawrence, MB A1 - Haskard, DO A1 - Ager, A J1 - Eur J Immunol Y1 - 2007/05// VL - 37 SN - 0014-2980 SP - 1243 EP - 1253 N2 - L-selectin mediates tethering and rolling of lymphocytes in high endothelial venules (HEV) of lymph nodes (LN) and of leukocytes at inflammatory sites. We used transgenic mice expressing varying levels of wild-type or a non-cleavable mutant form of L-selectin on T cells to determine the relationship between L-selectin density, tethering and rolling, and migration into LN. T cells expressing supraphysiological levels of either wild-type or non-cleavable L-selectin showed rolling parameters similar to C57BL/6 T cells in hydrodynamic flow assays and during rolling in Peyer's patch HEV. In contrast, PMA- or antigen-activated T cells and L-selectin(+/-) T cells expressing subphysiological levels of L-selectin showed reduced numbers of rolling cells with increased rolling velocity. Short-term homing studies showed that elevated expression of L-selectin above physiological levels had no effect on T cell migration to LN; however, low L-selectin expression resulted in reduced T cell homing to LN. Thus, T lymphocyte migration into LN is regulated by the density of cell surface L-selectin. In addition, there is a saturable density of L-selectin required for optimal homing to PLN in C57BL/6 mice, the L-selectin level on circulating naive T cells promotes optimal homing, and increased expression above saturating levels promotes no further increase in T cell recruitment. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17429841&query_hl=1 ER - TY - JFULL T1 - Early growth and adult respiratory function in men and women followed from the fetal period to adulthood. A1 - Canoy, D A1 - Pekkanen, J A1 - Elliott, P A1 - Pouta, A A1 - Laitinen, J A1 - Hartikainen, AL A1 - Zitting, P A1 - Patel, S A1 - Little, MP A1 - Järvelin, MR J1 - Thorax Y1 - 2007/05// VL - 62 SN - 0040-6376 SP - 396 EP - 402 N2 - BACKGROUND: While some studies suggest that poor fetal growth rate, as indicated by lower birth weight, is associated with poor respiratory function in childhood, findings among adults remain inconsistent. A study was undertaken to determine the association between early growth and adult respiratory function. METHODS: A longitudinal birth cohort study was performed of 5390 men and women born full term and prospectively followed from the fetal period to adulthood. Weight at birth and infancy were recorded, and forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were assessed by standard spirometry at age 31 years. RESULTS: Adult FEV(1) and FVC increased linearly with higher birth weight in both men and women with no apparent threshold. After adjustment for sex, adult height and other potential confounders operating through the life course, every 500 g higher birth weight was associated with a higher FEV(1) of 53.1 ml (95% CI 38.4 to 67.7) and higher FVC of 52.5 ml (95% CI 35.5 to 69.4). These positive associations persisted across categories of smoking, physical activity and body mass index, with the lowest respiratory function noted among those with lower birth weight who were smokers, led a sedentary lifestyle or were overweight. Weight gain in infancy was also positively associated with adult lung function. CONCLUSION: Birth weight is continuously and independently associated with adult respiratory function. It is plausible that poor growth in early life may restrict normal lung growth and development, which could have long-term consequences on lung function later in life. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17105780&query_hl=1 ER - TY - JFULL T1 - Genetics of sarcoidosis. A1 - Spagnolo, P A1 - du Bois, RM J1 - Clin Dermatol Y1 - 2007/05// VL - 25 SN - 0738-081X SP - 242 EP - 249 N2 - The predisposition to sarcoidosis is genetically determined, and genetics appears also to account for the variability in clinical phenotype and behaviour. Many genetic loci have been investigated to date, mainly in case-control association studies. However, only a small number of human leukocyte antigen (HLA) alleles have been consistently associated with sarcoidosis susceptibility/phenotype. In this regard, the association between Löfgren's syndrome and the extended HLA-DRB1*0301/DQB1*0201 haplotype is probably the most extensively reproduced. Several, generally less convincing, associations have been also reported. Of these, the chemokine receptor and butyrophilin-like 2 (BTNL2) associations are most promising. However, two major limitations of genetic studies are that the understanding of the biological relevance of gene variations in the genome is still incomplete and that the reported associations need to be verified in populations of different ethnicities. Despite a number of intriguing hypotheses, what causes sarcoidosis remains obscure. Genetic studies and, importantly, functional analysis of candidate genes will provide insight into pathogenesis and disease risk. However, if, as many believe, sarcoidosis is a heterogeneous collection of disorders, a critical step will be to carefully refine the clinical phenotype, as genetic studies of complex diseases are more rewording if a very specific disease subset is addressed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17560301&query_hl=1 ER - TY - JFULL T1 - Antiendothelial cell antibodies mediate enhanced leukocyte adhesion to cytokine-activated endothelial cells through a novel mechanism requiring cooperation between Fc{gamma}RIIa and CXCR1/2. A1 - Florey, OJ A1 - Johns, M A1 - Esho, OO A1 - Mason, JC A1 - Haskard, DO J1 - Blood Y1 - 2007/05/01/ VL - 109 SN - 0006-4971 SP - 3881 EP - 3889 N2 - Antiendothelial cell antibodies (AECAs) are commonly detectable in diseases associated with vascular injury, including systemic lupus erythematosus (SLE), systemic sclerosis, Takayasu arteritis, Wegener granulomatosis, Behçet syndrome, and transplant arteriosclerosis. Here, we explore the hypothesis that these antibodies might augment polymorphonuclear leukocyte (PMN) adhesion to endothelium in inflammation. Initially, we established that a mouse IgG mAb bound to endothelial cells (ECs) significantly increased PMN adhesion to cytokine-stimulated endothelium in an FcgammaRIIa-dependent manner. Neutralizing antibodies, and adenoviral transduction of resting ECs, demonstrated that the combination of E-selectin, CXCR1/2, and beta(2) integrins is both necessary and sufficient for this process. We observed an identical mechanism using AECA IgG isolated directly from patients with SLE. Assembled immune complexes also enhanced PMN adhesion to endothelium, but, in contrast to adhesion because of AECAs, this process did not require CXCR1/2, was not inhibited by pertussis toxin, and was FcgammaRIIIb rather than FcgammaRIIa dependent. These data are the first to demonstrate separate nonredundant FcgammaRIIa and FcgammaRIIIb-mediated mechanisms by which EC-bound monomeric IgG and assembled immune complexes amplify leukocyte adhesion under dynamic conditions. Furthermore, the observation that FcgammaRIIa and CXCR1/2 cooperate to enhance PMN recruitment in the presence of AECAs suggests a mechanism whereby AECAs may augment tissue injury during inflammatory responses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17244681&query_hl=1 ER - TY - JFULL T1 - Direct quantitative trait locus mapping of mammalian metabolic phenotypes in diabetic and normoglycemic rat models. A1 - Dumas, ME A1 - Wilder, SP A1 - Bihoreau, MT A1 - Barton, RH A1 - Fearnside, JF A1 - Argoud, K A1 - D'Amato, L A1 - Wallis, RH A1 - Blancher, C A1 - Keun, HC A1 - Baunsgaard, D A1 - Scott, J A1 - Sidelmann, UG A1 - Nicholson, JK A1 - Gauguier, D J1 - Nat Genet Y1 - 2007/05// VL - 39 SN - 1061-4036 SP - 666 EP - 672 N2 - Characterizing the relationships between genomic and phenotypic variation is essential to understanding disease etiology. Information-dense data sets derived from pathophysiological, proteomic and transcriptomic profiling have been applied to map quantitative trait loci (QTLs). Metabolic traits, already used in QTL studies in plants, are essential phenotypes in mammalian genetics to define disease biomarkers. Using a complex mammalian system, here we show chromosomal mapping of untargeted plasma metabolic fingerprints derived from NMR spectroscopic analysis in a cross between diabetic and control rats. We propose candidate metabolites for the most significant QTLs. Metabolite profiling in congenic strains provided evidence of QTL replication. Linkage to a gut microbial metabolite (benzoate) can be explained by deletion of a uridine diphosphate glucuronosyltransferase. Mapping metabotypic QTLs provides a practical approach to understanding genome-phenotype relationships in mammals and may uncover deeper biological complexity, as extended genome (microbiome) perturbations that affect disease processes through transgenomic effects may influence QTL detection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17435758&query_hl=1 ER - TY - JFULL T1 - Ontogeny of foetal exposure to maternal cortisol using midtrimester amniotic fluid as a biomarker. A1 - Sarkar, P A1 - Bergman, K A1 - Fisk, NM A1 - O'Connor, TG A1 - Glover, V J1 - Clin Endocrinol (Oxf) Y1 - 2007/05// VL - 66 SN - 0300-0664 SP - 636 EP - 640 N2 - OBJECTIVE: There is increasing evidence that antenatal stress has long-lasting effects on child development, but there is less accord on the mechanisms and the gestational window of susceptibility. One possible mechanism is by foetal exposure to maternal cortisol. To explore this, we investigated the relationship between cortisol in maternal plasma and amniotic fluid, and any moderating influence of gestational age. PATIENTS AND MEASUREMENTS: Two hundred and sixty-seven women awaiting amniocentesis for karyotyping were studied. Samples were collected between 0900 and 1730 h. Gestational age was determined to the nearest day by ultrasound biometry and time of collection noted to the nearest 15 min. Total cortisol was measured by radioimmunoassay in paired amniotic fluid and maternal blood samples (n = 267) [gestation range 15-37 weeks, median 17 weeks (119 days)]. RESULTS: Both maternal and amniotic fluid cortisol levels increased with gestation (r = 0.25, P < 0.001; r = 0.33 P < 0.001, respectively). Amniotic fluid cortisol was positively correlated with time of collection (r = 0.22, P < 0.001) and negatively with maternal age (r =-0.24, P < 0.001). There was a positive correlation between amniotic fluid cortisol with maternal plasma levels (r = 0.32, P < 0.001), which persisted after multivariate analysis controlling for gestation, time of collection and maternal age. The association appeared to be dependent on gestational age, being nonsignificant at 15-16 weeks' gestation and increasing in strength thereafter. CONCLUSION: This study shows a positive correlation between maternal and amniotic fluid cortisol levels, which becomes robust from 17 to 18 weeks onwards. The results provide support for the hypothesis that alterations in maternal cortisol may be reflected in amniotic fluid levels from this gestation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17492950&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 - Use of ultrasound to enhance nonviral lung gene transfer in vivo. A1 - Xenariou, S A1 - Griesenbach, U A1 - Liang, HD A1 - Zhu, J A1 - Farley, R A1 - Somerton, L A1 - Singh, C A1 - Jeffery, PK A1 - Ferrari, S A1 - Scheule, RK A1 - Cheng, SH A1 - Geddes, DM A1 - Blomley, M A1 - Alton, EW J1 - Gene Ther Y1 - 2007/05// VL - 14 SN - 0969-7128 SP - 768 EP - 774 N2 - We have assessed if high-frequency ultrasound (US) can enhance nonviral gene transfer to the mouse lung. Cationic lipid GL67/pDNA, polyethylenimine (PEI)/pDNA and naked plasmid DNA (pDNA) were delivered via intranasal instillation, mixed with Optison microbubbles, and the animals were then exposed to 1 MHz US. Addition of Optison alone significantly reduced the transfection efficiency of all three gene transfer agents. US exposure did not increase GL67/pDNA or PEI/pDNA gene transfer compared to Optison-treated animals. However, it increased naked pDNA transfection efficiency by approximately 15-fold compared to Optison-treated animals, suggesting that despite ultrasound being attenuated by air in the lung, sufficient energy penetrates the tissue to increase gene transfer. US-induced lung haemorrhage, assessed histologically, increased with prolonged US exposure. The left lung was more affected than the right and this was mirrored by a lesser increase in naked pDNA gene transfer, in the left lung. The positive effect of US was dependent on Optison, as in its absence US did not increase naked pDNA transfection efficiency. We have thus established proof of principle that US can increase nonviral gene transfer, in the air-filled murine lung. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17301842&query_hl=1 ER - TY - JFULL T1 - Intraperitoneal chemotherapy as first-line treatment in the management of epithelial ovarian cancer. A1 - Rekhraj, S A1 - Kinross, J A1 - Prabhudesai, S A1 - Darzi, A A1 - Ziprin, P J1 - Mini Rev Med Chem Y1 - 2007/05// VL - 7 SN - 1389-5575 SP - 509 EP - 517 N2 - Recent evidence has suggested improved outcomes following incorporation of intraperitoneal chemotherapy administration with intravenous systemic chemotherapy as first-line treatment of small volume residual epithelial ovarian cancer. This review focuses on the mechanism of actions of the chemotherapeutic drugs and reviews the possible reasons for the superior outcomes of intraperitoneal chemotherapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17504186&query_hl=1 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 - The permeability transition pore in cell death. A1 - Grimm, S A1 - Brdiczka, D J1 - Apoptosis Y1 - 2007/05// VL - 12 SN - 1360-8185 SP - 841 EP - 855 N2 - The permeability transition pore (PT-pore) is a multi-component protein aggregate in mitochondria that comprises factors in the inner as well as in the outer mitochondrial membrane. This complex has two functions: firstly, it regulates the integration of oxidative phosphorylation into the cellular energy household and secondly, it induces cell death when converted into an unspecific channel. The latter causes a collapse of the mitochondrial membrane potential and activates a chain of events that culminate in the demise of the cell. It has been controversial for some time whether the PT-pore is causative for or only amplifies a signal of cell death but novel results confirm a central role of this protein complex for cell death induction. While a considerable body of data exist on its subunit composition, recent genetic knock-out experiments suggest that the identity of the core factors of the PT-pore is still unresolved. Moreover, accumulating evidence point to a much more complex composition of this protein complex than anticipated. Here, we review the current knowledge of its subunit composition, the evidence of a role in cell death, and we propose a model for the activation of the PT-pore for cell death. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17453156&query_hl=1 ER - TY - JFULL T1 - Let science speak for itself A1 - Butler, D A1 - Chambon, P A1 - Brezin, E A1 - Corrignan, M A1 - Trautmann, A A1 - Choulika, A A1 - Froguel, P A1 - Rutherford, W J1 - NATURE Y1 - 2007/04/19/ VL - 446 SN - 0028-0836 SP - 850 EP - U1 ER - TY - JFULL T1 - Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. A1 - Crozat, K A1 - Hoebe, K A1 - Ugolini, S A1 - Hong, NA A1 - Janssen, E A1 - Rutschmann, S A1 - Mudd, S A1 - Sovath, S A1 - Vivier, E A1 - Beutler, B J1 - J Exp Med Y1 - 2007/04/16/ VL - 204 SN - 0022-1007 SP - 853 EP - 863 N2 - Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea-induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60-million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17420270&query_hl=1 ER - TY - JFULL T1 - Upregulation of the TGF beta signalling pathway by Bcr-Abl: Implications for haemopoietic cell growth and chronic myeloid leukaemia A1 - Moller, GMO A1 - Frost, V A1 - Melo, JV A1 - Chantry, A J1 - FEBS LETT Y1 - 2007/04/03/ VL - 581 SN - 0014-5793 SP - 1329 EP - 1334 N2 - Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by uncontrolled growth of progenitor cells expressing the tyrosine kinase fusion gene product, Bcr-Abl. At present, little is known regarding how TGF beta, and downstream Smad transcription factors, influence CML cell proliferation in the context of Bcr-Abl expression. Here we show that ectopic Bcr-Abl expression dramatically increases TGF beta/Smad-dependent transcriptional activity in Cosl cells, and that this may be due to enhancement of Smad promoter activity. Bcr-Abl expressing TF-1 myeloid cells are more potently growth arrested by TGF beta compared to the parental TF-1 cell line. Additionally, growth of Bcr-Abl-expressing CD34+ cells from chronic phase CML patients is inhibited by TGF beta and, interestingly, treatment of a non-proliferating CD34+ CML cell subpopulation with the TGF beta kinase inhibitor SB431542 enhanced cell death mediated by the Bcr-Abl inhibitor imatinib. Our data suggest that the expression of Bcr-Abl leads to hyper-responsiveness of myeloid cells to TGF beta, and we hypothesise that this novel cross-regulatory mechanism might play an important role in maintaining the transformed progenitor cell population in CML. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. ER - TY - JFULL T1 - The potential of cardiac stem cell therapy for heart failure. A1 - Lyon, A A1 - Harding, S J1 - Curr Opin Pharmacol Y1 - 2007/04// VL - 7 SN - 1471-4892 SP - 164 EP - 170 N2 - Cardiac failure is characterised by the loss of cardiomyocytes, and several strategies to replace the lost cell mass are being developed. Animal models have demonstrated the therapeutic potential of several cell types, and both autologous skeletal myoblasts and bone marrow progenitor cells have been tested in preliminary clinical trials. However functional improvements have been modest and the mechanism of benefit is unclear, although myocardial regeneration is not a significant factor. Alternative strategies using autologous resident cardiac progenitor cells or embryonic stem cell-derived cardiomyocytes could recreate de novo myocardium with higher efficiency, although various hurdles must be overcome before these strategies are translated to the clinic. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17275411&query_hl=1 ER - TY - JFULL T1 - The effects of various leukocyte filtration strategies in cardiac surgery. A1 - Warren, O A1 - Alexiou, C A1 - Massey, R A1 - Leff, D A1 - Purkayastha, S A1 - Kinross, J A1 - Darzi, A A1 - Athanasiou, T J1 - Eur J Cardiothorac Surg Y1 - 2007/04// VL - 31 SN - 1010-7940 SP - 665 EP - 676 N2 - It is known that cardiopulmonary bypass causes an inflammatory reaction with an associated morbidity and mortality. Several anti-inflammatory strategies have been implemented to reduce this response, including leukocyte removal from the circulation using specialised filters. The aim of this study is to systematically review the available evidence on leukocyte filtration in cardiac surgery, focusing on its effect on systemic inflammation and whether this has influenced clinical outcomes. Five electronic databases were systematically searched for studies reporting the effect of leukocyte filtration at any point within the cardiopulmonary bypass circuit in humans. Reference lists of all identified studies were checked for any missing publications. Two authors independently extracted the data from the included studies. Whilst systemic leukodepleting filters do not appear to consistently lower leukocyte counts, they may preferentially remove activated leukocytes. Small improvements in early post-operative lung function in patients receiving systemic leukodepletion have been reported, but this does not lead to reduced hospital stay or decreased mortality. There is substantial evidence that cardioplegic leukocyte filtration attenuates the reperfusion injury at a cellular level, but this has not been translated into clinical improvements. Finally, whilst various strategies involving multiple leukocyte filters, or the incorporation of pharmacological agents into leukocyte-depleting protocols have been evaluated, the current available results are not conclusive. Our study suggests that there is not enough high quality or consistent evidence to draw guidelines regarding the use of leukocyte-depleting filters within routine cardiac surgical practice. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17240156&query_hl=1 ER - TY - JFULL T1 - Positional cloning of susceptibility genes for atopic dermatitis in the epidermal differentiation complex A1 - Morar, N A1 - Edster, P A1 - Street, TL A1 - Weidinger, S A1 - Di, W A1 - Dixon, AL A1 - Taylor, M A1 - Holt, R A1 - Broxholme, J A1 - Kloop, N A1 - Novak, N A1 - Bockelbrinck, A A1 - Ragoussis, J A1 - Illig, T A1 - Harper, JI A1 - Cookson, WO A1 - Moffatt, MF J1 - J INVEST DERMATOL Y1 - 2007/04// VL - 127 SN - 0022-202X SP - S89 EP - S89 ER - TY - JFULL T1 - Formyl peptide receptors and the regulation of ACTH secretion: targets for annexin A1, lipoxins, and bacterial peptides. A1 - John, CD A1 - Sahni, V A1 - Mehet, D A1 - Morris, JF A1 - Christian, HC A1 - Perretti, M A1 - Flower, RJ A1 - Solito, E A1 - Buckingham, JC J1 - FASEB J Y1 - 2007/04// VL - 21 SN - 1530-6860 SP - 1037 EP - 1046 N2 - The N-formyl peptide receptors (FPRs) are a family of G-protein coupled receptors that respond to proinflammatory N-formylated bacterial peptides (e.g., formyl-Met-Leu-Phe, fMLF) and, thus, contribute to the host response to bacterial infection. Paradoxically, a growing body of evidence suggests that some members of this receptor family may also be targets for certain anti-inflammatory molecules, including annexin A1 (ANXA1), which is an important mediator of glucocorticoid (GC) action. To explore further the potential role of FPRs in mediating ANXA1 actions, we have focused on the pituitary gland, where ANXA1 has a well-defined role as a cell-cell mediator of the inhibitory effects of GCs on the secretion of corticotrophin (ACTH), and used molecular, genetic, and pharmacological approaches to address the question in well-established rodent models. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis identified mRNAs for four FPR family members in the mouse anterior pituitary gland, Fpr-rs1, Fpr-rs2, Fpr-rs6, and Fpr-rs7. Functional studies confirmed that, like dexamethasone, ANXA1 and two ANXA1-derived peptides (ANXA1(1-188) and ANXA1(Ac2-26)) inhibit the evoked release of ACTH from rodent anterior pituitary tissue in vitro. Fpr1 gene deletion failed to modify the pituitary responses to dexamethasone or ANXA1(Ac2-26). However, lipoxin A4 (LXA4, 0.02-2 microM, a lipid mediator with high affinity for Fpr-rs1) mimicked the inhibitory effects of ANXA1 on ACTH release as also did fMLF in high (1-100 microM) but not lower (10-100 nM) concentrations. Additionally, a nonselective FPR antagonist (Boc1, 100 microM) overcame the effects of dexamethasone, ANXA1(1-188), ANXA1(Ac2-26), fMLF, and LXA4 on ACTH release, although at a lower concentration (50 microM), it was without effect. Together, the results suggest that the actions of ANXA1 in the pituitary gland are independent of Fpr1 but may involve other FPR family members, in particular, Fpr-rs1 or a closely related receptor. They thus provide the first evidence for a role of the FPR family in the regulation of neuroendocrine function. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17218541&query_hl=1 ER - TY - JFULL T1 - Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28. A1 - Mirenda, V A1 - Jarmin, SJ A1 - David, R A1 - Dyson, J A1 - Scott, D A1 - Gu, Y A1 - Lechler, RI A1 - Okkenhaug, K A1 - Marelli-Berg, FM J1 - Blood Y1 - 2007/04/01/ VL - 109 SN - 0006-4971 SP - 2968 EP - 2977 N2 - Productive T-cell immunity requires both the activation and the migration of specific T cells to the antigenic tissue. The costimulatory molecule CD28 plays an essential role in the initiation of T-cell-mediated immunity. We investigated the possibility that CD28 may also regulate migration of primed T cells to target tissue. In vitro, CD28-mediated signals enhanced T-cell transendothelial migration, integrin clustering, and integrin-mediated migration. In vivo, T cells bearing a mutation in the CD28 cytoplasmic domain, which abrogates PI3K activation, displayed normal clonal expansion but defective localization to antigenic sites following antigenic rechallenge. Importantly, antibody-mediated CD28 stimulation led to unregulated memory T-cell migration to extra-lymphoid tissue, which occurred independently of T-cell receptor (TCR)-derived signals and homing-receptor expression. Finally, we provide evidence that CD28- and CTLA-4-mediated signals exert opposite effects on T-cell trafficking in vivo. These findings highlight a novel physiologic function of CD28 that has crucial implications for the therapeutic manipulation of this and other costimulatory molecules. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17119120&query_hl=1 ER - TY - JFULL T1 - A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population A1 - Horikoshi, M A1 - Hara, K A1 - Ito, C A1 - Nagai, R A1 - Froguel, P A1 - Kadowaki, T J1 - DIABETOLOGIA Y1 - 2007/04// VL - 50 SN - 0012-186X SP - 747 EP - 751 N2 - It has been suggested that transcription factor 7-like 2 protein (TCF7L2) plays an important role in glucose metabolism by regulating the production level of glucagon-like peptide-1, a hormone which modifies glucose-dependent insulin secretion. Recently, variants of TCF7L2 gene were reported to confer an increased risk of type 2 diabetes in three different samples from European and European-origin populations. We studied whether the single nucleotide polymorphisms (SNPs) in TCF7L2 were associated with type 2 diabetes in samples from a Japanese population.Five SNPs were genotyped in three different sample sets. Association with type 2 diabetes was investigated in each, as well as in combined sample sets.The SNP rs7903146 was nominally associated with type 2 diabetes in the initial (p = 0.08) and two replication sample sets (p = 0.05 and 0.06). For the combined sample set, in which we successfully genotyped 1,174 type 2 diabetes patients and 823 control subjects, rs7903146 showed a significant association with type 2 diabetes (odds ratio = 1.69 [95% CI 1.21-2.36], p = 0.002) with the same direction as the previous reports in samples from European and European-origin populations. SNPs rs7903146 and rs7901695 were in complete linkage disequilibrium. The rest of the five SNPs (rs7895340, rs11196205 and rs12255372) did not show any significant associations with type 2 diabetes.The consistent association between rs7903146 in TCF7L2 and type 2 diabetes in different ethnic groups, including the Japanese population, suggests that TCF7L2 is a common susceptibility gene for type 2 diabetes. ER - TY - JFULL T1 - Peritoneal mesothelioma: an unusual cause of an acute phase response presenting to the rheumatologist. A1 - Hamdulay, SS A1 - Cook, HT A1 - Strickland, N A1 - Davies, KA A1 - Mason, JC J1 - Clin Rheumatol Y1 - 2007/04// VL - 26 SN - 0770-3198 SP - 584 EP - 586 N2 - The presence of an acute phase response may pre-date the eventual diagnosis of malignant disease by months or even years. We describe two patients referred to the rheumatology clinic, in which extensive investigation failed to identify an underlying cause to account for the presenting symptoms and an associated acute phase response. Several months later, repeated abdominal CT scans revealed an abnormality and subsequent laparoscopic biopsy confirmed a diagnosis of peritoneal mesothelioma. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16416032&query_hl=1 ER - TY - JFULL T1 - Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. A1 - Jungbluth, H A1 - Zhou, H A1 - Sewry, CA A1 - Robb, S A1 - Treves, S A1 - Bitoun, M A1 - Guicheney, P A1 - Buj-Bello, A A1 - Bönnemann, C A1 - Muntoni, F J1 - Neuromuscul Disord Y1 - 2007/04// VL - 17 SN - 0960-8966 SP - 338 EP - 345 N2 - Centronuclear myopathy is a genetically heterogeneous congenital myopathy. Whilst mutations in the myotubularin (MTM1) gene are implicated in the X-linked variant, mutations in the dynamin 2 (DNM2) gene have been recently associated with dominant inheritance. We report a 16-year-old girl with clinical features of a congenital myopathy and external ophthalmoplegia. Multiple central nuclei affecting up to 50% of fibres and central accumulation of oxidative enzyme stains were the most prominent findings on muscle biopsy obtained at 1 year. However, some core-like areas appeared on repeat biopsy 8 years later; in addition, muscle MRI was compatible with the pattern we previously reported in patients with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Mutational analysis identified a de novo dominant RYR1 missense mutation (c.12335C>T; Ser4112Leu) affecting a highly conserved domain of the protein. Our findings expand the phenotypical spectrum associated with RYR1 mutations and indicate that RYR1 screening should be considered in centronuclear myopathy patients without MTM1 or DNM2 mutations; muscle MRI may aid selection of appropriate genetic testing. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17376685&query_hl=1 ER - TY - JFULL T1 - Mechanisms of disease: genetic causes of familial hypercholesterolemia. A1 - Soutar, AK A1 - Naoumova, RP J1 - Nat Clin Pract Cardiovasc Med Y1 - 2007/04// VL - 4 SN - 1743-4300 SP - 214 EP - 225 N2 - Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease. FH results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway, commonly caused by a loss-of-function mutation in the LDL-receptor gene (LDLR) or by a mutation in the gene encoding apolipoprotein B (APOB). FH is primarily an autosomal dominant disorder with a gene-dosage effect. An autosomal recessive form of FH caused by loss-of-function mutations in LDLRAP1, which encodes a protein required for clathrin-mediated internalization of the LDL receptor by liver cells, has also been documented. The most recent addition to the database of genes in which defects cause FH is one encoding a member of the proprotein convertase family, PCSK9. Rare dominant gain-of-function mutations in PCSK9 cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally downregulates the LDL-receptor pathway by indirectly causing degradation of LDL-receptor protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels. Thus, PCSK9 is an attractive target for new drugs aimed at lowering serum LDL cholesterol, which should have additive lipid-lowering effects to the statins currently used. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17380167&query_hl=1 ER - TY - JFULL T1 - A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. A1 - Khor, CC A1 - Chapman, SJ A1 - Vannberg, FO A1 - Dunne, A A1 - Murphy, C A1 - Ling, EY A1 - Frodsham, AJ A1 - Walley, AJ A1 - Kyrieleis, O A1 - Khan, A A1 - Aucan, C A1 - Segal, S A1 - Moore, CE A1 - Knox, K A1 - Campbell, SJ A1 - Lienhardt, C A1 - Scott, A A1 - Aaby, P A1 - Sow, OY A1 - Grignani, RT A1 - Sillah, J A1 - Sirugo, G A1 - Peshu, N A1 - Williams, TN A1 - Maitland, K A1 - Davies, RJ A1 - Kwiatkowski, DP A1 - Day, NP A1 - Yala, D A1 - Crook, DW A1 - Marsh, K A1 - Berkley, JA A1 - O'Neill, LA A1 - Hill, AV J1 - Nat Genet Y1 - 2007/04// VL - 39 SN - 1061-4036 SP - 523 EP - 528 N2 - Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17322885&query_hl=1 ER - TY - JFULL T1 - Backache in a Duchenne boy. A1 - Kinali, M A1 - Robinson, R A1 - Manzur, AY A1 - Burren, CP A1 - Robb, SA J1 - Neuromuscul Disord Y1 - 2007/04// VL - 17 SN - 0960-8966 SP - 346 EP - 348 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17339110&query_hl=1 ER - TY - JFULL T1 - Leptin receptor genotype at Gln223Arg is associated with body composition, BMD, and vertebral fracture in postmenopausal Danish women. A1 - Fairbrother, UL A1 - Tankó, LB A1 - Walley, AJ A1 - Christiansen, C A1 - Froguel, P A1 - Blakemore, AI J1 - J Bone Miner Res Y1 - 2007/04// VL - 22 SN - 0884-0431 SP - 544 EP - 550 N2 - Leptin is emerging as a key regulator of bone remodeling. In a population-based study of 1306 postmenopausal Danish women, nonsynonymous LEPR SNPs were associated with risk of adiposity, BMD, and vertebral fracture. Smoking exacerbates this LEPR-associated fracture risk. INTRODUCTION: Nonsynonymous single nucleotide polymorphisms (SNPs) in the human LEPR gene have been associated with adiposity in a number of studies, but there have been no large-scale studies of their implications for BMD and osteoporotic fracture risk in postmenopausal women. MATERIALS AND METHODS: We carried out a population-based study of 1430 women. Three well-known nonsynonymous leptin receptor (LEPR) SNPs (Lys109Arg, Gln223Arg, and Lys656Asn) were genotyped for qualitative and quantitative association analysis. Phenotype characteristics of main interest were DXA measures of body fat and lean tissue mass, BMD, and radiographic vertebral fractures. RESULTS: Gln223Arg associated with risk of vertebral fracture (overall OR = 1.76; OR in smokers = 2.31; p = 0.0004), in addition to BMD of the femoral neck and total hip (p = 0.036 and 0.008, respectively). Heterozygote carriers showed lower BMD at both sites. Gln223Arg was also associated with adiposity (p = 0.001 for total fat mass). For adiposity, the at-risk allele was G (resulting in an arginine at position 223). CONCLUSIONS: Variation in LEPR seemed to contribute to the variation in BMD and fracture risk in Danish postmenopausal women; the heterozygous genotype was associated with increased risk of manifest osteoporosis. Further studies are needed to replicate these data and to clarify the mechanisms involved. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17243864&query_hl=1 ER - TY - JFULL T1 - The cellular origin and proliferative status of regenerating renal parenchyma after mercuric chloride damage and erythropoietin treatment A1 - Yen, TH A1 - Alison, MR A1 - Cook, HT A1 - Jeffery, R A1 - Otto, WR A1 - Wright, NA A1 - Poulsom, R J1 - CELL PROLIFERAT Y1 - 2007/04// VL - 40 SN - 0960-7722 SP - 143 EP - 156 N2 - Objectives: In this study, we have sought to establish the cellular origin and proliferative status of the renal parenchyma as it regenerates after damage induced by mercuric chloride, with or without erythropoietin treatments, that might alter the response. Materials and methods: Female mice were irradiated and male whole bone marrow was transplanted into them. Six weeks later recipient mice were assigned to one of four groups: control, mercuric chloride treated, erythropoietin treated and treated with mercuric chloride plus erythropoietin. Results: Tubular injury scores were high 3 days after mercuric chloride and had recovered partially after 14 days, in line with serum urea nitrogen levels. Confocal microscopy confirmed the tubular location of bone marrow-derived cells. A 'four-in-one' analytical technique (identifying cell origin, tubular phenotype, tubular basement membranes and S-phase status) revealed that tubular necrosis increased bone marrow derivation of renal tubular epithelium from a baseline of similar to 1.3% to similar to 4.0%. Erythropoietin increased the haematocrit, but no other effects were detected. Conclusion: As 1 in 12 proximal tubular cells in S-phase was derived from bone marrow, we conclude that in the kidney, the presence of bone marrow-derived cells makes a minor but important regenerative contribution after tubular necrosis. ER - TY - JFULL T1 - AMP-activated protein kinase and the regulation of energy metabolism A1 - Carling, D J1 - FASEB J Y1 - 2007/04// VL - 21 SN - 0892-6638 SP - A206 EP - A206 ER - TY - JFULL T1 - Identifying cardiorespiratory neurocircuitry involved in central command during exercise in humans A1 - Green, A A1 - Wang, SW A1 - Purvis, S A1 - Owen, SLF A1 - Bain, PG A1 - Stein, JF A1 - Guz, A A1 - Aziz, TZ A1 - Paterson, DJ J1 - FASEB J Y1 - 2007/04// VL - 21 SN - 0892-6638 SP - A566 EP - A566 ER - TY - JFULL T1 - Inhibition of p38 mitogen-activated protein kinase is effective in the treatment of experimental crescentic glomerulonephritis and suppresses monocyte chemoattractant protein-1 but not IL-1beta or IL-6. A1 - Sheryanna, A A1 - Bhangal, G A1 - McDaid, J A1 - Smith, J A1 - Manning, A A1 - Foxwell, BM A1 - Feldmann, M A1 - Cook, HT A1 - Pusey, CD A1 - Tam, FW J1 - J Am Soc Nephrol Y1 - 2007/04// VL - 18 SN - 1046-6673 SP - 1167 EP - 1179 N2 - Activation of p38 mitogen-activated protein kinase (MAPK) is known to be important in cytokine production and cell survival in inflammation. This study examined the effect of inhibiting p38 MAPK after onset of renal injury in an experimental model of crescentic glomerulonephritis. Furthermore, this study investigated whether p38 MAPK inhibition would cause widespread suppression of the cytokine network in vivo or uncontrolled apoptosis. In the in vivo studies, daily treatment with a p38 MAPKalpha/beta inhibitor was started 1 h (early treatment study) or 4 d (late treatment study) after induction of nephrotoxic nephritis in Wistar Kyoto rats. The treated rats remained healthy with normal weight gain during the study. Both early and late treatment with p38 MAPK inhibitor reduced renal monocyte chemoattractant protein-1 (MCP-1) levels, the number of glomerular macrophages, the severity of tissue injury, and proteinuria compared with the vehicle group. Unexpected, treatment with p38 MAPK inhibitor did not suppress renal levels of IL-1beta or IL-6. In the in vitro study, the p38 MAPKalpha/beta inhibitor reduced production of MCP-1 and IL-6 by TNF-alpha-or IL-1beta-stimulated mesangial cells without any effect on cell viability or apoptosis. In conclusion, p38 MAPK inhibition is effective in reducing the severity of crescentic glomerulonephritis even when treatment is started after onset of disease. The therapeutic effect is associated with selective suppression of MCP-1, without widespread suppression of cytokine production or increased apoptosis. Therefore, p38 MAPK therapeutic blockade is a promising strategy in the treatment of antibody-mediated glomerulonephritis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17314328&query_hl=1 ER - TY - JFULL T1 - The Bxs6 locus of BXSB mice is sufficient for high-level expression of gp70 and the production of gp70 immune complexes. A1 - Rankin, J A1 - Boyle, JJ A1 - Rose, SJ A1 - Gabriel, L A1 - Lewis, M A1 - Thiruudaian, V A1 - Rogers, NJ A1 - Izui, S A1 - Morley, BJ J1 - J Immunol Y1 - 2007/04/01/ VL - 178 SN - 0022-1767 SP - 4395 EP - 4401 N2 - High levels of the retroviral envelope protein gp70 and gp70 immune complexes have been linked to a single locus on chromosome 13 (Bxs6) in the BXSB model, to which linkage of nephritis was also seen. Congenic lines containing the BXSB Bxs6 interval on a non-autoimmune C57BL/10 background were bred in the presence or absence of the BXSB Y chromosome autoimmune accelerator gene (Yaa), which accelerates disease in male mice. In these mice, we have shown that Bxs6 is sufficient to cause high-level expression of gp70 and the production of gp70 autoantibodies, independently of Yaa, with gp70 immune complex levels enhanced by Yaa. In the presence of Yaa, Bxs6 also causes mild nephritis, and interestingly the sporadic production of high levels of anti-DNA Abs in some mice. Fine mapping using rare recombinant mice suggested that Bxs6 lies between 59.7 and 74.8 megabases (Mb), although the interval of 0.6 Mb between 73.6 and 78.6 Mb on chromosome 13 cannot be excluded in this study. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17371996&query_hl=1 ER - TY - JFULL T1 - A spatial probit model for fine-scale mapping of disease genes. A1 - De Iorio, M A1 - Verzilli, CJ J1 - Genet Epidemiol Y1 - 2007/04// VL - 31 SN - 0741-0395 SP - 252 EP - 260 N2 - We present a novel statistical method for linkage disequilibrium (LD) mapping of disease susceptibility loci in case-control studies. Such studies exploit the statistical correlation or LD that exist between variants physically close along the genome to identify those that correlate with disease status and might thus be close to a causative mutation, generally assumed unobserved. LD structure, however, varies markedly over short distances because of variation in local recombination rates, mutation and genetic drift among other factors. We propose a Bayesian multivariate probit model that flexibly accounts for the local spatial correlation between markers. In a case-control setting, we use a retrospective model that properly reflects the sampling scheme and identify regions where single- or multi-locus marker frequencies differ across cases and controls. We formally quantify these differences using information-theoretic distance measures while the fully Bayesian approach naturally accommodates unphased or missing genotype data. We demonstrate our approach on simulated data and on real data from the CYP2D6 region that has a confirmed role in drug metabolism. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17266116&query_hl=1 ER - TY - JFULL T1 - Adenovirus 5 fibers mutated at the putative HSPG-binding site show restricted retargeting with targeting peptides in the HI loop A1 - Kritz, AB A1 - Nicol, CG A1 - Dishart, KL A1 - Nelson, R A1 - Holbeck, S A1 - Von Seggern, DJ A1 - Work, LM A1 - Mcvey, JH A1 - Nicklin, SA A1 - Baker, AH J1 - MOL THER Y1 - 2007/04// VL - 15 SN - 1525-0016 SP - 741 EP - 749 N2 - Adenoviral vectors are commonly used for liver-directed gene therapy following systemic administration owing to their strong propensity for hepatocyte transduction. However, many disease applications would benefit from the delivery of adenoviruses to alternate tissues via this route. Research has thus focused on stripping the virus of native hepatic tropism in conjunction with modifying virus capsid proteins to incorporate novel tropism. Recently, the KO1S* adenovirus serotype 5 fiber mutant, devoid of both coxsackie and adenovirus receptor binding in the fiber knob domain and mutated at the putative heparan sulphate proteoglycan binding site in the fiber shaft, was shown to possess strikingly poor hepatic tropism in mice, rats, and non-human primates. Thus, it is an ideal candidate for retargeting strategies. We therefore assessed the ability of peptide-modified KO1S* fibers to retarget adenovirus. Peptide insertions were well tolerated and virions produced to high titers. However, expected retargeting at the level of transduction was not observed, despite cell-binding studies showing enhanced vector targeting at the cell surface. Cy3 labeling studies showed retarded trafficking of S*-containing fibers. Taken together, our data demonstrates that KO1S* mutant fibers are ineffective for cell retargeting strategies. ER - TY - JFULL T1 - Agonist-dependent internalization of D2 receptors: Imaging quantification by confocal microscopy. A1 - Goggi, JL A1 - Sardini, A A1 - Egerton, A A1 - Strange, PG A1 - Grasby, PM J1 - Synapse Y1 - 2007/04// VL - 61 SN - 0887-4476 SP - 231 EP - 241 N2 - In positron emission tomography and single photon emission computed tomography studies using D2 dopamine (DA) receptor radiotracers, a decrease in radiotracer binding potential (BP) is usually interpreted in terms of increased competition with synaptic DA. However, some data suggest that this signal may also reflect agonist (DA)-induced increases in D2 receptor (D2R) internalization, a process which would presumably also decrease the population of receptors available for binding to hydrophilic radioligands. To advance interpretation of alterations in D2 radiotracer BP, direct methods of assessment of D2R internalization are required. Here, we describe a confocal microscopy-based approach for the quantification of agonist-dependent receptor internalization. The method relies upon double-labeling of the receptors with antibodies directed against intracellular as well as extracellular epitopes. Following agonist stimulation, DA D2R internalization was quantified by differentiating, in optical cell sections, the signal due to the staining of the extracellular from intracellular epitopes of D2Rs. Receptor internalization was increased in the presence of the D2 agonists DA and bromocriptine, but not the D1 agonist SKF38393. Pretreatment with either the D2 antagonist sulpiride, or inhibitors of internalization (phenylarsine oxide and high molarity sucrose), blocked D2-agonist induced receptor internalization, thus validating this method in vitro. This approach therefore provides a direct and streamlined methodology for investigating the pharmacological and mechanistic aspects of D2R internalization, and should inform the interpretation of results from in vivo receptor imaging studies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17230553&query_hl=1 ER - TY - JFULL T1 - Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. A1 - Sanders, MJ A1 - Grondin, PO A1 - Hegarty, BD A1 - Snowden, MA A1 - Carling, D J1 - Biochem J Y1 - 2007/04/01/ VL - 403 SN - 1470-8728 SP - 139 EP - 148 N2 - AMPK (AMP-activated protein kinase) is activated allosterically by AMP and by phosphorylation of Thr172 within the catalytic alpha subunit. Here we show that mutations in the regulatory gamma subunit reduce allosteric activation of the kinase by AMP. In addition to its allosteric effect, AMP significantly reduces the dephosphorylation of Thr172 by PP (protein phosphatase)2Calpha. Moreover, a mutation in the gamma subunit almost completely abolishes the inhibitory effect of AMP on dephosphorylation. We were unable to detect any effect of AMP on Thr172 phosphorylation by either LKB1 or CaMKKbeta (Ca2+/calmodulin-dependent protein kinase kinase beta) using recombinant preparations of the proteins. However, using partially purified AMPK from rat liver, there was an apparent AMP-stimulation of Thr172 phosphorylation by LKB1, but this was blocked by the addition of NaF, a PP inhibitor. Western blotting of partially purified rat liver AMPK and LKB1 revealed the presence of PP2Calpha in the preparations. We suggest that previous studies reporting that AMP promotes phosphorylation of Thr172 were misinterpreted. A plausible explanation for this effect of AMP is inhibition of dephosphorylation by PP2Calpha, present in the preparations of the kinases used in the earlier studies. Taken together, our results demonstrate that AMP activates AMPK via two mechanisms: by direct allosteric activation and by protecting Thr172 from dephosphorylation. On the basis of our new findings, we propose a simple model for the regulation of AMPK in mammalian cells by LKB1 and CaMKKbeta. This model accounts for activation of AMPK by two distinct signals: a Ca2+-dependent pathway, mediated by CaMKKbeta and an AMP-dependent pathway, mediated by LKB1. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17147517&query_hl=1 ER - TY - JFULL T1 - Desmin immunolocalisation in autosomal dominant Emery-Dreifuss muscular dystrophy. A1 - Piercy, RJ A1 - Zhou, H A1 - Feng, L A1 - Pombo, A A1 - Muntoni, F A1 - Brown, SC J1 - Neuromuscul Disord Y1 - 2007/04// VL - 17 SN - 0960-8966 SP - 297 EP - 305 N2 - Autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) is one of a number of allelic disorders caused by mutations in the nuclear lamina proteins, lamins A and C. The disorder is characterised by the early onset of skeletal muscle weakness and joint contractures and later, by dilated cardiomyopathy and cardiac arrythmias. Although the pathophysiology is not understood, one theory suggests that disordered structural organisation at weakened nuclei in contractile cells may underlie the disease. Previous work shows that mice deficient in lamin A/C develop similar skeletal and cardiac muscle signs to patients with AD-EDMD and ultrastructural examination of muscle from these mice shows abnormal localisation of desmin. We hypothesised therefore that desmin localisation may be abnormal in muscle or cells from patients with AD-EDMD and/or in cells expressing mutant lamins. In order to evaluate this, desmin immunolocalisation was determined in skeletal muscle biopsy sections from patients with AD-EDMD and cell lines including MyoD-transfected fibroblast-derived myotubes from AD-EDMD patients and murine embryonic stem cell-derived cardiomyocytes stably transfected with mutant human lamin A. Ultrastructural examination of patient muscle was also performed. Desmin was expressed and localised normally in patient muscle and cell lines and ultrastructural examination was similar to controls. These results fail to provide any evidence that dominant mutations in lamin A/C lead to a disorganisation of the desmin associated cytoskeleton. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17329105&query_hl=1 ER - TY - JFULL T1 - Oscillations in the immune system. A1 - Stark, J A1 - Chan, C A1 - George, AJ J1 - Immunol Rev Y1 - 2007/04// VL - 216 SN - 0105-2896 SP - 213 EP - 231 N2 - Oscillations are surprisingly common in the immune system, both in its healthy state and in disease. The most famous example is that of periodic fevers caused by the malaria parasite. A number of hereditary disorders, which also cause periodic fevers, have also been known for a long time. Various reports of oscillations in cytokine concentrations following antigen challenge have been published over at least the past three decades. Oscillations can also occur at the intracellular level. Calcium oscillations following T-cell activation are familiar to all immunologists, and metabolic and reactive oxygen species oscillations in neutrophils have been well documented. More recently, oscillations in nuclear factor kappaB activity following stimulation by tumor necrosis factor alpha have received considerable publicity. However, despite all of these examples, oscillations in the immune system still tend to be considered mainly as pathological aberrations, and their causes and significance remained largely unknown. This is partly because of a lack of awareness within the immunological community of the appropriate theoretical frameworks for describing and analyzing such behavior. We provide an introduction to these frameworks and give a survey of the currently known oscillations that occur within the immune system. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17367345&query_hl=1 ER - TY - JFULL T1 - A review of the functional role and of the expression profile of retinoid signaling and of nuclear receptors in human spinal cord. A1 - Malaspina, A A1 - Turkheimer, F J1 - Brain Res Bull Y1 - 2007/03/15/ VL - 71 SN - 0361-9230 SP - 437 EP - 446 N2 - Spinal cord degenerative pathologies in humans cause extensive disability and require a broad range of specialist and palliative medical interventions. In amyotrophic lateral sclerosis (ALS), motor cell loss leads to extensive paralysis and to death from respiratory failure in 3-5 years form disease onset. A wide range of molecular changes forms the basis of spinal cord involvement in ALS, including the reactivation of molecular pathways with potentially neurorestorative properties. Central to this tissue repair mechanism is the differential regulation of components of the retinoid signaling (ReS), a molecular pathway encompassing a variety of proteins functioning as transporters, signaling factors and metabolizing enzymes for retinoic acid. In this paper, we review the strong body of experimental evidence supporting retinoid signaling's primary role in spinal cord embryonic differentiation and its likely survival-promoting function in ALS. We discuss the potential involvement in ALS pathogenesis of a subgroup of nuclear receptors (NRs) that act as functional partners of retinoid receptors in human spinal cord. We also provide a review of the expression profile of 25 ReS and NRs genes in human adult spinal cord and in motor neurons of healthy and ALS individuals, using data retrieved from independent datasets obtained through serial analysis of gene expression and array investigations. Based on published expression data, we outline a tentative expression profile of ReS and functionally synergic NR genes in human spinal cord that could guide further experiments to clarify the role of these molecules in mature nervous tissue and suggest potential treatment strategies that could have therapeutic potentials in ALS. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17259011&query_hl=1 ER - TY - JFULL T1 - Natural regulation of immunity to minor histocompatibility antigens. A1 - Robertson, NJ A1 - Chai, JG A1 - Millrain, M A1 - Scott, D A1 - Hashim, F A1 - Manktelow, E A1 - Lemonnier, F A1 - Simpson, E A1 - Dyson, J J1 - J Immunol Y1 - 2007/03/15/ VL - 178 SN - 0022-1767 SP - 3558 EP - 3565 N2 - MHC-matched hemopoietic stem cell transplantation is commonly used for the treatment of some forms of leukemia. Conditioning regimens before transplant act to reduce the burden of leukemic cells and the graft-vs-leukemia (GvL) effect can eliminate residual disease. The GvL effect results largely from the recognition of minor histocompatibility Ags by donor T cells on recipient tissues. These Ags are generally widely expressed and also provoke graft-vs-host (GvH) disease. Manipulation of immunity to promote GvL while curtailing GvH would greatly improve clinical outcome. To develop strategies that may achieve this, the parameters which control immunity to minor histocompatibility Ags need to be defined. In this study, we have analyzed responses to the mouse HY minor histocompatibility Ag using hemopoietic cell and skin grafts as surrogate GvL and GvH targets, respectively. We show that natural regulation of CD8 T cell responses to HY operates at multiple levels. First, CD4 T cell help is required for primary CD8 responses directed at hemopoietic cells. However, although CD4 T cells of H2(k) mouse strains recognize HY, they provide ineffective help associated with a proportion of recipients developing tolerance. This was further investigated using TCR-transgenic mice which revealed H2(k)-restricted HY-specific CD4 T cells are highly susceptible to regulation by CD25(+) regulatory T cells which expand in tolerant recipients. A second level of regulation, operating in the context of skin grafts, involves direct inhibition of CD8 T cell responses by CD94/NKG2 engagement of the nonclassical MHC class I molecule Qa1. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17339452&query_hl=1 ER - TY - JFULL T1 - Effect of particle size on hydroxyapatite crystal-induced tumor necrosis factor alpha secretion by macrophages. A1 - Nadra, I A1 - Boccaccini, AR A1 - Philippidis, P A1 - Whelan, LC A1 - McCarthy, GM A1 - Haskard, DO A1 - Landis, RC J1 - Atherosclerosis Y1 - 2007/03/08/ SN - 0021-9150 N2 - Macrophages may promote a vicious cycle of inflammation and calcification in the vessel wall by ingesting neointimal calcific deposits (predominantly hydroxyapatite) and secreting tumor necrosis factor (TNF)alpha, itself a vascular calcifying agent. Here we have investigated whether particle size affects the proinflammatory potential of hydroxyapatite crystals in vitro and whether the nuclear factor (NF)-kappaB pathway plays a role in the macrophage TNFalpha response. The particle size and nano-topography of nine different crystal preparations was analyzed by X-ray diffraction, Raman spectroscopy, scanning electron microscopy and gas sorbtion analysis. Macrophage TNFalpha secretion was inversely related to hydroxyapatite particle size (P=0.011, Spearman rank correlation test) and surface pore size (P=0.014). A necessary role for the NF-kappaB pathway was demonstrated by time-dependent IkappaBalpha degradation and sensitivity to inhibitors of IkappaBalpha degradation. To test whether smaller particles were intrinsically more bioactive, their mitogenic activity on fibroblast proliferation was examined. This showed close correlation between TNFalpha secretion and crystal-induced fibroblast proliferation (P=0.007). In conclusion, the ability of hydroxyapatite crystals to stimulate macrophage TNFalpha secretion depends on NF-kappaB activation and is inversely related to particle and pore size, with crystals of 1-2mum diameter and pore size of 10-50A the most bioactive. Microscopic calcific deposits in early stages of atherosclerosis may therefore pose a greater inflammatory risk to the plaque than macroscopically or radiologically visible deposits in more advanced lesions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17350022&query_hl=1 ER - TY - JFULL T1 - A multi-compartment cell repopulation model allowing for inter-compartmental migration following radiation exposure, applied to leukaemia. A1 - Little, MP J1 - J Theor Biol Y1 - 2007/03/07/ VL - 245 SN - 0022-5193 SP - 83 EP - 97 N2 - There is much uncertainty about cancer risks at the high radiation doses used in radiotherapy (RT). It has generally been assumed that cancer induction decreases rapidly at high doses due to cell killing. However, this is not seen in all RT groups, and a model recently developed by Sachs and Brenner [2005. Solid tumor risks after high doses of ionizing radiation. Proc. Natl Acad. Sci. USA 102, 13040-13045] proposed a mechanism for repopulation of cells after radiation exposure that explained why this might happen, at least for solid tumours. In this paper, this model is generalized to allow for heterogeneity in the dose received, and various alternate patterns of repopulation are also considered. The model is fitted to the Japanese atomic bomb survivor leukaemia incidence data, and data for various therapeutically irradiated groups. Two sets of parameters from these model fits are used to assess the sensitivity of model predictions. It is shown that in general allowing for heterogeneity in dose distribution and haematopoietic stem cell migration results in lower risks than the same average dose administered uniformly and without such migration, although this does not hold in the limiting case of complete stem cell repopulation between radiation dose fractions. We also investigate the difference made by assuming a compartmental repopulation signal, and a global repopulation signal. In general we show that in the absence of stochastic extinction, compartmental repopulation always predicts a larger number of mutated cells than global repopulation. However, in certain dose regimes stochastic extinction cannot be ignored, and in these cases the numbers of mutated cells predicted with global repopulation can exceed that for compartmental repopulation. In general, mutant cell numbers are highly overdispersed, with variance much greater than the mean. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17092522&query_hl=1 ER - TY - JFULL T1 - Increased nitric oxide production regulates T cell function in rheumatoid arthritis A1 - Nagy, G A1 - Clark, JM A1 - Buzas, E A1 - Gorman, C A1 - Falus, A A1 - Cope, AP J1 - ANN RHEUM DIS Y1 - 2007/03/01/ VL - 66 SN - 0003-4967 SP - A69 EP - A69 ER - TY - JFULL T1 - Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions A1 - Yamauchi, T A1 - Nio, Y A1 - Maki, T A1 - Kobayashi, M A1 - Takazawa, T A1 - Iwabu, M A1 - Okada-Iwabu, M A1 - Kawamoto, S A1 - Kubota, N A1 - Kubota, T A1 - Ito, Y A1 - Kamon, J A1 - Tsuchida, A A1 - Kumagai, K A1 - Kozono, H A1 - Hada, Y A1 - Ogata, H A1 - Tokuyama, K A1 - Tsunoda, M A1 - Ide, T A1 - Murakami, K A1 - Awazawa, M A1 - Takamoto, I A1 - Froguel, P A1 - Hara, K A1 - Tobe, K A1 - Nagai, R A1 - Ueki, K A1 - Kadowaki, T J1 - NAT MED Y1 - 2007/03// VL - 13 SN - 1078-8956 SP - 332 EP - 339 N2 - Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo. ER - TY - JFULL T1 - TNF polymorphism and bronchoalveolar lavage cell TNF-alpha levels in chronic beryllium disease and beryllium sensitization. A1 - Sato, H A1 - Silveira, L A1 - Fingerlin, T A1 - Dockstader, K A1 - Gillespie, M A1 - Lagan, AL A1 - Lympany, P A1 - Sawyer, RT A1 - du Bois, RM A1 - Welsh, KI A1 - Maier, LA J1 - J Allergy Clin Immunol Y1 - 2007/03// VL - 119 SN - 0091-6749 SP - 687 EP - 696 N2 - BACKGROUND: Beryllium stimulates TNF-alpha from chronic beryllium disease (CBD) bronchoalveolar lavage (BAL) cells. OBJECTIVE: We sought to relate TNF polymorphisms to beryllium-stimulated TNF-alpha production, to the development of CBD, and to the risk of more severe CBD over time. METHODS: We recruited 147 patients with CBD, 112 beryllium-sensitized subjects, and 323 control subjects; genotyped 5 TNF promoter polymorphisms; and measured beryllium-stimulated and unstimulated BAL cell TNF-alpha production from a subset of subjects. RESULTS: Beryllium-stimulated, but not beryllium-unstimulated, BAL cell TNF-alpha production was significantly increased in patients with CBD compared with that seen in those only sensitized (P = .0002). Those subjects with the TNF -857T allele and the only haplotype (haplotype 4) containing this allele demonstrated significantly lower unstimulated BAL cell TNF-alpha production compared with that seen in noncarriers (P = .009). Patients with CBD alone and combined with sensitized subjects carrying the TNF haplotype 1 compared with those without this haplotype had significantly increased beryllium-stimulated BAL cell TNF-alpha levels (P = .02). We found no significant association between patients with CBD, sensitized subjects, and control subjects with any of the TNF promoter polymorphisms or haplotypes. A greater decrease in Pao(2) at maximum exercise was noted in patients with CBD with the -1031C allele (P = .03) and with haplotypes other than the TNF haplotype 1 (P = .01), 3 (from 5) of which contain the -1031C allele. CONCLUSIONS: The -857T allele and haplotype 1 are associated with BAL cell TNF-alpha production, indicating a potential role of TNF promoter variants in regulation of TNF production in sensitized subjects and patients with CBD. CLINICAL IMPLICATIONS: TNF promoter variants are not risk factors for CBD or sensitization. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17208287&query_hl=1 ER - TY - JFULL T1 - Serial casting of the ankles in Duchenne muscular dystrophy: can it be an alternative to surgery? A1 - Main, M A1 - Mercuri, E A1 - Haliloglu, G A1 - Baker, R A1 - Kinali, M A1 - Muntoni, F J1 - Neuromuscul Disord Y1 - 2007/03// VL - 17 SN - 0960-8966 SP - 227 EP - 230 N2 - The aim of this non-randomized pilot study was to assess whether serial casting can be used in Duchenne muscular dystrophy (DMD) patients to reduce tendo-achilles (TA) contractures and to allow the fitting of the knee-ankle-foot orthoses (KAFOs) at the end of the functional walking. TA range and age at loss of standing with KAFOs were prospectively assessed in nine DMD patients who underwent serial casting prior to rehabilitation into KAFOs and compared to a group of 20 DMD patients who had TA (group II) or TA and iliotibial band (ITB) surgical resection (group III). TA range after casting was reduced at least to plantargrade/neutral in 8 of the 9 patients studied although patients who had surgery had better correction of TA angles. The mean interval between rehabilitation and loss of standing ability with KAFOs was only minimally different among the three groups 1.8 years (9 months-2.8 years) in group I, 2 years (1 month-4.3 years) in group II, 1.9 years (6 months-4.7 years) in group III. The results of this pilot study suggest that serial casting of the TAs can be considered in DMD patients with moderate TA contractures and in whom there are no significant iliotibial band (ITB) tightness, although this intervention is probably not as effective as surgery in maintaining long-term TA range. This procedure may therefore be considered both in patients with medical contraindication to surgery, and also in patients or families who are not prepared to cope with the stress and discomfort of TA surgery. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17303425&query_hl=1 ER - TY - JFULL T1 - Changing viral tropism using immunoliposomes alters the stability of gene expression: implications for viral vector design. A1 - Tan, PH A1 - Xue, SA A1 - Wei, B A1 - Holler, A A1 - Voss, RH A1 - George, AJ J1 - Mol Med Y1 - 2007/03// VL - 13 SN - 1076-1551 SP - 216 EP - 226 N2 - Many strategies for redirecting the tropism of murine Moloney leukemia virus (MMLV) have been described. Preformed virion-liposome complexes, termed virosomes, have been reported to be relatively stable. Virosomes mediate envelope-independent transduction that allows efficient superinfection of resistant cell lines; however, virosome-mediated transduction behaves in a non-target-specific manner. We developed a novel method using antibodies to direct MMLV to vascular endothelium. We have given the term immunovirosomes to the complexes formed between viruses, liposomes, and antibodies. These immunovirosomes improve the transduction efficiency of the viruses and alter their tropism. We have shown improved transduction when immunovirosomes were targeted at the endocytic receptors CD71 and CD62E/P and rather less good delivery when targeted at CD106. The enhancement of the transduction efficiency was transient, however, suggesting that rerouting the entry pathway of viruses alters the expression properties of the viruses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17592557&query_hl=1 ER - TY - JFULL T1 - Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? A1 - Talge, NM A1 - Neal, C A1 - Glover, V A1 - Early Stress Transnational Res Pre J1 - J CHILD PSYCHOL PSYC Y1 - 2007/03// VL - 48 SP - 245 EP - 261 N2 - We review a significant body of evidence from independent prospective studies that if a mother is stressed while pregnant, her child is substantially more likely to have emotional or cognitive problems, including an increased risk of attentional deficit/hyperactivity, anxiety, and language delay. These findings are independent of effects due to maternal postnatal depression and anxiety. We still do not know what forms of anxiety or stress are most detrimental, but research suggests that the relationship with the partner can be important in this respect. The magnitude of these effects is clinically significant, as the attributable load of emotional/behavioral problems due to antenatal stress and/or anxiety is approximately 15%. Animal models suggest that activity of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and its hormonal end-product cortisol are involved in these effects in both mother and offspring. The fetal environment can be altered if stress in the mother changes her hormonal profile, and in humans, there is a strong correlation between maternal and fetal cortisol levels. However, many problems remain in understanding the mechanisms involved in this interaction. For example, maternal cortisol responses to stress decline over the course of pregnancy, and earlier in pregnancy, the link between maternal and fetal cortisol is less robust. It is possible that the effects of maternal anxiety and stress on the developing fetus and child are moderated by other factors such as a maternal diet (e.g., protein load). It is suggested that extra vigilance or anxiety, readily distracted attention, or a hyper-responsive HPA axis may have been adaptive in a stressful environment during evolution, but exists today at the cost of vulnerability to neurodevelopmental disorders. ER - TY - JFULL T1 - Activating transcription factor 6 (ATF6) sequence polymorphisms in type 2 diabetes and pre-diabetic traits A1 - Chu, WS A1 - Das, SK A1 - Wang, H A1 - Chan, JC A1 - Deloukas, P A1 - Froguel, P A1 - Baier, LJ A1 - Jia, WP A1 - McCarthy, MI A1 - Ng, MCY A1 - Damcott, C A1 - Shuldiner, AR A1 - Zeggini, E A1 - Elbein, SC J1 - DIABETES Y1 - 2007/03// VL - 56 SN - 0012-1797 SP - 856 EP - 862 N2 - Activating transcription factor 6 (ATF6) is located within the region of linkage to type 2 diabetes on chromosome 1q21-q23 and is a key activator of the endoplasmic reticulum stress response. We evaluated 78 single nucleotide polymorphisms (SNPs) spanning > 213 kb in 95 people, from which we selected 64 SNPs for evaluation in 191 Caucasian case subjects from Utah and between 165 and 188 control subjects. Six SNPs showed nominal associations with type 2 diabetes (P = 0.001-0.04), including the nonsynonymous SNP rs1058405 (M67V) in exon 3 and rs11579627 in the 3' flanking region. Only rs1159627 remained significant on permutation testing. The associations were not replicated in 353 African-American case subjects and 182 control subjects, nor were ATF6 SNPs associated with altered insulin secretion or insulin sensitivity in nondiabetic Caucasian individuals. No association with type 2 diabetes was found in a subset of 44 SNPs in Caucasian (a = 2,099), Pima Indian (n = 293), and Chinese (n = 287) samples. Allelic expression imbalance was found in transformed lymphocyte cDNA for 3' untranslated region variants, thus suggesting cis-acting regulatory variants. ATF6 does not appear to play a major role in type 2 diabetes, but further work is required to identify the cause of the allelic expression imbalance. ER - TY - JFULL T1 - Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes - Association analyses in 9,518 subjects A1 - Owen, KR A1 - Groves, CJ A1 - Hanson, RL A1 - Knowler, WC A1 - Shuldiner, AR A1 - Elbein, SC A1 - Mitchell, BD A1 - Froguel, P A1 - Ng, MCY A1 - Chan, JC A1 - Jia, WP A1 - Deloukas, P A1 - Hitman, GA A1 - Walker, M A1 - Frayling, TM A1 - Hattersley, AT A1 - Zeggini, E A1 - McCarthy, MI A1 - Int Type 2 Diabetes 1q Consortium J1 - DIABETES Y1 - 2007/03// VL - 56 SN - 0012-1797 SP - 879 EP - 883 N2 - Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing > 90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001). ER - TY - JFULL T1 - Expression and externalization of annexin 1 in the adrenal gland: structure and function of the adrenal gland in annexin 1-null mutant mice. A1 - Davies, E A1 - Omer, S A1 - Buckingham, JC A1 - Morris, JF A1 - Christian, HC J1 - Endocrinology Y1 - 2007/03// VL - 148 SN - 0013-7227 SP - 1030 EP - 1038 N2 - Annexin 1 (ANXA1) is a member of the annexin family of phospholipid- and calcium-binding proteins with a well demonstrated role in early delayed (30 min to 3 h) inhibitory feedback of glucocorticoids in the hypothalamus and pituitary gland. This study used adrenal gland tissue from ANXA1-null transgenic mice, in which a beta-galactosidase (beta-Gal) reporter gene was controlled by the ANXA1 promoter, and wild-type control mice to explore the potential role of ANXA1 in adrenal function. RT-PCR and Western blotting revealed strong expression of ANXA1 mRNA and protein in the adrenal gland. Immunofluorescence labeling of ANXA1 in wild-type and beta-Gal expression in ANXA1-null adrenals localized intense staining in the outer perimeter cell layers. Immunogold electron microscopy identified cytoplasmic and nuclear ANXA1 labeling in outer cortical cells and capsular cells. Exposure of adrenal segments in vitro to dexamethasone (0.1 mum, 3 h) caused an increase in the amount of ANXA1 in the intracellular compartment and attached to the surface of the cells. The N-terminal peptide ANXA1(Ac2-26) inhibited corticosterone release. Corticosterone release was significantly greater from ANXA1-null adrenal cells compared with wild type in response to ACTH (10 pm to 5 nm). In contrast, basal and ACTH-stimulated aldosterone release from ANXA1-null adrenal cells was not different from wild type. Morphometry studies demonstrated that ANXA1 null adrenal glands were smaller than wild-type, and the cortical/medullary area ratio was significantly reduced. These results suggest ANXA1 is a regulator of adrenocortical size and corticosterone secretion. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17158208&query_hl=1 ER - TY - JFULL T1 - Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian inheritance on chromosome 7p13-15. A1 - Zondervan, KT A1 - Treloar, SA A1 - Lin, J A1 - Weeks, DE A1 - Nyholt, DR A1 - Mangion, J A1 - MacKay, IJ A1 - Cardon, LR A1 - Martin, NG A1 - Kennedy, SH A1 - Montgomery, GW J1 - Hum Reprod Y1 - 2007/03// VL - 22 SN - 0268-1161 SP - 717 EP - 728 N2 - BACKGROUND: Endometriosis is a common disease with a heritable component. The collaborative International Endogene Study consists of two data sets (Oxford and Australia) comprising 1176 families with multiple affected. The aim was to investigate whether the apparent concentration of cases in a proportion of families could be explained by one or more rare variants with (near-)Mendelian autosomal inheritance. METHODS AND RESULTS: Linkage analyses (aimed at finding chromosomal regions harbouring disease-predisposing genes) were conducted in families with three or more affected (Oxford: n = 52; Australia: n = 196). In the Oxford data set, a non-parametric linkage score (Kong & Cox (K&C) Log of ODds (LOD)) of 3.52 was observed on chromosome 7p (genome-wide significance P = 0.011). A parametric MOD score (equal to maximum LOD maximized over 357 possible inheritance models) of 3.89 was found at 65.72 cM (D7S510) for a dominant model with reduced penetrance. After including the Australian data set, the non-parametric K&C LOD of the combined data set was 1.46 at 57.3 cM; the parametric analysis found an MOD score of 3.30 at D7S484 (empirical significance: P = 0.035) for a recessive model with high penetrance. Critical recombinant analysis narrowed the probable region of linkage down to overlapping 6.4 Mb and 11 Mb intervals containing 48 and 96 genes, respectively. CONCLUSIONS: This is the first report to suggest that there may be one or more high-penetrance susceptibility loci for endometriosis with (near-)Mendelian inheritance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17158817&query_hl=1 ER - TY - JFULL T1 - The CXC chemokine MIG/CXCL9 is important in innate immunity against Streptococcus pyogenes. A1 - Egesten, A A1 - Eliasson, M A1 - Johansson, HM A1 - Olin, AI A1 - Morgelin, M A1 - Mueller, A A1 - Pease, JE A1 - Frick, IM A1 - Bjorck, L J1 - J Infect Dis Y1 - 2007/03/01/ VL - 195 SN - 0022-1899 SP - 684 EP - 693 N2 - Pharyngitis caused by Streptococcus pyogenes is one of the most common bacterial infections in humans and is also a starting point for invasive S. pyogenes infection. Here, we describe that tonsil fluid from patients with streptococcal pharyngitis contains high amounts of the interferon (IFN)-dependent CXC chemokine known as monokine induced by IFN- gamma (MIG)/CXCL9. Also in vitro, inflamed pharyngeal epithelium produced large amounts of MIG/CXCL9 in the presence of bacteria. The CXC chemokines MIG/CXCL9, IFN-inducible protein-10/CXCL10, and IFN-inducible T cell alpha -chemoattractant/CXCL11 all showed antibacterial activity against S. pyogenes, and inhibition of MIG/CXCL9 expression reduced the antibacterial activity at the surface of inflamed pharyngeal cells. S. pyogenes of the clinically important M1 serotype secrets the protein streptococcal inhibitor of complement (SIC), which inhibited the antibacterial activity of the chemokines. As exemplified by S. pyogenes pharyngitis, the data identify a novel innate defense mechanism against invasive bacteria on epithelial surfaces. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17262710&query_hl=1 ER - TY - JFULL T1 - Rab27a is a key component of the secretory machinery of azurophilic granules in granulocytes. A1 - Munafó, DB A1 - Johnson, JL A1 - Ellis, BA A1 - Rutschmann, S A1 - Beutler, B A1 - Catz, SD J1 - Biochem J Y1 - 2007/03/01/ VL - 402 SN - 1470-8728 SP - 229 EP - 239 N2 - Neutrophils kill micro-organisms using microbicidal products that they release into the phagosome or into the extracellular space. The secretory machinery utilized by neutrophils is poorly characterized. We show that the small GTPase Rab27a is an essential component of the secretory machinery of azurophilic granules in granulocytes. Rab27a-deficient mice have impaired secretion of MPO (myeloperoxidase) into the plasma in response to lipopolysaccharide. Cell fractionation analysis revealed that Rab27a and the Rab27a effector protein JFC1/Slp1 (synaptotagmin-like protein 1) are distributed principally in the low-density fraction containing a minor population of MPO-containing granules. By immunofluorescence microscopy, we detected Rab27a and JFC1/Slp1 in a minor subpopulation of MPO-containing granules. Interference with the JFC1/Slp1-Rab27a secretory machinery impaired secretion of MPO in permeabilized neutrophils. The expression of Rab27a was dramatically increased when promyelocytic HL-60 cells were differentiated into granulocytes but not when they were differentiated into monocytes. Down-regulation of Rab27a in HL-60 cells by RNA interference did not affect JFC1/Slp1 expression but significantly decreased the secretion of MPO. Neither Rab27a nor JFC1/Slp1 was integrated into the phagolysosome membrane during phagocytosis. Neutrophils from Rab27a-deficient mice efficiently phagocytose zymosan opsonized particles and deliver MPO to the phagosome. We conclude that Rab27a and JFC1/Slp1 permit MPO release into the surrounding milieu and constitute key components of the secretory machinery of azurophilic granules in granulocytes. Our results suggest that the granules implicated in cargo release towards the surrounding milieu are molecularly and mechanistically different from those involved in their release towards the phagolysosome. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17090228&query_hl=1 ER - TY - JFULL T1 - In silico prediction of FVIII epitopes recognised by natural autoantibodies in polyvalent immunoglobulin concentrates. A1 - Di Giambattista, M A1 - Branckaert, T A1 - Hougardy, V A1 - Kemball-Cook, G A1 - Laub, R J1 - Mol Immunol Y1 - 2007/03// VL - 44 SN - 0161-5890 SP - 1903 EP - 1913 N2 - Inhibitory antibodies directed against blood coagulation factor VIII (FVIII) impair FVIII replacement therapy, constituting a serious complication in haemophilic and autoimmune patients. Identifying B-cell FVIII epitopes and mapping them on the molecule remain important challenges. Using a combination of different algorithms, more than 30 hypothetical linear epitopes were predicted on the FVIII molecule surface. We selected several major predicted sequences, spanning all FVIII domains, for specific antibody induction in rabbits. All peptides tested successfully induced production of specific anti-FVIII rabbit antibodies, supporting the relevance of our approach. To investigate the presence of FVIII-reactive antibodies in the healthy donor population, a pooled fraction rich in all IgG subclasses was purified on peptide-Sepharose columns. Substantial amounts of Ig, specific for each FVIII peptide, were purified with yields ranging from 8 to 223 ng/mg immunoglobulins. Our results confirm the diversity of FVIII epitopes recognised by natural human anti-FVIII autoantibodies. All IgG subclasses were found in the affinity-isolated anti-peptide material, with overrepresentation of IgG2 and IgG4. Evidence was also found for new FVIII epitopes. Five human anti-peptide preparations displayed FVIII-neutralising activity, ranging from 1.3 to 5.3 BU/mg. Although the presence of naturally occurring anti-FVIII antibodies in healthy donors has been previously described, our methodology has allowed, for the first time, a fine mapping of several inhibitory and non-inhibitory epitopes. Our observations support the hypothesis that FVIII inhibitors in haemophilia A and autoimmune disease may originate from the proliferation of natural FVIII-specific B-cell clones. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17113150&query_hl=1 ER - TY - JFULL T1 - QUIPP: A novel tyrosine phosphoprotein implicated in toll like receptor signalling A1 - Peirce, MJ A1 - Testar, J A1 - Brook, M A1 - Begum, S A1 - Wait, R A1 - Hussell, T A1 - Cope, AP J1 - ANN RHEUM DIS Y1 - 2007/03/01/ VL - 66 SN - 0003-4967 SP - A17 EP - A17 ER - TY - JFULL T1 - TCR-zeta dim T cells define a population of circulating effector cells that migrate to inflamed tissues A1 - Gorman, CL A1 - Zhang, Z A1 - Vermi, AC A1 - Monaco, C A1 - Marelli-Berg, F A1 - Dazzi, F A1 - Cope, AP J1 - ANN RHEUM DIS Y1 - 2007/03/01/ VL - 66 SN - 0003-4967 SP - A17 EP - A17 ER - TY - JFULL T1 - ClC-3 expression enhances etoposide resistance by increasing acidification of the late endocytic compartment. A1 - Weylandt, KH A1 - Nebrig, M A1 - Jansen-Rosseck, N A1 - Amey, JS A1 - Carmena, D A1 - Wiedenmann, B A1 - Higgins, CF A1 - Sardini, A J1 - Mol Cancer Ther Y1 - 2007/03// VL - 6 SN - 1535-7163 SP - 979 EP - 986 N2 - Resistance to anticancer drugs and consequent failure of chemotherapy is a complex problem severely limiting therapeutic options in metastatic cancer. Many studies have shown a role for drug efflux pumps of the ATP-binding cassette transporters family in the development of drug resistance. ClC-3, a member of the CLC family of chloride channels and transporters, is expressed in intracellular compartments of neuronal cells and involved in vesicular acidification. It has previously been suggested that acidification of intracellular organelles can promote drug resistance by increasing drug sequestration. Therefore, we hypothesized a role for ClC-3 in drug resistance. Here, we show that ClC-3 is expressed in neuroendocrine tumor cell lines, such as BON, LCC-18, and QGP-1, and localized in intracellular vesicles co-labeled with the late endosomal/lysosomal marker LAMP-1. ClC-3 overexpression increased the acidity of intracellular vesicles, as assessed by acridine orange staining, and enhanced resistance to the chemotherapeutic drug etoposide by almost doubling the IC(50) in either BON or HEK293 cell lines. Prevention of organellar acidification, by inhibition of the vacuolar H(+)-ATPase, reduced etoposide resistance. No expression of common multidrug resistance transporters, such as P-glycoprotein or multidrug-related protein-1, was detected in either the BON parental cell line or the derivative clone overexpressing ClC-3. The probable mechanism of enhanced etoposide resistance can be attributed to the increase of vesicular acidification as consequence of ClC-3 overexpression. This study therefore provides first evidence for a role of intracellular CLC proteins in the modulation of cancer drug resistance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17363491&query_hl=1 ER - TY - JFULL T1 - Chemokines as modulators of neuroendocrine functions A1 - Rostene, W A1 - Buckingham, JC J1 - J MOL ENDOCRINOL Y1 - 2007/03// VL - 38 SN - 0952-5041 SP - 351 EP - 353 N2 - Chemokines are small secreted proteins with chemoattractant properties for immune cells. Besides their role in the immune system, chemokines and their receptors may play important roles in the central nervous system. Neurodegenerative disorders that involve neuroinflammation such as multiple sclerosis, stroke, Alzheimer's disease, Parkinson's disease and HIV-associated dementia are commonly associated with local upregulation and release of chemokines. However, recent work has established that certain chemokines, constitutively expressed in the brain, exert functions in the brain that are distinct from inflammation. These chemokines regulate neuronal migration during brain development, modulate neuronal activity and play a role in various neurodegenerative diseases, pain and more recently in neuroendocrine functions. All these novel aspects, mainly focused on the chemokine stromal cell-derived factor-1/CXCL12 and its receptor CXCR4, were presented by pioneers in the field during the symposium held at the sixth International Congress of Neuroendocrinology in Pittsburgh, Pennsylvania, USA in June 2006. ER - TY - JFULL T1 - BXSB/long-lived is a recombinant inbred strain containing powerful disease suppressor loci A1 - Gabriel, L A1 - Haywood, MEK A1 - Rose, SJ A1 - Rogers, NJ A1 - Izui, S A1 - Morley, BJ J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 72 EP - 72 ER - TY - JFULL T1 - No contribution of angiotensin-converting enzyme (ACE) gene variants to severe obesity: a model for comprehensive case/control and quantitative cladistic analysis of ACE in human diseases. A1 - Bell, CG A1 - Meyre, D A1 - Petretto, E A1 - Levy-Marchal, C A1 - Hercberg, S A1 - Charles, MA A1 - Boyle, C A1 - Weill, J A1 - Tauber, M A1 - Mein, CA A1 - Aitman, TJ A1 - Froguel, P A1 - Walley, AJ J1 - Eur J Hum Genet Y1 - 2007/03// VL - 15 SN - 1018-4813 SP - 320 EP - 327 N2 - Candidate gene analyses are often inconclusive owing to genetic or phenotypic heterogeneity, low statistical power, selection of nonfunctional SNPs, and inadequate statistical analysis of the genetic architecture. Angiotensin-converting enzyme (ACE) is involved in adipocyte growth and function and the ACE-processed angiotensin II inhibits adipocyte differentiation. Associations between body mass index (BMI) and ACE polymorphisms have been reported in general populations, but the contribution to severe obesity of this gene, which is located under an obesity genome-scan linkage peak on 17q23, is unknown. ACE is one of the most studied genes and markers responsible for variation in circulating ACE enzyme levels have been extensively characterised. Eight of these variants were genotyped in 1054 severely obese cases and 918 nonobese controls, as well as 116 nuclear families from the genome scan (n=447), enabling the known clades to be inferred. Qualitative analysis of individual single-nucleotide polymorphisms (SNPs), haplotypes, clades, and diploclades demonstrated no significant associations (P<0.05) after minimal correction for multiple testing. Quantitative analysis of clades and diploclades for BMI, waist-to-hip ratio, or ZBMI in children were also not significant. This rigorous, large-scale study of common, well-defined, severe polygenic obesity provides strong evidence that functionally relevant sequence variation in ACE, whether it is defined at the level of SNPs, haplotypes, or clades, is not associated with severe obesity in French Caucasians. Such a study design exemplifies the strategy needed to clearly define the contribution of the ACE gene to the plethora of complex genetic diseases where weak associations have been previously reported. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17164796&query_hl=1 ER - TY - JFULL T1 - Single nucleotide polymorphisms in the neuropeptide Y2 receptor (NPY2R) gene and association with severe obesity in French white subjects. A1 - Siddiq, A A1 - Gueorguiev, M A1 - Samson, C A1 - Hercberg, S A1 - Heude, B A1 - Levy-Marchal, C A1 - Jouret, B A1 - Weill, J A1 - Meyre, D A1 - Walley, A A1 - Froguel, P J1 - Diabetologia Y1 - 2007/03// VL - 50 SN - 0012-186X SP - 574 EP - 584 N2 - AIMS/HYPOTHESIS: Genetic variants of genes for peptide YY (PYY), neuropeptide Y2 receptor (NPY2R) and pancreatic polypeptide (PPY) were investigated for association with severe obesity. SUBJECTS AND METHODS: The initial screening of the genes for variants was performed by sequencing in a group of severely obese subjects (n=161). Case-control analysis of the common variants was then carried out in 557 severely obese adults, 515 severely obese children and 1,163 non-obese/non-diabetic control subjects. Rare variants were genotyped in 700 obese children and the non-obese/non-diabetic control subjects (n=1,163). RESULTS: Significant association was found for a 5' variant (rs6857715) in the NPY2R gene with both severe adult obesity (p=0.002) and childhood obesity (p=0.02). This significant association was further supported by a pooled allelic analysis of all obese cases (adults and children, n=928) vs the control subjects (n=938) (p=0.0004, odds ratio=1.3, 95% CI 1.1-1.5). Quantitative trait analysis of BMI and WHR was performed and significant association was observed for SNP rs1047214 in NPY2R with an increase in WHR in the severely obese children (co-dominant model p=0.005, recessive model p=0.001). Association was also observed for an intron 3 variant (rs162430) in the PYY gene with childhood obesity (p=0.04). No significant associations were observed for PPY variants. Only one rare variant in the NPY2R gene (C-5641T) was not found in lean individuals and this was found to co-segregate with obesity in one family. CONCLUSIONS/INTERPRETATION: These results provide evidence of association for NPY2R and PYY gene variants with obesity and none for PPY variants. A rare variant of the NPY2R gene showed evidence of co-segregation with obesity and its contribution to obesity should be investigated further. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17235527&query_hl=1 ER - TY - JFULL T1 - Physiological and aberrant regulation of memory T cell trafficking by the co-stimulatory molecule CD28 A1 - Mirenda, V A1 - Jarmin, SJ A1 - David, R A1 - Dyson, J A1 - Scott, D A1 - Gu, Y A1 - Lechler, RI A1 - Okkenhaug, K A1 - Marelli-Berg, FM J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 31 EP - 31 ER - TY - JFULL T1 - Common ABCB1 polymorphisms are not associated with multidrug resistance in epilepsy using a gene-wide tagging approach. A1 - Leschziner, GD A1 - Andrew, T A1 - Leach, JP A1 - Chadwick, D A1 - Coffey, AJ A1 - Balding, DJ A1 - Bentley, DR A1 - Pirmohamed, M A1 - Johnson, MR J1 - Pharmacogenet Genomics Y1 - 2007/03// VL - 17 SN - 1744-6872 SP - 217 EP - 220 N2 - P-glycoprotein, the product of the ABCB1 gene, is a proposed mechanism of pharmacoresistance in epilepsy. Previous attempts to correlate the ABCB1 C3435T SNP, or a three-SNP haplotype containing C3435T with epilepsy pharmacoresistance have produced discordant findings. We analysed these single nucleotide polymorphisms (SNPs), plus a more comprehensive set of tagging SNPs describing common variation in ABCB1 in a case-control study. No significant association of C3435T (P=0.55), the three-SNP haplotype (lowest P=0.14) or any gene-wide tagging SNP (lowest P=0.17) with multidrug resistance in epilepsy was identified. Meta-analysis of studies using the same definition of multidrug resistance (n=1064) also demonstrated no significant association of C3435T with multidrug resistance (P=0.31). These findings suggest that C3435T is unlikely to be a marker for epilepsy multidrug resistance. In addition, no evidence for a role of other common ABCB1 polymorphisms was found using a potentially more powerful gene-wide tagging approach. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17460550&query_hl=1 ER - TY - JFULL T1 - Increased positive selection of B1 cells and reduced B cell tolerance to intracellular antigens in C1q-deficient mice A1 - Ferry, H A1 - Potter, PK A1 - Crockford, TL A1 - Nijnik, A A1 - Ehrenstein, MR A1 - Walport, MJ A1 - Botto, M A1 - Cornall, RJ J1 - J IMMUNOL Y1 - 2007/03/01/ VL - 178 SN - 0022-1767 SP - 2916 EP - 2922 N2 - Inherited deficiency of early components of the classical complement pathway is strongly associated with the targeting of intracellular self Ags in systemic lupus erythematosus, but the reasons for this association are debated. In this study, we show that C1q deficiency increases the positive selection of B1b B cells and IgM autoantibodies by an intracellular self Ag, which is exposed on dying cells, and decreases the negative selection of autoreactive conventional B cells by the same Ag. These effects are specific to intracellular Ag because C1q deficiency does not affect negative selection by extracellular self Ag or increase the positive selection of naive B cells. The B1-derived IgM autoantibody binds to the intracellular Ag when it is expressed on dying cells, leading to fixation of C1q and clearance of cells by phagocytosis. These findings suggest that the positive selection of autoreactive B1 cells by self Ags may contribute to the IgM and C1q-dependent clearance of dying cells in a feedback loop that limits exposure of conventional B cells to immunogenic self Ags. We show that exposure of intracellular Ag leads to the activation of conventional B cells, when there is a source of T cell help in vivo. ER - TY - JFULL T1 - Hypothalamic mapping of orexigenic action and Fos-like immunoreactivity following relaxin-3 administration in male Wistar rats. A1 - McGowan, BM A1 - Stanley, SA A1 - White, NE A1 - Spangeus, A A1 - Patterson, M A1 - Thompson, EL A1 - Smith, KL A1 - Donovan, J A1 - Gardiner, JV A1 - Ghatei, MA A1 - Bloom, SR J1 - Am J Physiol Endocrinol Metab Y1 - 2007/03// VL - 292 SN - 0193-1849 SP - E913 EP - E919 N2 - The insulin superfamily, characterized by common disulphide bonds, includes not only insulin but also insulin-like peptides such as relaxin-1 and relaxin-3. The actions of relaxin-3 are largely unknown, but recent work suggests a role in regulation of food intake. Relaxin-3 mRNA is highly expressed in the nucleus incertus, which has extensive projections to the hypothalamus, and relaxin immunoreactivity is present in several hypothalamic nuclei. In the rat, relaxin-3 binds and activates both relaxin family peptide receptor 1, which also binds relaxin-1, and a previously orphaned G protein-coupled receptor, RXFP3. These receptors are extensively expressed in the hypothalamus. The aims of these studies were twofold: 1) map the hypothalamic site(s) of the orexigenic action of relaxin-3 and 2) examine the site(s) of neuronal activation following central relaxin-3 administration. After microinjection into hypothalamic sites, human relaxin-3 (H3; 180 pmol) significantly stimulated 0- to 1-h food intake in the supraoptic nucleus (SON), arcuate nucleus (ARC), and the anterior preoptic area (APOA) [SON 0.4+/-0.2 (vehicle) vs. 2.9+/-0.5 g (H3), P<0.001; ARC 0.7+/-0.3 (vehicle) vs. 2.7+/-0.2 g (H3), P<0.05; and APOA 0.8+/-0.1 (vehicle) vs. 2.2+/-0.2 g (H3), P<0.05]. Cumulative food intake was significantly increasedT. Subjects bearing the -3608 C allele present a plasma lipid profile protective against atherogenesis: decrease of plasma LDL-cholesterol level (p=0.001) and of the LDL/HDL ratio (p=0.0003). This result offers new evidences for a potential implication of the CART gene in lipid metabolism and in atherogenesis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17008116&query_hl=1 ER - TY - JFULL T1 - The secret life of the multilocus sequence type. A1 - Turner, KM A1 - Feil, EJ J1 - Int J Antimicrob Agents Y1 - 2007/02// VL - 29 SN - 0924-8579 SP - 129 EP - 135 N2 - Such are the challenges, and the potential, presented by complete genome sequences that the eventual erosion of the boundaries between biochemistry, ecology, bioinformatics, population biology, epidemiology and medical microbiology will perhaps be the most profound legacy of the genomics revolution. The development of nucleotide sequence-based typing schemes (multilocus sequence typing (MLST)) represents a similar synthesis, for this technique both matches the practical requirements for a highly portable standard for strain characterisation whilst also being firmly grounded in the population biology principles of multilocus enzyme electrophoresis (MLEE). Contrary to recent claims that population biology analyses of public health-oriented MLST data 'obscures its utility in applied microbiology' [Maiden MC. Multilocus sequence typing of bacteria. Annu Rev Microbiol 2006;60:561-88.], we argue that such an emphasis is essential for full interpretation of the data. Here we note a pertinent case in point; how a consideration of the rates of genetic recombination can help to explain why MLST data tend to correlate with virulence properties in some species (Neisseria meningitidis) but not in others (Staphylococcus aureus). We also discuss how the argument applies to the identification of recently emerged methicillin-resistant S. aureus (MRSA) clones using MLST. We conclude with a speculative rationale for promoting the 'clonal complexes' of S. aureus to species status. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17204401&query_hl=1 ER - TY - JFULL T1 - Stochastic modelling of colon cancer: is there a role for genomic instability? A1 - Little, MP A1 - Li, G J1 - Carcinogenesis Y1 - 2007/02// VL - 28 SN - 0143-3334 SP - 479 EP - 487 N2 - Three stochastic models of genomic instability recently developed by Little and Wright (Math. Biosci., (2003) 183, 111-34), with two, three and five stages, and the two-stage genomic instability model of Nowak et al. (Proc. Natl Acad. Sci. USA, (2002) 99, 16226-16231) are compared with the four-stage model proposed by Luebeck and Moolgavkar (Proc. Natl Acad. Sci. USA, (2002) 99, 15095-15100) that does not assume such an instability mechanism. All models are fitted to US colon cancer incidence data. The best fitting models are the two-stage model of Nowak et al. and the two-stage model of Little and Wright, with the four-stage model of Luebeck and Moolgavkar not markedly inferior. The fits of the three-stage and five-stage models are somewhat worse (P<0.05), the five-stage model fitting particularly poorly (P<0.01). Both optimal genomic instability models predict cellular mutation rates that are at least 10 000 times higher after genomic destabilization, for both sexes. Therefore, the results of this paper are somewhat at variance with those of previous analyses of Little and Wright in suggesting that equivalently good fit may be obtained by models that do not assume a role for genomic destabilization in the induction of colon cancer as for those that do. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16973671&query_hl=1 ER - TY - JFULL T1 - Role of calcineurin in the regulation of human lung mast cell and basophil function by cyclosporine and FK506. A1 - Harrison, CA A1 - Bastan, R A1 - Peirce, MJ A1 - Munday, MR A1 - Peachell, PT J1 - Br J Pharmacol Y1 - 2007/02// VL - 150 SN - 0007-1188 SP - 509 EP - 518 N2 - BACKGROUND AND PURPOSE: Cyclosporine and FK506 are thought to act by targeting the Ca2+-dependent protein phosphatase, calcineurin. The aim of the present study was to determine whether cyclosporine and FK506 stabilize mast cells and basophils by interacting with calcineurin. EXPERIMENTAL APPROACH: The effects of cyclosporine and FK506 on the IgE-mediated release of histamine from mast cells and basophils were evaluated. The presence of calcineurin in cells was determined by Western blotting. Ca2+-dependent protein phosphatase activities were assessed in cell extracts using a synthetic phosphorylated peptide that is known to serve as a substrate for calcineurin. KEY RESULTS: FK506 was about 100-fold more potent than cyclosporine as an inhibitor of IgE-dependent histamine release from mast cells and basophils. Immunoblotting of solubilized preparations of purified cells demonstrated the presence of calcineurin in mast cells and basophils. In enzyme assays, mast cells expressed approximately 7-fold higher Ca2+-dependent protein phosphatase activity than basophils. Whereas cyclosporine effectively inhibited Ca2+-dependent protein phosphatase activity in cell extracts, FK506 was considerably less effective. CONCLUSIONS AND IMPLICATIONS: FK506 and cyclosporine inhibit the stimulated release of histamine from mast cells and basophils. However, the ability of cyclosporine, but not FK506, to inhibit Ca2+-dependent protein phosphatase activity questions whether FK506 stabilizes mast cells and basophils by interacting with calcineurin. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17200674&query_hl=1 ER - TY - JFULL T1 - Optimizing aerosol gene delivery and expression in the ovine lung A1 - McLachlan, G A1 - Baker, A A1 - Tennant, P A1 - Gordon, C A1 - Vrettou, C A1 - Renwick, L A1 - Blundell, R A1 - Cheng, SH A1 - Scheule, RK A1 - Davies, L A1 - Painter, H A1 - Coles, RL A1 - Lawton, AE A1 - Marriott, C A1 - Gill, DR A1 - Hyde, SC A1 - Griesenbach, U A1 - Alton, EWFW A1 - Boyd, AC A1 - Porteous, DJ A1 - Collie, DDS J1 - MOL THER Y1 - 2007/02// VL - 15 SN - 1525-0016 SP - 348 EP - 354 N2 - We have developed the sheep as a large animal model for optimizing cystic fibrosis gene therapy protocols. We administered aerosolized gene transfer agents (GTAs) to the ovine lung in order to test the delivery, efficacy, and safety of GTAs using a clinically relevant nebulizer. A preliminary study demonstrated GTA distribution and reporter gene expression throughout the lung after aerosol administration of plasmid DNA (pDNA): GL67 and pDNA: PEI complexes. A more comprehensive study examined the dose - response relationship for pDNA: PEI and assessed the influence of adjunct therapeutic agents. We found that the sheep model can differentiate between doses of GTA and that the anticholinergic, glycopyrrolate, enhanced transgene expression. Dose-related toxicity of GTA was reduced by aerosol administration compared to direct instillation. This large animal model will allow us to move toward clinical studies with greater confidence. ER - TY - JFULL T1 - Prenatal stressful life events predict child cognitive outcomes A1 - Bergman, KM A1 - Sarkar, P A1 - O'Connor, TG A1 - Modi, N A1 - Glover, V J1 - EARLY HUM DEV Y1 - 2007/02// VL - 83 SN - 0378-3782 SP - 136 EP - 136 ER - TY - JFULL T1 - Efficient clearance of opsonised apoptotic cells in the absence of PECAM-1. A1 - Potter, PK A1 - Larbi, KY A1 - Nourshargh, S A1 - Botto, M J1 - Mol Immunol Y1 - 2007/02// VL - 44 SN - 0161-5890 SP - 1135 EP - 1140 N2 - It is now accepted that the recognition and uptake of apoptotic cells by phagocytes is a complex process involving a large number of opsonins, receptors and ligands, however the relative contribution of all these molecules are still debated. Here we examined the role of CD31 (PECAM-1) in the recognition/uptake of apoptotic thymocytes by murine bone marrow-derived macrophages (BMDM) in vitro, and by resident peritoneal macrophages in vivo. In the absence of serum, CD31 deficiency, on either the phagocyte or the apoptotic cell, resulted in a reduction in the clearance of apoptotic thymocytes, when a high ratio of apoptotic cells to macrophages was applied. In the presence of serum however there was no discernible contribution of CD31 to the clearance of apoptotic cells by bone marrow-derived macrophages, irrespective of the ratio of cells used. In vivo peritoneal clearance experiments confirmed that in the presence of soluble opsonins CD31 deficiency had no effect on this process. These data suggest that the overall role played by CD31 in the ingestion of apoptotic cells is negligible and most likely overwhelmed by the effects of serum opsonins, such as complement components. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16911831&query_hl=1 ER - TY - JFULL T1 - CD59 protects against lesion formation in LDL receptor deficient mice: Evidence for complement activation in atherogenesis A1 - Yun, S A1 - Leung, V A1 - Botto, M A1 - Haskard, DO A1 - Boyle, JJ J1 - HEART Y1 - 2007/02// VL - 93 SN - 1355-6037 ER - TY - JFULL T1 - Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1. A1 - Yoshida, C A1 - Yoshida, F A1 - Sears, DE A1 - Hart, SM A1 - Ikebe, D A1 - Muto, A A1 - Basu, S A1 - Igarashi, K A1 - Melo, JV J1 - Blood Y1 - 2007/02/01/ VL - 109 SN - 0006-4971 SP - 1211 EP - 1219 N2 - The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the Bcr-Abl oncoprotein. We have previously reported that expression of the Bach2 transcription factor, which induces apoptosis in response to oxidative stress, is greatly reduced in CML cells. Because these cells are resistant to apoptosis, we tested whether Bach2 could also be regulated through posttranslational mechanisms that promote inhibition of the apoptotic response to mutagenic stimuli in CML. We found that Bach2 is phosphorylated on S521 via the phosphatidylinositol-3/S6 kinase pathway, and substitution of this site to alanine leads to nuclear accumulation of the protein, indicating that this phosphorylation is important for its subcellular localization. Ectopic expression of the S521 mutant imparts greater impairment to CML cell growth than the wild-type factor. Furthermore, we showed that Bach2 transcriptionally represses heme oxygenase-1, an antiapoptotic factor up-regulated in CML. Because CML cells are known to produce high levels of intracellular reactive oxygen species, overexpression of heme oxygenase-1 resulting from inhibition of Bach2 activity may contribute to their genomic instability and leukemic phenotype. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17018862&query_hl=1 ER - TY - JFULL T1 - Novel compounds with antiproliferative activity against imatinib-resistant cell lines. A1 - Lerma, EI A1 - Nguyen, VA A1 - Wang, T A1 - Tipping, A A1 - Melo, JV A1 - Kufe, D A1 - Austin, DJ A1 - Deisseroth, A J1 - Mol Cancer Ther Y1 - 2007/02// VL - 6 SN - 1535-7163 SP - 655 EP - 666 N2 - Chronic myelogenous leukemia is caused by the Bcr-Abl hybrid gene that encodes the p210Bcr-Abl chimeric oncoprotein. Although it reduces the total body burden of leukemia cells, the use of imatinib mesylate as a single agent may be accompanied by the evolution of resistance due mainly to the acquisition of point mutations. Imatinib has been combined with drugs that inhibit both the active and the inactive states of the p210Bcr-Abl kinase. These combinations have reduced but not completely eliminated the rate at which point mutations are acquired in the p210Bcr-Abl kinase. Thus, it is important to identify additional new inhibitors of the p210Bcr-Abl kinase. One possible method to prevent evolution of resistance is to simultaneously use multiple kinase inhibitors each with a different mechanism of action. To identify such a new class of inhibitors that could suppress the growth of chronic myelogenous leukemia cells and prevent the evolution of cells that are resistant to imatinib, we screened two low-complexity libraries of compounds based on planar and linear scaffolds. These libraries were screened using a cell-based assay for molecules that suppress p210Bcr-Abl-dependent cell growth. The application of this method resulted in the isolation of two new classes of drugs, both of which inhibited imatinib-resistant cells in the low micromolar range. Some of these drugs were potent inhibitors not only of Abl tyrosine kinase but also of the Src, Lyn, and Fyn tyrosine kinases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17267662&query_hl=1 ER - TY - JFULL T1 - Basal and hyperaemic myocardial blood flow in regionally denervated canine hearts: an in vivo study with positron emission tomography. A1 - Rimoldi, OE A1 - Drake-Holland, AJ A1 - Noble, MI A1 - Camici, PG J1 - Eur J Nucl Med Mol Imaging Y1 - 2007/02// VL - 34 SN - 1619-7070 SP - 197 EP - 205 N2 - PURPOSE: Positron emission tomography (PET) studies in patients with diabetic autonomic neuropathy (DAN) have demonstrated the impact of this disease on cardiac sympathetic innervation and myocardial blood flow (MBF). To investigate the effects of selective partial sympathetic denervation of the left ventricle (LV) on baseline and hyperaemic MBF, we measured myocardial presynaptic catecholamine re-uptake (uptake-1), beta-adrenoceptor (beta-AR) density and MBF non-invasively by means of PET in a canine model of regional sympathetic denervation. METHODS: In 11 anaesthetised dogs, the sympathetic nerves of the free wall and septum of the LV were removed by means of dissection and phenol painting. Three weeks later, the animals were studied with PET. MBF was measured at baseline and following i.v. adenosine (140 microg kg(-1) min(-1)) and dobutamine (20 microg kg(-1) min(-1)) using(15)O-labelled water. Sympathetic denervation was confirmed by an 80+/-12% decrease in the volume of distribution (V(d)) of [(11)C]hydroxyephedrine (HED) compared with innervated regions. Myocardial beta-AR density was measured using [(11)C]CGP12177. RESULTS: Innervated and denervated regions showed no differences in MBF at baseline and during adenosine or dobutamine. [(11)C]HED V(d)was inversely correlated with MBF in both regions at baseline, and the correlation was lost during hyperaemia in denervated regions. However, for any given value of MBF, [(11)C]HED V(d)was significantly lower in the denervated regions. beta-AR density was comparable in denervated and innervated regions (17.9+/-4.2 vs 18.4+/-3.3 pmol g(-1); p=NS). CONCLUSION: In this experimental model, selective, regional sympathetic denervation of the LV, which results in a profound reduction in [(11)C]HED V(d), did not affect baseline or hyperaemic MBF. In addition, we demonstrated that, under baseline conditions, there was a significant inverse correlation between [(11)C]HED V(d)and MBF in both denervated and innervated regions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16951953&query_hl=1 ER - TY - JFULL T1 - A congenital myopathy with diaphragmatic weakness not linked to the SMARD1 locus. A1 - Hartley, L A1 - Kinali, M A1 - Knight, R A1 - Mercuri, E A1 - Hubner, C A1 - Bertini, E A1 - Manzur, AY A1 - Jimenez-Mallebrera, C A1 - Sewry, CA A1 - Muntoni, F J1 - Neuromuscul Disord Y1 - 2007/02// VL - 17 SN - 0960-8966 SP - 174 EP - 179 N2 - Severe diaphragmatic weakness in infancy is rare. Common causes include structural myopathies, neuromuscular transmission defects, or anterior horn cell dysfunction (spinal muscular atrophy with respiratory distress, SMARD1). We describe a form of infantile diaphragmatic weakness without mutations in the SMARD1 gene, in which pathological and clinical features differ from known conditions, and investigations suggest a myopathy. We identified seven cases in four families. All presented soon after birth with feeding and breathing difficulties, marked head lag, facial weakness, and preserved antigravity movements in the limbs, with arms weaker than legs. All had paradoxical breathing and paralysis of at least one hemi-diaphragm. All required gastrostomy feeding, and all became ventilator-dependent. Investigations included myopathic EMG, muscle biopsy showing myopathic changes, normal electrophysiology and no mutations in SMN1 or IGHMBP2. These seven infants are affected by a myopathic condition clinically resembling SMARD1. However, its pathogenesis appears to be a myopathy affecting predominantly the diaphragm. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17236770&query_hl=1 ER - TY - JFULL T1 - Shear stress modulates endothelial responses to TNF alpha by suppressing proinflammatory transcripts and enhancing cytoprotective transcripts A1 - Partridge, J A1 - Enesa, K A1 - Kinderlerer, A A1 - Johns, M A1 - Mason, JC A1 - Haskard, DO A1 - Evans, PC J1 - HEART Y1 - 2007/02// VL - 93 SN - 1355-6037 ER - TY - JFULL T1 - Complement C1q and C3 are critical for the innate immune response to Streptococcus pneumoniae in the central nervous system A1 - Rupprecht, TA A1 - Angele, B A1 - Klein, M A1 - Heesemann, J A1 - Pfister, HW A1 - Botto, M A1 - Koedel, U J1 - J IMMUNOL Y1 - 2007/02/01/ VL - 178 SN - 0022-1767 SP - 1861 EP - 1869 N2 - Previous studies suggest that the complement system can contribute to limiting pneumococcal outgrowth within the CNS. In this study, we evaluated the role of the complement system in the activation of the innate immune response and the development of the prognosis-relevant intracranial complications in a murine model of pneumococcal meningitis. Thereby, we used mice deficient in C1q, lacking only the classical pathway, and C3, lacking all three complement activation pathways. At 24 h after intracisternal infection, bacterial titers in the CNS were almost 12- and 20-fold higher in C1q- and C3-deficient-mice, respectively, than in wild-type mice. Mean CSF leukocyte counts were reduced by 47 and 73% in C1q- and O-deficient-mice, respectively. Intrathecal reconstitution with wild-type serum in C3-deficient mice restored both the ability of mice to combat pneumococcal infection of the CSF and the ability of leukocytes to egress into the CSF. The altered recruitment of leukocytes into the CSF of C3-deficient mice was paralleled by a strong reduction of the brain expression of cytokines and chemokines. The dampened immune response in C3-deficient mice was accompanied by a reduction of meningitis-induced intracranial complications, but, surprisingly, also with a worsening of short-term outcome. The latter seems to be due to more severe bacteremia (12- and 120-fold higher in C1q- and C3-deficient-mice, respectively) and, consecutively, more severe systemic complications. Thus, our study demonstrated for the first time that the complement system plays an integral role in mounting the intense host immune response to Streptococcus pneumoniae infection of the CNS. ER - TY - JFULL T1 - Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. A1 - Ioannidis, JP A1 - Ng, MY A1 - Sham, PC A1 - Zintzaras, E A1 - Lewis, CM A1 - Deng, HW A1 - Econs, MJ A1 - Karasik, D A1 - Devoto, M A1 - Kammerer, CM A1 - Spector, T A1 - Andrew, T A1 - Cupples, LA A1 - Duncan, EL A1 - Foroud, T A1 - Kiel, DP A1 - Koller, D A1 - Langdahl, B A1 - Mitchell, BD A1 - Peacock, M A1 - Recker, R A1 - Shen, H A1 - Sol-Church, K A1 - Spotila, LD A1 - Uitterlinden, AG A1 - Wilson, SG A1 - Kung, AW A1 - Ralston, SH J1 - J Bone Miner Res Y1 - 2007/02// VL - 22 SN - 0884-0431 SP - 173 EP - 183 N2 - Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. INTRODUCTION: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. MATERIALS AND METHODS: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. RESULTS: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. CONCLUSIONS: This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17228994&query_hl=1 ER - TY - JFULL T1 - Maternally imprinted microRNAs are differentially expressed during mouse and human lung development. A1 - Williams, AE A1 - Moschos, SA A1 - Perry, MM A1 - Barnes, PJ A1 - Lindsay, MA J1 - Dev Dyn Y1 - 2007/02// VL - 236 SN - 1058-8388 SP - 572 EP - 580 N2 - MicroRNAs (miRNAs) are a recently discovered class of noncoding genes that regulate the translation of target mRNA. More than 300 miRNAs have now been discovered in humans, although the function of most is still unknown. A highly sensitive, semiquantitative real-time polymerase chain reaction method was used to reveal the differential expression of several miRNAs during the development of both mouse and human lung. Of note was the up-regulation in neonatal mouse and fetal human lung of a maternally imprinted miRNA cluster located at human chromosome 14q32.31 (mouse chromosome 12F2), which includes the miR-154 and miR-335 families and is situated within the Gtl2-Dio3 domain. Conversely, several miRNAs were up-regulated in adult compared with neonatal/fetal lung, including miR-29a and miR-29b. Differences in the spatial expression patterns of miR-154, miR-29a, and miR-26a was demonstrated using in situ hybridization of mouse neonatal and adult tissue using miRNA-specific locked nucleic acid (LNA) probes. Of interest, miR-154 appeared to be localized to the stroma of fetal but not adult lungs. The overall expression profile was similar for mouse and human tissue, suggesting evolutionary conservation of miRNA expression during lung development and demonstrating the importance of maternally imprinted miRNAs in the developmental process. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17191223&query_hl=1 ER - TY - JFULL T1 - Computed tomography and cystic fibrosis: promises and problems. A1 - Aziz, ZA A1 - Davies, JC A1 - Alton, EW A1 - Wells, AU A1 - Geddes, DM A1 - Hansell, DM J1 - Thorax Y1 - 2007/02// VL - 62 SN - 0040-6376 SP - 181 EP - 186 N2 - Computed tomography (CT) has two potential roles in the evaluation of patients with cystic fibrosis (CF) lung disease: as a diagnostic test primarily for the detection of supervening complications and as a monitoring tool in clinical research. Interest in the latter role has gained momentum in the last 5 years because of two factors: (1) therapeutic options for CF lung disease are developing rapidly, hence the need for an outcome measure that can be applied in clinical intervention trials; and (2) it has become clear that traditional outcome measures such as pulmonary function tests are relatively insensitive to the early structural damage that occurs in CF. Several recent studies have shown that CT can be used as a potential surrogate outcome measure, although its suitability for this specific role is controversial and still under investigation. This review summarises current concepts relating to the research applications of CT in CF, with particular emphasis on the evidence supporting the use of CT as a surrogate outcome measure in clinical trials. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17287306&query_hl=1 ER - TY - JFULL T1 - Climate change and outbreaks of amphibian chytridiomycosis in a montane area of Central Spain; is there a link? A1 - Bosch, J A1 - Carrascal, LM A1 - Duran, L A1 - Walker, S A1 - Fisher, MC J1 - P R SOC B Y1 - 2007/01/22/ VL - 274 SP - 253 EP - 260 N2 - Amphibian species are declining at an alarming rate on a global scale in large part owing to an infectious disease caused by the chytridiomycete fungus, Batrachochytrium dendrobatidis. This disease of amphibians has recently emerged within Europe, but knowledge of its effects on amphibian assemblages remains poor. Importantly, little is known about the environmental envelope that is associated with chytridiomycosis in Europe and the potential for climate change to drive future disease dynamics. Here, we use long-term observations on amphibian population dynamics in the Penalara Natural Park, Spain, to investigate the link between climate change and chytridiomycosis. Our analysis shows a significant association between change in local climatic variables and the occurrence of chytridiomycosis within this region. Specifically, we show that rising temperature is linked to the occurrence of chytrid-related disease, consistent with the chytrid-thermal-optimum hypothesis. We show that these local variables are driven by general circulation patterns, principally the North Atlantic Oscillation. Given that B. dendrobatidis is known to be broadly distributed across Europe, there is now an urgent need to assess the generality of our finding and determine whether climate-driven epidemics may be expected to impact on amphibian species across the wider region. ER - TY - JFULL T1 - Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase A1 - Kuramoto, N A1 - Wilkins, ME A1 - Fairfax, BP A1 - Revilla-Sanchez, R A1 - Terunuma, M A1 - Tamaki, K A1 - Iemata, M A1 - Warren, N A1 - Couve, A A1 - Calver, A A1 - Horvath, Z A1 - Freeman, K A1 - Carling, D A1 - Huang, L A1 - Gonzales, C A1 - Cooper, E A1 - Smart, TG A1 - Pangalos, MN A1 - Moss, SJ J1 - NEURON Y1 - 2007/01/18/ VL - 53 SN - 0896-6273 SP - 233 EP - 247 N2 - GABA(B) receptors are heterodimeric G protein-coupled receptors composed of R1 and R2 subunits that mediate slow synaptic inhibition in the brain by activating inwardly rectifying K+ channels (GIRKs) and inhibiting Ca2+, channels. We demonstrate here that GABAB receptors are intimately associated with 5'AMP-dependent protein kinase (AMPK). AMPK acts as a metabolic sensor that is potently activated by increases in 5'AMP concentration that are caused by enhanced metabolic activity, anoxia, or ischemia. AMPK binds the R1 subunit and directly phosphorylates S783 in the R2 subunit to enhance GABAB receptor activation of GIRKs. Phosphorylation of S783 is evident in many brain regions, and is increased dramatically after ischemic injury. Finally, we also reveal that S783 plays a critical role in enhancing neuronal survival after ischemia. Together our results provide evidence of a neuroprotective mechanism, which, under conditions of metabolic stress or after ischemia, increases GABAB receptor function to reduce excitotoxicity and thereby promotes neuronal survival. ER - TY - JFULL T1 - Identifying cardiorespiratory neurocircuitry involved in central command during exercise in humans. A1 - Green, AL A1 - Wang, S A1 - Purvis, S A1 - Owen, SL A1 - Bain, PG A1 - Stein, JF A1 - Guz, A A1 - Aziz, TZ A1 - Paterson, DJ J1 - J Physiol Y1 - 2007/01/15/ VL - 578 SN - 0022-3751 SP - 605 EP - 612 N2 - For almost one hundred years, the exact role of human brain structures controlling the cardiorespiratory response to exercise ('central command') has been sought. Animal experiments and functional imaging studies have provided clues, but the underlying electrophysiological activity of proposed relevant neural sites in humans has never been measured. In this study, local field potentials were directly recorded in a number of 'deep' brain nuclei during an exercise task designed to dissociate the exercise from peripheral feedback mechanisms. Several patient groups had electrodes implanted sterotaxically for the treatment of movement disorder or chronic pain. Fast Fourier transform analysis was applied to the neurograms to identify the power of fundamental spectral frequencies. Anticipation of exercise resulted in increases in heart rate, blood pressure and ventilation. The greatest neural changes were found in the periaqueductal grey area (PAG) where anticipation of exercise was accompanied by an increase of 43% in the power of the 12-25 Hz frequency band (P = 0.007). Exercise increased the activity by 87% compared to rest (P = 0.006). Changes were also seen in the 60-90 Hz band when anticipation or exercise increased power by 32% (P = 0.006) and 109% (P < 0.001), respectively. In the subthalamic nucleus there was a reduction in the power of the beta frequency during both anticipation (7.6 +/- 0.68% P = 0.001) and exercise (17.3 +/- 0.96% P < 0.001), whereas an increase was seen with exercise only at higher frequencies (93 +/- 1.8% P = 0.007). No significant changes were seen in the globus pallidus during anticipation of exercise. We provide direct electrophysiological evidence highlighting the PAG as an important subcortical area in the neural circuitry of the cardiorespiratory response to exercise, since stimulation of this structure is known to alter blood pressure in awake humans. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17082229&query_hl=1 ER - TY - JFULL T1 - Comment on "A common genetic variant is associated with adult and childhood obesity". A1 - Dina, C A1 - Meyre, D A1 - Samson, C A1 - Tichet, J A1 - Marre, M A1 - Jouret, B A1 - Charles, MA A1 - Balkau, B A1 - Froguel, P J1 - Science Y1 - 2007/01/12/ VL - 315 SN - 1095-9203 SP - 187; author reply 187 EP - 187; author reply 187 N2 - Herbert et al. (Reports, 14 April 2006, p. 279) reported an association between the INSIG2 gene variant rs7566605 and obesity in four sample populations, under a recessive model. We attempted to replicate this result in 10,265 Caucasian individuals, combining family-based, case-control, and general population studies, but found no support for a major role of this variant in obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17218508&query_hl=1 ER - TY - JFULL T1 - PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pah(enu2) mice A1 - Embury, JE A1 - Charron, CE A1 - Martynyuk, A A1 - Zori, AG A1 - Liu, B A1 - Ali, SF A1 - Rowland, NE A1 - Laipis, PJ J1 - BRAIN RES Y1 - 2007/01/05/ VL - 1127 SN - 0006-8993 SP - 136 EP - 150 N2 - Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pub(enu2) mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of pah(enu2) mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to pah(enu2) mice and corresponded to rapid reduction of serum Phe levels. (c) 2006 Elsevier B.V. All rights reserved. ER - TY - JFULL T1 - Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy. A1 - Mercuri, E A1 - Bertini, E A1 - Messina, S A1 - Solari, A A1 - D'Amico, A A1 - Angelozzi, C A1 - Battini, R A1 - Berardinelli, A A1 - Boffi, P A1 - Bruno, C A1 - Cini, C A1 - Colitto, F A1 - Kinali, M A1 - Minetti, C A1 - Mongini, T A1 - Morandi, L A1 - Neri, G A1 - Orcesi, S A1 - Pane, M A1 - Pelliccioni, M A1 - Pini, A A1 - Tiziano, FD A1 - Villanova, M A1 - Vita, G A1 - Brahe, C J1 - Neurology Y1 - 2007/01/02/ VL - 68 SN - 1526-632X SP - 51 EP - 55 N2 - OBJECTIVE: To assess the efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy in a randomized, double-blind, placebo-controlled trial involving 10 Italian centers. METHODS: One hundred seven children were assigned to receive PB (500 mg/kg/day) or matching placebo on an intermittent regimen (7 days on/7 days off) for 13 weeks. The Hammersmith functional motor scale (primary outcome measure), myometry, and forced vital capacity were assessed at baseline and at weeks 5 and 13. RESULTS: Between January and September 2004, 107 patients aged 30 to 154 months were enrolled. PB was well tolerated, with only one child withdrawing because of adverse events. Mean improvement in functional score was 0.60 in the PB arm and 0.73 in placebo arm (p = 0.70). Changes in the secondary endpoints were also similar in the two study arms. CONCLUSIONS: Phenylbutyrate was not effective at the regimen, schedule, and duration used in this study. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17082463&query_hl=1 ER - TY - JFULL T1 - Cardiac troponin I is a potential novel substrate for AMP-activated protein kinase A1 - Oliveira, SM A1 - Davies, J A1 - Carling, D A1 - Watkins, H A1 - Redwood, C J1 - BIOPHYS J Y1 - 2007/01// SN - 0006-3495 SP - 180A EP - 180A ER - TY - JFULL T1 - Nuclear positioning of the BACH2 gene in BCR-ABL positive leukemic cells A1 - Ono, A A1 - Kono, K A1 - Ikebe, D A1 - Muto, A A1 - Sun, JY A1 - Kobayashi, M A1 - Ueda, K A1 - Melo, JV A1 - Igarashi, K A1 - Tashiro, S J1 - GENE CHROMOSOME CANC Y1 - 2007/01// VL - 46 SN - 1045-2257 SP - 67 EP - 74 N2 - BACH2 is a B-cell-specific transcription repressor and is also know as a tumor suppressor in B cell malignancy. Expression of BACH2 is induced in BCR-ABL positive lymphoid cell lines including BV173 by imatinib, a molecular targeting agent for the treatment of chronic myeloid leukemia (CML). Here we show that the activity of the BACH2 gene is related to the nuclear positioning of the gene loci. We examined the spatial association of the BACH2 gene with the centromeric heterochromatin, a transcriptionally repressive subnuclear compartment, by comparing cells with low (BV173 and K562) and high (NAMALWA) levels of BACH2 mRNA. The BACH2 gene was located closer to the centromeric heterochromatin in BV173 and K562 cells as compared to NAMALWA cells. In BV173 cells, the BACH2-centromere distance increased after imatinib treatment to levels similar to those in NAMALWA cells. We also found that diethylmaleate, an oxidative stressor, enhanced the antiproliferative effect of imatinib in only BV173 cells. Since BACH2 induces apoptosis by oxidative stress, these observations suggest that down-regulation of the BACH2 gene through the interaction with centromeric heterochromatin would take part in leukomogenesis of BCR-ABL positive lymphoid leukemia. 2006 Wiley-Liss, Inc. ER - TY - JFULL T1 - Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia A1 - Pocaly, M A1 - Lagarde, V A1 - Etienne, G A1 - Ribeil, JA A1 - Claverol, S A1 - Bonneu, M A1 - Moreau-Gaudry, F A1 - Guyonnet-Duperat, V A1 - Hermine, O A1 - Melo, JV A1 - Dupouy, M A1 - Turcq, B A1 - Mahon, FX A1 - Pasquet, JM J1 - LEUKEMIA Y1 - 2007/01// VL - 21 SN - 0887-6924 SP - 93 EP - 101 N2 - Imatinib is an effective therapy for chronic myeloid leukemia ( CML), a myeloproliferative disorder characterized by the expression of the recombinant oncoprotein Bcr-AbI. In this investigation, we studied an imatinib-resistant cell line ( K562-r) generated from the K562 cell line in which none of the previously described mechanisms of resistance had been detected. A threefold increase in the expression of the heat-shock protein 70 ( Hsp70) was detected in these cells. This increase was not associated to heat-shock transcription factor-1 ( HSF-1) overexpression or activation. RNA silencing of Hsp70 decreased dramatically its expression ( 90%), and was accompanied by a 34% reduction in cell viability. Overexpression of Hsp70 in the imatinib-sensitive K562 line induced resistance to imatinib as detected by a large reduction in cell death in the presence of 1 mu M of imatinib. Hsp70 level was also increased in blast cells of CML patients resistant to imatinib, whereas the level remained low in responding patients. Taken together, the results demonstrate that overexpression of Hsp70 can lead to both in vitro and in vivo resistance to imatinib in CML cells. Moreover, the overexpression of Hsp70 detected in imatinib-resistant CML patients supports this mechanism and identifies potentially a marker and a therapeutic target of CML evolution. ER - TY - JFULL T1 - Combined C1q and C8 beta deficiency in a patient with recurrent childhood infections and adult-onset systemic lupus erythematosus A1 - Pickering, MC A1 - Fish, J A1 - Macor, P A1 - Durigutto, P A1 - Bossi, F A1 - Botto, M A1 - Tedesco, F J1 - MOL IMMUNOL Y1 - 2007/01// VL - 44 SN - 0161-5890 SP - 228 EP - 228 ER - TY - JFULL T1 - Family-based association analysis with ordered categorical phenotypes, covariates and interactions. A1 - Baksh, MF A1 - Balding, DJ A1 - Vyse, TJ A1 - Whittaker, JC J1 - Genet Epidemiol Y1 - 2007/01// VL - 31 SN - 0741-0395 SP - 1 EP - 8 N2 - Genetic association analyses of family-based studies with ordered categorical phenotypes are often conducted using methods either for quantitative or for binary traits, which can lead to suboptimal analyses. Here we present an alternative likelihood-based method of analysis for single nucleotide polymorphism (SNP) genotypes and ordered categorical phenotypes in nuclear families of any size. Our approach, which extends our previous work for binary phenotypes, permits straightforward inclusion of covariate, gene-gene and gene-covariate interaction terms in the likelihood, incorporates a simple model for ascertainment and allows for family-specific effects in the hypothesis test. Additionally, our method produces interpretable parameter estimates and valid confidence intervals. We assess the proposed method using simulated data, and apply it to a polymorphism in the c-reactive protein (CRP) gene typed in families collected to investigate human systemic lupus erythematosus. By including sex interactions in the analysis, we show that the polymorphism is associated with anti-nuclear autoantibody (ANA) production in females, while there appears to be no effect in males. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17096343&query_hl=1 ER - TY - JFULL T1 - microRNA expression in the aging mouse lung. A1 - Williams, AE A1 - Perry, MM A1 - Moschos, SA A1 - Lindsay, MA J1 - BMC Genomics Y1 - 2007/// VL - 8 SN - 1471-2164 SP - 172 EP - 172 N2 - BACKGROUND: MicroRNAs (miRNAs) are a novel class of short double stranded RNA that mediate the post-transcriptional regulation of gene expression. Previous studies have implicated changes in miRNA expression in the regulation of development and the induction of diseases such as cancer. However, although miRNAs have been implicated in the process of aging in C. elegans, nothing is known of their role in mammalian tissues. RESULTS: To address this question, we have used a highly-sensitive, semi-quantitative RT-PCR based approach to measure the expression profile of 256 of the 493 currently identified miRNAs in the lungs from 6 month (adult) and 18 month (aged) old female BALB/c mice. We show that, despite the characteristic changes in anatomy and gene expression associated with lung aging, there were no significant changes in the expression of 256 miRNAs. CONCLUSION: Overall, these results show that miRNA transcription is unchanged during lung aging and suggests that stable expression of miRNAs might instead buffer age related changes in the expression of protein-encoding genes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17573962&query_hl=1 ER - TY - JFULL T1 - C-terminal regions of topoisomerase IIalpha and IIbeta determine isoform-specific functioning of the enzymes in vivo. A1 - Linka, RM A1 - Porter, AC A1 - Volkov, A A1 - Mielke, C A1 - Boege, F A1 - Christensen, MO J1 - Nucleic Acids Res Y1 - 2007/// VL - 35 SN - 1362-4962 SP - 3810 EP - 3822 N2 - Topoisomerase II removes supercoils and catenanes generated during DNA metabolic processes such as transcription and replication. Vertebrate cells express two genetically distinct isoforms (alpha and beta) with similar structures and biochemical activities but different biological roles. Topoisomerase IIalpha is essential for cell proliferation, whereas topoisomerase IIbeta is required only for aspects of nerve growth and brain development. To identify the structural features responsible for these differences, we exchanged the divergent C-terminal regions (CTRs) of the two human isoforms (alpha 1173-1531 and beta 1186-1621) and tested the resulting hybrids for complementation of a conditional topoisomerase IIalpha knockout in human cells. Proliferation was fully supported by all enzymes bearing the alpha CTR. The alpha CTR also promoted chromosome binding of both enzyme cores, and was by itself chromosome-bound, suggesting a role in enzyme targeting during mitosis. In contrast, enzymes bearing the beta CTR supported proliferation only rarely and when expressed at unusually high levels. A similar analysis of the divergent N-terminal regions (alpha 1-27 and beta 1-43) revealed no role in isoform-specific functions. Our results show that it is the CTRs of human topoisomerase II that determine their isoform-specific functions in proliferating cells. They also indicate persistence of some functional redundancy between the two isoforms. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17526531&query_hl=1 ER - TY - JFULL T1 - RYR1 mutations and multi-minicore disease A1 - Treves, S A1 - Jungbluth, H A1 - Zhou, H A1 - Yamaguchi, N A1 - Meissner, G A1 - Sewry'Md, C A1 - Zorzato, F A1 - Muntoni, F J1 - BIOPHYS J Y1 - 2007/01// SN - 0006-3495 SP - 24A EP - 24A ER - TY - JFULL T1 - Reference and target region modeling of [11C]-(R)-PK11195 brain studies. A1 - Turkheimer, FE A1 - Edison, P A1 - Pavese, N A1 - Roncaroli, F A1 - Anderson, AN A1 - Hammers, A A1 - Gerhard, A A1 - Hinz, R A1 - Tai, YF A1 - Brooks, DJ J1 - J Nucl Med Y1 - 2007/01// VL - 48 SN - 0161-5505 SP - 158 EP - 167 N2 - PET with [(11)C]-(R)-PK11195 is currently the modality of choice for the in vivo imaging of microglial activation in the human brain. In this work we devised a supervised clustering procedure and a new quantification methodology capable of producing binding potential (BP) estimates quantitatively comparable with those derived from plasma input with robust quantitative implementation at the pixel level. METHODS: The new methodology uses predefined kinetic classes to extract a gray matter reference tissue without specific tracer binding and devoid of spurious signals (in particular, blood pool and muscle). Kinetic classes were derived from an historical database of 12 healthy control subjects and from 3 patients with Huntington's disease. BP estimates were obtained using rank-shaping exponential spectral analysis (RS-ESA) (both plasma and reference input) and the simplified reference tissue model (SRTM). Comparison between plasma- derived BPs and those produced with the new reference methodology was performed using 6 additional healthy control subjects. Reliability of the new methodology was performed on 4 test-retest studies of patients with Alzheimer's disease. RESULTS: The new algorithm selected reference voxels in gray matter tissue avoiding regions with specific binding located, in particular, in the venous and arterial circulation. Using the new reference, BP values obtained using a plasma input and a reference input were in excellent agreement and highly correlated (r = 0.811, P < 10(-5)) when calculated with RS-ESA and less so (r = 0.507, P < 0.005) when SRTM was used. In the production of parametric maps, SRTM was used with the new reference extraction, resulting in test-retest variability (10.6%; mean ICC = 0.878) that was superior to that obtained using the previous unsupervised clustering approach (mean ICC = 0.596). CONCLUSION: Reference region modeling combined with supervised reference tissue extraction produces a robust and reproducible quantitative assessment of [(11)C]-(R)-PK11195 studies in the human brain. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17204713&query_hl=1 ER - TY - JFULL T1 - Stringent and reproducible tetracycline-regulated transgene expression by site-specific insertion at chromosomal loci with pre-characterised induction characteristics. A1 - Brough, R A1 - Papanastasiou, AM A1 - Porter, AC J1 - BMC Mol Biol Y1 - 2007/// VL - 8 SN - 1471-2199 SP - 30 EP - 30 N2 - BACKGROUND: The ability to regulate transgene expression has many applications, mostly concerning the analysis of gene function. Desirable induction characteristics, such as low un-induced expression, high induced expression and limited cellular heterogeneity, can be seriously impaired by chromosomal position effects at the site of transgene integration. Many clones may therefore need to be screened before one with optimal induction characteristics is identified. Furthermore, such screens must be repeated for each new transgene investigated, and comparisons between clones with different transgenes is complicated by their different integration sites. RESULTS: To circumvent these problems we have developed a "screen and insert" strategy in which clones carrying a transgene for a fluorescent reporter are first screened for those with optimal induction characteristics. Site-specific recombination (SSR) is then be used repeatedly to insert any new transgene at the reporter transgene locus of such clones so that optimal induction characteristics are conferred upon it. Here we have tested in a human fibrosarcoma cell line (HT1080) two of many possible implementations of this approach. Clones (e.g. Rht14-10) in which a GFP reporter gene is very stringently regulated by the tetracycline (tet) transactivator (tTA) protein were first identified flow-cytometrically. Transgenes encoding luciferase, I-SceI endonuclease or Rad52 were then inserted by SSR at a LoxP site adjacent to the GFP gene resulting stringent tet-regulated transgene expression. In clone Rht14-10, increases in expression from essentially background levels (+tet) to more than 104-fold above background (-tet) were reproducibly detected after Cre-mediated insertion of either the luciferase or the I-SceI transgenes. CONCLUSION: Although previous methods have made use of SSR to integrate transgenes at defined sites, none has effectively combined this with a pre-selection step to identify integration sites that support optimal regulatory characteristics. Rht14-10 and similar HT1080-derived clones can now be used in conjunction with a convenient delivery vector (pIN2-neoMCS), in a simple 3-step protocol leading to stringent and reproducible transgene regulation. This approach will be particularly useful for transgenes whose products are very active at low concentrations and/or for comparisons of multiple related transgenes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17493262&query_hl=1 ER - TY - JFULL T1 - The influence of pharmacogenetics on fatty liver disease in the wistar and kyoto rats: a combined transcriptomic and metabonomic study. A1 - Griffin, JL A1 - Scott, J A1 - Nicholson, JK J1 - J Proteome Res Y1 - 2007/01// VL - 6 SN - 1535-3893 SP - 54 EP - 61 N2 - Although fatty liver disease is caused by a number of toxicological insults and the metabolic syndrome, the exact mechanisms by which many of these pathophysiological stimulii induce fatty liver are unknown. The rapid and profound steatosis caused by orotic acid, resulting from an impairment in the production of ApoB, has been investigated in the Wistar strain rat using a combined transcriptomic and metabonomic/metabolomic approach. Analysis of liver tissue from rats exposed to orotic acid for 1, 3, and 14 days was performed by DNA microarrays and high resolution 1H NMR spectroscopy based metabonomics of both tissue extracts and intact tissue (n = 3). Data were analyzed using a combination of ANOVA and principal components analysis, used as a data reduction tool to visualize the most perturbed transcripts and metabolites. Orotic acid produced a profound 8-fold increase in total lipids, and in particular increases in resonances associated with polyunsaturated fats (CH=CH and CH2CH=CH groups). This was accompanied by increases in the concentrations of trimethylamine-oxide (TMAO), betaine, choline, and phosphocholine, as well as a relative decrease in glucose and glycogen. At the transcriptional level, perturbations were detected in both oxidative stress and osmoregulation/pH homeostasis. However, this contrasts with a previous transcriptomic/metabolic study of fatty liver disease in a combined data set of Wistar (out-bred) and Kyoto (in-bred) strains of rats, with only 4 transcripts being found to be in common between the two analyses. This emphasizes the need to understand how strain background interacts with a given toxic lesion or genetic modification. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17203948&query_hl=1 ER - TY - JFULL T1 - Increased susceptibility of heterozygous factor H deficient mice to accelerated serum nephrotoxic nephritis A1 - Pickering, MC A1 - Rose, KL A1 - Carlucci, F A1 - Howard, J A1 - Cook, HT A1 - Botto, M J1 - MOL IMMUNOL Y1 - 2007/01// VL - 44 SN - 0161-5890 SP - 228 EP - 228 ER - TY - JFULL T1 - Bayesian logistic regression using a perfect phylogeny. A1 - Clark, TG A1 - De Iorio, M A1 - Griffiths, RC J1 - Biostatistics Y1 - 2007/01// VL - 8 SN - 1465-4644 SP - 32 EP - 52 N2 - Haplotype data capture the genetic variation among individuals in a population and among populations. An understanding of this variation and the ancestral history of haplotypes is important in genetic association studies of complex disease. We introduce a method for detecting associations between disease and haplotypes in a candidate gene region or candidate block with little or no recombination. A perfect phylogeny demonstrates the evolutionary relationship between single-nucleotide polymorphisms (SNPs) in the haplotype blocks. Our approach extends the logic regression technique of Ruczinski and others (2003) to a Bayesian framework, and constrains the model space to that of a perfect phylogeny. Environmental factors, as well as their interactions with SNPs, may be incorporated into the regression framework. We demonstrate our method on simulated data from a coalescent model, as well as data from a candidate gene study of sarcoidosis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16556611&query_hl=1 ER - TY - JFULL T1 - Localization of a long-range cis-regulatory element of IL13 by allelic transcript ratio mapping. A1 - Forton, JT A1 - Udalova, IA A1 - Campino, S A1 - Rockett, KA A1 - Hull, J A1 - Kwiatkowski, DP J1 - Genome Res Y1 - 2007/01// VL - 17 SN - 1088-9051 SP - 82 EP - 87 N2 - It appears that, for many genes, the two alleles possessed by an individual may produce different amounts of transcript. When such allelic differences in transcription are observed for some individuals but not others, a plausible explanation is genetic variation in the cis-acting elements that regulate the gene in question. Here we describe a novel analytical approach that uses such observations, combined with genotyping data from the HapMap project, to define the genomic location of cis-acting regulatory elements. When applied to the human 5q31 chromosomal region, where complex regulatory mechanisms are known to exist, we demonstrate the sensitivity of this approach by locating a highly significant cis-regulatory element operating on IL13 at long range from a position 250 kb upstream from the gene (P = 2 x 10(-6)). As this method is unaffected by other sources of variation, such as environmental and trans-acting genetic factors, it provides a tractable approach for dissecting the complexities of genetic variation in gene regulation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17135570&query_hl=1 ER - TY - JFULL T1 - Two Caucasian families with the hepatocyte nuclear factor-1 alpha mutation Tyr218Cys A1 - Hummel, M A1 - Vasseur, F A1 - Mathieu, C A1 - Bellanne-Chantelot, C A1 - Froguel, P A1 - Standl, E A1 - Fuchtenbusch, M J1 - EXP CLIN ENDOCR DIAB Y1 - 2007/01// VL - 115 SN - 0947-7349 SP - 62 EP - 64 N2 - We report on the first two Caucasian families with the MODY3 HNF-1alpha mutation Tyr-218Cys. Clinical and laboratory examinations are shown in detail. Patients with HNF-1 alpha related MODY may develop the full spectrum of diabetic complications. Therefore, early detection of family members with MODY3 is warranted. ER - TY - JFULL T1 - C1q can alter the levels of IgM autoantibody production in anti-DNA transgenic models A1 - Fossati-Jimack, L A1 - Cortes-Hernandez, J A1 - Norsworthy, P A1 - Cook, HT A1 - Botto, M J1 - MOL IMMUNOL Y1 - 2007/01// VL - 44 SN - 0161-5890 SP - 171 EP - 171 ER - TY - JFULL T1 - Dectin-1 is required for beta-glucan recognition and control of fungal infection A1 - Taylor, PR A1 - Tsoni, SV A1 - Willment, JA A1 - Dennehy, KM A1 - Rosas, M A1 - Findon, H A1 - Haynes, K A1 - Steele, C A1 - Botto, M A1 - Gordon, S A1 - Brown, GD J1 - NAT IMMUNOL Y1 - 2007/01// VL - 8 SN - 1529-2908 SP - 31 EP - 38 N2 - beta-Glucan is one of the most abundant polysaccharides in fungal pathogens, yet its importance in antifungal immunity is unclear. Here we show that deficiency of dectin-1, the myeloid receptor for beta-glucan, rendered mice susceptible to infection with Candida albicans. Dectin-1-deficient leukocytes demonstrated significantly impaired responses to fungi even in the presence of opsonins. Impaired leukocyte responses were manifested in vivo by reduced inflammatory cell recruitment after fungal infection, resulting in substantially increased fungal burdens and enhanced fungal dissemination. Our results establish a fundamental function for beta-glucan recognition by dectin-1 in antifungal immunity and demonstrate a signaling non-Toll-like pattern-recognition receptor required for the induction of protective immune responses. ER - TY - JFULL T1 - Expansion of CD8+ cytotoxic T cells in vitro and in vivo using MHC class I tetramers. A1 - Savage, P A1 - Millrain, M A1 - Dimakou, S A1 - Stebbing, J A1 - Dyson, J J1 - Tumour Biol Y1 - 2007/// VL - 28 SN - 1010-4283 SP - 70 EP - 76 N2 - BACKGROUND: The expansion of cytotoxic CD8+ T lymphocytes (CTLs) which recognize peptide epitopes of tumour or viral origin has been a major aim of immunotherapy research for the past decade. Alongside the established dendritic cell-based methods, more recent approaches using recombinant MHC class I peptide complexes have been developed. METHODS: In this study we have explored the potential of a simplified system using soluble streptavidin-linked MHC class I tetramers to expand antigen-specific CTLs in vitro and in vivo. RESULTS: In vitro tetramer-mediated expansion of CD8+ CTLs recognizing HLA-2/Melan-A and HLA-A2/Gag complexes was demonstrated with PBMCs from healthy donors or HIV+ donors, respectively. With 3 weekly rounds of tetramer stimulation, cell numbers expanded 100-fold from 0.05 to 5.0%. The lytic function of HLA-A2/Melan-A-expanded cells was demonstrated in 51Cr release assays by specific killing of T2 cells pulsed with Melan-A, but not other peptides. Similarly, murine CD8+ T cells specific for the HY epitope H2-Db/Uty could be expanded in vitro over a wide range of tetramer concentrations (0.008-1.0 microg/ml), with a single exposure producing substantial T cell expansion from 0.11 to 36%. Intraperitoneal administration of H2-Db/Uty tetramers to primed C57BL/6 mice produced over 5-fold expansion of Db/Uty-specific CTL in vivo. CONCLUSION: The results in this paper demonstrate that simple, multimeric MHC complexes may be of value in expanding CTLs in vitro for adoptive immunotherapy and also potentially in vivo. Further studies will be necessary to clarify the optimum protocols and schedules of administration for T cell expansion using recombinant MHC multimers. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17264539&query_hl=1 ER - TY - JFULL T1 - Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids. A1 - Moschos, SA A1 - Williams, AE A1 - Perry, MM A1 - Birrell, MA A1 - Belvisi, MG A1 - Lindsay, MA J1 - BMC Genomics Y1 - 2007/// VL - 8 SN - 1471-2164 SP - 240 EP - 240 N2 - BACKGROUND: At present, nothing is known of the role of miRNAs in the immune response in vivo despite the fact that inflammation is thought to underlie multiple acute and chronic diseases. In these circumstances, patients are commonly treated with corticosteroids such as dexamethasone. RESULTS: To address this question, we have examined the differential expression of 104 miRNAs using real-time PCR during the innate immune response in mouse lung following exposure to aerosilised lipopolysaccharide (LPS). Following challenge, we observed rapid and transient increase in both the mean (4.3-fold) and individual levels of miRNA expression (46 miRNAs) which peaked at 3 hrs. Crucially, this increase was correlated with a reduction in the expression of tumour necrosis factor (TNF)-alpha, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2, suggesting a potential role for miRNAs in the regulation of inflammatory cytokine production. Examination of the individual miRNA expression profiles showed time dependent increases in miR-21, -25, -27b, -100, 140, -142-3p, -181c, 187, -194, -214, -223 and -224. Corticosteroid studies showed that pre-treatment with dexamethasone at concentrations that inhibited TNF-alpha production, had no effect either alone or upon the LPS-induced miRNA expression profile. CONCLUSION: We have shown that the LPS-induced innate immune response is associated with widespread, rapid and transient increases in miRNA expression in the mouse lung and we speculate that these changes might be involved in the regulation of the inflammatory response. In contrast, the lack of effect of dexamethasone in either control or challenged animals implies that the actions of glucocorticoids per se are not mediated through changes in miRNAs expression and that LPS-induced increases in miRNA expression are not mediated via classical inflammatory transcription factors. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17640343&query_hl=1 ER - TY - JFULL T1 - TCF7L2 rs7903146 variant does not associate with smallness for gestational age in the French population. A1 - Cauchi, S A1 - Meyre, D A1 - Choquet, H A1 - Deghmoun, S A1 - Durand, E A1 - Gaget, S A1 - Lecoeur, C A1 - Froguel, P A1 - Levy-Marchal, C J1 - BMC Med Genet Y1 - 2007/// VL - 8 SN - 1471-2350 SP - 37 EP - 37 N2 - BACKGROUND: In adults, the TCF7L2 rs7903146 T allele, commonly associated with type 2 diabetes (T2D), has been also associated with a lower body mass index (BMI) in T2D individuals and with a smaller waist circumference in subjects with impaired glucose tolerance. METHODS: The present association study aimed at analyzing the contribution of the rs7903146 SNP to smallness for gestational age (SGA) and metabolic profiles in subjects with SGA or appropriate for gestational age birth weight (AGA). Two groups of French Caucasian subjects were selected on birth data: SGA (birth weight < 10th percentile; n = 764), and AGA (25th < birth weight < 75th percentile; n = 627). Family-based association tests were also performed in 3,012 subjects from 628 SGA and AGA pedigrees. RESULTS: The rs7903146 genotypic distributions between AGA (30.7%) and SGA (29.0%) were not statistically different (allelic OR = 0.92 [0.78-1.09], p = 0.34). Family association-based studies did not show a distortion of T allele transmission in SGA subjects (p = 0.52). No significant effect of the T allele was detected on any of the metabolic parameters in the SGA group. However, in the AGA group, trends towards a lower insulin secretion (p = 0.03) and a higher fasting glycaemia (p = 0.002) were detected in carriers of the T allele. CONCLUSION: The TCF7L2 rs7903146 variant neither increases the risk for SGA nor modulates birth weight and young adulthood glucose homeostasis in French Caucasian subjects born with SGA. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17593304&query_hl=1 ER - TY - JFULL T1 - Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice. A1 - Bhatia, VK A1 - Yun, S A1 - Leung, V A1 - Grimsditch, DC A1 - Benson, GM A1 - Botto, MB A1 - Boyle, JJ A1 - Haskard, DO J1 - Am J Pathol Y1 - 2007/01// VL - 170 SN - 0002-9440 SP - 416 EP - 426 N2 - We explored the role of the classic complement pathway in atherogenesis by intercrossing C1q-deficient mice (C1qa-/-) with low-density lipoprotein receptor knockout mice (Ldlr-/-). Mice were fed a normal rodent diet until 22 weeks of age. Aortic root lesions were threefold larger in C1qa-/-/Ldlr-/- mice compared with Ldlr-/- mice (3.72 +/- 1.0% aortic root versus 1.1 +/- 0.4%; mean +/- SEM, P < 0.001). Furthermore, the cellular composition of lesions in C1qa-/-/Ldlr-/- was more complex, with an increase in vascular smooth muscle cells. The greater aortic root lesion size in C1qa-/-/Ldlr-/- mice occurred despite a significant reduction in C5b-9 deposition per lesion unit area, suggesting the critical importance of proximal pathway activity. Apoptotic cells were readily detectable by cleaved caspase-3 staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electron microscopy in C1qa-/-/Ldlr-/-, whereas apoptotic cells were not detected in Ldlr-/- mice. This is the first direct demonstration of a role for the classic complement pathway in atherogenesis. The greater lesion size in C1qa-/-/Ldlr-/- mice is consistent with the emerging homeostatic role for C1q in the disposal of dying cells. This study suggests the importance of effective apoptotic cell removal for containing the size and complexity of early lesions in atherosclerosis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17200212&query_hl=1 ER - TY - JFULL T1 - Assessing the reliability of eBURST using simulated populations with known ancestry. A1 - Turner, KM A1 - Hanage, WP A1 - Fraser, C A1 - Connor, TR A1 - Spratt, BG J1 - BMC Microbiol Y1 - 2007/// VL - 7 SN - 1471-2180 SP - 30 EP - 30 N2 - BACKGROUND: The program eBURST uses multilocus sequence typing data to divide bacterial populations into groups of closely related strains (clonal complexes), predicts the founding genotype of each group, and displays the patterns of recent evolutionary descent of all other strains in the group from the founder. The reliability of eBURST was evaluated using populations simulated with different levels of recombination in which the ancestry of all strains was known. RESULTS: For strictly clonal simulations, where all allelic change is due to point mutation, the groups of related strains identified by eBURST were very similar to those expected from the true ancestry and most of the true ancestor-descendant relationships (90-98%) were identified by eBURST. Populations simulated with low or moderate levels of recombination showed similarly high performance but the reliability of eBURST declined with increasing recombination to mutation ratio. Populations simulated under a high recombination to mutation ratio were dominated by a single large straggly eBURST group, which resulted from the incorrect linking of unrelated groups of strains into the same eBURST group. The reliability of the ancestor-descendant links in eBURST diagrams was related to the proportion of strains in the largest eBURST group, which provides a useful guide to when eBURST is likely to be unreliable. CONCLUSION: Examination of eBURST groups within populations of a range of bacterial species showed that most were within the range in which eBURST is reliable, and only a small number (e.g. Burkholderia pseudomallei and Enterococcus faecium) appeared to have such high rates of recombination that eBURST is likely to be unreliable. The study also demonstrates how three simple tests in eBURST v3 can be used to detect unreliable eBURST performance and recognise populations in which there appears to be a high rate of recombination relative to mutation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17430587&query_hl=1 ER - TY - JFULL T1 - Interpretation of renal biopsies in IgA nephropathy. A1 - Cook, HT J1 - Contrib Nephrol Y1 - 2007/// VL - 157 SN - 0302-5144 SP - 44 EP - 49 N2 - The renal biopsy is essential for the diagnosis of IgA nephropathy. It should also be possible to derive important information from the biopsy about prognosis and likely response to treatment. Biopsy features that are associated with progression to end-stage renal disease are glomerulosclerosis and tubulointerstitial scarring, marked crescent formation and marked arteriolar hyalinosis. However, with our present classification systems the renal biopsy adds little over and above clinical features in predicting outcome. It may be possible to improve the predictive value of the renal biopsy by adopting the following recommendations in developing new classifications: (1) looking at the ability of the biopsy to predict changes in renal function in the short term after biopsy rather than prediction of progression to end stage renal disease; (2) examining subgroups of patients where the biopsy is likely to be most informative; (3) distinguishing the effects of reversible and irreversible changes particularly with regard to response to treatment; (4) ensuring uniformity of definitions between pathologists, and (5) paying attention to small lesions and considering including additional biopsy features. The most important role for the renal biopsy in the future is likely to be in predicting response to therapy rather than predicting progression to end-stage renal disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17495436&query_hl=1 ER - TY - JFULL T1 - Impact of multiple treatment interruptions on virus-host interactions in HBeAg-positive chronic hepatitis B (CHB) A1 - Chokshi, S A1 - Petretto, E A1 - Cooksley, H A1 - Mangion, J A1 - Hill, J A1 - Naoumov, N J1 - J HEPATOL Y1 - 2007/01// VL - 46 SN - 0168-8278 SP - S154 EP - S154 ER - TY - JFULL T1 - The role of complement in innate, acquired and eosinophil-mediated immunity to the nematode Nippostrongylus brasiliensis A1 - Giacomin, P A1 - Gordon, D A1 - Botto, M A1 - Dent, L J1 - MOL IMMUNOL Y1 - 2007/01// VL - 44 SN - 0161-5890 SP - 176 EP - 177 ER - TY - JFULL T1 - Spontaneous haemolytic uraemic syndrome (HUS) in factor H-deficient mice transgenic for murine factor H protein lacking the five C-terminal domains (FH Delta 16-20) A1 - Pickering, MC A1 - de Jorge, EG A1 - Rose, KL A1 - Moss, J A1 - Cook, HT A1 - de Cordoba, SR A1 - Botto, M J1 - MOL IMMUNOL Y1 - 2007/01// VL - 44 SN - 0161-5890 SP - 227 EP - 228 ER - TY - JFULL T1 - No major contribution of TCF7L2 sequence variants to maturity onset of diabetes of the young (MODY) or neonatal diabetes mellitus in French white subjects. A1 - Cauchi, S A1 - Vaxillaire, M A1 - Choquet, H A1 - Durand, E A1 - Duval, A A1 - Polak, M A1 - Froguel, P J1 - Diabetologia Y1 - 2007/01// VL - 50 SN - 0012-186X SP - 214 EP - 216 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17093940&query_hl=1 ER - TY - JFULL T1 - Statistical tools for synthesizing lists of differentially expressed features in related experiments. A1 - Blangiardo, M A1 - Richardson, S J1 - Genome Biol Y1 - 2007/// VL - 8 SN - 1465-6914 SP - R54 EP - R54 N2 - We propose a novel approach for finding a list of features that are commonly perturbed in two or more experiments, quantifying the evidence of dependence between the experiments by a ratio. We present a Bayesian analysis of this ratio, which leads us to suggest two rules for choosing a cut-off on the ranked list of p values. We evaluate and compare the performance of these statistical tools in a simulation study, and show their usefulness on two real datasets. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17428330&query_hl=1 ER - TY - JFULL T1 - Accuracy and reproducibility of protein-DNA microarray technology. A1 - Field, S A1 - Udalova, I A1 - Ragoussis, J J1 - Adv Biochem Eng Biotechnol Y1 - 2007/// VL - 104 SN - 0724-6145 SP - 87 EP - 110 N2 - Microarray-based methods for understanding protein-DNA interactions have been developed in the last 6 years due to the need to introduce high-throughput technologies in this field. Protein-DNA microarrays utilise chips upon which a large number of DNA sequences may be printed or synthesised. Any DNA-binding protein may then be interrogated by applying either purified sample or cellular/nuclear extracts, subject to availability of a suitable detection system. Protein is simply added to the microarray slide surface, which is then washed and subjected to at least one further incubation with a labelled molecule which binds specifically to the protein of interest. The signal obtained is proportional to the level of DNA-binding protein bound to each DNA feature, enabling relative affinities to be calculated. Key factors for reproducible and accurate quantification of protein binding are: microarray surface chemistry; length of oligonucleotides; position of the binding site sequence; quality of the protein and antibodies; and hybridisation conditions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17290820&query_hl=1 ER - TY - JFULL T1 - Early events in the thymus affect the balance of effector and regulatory T cells A1 - Pennington, DJ A1 - Silva-Santos, B A1 - Silberzahn, T A1 - Escorcio-Correia, M A1 - Woodward, MJ A1 - Roberts, SJ A1 - Smith, AL A1 - Dyson, PJ A1 - Hayday, AC J1 - NATURE Y1 - 2006/12/21/ VL - 444 SN - 0028-0836 SP - 1073 EP - 1077 N2 - In cellular immunology the critical balance between effector and regulatory mechanisms is highlighted by serious immunopathologies attributable to mutations in Foxp3, a transcription factor required for a major subset of regulatory T (T-R) cells(1-3). Thus, many studies have focused on the developmental origin of T-R cells, with the prevailing view that they emerge in the thymus from late-stage T-cell progenitors whose T-cell receptors (TCRs) engage high affinity (agonist) ligands(4-6). This study questions the completeness of that interpretation. Here we show that without any obvious effect on TCR-mediated selection, the normal differentiation of mouse gamma delta T cells into potent cytolytic and interferon-gamma-secreting effector cells is switched towards an aggregate regulatory phenotype by limiting the capacity of CD4(+) CD8(+) T-cell progenitors to influence in trans early gamma delta cell progenitors. Unexpectedly, we found that the propensity of early TCR-alpha beta(+) progenitors to differentiate into Foxp3 1 T-R cells is also regulated in trans by CD4(+) CD8(+) T-cell progenitor cells, before agonist selection. ER - TY - JFULL T1 - Aspirin modified dendritic cells are potent inducers of allo-specific regulatory T-cells A1 - Buckland, M A1 - Jago, C A1 - Fazekesova, H A1 - George, A A1 - Lechler, R A1 - Lombardi, G J1 - INT IMMUNOPHARMACOL Y1 - 2006/12/20/ VL - 6 SN - 1567-5769 SP - 1895 EP - 1901 N2 - Salicylic acid (aspirin) is a widely used pharmacological agent with immunodmodulatory properties. Dendritic cells are key regulators of the immune response, and are capable of inducing hyporesponsiveness and regulatory activity in CD4(+) T-cells. We have demonstrated that aspirin-treated dendritic cells are effective at antigen processing and presentation, and possess a unique potency for inducing regulatory activity in responder T-cells. Unlike immature dendritic cells, aspirin DCs are resistant to the effects of maturational stimuli, as determined by low levels of CD40, CD80, CD83 and CD86 expression. Aspirin DCs were demonstrated to express high levels of the co-inhibitor of T-cell activation ILT-3. Aspirin DCs themselves produce less IL-10 and more IL-12 than immature DCs, but no specific cytokine is necessary for their tolerogenic capacity. When naive CD4(+) T-cells are exposed to aspirin DCs they produce significant levels of IFN gamma but these same T-cells are hypo-proliferative. Aspirin-treated DCs demonstrate the characteristics of a potential immunotherapy for controlling unwanted immune-responses Such as the indirect pathway of allo-recognition that drives chronic allograft rejection. (c) 2006 Elsevier B.V. All rights reserved. ER - TY - JFULL T1 - Radiation-induced leukemia at doses relevant to radiation therapy: modeling mechanisms and estimating risks. A1 - Shuryak, I A1 - Sachs, RK A1 - Hlatky, L A1 - Little, MP A1 - Hahnfeldt, P A1 - Brenner, DJ J1 - J Natl Cancer Inst Y1 - 2006/12/20/ VL - 98 SN - 1460-2105 SP - 1794 EP - 1806 N2 - BACKGROUND: Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation-induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. METHODS: To extend the model to radiation-induced leukemias, we analyzed--in addition to cellular initiation, inactivation, and proliferation--a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors who were subjected to much lower radiation doses. RESULTS: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110,000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose-rate dose to the bone marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% CI = -0.2 to 1.9). CONCLUSIONS: An extended, biologically based model for leukemia that includes HSC initiation, inactivation, proliferation, and, uniquely for leukemia, long-range HSC migration predicts, with reasonable accuracy, risks for radiation-induced leukemia associated with exposure to therapeutic doses of radiation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17179481&query_hl=1 ER - TY - JFULL T1 - Smooth muscle cell proliferation but not neointimal formation is dependent on alloantibody in a murine model of intimal hyperplasia. A1 - Soleimani, B A1 - Katopodis, A A1 - Wieczorek, G A1 - George, AJ A1 - Hornick, PI A1 - Heusser, C J1 - Clin Exp Immunol Y1 - 2006/12// VL - 146 SN - 0009-9104 SP - 509 EP - 517 N2 - Transplant coronary artery disease is the pre-eminent cause of late cardiac allograft failure. It is primarily characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). Although the pathogenesis of TIH is predominately immune driven, the specific role of alloantibodies in the disease process remains undefined. In this study we investigated the contribution of alloantibodies to the development of TIH in a murine model. Orthotopic, carotid artery transplantation was performed between B10A(2R) (H-2(h2)) donor mice and B-cell deficient muMT(-/-) knockout or wild-type C57BL/6 (H-2(b)) recipients in the absence of immunosuppression. Grafts were harvested at 35 days and subjected to planimetry and immunohistochemistry. Alloantibodies were detectable in wild-type recipients within 7 days of transplantation and recipients developed marked TIH at 35 days. Allografts harvested from B-cell deficient recipient mice also developed TIH, which was comparable in severity with wild-type recipients. However, whereas allografts from wild-type recipients showed marked intimal smooth muscle cell (SMC) proliferation, the neointima in B-cell deficient recipients lacked SMCs. Post-transplantation administration of anti-donor serum to muMT(-/-) recipients restored neointimal SMC population but did not influence the severity of TIH. Significant neointimal formation occurs in the absence of alloantibodies but lacks a SMC component. Therefore, SMC migration and proliferation is antibody dependent. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17100772&query_hl=1 ER - TY - JFULL T1 - Heme oxygenase-1 is induced in human neutrophils following surgery requiring cardiopulmonary bypass A1 - Melley, DD A1 - Lagan, AL A1 - Quinlan, GJ A1 - Evans, TW J1 - THORAX Y1 - 2006/12// VL - 61 SN - 0040-6376 SP - II50 EP - II51 ER - TY - JFULL T1 - Modelling the effectiveness of chlamydia screening in England. A1 - Turner, KM A1 - Adams, EJ A1 - Lamontagne, DS A1 - Emmett, L A1 - Baster, K A1 - Edmunds, WJ J1 - Sex Transm Infect Y1 - 2006/12// VL - 82 SN - 1368-4973 SP - 496 EP - 502 N2 - BACKGROUND: Several developed countries have initiated chlamydia screening programmes. Screening for a sexually transmitted infection has both direct individual and indirect population-wide effects. Mathematical models can incorporate these non-linear effects and estimate the likely impact of different screening programmes and identify areas where more data are needed. METHODS: A stochastic, individual based dynamic network model, parameterised from UK screening studies and data on sexual behaviour and chlamydia epidemiology, was used to investigate the likely impact of opportunistic screening on chlamydia prevalence. Three main strategies were considered for <25 year olds: (1) annual offer to women; (2) annual offer to women or if changed partner within last 6 months; (3) annual offer to men and women. Sensitivity analyses were performed for key screening parameters including uptake rate, targeted age range, percentage of partners notified, and screening interval. RESULTS: Under strategy 1, continuous opportunistic screening of women <25 years of age is expected to reduce the population prevalence by over 50% after 5 years. Prevalence is also expected to decrease in unscreened older women and in men. For all three strategies screening those aged over 25 results in small additional reductions in prevalence. Including men led to a faster and greater reduction in overall prevalence, but involved approximately twice as many tests as strategy 1 and 10% more than strategy 2. The frequency of attendance at healthcare sites limits the number of opportunities to screen and the effect of changing the screening interval. CONCLUSIONS: The model suggests that continuous opportunistic screening at high uptake rates could significantly reduced chlamydia prevalence within a few years. Opportunistic programmes depend on regular attendance at healthcare providers, but there is a lack of high quality data on patterns of attendance. Inequalities in coverage may result in a less efficient and less equitable outcome. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17151036&query_hl=1 ER - TY - JFULL T1 - ABCB1 polymorphisms and haplotype previously associated with drug resistant epilepsy have no effect on therapeutic or adverse drug response in a large prospective epilepsy cohort A1 - Leschziner, G A1 - Jorgensen, A A1 - Andrew, T A1 - Middleditch, C A1 - Pirmohamed, M A1 - Williamson, P A1 - Marson, A A1 - Coffey, AJ A1 - Rogers, J A1 - Bentley, DR A1 - Chadwick, D A1 - Johnson, MR J1 - J NEUROL NEUROSUR PS Y1 - 2006/12// VL - 77 SN - 0022-3050 SP - 1394 EP - 1394 ER - TY - JFULL T1 - Analysis of the HHT3 locus on chromosome 5, encoding a new gene for hereditary haemorrhagic telangiectasia A1 - Govani, FS A1 - Cole, SC A1 - Johns, M A1 - Jones, MD A1 - Shovlin, CL J1 - THORAX Y1 - 2006/12// VL - 61 SN - 0040-6376 SP - II10 EP - II11 ER - TY - JFULL T1 - ATLS versus ETC: time for a decision? A1 - Kinross, J A1 - Warren, O A1 - Darzi, A J1 - Ann Emerg Med Y1 - 2006/12// VL - 48 SN - 1097-6760 SP - 761 EP - 762 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17112943&query_hl=1 ER - TY - JFULL T1 - Persistent gene expression over the life-time of airway epithelial cells transduced by lentiviral vector pseudotyped with envelope proteins F and HN from Sendai virus A1 - Mitomo, K A1 - Griesenbach, U A1 - Inoue, M A1 - Tabata, T A1 - Geddes, DM A1 - Alton, EWFW A1 - Hasegawa, M J1 - J GENE MED Y1 - 2006/12// VL - 8 SN - 1099-498X SP - 1444 EP - 1444 ER - TY - JFULL T1 - Primitive, quiescent and difficult to kill: the role of non-proliferating stem cells in chronic myeloid leukemia. A1 - Barnes, DJ A1 - Melo, JV J1 - Cell Cycle Y1 - 2006/12// VL - 5 SN - 1551-4005 SP - 2862 EP - 2866 N2 - Recent studies have identified primitive, malignant stem cells which have entered the G0-phase of the cell cycle to become 'quiescent' and which are present, in small numbers, in all chronic myeloid leukaemia (CML) patients. These cells have attracted intense scrutiny because they are proving exceptionally refractory to attempts to kill them, in vitro, using imatinib mesylate, the current first-line therapy for CML, or conventional chemotherapeutic agents, such as cytosine arabinoside. This insensitivity, or resistance, to drug treatment is ominous and has important implications for the clinical management of CML, particularly with regard to relapse following an imatinib-induced remission. In this review, we consider the known properties of this cell population, including recent evidence which suggests that transcription of BCR-ABL occurs at an exceptionally high level in these cells despite them having only a single copy of the oncogene. We also discuss possible alternative, Bcr-Abl-independent, mechanisms for the insensitivity of these cells to agents which promote apoptosis, including the putative role of transporter proteins in causing abnormal drug influx or efflux. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17172863&query_hl=1 ER - TY - JFULL T1 - Cell therapy for renal regeneration-time for some joined-up thinking? A1 - Poulsom, R A1 - Prodromidi, EI A1 - Pusey, CD A1 - Cook, HT J1 - NEPHROL DIAL TRANSPL Y1 - 2006/12// VL - 21 SN - 0931-0509 SP - 3349 EP - 3353 ER - TY - JFULL T1 - A new syndrome of congenital insensitivity to pain diagnosed by skin biopsy and contact heat evoked potentials (CHEPS) A1 - Facer, P A1 - Atherton, D A1 - Roberts, K A1 - Misra, VP A1 - Kinali, M A1 - Manzur, AY A1 - Muntoni, F A1 - Anand, P J1 - J NEUROL NEUROSUR PS Y1 - 2006/12// VL - 77 SN - 0022-3050 SP - 1400 EP - 1400 ER - TY - JFULL T1 - Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. A1 - Humphries, SE A1 - Whittall, RA A1 - Hubbart, CS A1 - Maplebeck, S A1 - Cooper, JA A1 - Soutar, AK A1 - Naoumova, R A1 - Thompson, GR A1 - Seed, M A1 - Durrington, PN A1 - Miller, JP A1 - Betteridge, DJ A1 - Neil, HA A1 - Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee J1 - J Med Genet Y1 - 2006/12// VL - 43 SN - 1468-6244 SP - 943 EP - 949 N2 - AIMS: To determine the relative frequency of mutations in three different genes (low-density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK. Patients and METHODS: 409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single-strand conformational polymorphism (SSCP) (exons 3, 4, 6-10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP. RESULTS: Mutations were detected in 253 (61.9%) PATIENTS: 236 (57.7%) carried LDLR, 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9. After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels (LDLR, PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post-statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL-C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL-C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03). CONCLUSIONS: The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17142622&query_hl=1 ER - TY - JFULL T1 - Gene deletion reveals roles for annexin A1 in the regulation of lipolysis and IL-6 release in epididymal adipose tissue. A1 - Warne, JP A1 - John, CD A1 - Christian, HC A1 - Morris, JF A1 - Flower, RJ A1 - Sugden, D A1 - Solito, E A1 - Gillies, GE A1 - Buckingham, JC J1 - Am J Physiol Endocrinol Metab Y1 - 2006/12// VL - 291 SN - 0193-1849 SP - E1264 EP - E1273 N2 - In this study, epididymal adipose tissue from male annexin 1 (ANXA1)-null and wild-type control mice were used to explore the potential role of ANXA1 in adipocyte biology. ANXA1 was detected by Western blot analysis in wild-type tissue and localized predominantly to the stromal-vascular compartment. Epididymal fat pad mass was reduced by ANXA1 gene deletion, but adipocyte size was unchanged, suggesting that ANXA1 is required for the maintenance of adipocyte and/or preadipocyte cell number. Epididymal tissue from wild-type mice responded in vitro to noradrenaline and isoprenaline with increased glycerol release, reduced IL-6 release, and increased cAMP accumulation. Qualitatively similar but significantly attenuated responses to the catecholamines were observed in tissue from ANXA1-null mice, an effect that was not associated with changes in beta-adrenoceptor mRNA expression. Lipopolysaccharide (LPS) also stimulated lipolysis in vitro, but its effects were muted by ANXA1 gene deletion. By contrast, LPS failed to influence IL-6 release from wild-type tissue but stimulated the release of the cytokine from tissue from ANXA1-null mice. ANXA1 gene deletion did not affect glucocorticoid receptor expression or the ability of dexamethasone to suppress catecholamine-induced lipolysis. It did, however, augment IL-6 expression and modify the inhibitory effects of glucocorticoids on IL-6 release. Collectively, these studies suggest that ANXA1 supports aspects of adipose tissue mass and alters the sensitivity of epididymal adipose tissue to catecholamines, glucocorticoids, and LPS, thereby modulating lipolysis and IL-6 release. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16835395&query_hl=1 ER - TY - JFULL T1 - Time-specific effects of perinatal glucocorticoid treatment on anterior pituitary morphology, annexin 1 expression and adrenocorticotrophic hormone secretion in the adult female rat. A1 - John, CD A1 - Theogaraj, E A1 - Christian, HC A1 - Morris, JF A1 - Smith, SF A1 - Buckingham, JC J1 - J Neuroendocrinol Y1 - 2006/12// VL - 18 SN - 0953-8194 SP - 949 EP - 959 N2 - Perinatal glucocorticoid (GC) treatment is increasingly associated with long-term disturbances in hypothalamo-pituitary-adrenocortical function. In the male rat, such treatment induces profound molecular, morphological and functional changes in the anterior pituitary gland at adulthood. To determine whether these effects are sex-specific, we have examined the effects of perinatal dexamethasone treatment on the female pituitary gland, focusing on (i) the integrity of the annexin 1 (ANXA1) dependent regulatory effects of GCs on adrenocorticotrophic hormone (ACTH) release and (ii) corticotroph and folliculo-stellate (FS) cell morphology. Dexamethasone was given to pregnant (gestational days 16-19) or lactating (days 1-7 post partum) rats via the drinking water (1 microg/ml); controls received normal drinking water. Pituitary tissue from the female offspring was examined ex vivo at adulthood (60-90 days). Both treatment regimes reduced the intracellular and cell surface ANXA1 expression, as determined by western blot analysis and quantitative immunogold electron microscopic histochemistry. In addition, they compromised the ability of dexamethasone to suppress the evoked release of ACTH from the excised tissue in vitro, a process which requires the translocation of ANXA1 from the cytoplasm to the cell surface of FS cells. Although neither treatment regime affected the number of FS cells or corticotrophs, both altered the subcellular morphology of these cells. Thus, prenatal dexamethasone treatment increased while neonatal treatment decreased FS cell size and cytoplasmic area. By contrast, corticotroph size was unaffected by either treatment, as also was the size of the secretory granules. Corticotroph granule density and margination were, however, increased markedly by the prenatal treatment, while the neonatal treatment had no effect on granule density but decreased granule margination. Thus, perinatal dexamethasone treatment exerts long-term effects on the female pituitary gland, altering gene expression, cell morphology and the ANXA1-dependent GC regulation of ACTH secretion. The changes are similar but not identical to those reported in the male. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17076770&query_hl=1 ER - TY - JFULL T1 - Genotype-by-nutrient interactions assessed in European obese women - A case-only study A1 - Santos, JL A1 - Boutin, P A1 - Verdich, C A1 - Holst, C A1 - Larsen, LH A1 - Toubro, S A1 - Dina, C A1 - Saris, WHM A1 - Blaak, EE A1 - Hoffstedt, J A1 - Taylor, MA A1 - Polak, J A1 - Clement, K A1 - Langin, D A1 - Astrup, A A1 - Froguel, P A1 - Pedersen, O A1 - Sorensen, TIA A1 - Martinez, JA A1 - NUGENOB consortium J1 - EUR J NUTR Y1 - 2006/12// VL - 45 SN - 1436-6207 SP - 454 EP - 462 N2 - The development of obesity is influenced by both genetic and environmental risk factors. Whereas changes in the environment appear to be responsible for the increasing prevalence of obesity, genetic factors interacting with environmental factors would contribute to explain obesity onset and severity.To explore epidemiologic genotype-by-nutrient interactions in obesity.A total of 42 polymorphisms of 26 candidate genes for obesity were genotyped in 549 adult obese women recruited from eight European centres in a case-only study. The nutritional variables assessed in this study were the dietary fibre intake (grams per day), the ratio of dietary polyunsaturated fat to saturated fat (P:S ratio) and the percentage of energy derived from fat in the diet as calculated from a weighed three-day food record (%E). Under the assumption of genotype-nutrient independence in the population, the odds ratio calculated in a sample of obese women would indicate the existence of genotype-by-nutrient interactions, measured as deviations from the multiplicative effects of the genetic and the nutrient factors separately.No new but confirmaty evidences for genotype-by-nutrient interactions in obesity were detected in this case-only study. The test of interaction between fibre intake and the -514 C > T polymorphism of the hepatic lipase gene (LIPC) yielded P-values of 0.01 across different statistical models. Likewise, the -11377G > C polymorphism of the adiponectin gene (ADIPOQ) and the -681 C > G polymorphism of the PPARG3 gene might interact with the percentage of energy derived from fat in the diet for the development of obesity (P-values in the range of 0.01-0.05 across different statistical models). The P-values were not adjusted for multiple testing, so these results should be considered with caution.Although the use of obese-only samples is theoretically a useful approach to detect interactions, few genotype-by-nutrient interactions have been suggested in obese European women after the analysis of candidate polymorphisms and the selected nutrient variables. The most remarkable multiplicative interaction found in this study refers to the combination of the hepatic lipase gene polymorphism -514 C > T and fibre intake. ER - TY - JFULL T1 - Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling A1 - Steinberg, GR A1 - Michell, BJ A1 - van Denderen, BJW A1 - Watt, MJ A1 - Carey, AL A1 - Fam, BC A1 - Andrikopoulos, S A1 - Proietto, J A1 - Gorgun, CZ A1 - Carling, D A1 - Hotamisligil, GS A1 - Febbraio, MA A1 - Kay, TW A1 - Kemp, BE J1 - CELL METAB Y1 - 2006/12// VL - 4 SN - 1550-4131 SP - 465 EP - 474 N2 - Elevated levels of tumor necrosis factor (TNF alpha) are implicated in the development of insulin resistance, but the mechanisms mediating these chronic effects are not completely understood. We demonstrate that TNF alpha signaling through TNF receptor (TNFR) 1 suppresses AMPK activity via transcriptional upregulation of protein phosphatase 2C (PP2C). This in turn reduces ACC phosphorylation, suppressing fatty-acid oxidation, increasing intramuscular diacylglycerol accumulation, and causing insulin resistance in skeletal muscle, effects observed both in vitro and in vivo. Importantly even at pathologically elevated levels of TNF alpha observed in obesity, the suppressive effects of TNF alpha on AMPK signaling are reversed in mice null for both TNFR1 and 2 or following treatment with a TNF alpha neutralizing antibody. Our data demonstrate that AMPK is an important TNF alpha signaling target and is a contributing factor to the suppression of fatty-acid oxidation and the development of lipid-induced insulin resistance in obesity. ER - TY - JFULL T1 - Intravenously administered oligonucleotides can be delivered to conducting airway epithelium via the bronchial circulation. A1 - Holder, E A1 - Griesenbach, U A1 - Li, S A1 - Huang, L A1 - Rogers, DF A1 - Jeffery, PK A1 - Geddes, DM A1 - Alton, EW J1 - Gene Ther Y1 - 2006/12// VL - 13 SN - 0969-7128 SP - 1628 EP - 1638 N2 - Topical gene transfer to the airways of cystic fibrosis (CF) patients has been inefficient, partly due to extracellular barriers such as sputum. In an attempt to circumvent these, we assessed whether airway epithelial cells can be transfected by intravenous (i.v.) administration of liposome-complexed or "naked" oligonucleotides (ODNs). The conducting airways are the likely target for CF therapy and are supplied by the bronchial circulation. Consequently, we assessed ODN transfer in the mouse trachea and main bronchi as these are supplied by the bronchial circulation. Liposome-protamine-DNA (LPD) complexes were detected in the bronchial circulation but did not transfect conducting airway epithelial cells, even in the presence of microvascular leakage. In contrast, 'naked' ODNs were delivered to 17% (inter-quartile range (IQR) 10-34%) and 35% (IQR 24-59%) of epithelial cells when injected at 500 microg/animal, without and with microvascular leakage, respectively. Two types of nuclear signal were observed; punctate in cells throughout the airways (3%, IQR 2-6%, and 6%, IQR 4-7%, of cells when delivered without and with microvascular leakage, respectively) and diffuse in a small number of epithelial cells in the proximal trachea. ODNs may be relevant to CF in a variety of ways and these data suggest one way towards implementing their use. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16791284&query_hl=1 ER - TY - JFULL T1 - Prospective epilepsy DNA bank: SANAD and MESS linked DNA repository A1 - Johnson, M A1 - Allen, J A1 - Alwaidh, M A1 - Andrews, J A1 - Appleton, R A1 - Arbery, H A1 - Beck, D A1 - Bennett, R A1 - Bentley, DR A1 - Burt, P A1 - Cleland, P A1 - Cock, H A1 - Cockerell, OC A1 - Coffey, AJ A1 - Cooper, PN A1 - Corston, RN A1 - Cramp, CE A1 - Crawford, P A1 - Dafalla, BEA A1 - Esmonde, T A1 - Fuller, G A1 - Geldard, J A1 - Goulding, PJ A1 - Hawkins, E A1 - Hinde, F A1 - Howard, E A1 - Howell, SJ A1 - Hughes, A A1 - Jackson, M A1 - Jamieson, S A1 - Johnson, MR A1 - Kellett, MW A1 - Kindley, AD A1 - Lauder, R A1 - Lawden, M A1 - Leschziner, G A1 - Liddle, J A1 - Litherland, G A1 - Macdonald, S A1 - Marson, AG A1 - McCoy, L A1 - McLean, B A1 - Middleditch, C A1 - Newton, R A1 - Nicholl, DJ A1 - North, L A1 - Owen, L A1 - Parratt, M A1 - Pirmohamed, P A1 - Reuber, M A1 - Roberts, R A1 - Rogers, J A1 - Sharrack, B A1 - Silver, NC A1 - Smith, D A1 - Smith, PEM A1 - Steward, S A1 - Stewart, J A1 - Thompson, C A1 - Tidswell, P A1 - Von Oertzen, T A1 - Weishmann, U A1 - White, K A1 - Williamson, P A1 - Chadwick, D J1 - J NEUROL NEUROSUR PS Y1 - 2006/12// VL - 77 SN - 0022-3050 SP - 1394 EP - 1394 ER - TY - JFULL T1 - Structure/function relationships of CCR8 agonists and antagonists. Amino-terminal extension of CCL1 by a single amino acid generates a partial agonist. A1 - Fox, JM A1 - Najarro, P A1 - Smith, GL A1 - Struyf, S A1 - Proost, P A1 - Pease, JE J1 - J Biol Chem Y1 - 2006/12/01/ VL - 281 SN - 0021-9258 SP - 36652 EP - 36661 N2 - We describe here the interactions of CCR8 with its ligands using both CCR8 transfectants and a T-cell line expressing the receptor endogenously. Of the CCR8 agonists reported previously, only CCL1 and vMIP-I exhibited potency in assays of intracellular calcium flux, chemotaxis, and receptor internalization, this latter mechanism being dependent upon the expression of beta-arrestins 1 and 2 but independent of Galpha(i) signaling. NH(2)-terminal extension of the mature CCL1 sequence by a serine residue (Ser-CCL1) resulted in a partial agonist with a reduced affinity for CCR8, suggesting that the NH(2) terminus of the ligand plays a role in ligand binding to an intrahelical site. Attempts to identify key residues within this site revealed that the conserved glutamic acid residue in transmembrane helix 7, Glu-286, is crucial for trafficking of the receptor to the cell surface, while Asp-97 of transmembrane helix 2 is dispensable. CCL7 was found to inhibit both Ser-CCL1 and vMIP-I responses but not those of CCL1 itself. Similarly, vMIP-I responses were more than 2 orders of magnitude more sensitive to the specific CCR8 antagonist MC148 than those induced by CCL1, which is difficult to reconcile with the reported affinities for the receptor. Collectively, these data suggest that the CCR8 ligands are allotropic, binding to distinct sites within CCR8 and that the human immune system may have evolved to use CCL7 as a selective antagonist of viral chemokine activity at CCR8 but not those of the host ligand. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17023422&query_hl=1 ER - TY - JFULL T1 - Correction of head movement on PET studies: comparison of methods. A1 - Montgomery, AJ A1 - Thielemans, K A1 - Mehta, MA A1 - Turkheimer, F A1 - Mustafovic, S A1 - Grasby, PM J1 - J Nucl Med Y1 - 2006/12// VL - 47 SN - 0161-5505 SP - 1936 EP - 1944 N2 - Head movement presents a continuing problem in PET studies. Head restraint minimizes movement but is unreliable, resulting in the need to develop alternative strategies. These include frame-by-frame (FBF) realignment or use of motion tracking (MT) during the scan to realign PET acquisition data. Here we present a comparative analysis of these 2 methods of motion correction. METHODS: Eight volunteers were examined at rest using (11)C-raclopride PET with the radioligand administered as a bolus followed by constant infusion to achieve steady state. Binding potential (BP) was estimated using the ratio method during 2 periods of the scan at steady state. Head movement was compensated by using coregistration between frames (FBF) and 3 methods using MT measurements of head position acquired with a commercially available optical tracking system. RESULTS: All methods of realignment improved test-retest reliability and noise characteristics of the raw data, with important consequences for the power to detect small changes in radiotracer binding, and the potential to reduce false-positive and false-negative results. MT methods were superior to FBF realignment using coregistration on some indices. CONCLUSION: Such methods have considerable potential to improve the reliability of PET data with important implications for the numbers of volunteers required to test hypotheses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17138736&query_hl=1 ER - TY - JFULL T1 - Introduction: species and speciation in micro-organisms. A1 - Spratt, BG A1 - Staley, JT A1 - Fisher, MC J1 - Philos Trans R Soc Lond B Biol Sci Y1 - 2006/11/29/ VL - 361 SN - 0962-8436 SP - 1897 EP - 1898 N2 - L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17062408&query_hl=1 ER - TY - JFULL T1 - Modelling bacterial speciation. A1 - Hanage, WP A1 - Spratt, BG A1 - Turner, KM A1 - Fraser, C J1 - Philos Trans R Soc Lond B Biol Sci Y1 - 2006/11/29/ VL - 361 SN - 0962-8436 SP - 2039 EP - 2044 N2 - A central problem in understanding bacterial speciation is how clusters of closely related strains emerge and persist in the face of recombination. We use a neutral Fisher-Wright model in which genotypes, defined by the alleles at 140 house-keeping loci, change in each generation by mutation or recombination, and examine conditions in which an initially uniform population gives rise to resolved clusters. Where recombination occurs at equal frequency between all members of the population, we observe a transition between clonal structure and sexual structure as the rate of recombination increases. In the clonal situation, clearly resolved clusters are regularly formed, break up or go extinct. In the sexual situation, the formation of distinct clusters is prevented by the cohesive force of recombination. Where the rate of recombination is a declining log-linear function of the genetic distance between the donor and recipient strain, distinct clusters emerge even with high rates of recombination. These clusters arise in the absence of selection, and have many of the properties of species, with high recombination rates and thus sexual cohesion within clusters and low rates between clusters. Distance-scaled recombination can thus lead to a population splitting into distinct genotypic clusters, a process that mimics sympatric speciation. However, empirical estimates of the relationship between sequence divergence and recombination rate indicate that the decline in recombination is an insufficiently steep function of genetic distance to generate species in nature under neutral drift, and thus that other mechanisms should be invoked to explain speciation in the presence of recombination. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17062418&query_hl=1 ER - TY - JFULL T1 - BMS-214662 eliminates CML stem cells and is active against blast crisis CML and cells expressing BCR-ABL kinase mutations. A1 - Copland, M A1 - Richmond, L A1 - Hamilton, A A1 - Allan, EK A1 - Melo, JV A1 - Holyoake, TL J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 222A EP - 222A ER - TY - JFULL T1 - Abnormally small BCR-ABL transcripts in CML patients before and during imatinib treatment. A1 - Khorashad, JS A1 - Lipton, JH A1 - Marin, D A1 - Milojkovic, D A1 - Cross, NCP A1 - Dibb, N A1 - Melo, JV A1 - Kamel-Reid, S A1 - Goldman, JM A1 - Apperley, JF A1 - Kaeda, JS J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 611A EP - 611A ER - TY - JFULL T1 - Abnormalities in glucose uptake and metabolism in imatinib-resistant Bcr-Abl positive cells. A1 - Serkova, NJ A1 - Kominsky, DJ A1 - Brown, JL A1 - Miljus, J A1 - Boros, LG A1 - Eckhardt, GS A1 - Melo, JV J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 662A EP - 662A ER - TY - JFULL T1 - A model for enhanced nucleation of protein crystals on a fractal porous substrate. A1 - Stolyarova, S A1 - Saridakis, E A1 - Chayen, NE A1 - Nemirovsky, Y J1 - Biophys J Y1 - 2006/11/15/ VL - 91 SN - 0006-3495 SP - 3857 EP - 3863 N2 - The phenomenon of enhanced nucleation and crystallization of proteins on porous silicon (PS) is theoretically studied and explained. The PS layer is treated as a fractal structure, and a new mechanism of local supersaturation associated with the fractality is proposed. It is shown that the number of adsorbed molecules on a fragment with a fractal surface significantly exceeds that on one with flat surfaces. For a fractal PS surface, a local concentration of molecules that is sufficient for nucleation is possible inside and in the close vicinity of the pores, even when the average conditions in the bulk of the solution correspond to metastability. The wide distribution of fractal pore size is favorable for the crystallization of a wide range of macromolecules using the same sample. In addition, the PS technology is very flexible, allowing tailoring the pore size and concentration as well as the fractal properties to specific proteins by changing the fabrication conditions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16920829&query_hl=1 ER - TY - JFULL T1 - Imaging molecular and cellular events in transplantation. A1 - George, AJ A1 - Bhakoo, KK A1 - Haskard, DO A1 - Larkman, DJ A1 - Reynolds, PR J1 - Transplantation Y1 - 2006/11/15/ VL - 82 SN - 0041-1337 SP - 1124 EP - 1129 N2 - Imaging methods such as nuclear medicine (including positron emission tomography), magnetic resonance imaging, ultrasound, and optical imaging can be used to provide information about the expression of genes, and the location of molecules and cells in intact animals or patients. In the setting of transplantation, this will allow monitoring of inflammatory responses, as well as the state of the graft. In this review, the advantages and disadvantages of different approaches to imaging will be discussed, as well as their potential application to transplantation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17102760&query_hl=1 ER - TY - JFULL T1 - Genetic defects causing familial hypercholesterolaemia: Identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic. A1 - Tosi, I A1 - Toledo-Leiva, P A1 - Neuwirth, C A1 - Naoumova, RP A1 - Soutar, AK J1 - Atherosclerosis Y1 - 2006/11/07/ SN - 0021-9150 N2 - Familial hypercholesterolaemia (FH) results from defective catabolism of low density lipoproteins (LDL), leading to premature atherosclerosis and early coronary heart disease. It is commonly caused by mutations in LDLR, encoding the LDL receptor that mediates hepatic uptake of LDL, or in APOB, encoding its major ligand. More rarely, dominant mutations in PCSK9 or recessive mutations in LDLRAP1 (ARH) cause FH, gene defects that also affect the LDL-receptor pathway. We have used multiplex ligation-dependent probe amplification (MLPA) to identify deletions and rearrangements in LDLR, some not detectable by Southern blotting, thus completing our screening for mutations causing FH in a group of FH patients referred to a Lipid Clinic in London. To summarise, mutations in LDLR were found in 153 unrelated heterozygous FH patients and 24 homozygotes/compound heterozygotes, and in over 200 relatives of 80 index patients. LDLR mutations included 85 different point mutations (7 not previously described) and 13 different large rearrangements. The APOB R3500Q mutation was present in 14 heterozygous patients and a mutation in PCSK9 in another 4; LDLRAP1 mutations were found in 4 "homozygous" FH patients. Our data confirm that DNA-based diagnosis provides information that is important for management of FH in a considerable number of families. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17094996&query_hl=1 ER - TY - JFULL T1 - The human ClC-4 protein, a member of the CLC chloride channel/transporter family, is localized to the endoplasmic reticulum by its N-terminus. A1 - Okkenhaug, H A1 - Weylandt, KH A1 - Carmena, D A1 - Wells, DJ A1 - Higgins, CF A1 - Sardini, A J1 - FASEB J Y1 - 2006/11// VL - 20 SN - 1530-6860 SP - 2390 EP - 2392 N2 - Despite considerable similarity in their amino acid sequences and structural features, the mammalian members of the CLC chloride channel/transporter family have different subcellular locations. The subcellular location and function of one of these members, hClC-4, is controversial. To characterize its cellular function, we investigated its tissue distribution and subcellular location. Expression was high in excitable tissues such as the nervous system and skeletal muscle. When heterologously expressed in HEK293 cells and in skeletal muscle fibers, hClC-4 localizes to the endoplasmic/sarcoplasmic reticulum (ER/SR) membranes, in contrast to hClC-3, which localizes to vesicular structures. This location was confirmed by identification of endogenous ClC-4 in membrane fractions from mouse brain homogenate enriched for the sarco-endoplasmic reticulum ATPase SERCA2, an ER/SR marker. To identify the motif responsible for ER localization of hClC-4, we generated hClC-4 truncations and chimeras between hClC-4 and hClC-3 or the unrelated plasma membrane protein Ly49E. A stretch of amino acids, residues 14-63, at the N-terminus constitutes a novel motif both necessary and sufficient for targeting hClC-4 and other membrane proteins to the ER. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17023393&query_hl=1 ER - TY - JFULL T1 - TCF7L2 variation predicts hyperglycemia incidence in a French general population: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study. A1 - Cauchi, S A1 - Meyre, D A1 - Choquet, H A1 - Dina, C A1 - Born, C A1 - Marre, M A1 - Balkau, B A1 - Froguel, P A1 - DESIR Study Group J1 - Diabetes Y1 - 2006/11// VL - 55 SN - 0012-1797 SP - 3189 EP - 3192 N2 - Recently, case-control studies demonstrated that a TCF7L2 (transcription factor 7-like 2 gene) noncoding variant (rs7903146 T at-risk allele) was strongly associated with an increased risk of type 2 diabetes. However, the predictive value of this marker in a nonselected general population remains unknown. In this study, our aim was to assess the contribution of this variant to the prevalence and incidence of hyperglycemia (type 2 diabetes and impaired fasting glucose) and insulin regulation in a 9-year prospective study of 4,976 middle-aged participants in the French DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) cohort. Our data support previous studies associating the T at-risk allele with a higher prevalence of hyperglycemia at baseline (P = 0.049) and a higher incidence of hyperglycemia after 9 years of follow-up (P = 0.014). The population-attributable risk to develop hyperglycemia due to the T at-risk allele was estimated to be 10.4% at the end of the prospective study. The most likely inheritance model was found to be additive (P = 0.002) rather than deviating from linearity (hazard ratio 1.21 [95% CI 1.05-1.39], P = 0.008) [corrected] An increase in the incidence of hyperglycemia was confirmed by survival analyses among C/C, C/T, and T/T carriers during the 9 years of follow-up (P = 0.028 by log-rank test). Interestingly, in control individuals, there was weak evidence of association of the T at-risk allele with reduced fasting insulin levels and insulin secretion index (homeostasis model assessment of beta-cell function) in control individuals. We conclude that the TCF7L2 T at-risk allele variation (rs7903146) predicts hyperglycemia incidence in a general French population, possibly through a deleterious effect on insulin secretion. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17065361&query_hl=1 ER - TY - JFULL T1 - What is the appropriate oxygen tension for in vitro culture? A1 - Sullivan, M A1 - Galea, P A1 - Latif, S J1 - Mol Hum Reprod Y1 - 2006/11// VL - 12 SN - 1360-9947 SP - 653 EP - 653 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17008346&query_hl=1 ER - TY - JFULL T1 - Tails of the unexpected - an atypical receptor for the chemokine RANTES/CCL5 expressed in brain. A1 - Pease, JE J1 - Br J Pharmacol Y1 - 2006/11// VL - 149 SN - 0007-1188 SP - 460 EP - 462 N2 - Chemokines and their receptors play a central role in the trafficking of leukocytes within the body, a process which is amenable to antagonism by small molecules and which holds promise as a treatment for clinically important diseases. In the issue of the British Journal of Pharmacology accompanying this commentary, Ignatov and colleagues describe an unexpected role for the chemokine RANTES/CCL5, namely an ability to signal via the orphan G protein-coupled receptor named GPR75. This receptor bears little homology to other chemokine receptors, most strikingly within the putative intracellular domains, with the third loop and C-terminal tail dwarfing those of other known chemokine receptors. This most likely accounts for the atypical pertussis toxin-insensitive signalling induced by RANTES. Intriguingly, this signalling is neuro-protective, inducing the survival of a hippocampal cell line following insult with the neurotoxic amyloid-beta peptide. Since this peptide is implicated in the pathogenesis of Alzheimer's disease, it may be that exploitation of this signalling pathway presents itself as a future therapeutic treatment. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17001302&query_hl=1 ER - TY - JFULL T1 - Bone marrow-derived cells contribute to podocyte regeneration and amelioration of renal disease in a mouse model of Alport syndrome. A1 - Prodromidi, EI A1 - Poulsom, R A1 - Jeffery, R A1 - Roufosse, CA A1 - Pollard, PJ A1 - Pusey, CD A1 - Cook, HT J1 - Stem Cells Y1 - 2006/11// VL - 24 SN - 1066-5099 SP - 2448 EP - 2455 N2 - In a model of autosomally recessive Alport syndrome, mice that lack the alpha3 chain of collagen IV (Col4alpha3(-/-)) develop progressive glomerular damage leading to renal failure. The proposed mechanism is that podocytes fail to synthesize normal glomerular basement membrane, so the collagen IV network is unstable and easily degraded. We used this model to study whether bone marrow (BM) transplantation can rectify this podocyte defect by correcting the deficiency in Col4alpha3. Female C57BL/6 Col4alpha3(-/-) (-/-) mice were transplanted with whole BM from male wild-type (+/+) mice. Control female -/- mice received BM from male -/- littermates. Serum urea and creatinine levels were significantly lower in recipients of +/+ BM compared with those of -/- BM 20 weeks post-transplant. Glomerular scarring and interstitial fibrosis were also significantly decreased. Donor-derived cells were detected by in situ hybridization (ISH) for the Y chromosome, and fluorescence and confocal microscopy indicated that some showed an apparent podocyte phenotype in mice transplanted with +/+ BM. Glomeruli of these mice showed small foci of staining for alpha3(IV) protein by immunofluorescence. alpha3(IV) mRNA was detectable by reverse transcription-polymerase chain reaction and ISH in some mice transplanted with +/+ BM but not -/- BM. However, a single injection of mesenchymal stem cells from +/+ mice to irradiated -/- recipients did not improve renal disease. Our data show that improved renal function in Col4alpha3(-/-) mice results from BM transplantation from wild-type donors, and the mechanism by which this occurs may in part involve generation of podocytes without the gene defect. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16873763&query_hl=1 ER - TY - JFULL T1 - Epistasis between type 2 diabetes susceptibility loci on chromosomes 1q21-25 and 10q23-26 in northern Europeans A1 - Wiltshire, S A1 - Bell, JT A1 - Groves, CJ A1 - Dina, C A1 - Hattersley, AT A1 - Frayling, TM A1 - Walker, M A1 - Hitman, GA A1 - Vaxillaire, M A1 - Farrall, M A1 - Froguel, P A1 - McCarthy, MI J1 - ANN HUM GENET Y1 - 2006/11// VL - 70 SN - 0003-4800 SP - 726 EP - 737 N2 - Characterisation of the interactions between susceptibility loci (epistasis) is central to a full understanding of the genetic aetiology and the molecular pathology of complex diseases. We have examined, in British and French pedigrees, evidence for epistasis between the type 2 diabetes susceptibility loci on chromosomes 1q21-25 and 10q23-26 using two complementary linkage-based approaches. Joint two-locus linkage analysis of 1q and 10q in British pedigrees provided significant evidence for interaction (P <= 0.003) when comparing a general epistasis model with multiplicative or additive-effects-only models. Conditional linkage analysis (which models epistasis as a deviation from multiplicativity only) confirmed these findings, with significant LOD score increases at the 1q (P = 0.0002) and 10q (P = 0.0023) loci. These analyses provided sizeable reductions in the 1-LOD support intervals for both loci. Analyses of the British and French pedigrees together yielded comparable, but not enhanced, findings, with significant (P <= 0.003) evidence for epistasis in joint two-locus linkage analysis, and during conditional linkage analysis significant increases in linkage evidence at the 1q (P = 0.0002) and 10q (P = 0.0036) loci. Our findings of epistasis nevertheless substantiate the evidence for genuine genetic effects at both loci, facilitate endeavours to fine-map these loci in population samples, and support further examination of this interaction at the nucleotide level by providing a robust prior hypothesis. ER - TY - JFULL T1 - Knockdown of mouse VCAM-1 by vector-based siRNA. A1 - Alam, AK A1 - Florey, O A1 - Weber, M A1 - Pillai, RG A1 - Chan, C A1 - Tan, PH A1 - Lechler, RI A1 - McClure, MO A1 - Haskard, DO A1 - George, AJ J1 - Transpl Immunol Y1 - 2006/11// VL - 16 SN - 0966-3274 SP - 185 EP - 193 N2 - Graft rejection is critically dependent on the recruitment of leukocytes via adhesion molecules on the endothelium, and inhibition of these interactions can prolong graft survival. We have therefore developed an approach using siRNA to inhibit the expression of VCAM-1 in endothelial cells. We transfected siRNA constructs into murine corneal and vascular endothelium and looked at expression of VCAM-1 and other surface molecules by flow cytometry. Adhesion assays (both static and under flow) were used to determine the effect of VCAM-1 inhibition. The activation of cellular stress responses was assessed by RT-PCR. Constructs encoding siRNA can block expression of VCAM-1 in both corneal and vascular endothelial cells (in the latter case after cytokine stimulation). Inhibition of VCAM-1 expression reduced the ability of T cells to adhere to endothelium. However, there were non-specific effects of siRNA expression, including upregulation of (Programmed Death Ligand 1) PDL1 and decreased cell growth. Analysis of stress pathways showed that the endothelial cells transfected with siRNA had upregulated molecules associated with cell stress. While these data are supportive of a potential therapeutic role for siRNA constructs in blocking the expression of adhesion molecules, they also highlight potential non-specific effects of siRNA that must be carefully considered in any application of this technology. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17138052&query_hl=1 ER - TY - JFULL T1 - Lies, damned lies and mortality statistics? A1 - Hansell, AL J1 - Thorax Y1 - 2006/11// VL - 61 SN - 0040-6376 SP - 923 EP - 924 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17071829&query_hl=1 ER - TY - JFULL T1 - Reply. A1 - Little, MP A1 - Elliott, P A1 - Steer, PJ J1 - Am J Obstet Gynecol Y1 - 2006/11// VL - 195 SN - 1097-6868 SP - 1500 N2 - L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16626606&query_hl=1 ER - TY - JFULL T1 - Using magnetic forces to enhance non-viral gene transfer to airway epithelium in vivo. A1 - Xenariou, S A1 - Griesenbach, U A1 - Ferrari, S A1 - Dean, P A1 - Scheule, RK A1 - Cheng, SH A1 - Geddes, DM A1 - Plank, C A1 - Alton, EW J1 - Gene Ther Y1 - 2006/11// VL - 13 SN - 0969-7128 SP - 1545 EP - 1552 N2 - We have assessed whether magnetic forces (magnetofection) can enhance non-viral gene transfer to the airways. TransMAG(PEI), a superparamagnetic particle was coupled to Lipofectamine 2000 or cationic lipid 67 (GL67)/plasmid DNA (pDNA) liposome complexes. In vitro transfection with these formulations resulted in approximately 300- and 30-fold increase in reporter gene expression, respectively, after exposure to a magnetic field, but only at suboptimal pDNA concentrations. Because GL67 has been formulated for in vivo use, we next assessed TransMAG(PEI) in the murine nasal epithelium in vivo, and compared this to naked pDNA. At the concentrations required for in vivo experiments, precipitation of magnetic complexes was seen. After extensive optimization, addition of non-precipitated magnetic particles resulted in approximately seven- and 90-fold decrease in gene expression for naked pDNA and GL67/pDNA liposome complexes, respectively, compared to non-magnetic particles. Thus, whereas exposure to a magnetic field improved in vitro transfection efficiency, translation to the in vivo setting remains difficult. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16738690&query_hl=1 ER - TY - JFULL T1 - Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies. A1 - Zhou, H A1 - Brockington, M A1 - Jungbluth, H A1 - Monk, D A1 - Stanier, P A1 - Sewry, CA A1 - Moore, GE A1 - Muntoni, F J1 - Am J Hum Genet Y1 - 2006/11// VL - 79 SN - 0002-9297 SP - 859 EP - 868 N2 - Epigenetic regulation of gene expression is a source of genetic variation, which can mimic recessive mutations by creating transcriptional haploinsufficiency. Germline epimutations and genomic imprinting are typical examples, although their existence can be difficult to reveal. Genomic imprinting can be tissue specific, with biallelic expression in some tissues and monoallelic expression in others or with polymorphic expression in the general population. Mutations in the skeletal-muscle ryanodine-receptor gene (RYR1) are associated with malignant hyperthermia susceptibility and the congenital myopathies central core disease and multiminicore disease. RYR1 has never been thought to be affected by epigenetic regulation. However, during the RYR1-mutation analysis of a cohort of patients with recessive core myopathies, we discovered that 6 (55%) of 11 patients had monoallelic RYR1 transcription in skeletal muscle, despite being heterozygous at the genomic level. In families for which parental DNA was available, segregation studies showed that the nonexpressed allele was maternally inherited. Transcription analysis in patients' fibroblasts and lymphoblastoid cell lines indicated biallelic expression, which suggests tissue-specific silencing. Transcription analysis of normal human fetal tissues showed that RYR1 was monoallelically expressed in skeletal and smooth muscles, brain, and eye in 10% of cases. In contrast, 25 normal adult human skeletal-muscle samples displayed only biallelic expression. Finally, the administration of the DNA methyltransferase inhibitor 5-aza-deoxycytidine to cultured patient skeletal-muscle myoblasts reactivated the transcription of the silenced allele, which suggests hypermethylation as a mechanism for RYR1 silencing. Our data indicate that RYR1 undergoes polymorphic, tissue-specific, and developmentally regulated allele silencing and that this unveils recessive mutations in patients with core myopathies. Furthermore, our data suggest that imprinting is a likely mechanism for this phenomenon and that similar mechanisms could play a role in human phenotypic heterogeneity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17033962&query_hl=1 ER - TY - JFULL T1 - Detection of vascular expression of E-selectin in vivo with MR imaging. A1 - Reynolds, PR A1 - Larkman, DJ A1 - Haskard, DO A1 - Hajnal, JV A1 - Kennea, NL A1 - George, AJ A1 - Edwards, AD J1 - Radiology Y1 - 2006/11// VL - 241 SN - 0033-8419 SP - 469 EP - 476 N2 - PURPOSE: To develop a contrast agent for targeting E-selectin expressed on activated vascular endothelium and to evaluate detection of the agent with magnetic resonance (MR) imaging in an in vivo mouse model of inflammation. MATERIALS AND METHODS: All animal experiments were approved according to animal welfare and local ethics committee regulations. An anti-murine E-selectin F(ab')2 monoclonal antibody, MES-1, was conjugated with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. Flow cytometry, Perl Prussian blue staining for iron, and MR imaging were performed by using Chinese hamster ovary (CHO) cells expressing mouse E-selectin to detect binding of the conjugate in vitro, and a mouse model of contact hypersensitivity to oxazolone in the ear was used to investigate the in vivo characteristics of the MES-1-USPIO. Serial imaging was performed by using a 9.4-T MR imaging system with a custom receive-only coil. Tissue slices were stained to define distribution of E-selectin expression and localization of the MES-1-USPIO conjugate. RESULTS: MES-1-USPIO was shown to bind to CHO cells expressing mouse E-selectin in vitro. After injection of MES-1-USPIO in vivo, distinct changes in R2 relaxation rate (1/T2) characteristics were detected in inflamed ears when they were compared with control ears. Histologic analysis confirmed the vascular endothelial distribution of MES-1-USPIO. CONCLUSION: E-selectin expression in vivo can be selectively and directly imaged noninvasively with MR. This has the potential to be useful in the study of inflammatory disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17005768&query_hl=1 ER - TY - JFULL T1 - Immunotherapy with antibody targeted MHC complexes: Results of in vivo tumour cell killing and therapeutic vaccination A1 - Savage, P A1 - Dyson, J A1 - French, R A1 - Glennie, M J1 - J IMMUNOTHER Y1 - 2006/11// VL - 29 SN - 1524-9557 SP - 636 EP - 637 ER - TY - JFULL T1 - Annexin 1, glucocorticoids, and the neuroendocrine-immune interface. A1 - Buckingham, JC A1 - John, CD A1 - Solito, E A1 - Tierney, T A1 - Flower, RJ A1 - Christian, H A1 - Morris, J J1 - Ann N Y Acad Sci Y1 - 2006/11// VL - 1088 SN - 0077-8923 SP - 396 EP - 409 N2 - Annexin 1 (ANXA1) was originally identified as a mediator of the anti-inflammatory actions of glucocorticoids (GCs) in the host defense system. Subsequent work confirmed and extended these findings and also showed that the protein fulfills a wider brief and serves as a signaling intermediate in a number of systems. ANXA1 thus contributes to the regulation of processes as diverse as cell migration, cell growth and differentiation, apoptosis, vesicle fusion, lipid metabolism, and cytokine expression. Here we consider the role of ANXA1 in the neuroendocrine system, particularly the hypothalamo-pituitary-adrenocortical (HPA) axis. Evidence is presented that ANXA1 plays a critical role in effecting the negative feedback effects of GCs on the release of corticotrophin (ACTH) and its hypothalamic-releasing hormones and that it is particularly pertinent to the early-onset actions of the steroids that are mediated via a nongenomic mechanism. The paracrine/juxtacrine mode of ANXA1 action is discussed in detail, with particular reference to the significance of the secondary processing of ANXA1, the processes that control the intracellular and transmembrane trafficking of the protein of the molecule and the mechanism of ANXA1 action on its target cells. In addition, the role of ANXA1 in the perinatal programming of the HPA axis is discussed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17192583&query_hl=1 ER - TY - JFULL T1 - Evaluation of deletions in 7q11.2 and 8p12-p21 as prognostic indicators of tumour development following molar pregnancy. A1 - Burke, B A1 - Sebire, NJ A1 - Moss, J A1 - Hodges, MD A1 - Seckl, MJ A1 - Newlands, ES A1 - Fisher, RA J1 - Gynecol Oncol Y1 - 2006/11// VL - 103 SN - 0090-8258 SP - 642 EP - 648 N2 - OBJECTIVES: Previous studies have identified loss of chromosomal regions 7p12-q11.2 and 8p12-p21 in choriocarcinoma suggesting that suppressor genes involved in tumour development may be located within these regions. Our objectives were to refine the regions of loss and evaluate these deletions as prognostic indicators of trophoblastic tumour development following molar pregnancy. METHODS: Fluorescent microsatellite genotyping was used to perform deletion mapping in a series of thirty-nine gestational trophoblastic tumours (GTT) including both choriocarcinoma and placental site trophoblastic tumours. RESULTS: Significant loss of heterozygosity (LOH) was found for both regions in GTT that originated in non-molar pregnancies. Although no common interval of loss was found in those GTT with LOH for the 7q11.2 region, for the 8p12-p21 locus, markers D8S1731 and NEFL defined a minimal region of loss in all tumours showing LOH. However, complete LOH of either region occurred in only a minority of tumours (20%; chromosome 7: 24%; chromosome 8) suggesting that loss of neither region is likely to be a primary event in the development of GTT. This was further supported by the observation that no deletions were found in either region for the fourteen GTT that followed complete molar pregnancies. CONCLUSIONS: While we have defined a minimal interval in 8p12-p21 in which tumour suppressor genes involved in GTT are likely to be located, the data suggest that deletions in 7q11.2 or 8p12-p21 are unlikely to be useful prognostic indicators in the management of patients with molar pregnancies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16806440&query_hl=1 ER - TY - JFULL T1 - Antileukemic activity of lysophosphatidic acid acyltransferase-beta inhibitor CT32228 in chronic myelogenous leukemia sensitive and resistant to imatinib A1 - La Rosee, P A1 - Jia, TP A1 - Demehri, S A1 - Hartel, N A1 - de Vries, P A1 - Bonham, L A1 - Hollenback, D A1 - Singer, JW A1 - Melo, JV A1 - Druker, BJ A1 - Deininger, MW J1 - CLIN CANCER RES Y1 - 2006/11/01/ VL - 12 SN - 1078-0432 SP - 6540 EP - 6546 N2 - Purpose: Lysophosphatidic acid acyltransferase (LPAAT)-beta catalyzes the conversion of lysophosphatidic acid to phosphatidic acid, an essential component of several signaling pathways, including the Ras/mitogen-activated protein kinase pathway. Inhibition of LPAAT-beta induces growth arrest and apoptosis in cancer cell lines, implicating LPAAT-beta as a potential drug target in neoplasia.Experimental Design: In this study, we investigated the effects of CT32228, a specific LPAAT-inhibitor, on BCR-ABL-transformed cell lines and primary cells from patients with chronic myelogenous leukemia.Results: CT32228 had antiproliferative activity against BCR-ABL-positive cell lines in the nanomolar dose range, evidenced by cell cycle arrest in G(2)-M and induction of apoptosis. Treatment of K562 cells with CT32228 led to inhibition of extracellular signal-regulated kinase 1/2 phosphorylation, consistent with inhibition of mitogen-activated protein kinase signaling. Importantly, CT32228 was highly active in cell lines resistant to the Bcr-Abl kinase inhibitor imatinib. Combination of CT32228 with imatinib produced additive inhibition of proliferation in cell lines with residual sensitivity toward imatinib. In short-term cultures in the absence of growth factors, CT32228 preferentially inhibited the growth of granulocyte-macrophage colony-forming units from chronic myelogenous leukemia patients compared with healthy controls.Conclusion: These data establish LPAAT-beta as a potential drug target for the treatment of BCR-ABL-positive leukemias. ER - TY - JFULL T1 - CFTR gene transfer to human cystic fibrosis pancreatic duct cells upregulates apical CL-/HCO3(-) exchange activity A1 - Rakonczay, Z A1 - Hegyi, P A1 - Hasegawa, M A1 - Inoue, M A1 - You, J A1 - Iida, A A1 - Ignath, I A1 - Alton, EWFW A1 - Griesenbach, U A1 - Ovari, G A1 - Da Paula, AC A1 - Varga, G A1 - Amaral, MD A1 - Argent, BE A1 - Gray, MA J1 - PANCREAS Y1 - 2006/11// VL - 33 SN - 0885-3177 SP - 492 EP - 492 ER - TY - JFULL T1 - Lack of annexin 1 results in an increase in corticotroph number in male but not female mice A1 - Morris, JF A1 - Omer, S A1 - Davies, E A1 - Wang, E A1 - John, C A1 - Afzal, T A1 - Wain, S A1 - Buckingham, JC A1 - Flower, RJ A1 - Christian, HC J1 - J NEUROENDOCRINOL Y1 - 2006/11// VL - 18 SN - 0953-8194 SP - 835 EP - 846 N2 - Annexin 1 (ANXA1) is a member of the annexin family of phospholipid- and calcium-binding proteins with a well demonstrated role in early delayed (30 min to 3 h) inhibitory feedback of glucocorticoids in the pituitary. We have examined corticotrophs in wild-type and ANXA1 knockout mice to determine the effects of lack of ANXA1 in male and female animals. Anterior pituitary tissue from ANXA1 wild-type, heterozygote and null mice was fixed and examined (i) by confocal immunocytochemistry to determine the number of corticotrophs and (ii) by electron microscopy to examine the size, secretory granule population and secretory machinery of corticotrophs. No differences in these parameters were detected in female mice. In male ANXA1 null mice, there were approximately four-fold more corticotrophs than in wild-type animals. However, the corticotrophs in ANXA1 null mice were smaller and had reduced numbers of secretory granules (the reduction in granules paralleled the reduction in cell size). No differences in the numerical density of folliculo-stellate, gonadotroph, lactotroph or somatotroph cells were detected in male ANXA1 null mice. Plasma corticosterone, adrenocorticotrophic hormone (ACTH) and pituitary pro-opiomelanocortin mRNA were unchanged but pituitary ACTH content was increased in male ANXA1 null mice. Interleukin (IL)-6 pituitary content was significantly elevated in male and reduced in female ANXA1 null mice compared to wild-type. In conclusion, these data indicate that ANXA1 deficiency is associated with gender-specific changes in corticotroph number and structure, via direct actions of ANXA1 and/or indirect changes in factors such as IL-6. ER - TY - JFULL T1 - Regardless of cell-delivery route, skeletal myoblast transplantation into chronic heart failure induces transient therapeutic effects with persistent arrhythmogenesis A1 - Fukushima, S A1 - Varela-Carver, A A1 - Coppen, SR A1 - Yamahara, K A1 - Felkin, LE A1 - Lyon, A A1 - Barton, PJ A1 - Yacoub, MH A1 - Suzuki, K J1 - CIRCULATION Y1 - 2006/10/31/ VL - 114 SN - 0009-7322 SP - 415 EP - 415 ER - TY - JFULL T1 - A role for Dicer in immune regulation. A1 - Cobb, BS A1 - Hertweck, A A1 - Smith, J A1 - O'Connor, E A1 - Graf, D A1 - Cook, T A1 - Smale, ST A1 - Sakaguchi, S A1 - Livesey, FJ A1 - Fisher, AG A1 - Merkenschlager, M J1 - J Exp Med Y1 - 2006/10/30/ VL - 203 SN - 0022-1007 SP - 2519 EP - 2527 N2 - Micro RNAs (miRNAs) regulate gene expression at the posttranscriptional level. Here we show that regulatory T (T reg) cells have a miRNA profile distinct from conventional CD4 T cells. A partial T reg cell-like miRNA profile is conferred by the enforced expression of Foxp3 and, surprisingly, by the activation of conventional CD4 T cells. Depleting miRNAs by eliminating Dicer, the RNAse III enzyme that generates functional miRNAs, reduces T reg cell numbers and results in immune pathology. Dicer facilitates, in a cell-autonomous fashion, the development of T reg cells in the thymus and the efficient induction of Foxp3 by transforming growth factor beta. These results suggest that T reg cell development involves Dicer-generated RNAs. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17060477&query_hl=1 ER - TY - JFULL T1 - Heritability and tissue specificity of expression quantitative trait loci. A1 - Petretto, E A1 - Mangion, J A1 - Dickens, NJ A1 - Cook, SA A1 - Kumaran, MK A1 - Lu, H A1 - Fischer, J A1 - Maatz, H A1 - Kren, V A1 - Pravenec, M A1 - Hubner, N A1 - Aitman, TJ J1 - PLoS Genet Y1 - 2006/10/20/ VL - 2 SN - 1553-7404 SP - e172 EP - e172 N2 - Variation in gene expression is heritable and has been mapped to the genome in humans and model organisms as expression quantitative trait loci (eQTLs). We applied integrated genome-wide expression profiling and linkage analysis to the regulation of gene expression in fat, kidney, adrenal, and heart tissues using the BXH/HXB panel of rat recombinant inbred strains. Here, we report the influence of heritability and allelic effect of the quantitative trait locus on detection of cis- and trans-acting eQTLs and discuss how these factors operate in a tissue-specific context. We identified several hundred major eQTLs in each tissue and found that cis-acting eQTLs are highly heritable and easier to detect than trans-eQTLs. The proportion of heritable expression traits was similar in all tissues; however, heritability alone was not a reliable predictor of whether an eQTL will be detected. We empirically show how the use of heritability as a filter reduces the ability to discover trans-eQTLs, particularly for eQTLs with small effects. Only 3% of cis- and trans-eQTLs exhibited large allelic effects, explaining more than 40% of the phenotypic variance, suggestive of a highly polygenic control of gene expression. Power calculations indicated that, across tissues, minor differences in genetic effects are expected to have a significant impact on detection of trans-eQTLs. Trans-eQTLs generally show smaller effects than cis-eQTLs and have a higher false discovery rate, particularly in more heterogeneous tissues, suggesting that small biological variability, likely relating to tissue composition, may influence detection of trans-eQTLs in this system. We delineate the effects of genetic architecture on variation in gene expression and show the sensitivity of this experimental design to tissue sampling variability in large-scale eQTL studies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17054398&query_hl=1 ER - TY - JFULL T1 - Classical and non-classical ruthenium-based anticancer drugs: Towards targeted chemotherapy A1 - Ang, WH A1 - Dyson, PJ J1 - EUR J INORG CHEM Y1 - 2006/10/16/ SN - 1434-1948 SP - 4003 EP - 4018 N2 - Ruthenium-based anticancer chemotherapies are making significant advances in clinical trials. Until recently, the focus has been on coordination complexes, and mechanisms such as "activation by reduction" and "transferrin-targeted delivery" have been proposed to account for the excellent cytotoxicity and low general toxicity of these complexes. More recently organoruthenium compounds, which to some extent appear not to follow the established rules, have started to be investigated. Despite such differences, similar activities between certain coordination and organometallic compounds suggest similar modes of action are present. DNA, the classic target, is believed to be the dominant mechanism for cytotoxicity with certain ruthenium drugs, while with others, non-classical targets are thought to be more important. In this article we describe these features and show how both ruthenium coordination complexes and organoruthenium compounds represent an ideal scaffold for further drug design and optimisation. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006). ER - TY - JFULL T1 - Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes. A1 - Parker, AL A1 - Waddington, SN A1 - Nicol, CG A1 - Shayakhmetov, DM A1 - Buckley, SM A1 - Denby, L A1 - Kemball-Cook, G A1 - Ni, S A1 - Lieber, A A1 - McVey, JH A1 - Nicklin, SA A1 - Baker, AH J1 - Blood Y1 - 2006/10/15/ VL - 108 SN - 0006-4971 SP - 2554 EP - 2561 N2 - Upon local delivery, adenovirus (Ad) serotype 5 viruses use the coxsackie and Ad receptor (CAR) for cell binding and alpha(v) integrins for internalization. When administered systemically, however, their role in liver tropism is limited because CAR-permissive and mutated viruses show similar biodistribution, a finding recently attributed to blood coagulation factor (F) IX or complement protein C4BP binding to the adenovirus fiber and "bridging" to either low-density lipoprotein receptor-related protein or heparan sulfate proteoglycans. Here, we show that hepatocyte transduction in vitro can be enhanced by the vitamin K-dependent factors FX, protein C, and FVII in addition to FIX but not by prothrombin (FII), FXI, and FXII. This phenomenon was not dependent on proteolytic activation or cell signaling activity and for FX was mediated by direct virus-factor binding. Human FX substantially enhanced hepatocyte transduction by CAR-permissive and mutated viruses in an ex vivo liver perfusion model. In vivo, global down-regulation of vitamin K-dependent zymogens by warfarin significantly diminished liver uptake of CAR-deleted Ads; however, this phenomenon was fully rescued by acute infusion of human FX. Our results indicate a common and pivotal role for distinct vitamin K-dependent coagulation factors in mediating hepatocyte transduction by adenoviruses in vitro and in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16788098&query_hl=1 ER - TY - JFULL T1 - Genetics of obesity and the prediction of risk for health. A1 - Walley, AJ A1 - Blakemore, AI A1 - Froguel, P J1 - Hum Mol Genet Y1 - 2006/10/15/ VL - 15 Spec No 2 SN - 0964-6906 SP - R124 EP - R130 N2 - Obesity has always existed in human populations, but until very recently was comparatively rare. The availability of abundant, energy-rich processed foods in the last few decades has, however, resulted in a sharp rise in the prevalence of obesity in westernized countries. Although it is the obesogenic environment that has resulted in this major healthcare problem, it is acting by revealing a sub-population with a pre-existing genetic predisposition to excess adiposity. There is substantial evidence for the heritability of obesity, and research in both rare and common forms of obesity has identified genes with significant roles in its aetiology. Application of this understanding to patient care has been slower. Until very recently, the health risks of obesity were thought to be well understood, with a straightforward correlation between increasing obesity and increasing risk of health problems such as type 2 diabetes, coronary heart disease, hypertension, arthritis and cancer. It is becoming clear, however, that the location of fat deposition, variation in the secretion of adipokines and other factors govern whether a particular obese person develops such complications. Prediction of the health risks of obesity for individual patients is not straightforward, but continuing advances in understanding of genetic factors influencing obesity risk and improved diagnostic technologies mean that the future for such prediction is looking increasingly bright. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16987875&query_hl=1 ER - TY - JFULL T1 - A novel mechanism for complement activation at the surface of B cells following antigen binding A1 - Manderson, AP A1 - Quah, B A1 - Botto, M A1 - Goodnow, CC A1 - Walport, MJ A1 - Parish, CR J1 - J IMMUNOL Y1 - 2006/10/15/ VL - 177 SN - 0022-1767 SP - 5155 EP - 5162 N2 - Coligation of CD21 with BCR on the surface of B cells provides a costimulatory signal essential for efficient Ab responses to T-dependent Ags. To achieve this, Ag must be directly linked to C3 fragments, but how this occurs in vivo is not fully understood. Using BCR transgenic mice, we demonstrated that C3 was deposited on the surface of B cells following both high- and moderate-affinity Ag binding. This was dependent on the specific binding of IgM to the BCR-bound Ag and can occur independently of soluble immune complex formation. Based on these data, we propose a novel model in which immune complexes can form directly on the surface of the B cell following Ag binding. This model has implications for our understanding of B lymphocyte activation. ER - TY - JFULL T1 - Distinct impaired regulation of SOCS3 and long and short isoforms of the leptin receptor in visceral and subcutaneous fat of lean and obese women. A1 - Séron, K A1 - Corset, L A1 - Vasseur, F A1 - Boutin, P A1 - Gómez-Ambrosi, J A1 - Salvador, J A1 - Frühbeck, G A1 - Froguel, P J1 - Biochem Biophys Res Commun Y1 - 2006/10/06/ VL - 348 SN - 0006-291X SP - 1232 EP - 1238 N2 - Animal studies have illustrated the importance of the expression in adipose tissue of the leptin receptor (OB-R), and of SOCS3 an inhibitor of the leptin signaling pathway, in body weight regulation. The aim of the present study was to investigate in human adipose tissues of the same patients the OB-R isoforms and SOCS3 expression. Subcutaneous and omental adipose tissues were obtained from 6 lean and 18 morbidly obese women. The long isoform OB-Rb mRNA mediating leptin signaling, and SOCS3 mRNA are abundantly present in the subcutaneous fat of lean women, but are 90% and 70% decreased (P<0.0001) in obese women. In visceral fat from lean and obese women, both OB-Rb and SOCS3 mRNA are detected at very low levels. Subcutaneous/visceral ratios for OB-Ra the short OB-R isoform, OB-Rb, and SOCS3 mRNA abundance strongly correlate with the insulin sensitivity index, HOMA-% S, (r=0.49, P<0.0001, r=0.42, P=0.0002 and r=0.38, P=0.0002, respectively) in both lean and obese patients without type 2 diabetes. The near absence of OB-Rb mRNA and the similarly decreased SOCS3 expression in obese adipose tissue may reflect a defective leptin signaling pathway that could play a role in the impairment of insulin sensitivity associated with excess adiposity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16920065&query_hl=1 ER - TY - JFULL T1 - Genetic and environmental effects on complex traits in mice. A1 - Valdar, W A1 - Solberg, LC A1 - Gauguier, D A1 - Cookson, WO A1 - Rawlins, JN A1 - Mott, R A1 - Flint, J J1 - Genetics Y1 - 2006/10// VL - 174 SN - 0016-6731 SP - 959 EP - 984 N2 - The interaction between genotype and environment is recognized as an important source of experimental variation when complex traits are measured in the mouse, but the magnitude of that interaction has not often been measured. From a study of 2448 genetically heterogeneous mice, we report the heritability of 88 complex traits that include models of human disease (asthma, type 2 diabetes mellitus, obesity, and anxiety) as well as immunological, biochemical, and hematological phenotypes. We show that environmental and physiological covariates are involved in an unexpectedly large number of significant interactions with genetic background. The 15 covariates we examined have a significant effect on behavioral and physiological tests, although they rarely explain >10% of the variation. We found that interaction effects are more frequent and larger than the main effects: half of the interactions explained >20% of the variance and in nine cases exceeded 50%. Our results indicate that assays of gene function using mouse models should take into account interactions between gene and environment. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16888333&query_hl=1 ER - TY - JFULL T1 - Activation of AMPK alpha- and gamma-isoform complexes in the intact ischemic rat heart A1 - Li, J A1 - Coven, DL A1 - Miller, EJ A1 - Hu, XY A1 - Young, ME A1 - Carling, D A1 - Sinusas, AJ A1 - Young, LH J1 - AM J PHYSIOL-HEART C Y1 - 2006/10// VL - 291 SN - 0363-6135 SP - H1927 EP - H1934 N2 - AMP-activated protein kinase (AMPK) plays a key role in modulating cellular metabolic processes. AMPK, a serine-threonine kinase, is a heterotrimeric complex of catalytic alpha-subunits and regulatory beta- and gamma-subunits with multiple isoforms. Mutations in the cardiac gamma(2)-isoform have been associated with hypertrophic cardiomyopathy and pre-excitation syndromes. However, physiological regulation of AMPK complexes containing different subunit isoforms is not well defined and is important for an understanding of the function of this signaling pathway in the intact heart. We evaluated the kinase activity associated with heart AMPK complexes containing specific alpha- and gamma-subunit isoforms of AMPK in an in vivo rat model of regional ischemia. Left coronary artery occlusion activated the immunoprecipitated alpha(1)-isoform (6-fold, P < 0.01) and alpha(2)-isoform (9-fold, P < 0.01) in the ischemic left ventricle compared with sham controls. The degree of alpha-subunit activation depended on the extent of ischemia and paralleled echocardiographic contractile dysfunction. The regulatory gamma(1)- and gamma(2)-isoforms were expressed in the heart. The gamma(1)- and gamma(2)-isoforms coimmunoprecipitated with alpha(1)- and alpha(2)-isoforms in proportion to gamma(2)-subunit content. gamma(1)-Isoform immunocomplexes accounted for 70% of AMPK activity and AMPK phosphorylation (Thr(172)) in hearts. Ischemia similarly increased AMPK activity associated with the gamma(1)- and gamma(2)-isoform complexes threefold (P < 0.01 for each). Thus AMPK catalytic alpha 1- and alpha(2)-isoforms are activated by regional ischemia in vivo in the heart, irrespective of the regulatory gamma(1)-or gamma(2)-isoforms to which they are complexed. Despite the pathophysiological importance of gamma(2)-isoform mutations, gamma(1)-isoform complexes account for most of the AMPK activity in the ischemic heart. ER - TY - JFULL T1 - Molecular genetic analysis of 6 glycosyltransferases in a large population of dystroglycanopathy patients significantly widens the spectrum of phenotypes resulting from POMT1, POMGnT1 and Fukutin mutations A1 - Godfrey, C A1 - Mein, R A1 - Brockington, M A1 - Elson, E A1 - Topaloglu, H A1 - Smith, J A1 - Escolar, D A1 - Bertini, E A1 - Merlini, I A1 - Mercuri, E A1 - Bushby, K A1 - Straub, V A1 - North, K A1 - Abbs, S A1 - Muntoni, F J1 - NEUROMUSCULAR DISORD Y1 - 2006/10// VL - 16 SN - 0960-8966 SP - 683 EP - 683 ER - TY - JFULL T1 - Both Fcgamma and complement receptors mediate transfer of immune complexes from erythrocytes to human macrophages under physiological flow conditions in vitro. A1 - Hepburn, AL A1 - Mason, JC A1 - Wang, S A1 - Shepherd, CJ A1 - Florey, O A1 - Haskard, DO A1 - Davies, KA J1 - Clin Exp Immunol Y1 - 2006/10// VL - 146 SN - 0009-9104 SP - 133 EP - 145 N2 - Abnormal clearance by the mononuclear phagocytic system of immune complexes (IC) is important in the pathogenesis of systemic lupus erythematosus (SLE). We have developed an in vitro model to investigate the cellular mechanisms involved in the transfer of soluble IC from erythrocytes to human macrophages under physiological flow conditions. In this assay, erythrocytes bearing fluorescently labelled IC are perfused over monolayers of human monocytes or monocyte-derived macrophages in a parallel-plate flow chamber, and transfer quantified using confocal microscopy and flow cytometry. Using aggregated human IgG as a model IC, we have been able to demonstrate transfer of IC from erythrocytes to macrophages. Blocking studies with specific neutralizing antibodies have shown that both complement and Fcgamma receptors are required for IC transfer. Blockade of CR4 (alpha(x)beta(2) integrin), FcgammaRIIa or FcgammaRIII reduced transfer, while anti-CR3 (alpha(m)beta(2) integrin) had no effect. Blockade of CR3, FcgammaRIIa or FcgammaRIII also reduced the number of adhesive interactions between fluorescently labelled IC-bearing erythrocytes and macrophage monolayers. Taken together with the transfer data, this suggests differing roles for these receptors in the human IC transfer reaction that includes an adhesive function which facilitates IC processing by mononuclear phagocytes. Finally, a functional effect of the FcgammaRIIa R131/H131 polymorphism, important in susceptibility to SLE, has also been demonstrated using this model. Uptake of IgG(2) but not IgG(1)-containing soluble IC was reduced by macrophages from individuals homozygous for the R131 allelic variant of the receptor. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16968408&query_hl=1 ER - TY - JFULL T1 - Predictive factors for the development of scoliosis in Duchenne muscular dystrophy A1 - Kinali, M A1 - Knight, RK A1 - Main, M A1 - Mercuri, E A1 - Messina, S A1 - Manzur, AY A1 - Muntoni, F J1 - NEUROMUSCULAR DISORD Y1 - 2006/10// VL - 16 SN - 0960-8966 SP - 719 EP - 719 ER - TY - JFULL T1 - A tutorial on statistical methods for population association studies. A1 - Balding, DJ J1 - Nat Rev Genet Y1 - 2006/10// VL - 7 SN - 1471-0056 SP - 781 EP - 791 N2 - Although genetic association studies have been with us for many years, even for the simplest analyses there is little consensus on the most appropriate statistical procedures. Here I give an overview of statistical approaches to population association studies, including preliminary analyses (Hardy-Weinberg equilibrium testing, inference of phase and missing data, and SNP tagging), and single-SNP and multipoint tests for association. My goal is to outline the key methods with a brief discussion of problems (population structure and multiple testing), avenues for solutions and some ongoing developments. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16983374&query_hl=1 ER - TY - JFULL T1 - A phase I/II clinical trial in Duchenne muscular dystrophy using IM and IV delivered antisense oligonucleotides: The MDEX consortium A1 - Arechavala, V A1 - Bushby, K A1 - Dickson, G A1 - Graham, I A1 - Kinali, M A1 - Liu, K A1 - Morgan, J A1 - Muntoni, F A1 - Popplewell, L A1 - Partridge, T A1 - Thorogood, F A1 - Wells, K A1 - Wells, N A1 - Wood, M A1 - Yin, H J1 - NEUROMUSCULAR DISORD Y1 - 2006/10// VL - 16 SN - 0960-8966 SP - 685 EP - 685 ER - TY - JFULL T1 - The use of FRET analysis to look at the interaction of glycosyltransferases responsible for dystroglycanopathies A1 - Kaluarachchi, M A1 - Skordis, L A1 - Brockington, M A1 - Muntoni, F A1 - Brown, SC J1 - NEUROMUSCULAR DISORD Y1 - 2006/10// VL - 16 SN - 0960-8966 SP - 679 EP - 679 ER - TY - JFULL T1 - Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes. A1 - Cauchi, S A1 - Meyre, D A1 - Dina, C A1 - Choquet, H A1 - Samson, C A1 - Gallina, S A1 - Balkau, B A1 - Charpentier, G A1 - Pattou, F A1 - Stetsyuk, V A1 - Scharfmann, R A1 - Staels, B A1 - Frühbeck, G A1 - Froguel, P J1 - Diabetes Y1 - 2006/10// VL - 55 SN - 0012-1797 SP - 2903 EP - 2908 N2 - Recently, the transcription factor 7-like 2 (TCF7L2) gene has been associated with type 2 diabetes in subjects of European origin in the DeCode study. We genotyped the two most associated variants (rs7903146 and rs12255372) in 2,367 French type 2 diabetic subjects and in 2,499 control subjects. Both the T-allele of rs7903146 and the T-allele of rs12255372 significantly increase type 2 diabetes risk with an allelic odds ratio (OR) of 1.69 (95% CI 1.55-1.83) (P = 6.0 x 10(-35)) and 1.60 (1.47-1.74) (P = 7.6 x 10(-28)), respectively. In nonobese type 2 diabetic subjects (BMI <30 kg/m2, n = 1,346), the ORs increased to 1.89 (1.72-2.09) (P = 2.1 x 10(-38)) and 1.79 (1.62-1.97) (P = 5.7 x 10(-31)), respectively. The rs7903146 T at-risk allele associates with decreased BMI and earlier age at diagnosis in the type 2 diabetic subjects (P = 8.0 x 10(-3) and P = 3.8 x 10(-4), respectively), which is supported by quantitative family-based association tests. TCF7L2 is expressed in most human tissues, including mature pancreatic beta-cells, with the exception of the skeletal muscle. In the subcutaneous and omental fat from obese type 2 diabetic subjects, TCF7L2 expression significantly decreased compared with obese normoglycemic individuals. During rat fetal beta-cell differentiation, TCF7L2 expression pattern mimics the key marker NGN3 (neurogenin 3), suggesting a role in islet development. These data provide evidence that TCF7L2 is a major determinant of type 2 diabetes risk in European populations and suggests that this transcription factor plays a key role in glucose homeostasis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17003360&query_hl=1 ER - TY - JFULL T1 - Advances in the management of gestational trophoblastic disease - Presentations from the XIIIth World Congress on Gestational Trophoblastic Disease A1 - Berkowitz, RS A1 - Kohorn, EI A1 - Goldstein, DP A1 - Fisher, RA J1 - J REPROD MED Y1 - 2006/10// VL - 51 SN - 0024-7758 SP - 759 EP - 759 ER - TY - JFULL T1 - Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus. A1 - Heidari, Y A1 - Bygrave, AE A1 - Rigby, RJ A1 - Rose, KL A1 - Walport, MJ A1 - Cook, HT A1 - Vyse, TJ A1 - Botto, M J1 - Genes Immun Y1 - 2006/10// VL - 7 SN - 1466-4879 SP - 592 EP - 599 N2 - Systemic lupus erythematosus is an autoimmune disease in which complex interactions between genes and environmental factors determine the disease phenotype. We have shown that genes from the non-autoimmune strains 129 and C57BL/6 (B6), commonly used for generating gene-targeted animals, can induce a lupus-like disease. Here, we conducted a genome-wide scan analysis of a cohort of (129 x B6)F2 C1q-deficient mice to identify loci outside the C1qa locus contributing to the autoimmune phenotype described in these mice. The results were then confirmed in a larger dataset obtained by combining the data from the C1q-deficient mice with data from previously reported wild-type mice. Both analyses showed that a 129-derived interval on distal chromosome 1 is strongly linked to autoantibody production. The B6 genome contributed to anti-nuclear autoantibody production with an interval on chromosome 3. Two regions were linked to glomerulonephritis: a 129 interval on proximal chromosome 7 and a B6 interval on chromosome 13. These findings demonstrate that interacting loci between 129 and B6 mice can cause the expression of an autoimmune phenotype in gene-targeted animals in the absence of any disrupted gene. They also indicate that some susceptibility genes can be inherited from the genome of non-autoimmune parental strains. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16943797&query_hl=1 ER - TY - JFULL T1 - RYR1 genotype-phenotype correlative and functional studies in a large cohort of core myopathy patients with RYR1 mutations A1 - Zhou, H A1 - Jungbluth, H A1 - Treves, S A1 - Bertini, E A1 - Straub, V A1 - Bushby, K A1 - Sewry, C A1 - Muntoni, F J1 - NEUROMUSCULAR DISORD Y1 - 2006/10// VL - 16 SN - 0960-8966 SP - 687 EP - 687 ER - TY - JFULL T1 - Postinjury vascular intimal hyperplasia in mice is completely inhibited by CD34+ bone marrow-derived progenitor cells expressing membrane-tethered anticoagulant fusion proteins. A1 - Chen, D A1 - Weber, M A1 - Shiels, PG A1 - Dong, R A1 - Webster, Z A1 - McVey, JH A1 - Kemball-Cook, G A1 - Tuddenham, EG A1 - Lechler, RI A1 - Dorling, A J1 - J Thromb Haemost Y1 - 2006/10// VL - 4 SN - 1538-7933 SP - 2191 EP - 2198 N2 - BACKGROUND: Coagulation proteins promote neointimal hyperplasia and vascular remodelling after vessel injury, but the precise mechanisms by which they act in vivo remain undetermined. OBJECTIVES: This study, using an injury model in which the neointima is derived from bone marrow (BM)-derived cells, compared inhibition of tissue factor or thrombin on either BM-derived or existing vascular smooth muscle cells. METHODS: Two transgenic (Tg) mouse strains expressing membrane-tethered tissue factor pathway inhibitor (TFPI) or hirudin (Hir) fusion proteins driven by an alpha smooth muscle actin (SMA) promoter were generated (alpha-TFPI-Tg and alpha-Hir-Tg) and the phenotype after wire-induced endovascular injury was compared with that in wild-type (WT) controls. Results: WT mice developed progressive neointimal expansion, whereas injury in either Tg was followed by repair back to a preinjured state. This was also seen when WT mice were reconstituted with BM from Tg mice but not when Tgs were reconstituted with WT BM, in which injury was followed by slowly progressive neointimal expansion. Injection of CD34+ cells from Tg mice into injured WT mice resulted in the accumulation of fusion protein-expressing cells from day 3 onwards and an absence of neointimal hyperplasia in those areas. CONCLUSIONS: Neointimal development after wire-induced endovascular injury in mice was completely inhibited when BM-derived cells infiltrating the damaged artery expressed membrane tethered anticoagulant fusion proteins under an alpha-SMA promoter. These findings enhance our understanding of the pathological role that coagulation proteins play in vascular inflammation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16803463&query_hl=1 ER - TY - JFULL T1 - UK physicians' attitudes and practices in long-term non-invasive ventilation of Duchenne Muscular Dystrophy. A1 - Kinali, M A1 - Manzur, AY A1 - Mercuri, E A1 - Gibson, BE A1 - Hartley, L A1 - Simonds, AK A1 - Muntoni, F J1 - Pediatr Rehabil Y1 - 2006/10// VL - 9 SN - 1363-8491 SP - 351 EP - 364 N2 - Previous studies have shown that long-term non-invasive ventilation (NIV) is not always routinely offered by all physicians in Duchenne Muscular Dystrophy (DMD), despite evidence that this treatment improves quality of life and survival. This study examined UK physicians' practices related to respiratory follow-up and DMD ventilation. A mailed questionnaire was used. Thirty-eight of the 59 (64%) UK physicians identified via the Muscular Dystrophy Campaign (MDC) responded. Eighty-one per cent of respondents felt ethically obliged to discuss NIV with families while 13% believed that NIV results in poor quality of life. Forty-seven per cent of physicians discuss in-depth the use of NIV when the patient is in respiratory failure. Eighty-four ventilated DMD patients in the respondents' practice use NIV (via Bi-Pap Nasal mask). Nearly 66% of physicians do not consider the public cost to be an impediment to offering NIV, despite significant problems with resources' allocation in their area. While the majority of UK physicians have comparable attitudes and practices regarding NIV, the questionnaire highlighted that not all specialists were aware of the existence of consensus guidelines regarding respiratory monitoring. In addition, different practices of disclosure of life-prolonging ventilation options were used by different physicians. Seventy-one per cent of physicians wished for national consensus guidelines for different DMD age groups. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17111551&query_hl=1 ER - TY - JFULL T1 - Bardet-Biedl syndrome gene variants are associated with both childhood and adult common obesity in French Caucasians. A1 - Benzinou, M A1 - Walley, A A1 - Lobbens, S A1 - Charles, MA A1 - Jouret, B A1 - Fumeron, F A1 - Balkau, B A1 - Meyre, D A1 - Froguel, P J1 - Diabetes Y1 - 2006/10// VL - 55 SN - 0012-1797 SP - 2876 EP - 2882 N2 - Bardet-Biedl syndrome (BBS) is a rare developmental disorder with the cardinal features of abdominal obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, hypertension, and diabetes. BBS is genetically heterogeneous, with nine genes identified to date and evidence for additional loci. In this study, we performed mutation analysis of the coding and conserved regions of BBS1, BBS2, BBS4, and BBS6 in 48 French Caucasian individuals. Among the 36 variants identified, 12 were selected and genotyped in 1,943 French-Caucasian case subjects and 1,299 French-Caucasian nonobese nondiabetic control subjects. Variants in BBS2, BBS4, and BBS6 showed evidence of association with common obesity in an age-dependent manner, the BBS2 single nucleotide polymorphism (SNP) being associated with common adult obesity (P = 0.0005) and the BBS4 and BBS6 SNPs being associated with common early-onset childhood obesity (P = 0.0003) and common adult morbid obesity (0.0003 < P < 0.007). The association of the BBS4 rs7178130 variant was found to be supported by transmission disequilibrium testing (P = 0.006). The BBS6 variants also showed nominal evidence of association with quantitative components of the metabolic syndrome (e.g., dyslipidemia, hyperglycemia), a complication previously described in BBS patients. In summary, our preliminary data suggest that variations at BBS genes are associated with risk of common obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17003356&query_hl=1 ER - TY - JFULL T1 - Limitation of neck movement may be a feature of most of the childhood neuromuscular disorders A1 - Main, M A1 - Kinali, M A1 - Muntoni, F J1 - NEUROMUSCULAR DISORD Y1 - 2006/10// VL - 16 SN - 0960-8966 SP - 664 EP - 664 ER - TY - JFULL T1 - Breaking the silence in Friedreich's ataxia. A1 - Festenstein, R J1 - Nat Chem Biol Y1 - 2006/10// VL - 2 SN - 1552-4450 SP - 512 EP - 513 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16983383&query_hl=1 ER - TY - JFULL T1 - The emerging amphibian pathogen Batrachochytrium dendrobatidis globally infects introduced populations of the North American bullfrog, Rana catesbeiana A1 - Garner, TWJ A1 - Perkins, MW A1 - Govindarajulu, P A1 - Seglie, D A1 - Walker, S A1 - Cunningham, AA A1 - Fisher, MC J1 - BIOL LETT-UK Y1 - 2006/09/22/ VL - 2 SN - 1744-9561 SP - 455 EP - 459 N2 - Batrachochytrium dendrobatidis is the chytridiomycete fungus which has been implicated in global amphibian declines and numerous species extinctions. Here, we show that introduced North American bullfrogs (Rana catesbeiana) consistently carry this emerging pathogenic fungus. We detected infections by this fungus on introduced bullfrogs from seven of eight countries using both PCR and microscopic techniques. Only native bullfrogs from eastern Canada and introduced bullfrogs from Japan showed no sign of infection. The bullfrog is the most commonly farmed amphibian, and escapes and subsequent establishment of feral populations regularly occur. These factors taken together with our study suggest that the global threat of B. dendrobatidis disease transmission posed by bullfrogs is significant. ER - TY - JFULL T1 - Characterization of recessive RYR1 mutations in core myopathies. A1 - Zhou, H A1 - Yamaguchi, N A1 - Xu, L A1 - Wang, Y A1 - Sewry, C A1 - Jungbluth, H A1 - Zorzato, F A1 - Bertini, E A1 - Muntoni, F A1 - Meissner, G A1 - Treves, S J1 - Hum Mol Genet Y1 - 2006/09/15/ VL - 15 SN - 0964-6906 SP - 2791 EP - 2803 N2 - We have characterized at the molecular level, three families with core myopathies carrying apparent recessive mutations in their RYR1 gene and studied the pharmacological properties of myotubes carrying endogenous mutations as well as the properties of mutant channels expressed in HEK293 cells. The proband of family 1 carried p.Ala1577Thr+p.Gly2060Cys in trans, having inherited a mutation from each parent. Immunoblot analysis of proteins from the patient's skeletal muscle revealed low levels of ryanodine receptor (RyR1) but neither substitution alone or in combination affected the functional properties of RyR1 channels in a discernable way. Two affected siblings in family 2 carried p.Arg109Trp+p.Met485Val substitutions in cis, inherited from the unaffected father. Interestingly, both affected siblings only transcribed the mutated paternal allele in skeletal muscle, whereas the maternal allele was silent. Single-channel measurements showed that recombinant, mutant RyR1 channels carrying both substitutions lost the ability to conduct Ca2+. In this case as well, low levels of RyR1 were present in skeletal muscle extracts. The proband of family 3 carried p.Ser71Tyr+p.Asn2283His substitutions in trans. Recombinant channels with Asn2283His substitution showed an increased activity, whereas recombinant channels with p.Ser71Tyr+p.Asn2283His substitution lost activity upon isolation. Taken together, our data suggest major differences in the ways RYR1 mutations may affect patients with core myopathies, by compromising RyR1 protein expression, stability and/or activity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16940308&query_hl=1 ER - TY - JFULL T1 - Predictions of CCR1 chemokine receptor structure and BX 471 antagonist binding followed by experimental validation. A1 - Vaidehi, N A1 - Schlyer, S A1 - Trabanino, RJ A1 - Floriano, WB A1 - Abrol, R A1 - Sharma, S A1 - Kochanny, M A1 - Koovakat, S A1 - Dunning, L A1 - Liang, M A1 - Fox, JM A1 - de Mendonça, FL A1 - Pease, JE A1 - Goddard, WA A1 - Horuk, R J1 - J Biol Chem Y1 - 2006/09/15/ VL - 281 SN - 0021-9258 SP - 27613 EP - 27620 N2 - A major challenge in the application of structure-based drug design methods to proteins belonging to the superfamily of G protein-coupled receptors (GPCRs) is the paucity of structural information (1). The 19 chemokine receptors, belonging to the Class A family of GPCRs, are important drug targets not only for autoimmune diseases like multiple sclerosis but also for the blockade of human immunodeficiency virus type 1 entry (2). Using the MembStruk computational method (3), we predicted the three-dimensional structure of the human CCR1 receptor. In addition, we predicted the binding site of the small molecule CCR1 antagonist BX 471, which is currently in Phase II clinical trials (4). Based on the predicted antagonist binding site we designed 17 point mutants of CCR1 to validate the predictions. Subsequent competitive ligand binding and chemotaxis experiments with these mutants gave an excellent correlation to these predictions. In particular, we find that Tyr-113 and Tyr-114 on transmembrane domain 3 and Ile-259 on transmembrane 6 contribute significantly to the binding of BX 471. Finally, we used the predicted and validated structure of CCR1 in a virtual screening validation of the Maybridge data base, seeded with selective CCR1 antagonists. The screen identified 63% of CCR1 antagonists in the top 5% of the hits. Our results indicate that rational drug design for GPCR targets is a feasible approach. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16837468&query_hl=1 ER - TY - JFULL T1 - Complement activation contributes to both glomerular and tubulointerstitial damage in adriamycin nephropathy in mice. A1 - Turnberg, D A1 - Lewis, M A1 - Moss, J A1 - Xu, Y A1 - Botto, M A1 - Cook, HT J1 - J Immunol Y1 - 2006/09/15/ VL - 177 SN - 0022-1767 SP - 4094 EP - 4102 N2 - Adriamycin nephropathy is a model of focal segmental glomerulosclerosis, characterized by proteinuria and progressive glomerulosclerosis and tubulointerstitial damage. In this study, we examined the role of complement in the etiology of adriamycin nephropathy in mice. We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls. C3 deposition occurred in the glomeruli of wild-type mice as early as 48 h following a single i.v. injection of adriamycin. C3-deficient mice developed significantly less proteinuria and less podocyte injury at day 3 postadriamycin than controls, suggesting that complement is important in mediating the early podocyte injury. At later time points, C3-deficient mice were protected from glomerulosclerosis, tubulointerstitial injury, and renal dysfunction. Factor D-deficient mice were also protected from renal disease, confirming the importance of alternative pathway activation in this model. In contrast, C1q-deficient mice developed similar disease to controls, indicating that the complement cascade was not activated via the classical pathway. CD59-deficient mice, which lack adequate control of C5b-9 formation, developed significantly worse histological and functional markers of renal disease than controls. Interestingly, although more C9 deposited in glomeruli of CD59-deficient mice than controls, in neither group was tubulointerstitial C9 staining apparent. We have demonstrated for the first time that alternative pathway activation of complement plays an important role in mediating the initial glomerular damage in this in vivo model of focal segmental glomerulosclerosis. Lack of CD59, which regulates the membrane attack complex, led to greater glomerular and tubulointerstitial injury. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16951374&query_hl=1 ER - TY - JFULL T1 - Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats. A1 - McGowan, BM A1 - Stanley, SA A1 - Smith, KL A1 - Minnion, JS A1 - Donovan, J A1 - Thompson, EL A1 - Patterson, M A1 - Connolly, MM A1 - Abbott, CR A1 - Small, CJ A1 - Gardiner, JV A1 - Ghatei, MA A1 - Bloom, SR J1 - Regul Pept Y1 - 2006/09/11/ VL - 136 SN - 0167-0115 SP - 72 EP - 77 N2 - The effects of acute and repeated intraparaventricular (iPVN) administration of human relaxin-3 (H3) were examined on food intake, energy expenditure, and the hypothalamo-pituitary thyroid axis in male Wistar rats. An acute high dose iPVN injection of H3 significantly increased food intake 1 h post-administration [0.4+/-0.1 g (vehicle) vs 1.6+/-0.5 g (180 pmol H3), 2.4+/-0.5 g (540 pmol H3) and 2.2+/-0.5 g (1,620 pmol H3), p<0.05 for all doses vs vehicle]. Repeated iPVN H3 injection (180 pmol/twice a day for 7 days) significantly increased cumulative food intake in ad libitum fed animals compared with vehicle [211.8+/-7.1 g (vehicle) vs 261.6+/-6.7 g (ad libitum fed H3), p<0.05]. Plasma leptin was increased in the H3 ad libitum fed group. Plasma thyroid stimulating hormone was significantly decreased after acute and repeated administration of H3. These data suggest H3 may play a role in long-term control of food intake. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16764952&query_hl=1 ER - TY - JFULL T1 - Endothelin axis polymorphisms in patients with scleroderma. A1 - Fonseca, C A1 - Renzoni, E A1 - Sestini, P A1 - Pantelidis, P A1 - Lagan, A A1 - Bunn, C A1 - McHugh, N A1 - Welsh, KI A1 - Du Bois, RM A1 - Denton, CP A1 - Black, C A1 - Abraham, D J1 - Arthritis Rheum Y1 - 2006/09// VL - 54 SN - 0004-3591 SP - 3034 EP - 3042 N2 - OBJECTIVE: To evaluate the distribution of polymorphisms in the endothelin 1 (EDN1), endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) genes in systemic sclerosis (SSc; scleroderma) and SSc subsets. METHODS: Two hundred five patients with SSc and 255 healthy controls were screened for polymorphisms in EDN1, EDNRA, and EDNRB, using sequence-specific primer-polymerase chain reaction. The polymorphisms studied were at the following positions: for EDN1, -1370 (T-1370G) of the promoter, +138 of exon 1 (+138 A/-), +85 of exon 3 (E106E), and +23 of exon 5 (K198N); for EDNRA, -231 of exon 1 (G-231A), and +69(H323H) and +105 (E335E) of exon 6; for EDNRB, +2841 of exon 2 (EDNRB-3), -2547 of exon 3 (EDNRB-2), and -2446 of exon 3 (EDNRB-1). RESULTS: No significant differences between the SSc group as a whole and control subjects were observed for any of the investigated polymorphisms in EDN1, EDNRA, and EDNRB. However, compared with patients with limited cutaneous SSc, patients with diffuse skin involvement had an increased frequency of allele carriage of EDNRB-1A (76.8% versus 54.4%; P = 0.002), EDNRB-2A (79.7% versus 60.2%; P = 0.006), and EDNRB-3G (79.7% versus 56.6%; P = 0.001). Significantly increased carriage frequencies for EDNRA alleles H323H/C and E335E/A were observed in SSc patients with anti-RNA polymerase (anti-RNAP) antibodies, compared with both anti-RNAP-negative SSc patients (P < 0.05) and control subjects (P < 0.005). CONCLUSION: The finding of associations between endothelin receptors A and B and distinct clinical and immunologic SSc subsets supports the role of endothelin and its receptors in the pathogenesis of SSc. However, these findings and their functional significance need to be confirmed and investigated in future studies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16947775&query_hl=1 ER - TY - JFULL T1 - Protein kinase C epsilon (PKC epsilon) regulates BCL-2 expression in vascular endothelial cells (EC) and protects against apoptosis A1 - Steinberg, R A1 - Harari, O A1 - Lidington, E A1 - Samarel, A A1 - Ohba, M A1 - Haskard, DO A1 - Mason, JC J1 - VASC PHARMACOL Y1 - 2006/09// VL - 45 SN - 1537-1891 SP - 192 EP - 192 ER - TY - JFULL T1 - Association of the calpain-10 gene with type 2 diabetes in Europeans: Results of pooled and meta-analyses A1 - Tsuchiya, T A1 - Schwarz, PEH A1 - del Bosque-Plata, L A1 - Hayes, MG A1 - Dina, C A1 - Froguel, P A1 - Towers, GW A1 - Fischer, S A1 - Temelkova-Kurktschiev, T A1 - Rietzsch, H A1 - Graessler, J A1 - Vcelak, J A1 - Palyzova, D A1 - Selisko, T A1 - Bendlova, B A1 - Schulze, J A1 - Julius, U A1 - Hanefeld, M A1 - Weedon, MN A1 - Evans, JC A1 - Frayling, TM A1 - Hattersley, AT A1 - Orho-Melander, M A1 - Groop, L A1 - Malecki, MT A1 - Hansen, T A1 - Pedersen, O A1 - Fingerlin, TE A1 - Boehnke, M A1 - Hanis, CL A1 - Cox, NJ A1 - Bell, GI J1 - MOL GENET METAB Y1 - 2006/09// VL - 89 SN - 1096-7192 SP - 174 EP - 184 N2 - We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR) = 1.11 (95% confidence interval (0), 1.02-1.20), P = 0.01). Two haplotype combinations were associated with increased risk of T2D) (1-2-1/1-2-1, OR = 1.20 (1.03-1.41), P = 0.02; and 1-1-2/1-2-1, OR = 1.26 (1.01-1.59), P = 0.04) and one with decreased risk (1-1-1/2-2-1, OR = 0.86 (0.75-0.99), P = 0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR = 1.25 (1.05-1.50), P = 0.01). However, there was evidence for heterogeneity with respect to this effect (P = 0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P = 0.89) and strengthened the evidence for association with T2D) in both the pooled (SNP-43*G, OR = 1.19 (1.07-1.32), P = 0.001; 1-2-1/1-2-1 haplogenotype, OR = 1.46 (1.19-1.78), P = 0.0003; 1-1-2/1-2-1 haplogenotype, OR = 1.52 (1.12-2.06), P = 0.007; and 1-1-1/2-2-1 haplogenotype, OR = 0.83 (0.70-0.99), P = 0.03) and the meta-analysis (SNP-43*G, OR = 1.18 (1.05-1.32), P = 0.005; 1-2-1/1-2-1 haplogenotype, OR = 1.68 (1.33-2.11), P = 0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans. (c) 2006 Elsevier Inc. All rights reserved. ER - TY - JFULL T1 - Association of KLF11 with insulin resistance is mediated via STAT3 binding to KLF11 variant -1659 G > C A1 - Gutierrez-Aguilar, R A1 - Hamid, YH A1 - Vaillant, E A1 - Benmezroua, Y A1 - Jorgensen, T A1 - Borch-Johnsen, K A1 - Hansen, T A1 - Froguel, P A1 - Pedersen, O A1 - Neve, B J1 - DIABETOLOGIA Y1 - 2006/09// VL - 49 SN - 0012-186X SP - 162 EP - 163 ER - TY - JFULL T1 - TCF7L2 gene strongly associates with type 2 diabetes, with lower age of onset and BMI in the French population, and its adipose expression is impaired in diabetes A1 - Cauchi, S A1 - Meyrel, D A1 - Choquet, H A1 - Samson, C A1 - Polychronakos, C A1 - Balkau, B A1 - Scharfmann, R A1 - Fruhbeck, G A1 - Charpentier, G A1 - Sladek, R A1 - Froguel, P J1 - DIABETOLOGIA Y1 - 2006/09// VL - 49 SN - 0012-186X SP - 14 EP - 15 ER - TY - JFULL T1 - Polymorphisms in the glucokinase-associated, dual-specificity phosphatase 12 (DUSP12) gene under chromosome 1q21 linkage peak are associated with type 2 diabetes A1 - Das, SK A1 - Chu, WS A1 - Hale, TC A1 - Wang, XQ A1 - Craig, RI A1 - Wang, H A1 - Shuldiner, AR A1 - Froguel, P A1 - Deloukas, P A1 - McCarthy, MI A1 - Zeggini, E A1 - Hasstedt, SJ A1 - Elbein, SC J1 - DIABETES Y1 - 2006/09// VL - 55 SN - 0012-1797 SP - 2631 EP - 2639 N2 - Linkage of type 2 diabetes to chromosome 1q21-q23 is well replicated across populations. In an initial 50-kb marker map (580 markers) across the linked region, one of the two strongest associations observed in Utah Caucasians was at marker rs1503814 (P < 0.00001 in pools, P < 0.004 in individuals). Based on this association, we typed additional markers and screened for sequence variation in the nearby DUSP12 gene. The strongest associations mapped to a highly conserved nongenic sequence just telomeric to rs1503814 and extended 10 kb telomeric through the DUSP12 gene and into the 5' end of the adjacent ATF6 gene. No coding variant could explain the association in the DUSP12 gene. An extended haplotype encompassing markers from -8,379 to +10,309 bp relative to the ATG start was more common in Caucasian case (0.381) than control subjects (0.285, P = 0.005) and was uniquely tagged by a 194-bp allele at either of two simple tandem repeat variants or by the T allele at marker +7,580. Markers -8,379 and +7,580 were nominally associated with type 2 diabetes in African-American subjects (P < 0.05), but with different alleles. Marker rs1503814 was strongly associated with postchallenge insulin levels among family members (P = 0.000002), but sequence variation in this region was not associated with type 2 diabetes in three other populations of European ancestry. Our data suggest that sequences in or upstream of DUSP12 may contribute to type 2 diabetes susceptibility, but the lack of replication suggests a small effect size. ER - TY - JFULL T1 - Breathlessness measured by clamping end-tidal carbon dioxide: Limitations of the breathing system A1 - Pickering, E A1 - Guz, A A1 - Semple, S A1 - Murphy, K A1 - Holdcroft, A J1 - BRIT J ANAESTH Y1 - 2006/09// VL - 97 SN - 0007-0912 SP - 437P EP - 437P ER - TY - JFULL T1 - A combined linkage and expression study of rat heart to identify primary drivers of cardiac hypertrophy A1 - Sarwar, R A1 - Petretto, E A1 - Mangion, J A1 - Pravenec, M A1 - Aitman, T A1 - Cook, S J1 - HEART Y1 - 2006/09// VL - 92 SN - 1355-6037 ER - TY - JFULL T1 - Cannabinoid receptor 1 gene variation increases risk for obesity and type 2 diabetes and modulates phenotypes related to endocannabinoid-mediated physiological pathways A1 - Ward, KJ A1 - Boutin, P A1 - Chevre, JC A1 - Lobbens, S A1 - Lecoeur, C A1 - Wachter, C A1 - Dina, C A1 - Larsen, PJ A1 - Tanko, LB A1 - Horber, FF A1 - Charpentier, G A1 - Balkau, B A1 - Meyre, D A1 - Froguel, P J1 - DIABETOLOGIA Y1 - 2006/09// VL - 49 SN - 0012-186X SP - 215 EP - 216 ER - TY - JFULL T1 - Single-nucleotide polymorphism of the cannabinoid receptor 1 gene: A genetic link between osteoporosis and cardiovascular disease? A1 - Tanko, LB A1 - Boutin, P A1 - Larsen, P A1 - Froguel, P A1 - Christiansen, C J1 - J BONE MINER RES Y1 - 2006/09// VL - 21 SN - 0884-0431 SP - S148 EP - S148 ER - TY - JFULL T1 - River blindness: a success story under threat? A1 - Basáñez, MG A1 - Pion, SD A1 - Churcher, TS A1 - Breitling, LP A1 - Little, MP A1 - Boussinesq, M J1 - PLoS Med Y1 - 2006/09// VL - 3 SN - 1549-1676 SP - e371 EP - e371 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17002504&query_hl=1 ER - TY - JFULL T1 - Feeding problems and weight gain in Duchenne muscular dystrophy A1 - Pane, M A1 - Vasta, I A1 - Messina, S A1 - Sorleti, D A1 - Aloysius, A A1 - Sciarra, F A1 - Mangiola, F A1 - Kinali, M A1 - Ricci, E A1 - Mercuri, E J1 - EUR J PAEDIATR NEURO Y1 - 2006/09// VL - 10 SN - 1090-3798 SP - 231 EP - 236 N2 - The aim of the study was to conduct a survey using a dedicated questionnaire to estimate feeding difficulties, gastrointestinal involvement and weight gain in a population of 118 Duchenne muscular dystrophy (DMD) patients (age range 13.80-35.8 years). All the answers were entered in a database and the data analysed subdividing the cohort into age groups (3-9, 9-13, 13-18, 18-24, 24-30, 30-36 years). The results indicate that chewing difficulties are frequent and become increasingly present with age, associated with a progressive increase of the duration of meals. Episodes of choking or other clinical signs of swallowing difficulties are in contrast much less frequent even after age 18. Aspiration pneumonia were also not very frequent and only occurred in 7/118.Clinical signs of gastroesophageal. reflux requiring treatment were only found in 5 while 43/118 complained of constipation requiring treatment.Very few of our patients had their weight above 2 SD (n = 4) and this was always found in patients between 9 and 18 years while after this age there was an increasing number of patients with weight below 2 SD.The results of our survey suggest that although choking is one of the most feared complications in patients with DMD, clinical signs of swallowing abnormalities are infrequent when collecting clinical information retrospectively. Further studies using an objective evaluation such as videofluoroscopy are needed to identify minor si