TY - BOOK T1 - Atlas of Tropical Medicine and Parasitology A1 - Wallace Peters A1 - Geoffrey Pasvol Y1 - 2007/// VL - 6th PB - Elsevier CY - Philadelphia SP - 1 EP - 429 N2 - - ER - TY - BOOK T1 - Viral Hepatitis A1 - Thomas HC A1 - Lemon S A1 - Zuckerman AJ ED - Thomas HC; Lemon S; Zuckerman AJ Y1 - 2005/// VL - Third Edition PB - Blackwell Publishing CY - Oxford; UK SP - 1 EP - 876 N2 - - ER - TY - BOOK T1 - Viral Hepatitis A1 - Thomas HC, A1 - Lemon.S A1 - Zuckerman A ED - Thomas HC, Lemon S; and Zuckerman A Y1 - 2005/// VL - Third Edition PB - Blackwell Publishing CY - Oxford, UK SN - 1-4051-3005-9 SP - 3 EP - 876 N2 - - ER - TY - BOOK T1 - Oxford handbook of tropical medicine A1 - Eddleston M A1 - Davidson RN A1 - Wilkinson RJ A1 - Pierini S Y1 - 2004/// VL - 2 PB - Oxford University Press SN - 0-1985-2509-5 SP - 1 EP - 712 N2 - - ER - TY - BOOK T1 - Malaria A hematological perspective A1 - Pasvol G ED - Abdalla SH; Pasvol G Y1 - 2004/// PB - Imperial College Press SN - 1-86094-357-8 N2 - - ER - TY - BOOK T1 - Infection and Immunity A1 - Friedland JS A1 - Lightstone L Y1 - 2003/// PB - Martin Dunitz CY - London, UK SN - 1 84184 373 3 N2 - - ER - TY - BOOK T1 - WHO-UNAIDS Guidelines for Standard HIV Isolation and Characterisation Procedures A1 - Weber JN A1 - Fenyo EM Y1 - 2002/// SN - 9-2415-9021-1 N2 - - ER - TY - BOOK T1 - Tropical medicine and parasitology A1 - Peters W A1 - Pasvol G Y1 - 2002/// SN - 0-7234-3191-4 N2 - - ER - TY - BOOK T1 - New challenges to health: the threat of virus infection A1 - Smith GL Y1 - 2001/// SN - 0-5218-0614-3 EP - 4 N2 - - ER - TY - BOOK T1 - Meningitis: A Guide for Families A1 - Kroll, JS A1 - Pollard, AJ A1 - Habibi, P Y1 - 1997/// PB - Publishing Solutions CY - London SN - 1-901336-00-X SP - 5 EP - 112 N2 - - ER - TY - BOOK T1 - Meningitis - A Guide for Families A1 - Kroll S A1 - Pollard A A1 - Habibi P Y1 - 1997/// PB - Publishing Solutions (UK) Ltd N2 - - ER - TY - CHAP T1 - Infectious diseases: Gene therapy A1 - S Fidler ED - Thomson Scientific T2 - Encyclopdeia of Genetics Y1 - 2007/// VL - second M2 - 1 PB - thomson scientific CY - UK N2 - - ER - TY - CHAP T1 - Acute respiratory distress syndrome A1 - SJ Finney A1 - G Bellingan ED - G Laurent, S Shapio T2 - Encyclopaedia of Respiratory Medicine Y1 - 2006/03// VL - 1 M2 - 1 PB - Academic Press CY - London SN - 0-12-438360-2 SP - 11 EP - 18 N2 - - ER - TY - CHAP T1 - Recent advances in retroviral replication: Cellular machines and novel anti-viral defense mechanisms. A1 - Engelman, A A1 - Cherepanov, P ED - Hefferon, K L T2 - Recent Advances in RNA Virus Replication Y1 - 2006/// PB - Transworld Research Network CY - Kerala, India SN - 81-7895-214-9 SP - 91 EP - 129 N2 - - ER - TY - CHAP T1 - Impact of genome sequences on mutational analysis of fungal and bacterial pathogens A1 - Pelicic V A1 - Nassif X ED - Hacker J, Dobrindt U T2 - Pathogenomics: genome analysis of pathogenic microbes Y1 - 2006/// PB - John Wiley & Sons SN - 3-527-31265-X SP - 1 EP - 568 N2 - - ER - TY - CHAP T1 - Skin Manifestations of Meningogoccal Infection. A1 - Faust SN, Habibi P, Heyderman R A1 - Faust N A1 - Habibi p A1 - Hederman n ED - Ed. John Harper, Arnold Orange, Neil Prose. T2 - Text Book of Paediatric Dermatology Y1 - 2006/// VL - 2nd Ed M2 - Volume 1 PB - Blackwell Publishing Ltd. CY - Oxford SP - 471 EP - 485 N2 - - ER - TY - CHAP T1 - Models for the study of infection in populations A1 - John R Williams ED - P Michael Conn T2 - Handbook of models for human aging Y1 - 2006/// PB - Academic Press CY - San Diego, CA SN - 0-12-369391-8 SP - 165 EP - 182 N2 - - UR - http://www.elsevier.com/wps/find/bookdescription.cws_home/707448/description#description ER - TY - CHAP T1 - Host Genetics and Susceptibility to infection A1 - Wilkinson RJ A1 - Levin M ED - Guerrant R.L, Walker, D.H. and Weller, P.F. T2 - Tropical Infectious Diseases: Principles, pathogens and practice Y1 - 2006/// VL - 2 M2 - 1 PB - Churchill Livingstone CY - Philadelphia SN - 0-443-06668-X SP - 53 EP - 67 N2 - - ER - TY - CHAP T1 - Treatment of chronic hepatitis C A1 - Heathcote J A1 - Main J ED - Thomas H; Lemon S; Zuckerman A T2 - Viral Hepatitis Y1 - 2005/// PB - Blackwell N2 - - ER - TY - CHAP T1 - Nuclear Magnetic Resonance Spectroscopy in the Study of Human Liver A1 - Lim AKP A1 - Khan SA A1 - Cox IJ A1 - Taylor-Robinson SD ED - Tosi, R., Tugnoli, V. T2 - Nuclear Magnetic Resonance Spectroscopy in the Study of Neoplastic Tissue Y1 - 2005/// PB - Nova Science Publishers Inc. CY - New York SN - 1-59454-258-9 SP - 295 EP - 312 N2 - - ER - TY - CHAP T1 - Malaria A1 - Pasvol G ED - Eddlestone m, Davidson R, Wilkinson R, Pierini S T2 - Oxford handbook of tropical Medicine Y1 - 2005/// M2 - 2nd Edition PB - Oxford University Press SN - 0 19 852509 5 SP - 9 EP - 37 N2 - - ER - TY - CHAP T1 - Molecular variations in the core promoter, precore and core regions of hepatitis B virus, and their clinical significance. A1 - Karayiannis P A1 - Carman WF A1 - Thomas HC ED - Thomas HC; Lemon S; Zuckerman AJ T2 - Viral Hepatitis Y1 - 2005/// PB - Blackwell Publishing SN - 1-4051-30059 SP - 242 EP - 262 N2 - - ER - TY - CHAP T1 - Detection and Quantitation of HIV-1-Specific T Lymphocytes in HIV-1 Infected Individuals and Vaccine Recipients A1 - Nesrina Imami A1 - Antonio Pires ED - Liberman, A. P. T2 - Progress in AIDS Research Y1 - 2005/// PB - Nova Science Publishers CY - New York SN - 1-59454-181-7 SP - 109 EP - 137 N2 - - UR - http://www.novapublishers.com ER - TY - CHAP T1 - Hepatitis in HIV infected persons A1 - Main J A1 - McCarron B ED - Thomas H; Lemon S; Zuckerman A T2 - Viral Hepatitis Y1 - 2005/// PB - Blackwell N2 - - ER - TY - CHAP T1 - “Intracellular Models of M.tuberculosis Infection” A1 - Chan, John A1 - Silver, Richard A1 - Kampmann, Beate A1 - Wallis, Robert ED - Stuart Cole et al, T2 - “ Tuberculosis” Y1 - 2005/// PB - ASM Press, Washington (2005) N2 - - ER - TY - CHAP T1 - Hepatitis C Virus: Structure and Molecular Virology A1 - McGarvey MJ A1 - Houghton M ED - Howard C Thomas, Stanley Lemon, Arie J Zuckerman T2 - Viral Hepatitis Y1 - 2005/// M2 - Third Edition PB - Blackwell Publishing Inc. CY - Malden, Massachusetts SP - 381 EP - 406 N2 - - ER - TY - CHAP T1 - Hepatitis B surface antigen (HBsAg) variants. A1 - Carman WF A1 - Jazayeri M A1 - Basune A A1 - Thomas HC A1 - Karayiannis P ED - Thomas HC; Lemon S; Zuckerman AJ T2 - Viral Hepatitis Y1 - 2005/// PB - Blackwell Publishing SN - 1-4051-30059 SP - 225 EP - 241 N2 - - ER - TY - CHAP T1 - Central nervous system complications A1 - Forton DM A1 - Taylor-Robinson SD A1 - Cox IJ A1 - Thomas HC ED - Thomas HC, Lemon S, Zuckerman A. T2 - Viral Hepatitis Y1 - 2005/// VL - 3rd M2 - 29 PB - Blackwell Publishing Ltd CY - Oxford SN - 1-4051-3005-9 SP - 482 EP - 495 N2 - - ER - TY - CHAP T1 - The Human T Cell Lymphotropic Viruses A1 - Taylor GP ED - Zuckerman, AJ, Banatvala JE, Pattison JR, Griffiths PD, Schoub BD T2 - Principles and Practice of Clinical Virology 5th Ed Y1 - 2004/05// PB - John Wiley & Sons SN - 0-470-84338-1 SP - 759 EP - 777 N2 - - ER - TY - CHAP T1 - Malaria A1 - Pasvol G ED - Cohen, J and Powderly, WG T2 - Infectious Diseases Y1 - 2004/// PB - Mosby CY - London SP - 1579 EP - 1591 N2 - - ER - TY - CHAP T1 - Confusion and coma A1 - Pasvol G ED - Cohen, J and Powderly, WG T2 - Infectious Diseases Y1 - 2004/// PB - Mosby CY - London SP - 1459 EP - 1465 N2 - - ER - TY - CHAP T1 - Regulation of gene expression by ambient pH. A1 - Arst HN Jr A1 - Tilburn J ED - Brambl R and Marzluf GA T2 - The Mycota Vol. III. Biochemistry and Molecular Biology. Y1 - 2004/// VL - 2nd M2 - 3 PB - Springer-Verlag CY - Berlin SP - 121 EP - 128 N2 - - ER - TY - CHAP T1 - The application of magnetic resonance imaging and spectroscopy to gene therapy. A1 - Bhakoo KK A1 - Bell JD A1 - Cox IJ A1 - Taylor-Robinson SD ED - Conn MP T2 - Methods Enzymol. Y1 - 2004/// PB - Elsevier Academic Press SN - 0-12-182791-7 SP - 13 EP - 303 N2 - - ER - TY - CHAP T1 - Regulation of gene expression by ambient pH A1 - Arst HN Jr A1 - Tilburn J ED - Brambl R, Marzluf GA T2 - The Mycota: Biochemistry and Molecular Biology, 2nd ed Y1 - 2004/// M2 - III PB - Springer-Verlag CY - Berlin SP - 121 EP - 128 N2 - - ER - TY - CHAP T1 - Novel Vaccines Against Tuberculosis A1 - Wilkinson RJ ED - Myron M. Levine, James B. Kaper, Rino Rappuoli, Margaret Liu, and Michael F. Good T2 - New Generation Vaccines Y1 - 2004/// VL - 3 PB - Marcel Dekker CY - New York SP - 519 EP - 535 N2 - - ER - TY - CHAP T1 - B-Myb: a highly regulated member of the the Myb transcription factor family. A1 - Watson, RJ ED - Frampton, J T2 - Myb transcription factors: their role in growth, differentiation and disease Y1 - 2004/// VL - 1st M2 - Proteins and Cell Regulation V PB - Kluwer Academic Publishers CY - Dordrecht, Netherlands SN - 1-4020-2779-6 SP - 181 EP - 199 N2 - - ER - TY - CHAP T1 - Dendrimer drugs prevent scar tissue formation A1 - Shaunak S ED - Noel R. Rose T2 - Discovery Medicine Y1 - 2004/// PB - Peter H. Rheinstein SP - 464 EP - 469 N2 - - ER - TY - CHAP T1 - Definition, epidemiology, diagnosis and management of anemia of malaria A1 - Pasvol G A1 - Abdalla SH ED - Abdalla SH and Pasvol G T2 - Malaria A hematological perspective Y1 - 2004/// PB - Imperial College Press SN - 1-86094-357-8 N2 - - ER - TY - CHAP T1 - Pathogenesis of anemai of malaria A1 - Abdalla SH A1 - Pasvol G ED - Abdalla SH and Pasvol G T2 - Malaria A hematological perspective Y1 - 2004/// PB - Imperial College Press SN - 1-86094-357-8 N2 - - ER - TY - CHAP T1 - “ Acute Respiratory Infections” A1 - Kampmann, Beate ED - Eddleston M, Pierini S, Davidson RN and Wikinson RJ (eds) T2 - Oxford Handbook of Tropical Medicine Y1 - 2004/// VL - 2nd edition. CY - Oxford N2 - - ER - TY - CHAP T1 - The utility of self-propagating hepatitis C virus RNAs in the stidy of molecular biology and of antiviral agents A1 - Karayiannis P ED - Hadziyannis S T2 - Hepatitis B and C 2004 Y1 - 2004/// SP - 43 EP - 55 N2 - - ER - TY - CHAP T1 - IL-4 Knock-out mice A1 - Kropf P A1 - Muller I ED - Fantuzzi G T2 - Cytokine Knockouts, 2nd Edition Y1 - 2003/// PB - Humana Press CY - Totowa, New Jersey, USA SP - 187 EP - 202 N2 - - ER - TY - CHAP T1 - HIV and its manipulation of chemokine receptors A1 - Shaunak S ED - Friedland JS & Lightstone LB T2 - Postgraduate Medical Sciences Series. Infection and Immunity Y1 - 2003/// PB - Martin Dunitz Publishers SP - 177 EP - 190 N2 - - ER - TY - CHAP T1 - Tuberculosis A1 - Friedland JS ED - Cohen J & Powderly W T2 - Infectious Diseases Y1 - 2003/// PB - Mosby CY - London, UK SP - 401 EP - 418 N2 - - ER - TY - CHAP T1 - Hepatitis C in HIV infection A1 - Main J ED - Bassendine M, Foster GR, Miles A T2 - The effective management of hepatitis C infection Y1 - 2003/// PB - Aesulapius Medical Press SN - 1 903044 33 2 N2 - - ER - TY - CHAP T1 - Hepatitis C virus: Protein translation, IRES function and DNA immunisation. A1 - Karayiannis P ED - S.J. Hadziyannis T2 - Hepatitis B and C Y1 - 2003/// PB - Paschalides CY - Athens SN - 960-399-139-2 SP - 277 EP - 288 N2 - - ER - TY - CHAP T1 - Genetics and dynamics of the immune response to HTLV-I A1 - Bangham CRM T2 - Gann Monograph on Cancer Research Y1 - 2003/// PB - Karger CY - Basel SP - 149 EP - 170 N2 - - ER - TY - CHAP T1 - Hepatitis A1 - Main J A1 - Thomas HC ED - Finch RG, Greenwood D, Norrby SR, Whitley RJ T2 - Antibiotic and Chemotherapy Y1 - 2003/// N2 - - ER - TY - CHAP T1 - The hapatitis B virus: Genotypes, genome organisation and replication A1 - Karayiannis P ED - S.J. Hadziyannis T2 - Hepatitis B and C Y1 - 2003/// PB - Paschalides CY - Athens SN - 960-399-139-2 SP - 20 EP - 34 N2 - - ER - TY - CHAP T1 - Pathophysiology of sepsis: Role of nitric oxide A1 - Evans TW A1 - Finney SJ ED - Vincent JL, Carlet J, Opal S T2 - The Sepsis Text Y1 - 2002/02// PB - Kluwer Academic Publishers SN - 079237620X SP - 211 EP - 230 N2 - - ER - TY - CHAP T1 - Cell adhesion molecules and leukocyte trafficking in sepsis A1 - Finney SJ A1 - Evans TW A1 - Burke-Gaffney A ED - Vincent JL T2 - Yearbook of Intensive Care and Emergency Medicine Y1 - 2002/// PB - Springer Verlag CY - Berlin SP - 23 EP - 38 N2 - - ER - TY - CHAP T1 - Metabolic disorders of the newborn A1 - Patay Z A1 - Robertson NJ A1 - Cox IJ ED - Rutherford MA T2 - Magnetic Resonance Imaging of the Neonatal Brain Y1 - 2002/// PB - WB Saunders SN - 07020 25348 SP - 315 EP - 348 N2 - - ER - TY - CHAP T1 - The epidemiology of lymphatic filariasis control A1 - Michael E T2 - The filariae Y1 - 2002/// SN - 1-4020-7038-1 SP - 59 EP - 74 N2 - - ER - TY - CHAP T1 - Magnetic resonance spectroscopy of the neonatal brain A1 - Robertson NJ A1 - Cox IJ ED - Rutherford MA T2 - Magnetic Resonance Imaging of the Neonatal Brain Y1 - 2002/// PB - WB Saunders SN - 07020 25348 SP - 295 EP - 314 N2 - - ER - TY - CHAP T1 - The Leishmaniasis Model A1 - Kropf P A1 - Brunson K A1 - Muller I ED - Kaufmann SHE & Kabelitz D T2 - Immunology of Infection, part of Methods in Microbiology Series, 2nd Edition Y1 - 2002/// PB - Academic Press Ltd CY - London SP - 463 EP - 492 N2 - - ER - TY - CHAP T1 - Immune intervention in tuberculosis A1 - Young DB A1 - Robertson BD T2 - Immunology of Infectious Diseases Y1 - 2002/// SN - 1-5558-1214-7 SP - 439 EP - 451 N2 - - ER - TY - CHAP T1 - Gene therapy for AIDS and other ifnectious diseases A1 - john Frater A1 - Sarah Fidler ED - Gavin Brooks T2 - Gene Therapy; The use of DNA as a drug Y1 - 2002/// VL - 1 M2 - 1 PB - Pharmaceutical press CY - London UK SN - 0853694559 SP - 189 EP - 215 N2 - - ER - TY - CHAP T1 - Pulmonary vascular dysfunction in sepsis A1 - Finney SJ A1 - Wort SJ A1 - Evans TW ED - Fink M, Evans T T2 - Mechanisms of organ dysfunction in critical illness Y1 - 2002/01// PB - Springer Verlag CY - Berlin SP - 205 EP - 221 N2 - - ER - TY - CHAP T1 - The molecular biology of hepatitis B virus A1 - Karayiannis P ED - N.Tassopoulos T2 - Hepatitis B: 21st Century Y1 - 2002/// SN - 9-6086-8980-5 SP - 41 EP - 54 N2 - - ER - TY - CHAP T1 - HIV infection in children A1 - Tudor-Williams G A1 - Southall D T2 - International child health care:a practical manual for hospitals worldwide Y1 - 2002/// SN - 0-7279-1476-6 SP - 446 EP - 450 N2 - - UR - NULL ER - TY - CHAP T1 - Epidemiology and control of nematode infection and disease in humans A1 - Bundy DAP A1 - Guyatt HL A1 - Michael E ED - Lee D; T2 - Biology of Nematodes Y1 - 2001/// PB - Harwood Academic Publishers SP - 595 EP - 613 N2 - - ER - TY - CHAP T1 - Epidemiology and control of human helminthiases A1 - Bundy DAP A1 - Michael E Y1 - 2001/// SN - 1-5780-8164-5 SP - 179 EP - 223 N2 - - ER - TY - CHAP T1 - A promoter probe plasmid based on green fluorescent protein: a strategy for studying meningococcal gene expression A1 - Webb SAR A1 - Langford PR A1 - Kroll JS Y1 - 2001/// M2 - 39 SN - 0-8960-3849-1 SP - 663 EP - 677 N2 - - ER - TY - CHAP T1 - Generation of human type 1- and type 2-polarized dendritic cells from peripheral blood. A1 - Kalinski, P A1 - Vieira, PL A1 - Schiutemaker, JHN A1 - Cai, Q A1 - Kapsenberg, ML ED - D. Korholz, Humana Press T2 - Methods in Molecular Medicine – Cytokines and Colony Stimulating Factors Y1 - 2001/// N2 - - ER - TY - CHAP T1 - Anemia A1 - Pasvol G A1 - Abdalla SH ED - Guerrant R, Walker DH and Weller PF T2 - Essentials of Tropical Infectious Disease Y1 - 2001/// PB - Churchill Livingstone International CY - New York SN - 0-4430-7909-9 SP - 93 EP - 98 N2 - - ER - TY - CHAP T1 - Parasite epidemiology A1 - Bundy DAP A1 - Michael E Y1 - 2001/// SN - 0-4719-7729-2 SP - 21 EP - 25 N2 - - ER - TY - CHAP T1 - Liver in vivo magnetic resonance spectroscopy of humans. A1 - Cox IJ ED - Young IR, Grant DM, Harris RK. T2 - Methods in Biomedical Magnetic Resonance Imaging and Spectroscopy Y1 - 2000/10// PB - John Wiley & Sons CY - Chichester SN - 0471-98804-9 N2 - - ER - TY - CHAP T1 - Gene Therapy for ifnectious diseases A1 - S Fidler ED - N R Lemoine T2 - Understanding Gene therapy Y1 - 1999/// VL - 1 M2 - 1 PB - BIOS Scientific publishers Ltd CY - Oxford UK SN - 1-85996-180-0 SP - 99 EP - 125 N2 - - ER - TY - CHAP T1 - Stabilization and transport of critically ill children A1 - Britto J A1 - Habibi P ED - David TJ T2 - Recent Advances in Paediatrics Y1 - 1999/// PB - Churchill Livingstone SP - 85 EP - 113 N2 - - ER - TY - CHAP T1 - Skin Manifestations of Meningogoccal Infection A1 - Heyderman R A1 - Habibi P ED - John Harper, Arnold Orange, Neil Prose T2 - Text Book of Paediatric Dermatology Y1 - 1999/// M2 - 1 PB - Blackwell Publishing Ltd CY - Oxford SP - 384 EP - 394 N2 - - ER - TY - CONF T1 - CD4 cell counts of 800 cells/mm(3) or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm(3) or greater A1 - Gras, L A1 - Kesselring, AM A1 - Griffin, JT A1 - van Sighem, AI A1 - Fraser, C A1 - Ghani, AC A1 - Miedema, F A1 - Reiss, P A1 - Lange, JMA A1 - de Wolf, F A1 - ATHENA A1 - Natl Observational Cohort Study U1 - 13th Conference on Retroviruses and Opportunistic Infections Y1 - 2007/06/01/ Y2 - // VL - 45 SP - 183 EP - 192 N2 - - ER - TY - CONF T1 - Central nervous system involvement in hepatitis C virus infection: what to measure? A1 - Forton, DM A1 - Allsop, J A1 - Thomas, HC A1 - Taylor-Robinson, SD U1 - 12th International Symposium on Hepatic Encephalopathy and Nitrogen Metabolism Y1 - 2006/// Y2 - // SP - 284 EP - 290 N2 - - ER - TY - CONF T1 - Enhanced viral bronchiolitis during adult re-infection of neonatally primed mice is not dependent on host genotype. A1 - Tregoning JS A1 - Yamaguchi Y A1 - Mihm DM A1 - Openshaw PJM U1 - Frontiers in neonatal and infant immunology AD - Madrid, Spain Y1 - 2005/// Y2 - 2005/// N2 - - ER - TY - CONF T1 - Surveying the AIDS related risk behaviours of university students (Italy) A1 - Carducci A A1 - Calamusa A A1 - Manfredi P A1 - Williams JR A1 - Romano F A1 - Verani M A1 - Privitera G U1 - XV International AIDS conference AD - Bangkok Y1 - 2004/// Y2 - 2004/// PB - Medimond Publishing Co CY - Bologna SP - 153 EP - 158 N2 - - ER - TY - CONF T1 - Enhanced viral bronchiolitis during adult re-infection of neonatally primed mice is not dependent on host genotype. A1 - Tregoning JS A1 - Yamaguchi Y A1 - Mihm DM A1 - Openshaw PJM U1 - BSI Annual Congress AD - Harrogate, UK. Y1 - 2004/// Y2 - 2004/// VL - 113 PB - Immunology N2 - - ER - TY - CONF T1 - Reduced pallidal magnetisation transfer ratios are associated with fatigue in pre-cirrhotic patients with primary biliary cirrhosis A1 - Forton, DM A1 - Prince, M A1 - Allsop, J A1 - Patel, N A1 - Goldblatt, J A1 - Thomas, HC A1 - Bassendine, M A1 - Jones, DEJ A1 - Taylor-Robinson, SD U1 - 11th International Symposium on Hepatic Encephalopathy and Nitrogen Metabolism Y1 - 2003/// Y2 - // SP - 173 EP - 174 N2 - - ER - TY - CONF T1 - Toll-like receptor 4 contributes to the efficient control of infection with the protozoan parasite Leishmania major A1 - Kropf P A1 - Freudenberg M A1 - Modolell M A1 - Price H A1 - Herath S A1 - Antoniazi S A1 - Galanos C A1 - Smith I A1 - Muller I U1 - International Cytokine Society AD - Dublin, Ireland Y1 - 2003/// Y2 - 2003/09/20/ N2 - - ER - TY - CONF T1 - Bone marrow macrophages from TLR4-deficient mice display an impaired capacity to control the replication of Leishmania major parasites A1 - Kropf P A1 - Freudenberg M A1 - Modolell M A1 - Price H A1 - Herath S A1 - Antoniazi S A1 - Galanos C A1 - Smith S A1 - Muller I U1 - 17th Meeting of the EMDS AD - Leicester, UK Y1 - 2003/// N2 - - ER - TY - CONF T1 - The effect of different Onchocerca-Simulium combinations on the outcome of ivermectin-based control infections A1 - Basáñez M-G A1 - Kennedy S A1 - Williams JR U1 - 52nd (Centenary) Meeting of the American Society of Tropical Medicine and Hygiene AD - Philadelphia, USA Y1 - 2003/// Y2 - 2003/// PB - The American Journal of Tropical Medicine and Hygiene SP - 275 EP - 276 N2 - - UR - http://www.ajtmh.org/ ER - TY - CONF T1 - The sensitivity of a mathematical model for the transmission dynamics and control of human onchocerciasis to vector-related parameters A1 - Kennedy S A1 - Basáñez M-G A1 - Williams JR U1 - 52nd (Centenary) Meeting of the American Society of Tropical Medicine and Hygiene AD - Philadelphia, USA Y1 - 2003/// Y2 - 2003/// PB - The American Journal of Tropical Medicine and Hygiene SP - 283 N2 - - UR - http://www.ajtmh.org/ ER - TY - CONF T1 - Tobacco chloroplasts as a platform for vaccine production. A1 - Maliga P A1 - Tregoning J A1 - Kuroda H A1 - Svab Z A1 - Lutz K A1 - Corneille S A1 - Nixon P A1 - Clare S A1 - Bowe F A1 - Fairweather N A1 - Dougan G U1 - Plant Biotechnology 2002 and Beyond AD - Orlando, Florida, USA Y1 - 2003/// Y2 - 2003/// PB - Kluwer Academic Publishers SP - 397 EP - 400 N2 - - ER - TY - CONF T1 - TGF-beta and mycobacterial infection A1 - Roe T A1 - Lukey P A1 - Muller I A1 - Young D U1 - 5th International Congress on the Pathogenesis of Mycobacterial infections AD - Stockholm, Sweden Y1 - 2002/// Y2 - 2002/06/27/ N2 - - ER - TY - CONF T1 - Cross-talk between CD8* and cells in experimental cutaneous leishmaniasis A1 - Herath S A1 - Kropf P A1 - Muller I U1 - Immunoparasitology Meeting AD - Woods Hole, MA, USA Y1 - 2002/// Y2 - 2002/04/26/ N2 - - ER - TY - CONF T1 - Ageing alters the course of nonhealing Leishmania major infections in IL-4 deficient BALB/c mice A1 - Muller I A1 - Herath S A1 - Kropf P U1 - Immunoparasitology Meeting AD - Woods Hole, MA, USA Y1 - 2002/// Y2 - 2002/04/26/ N2 - - ER - TY - CONF T1 - Signalling through the T1/ST2 molecule is not necessary for Th2 differentiation, but is important for the regulation of type 1 responses in nonhealing Lesmania major infection A1 - Kropf P A1 - Herath S A1 - Klemenz R A1 - Muller I U1 - British Society for Parasitology, Trypanosomiasis and Leishmaniasis seminar AD - Edinburgh, UK Y1 - 2002/// Y2 - 2002/09/08/ N2 - - ER - TY - CONF T1 - The effects of immunotherapy with cytokines and/or vaccines in HAART treated patients A1 - Gotch, F A1 - Hardy, G A1 - Imami, N A1 - Sullivan, A A1 - Nelson, M A1 - Burton, C A1 - Pido-Lopez, J A1 - Pires, A A1 - Moss, R U1 - 14th International AIDS Conference Y1 - 2002/// Y2 - // SP - 279 EP - 284 N2 - - ER - TY - CONF T1 - Organ-specific distribution and cytokine production of CD4* T 1/ST2+ T cells in Leishmania major infected mice A1 - Kropf P A1 - Herath S A1 - Bickle Q A1 - Tewari R A1 - Syed N A1 - Klemenz R A1 - Muller I U1 - Immunoparasitology Meeting AD - Woods Hole, MA, USA Y1 - 2002/// Y2 - 2002/04/26/ N2 - - ER - TY - CONF T1 - A novel mucosal vaccine based on tetanus toxin fragment C expressed in tobacco chloroplasts. A1 - Tregoning JS A1 - Nixon P A1 - Kuroda H A1 - Svab Z A1 - Clare S A1 - Bowe F A1 - Fairweather N A1 - Ytterberg J A1 - van Wijk K A1 - Dougan G A1 - Maliga P U1 - 11th International Congress of Mucosal Immunology AD - Orlando, Florida Y1 - 2002/// Y2 - 2002/// PB - Curette, Tigon N2 - - ER - TY - CONF T1 - The use of transmission dynamics models of infectious diseases to improve HIV prevention trials and public health decisions A1 - Desai K A1 - Boily MC A1 - Williams JR A1 - Garnett G A1 - Masse BR U1 - International Society for Clinical Biostatisitics/Society for Clinical Trials AD - London Y1 - 2001/// Y2 - 2001/06// PB - Elsevier Science Inc. CY - New York N2 - - ER - TY - CONF T1 - Co-convenor Joint meeting of RSTMH/Wellcome Trust/UK MRC/DFID A1 - Moore DA U1 - Working in the tropics - how to do it Y1 - 2000/// Y2 - 2000/05/09/ N2 - - ER - TY - CONF T1 - Vaccinia virus entry and exit A1 - Smith, GL A1 - Vanderplasschen, A U1 - 2nd ICGEB-UCI Virology Symposium Y1 - 2000/// Y2 - // SP - 25 EP - 42 N2 - - ER - TY - CONF T1 - Targeting HIV-1 replication in gut-associated lymphoid tissue A1 - Shaunak, S A1 - Waterworth, C A1 - Lynn, WA U1 - 4th European Conference on Experimental AIDS Research Y1 - 1999/// Y2 - // SP - 163 EP - 166 N2 - - ER - TY - CONF T1 - Macrophage cell cultures continue to produce infectious HIV-1 long after acute cytopathic infection has subsided A1 - Teo, I A1 - Choi, JW A1 - Shaunak, S U1 - 4th European Conference on Experimental AIDS Research Y1 - 1999/// Y2 - // SP - 177 EP - 181 N2 - - ER - TY - CONF T1 - Tissue macrophages release MIP-1 alpha and MIP-1 beta but not TNF-alpha, IL-4, IL-6 or IFN-gamma after the internalisation of dextrin 2-sulphate A1 - Thornton, M A1 - Krausz, T A1 - Shaunak, S U1 - 4th European Conference on Experimental AIDS Research Y1 - 1999/// Y2 - // SP - 183 EP - 188 N2 - - ER - TY - CONF T1 - Development of a CTL inducing vaccine against Plasmodium falciparum using a combination of delivery systems A1 - Gilbert, SC A1 - Schneider, J A1 - Hannan, CM A1 - Plebanski, M A1 - Neuman, V A1 - Degano, P A1 - Blanchard, TJ A1 - Becker, M A1 - Smith, GL A1 - Hill, AVS U1 - 9th International Congress of Parasitology (ICOPA IX) Y1 - 1998/// Y2 - // SP - 439 EP - 444 N2 - - ER - TY - JFULL T1 - Replicative Competence of the T131I, K141E, and G145R Surface Variants of Hepatitis B Virus. A1 - Jammeh, S A1 - Thomas, HC A1 - Karayiannis, P J1 - J Infect Dis Y1 - 2007/10/01/ VL - 196 SN - 0022-1899 SP - 1010 EP - 1013 N2 - Variants of hepatitis B surface antigen have been described in different clinical settings, but their replicative capacity in vitro has remained unexplored. Point mutations leading to sT131I, sK141E, and sG145R amino-acid substitutions were engineered by site-directed mutagenesis into an infectious plasmid clone of the virus. The mutated constructs were transfected into Huh7 cells, and their replication capacity was documented by LightCycler (Roche Diagnostics) measurements of virion-associated hepatitis B virus (HBV) DNA, intracellular relaxed circular double-stranded DNA, and pregenomic RNA. The sT131I and sG145R variants replicated with efficiency equal to that of the wild type, whereas the sK141E variant was replication impaired. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17763322&query_hl=1 ER - TY - JFULL T1 - Eroding the resistance of Duffy negativity to invasion by Plasmodium vivax? A1 - Pasvol, G J1 - Trans R Soc Trop Med Hyg Y1 - 2007/10// VL - 101 SN - 0035-9203 SP - 953 EP - 954 N2 - Individuals possessing red cells negative for the Duffy blood group antigen are said to possess absolute resistance to infection by the malarial parasite Plasmodium vivax. Now in this issue of Transactions, initial evidence is presented from the Brazilian Amazon to suggest that P. vivax is being transmitted amongst Duffy-negative individuals. This supports data from East Africa where the same phenomenon has been observed. Thus the emerging picture is that P. vivax in both South America and in Africa is now evolving pathways other than Duffy to enter red cells. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17658565&query_hl=1 ER - TY - JFULL T1 - Structure of CrmE, a Virus-encoded Tumour Necrosis Factor Receptor. A1 - Graham, SC A1 - Bahar, MW A1 - Abrescia, NG A1 - Smith, GL A1 - Stuart, DI A1 - Grimes, JM J1 - J Mol Biol Y1 - 2007/09/21/ VL - 372 SN - 0022-2836 SP - 660 EP - 671 N2 - Vaccinia virus (VACV), the smallpox vaccine, encodes many proteins that subvert the host immune response. One of these, cytokine response modifier E (CrmE), is secreted by infected cells and protects these cells from apoptotic challenge by tumour necrosis factor alpha (TNFalpha). We have expressed recombinant CrmE from VACV strain Lister in Escherichia coli, shown that the purified protein is monomeric in solution and competent to bind TNFalpha, and solved the structure to 2.0 A resolution. This is the first structure of a virus-encoded tumour necrosis factor receptor (TNFR). CrmE shares significant sequence similarity with mammalian type 2 TNF receptors (TNFSFR1B, p75; TNFR type 2). The structure confirms that CrmE adopts the canonical TNFR fold but only one of the two "ligand-binding" loops of TNFRSF1A is conserved in CrmE, suggesting a mechanism for the higher affinity of poxvirus TNFRs for TNFalpha over lymphotoxin-alpha. The roles of dimerisation and pre-ligand-assembly domains (PLADs) in poxvirus and mammalian TNFR activity are discussed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17681535&query_hl=1 ER - TY - JFULL T1 - Structural insights into the transcriptional and translational roles of Ebp1. A1 - Monie, TP A1 - Perrin, AJ A1 - Birtley, JR A1 - Sweeney, TR A1 - Karakasiliotis, I A1 - Chaudhry, Y A1 - Roberts, LO A1 - Matthews, S A1 - Goodfellow, IG A1 - Curry, S J1 - EMBO J Y1 - 2007/09/05/ VL - 26 SN - 0261-4189 SP - 3936 EP - 3944 N2 - The ErbB3-binding protein 1 (Ebp1) is an important regulator of transcription, affecting eukaryotic cell growth, proliferation, differentiation and survival. Ebp1 can also affect translation and cooperates with the polypyrimidine tract-binding protein (PTB) to stimulate the activity of the internal ribosome entry site (IRES) of foot-and-mouth disease virus (FMDV). We report here the crystal structure of murine Ebp1 (p48 isoform), providing the first glimpse of the architecture of this versatile regulator. The structure reveals a core domain that is homologous to methionine aminopeptidases, coupled to a C-terminal extension that contains important motifs for binding proteins and RNA. It sheds new light on the conformational differences between the p42 and p48 isoforms of Ebp1, the disposition of the key protein-interacting motif ((354)LKALL(358)) and the RNA-binding activity of Ebp1. We show that the primary RNA-binding site is formed by a Lys-rich motif in the C terminus and mediates the interaction with the FMDV IRES. We also demonstrate a specific functional requirement for Ebp1 in FMDV IRES-directed translation that is independent of a direct interaction with PTB. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17690690&query_hl=1 ER - TY - JFULL T1 - Alternative Neisseria spp. type IV pilin glycosylation with a glyceramido acetamido trideoxyhexose residue. A1 - Chamot-Rooke, J A1 - Rousseau, B A1 - Lanternier, F A1 - Mikaty, G A1 - Mairey, E A1 - Malosse, C A1 - Bouchoux, G A1 - Pelicic, V A1 - Camoin, L A1 - Nassif, X A1 - Duménil, G J1 - Proc Natl Acad Sci U S A Y1 - 2007/09/05/ SN - 0027-8424 N2 - The importance of protein glycosylation in the interaction of pathogenic bacteria with their host is becoming increasingly clear. Neisseria meningitidis, the etiological agent of cerebrospinal meningitis, crosses cellular barriers after adhering to host cells through type IV pili. Pilin glycosylation genes (pgl) are responsible for the glycosylation of PilE, the major subunit of type IV pili, with the 2,4-diacetamido-2,4,6-trideoxyhexose residue. Nearly half of the clinical isolates, however, display an insertion in the pglBCD operon, which is anticipated to lead to a different, unidentified glycosylation. Here the structure of pilin glycosylation was determined in such a strain by "top-down" MS approaches. MALDI-TOF, nanoelectrospray ionization Fourier transform ion cyclotron resonance, and nanoelectrospray ionization quadrupole TOF MS analysis of purified pili preparations originating from N. meningitidis strains, either wild type or deficient for pilin glycosylation, revealed a glycan mass inconsistent with 2,4-diacetamido-2,4,6-trideoxyhexose or any sugar in the databases. This unusual modification was determined by in-source dissociation of the sugar from the protein followed by tandem MS analysis with collision-induced fragmentation to be a hexose modified with a glyceramido and an acetamido group. We further show genetically that the nature of the sugar present on the pilin is determined by the carboxyl-terminal region of the pglB gene modified by the insertion in the pglBCD locus. We thus report a previously undiscovered monosaccharide involved in posttranslational modification of type IV pilin subunits by a MS-based approach and determine the molecular basis of its biosynthesis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17804791&query_hl=1 ER - TY - JFULL T1 - Recent advances in the expression, evolution, and dynamics of prokaryotic genomes. A1 - Arraiano, CM A1 - Bamford, J A1 - Brüssow, H A1 - Carpousis, AJ A1 - Pelicic, V A1 - Pflüger, K A1 - Polard, P A1 - Vogel, J J1 - J Bacteriol Y1 - 2007/09// VL - 189 SN - 0021-9193 SP - 6093 EP - 6100 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17601780&query_hl=1 ER - TY - JFULL T1 - Effect of host lactate on gonococci and meningococci: new concepts on the role of metabolites in pathogenicity. A1 - Smith, H A1 - Tang, CM A1 - Exley, RM J1 - Infect Immun Y1 - 2007/09// VL - 75 SN - 0019-9567 SP - 4190 EP - 4198 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17562766&query_hl=1 ER - TY - JFULL T1 - Sexual Dimorphism in Superantigen Shock Involves Elevated TNF-{alpha} and TNF-{alpha} induced Hepatic Apoptosis. A1 - Faulkner, L A1 - Altmann, DM A1 - Ellmerich, S A1 - Huhtaniemi, I A1 - Stamp, G A1 - Sriskandan, S J1 - Am J Respir Crit Care Med Y1 - 2007/09/01/ VL - 176 SN - 1073-449X SP - 473 EP - 482 N2 - Rationale: There is conflicting evidence regarding sex differences in the outcome from severe sepsis and toxic shock. Superantigen-mediated toxic shock affects a higher proportion of female patients. Objectives: The objective of the current study was to investigate sexual dimorphism in superantigen-associated sepsis and in superantigen-mediated shock and to identify the key mechanisms responsible for this sex difference. Methods: We measured mortality and serum cytokines after induction of sepsis with isogenic superantigen-positive and superantigen-negative Streptococcus pyogenes in HLA class II transgenics. During superantigen-mediated toxic shock, we measured mortality, T-cell responses, systemic tumor necrosis factor (TNF)-alpha and TNF receptors, TNF-alpha-induced hepatocyte apoptosis, and conditioning of these responses by tamoxifen treatment. Measurements and Main Results: In both superantigen-associated sepsis and in superantigen-mediated shock, serum TNF-alpha was increased in females compared with males. This was not attributable to a detectable difference in splenic TNF-alpha transcription; rather, serum soluble TNF receptors were higher in males. Pretreatment of females with the estrogen receptor modulator tamoxifen increased serum soluble TNF receptors, reduced the early serum TNF-alpha response, and improved mortality in females challenged with staphylococcal enterotoxin B. Lethal superantigen shock was characterized by hepatocyte apoptosis, and was reproduced by injection of TNF-alpha. Females had enhanced susceptibility to TNF-alpha-mediated lethality. TNF-alpha-induced hepatocyte apoptosis was greater in females, and was reduced by tamoxifen pretreatment. Conclusions: Sexual dimorphism in experimental superantigen toxic shock results from increased systemic TNF-alpha in females, coupled with an increased susceptibility to TNF-alpha-induced hepatocyte apoptosis. Both processes are abrogated by estrogen receptor modulators. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17575097&query_hl=1 ER - TY - JFULL T1 - Synergistic inhibition of HIV-1 infection by combinations of soluble polyanions with other potential microbicides. A1 - Gantlett, KE A1 - Weber, JN A1 - Sattentau, QJ J1 - Antiviral Res Y1 - 2007/09// VL - 75 SN - 0166-3542 SP - 188 EP - 197 N2 - Several polyanionic compounds with potential for use as topically applied microbicides to prevent HIV-1 sexual transmission, such as PRO 2000, are currently in phase III clinical efficacy trials. Microbicidal formulations may well comprise combinations of inhibitors to increase potency, reduce dose and minimize problems of HIV-1 resistance. We have therefore evaluated in vitro, the anti-HIV-1 activity of two leading polyanionic microbicides combined with other antiretroviral agents with microbicidal potential. Dextran sulfate (DS) and PRO 2000 were combined with the neutralizing antibody IgG1b12, the peptide-based fusion inhibitor T20, the CCR5 antagonist TAK779 and the cyanobacterial protein cyanovirin-N. Anti-HIV-1 activity was assessed in a single cycle replication assay using pseudoviruses carrying a luciferase reporter gene and the envelope glycoproteins from HIV-1 isolates JR-FL (R5) and HxB2 (X4), against both immortalized and primary CD4+ cell targets. The data were analyzed for synergy using Calcusyntrade mark software. Results indicate that PRO 2000 and DS can act synergistically with most inhibitors tested, although the degree of synergy depends on inhibitor concentration and combination. These data provide a rational basis for testing of microbicide combinations in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17408760&query_hl=1 ER - TY - JFULL T1 - Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1-associated myelopathy/tropical spastic paraparesis patients. A1 - Lezin, A A1 - Gillet, N A1 - Olindo, S A1 - Signate, A A1 - Grandvaux, N A1 - Verlaeten, O A1 - Belrose, G A1 - Carvalho Bittencourt, M A1 - Hiscott, J A1 - Asquith, B A1 - Burny, A A1 - Smadja, D A1 - Cesaire, R A1 - Willems, L J1 - Blood Y1 - 2007/08/23/ SN - 0006-4971 N2 - Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the Human T-lymphotropic virus type 1 which is responsible for HTLV-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). A major determinant of disease progression is increased peripheral blood proviral load (PVL), possibly via the accumulation of infected cells in the central nervous system (CNS) creating a damaging inflammatory response. Current therapeutic approaches which focus on reducing either cell proliferation, viral replication or tissue invasion, are still unsatisfactory. Contrasting with these inhibitory strategies, we evaluated the efficacy of a novel approach aimed, paradoxically, at activating viral gene expression in order to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor which has been used for decades as a chronic, safe treatment for epileptic disorders. Based on in vitro and in vivo data, we provide evidence that transient activation of the latent viral reservoir causes its collapse, a process that may alleviate the condition of HAM/TSP. This represents the first such approach to treating HAM/TSP, using gene activation therapy to tilt the host-pathogen balance in favor of an existing antiviral response. This trial is registered at http://clinicaltrials.gov/ as #NCT00519181. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17717136&query_hl=1 ER - TY - JFULL T1 - Increased rates of preterm delivery are associated with the initiation of highly active antiretrovial therapy during pregnancy: a single-center cohort study. A1 - Martin, F A1 - Taylor, GP J1 - J Infect Dis Y1 - 2007/08/15/ VL - 196 SN - 0022-1899 SP - 558 EP - 561 N2 - It remains controversial whether in human immunodeficiency virus (HIV)-positive pregnant women an increased rate of preterm delivery is associated with highly active antiretroviral therapy (HAART). Since 1995 the management and outcome of all HIV-infected pregnant women delivering at St. Mary's Hospital London have been prospectively documented. The prevalence of preterm delivery and the correlation between gestational age and type of antiretroviral therapy were sought: preterm delivery occurred in 14.2% of the 211 deliveries. Initiation of HAART during pregnancy was associated with an increased risk of preterm delivery. This was independent of maternal health and class of antiretroviral therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17624841&query_hl=1 ER - TY - JFULL T1 - PalC, One of Two Bro1 Domain Proteins in the Fungal pH Signalling Pathway, Localizes to Cortical Structures and Binds Vps32. A1 - Galindo, A A1 - Hervás-Aguilar, A A1 - Rodríguez-Galán, O A1 - Vincent, O A1 - Arst, HN A1 - Tilburn, J A1 - Peñalva, MA J1 - Traffic Y1 - 2007/08/13/ SN - 1398-9219 N2 - PalC, distantly related to Saccharomyces cerevisiae peripheral endosomal sorting complexes required for transport III (ESCRT-III) component Bro1p and one of six Aspergillus nidulans pH signalling proteins, contains a Bro1 domain. Green fluorescent protein (GFP)-tagged PalC is recruited to plasma membrane-associated punctate structures upon alkalinization, when pH signalling is active. PalC recruitment to these structures is dependent on the seven transmembrane domain (7-TMD) receptor and likely pH sensor PalH. PalC is a two-hybrid interactor of the ESCRT-III Vps20/Vps32 subcomplex and binds Vps32 directly. This binding is largely impaired by Pro439Phe, Arg442Ala and Arg442His substitutions in a conserved region mediating interaction of Bro1p with Vps32p, but these substitutions do not prevent cortical punctate localization, indicating Vps32 independence. In contrast, Arg442Delta impairs Vps32 binding and prevents PalC-GFP recruitment to cortical structures. pH signalling involves a plasma membrane complex including the 7-TMD receptor PalH and the arrestin-like PalF and an endosomal membrane complex involving the PalB protease, the transcription factor PacC and the Vps32 binding, Bro1-domain-containing protein PalA. PalC, which localizes to cortical structures and can additionally bind a component of ESCRT-III, has the features required to bridge these two entities. A likely S. cerevisiae orthologue of PalC has been identified, providing the basis for a unifying hypothesis of gene regulation by ambient pH in ascomycetes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17696968&query_hl=1 ER - TY - JFULL T1 - Increased detection of Clostridium difficile during a norovirus outbreak. A1 - Barrett, SP A1 - Holmes, AH A1 - Newsholme, WA A1 - Richards, M J1 - J Hosp Infect Y1 - 2007/08// VL - 66 SN - 0195-6701 SP - 394 EP - 395 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17669553&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 - Streptococcus pyogenes under pressure. A1 - Turner, C A1 - Sriskandan, S J1 - Nat Med Y1 - 2007/08// VL - 13 SN - 1078-8956 SP - 909 EP - 910 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17680004&query_hl=1 ER - TY - JFULL T1 - Astrocyte-leucocyte interactions and the mechanisms regulating matrix degradation in CNS tuberculosis. A1 - Green, JA A1 - Friedland, JS J1 - Biochem Soc Trans Y1 - 2007/08// VL - 35 SN - 0300-5127 SP - 686 EP - 688 N2 - The CNS (central nervous system) has a unique pattern of immune response to infection. TB (tuberculosis) of the CNS is devastating with widespread tissue destruction. In TB, astrocyte-leucocyte interactions are key in regulating MMP (matrix metalloproteinase) activity and are regulated by complex signalling pathways. A synergistic interaction between interferon gamma and monocyte-derived mediators drives high-level astrocyte MMP-9 secretion; this and other networking effects are inhibited by steroids. Better understanding of regulatory mechanisms may identify potential switch points that could be future therapeutic targets. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17635122&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 - Recovery of genetically defined murine norovirus in tissue culture by using a fowlpox virus expressing T7 RNA polymerase. A1 - Chaudhry, Y A1 - Skinner, MA A1 - Goodfellow, IG J1 - J Gen Virol Y1 - 2007/08// VL - 88 SN - 0022-1317 SP - 2091 EP - 2100 N2 - Despite the significant disease burden caused by human norovirus infection, an efficient tissue-culture system for these viruses remains elusive. Murine norovirus (MNV) is an ideal surrogate for the study of norovirus biology, as the virus replicates efficiently in tissue culture and a low-cost animal model is readily available. In this report, a reverse-genetics system for MNV is described, using a fowlpox virus (FWPV) recombinant expressing T7 RNA polymerase to recover genetically defined MNV in tissue culture for the first time. These studies demonstrated that approaches that have proved successful for other members of the family Caliciviridae failed to lead to recovery of MNV. This was due to our observation that vaccinia virus infection had a negative effect on MNV replication. In contrast, FWPV infection had no deleterious effect and allowed the recovery of infectious MNV from cells previously transfected with MNV cDNA constructs. These studies also indicated that the nature of the 3'-terminal nucleotide is critical for efficient virus recovery and that inclusion of a hepatitis delta virus ribozyme at the 3' end can increase the efficiency with which virus is recovered. This system now allows the recovery of genetically defined noroviruses and will facilitate the analysis of the effects of genetic variation on norovirus pathogenesis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17622609&query_hl=1 ER - TY - JFULL T1 - Long-term follow-up of the hepatitis C HENCORE cohort: response to therapy and occurrence of liver-related complications. A1 - Pradat, P A1 - Tillmann, HL A1 - Sauleda, S A1 - Braconier, JH A1 - Saracco, G A1 - Thursz, M A1 - Goldin, R A1 - Winkler, R A1 - Alberti, A A1 - Esteban, JI A1 - Hadziyannis, S A1 - Rizzetto, M A1 - Thomas, H A1 - Manns, MP A1 - Trepo, C A1 - HENCORE Group J1 - J Viral Hepat Y1 - 2007/08// VL - 14 SN - 1352-0504 SP - 556 EP - 563 N2 - The aims of the study were to verify the long-term effect of time on viral clearance in hepatitis C virus (HCV) patients and to find out factors possibly associated with disease progression. A total of 1641 patients recruited from eight European centres in 1996-1997 were re-analysed 5-7 years after inclusion. The occurrence of decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation was analysed in relation to different host and viral factors. Ninety-three per cent of the HCV patients who had cleared the virus (spontaneously or after antiviral therapy) remained HCV-RNA-negative during follow up and may be considered as 'cured'. Among patients who were sustained responders at inclusion, 2.3% developed liver complications during follow up, and 31% of non-responders did. Advanced age at infection and presence of the human leucocyte antigen (HLA) DRB1*1201-3 allele were possibly associated with a higher rate of progression to decompensated cirrhosis or HCC. Decompensated cirrhosis might be further associated with male gender, non-response to previous therapy, and lack of HLA DRB1*1301 allele, whereas HCC seems to be associated with the presence of the HLA DQ02 allele. Long-term follow up of HCV patients indicates that virological response persists over time and is associated with a very low incidence of liver complications. Advanced age at inclusion, advanced age at infection, viral genotype 1, non-response to previous therapy and possibly some specific HLA alleles are factors independently associated with a faster rate of progression towards liver complications. The large proportion of patients lost to follow up stresses the need for a strengthened and optimized management of HCV patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17650289&query_hl=1 ER - TY - JFULL T1 - Falling into TRAPS - receptor misfolding in the TNF receptor 1-associated periodic fever syndrome. A1 - Kimberley, FC A1 - Lobito, AA A1 - Siegel, RM A1 - Screaton, GR J1 - Arthritis Res Ther Y1 - 2007/07/23/ VL - 9 SN - 1478-6362 SP - 217 EP - 217 N2 - ABSTRACT: TNF receptor-associated periodic syndrome (TRAPS) is a dominantly inherited disease caused by missense mutations in the TNF receptor 1 (TNFR1) gene. Patients suffer from periodic bouts of severe abdominal pain, localised inflammation, migratory rashes, and fever. More than 40 individual mutations have been identified, all of which occur in the extracellular domain of TNFR1. In the present review we discuss new findings describing aberrant trafficking and function of TNFR1 harbouring TRAPS mutations, challenging the hypothesis that TRAPS pathology is driven by defective receptor shedding, and we suggest that TNFR1 might acquire novel functions in the endoplasmic reticulum, distinct from its role as a cell surface receptor. We also describe the clinical manifestations of TRAPS, current treatment regimens, and the widening array of patient mutations. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17666110&query_hl=1 ER - TY - JFULL T1 - Two Epstein-Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt's lymphoma. A1 - Anderton, E A1 - Yee, J A1 - Smith, P A1 - Crook, T A1 - White, RE A1 - Allday, MJ J1 - Oncogene Y1 - 2007/07/23/ SN - 0950-9232 N2 - Epstein-Barr virus (EBV) contributes to the development of several human cancers including the endemic form of Burkitt's lymphoma (BL). In culture, EBV induces the continuous proliferation of primary B cells as lymphoblastoid cell lines (LCLs) and if EBV-negative BL-derived cells are infected with EBV, latency-associated viral factors confer resistance to various inducers of apoptosis. Nuclear proteins EBNA3A and EBNA3C (but not EBNA3B) are necessary to establish LCLs and their expression may be involved in the resistance of BL cells to cytotoxic agents. We have therefore created recombinant EBVs from which each of the EBNA3 genes has been independently deleted, and revertant viruses in which the genes have been re-introduced into the viral genome. Infection of EBV-negative BL cells with this panel of EBVs and challenge with various cytotoxic drugs showed that EBNA3A and EBNA3C cooperate as the main determinants of both drug resistance and the downregulation of the proapoptotic Bcl-2-family member Bcl-2-interacting mediator of cell death (Bim). The regulation of Bim is predominantly at the level of RNA, with little evidence of post-translational Bim stabilization by EBV. In the absence of Bim, EBNA3A and EBNA3C appear to provide no survival advantage. The level of Bim is a critical regulator of B cell survival and reduced expression is a major determinant of lymphoproliferative disease in mice and humans; moreover, Bim is uniquely important in the pathogenesis of BL. By targeting this tumour-suppressor for repression, EBV significantly increases the likelihood of B lymphomagenesis in general, and BL in particular. Our results may also explain the selection pressure that gives rise to a subset of BL that retain expression of the EBNA3 proteins.Oncogene advance online publication, 23 July 2007; doi:10.1038/sj.onc.1210668. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17653091&query_hl=1 ER - TY - JFULL T1 - CTLs target Th cells that acquire bystander MHC class I-peptide complex from APCs. A1 - Cox, JH A1 - McMichael, AJ A1 - Screaton, GR A1 - Xu, XN J1 - J Immunol Y1 - 2007/07/15/ VL - 179 SN - 0022-1767 SP - 830 EP - 836 N2 - CTLs can acquire MHC class I-peptide complexes from their target cells, whereas CD4(+) T cells obtain MHC class II-peptide complexes from APCs in a TCR-specific manner. As a consequence, Ag-specific CTL can kill each other (fratricide) or CD4(+) T cells become APCs themselves. The purpose of the acquisition is not fully understood and may be either inhibition or prolongation of an immunological response. In this study, we demonstrate that human CD4(+) Th cells are able to capture membrane fragments from APC during the process of immunological synapse formation. The fragments contain not only MHC class II-peptide complexes but also MHC class I-peptide complexes, rendering these cells susceptible to CTL killing in an Ag-specific manner. The control of CD4(+) Th cells by Ag-specific CTL, therefore, maybe another mechanism to regulate CD4(+) T cell expansion in normal immune responses or cause immunopathology during the course of viral infections such as HIV. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17617573&query_hl=1 ER - TY - JFULL T1 - A single dose of vitamin D enhances immunity to mycobacteria. A1 - Martineau, AR A1 - Wilkinson, RJ A1 - Wilkinson, KA A1 - Newton, SM A1 - Kampmann, B A1 - Hall, BM A1 - Packe, GE A1 - Davidson, RN A1 - Eldridge, SM A1 - Maunsell, ZJ A1 - Rainbow, SJ A1 - Berry, JL A1 - Griffiths, CJ J1 - Am J Respir Crit Care Med Y1 - 2007/07/15/ VL - 176 SN - 1073-449X SP - 208 EP - 213 N2 - RATIONALE: Vitamin D was used to treat tuberculosis (TB) in the preantibiotic era. Prospective studies to evaluate the effect of vitamin D supplementation on antimycobacterial immunity have not previously been performed. OBJECTIVES: To determine the effect of vitamin D supplementation on antimycobacterial immunity and vitamin D status. METHODS: A double-blind randomized controlled trial was conducted in 192 healthy adult TB contacts in London, United Kingdom. Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was assessed with a functional whole blood assay (BCG-lux assay), which measures the ability of whole blood to restrict luminescence, and thus growth, of recombinant reporter mycobacteria in vitro; the readout is expressed as a luminescence ratio (luminescence postinfection/baseline luminescence). IFN-gamma responses to the Mycobacterium tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay. Vitamin D supplementation significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro compared with placebo (mean luminescence ratio at follow-up, 0.57, vs. 0.71, respectively; 95% confidence interval for difference, 0.01-0.25; p=0.03) but did not affect antigen-stimulated IFN-gamma secretion. CONCLUSIONS: A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses. Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent TB infection. Clinical trial registered with www.clinicaltrials.gov (NCT 00157066). L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17463418&query_hl=1 ER - TY - JFULL T1 - LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. A1 - Shun, MC A1 - Raghavendra, NK A1 - Vandegraaff, N A1 - Daigle, JE A1 - Hughes, S A1 - Kellam, P A1 - Cherepanov, P A1 - Engelman, A J1 - Genes Dev Y1 - 2007/07/15/ VL - 21 SN - 0890-9369 SP - 1767 EP - 1778 N2 - LEDGF/p75 directly interacts with lentiviral integrase proteins and can modulate their enzymatic activities and chromosomal association. A novel genetic knockout model was established that allowed us for the first time to analyze HIV-1 integration in the absence of LEDGF/p75 protein. Supporting a crucial role for the cofactor in viral replication, HIV-1 vector integration and reporter gene expression were significantly reduced in LEDGF-null cells. Yet, integrase processed the viral cDNA termini normally and maintained its local target DNA sequence preference during integration. Preintegration complexes extracted from knockout cells moreover supported normal levels of DNA strand transfer activity in vitro. In contrast, HIV-1 lost its strong bias toward integrating into transcription units, displaying instead increased affinity for promoter regions and CpG islands. Our results reveal LEDGF/p75 as a critical targeting factor, commandeering lentiviruses from promoter- and/or CpG island-proximal pathways that are favored by other members of Retroviridae. Akin to yeast retrotransposons, disrupting the lentiviral targeting mechanism significantly perturbs overall integration. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17639082&query_hl=1 ER - TY - JFULL T1 - Increased duration of viral suppression is associated with lower viral rebound rates in patients with previous treatment failures. A1 - Benzie, AA A1 - Bansi, LK A1 - Sabin, CA A1 - Portsmouth, S A1 - Hill, T A1 - Johnson, M A1 - Gilson, R A1 - Easterbrook, P A1 - Gazzard, B A1 - Fisher, M A1 - Orkin, C A1 - Dunn, D A1 - Delpech, V A1 - Taylor, GP A1 - Walsh, JC A1 - Phillips, AN A1 - United Kingdom Collaborative HIV Cohort (CHIC) Study Group J1 - AIDS Y1 - 2007/07/11/ VL - 21 SN - 0269-9370 SP - 1423 EP - 1430 N2 - OBJECTIVE: We investigated whether the rate of viral rebound decreases with increasing duration of viral suppression and, if so, whether rebound rates in patients previously failing antiretroviral regimens ultimately decline to levels as low as those seen in patients who have never experienced virological failure. METHODS: All patients from the UK CHIC Study (n = 21 256) who achieved a viral load (VL) of < or = 50 copies/ml while receiving HAART were followed until viral rebound (two consecutive VL > 400 copies/ml). Patients could re-enter the analysis if they experienced a subsequent VL < or = 50 copies/ml. Rebound rates were calculated according to the number of regimens previously failed and duration of viral suppression. RESULTS: Of 12 648 patients on HAART 10 237 (80.9%) achieved a VL < or = 50 copies/ml. During 26 494 person-years (PY) of follow-up, 1853 (18.1%) patients experienced at least one viral rebound 'event', with 2460 events in total [rebound rate, 9.3 (range, 8.9-9.7)/100 PY). Within the first year of viral suppression, the rate of viral rebound was 8.3 (7.5-9.1)/100 PY in patients who had not previously failed treatment, increasing to 32.7 (27.6-37.8)/100 PY in patients who had failed more than four regimens. Irrespective of previous treatment failure, rebound rates in those who remained suppressed for > 4 years were similar to those in patients who had at no time experienced treatment failure. CONCLUSION: After around 4 years of viral suppression rebound rates in individuals with multiple prior treatment failures approach those of individuals with no prior treatment failure. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17589188&query_hl=1 ER - TY - JFULL T1 - Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance. A1 - Boffito, M A1 - Winston, A A1 - Jackson, A A1 - Fletcher, C A1 - Pozniak, A A1 - Nelson, M A1 - Moyle, G A1 - Tolowinska, I A1 - Hoetelmans, R A1 - Miralles, D A1 - Gazzard, B J1 - AIDS Y1 - 2007/07/11/ VL - 21 SN - 0269-9370 SP - 1449 EP - 1455 N2 - BACKGROUND: Cumulative antiretroviral exposure can result in multiclass HIV drug resistance. Experimental antiretroviral agents offer limited therapeutic benefit as resistance quickly develops after their introduction as a sole new agent. OBJECTIVE: To assess the pharmacokinetic profile, safety and virological response of two novel investigational antiretroviral agents when used in combination in HIV-1-infected subjects with multidrug-resistant virus. METHODS: HIV-1-infected subjects, with current virological failure on a stable antiretroviral regimen with no viable treatment options were assigned to a regimen comprising two new investigational agents, etravirine, a novel nonnucleoside reverse transcriptase inhibitor, and darunavir, a novel protease inhibitor, plus nucleoside reverse transcriptase inhibitors (and enfuvirtide in selected patients) for 24 weeks. Virological, immunological and safety parameters were collected. Detailed pharmacokinetic assessments of darunavir and etravirine were determined on days 7 and 28. RESULTS: Follow up of 24 weeks was achieved by 10/12 patients. Median reduction in HIV RNA was 2.7 log10 copies/ml (range, 2.3-3.9) and increase in CD4 lymphocytes was 113 cells/microl (range, 41-268). HIV RNA was < 40 copies/ml in nine. No serious adverse events were recorded. Plasma exposure to darunavir was similar to historic control data and exposure to etravirine similar to historic data when etravirine was administered with a boosted protease inhibitor. CONCLUSION: This first study to assess the use of etravirine and darunavir in HIV-1-infected subjects with no treatment options showed highly effective virological and immunological responses over 24 weeks of therapy with no new safety concerns or unexpected pharmacokinetic interactions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17589191&query_hl=1 ER - TY - JFULL T1 - Response to Mallet et al., 'Nodular regenerative hyperplasia is a new cause of chronic liver disease in HIV-infected patients'. A1 - Garvey, LJ A1 - Thomson, EC A1 - Lloyd, J A1 - Cooke, GS A1 - Goldin, RD A1 - Main, J J1 - AIDS Y1 - 2007/07/11/ VL - 21 SN - 0269-9370 SP - 1494 EP - 1495 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17589202&query_hl=1 ER - TY - JFULL T1 - International perspectives, progress, and future challenges of paediatric HIV infection A1 - Prendergast, A A1 - Tudor-Williams, G A1 - Jeena, P A1 - Burchett, S A1 - Goulder, P J1 - LANCET Y1 - 2007/07/07/ VL - 370 SN - 0140-6736 SP - 68 EP - 80 N2 - Paediatric HIV infection is a growing health challenge worldwide, with an estimated 1500 new infections every day. in developed countries, well established prevention programmes keep mother-to-child transmission rates at less than 2%. However, in developing countries, where transmission rates are 25-40%, interventions are available to only 5-10% of women. Children with untreated natural infection progress rapidly to disease, especially in resource-poor settings where mortality is greater than 50% by 2 years of age. As in adult infection, antiretroviral therapy has the potential to rewrite the natural history of HIV, but is accessible only to a small number of children needing therapy. We focus on the clinical and immunological features of HIV that are specific to paediatric infection, and the formidable challenges ahead to ensure that all children worldwide have access to interventions that have proved successful in developed countries. ER - TY - JFULL T1 - Enhanced ex vivo stimulation of Mycobacterium tuberculosis-specific T cells in human immunodeficiency virus-infected persons via antigen delivery by the Bordetella pertussis adenylate cyclase vector. A1 - Connell, TG A1 - Shey, MS A1 - Seldon, R A1 - Rangaka, MX A1 - van Cutsem, G A1 - Simsova, M A1 - Marcekova, Z A1 - Sebo, P A1 - Curtis, N A1 - Diwakar, L A1 - Meintjes, GA A1 - Leclerc, C A1 - Wilkinson, RJ A1 - Wilkinson, KA J1 - Clin Vaccine Immunol Y1 - 2007/07// VL - 14 SN - 1556-6811 SP - 847 EP - 854 N2 - The genetically detoxified Bordetella pertussis adenylate cyclase is a promising delivery system for immunodominant tuberculosis antigens in gamma interferon release assays. This system has not been evaluated in human immunodeficiency virus (HIV)-infected persons in high tuberculosis prevalence areas. A whole-blood gamma interferon release assay with Mycobacterium tuberculosis antigens (early-secreted antigenic target 6, culture filtrate protein 10, alpha-crystallin 2, and TB10.3) delivered by adenylate cyclase in addition to native tuberculosis antigens (without adenylate cyclase delivery) was evaluated in 119 adults in Khayelitsha Township, Cape Town, South Africa. Results were compared to tuberculin skin test results of 41 HIV-positive and 42 HIV-negative asymptomatic persons, in addition to 36 HIV-positive persons with recently diagnosed smear- or culture-positive pulmonary tuberculosis. Delivery of tuberculosis antigens by adenylate cyclase decreased by 10-fold the amount of antigen required to restimulate T cells. Furthermore, the responses of HIV-positive persons with a low response to native tuberculosis antigens were enhanced when these antigens were delivered by adenylate cyclase. When gamma interferon responses to the tuberculosis antigens (with or without delivery by adenylate cyclase) were combined, a significantly higher number of patients were scored positive than by tuberculin skin testing. Ex vivo responses to tuberculosis antigens delivered by adenylate cyclase are maintained in the context of HIV infection. Our findings suggest that the majority of those in this population are infected with tuberculosis, which is of significant public health importance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17522328&query_hl=1 ER - TY - JFULL T1 - The missing care bundle: antibiotic prescribing in hospitals. A1 - Cooke, FJ A1 - Holmes, AH J1 - Int J Antimicrob Agents Y1 - 2007/07// VL - 30 SN - 0924-8579 SP - 25 EP - 29 N2 - The care bundle involves grouping together key elements of care for procedures and the management of specific diagnoses in order to provide a systematic method to improve and monitor the delivery of clinical care processes. In short, care bundles aim to ensure that all patients consistently receive the best care or treatment, all of the time. This approach has been successfully applied to the management of various conditions, particularly in the critical care setting. The Institute for Healthcare Improvement's '100K lives campaign' consisted of six care bundles, three of which have addressed preventing hospital-acquired infection. The UK Department of Health's delivery programme to reduce healthcare-associated infections (HCAIs), including methicillin-resistant Staphylococcus aureus (MRSA), includes six 'high-impact interventions', which are care bundles to reduce HCAIs. However, we suggest that one key intervention is missing, and consider this intervention will be increasingly important if hospitals are to address the rising incidence of Clostridium difficile, to tackle antibiotic resistance and to improve patient care. The missing intervention addresses the process of antibiotic prescribing. We propose that the time is right to consider the application of the care bundle approach to improve the prescribing of antibiotics, both for treatment and prophylaxis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17499482&query_hl=1 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 - Zinc Cream and Reliability of Tuberculosis Skin Testing A1 - Rao, VB A1 - Pelly, TF A1 - Gilman, RH A1 - Cabrera, L A1 - Delgado, J A1 - Soto, G A1 - Friedland, JS A1 - Escombe, AR A1 - Black, RE A1 - Evans, CA J1 - Emerging Infectious Diseases Y1 - 2007/07// VL - 13 SP - 1101 EP - 1104 N2 - In 50 healthy Peruvian shantytown residents, zinc cream applied to tuberculosis skin-test sites caused a 32% increase in induration compared with placebo cream. Persons with lower plasma zinc had smaller skin-test reactions and greater augmentation with zinc cream. Zinc defi ciency caused false-negative skin-test results, and topical zinc supplementation augmented antimycobacterial immune responses enough to improve diagnosis. ER - TY - JFULL T1 - Neutrophil-mediated innate immune resistance to mycobacteria. A1 - Martineau, AR A1 - Newton, SM A1 - Wilkinson, KA A1 - Kampmann, B A1 - Hall, BM A1 - Nawroly, N A1 - Packe, GE A1 - Davidson, RN A1 - Griffiths, CJ A1 - Wilkinson, RJ J1 - J Clin Invest Y1 - 2007/07// VL - 117 SN - 0021-9738 SP - 1988 EP - 1994 N2 - Neutrophils contain antimicrobial peptides with antituberculous activity, but their contribution to immune resistance to tuberculosis (TB) infection has not been previously investigated to our knowledge. We determined differential white cell counts in peripheral blood of 189 adults who had come into contact with patients diagnosed with active TB in London, United Kingdom, and evaluated them for evidence of TB infection and capacity to restrict mycobacterial growth in whole-blood assays. Risk of TB infection was inversely and independently associated with peripheral blood neutrophil count in contacts of patients diagnosed with pulmonary TB. The ability of whole blood to restrict growth of Mycobacterium bovis bacille Calmette Guérin and Mycobacterium tuberculosis was impaired 7.3- and 3.1-fold, respectively, by neutrophil depletion. In microbiological media, human neutrophil peptides (HNPs) 1-3 killed M. tuberculosis. The neutrophil peptides cathelicidin LL-37 and lipocalin 2 restricted growth of the organism, the latter in an iron-dependent manner. Black African participants had lower neutrophil counts and lower circulating concentrations of HNP1-3 and lipocalin 2 than south Asian and white participants. Neutrophils contribute substantially to innate resistance to TB infection, an activity associated with their antimicrobial peptides. Elucidation of the regulation of neutrophil antimicrobial peptides could facilitate prevention and treatment of TB. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17607367&query_hl=1 ER - TY - JFULL T1 - Vaccinia virus gene F3L encodes an intracellular protein that affects the innate immune response. A1 - Froggatt, GC A1 - Smith, GL A1 - Beard, PM J1 - J Gen Virol Y1 - 2007/07// VL - 88 SN - 0022-1317 SP - 1917 EP - 1921 N2 - The Vaccinia virus BTB/kelch protein F3 has been characterized and its effects on virus replication in vitro and virus virulence in vivo have been determined. The loss of the F3L gene had no effect on virus growth, plaque phenotype or cytopathic effect in cell culture under the conditions tested. However, the virulence of a virus lacking F3L in an intradermal model was reduced compared with controls, and this was demonstrated by a significantly smaller lesion and alterations to the innate immune response to infection. The predicted molecular mass of the F3 protein is 56 kDa; however, immunoblotting of infected cell lysates using an antibody directed against recombinant F3 revealed two proteins of estimated sizes 37 and 25 kDa. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17554022&query_hl=1 ER - TY - JFULL T1 - High frequency of rapid immunological progression in African infants infected in the era of perinatal HIV prophylaxis. A1 - Mphatswe, W A1 - Blanckenberg, N A1 - Tudor-Williams, G A1 - Prendergast, A A1 - Thobakgale, C A1 - Mkhwanazi, N A1 - McCarthy, N A1 - Walker, BD A1 - Kiepiela, P A1 - Goulder, P J1 - AIDS Y1 - 2007/06/19/ VL - 21 SN - 0269-9370 SP - 1253 EP - 1261 N2 - OBJECTIVES: To determine the natural history of HIV infection following peripartum single-dose nevirapine (sd-NVP) prophylaxis in a resource-limited country, and to assess implications for antiretroviral therapy (ART) roll-out programmes. METHODS: Infants of HIV-infected mothers in KwaZulu-Natal, South Africa, were tested on days 1 and 28 to detect intrauterine (IU) and intrapartum (IP) infection. Infant follow-up included monthly viral load and CD4 cell measurement. ART was initiated at infant CD4 cell% < or = 20%. RESULTS: In 740 infants born to 719 HIV-infected women, mother-to-child transmission (MTCT) was 10.3% (69% IU, 31% IP). Median viral load was higher in mothers of infants infected IP than IU (279 000 versus 86 600 copies/ml; P = 0.039) and lower in mothers of uninfected infants (median 26 750 copies/ml; P < 0.001). Peak viraemia was higher in infants infected IP than IU (5 160 000 versus 984 000 copies/ml; P < 0.001). Median viral load at birth in IU-infected infants (155 000 copies/ml) fell 1.4 log to 6510 copies/ml by day 5 and was beneath the detection limit using dried blood spot analysis in 38% of infants. CD4 cell% declined rapidly, to < or = 20% in 70% and < or = 25% in 85% [current World Health Organization (WHO) criteria for initiating ART] of infants by 6 months. CONCLUSIONS: MTCT was reduced by sd-NVP through an effect on IP transmission. Where MTCT occurred despite NVP, two-thirds of transmissions arose IU; IP-infected babies were born to mothers with very high viral load. Disease progression was particularly rapid, 85% infants meeting WHO criteria for ART within 6 months. These findings argue for more effective MTCT-prevention programmes in resource-limited countries. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17545701&query_hl=1 ER - TY - JFULL T1 - Slower CD4 cell decline following cessation of a 3 month course of HAART in primary HIV infection: findings from an observational cohort. A1 - Fidler, S A1 - Fox, J A1 - Touloumi, G A1 - Pantazis, N A1 - Porter, K A1 - Babiker, A A1 - Weber, J J1 - AIDS Y1 - 2007/06/19/ VL - 21 SN - 0269-9370 SP - 1283 EP - 1291 N2 - OBJECTIVE: To investigate the effect of a short course of HAART during primary HIV infection (PHI) on rate of CD4 cell and viral load change. METHODS: Data following HAART cessation from 89 individuals (seroconverting 1999-2003) who chose to take a 3 month course of HAART at PHI were compared with 179 untreated controls in CASCADE, using linear and nonlinear random effects models. Participants were non-randomized but frequency matched for age, sex, risk factor, year of seroconversion and presentation within the first 6 months of seroconversion. Time to CD4 cell count < 350 cells/microl and initiation of clinically indicated antiretroviral therapy (ART) were also compared as competing risks. RESULTS: The rate of CD4 cell decline following therapy cessation appeared significantly slower among treated participants than untreated controls: losses of 51 cells/microl [95% confidence interval (CI), 32-69] and 77 cells/microl (95% CI, 65-89), respectively, 3 years after seroconversion (P = 0.011). Based on extrapolated data, viral loads also differed significantly at this point (4.09 and 4.53 copies/ml, respectively). At 2 years, there was no significant difference in mean viral load levels: 4.31 copies/ml (95% CI, 4.14-4.48) and 4.47 copies/ml (95% CI, 4.28-4.66), respectively. CASCADE seroconverters were more likely to reach CD4 cell count < 350 cells/microl or initiate clinically indicated ART (hazard ratio, 1.45; 95% CI, 1.02-2.05; P = 0.039). CONCLUSION: A short course of ART at PHI may delay CD4 cell decline. Confirmation of this requires a randomized clinical trial powered to address definitively the role of ART intervention in PHI (currently underway through SPARTAC). L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17545704&query_hl=1 ER - TY - JFULL T1 - Expression of PD-L1, a marker of disease status, is not reduced by HAART in aviraemic patients. A1 - Rosignoli, G A1 - Cranage, A A1 - Burton, C A1 - Nelson, M A1 - Steel, A A1 - Gazzard, B A1 - Gotch, F A1 - Imami, N J1 - AIDS Y1 - 2007/06/19/ VL - 21 SN - 0269-9370 SP - 1379 EP - 1381 N2 - Anergy and defective immune responses are characteristic of chronic HIV-1 infection. The programmed death 1 (PD-1)/PD-1 ligand (PD-L1) pathway appears to be involved in downregulating T-cell functionality. We found raised levels of PD-L1 in aviraemic chronically infected HIV-1-positive patients, which may contribute to incomplete immune reconstitution after treatment with HAART. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17545722&query_hl=1 ER - TY - JFULL T1 - Loss of discrete memory B cell subsets is associated with impaired immunization responses in HIV-1 infection and may be a risk factor for invasive pneumococcal disease. A1 - Hart, M A1 - Steel, A A1 - Clark, SA A1 - Moyle, G A1 - Nelson, M A1 - Henderson, DC A1 - Wilson, R A1 - Gotch, F A1 - Gazzard, B A1 - Kelleher, P J1 - J Immunol Y1 - 2007/06/15/ VL - 178 SN - 0022-1767 SP - 8212 EP - 8220 N2 - Invasive pneumococcal infection is an important cause of morbidity and mortality in HIV-1-infected individuals. B cells play an important role in maintaining serologic memory after infection. IgM memory B cells are significantly reduced in HIV-1-infected patients and their frequency is similar to that observed in other patient groups (splenectomized individuals and patients with primary Ab deficiency) who are also known to have an increased risk of invasive pneumococcal infection. Antiretroviral therapy does not restore marginal zone B cell percentages. Immunization with the 23-valent polysaccharide pneumococcal vaccine shows that HIV-1-infected patients have impaired total IgM and IgG pneumococcal vaccines compared with healthy controls. Loss of switched memory B cells was associated with impaired tetanus toxoid IgG vaccine responses. Results of this study demonstrate that defects in B cell memory subsets are associated with impaired humoral immune responses in HIV-1 patients who are receiving antiretroviral therapy and may be a contributory factor to the increased risk of invasive pneumococcal infection observed in HIV-1 infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17548660&query_hl=1 ER - TY - JFULL T1 - Clinical, immunological, and epidemiological importance of antituberculosis T cell responses in HIV-infected Africans A1 - Rangaka, MX A1 - Diwakar, L A1 - Seldon, R A1 - van Cutsem, G A1 - Meintjes, GA A1 - Morroni, C A1 - Mouton, P A1 - Shey, MS A1 - Maartens, G A1 - Wilkinson, KA A1 - Wilkinson, RJ J1 - CLIN INFECT DIS Y1 - 2007/06/15/ VL - 44 SN - 1058-4838 SP - 1639 EP - 1646 N2 - Background. Human immunodeficiency virus (HIV)-associated tuberculosis is a major cause of mortality in Africa. The assay of T cell interferon-gamma released in response to antigens of greater specificity than purified protein derivative is a useful improvement over the Mantoux tuberculin skin test, but few studies have evaluated interferon gamma secretion in HIV-infected individuals.Methods. Mycobacterium tuberculosis antigen-specific interferon-gamma secretion was assessed by whole blood assay and enzyme-linked immunospot, which were compared with the Mantoux tuberculin skin test in HIV-infected and HIV-uninfected individuals without active tuberculosis and HIV-infected patients with pulmonary tuberculosis in Khayelitsha, South Africa.Results. The skin test and whole blood assay responses to purified protein derivative in HIV-positive subjects were decreased, compared with responses in HIV-negative subjects (P < .001). By contrast, the responses to M. tuberculosis antigens (early secreted antigenic target 6, culture filtrate protein 10, TB10.3, and alpha-crystallin 2) were less affected, indicating a high prevalence of latent tuberculosis (similar to 80%) in both HIV-negative and HIV-positive subject groups. Whole blood assay responses did not differ between the HIV-positive subjects without tuberculosis and HIV-positive subjects with tuberculosis, but the enzyme-linked immunospot method response to early secreted antigenic target 6 and culture filtrate protein 10 was higher in the group of HIV-infected subjects with tuberculosis (P <= .04), although this group had lower CD4(+) cell counts. A ratio of the combined enzyme-linked immunospot method response divided by the CD4(+) cell count of 11.0 had 88% sensitivity and 80% specificity for active pulmonary tuberculosis in HIV-infected individuals.Conclusions. Interferon-gamma release appears to be less impaired than skin testing by HIV coinfection. The novel potential to relate the enzyme-linked immunospot method and CD4(+) cell count to assist diagnosis of active tuberculosis in patients with HIV infection is important and deserves further evaluation. ER - TY - JFULL T1 - Synergistic Up-regulation of Epithelial Cell Matrix Metalloproteinase-9 Secretion in Tuberculosis. A1 - Elkington, PT A1 - Green, JA A1 - Emerson, JE A1 - Lopez-Pascua, LD A1 - Boyle, JJ A1 - O'kane, CM A1 - Friedland, JS J1 - Am J Respir Cell Mol Biol Y1 - 2007/06/15/ SN - 1044-1549 N2 - Mycobacterium tuberculosis (MTb) kills approximately 2 million people each year. MTb must drive host tissue destruction to disseminate and also to cause pulmonary cavitation. Matrix metalloproteinase-9 (MMP-9, gelatinase B) is implicated in this Tb-related immunopathology. We demonstrate that conditioned media from MTb-infected monocytes (CoMTb) but not direct infection with MTb up-regulates MMP-9 gene expression and secretion from primary human bronchial epithelial cells (NHBE). MMP-9 secretion was increased 8.7-fold by CoMTb (p<0.05) as assayed by gelatin zymography. A549 and 16HBE14o epithelial cell MMP secretion was significantly less than primary NHBE secretion. MMP-9 secretion was decreased 53.2% by inhibition of the p38 MAPK by SB203580 (p<0.01) and 48.3% by inhibition of ERK with PD98059 (p<0.05). MMP-9 secretion was prostaglandin-independent. TNF-alpha was necessary but not sufficient for MMP-9 up-regulation by the monocyte-epithelial cell network. Soluble factors derived from Tb culture synergized with TNF-alpha to increase MMP-9 secretion by NHBE 6-fold (p<0.01 compared to either stimulus alone). Together these data reveal a new mechanism by which host- and pathogen-derived factors act together in MTb infection to drive MAPK-dependent MMP-9 secretion from respiratory epithelial cells. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17575075&query_hl=1 ER - TY - JFULL T1 - Kenneth Anthony ("Tony") Kalanyi Kebba - Obituary A1 - Gotch, F J1 - BRIT MED J Y1 - 2007/06/09/ VL - 334 SN - 0959-8146 SP - 1227 EP - 1227 ER - TY - JFULL T1 - The SPI-2 type III secretion system restricts motility of Salmonella-containing vacuoles. A1 - Ramsden, AE A1 - Mota, LJ A1 - Münter, S A1 - Shorte, SL A1 - Holden, DW J1 - Cell Microbiol Y1 - 2007/06/07/ SN - 1462-5814 N2 - Intracellular replication of Salmonella enterica occurs in membrane-bound compartments, called Salmonella-containing vacuoles (SCVs). Following invasion of epithelial cells, most SCVs migrate to a perinuclear region and replicate in close association with the Golgi network. The association of SCVs with the Golgi is dependent on the Salmonella-pathogenicity island-2 (SPI-2) type III secretion system (T3SS) effectors SseG, SseF and SifA. However, little is known about the dynamics of SCV movement. Here, we show that in epithelial cells, 2 h were required for migration of the majority of SCVs to within 5 mum from the microtubule organizing centre (MTOC), which is located in the same subcellular region as the Golgi network. This initial SCV migration was saltatory, bidirectional and microtubule-dependent. An intact Golgi, SseG and SPI-2 T3SS were dispensable for SCV migration to the MTOC, but were essential for maintenance of SCVs in that region. Live-cell imaging between 4 and 8 h post invasion revealed that the majority of wild-type SCVs displaced less than 2 mum in 20 min from their initial starting positions. In contrast, between 6 and 8 h post invasion the majority of vacuoles containing sseG, sseF or ssaV mutant bacteria displaced more than 2 mum in 20 min from their initial starting positions, with some undergoing large and dramatic movements. Further analysis of the movement of SCVs revealed that large displacements were a result of increased SCV speed rather than a change in their directionality, and that SseG influences SCV motility by restricting vacuole speed within the MTOC/Golgi region. SseG might function by tethering SCVs to Golgi-associated molecules, or by controlling microtubule motors, for example by inhibiting kinesin recruitment or promoting dynein recruitment. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17578517&query_hl=1 ER - TY - JFULL T1 - Inhibition of type I and type III interferons by a secreted glycoprotein from Yaba-like disease virus. A1 - Huang, J A1 - Smirnov, SV A1 - Lewis-Antes, A A1 - Balan, M A1 - Li, W A1 - Tang, S A1 - Silke, GV A1 - Pütz, MM A1 - Smith, GL A1 - Kotenko, SV J1 - Proc Natl Acad Sci U S A Y1 - 2007/06/05/ VL - 104 SN - 0027-8424 SP - 9822 EP - 9827 N2 - Type I (IFN-alpha/beta) and type III (IFN-lambdas) IFNs are important components of the host antiviral response. Although type III IFNs possess intrinsic antiviral activity similar to that of type I IFNs, they signal through a specific unique receptor complex, and their functional importance for antiviral resistance is largely uncharacterized. Here, we report the first virus defense mechanism that directly targets type III IFNs. Y136 from Yaba-like disease virus, a yatapoxvirus, is a secreted glycoprotein related to protein B18 from Vaccinia virus, a known type I IFN-binding protein and a member of the Ig superfamily. Surprisingly, whereas B18 inhibits only type I IFNs, Y136 inhibits both type I and type III IFNs. Y136 inhibits IFN-induced signaling and suppresses IFN-mediated biological activities including up-regulation of MHC class I antigen expression and induction of the antiviral state. These data demonstrate that poxviruses have developed unique strategies to counteract IFN-mediated antiviral protection and highlight the importance of type III IFNs in antiviral defense. These results suggest that type III IFNs may be an effective treatment for some poxviral infections. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17517620&query_hl=1 ER - TY - JFULL T1 - Bayesian network analysis of resistance pathways against HIV-1 protease inhibitors. A1 - Deforche, K A1 - Camacho, R A1 - Grossman, Z A1 - Silander, T A1 - Soares, MA A1 - Moreau, Y A1 - Shafer, RW A1 - Van Laethem, K A1 - Carvalho, AP A1 - Wynhoven, B A1 - Cane, P A1 - Snoeck, J A1 - Clarke, J A1 - Sirivichayakul, S A1 - Ariyoshi, K A1 - Holguin, A A1 - Rudich, H A1 - Rodrigues, R A1 - Bouzas, MB A1 - Cahn, P A1 - Brigido, LF A1 - Soriano, V A1 - Sugiura, W A1 - Phanuphak, P A1 - Morris, L A1 - Weber, J A1 - Pillay, D A1 - Tanuri, A A1 - Harrigan, PR A1 - Shapiro, JM A1 - Katzenstein, DA A1 - Kantor, R A1 - Vandamme, AM J1 - Infect Genet Evol Y1 - 2007/06// VL - 7 SN - 1567-1348 SP - 382 EP - 390 N2 - Interpretation of Human Immunodeficiency Virus 1 (HIV-1) genotypic drug resistance is still a major challenge in the follow-up of antiviral therapy in infected patients. Because of the high degree of HIV-1 natural variation, complex interactions and stochastic behaviour of evolution, the role of resistance mutations is in many cases not well understood. Using Bayesian network learning of HIV-1 sequence data from diverse subtypes (A, B, C, F and G), we could determine the specific role of many resistance mutations against the protease inhibitors (PIs) nelfinavir (NFV), indinavir (IDV), and saquinavir (SQV). Such networks visualize relationships between treatment, selection of resistance mutations and presence of polymorphisms in a graphical way. The analysis identified 30N, 88S, and 90M for nelfinavir, 90M for saquinavir, and 82A/T and 46I/L for indinavir as most probable major resistance mutations. Moreover we found striking similarities for the role of many mutations against all of these drugs. For example, for all three inhibitors, we found that the novel mutation 89I was minor and associated with mutations at positions 90 and 71. Bayesian network learning provides an autonomous method to gain insight in the role of resistance mutations and the influence of HIV-1 natural variation. We successfully applied the method to three protease inhibitors. The analysis shows differences with current knowledge especially concerning resistance development in several non-B subtypes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17127103&query_hl=1 ER - TY - JFULL T1 - Further characterization of the signaling proteolysis step in the Aspergillus nidulans pH signal transduction pathway. A1 - Peñas, MM A1 - Hervás-Aguilar, A A1 - Múnera-Huertas, T A1 - Reoyo, E A1 - Peñalva, MA A1 - Arst, HN A1 - Tilburn, J J1 - Eukaryot Cell Y1 - 2007/06// VL - 6 SN - 1535-9778 SP - 960 EP - 970 N2 - The Aspergillus nidulans pH-responsive transcription factor PacC is modulated by limited, two-step proteolysis. The first, pH-regulated cleavage occurs in the 24-residue highly conserved "signaling protease box" in response to the alkaline pH signal. This is transduced by the Pal signaling pathway, containing the predicted calpain-like cysteine protease and likely signaling protease, PalB. In this work, we carried out classical mutational analysis of the putative signaling protease PalB, and we describe 9 missense and 18 truncating loss-of-function (including null) mutations. Mutations in the region of and affecting directly the predicted catalytic cysteine strongly support the deduction that PalB is a cysteine protease. Truncating and missense mutations affecting the C terminus highlight the importance of this region. Analysis of three-hemagglutinin-tagged PalB in Western blots demonstrates that PalB levels are independent of pH and Pal signal transduction. We have followed the processing of MYC(3)-tagged PacC in Western blots. We show unequivocally that PalB is essential for signaling proteolysis and is definitely not the processing protease. In addition, we have replaced 15 residues of the signaling protease box of MYC(3)-tagged PacC (pacC900) with alanine. The majority of these substitutions are silent. Leu481Ala, Tyr493Ala, and Gln499Ala result in delayed PacC processing in response to shifting from acidic to alkaline medium, as determined by Western blot analysis. Leu498Ala reduces function much more markedly, as determined by plate tests and processing recalcitrance. Excepting Leu498, this demonstrates that PacC signaling proteolysis is largely independent of sequence in the cleavage region. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17416893&query_hl=1 ER - TY - JFULL T1 - The safety, efficacy, and pharmacokinetic profile of a switch in antiretroviral therapy to saquinavir, ritonavir, and atazanavir alone for 48 weeks and a switch in the saquinavir formulation. A1 - Winston, A A1 - Mallon, PW A1 - Satchell, C A1 - MacRae, K A1 - Williams, KM A1 - Schutz, M A1 - Law, M A1 - Cooper, DA A1 - Emery, S J1 - Clin Infect Dis Y1 - 2007/06/01/ VL - 44 SN - 1537-6591 SP - 1475 EP - 1483 N2 - BACKGROUND: Toxicities observed with current combination antiretroviral therapy (CART) warrant a search for novel options, such as class-sparing regimens. Ritonavir-boosted double-protease inhibitor (PI)-only regimens are such an option but are prone to pharmacokinetic interactions. METHODS: This 48-week randomized study examined the safety and efficacy of a switch in CART to a once-daily regimen of saquinavir (SQV), ritonavir (RTV), and atazanavir (ATV) that did not include nucleoside reverse-transcriptase inhibitors (NRTIs). The study also assessed the pharmacokinetic profile of a change in the SQV formulation, from 200 mg to 500 mg, in 2 regimens (SQV-RTV twice per day plus NRTIs [arm 1] and SQV-RTV-ATV once per day without NRTIs [arm 2]) in human immunodeficiency virus type 1-infected subjects (plasma human immunodeficiency virus RNA level, <50 copies/mL). Patients underwent an initial SQV formulation change or a CART change to SQV-RTV-ATV with intense pharmacokinetic sampling. All patients were subsequently assigned to receive SQV-RTV-ATV (1500, 100, and 300 mg once per day, respectively) without NRTIs for 48 weeks. The primary end point was the percentage of patients who experienced virologic failure. RESULTS: Of 25 subjects enrolled, scleral icterus was the most common adverse event (3 patients [12.5%]). Three subjects (12.5%) experienced virologic failure; and mean (+/- standard error of the mean) increase in the CD4(+) lymphocyte count was 63 +/- 36 cells/ mu L over 48 weeks (P=.012). The SQV geometric mean area under the time curve parameters were not significantly altered for the 2 SQV formulations (arm 1, 23.32 vs. 18.76 ngxh/mL [geometric mean ratio, 0.80] for the 200-mg vs. 500-mg formulations, respectively; arm 2, 50.31 vs. 44.79 ngxh/mL [geometric mean ratio, 0.88], for the 200-mg vs. 500-mg formulations, respectively). CONCLUSIONS: A CART regimen of SQV-RTV-ATV alone demonstrated sustained virologic efficacy and was associated with significant increases in the CD4(+) lymphocyte count. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17479946&query_hl=1 ER - TY - JFULL T1 - CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. A1 - Gras, L A1 - Kesselring, AM A1 - Griffin, JT A1 - van Sighem, AI A1 - Fraser, C A1 - Ghani, AC A1 - Miedema, F A1 - Reiss, P A1 - Lange, JM A1 - de Wolf, F A1 - ATHENA, Netherlands National Observational Cohort Study J1 - J Acquir Immune Defic Syndr Y1 - 2007/06/01/ VL - 45 SN - 1525-4135 SP - 183 EP - 192 N2 - OBJECTIVE: CD4 cell count changes in therapy-naive patients were investigated during 7 years of highly active antiretroviral therapy (HAART) in an observational cohort. METHODS: Three endpoints were studied: (1) time to >or=800 CD4 cells/mm in 5299 therapy-naive patients starting HAART, (2) CD4 cell count changes during 7 years of uninterrupted HAART in a subset of 544 patients, and (3) reaching a plateau in CD4 cell restoration after 5 years of HAART in 366 virologically suppressed patients. RESULTS: Among patients with <50, 50 to 200, 200 to 350, 350 to 500, and >or=500 CD4 cells/mm at baseline, respectively, 20%, 26%, 46%, 73%, and 87% reached >or=800 CD4 cells/mm within 7 years of starting HAART. Periods with HIV RNA levels >500 copies/mL and age >or=50 years were associated with lesser increases in CD4 cell counts between 6 months and 7 years. Having reached >or=800 CD4 cells/mm at 5 years, age >or=50 years, and >or=1 HIV RNA measurement >1000 copies/mL between 5 and 7 years were associated with a plateau in CD4 cell restoration. CONCLUSIONS: Restoration to CD4 cell counts >or=800 cells/mm is feasible within 7 years of HAART in most HIV-infected patients starting with >or=350 cells/mm and achieving sufficient suppression of viral replication. Particularly in patients >or=50 years of age, it may be beneficial to start earlier than current guidelines recommend. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17414934&query_hl=1 ER - TY - JFULL T1 - Evidence for boosting Mycobacterium tuberculosis-specific IFN-gamma responses at 6 weeks following tuberculin skin testing A1 - Naseer, A A1 - Naqvi, S A1 - Kampmann, B J1 - EUR RESPIR J Y1 - 2007/06// VL - 29 SN - 0903-1936 SP - 1282 EP - 1283 ER - TY - JFULL T1 - IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37. A1 - Martineau, AR A1 - Wilkinson, KA A1 - Newton, SM A1 - Floto, RA A1 - Norman, AW A1 - Skolimowska, K A1 - Davidson, RN A1 - Sørensen, OE A1 - Kampmann, B A1 - Griffiths, CJ A1 - Wilkinson, RJ J1 - J Immunol Y1 - 2007/06/01/ VL - 178 SN - 0022-1767 SP - 7190 EP - 7198 N2 - Vitamin D deficiency is associated with susceptibility to tuberculosis, and its biologically active metabolite, 1alpha,25 dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), has pleiotropic immune effects. The mechanisms by which 1alpha,25(OH)(2)D(3) protects against tuberculosis are incompletely understood. 1alpha,25(OH)(2)D(3) reduced the growth of mycobacteria in infected human PBMC cultures in a dose-dependent fashion. Coculture with agonists or antagonists of the membrane or nuclear vitamin D receptors indicated that these effects were primarily mediated by the nuclear vitamin D receptors. 1alpha,25(OH)(2)D(3) reduced transcription and secretion of protective IFN-gamma, IL-12p40, and TNF in infected PBMC and macrophages, indicating that 1alpha,25(OH)(2)D(3) does not mediate protection via these cytokines. Although NOS2A was up-regulated by 1alpha,25(OH)(2)D(3), inhibition of NO formation marginally affected the suppressive effect of 1alpha,25(OH)(2)D(3) on bacillus Calmette Guérin in infected cells. By contrast, 1alpha,25(OH)(2)D(3) strongly up-regulated the cathelicidin hCAP-18 gene, and some hCAP-18 polypeptide colocalized with CD14 in 1alpha,25(OH)(2)D(3) stimulated PBMC, although no detectable LL-37 peptide was found in supernatants from similar 1alpha,25(OH)(2)D(3)-stimulated PBMC cultures. A total of 200 mug/ml of the active peptide LL-37, in turn, reduced the growth of Mycobacterium tuberculosis in culture by 75.7%. These findings suggest that vitamin D contributes to protection against TB by "nonclassical" mechanisms that include the induction of antimicrobial peptides. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17513768&query_hl=1 ER - TY - JFULL T1 - Mutagenesis of the herpesvirus saimiri terminal repeat region reveals important elements for virus production. A1 - White, RE A1 - Carline, L A1 - Allday, MJ J1 - J Virol Y1 - 2007/06// VL - 81 SN - 0022-538X SP - 6765 EP - 6770 N2 - Deletion of the terminal repeats (TR) from herpesvirus saimiri (HVS) renders it unable to produce infectious virus or generate plaques. However, a TR-deleted HVS bacterial artificial chromosome can form replication compartments. Complementation of this mutant shows that one copy of the TR, plus the right junction of the genome with the TR, is sufficient for efficient plaque formation and generation of infectious virus. Within the TR unit, the region around the cleavage site of the genome appears both necessary and sufficient for virus production. Analysis of episomes from productive cells indicates a propensity to amplify TR numbers during the lytic cycle. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17428860&query_hl=1 ER - TY - JFULL T1 - Prospective study of sputum induction, gastric washing, and bronchoalveolar lavage for the diagnosis of pulmonary tuberculosis in patients who are unable to expectorate. A1 - Brown, M A1 - Varia, H A1 - Bassett, P A1 - Davidson, RN A1 - Wall, R A1 - Pasvol, G J1 - Clin Infect Dis Y1 - 2007/06/01/ VL - 44 SN - 1537-6591 SP - 1415 EP - 1420 N2 - BACKGROUND: Many adults with pulmonary tuberculosis are unable to expectorate. Gastric washing, sputum induction using nebulized hypertonic saline, and bronchoscopy with bronchoalveolar lavage have all been used to obtain specimens for diagnosis, but to our knowledge, the timing and volume of induced sputum have not been well studied, and these 3 methods have not been compared. METHODS: The study recruited consecutive adult inpatients with chest radiography findings suggestive of tuberculosis who were unable to expectorate. Subjects provided 3 induced sputum samples for culture on day 1 and additional samples on days 2 and 3. In addition, gastric washing specimens were collected on days 1, 2, and 3. A proportion of subjects with negative smear results underwent bronchoalveolar lavage. RESULTS: The study recruited 140 subjects. Among 107 subjects who provided 3 gastric washing specimens and at least 3 induced sputum specimens, 43% had cultures positive for Mycobacterium tuberculosis. Use of 3 induced sputum samples detected more cases than did use of 3 gastric washings (39% vs. 30%; P=.03). Among 79 subjects with culture results for all 5 induced sputum specimens, there was no difference in yield between samples obtained by induced sputum induction performed in a single day or that performed over 3 days (34% vs. 37%; P=.63). There was no association between sputum volume and positive culture results. No additional cases were diagnosed in the 21 patients who underwent bronchoscopy. CONCLUSIONS: Use of 3 induced sputum samples was more sensitive than use of 3 gastric washings for diagnosis of tuberculosis in patients who could not expectorate spontaneously. Use of bronchoscopy with bronchoalveolar lavage did not increase diagnostic sensitivity. Samples could be collected in 1 day, allowing for faster diagnosis, faster initiation of treatment, and shorter hospital stay. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17479935&query_hl=1 ER - TY - JFULL T1 - In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. A1 - Zhang, Y A1 - Wallace, DL A1 - de Lara, CM A1 - Ghattas, H A1 - Asquith, B A1 - Worth, A A1 - Griffin, GE A1 - Taylor, GP A1 - Tough, DF A1 - Beverley, PC A1 - Macallan, DC J1 - Immunology Y1 - 2007/06// VL - 121 SN - 0019-2805 SP - 258 EP - 265 N2 - Human natural killer (NK) cells form a circulating population in a state of dynamic homeostasis. We investigated NK cell homeostasis by labelling dividing cells in vivo using deuterium-enriched glucose in young and elderly healthy subjects and patients with viral infection. Following a 24-hr intravenous infusion of 6,6-D(2)-glucose, CD3(-) CD16(+) NK cells sorted from peripheral blood mononuclear cells (PBMC) by fluorescence-activated cell sorter (FACS) were analysed for DNA deuterium content by gas chromatography mass spectrometry to yield minimum estimates for proliferation rate (p). In healthy young adults (n=5), deuterium enrichment was maximal approximately 10 days after labelling, consistent with postmitotic maturation preceding circulation. The mean (+/- standard deviation) proliferation rate was 4 x 3 +/- 2 x 4%/day (equivalent to a doubling time of 16 days) and the total production rate was 15 +/- (7 x 6) x 10(6) cells/l/day. Labelled cells disappeared from the circulation at a similar rate [6 x 9 +/- 4 x 0%/day; half-life (T((1/2))) < 10 days]. Healthy elderly subjects (n=8) had lower proliferation and production rates (P=2 x 5 +/- 1 x 0%/day and 7 x 3 +/- (3 x 7) x 10(6) cells/l/day, respectively; P=0 x 04). Similar rates were seen in patients chronically infected with human T-cell lymphotropic virus type I (HTLV-I) (P=3 x 2 +/- 1 x 9%/day). In acute infectious mononucleosis (n=5), NK cell numbers were increased but kinetics were unaffected (P=2 x 8 +/- 1 x 0%/day) a mean of 12 days after symptom onset. Human NK cells have a turnover time in blood of about 2 weeks. Proliferation rates appear to fall with ageing, remain unperturbed by chronic HTLV-I infection and normalize rapidly following acute Epstein-Barr virus infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17346281&query_hl=1 ER - TY - JFULL T1 - Glucose control in the critically ill-still so many questions. A1 - Finney, SJ J1 - J Crit Care Y1 - 2007/06// VL - 22 SN - 0883-9441 SP - 118 EP - 119 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17548022&query_hl=1 ER - TY - JFULL T1 - TLR9 polymorphisms determine murine lymphocyte responses to Helicobacter: results from a genome-wide scan. A1 - Anderson, AE A1 - Worku, ML A1 - Khamri, W A1 - Bamford, KB A1 - Walker, MM A1 - Thursz, MR J1 - Eur J Immunol Y1 - 2007/06// VL - 37 SN - 0014-2980 SP - 1548 EP - 1561 N2 - Immune responses to microorganisms in the gastrointestinal tract must be carefully controlled to avoid disease. Helicobacter are Gram-negative bacteria which cause persistent infection and, in a minority of hosts, peptic ulceration or gastric cancer. Lymphocyte responses are important determinants of the outcome of infection. Therefore, it is important to identify the genetic determinants of lymphocyte responses to this mucosal pathogen. Using a (C57BL/6xBALB/c) F2 mouse model of Helicobacter infection, we mapped a region of linkage for lymphoproliferation to chromosome 9. Analysis of candidate genes in this region revealed variation of DNA sequence and gene expression in the TLR9 gene between C57BL/6 and BALB/c mouse strains. Reporter assays demonstrated higher levels of TLR9 transcriptional activity and increased NF-kappaB activation associated with the C57BL/6 TLR9 promoter and coding sequences. The importance of TLR9 in the control of lymphocyte responses was confirmed by demonstrating that lymphoproliferation and IFN-gamma secretion was diminished in the TLR9-/- mouse. Furthermore, neutrophil infiltration of the gastric epithelium is reduced in the absence of TLR9. Regulation of TLR9 expression and signalling therefore appears to play an important role in the control of lymphocyte responses to Helicobacter and potentially other luminal microorganisms. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17474149&query_hl=1 ER - TY - JFULL T1 - Functional and structural studies of the vaccinia virus virulence factor N1 reveal a Bcl-2-like anti-apoptotic protein. A1 - Cooray, S A1 - Bahar, MW A1 - Abrescia, NG A1 - McVey, CE A1 - Bartlett, NW A1 - Chen, RA A1 - Stuart, DI A1 - Grimes, JM A1 - Smith, GL J1 - J Gen Virol Y1 - 2007/06// VL - 88 SN - 0022-1317 SP - 1656 EP - 1666 N2 - Vaccinia virus (VACV) encodes many immunomodulatory proteins, including inhibitors of apoptosis and modulators of innate immune signalling. VACV protein N1 is an intracellular homodimer that contributes to virus virulence and was reported to inhibit nuclear factor (NF)-kappaB signalling. However, analysis of NF-kappaB signalling in cells infected with recombinant viruses with or without the N1L gene showed no difference in NF-kappaB-dependent gene expression. Given that N1 promotes virus virulence, other possible functions of N1 were investigated and this revealed that N1 is an inhibitor of apoptosis in cells transfected with the N1L gene and in the context of VACV infection. In support of this finding virally expressed N1 co-precipitated with endogenous pro-apoptotic Bcl-2 proteins Bid, Bad and Bax as well as with Bad and Bax expressed by transfection. In addition, the crystal structure of N1 was solved to 2.9 A resolution (0.29 nm). Remarkably, although N1 shows no sequence similarity to cellular proteins, its three-dimensional structure closely resembles Bcl-x(L) and other members of the Bcl-2 protein family. The structure also reveals that N1 has a constitutively open surface groove similar to the grooves of other anti-apoptotic Bcl-2 proteins, which bind the BH3 motifs of pro-apoptotic Bcl-2 family members. Molecular modelling of BH3 peptides into the N1 surface groove, together with analysis of their physico-chemical properties, suggests a mechanism for the specificity of peptide recognition. This study illustrates the importance of the evolutionary conservation of structure, rather than sequence, in protein function and reveals a novel anti-apoptotic protein from orthopoxviruses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17485524&query_hl=1 ER - TY - JFULL T1 - Influenza pandemic vaccines: spread them thin? A1 - Fraser, C J1 - PLoS Med Y1 - 2007/06// VL - 4 SN - 1549-1676 SP - e228 EP - e228 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17579513&query_hl=1 ER - TY - JFULL T1 - Risk of HIV transmission in discordant partners. A1 - Fox, J A1 - Fidler, S J1 - J HIV Ther Y1 - 2007/06// VL - 12 SN - 1462-0308 SP - 48 EP - 53 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17641573&query_hl=1 ER - TY - JFULL T1 - Mechanical and cold hypersensitivity in nerve-injured C57BL/6J mice is not associated with fear-avoidance- and depression-related behaviour. A1 - Hasnie, FS A1 - Wallace, VC A1 - Hefner, K A1 - Holmes, A A1 - Rice, AS J1 - Br J Anaesth Y1 - 2007/06// VL - 98 SN - 0007-0912 SP - 816 EP - 822 N2 - BACKGROUND: Neuropathic pain is associated with significant co-morbidity, including anxiety and depression, which impact considerably on the overall patient experience. However, pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. To improve the clinical validity of a widely used rodent model of traumatic peripheral neuropathy, we have investigated fear-avoidance- and depression-related behaviours in nerve-injured and sham-operated mice over a 4 week period. METHODS: Male C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) or sham surgery and were assessed on days 7, 14, and 28 after operation. Withdrawal thresholds to punctate mechanical and cooling stimuli were measured. Mice were tested on the novel open-field and elevated plus-maze tests for fear-avoidance behaviour, and on the tail suspension test for depression-related behaviour. RESULTS: Hypersensitivity to punctate mechanical and cool stimuli was evident up to day 28 after PSNL. However, there was no change in fear-avoidance- or depression-related behaviours regardless of interval after-surgery. CONCLUSION: These data demonstrate that pain behaviour in nerve-injured C57BL/6J mice was not associated with alterations in emotion-related behaviours. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17478455&query_hl=1 ER - TY - JFULL T1 - Can organisational change reduce hospital acquired infections? A1 - Holmes, AH J1 - J Hosp Infect Y1 - 2007/06// VL - 65 Suppl 2 SN - 0195-6701 SP - 191 EP - 192 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17540269&query_hl=1 ER - TY - JFULL T1 - Camelpox virus encodes a schlafen-like protein that affects orthopoxvirus virulence. A1 - Gubser, C A1 - Goodbody, R A1 - Ecker, A A1 - Brady, G A1 - O'Neill, LA A1 - Jacobs, N A1 - Smith, GL J1 - J Gen Virol Y1 - 2007/06// VL - 88 SN - 0022-1317 SP - 1667 EP - 1676 N2 - Camelpox virus (CMLV) gene 176R encodes a protein with sequence similarity to murine schlafen (m-slfn) proteins. In vivo, short and long members of the m-slfn family inhibited T-cell development, whereas in vitro, only short m-slfns caused arrest of fibroblast growth. CMLV 176 protein (v-slfn) is most closely related to short m-slfns; however, when expressed stably in mammalian cells, v-slfn did not inhibit cell growth. v-slfn is a predominantly cytoplasmic 57 kDa protein that is expressed throughout infection. Several other orthopoxviruses encode v-slfn proteins, but the v-slfn gene is fragmented in all sequenced variola virus and vaccinia virus (VACV) strains. Consistent with this, all 16 VACV strains tested do not express a v-slfn detected by polyclonal serum raised against the CMLV protein. In the absence of a small animal model to study CMLV pathogenesis, the contribution of CMLV v-slfn to orthopoxvirus virulence was studied via its expression in an attenuated strain of VACV. Recombinant viruses expressing wild-type v-slfn or v-slfn tagged at its C terminus with a haemagglutinin (HA) epitope were less virulent than control viruses. However, a virus expressing v-slfn tagged with the HA epitope at its N terminus had similar virulence to controls, implying that the N terminus has an important function. A greater recruitment of lymphocytes into infected lung tissue was observed in the presence of wild-type v-slfn but, interestingly, these cells were less activated. Thus, v-slfn is an orthopoxvirus virulence factor that affects the host immune response to infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17485525&query_hl=1 ER - TY - JFULL T1 - Quantifying HTLV-I dynamics. A1 - Asquith, B A1 - Bangham, CR J1 - Immunol Cell Biol Y1 - 2007/06// VL - 85 SN - 0818-9641 SP - 280 EP - 286 N2 - Despite significant advances in our understanding of the immune response to persistent viruses like human T-cell lymphotropic virus type I (HTLV-I), many important questions remain unanswered. Mathematical modelling enables us to interpret and synthesise diverse experimental data in new ways and thus can contribute to our understanding. Here, we review recent advances in mathematical modelling of HTLV-I infection and illustrate how mathematics has enabled us to identify factors that determine an individual's viral burden and risk of developing HTLV-I-associated diseases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17372609&query_hl=1 ER - TY - JFULL T1 - RSV-infected airway epithelial cells cause biphasic up-regulation of CCR1 expression on human monocytes. A1 - Morrison, PT A1 - Thomas, LH A1 - Sharland, M A1 - Friedland, JS J1 - J Leukoc Biol Y1 - 2007/06// VL - 81 SN - 0741-5400 SP - 1487 EP - 1495 N2 - Respiratory syncytial virus (RSV) infection can cause extensive airway inflammation, which is orchestrated by chemokines and their receptors. RSV-infected epithelial cells secrete many cytokines and chemokines, but little is known about regulation of chemokine receptors on target cells. We investigated the effects of conditioned media (CM) from RSV-infected epithelial cells on monocyte CCR1, CCR2, and CCR5 expression. RSV-CM but not control-CM stimulated a biphasic increase in cell-surface CCR1, and levels peaked at 36 h and 96 h poststimulation. Similar CCR1 up-regulation occurred on monocyte-derived macrophages. Cytochlasin D and colchicine blocked both peaks of expression, demonstrating requirement of a functional cytoskeleton. Intracellular staining revealed little internal sequestration of CCR1 protein, and CCR1 up-regulation was inhibited by actinomycin D and cycloheximide, indicating that both waves of RSV-CM-induced surface CCR1 expression were dependent on de novo transcription and protein synthesis. Cytokine-neutralizing experiments showed that the effects of RSV-CM were decreased by blocking TNF-alpha (percent inhibition=51+/-2.3% at 36 h peak and 42+/-7.7% at 96 h peak) and to a lesser extent, IL-1 (percent inhibition=32+/-7.2% at 36 h and 23+/-2.9% at 96 h). In summary, RSV-CM causes a biphasic up-regulation of surface CCR1 on monocytes, which is dependent on an intact cytoskeleton, requires new gene transcription and protein synthesis, and is mediated in part by the proinflammatory cytokines TNF-alpha and IL-1. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17389578&query_hl=1 ER - TY - JFULL T1 - Fishing injury resulting in Mycobacterium fortuitum palmar abscess. A1 - Patel, B A1 - Nanchalal, J A1 - Friedland, JS J1 - Eur J Clin Microbiol Infect Dis Y1 - 2007/06// VL - 26 SN - 0934-9723 SP - 427 EP - 429 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17458567&query_hl=1 ER - TY - JFULL T1 - Chemokines and their receptors in respiratory disease: a therapeutic target for respiratory syncytial virus infection. A1 - Thomas, LH A1 - Friedland, JS A1 - Sharland, M J1 - Expert Rev Anti Infect Ther Y1 - 2007/06// VL - 5 SN - 1744-8336 SP - 415 EP - 425 N2 - Cell recruitment is a multistep process orchestrated by chemokines and their receptors. The chemokine/receptor system is central to many inflammatory diseases, making it a key target for therapeutic intervention. Despite complexity and redundancy within the system, effective antagonists are in development and undergoing clinical trials, for example, maraviroc, for use in HIV treatment. Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in infants, with global annual infection estimated at 64 million people. Current treatment is purely supportive, with no effective vaccine available. RSV pathology is partly due to excessive airway inflammation. Evidence is growing for a key role for chemokine receptors. Receptor blockade may therefore provide a feasible therapeutic option to inhibit RSV-induced inflammation and thereby reduce disease severity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17547506&query_hl=1 ER - TY - JFULL T1 - Entrepreneurial experiences A1 - Shaunak, S A1 - Brocchini, S J1 - NAT REV DRUG DISCOV Y1 - 2007/06// VL - 6 SN - 1474-1776 SP - 499 EP - 499 ER - TY - JFULL T1 - Natural Ventilation for Prevention of Airborne Contagion: Authors' Reply. A1 - Escombe, AR A1 - Moore, DA A1 - Friedland, JS A1 - Evans, CA A1 - Gilman, RH J1 - PLoS Med Y1 - 2007/05/29/ VL - 4 SN - 1549-1676 SP - e195 N2 - L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17535109&query_hl=1 ER - TY - JFULL T1 - Modeling the long-term antibody response of a human papillomavirus (HPV) virus-like particle (VLP) type 16 prophylactic vaccine. A1 - Fraser, C A1 - Tomassini, JE A1 - Xi, L A1 - Golm, G A1 - Watson, M A1 - Giuliano, AR A1 - Barr, E A1 - Ault, KA J1 - Vaccine Y1 - 2007/05/22/ VL - 25 SN - 0264-410X SP - 4324 EP - 4333 N2 - The duration over which antibody responses persist following HPV vaccination is unknown. To estimate the longevity of responses induced by HPV-16 vaccination, two models were fitted to serum anti-HPV-16 levels measured during a 48-month study period. The first was a conventional model of antibody decay and the second was a modified model that accounts for long-lived immune memory. Using the antibody decay model, it was estimated that following administration of a three-dose regimen of HPV-16 vaccine in women aged 16-23 years, anti-HPV-16 levels will remain above those induced naturally by HPV-16 infection for 12 years, and above detectable levels for 32 years in 50% of vaccinees. With the modified model, which fitted the data better (p<0.001), it was estimated that near life-long persistence of anti-HPV-16 following vaccination is expected at titer levels above those associated with reduction of natural HPV-16 infection in 76% of these subjects, and above detectable levels in 99% of these subjects. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17445955&query_hl=1 ER - TY - JFULL T1 - The detection of airborne transmission of tuberculosis from HIV-infected patients, using an in vivo air sampling model. A1 - Escombe, AR A1 - Oeser, C A1 - Gilman, RH A1 - Navincopa, M A1 - Ticona, E A1 - Martínez, C A1 - Caviedes, L A1 - Sheen, P A1 - Gonzalez, A A1 - Noakes, C A1 - Moore, DA A1 - Friedland, JS A1 - Evans, CA J1 - Clin Infect Dis Y1 - 2007/05/15/ VL - 44 SN - 1537-6591 SP - 1349 EP - 1357 N2 - BACKGROUND: Nosocomial transmission of tuberculosis remains an important public health problem. We created an in vivo air sampling model to study airborne transmission of tuberculosis from patients coinfected with human immunodeficiency virus (HIV) and to evaluate environmental control measures. METHODS: An animal facility was built above a mechanically ventilated HIV-tuberculosis ward in Lima, Peru. A mean of 92 guinea pigs were continuously exposed to all ward exhaust air for 16 months. Animals had tuberculin skin tests performed at monthly intervals, and those with positive reactions were removed for autopsy and culture for tuberculosis. RESULTS: Over 505 consecutive days, there were 118 ward admissions by 97 patients with pulmonary tuberculosis, with a median duration of hospitalization of 11 days. All patients were infected with HIV and constituted a heterogeneous group with both new and existing diagnoses of tuberculosis. There was a wide variation in monthly rates of guinea pigs developing positive tuberculin test results (0%-53%). Of 292 animals exposed to ward air, 159 developed positive tuberculin skin test results, of which 129 had laboratory confirmation of tuberculosis. The HIV-positive patients with pulmonary tuberculosis produced a mean of 8.2 infectious quanta per hour, compared with 1.25 for HIV-negative patients with tuberculosis in similar studies from the 1950s. The mean monthly patient infectiousness varied greatly, from production of 0-44 infectious quanta per hour, as did the theoretical risk for a health care worker to acquire tuberculosis by breathing ward air. CONCLUSIONS: HIV-positive patients with tuberculosis varied greatly in their infectiousness, and some were highly infectious. Use of environmental control strategies for nosocomial tuberculosis is therefore a priority, especially in areas with a high prevalence of both tuberculosis and HIV infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17443474&query_hl=1 ER - TY - JFULL T1 - In vivo T lymphocyte dynamics in humans and the impact of human T-lymphotropic virus 1 infection. A1 - Asquith, B A1 - Zhang, Y A1 - Mosley, AJ A1 - de Lara, CM A1 - Wallace, DL A1 - Worth, A A1 - Kaftantzi, L A1 - Meekings, K A1 - Griffin, GE A1 - Tanaka, Y A1 - Tough, DF A1 - Beverley, PC A1 - Taylor, GP A1 - Macallan, DC A1 - Bangham, CR J1 - Proc Natl Acad Sci U S A Y1 - 2007/05/08/ VL - 104 SN - 0027-8424 SP - 8035 EP - 8040 N2 - Human T-lymphotropic virus type 1 (HTLV-1) is a persistent CD4+ T-lymphotropic retrovirus. Most HTLV-1-infected individuals remain asymptomatic, but a proportion develop adult T cell leukemia or inflammatory disease. It is not fully understood how HTLV-1 persists despite a strong immune response or what determines the risk of HTLV-1-associated diseases. Until recently, it has been difficult to quantify lymphocyte kinetics in humans in vivo. Here, we used deuterated glucose labeling to quantify in vivo lymphocyte dynamics in HTLV-1-infected individuals. We then used these results to address four questions. (i) What is the impact of HTLV-1 infection on lymphocyte dynamics? (ii) How does HTLV-1 persist? (iii) What is the extent of HTLV-1 expression in vivo? (iv) What features of lymphocyte kinetics are associated with HTLV-1-associated myelopathy/tropical spastic paraparesis? We found that CD4+CD45RO+ and CD8+CD45RO+ T lymphocyte proliferation was elevated in HTLV-1-infected subjects compared with controls, with an extra 10(12) lymphocytes produced per year in an HTLV-1-infected subject. The in vivo proliferation rate of CD4+CD45RO+ cells also correlated with ex vivo viral expression. Finally, the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis was associated with significantly increased CD4+CD45RO+ cell proliferation. We suggest that there is persistent viral gene expression in vivo, which is necessary for the maintenance of the proviral load and determines HTLV-1-associated myelopathy/tropical spastic paraparesis risk. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17483473&query_hl=1 ER - TY - JFULL T1 - The interferon inducing pathways and the hepatitis C virus. A1 - Meurs, EF A1 - Breiman, A J1 - World J Gastroenterol Y1 - 2007/05/07/ VL - 13 SN - 1007-9327 SP - 2446 EP - 2454 N2 - The innate immune response is triggered by a variety of pathogens, including viruses, and requires rapid induction of type I interferons (IFN), such as IFNbeta and IFNalpha. IFN induction occurs when specific pathogen motifs bind to specific cellular receptors. In non-professional immune, virally-infected cells, IFN induction is essentially initiated after the binding of dsRNA structures to TLR3 receptors or to intracytosolic RNA helicases, such as RIG-I/MDA5. This leads to the recruitment of specific adaptors, such as TRIF for TLR3 and the mitochondrial-associated IPS-1/VISA/MAVS/CARDIF adapter protein for the RNA helicases, and the ultimate recruitment of kinases, such as MAPKs, the canonical IKK complex and the TBK1/IKKepsilon kinases, which activate the transcription factors ATF-2/c-jun, NF-kappaB and IRF3, respectively. The coordinated action of these transcription factors leads to induction of IFN and of pro-inflammatory cytokines and to the establishment of the innate immune response. HCV can cleave both the adapters TRIF and IPS-1/VISA/MAVS/CARDIF through the action of its NS3/4A protease. This provokes abrogation of the induction of the IFN and cytokine pathways and favours viral propagation and presumably HCV chronic infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17552028&query_hl=1 ER - TY - JFULL T1 - Sepsis since the discovery of Toll-like receptors: disease concepts and therapeutic opportunities. A1 - Leaver, SK A1 - Finney, SJ A1 - Burke-Gaffney, A A1 - Evans, TW J1 - Crit Care Med Y1 - 2007/05// VL - 35 SN - 0090-3493 SP - 1404 EP - 1410 N2 - OBJECTIVE: Sepsis and its sequelae are the leading cause of death in critically ill patients. Discovery in the late 1990s of Toll-like receptors as primary sensors of microbial infection led to significant advances in understanding the pathogenesis of sepsis, including emerging differences between Gram-positive and Gram-negative infection and the potential for the manipulation of Toll-like receptors for the treatment of sepsis. This review describes these advances. METHODS: Bibliographic search of the literature since 1999, with particular emphasis on the conceptual and therapeutic implications of Toll-like receptors for patients with systemic sepsis. RESULTS AND CONCLUSIONS: Toll-like receptors initiate the inflammatory processes that underlie the clinical response to infection and therefore represent an important putative target for therapeutic intervention. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17414083&query_hl=1 ER - TY - JFULL T1 - Unusual features of the cell cycle in mycobacteria: polar-restricted growth and the snapping-model of cell division. A1 - Thanky, NR A1 - Young, DB A1 - Robertson, BD J1 - Tuberculosis (Edinb) Y1 - 2007/05// VL - 87 SN - 1472-9792 SP - 231 EP - 236 N2 - Cell division patterns in mycobacteria have been examined in order to further our understanding of how these important organisms grow in the apparent absence of key systems required for the growth of rod-shaped bacteria. Analysis of the distribution of cell lengths in the population during different phases of growth showed that the modal cell length decreases during later phases of growth, declining from 3.5 to 2.5 microm for Mycobacterium bovis BCG cells sampled in log phase and stationary phase, respectively. The population also became more homogeneous, as indicated by the proportion of cells in the most common class increasing from 15% to 28%. Similar patterns were observed for Mycobacterium smegmatis and Mycobacterium tuberculosis. Consistent with other actinomycetes, and in contrast to most rod-shaped bacteria, the deposition of newly synthesised peptidoglycan in mycobacteria is restricted to the poles of the cell, as evidenced by staining with fluorescently labelled vancomycin. A "V-form" of bacteria was observed in cultures at all stages of growth, but the proportion decreased in older cultures. The V-shape appears to be a result of the uneven splitting of the exterior cell envelope at the new septum; this exposes the new peptidoglycan which is illustrated by spots of fluorescent vancomycin staining associated with the exterior side of the "V", and supports the 'snapping division model'. The restriction of growth to the poles of the cell differs from the pattern observed in other rod-shaped bacteria, in which the cell poles are inert and lateral growth occurs by deposition of peptidoglycan along the body of the cylinder. The mechanisms that maintain the shape of mycobacteria and that identify the mid-point for cell division remain to be determined. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17287144&query_hl=1 ER - TY - JFULL T1 - Interactions between Neisseria meningitidis and the complement system. A1 - Schneider, MC A1 - Exley, RM A1 - Ram, S A1 - Sim, RB A1 - Tang, CM J1 - Trends Microbiol Y1 - 2007/05// VL - 15 SN - 0966-842X SP - 233 EP - 240 N2 - Meningococcal infection remains a worldwide health problem, and understanding the mechanisms by which Neisseria meningitidis evades host innate and acquired immunity is crucial. The complement system is vital for protecting individuals against N. meningitidis. However, this pathogen has evolved several mechanisms to avoid killing by human complement. Bacterial structures such as polysaccharide capsule and those which mimic or bind host molecules function to prevent complement-mediated lysis and phagocytosis. This review provides an update on the recent findings on the diverse mechanisms by which N. meningitidis avoids complement-mediated killing, and how polymorphisms in genes encoding human complement proteins affect susceptibility to this important human pathogen. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17398100&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 - Humidity control as a strategy for lattice optimization applied to crystals of HLA-A*1101 complexed with variant peptides from dengue virus. A1 - Chotiyarnwong, P A1 - Stewart-Jones, GB A1 - Tarry, MJ A1 - Dejnirattisai, W A1 - Siebold, C A1 - Koch, M A1 - Stuart, DI A1 - Harlos, K A1 - Malasit, P A1 - Screaton, G A1 - Mongkolsapaya, J A1 - Jones, EY J1 - Acta Crystallogr Sect F Struct Biol Cryst Commun Y1 - 2007/05/01/ VL - 63 SN - 1744-3091 SP - 386 EP - 392 N2 - T-cell recognition of the antigenic peptides presented by MHC class I molecules normally triggers protective immune responses, but can result in immune enhancement of disease. Cross-reactive T-cell responses may underlie immunopathology in dengue haemorrhagic fever. To analyze these effects at the molecular level, the functional MHC class I molecule HLA-A*1101 was crystallized bound to six naturally occurring peptide variants from the dengue virus NS3 protein. The crystals contained high levels of solvent and required optimization of the cryoprotectant and dehydration protocols for each complex to yield well ordered diffraction, a process that was facilitated by the use of a free-mounting system. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17565177&query_hl=1 ER - TY - JFULL T1 - C-terminal antibodies (CTAbs): a simple and broadly applicable approach for the rapid generation of protein-specific antibodies with predefined specificity. A1 - Edwards, RJ A1 - Wrigley, A A1 - Bai, Z A1 - Bateman, M A1 - Russell, H A1 - Murray, S A1 - Lu, H A1 - Taylor, GW A1 - Boobis, AR A1 - Sriskandan, S J1 - Proteomics Y1 - 2007/05// VL - 7 SN - 1615-9853 SP - 1364 EP - 1372 N2 - Recent advances in proteomic techniques have resulted in an ever-increasing need to produce antibodies. Here, to address this problem, a technically simple approach of targeting the extreme C-termini of proteins with antibodies (CTAbs) was investigated in proteins secreted by the human pathogen Streptococcus pyogenes. Target proteins were identified by a conventional proteomic approach and CTAbs produced against synthetic five amino acid peptides representing the C-terminus of each target protein. In every case where protein secretion was demonstrated (n = 20), CTAbs were successfully produced and bound specifically to the target protein (100% success rate). The apparent specificity was consistent with the structural heterogeneity of the C-termini of S. pyogenes proteins. The global specificity of CTAb binding was defined using a combinatorial library of synthetic peptides representing structural variants of the original synthetic immunogen. This is a systematic and comprehensive approach for the development of antibodies with defined specificity that can be used in a range of applications. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17407178&query_hl=1 ER - TY - JFULL T1 - Relation between chemokine receptor use, disease stage, and HIV-1 subtypes A and D: results from a rural Ugandan cohort. A1 - Kaleebu, P A1 - Nankya, IL A1 - Yirrell, DL A1 - Shafer, LA A1 - Kyosiimire-Lugemwa, J A1 - Lule, DB A1 - Morgan, D A1 - Beddows, S A1 - Weber, J A1 - Whitworth, JA J1 - J Acquir Immune Defic Syndr Y1 - 2007/05/01/ VL - 45 SN - 1525-4135 SP - 28 EP - 33 N2 - OBJECTIVES: To determine whether there are differences in coreceptor use in subjects infected with HIV-1 envelope subtypes A and D that could explain the differences in progression rates between these subtypes in a rural Ugandan cohort. METHODS: HIV-1 was subtyped in env by V3 sequencing or heteroduplex mobility assay. Coreceptor use was determined by the ability of the isolates to replicate in U87 CD4 cells expressing different coreceptors. The Fisher exact test was used to examine the relation between coreceptor use and subtype, clinical stage, and V3 charge. The Kruskall-Wallis nonparametric test was used to examine the association between median CD4 cell counts, coreceptor use, and subtype. Logistic regression was used to examine predicted coreceptor use at different CD4 groupings. RESULTS: Isolates from 66 participants were analyzed. Thirty-one were infected with subtype A, and 35 were infected with subtype D. Although this work was based on a small sample size, we found statistically significant differences. The probability of having an X4 virus was higher in subtype D infections than in subtype A infections among those with a non-AIDS clinical status (Fisher exact test, P = 0.040). Logistic regression analysis, in which we predicted X4 use by subtype and stratified by CD4 group, confirmed these findings among those with a CD4 count >200 cells/microL (likelihood ratio test, P = 0.003). R5 viruses were associated with higher median CD4 cell counts than X4 or X4/R5 (Kruskall-Wallis test, P = 0.0045). A V3 charge of +5 and greater was highly associated with X4 virus (Fisher exact test, P = 0.006). CONCLUSIONS: These subtype differences in coreceptor use may partially explain the faster progression rates we have previously reported in individuals infected with subtype D compared with subtype A. Our observations may have implications for the future use of coreceptor inhibitors in this population. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17310935&query_hl=1 ER - TY - JFULL T1 - Invasive group A streptococcal infection in injecting drug users and non-drug users in a single UK city. A1 - Curtis, SJ A1 - Tanna, A A1 - Russell, HH A1 - Efstratiou, A A1 - Paul, J A1 - Cubbon, M A1 - Sriskandan, S J1 - J Infect Y1 - 2007/05// VL - 54 SN - 0163-4453 SP - 422 EP - 426 N2 - OBJECTIVES: Injecting drug users (IDU) represent an increasing proportion of patients with invasive group A streptococcal (GAS) disease. Our aims were to characterise the clinical presentation and strains causing GAS bacteremia in IDU from a single UK city (Brighton and Hove), and to compare this patient group with non-drug users (non-DU) with GAS bacteremia. METHODS: Consecutive GAS blood culture isolates from twenty-two IDU and twenty-two non-DU presenting to the city hospital were studied. Clinical features, strain emm typing and superantigen toxin genotyping were investigated. RESULTS: GAS invasive disease presented differently in IDU compared to non-DU with a predominance of injection site abscesses and lower mortality in IDU. GAS strains from IDU were predominantly emm82 and emm83 types, which are uncommon in the UK and emm82 strains appeared clonal. The non-DU GAS strains demonstrated a broader range of emm types including most frequently emm1 and emm89. There was no major difference in superantigen gene profile between the isolate groups. CONCLUSION: The distinct presentation of invasive GAS disease in IDU compared with non-DU was associated with distinct emm types, a predominance of abscesses, and low mortality, although the small numbers preclude definitive conclusions. Further study is required to establish if these findings reflect strain differences or epidemiological differences in colonisation patterns and injecting practice. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17116332&query_hl=1 ER - TY - JFULL T1 - Targeting an E2F site in the mouse genome prevents promoter silencing in quiescent and post-mitotic cells. A1 - Tavner, F A1 - Frampton, J A1 - Watson, RJ J1 - Oncogene Y1 - 2007/04/26/ VL - 26 SN - 0950-9232 SP - 2727 EP - 2735 N2 - Previous studies have shown that the cell cycle-regulated B-myb promoter contains a conserved E2F binding site that is critical for repressing transcription in quiescent cells. To investigate its significance for permanent promoter silencing, we have inactivated this binding site in the mouse genome. Mice homozygous for the mutant B-mybmE2F allele were fully viable, however, B-myb transcription was derepressed during quiescence in mouse embryo fibroblasts (MEFs) derived from mutant animals. Moreover, it was found that mutation of the E2F site resulted in abnormal maintenance of B-myb expression in senescent MEFs and in differentiated brain tissue. These findings therefore reveal a direct and primary role for repressive E2F complexes in silencing gene expression in post-mitotic cells. Analysis of histone modifications at the promoter showed that histone H3 lysine 9 was constitutively acetylated throughout the cell cycle in homozygous mutant MEFs. This mouse system is the first description of an E2F site mutation in situ and will facilitate the study of E2F function in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17072340&query_hl=1 ER - TY - JFULL T1 - Dynamin 2 is required for the enhancement of HIV-1 infectivity by Nef. A1 - Pizzato, M A1 - Helander, A A1 - Popova, E A1 - Calistri, A A1 - Zamborlini, A A1 - Palù, G A1 - Göttlinger, HG J1 - Proc Natl Acad Sci U S A Y1 - 2007/04/17/ VL - 104 SN - 0027-8424 SP - 6812 EP - 6817 N2 - Nef is a virulence factor of HIV-1 and other primate lentiviruses that is crucial for rapid progression to AIDS. In cell culture, Nef increases the infectivity of HIV-1 progeny virions by an unknown mechanism. We now show that dynamin 2 (Dyn2), a key regulator of vesicular trafficking, is a binding partner of Nef that is required for its ability to increase viral infectivity. Dominant-negative Dyn2 or the depletion of Dyn2 by small interfering RNA potently inhibited the effect of Nef on HIV-1 infectivity. Furthermore, in Dyn2-depleted cells, this function of Nef could be rescued by ectopically expressed Dyn2 but not by Dyn1, a closely related isoform that does not bind Nef. The infectivity enhancement by Nef also depended on clathrin, because it was diminished in clathrin-depleted cells and profoundly inhibited in cells expressing the clathrin-binding domain of AP180, which blocks clathrin-coated pit formation but not clathrin-independent endocytosis. Together, these findings imply that the infectivity enhancement activity of Nef depends on Dyn2- and clathrin-mediated membrane invagination events. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17412836&query_hl=1 ER - TY - JFULL T1 - Evidence guiding the treatment of children with mycobacterial diseases - Editorial commentary A1 - Nicol, MP A1 - Wilkinson, RJ J1 - CLIN INFECT DIS Y1 - 2007/04/15/ VL - 44 SN - 1058-4838 SP - 1065 EP - 1066 ER - TY - JFULL T1 - Cowpox virus pneumonia in a domestic cat in Great Britain A1 - Schoniger, S A1 - Chan, DL A1 - Hollinshead, M A1 - Humm, K A1 - Smith, GL A1 - Beard, PM J1 - VET REC Y1 - 2007/04/14/ VL - 160 SN - 0042-4900 SP - 522 EP - 523 ER - TY - JFULL T1 - In vivo CD8+ T cell control of immunodeficiency virus infection in humans and macaques. A1 - Asquith, B A1 - McLean, AR J1 - Proc Natl Acad Sci U S A Y1 - 2007/04/10/ VL - 104 SN - 0027-8424 SP - 6365 EP - 6370 N2 - Forty million people are estimated to be infected with HIV-1, and only a small fraction of those have access to life-prolonging antiretroviral treatment. As the epidemic grows there is an urgent need for effective therapeutic and prophylactic vaccines. Nonhuman primate models of immunodeficiency virus infection are essential for the preclinical evaluation of candidate vaccines. To interpret the results of these trials, comparative studies of the human and macaque immune responses are needed. Despite the widespread use of macaques to evaluate vaccines designed to elicit a CD8(+) cytotoxic T lymphocyte (CTL) response, the efficiency with which CTL control immunodeficiency virus infections has not been compared between humans and macaques, largely because of difficulties in assaying the functional CTL response. We recently developed a method for estimating the rate at which CTLs kill cells productively infected with HIV-1 in humans in vivo. Here, using the same technique, we quantify the rate at which CTLs kill infected cells in macaque models of HIV infection. We show that CTLs kill productively infected cells significantly faster (P = 0.004) and that escape variants have significantly higher fitness costs (P = 0.003) in macaques compared with humans. These results suggest that it may be easier to elicit a protective CTL response in macaques than in humans and that vaccine studies conducted in macaques need to be interpreted accordingly. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17404226&query_hl=1 ER - TY - JFULL T1 - Recent HIV-1 infection in a high-risk Ugandan cohort: implications for Phase IIB test-of-concept HIV vaccine trials. A1 - Kebba, A A1 - Imami, N A1 - Bugembe-Lule, D A1 - Senkaali, D A1 - Kaleebu, P A1 - Grosskurth, H A1 - Gotch, F J1 - Pharmacogenomics Y1 - 2007/04// VL - 8 SN - 1462-2416 SP - 409 EP - 414 N2 - Assessment of vaccine efficacy on end points used in Phase IIB test-of-concept trials will require taking into consideration the effect of variables correlated with the end points and distribution of the variables within subgroups of the trial population. Here we report that evaluation of sexual activity in vaccinees and longitudinal collection of plasma viral load data from putative transmitters prior to transmission will contribute to the plausible assessment of efficacy against acquisition of infection. Data also suggest that efficacy on post-infection end points may depend on whether transmission pairs are matched or mismatched for HLA class I alleles. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17391079&query_hl=1 ER - TY - JFULL T1 - Which outcome measures to use for HTLV-1-Associated myelopathy? A1 - Adonis, AB A1 - Taylor, GP J1 - AIDS RES HUM RETROV Y1 - 2007/04// VL - 23 SN - 0889-2229 SP - 626 EP - 627 ER - TY - JFULL T1 - Activation of latent provirus: nEw therapy for HTLV-1-associated myelopathy/tropical spastic paraparesis? (a proof-of-concept study) A1 - Lezin, A A1 - Gillet, N A1 - Olindo, S A1 - Belrose, G A1 - Verlaeten, O A1 - Asquith, B A1 - Grandvaux, N A1 - Burny, A A1 - Smadja, D A1 - Cesaire, R A1 - Willems, L J1 - AIDS RES HUM RETROV Y1 - 2007/04// VL - 23 SN - 0889-2229 SP - 643 EP - 644 ER - TY - JFULL T1 - Helicobacter infection in the surfactant protein D-deficient mouse. A1 - Khamri, W A1 - Worku, ML A1 - Anderson, AE A1 - Walker, MM A1 - Hawgood, S A1 - Reid, KB A1 - Clark, HW A1 - Thursz, MR J1 - Helicobacter Y1 - 2007/04// VL - 12 SN - 1083-4389 SP - 112 EP - 123 N2 - BACKGROUND: Surfactant protein D (SP-D), a component of innate immunity, is expressed in the gastric mucosa and is up-regulated in the presence of Helicobacter infection. SP-D binds to Helicobacter in vitro, suggesting the involvement of SP-D in Helicobacter-induced immune responses. The aim of this study was to determine the role of SP-D in gastric epithelial defense in vivo. METHODS: Specific pathogen-free SP-D-deficient mice (SP-D(-/-)) and C57BL/6 wild-type controls were challenged by gavage with different doses of Helicobacter felis, a mouse-adapted Helicobacter strain. Mice were assessed for colonization rates and density of infection. Inflammatory responses were measured by neutrophil counting and T-cell responses by proliferation assays on spleen cells stimulated with H. felis sonicate. The in vitro effect of SP-D on Helicobacter uptake by monocyte-derived dendritic cells was assessed by confocal microscopy and FACS analyses. RESULTS: SP-D(-/-) mice were more susceptible to low-dose infectious challenge than C57BL/6 controls (p = .02). The density of colonization was higher in the SP-D(-/-) infected mice. Neutrophil infiltrates were lower in the SP-D(-/-) mice, particularly in the acid-secreting regions of the stomach. T-cell proliferative responses to Helicobacter antigen were reduced in SP-D(-/-) mice (p = .001) after 12 weeks infection. In vitro uptake of Helicobacter by dendritic cells was significantly enhanced in the presence of SP-D (p = .001). CONCLUSION: In the absence of SP-D, Helicobacter uptake by dendritic cells is impaired. This provides an explanation for the diminished inflammation and immune responses in the SP-D(-/-) mice. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17309747&query_hl=1 ER - TY - JFULL T1 - HTLV-1 can infect human lung epithelial cells and induce gene expression of cytokines, chemokines, and cell adhesion molecules A1 - Gillet, N A1 - Lezin, A A1 - Mosley, A A1 - Defoiche, J A1 - Belrose, G A1 - Verlaten, O A1 - Olindo, S A1 - Smadja, D A1 - Cesaire, R A1 - Macallan, D A1 - Asquith, B A1 - Bangham, C A1 - Burny, A A1 - Willems, L J1 - AIDS RES HUM RETROV Y1 - 2007/04// VL - 23 SN - 0889-2229 SP - 618 EP - 619 ER - TY - JFULL T1 - Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy. A1 - Kropf, P A1 - Baud, D A1 - Marshall, SE A1 - Munder, M A1 - Mosley, A A1 - Fuentes, JM A1 - Bangham, CR A1 - Taylor, GP A1 - Herath, S A1 - Choi, BS A1 - Soler, G A1 - Teoh, T A1 - Modolell, M A1 - Müller, I J1 - Eur J Immunol Y1 - 2007/04// VL - 37 SN - 0014-2980 SP - 935 EP - 945 N2 - Complex regulation of T cell functions during pregnancy is required to ensure materno-fetal tolerance. Here we reveal a novel pathway for the temporary suppression of maternal T cell responses in uncomplicated human pregnancies. Our results show that arginase activity is significantly increased in the peripheral blood of pregnant women and remarkably high arginase activities are expressed in term placentae. High enzymatic activity results in high turnover of its substrate L-arginine and concomitant reduction of this amino acid in the microenvironment. Amino acid deprivation is emerging as a regulatory pathway of lymphocyte responses and we assessed the consequences of this enhanced arginase activity on T cell responses. Arginase-mediated L-arginine depletion induces down-regulation of CD3 zeta, the main signalling chain of the TCR, and functional T cell hyporesponsiveness. Importantly, this arginase-mediated T cell suppression was reversible, as inhibition of arginase activity or addition of exogenous L-arginine restored CD3 zeta chain expression and T cell proliferation. Thus, L-arginine metabolism constitutes a novel physiological mechanism contributing to the temporary suppression of the maternal immune response during human pregnancy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17330821&query_hl=1 ER - TY - JFULL T1 - Control of CTL response to HTLV-1 virus by regulatory T cells in asymptomatic carriers, HAM/TSP patients, and ATL patients A1 - Toulza, F A1 - Nosaka, K A1 - Takiguchi, M A1 - Mitsuya, H A1 - Taylor, GP A1 - Bangham, CRM J1 - AIDS RES HUM RETROV Y1 - 2007/04// VL - 23 SN - 0889-2229 SP - 583 EP - 583 ER - TY - JFULL T1 - The role of T cell costimulatory molecule expression in human T-lymphotropic virus type-1 infection A1 - Kattan, TT A1 - Mosley, AAJ A1 - Tanaka, YY A1 - Taylor, GP A1 - Bangham, CRM J1 - AIDS RES HUM RETROV Y1 - 2007/04// VL - 23 SN - 0889-2229 SP - 610 EP - 610 ER - TY - JFULL T1 - Cell dynamics and immune response to BLV infection: A unifying model A1 - Florins, A A1 - Gillet, N A1 - Asquith, B A1 - Mortreux, F A1 - Wattel, E A1 - Burny, A A1 - Kettmann, R A1 - Bangham, C A1 - Willems, L J1 - AIDS RES HUM RETROV Y1 - 2007/04// VL - 23 SN - 0889-2229 SP - 589 EP - 589 ER - TY - JFULL T1 - Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity A1 - Fuselli, S A1 - Gilman, RH A1 - Chanock, SJ A1 - Bonatto, SL A1 - De Stefano, G A1 - Evans, CA A1 - Labuda, D A1 - Luiselli, D A1 - Salzano, FM A1 - Soto, G A1 - Vallejo, G A1 - Sajantila, A A1 - Pettener, D A1 - Tarazona-Santos, E J1 - PHARMACOGENOMICS J Y1 - 2007/04// VL - 7 SN - 1470-269X SP - 144 EP - 152 N2 - N-acetyltransferase 2 (NAT2), an important enzyme in clinical pharmacology, metabolizes antibiotics such as isoniazid and sulfamethoxazole, and catalyzes the transformation of aromatic and heterocyclic amines from the environment and diet into carcinogenic intermediates. Polymorphisms in NAT2 account for variability in the acetylator phenotype and the pharmacokinetics of metabolized drugs. Native Americans, settled in rural areas and large cities of Latin America, are under-represented in pharmacogenetics studies; therefore, we sequenced the coding region of NAT2 in 456 chromosomes from 13 populations from the Americas, and two from Siberia, detecting nine substitutions and 11 haplotypes. Variants *4 (37%), *5B (23%) and *7B (24%) showed high frequencies. Average frequencies of fast, intermediate and slow acetylators across Native Americans were 18, 56 and 25%, respectively. NAT2 intra-population genetic diversity for Native Americans is higher than East Asians and similar to the rest of the world, and NAT2 variants are homogeneously distributed across native populations of the continent. ER - TY - JFULL T1 - Future prospects for the MODS assay in multidrug-resistant tuberculosis diagnosis. A1 - Moore, DA J1 - Future Microbiol Y1 - 2007/04// VL - 2 SN - 1746-0921 SP - 97 EP - 101 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17661646&query_hl=1 ER - TY - JFULL T1 - Monocyte-dependent fibroblast CXCL8 secretion occurs in tuberculosis and limits survival of mycobacteria within macrophages. A1 - O'Kane, CM A1 - Boyle, JJ A1 - Horncastle, DE A1 - Elkington, PT A1 - Friedland, JS J1 - J Immunol Y1 - 2007/03/15/ VL - 178 SN - 0022-1767 SP - 3767 EP - 3776 N2 - CXCL8 is a chemokine that is implicated in the formation of tuberculous (TB) granulomas and in immunity to Mycobacterium tuberculosis (Mtb). Fibroblast chemokine secretion is important for modulating inflammatory responses in chronic lung disease and inflammatory arthritis but has not been investigated in the pathophysiology of TB. In this study, we used a cellular model to examine monocyte/macrophage-dependent stimulation of fibroblasts by Mtb in the regulation of chemokine secretion, particularly that of CXCL8. Human lung fibroblasts grown in collagen were stimulated with conditioned medium from Mtb-infected monocytes (CoMTb). CoMTb-induced prolonged dose-dependent, p38-mediated expression of stable CXCL8 mRNA by fibroblasts accompanied by a >10-fold increase in CXCL8 secretion (487 +/- 88 ng/ml vs 48.6 +/- 34 ng/ml in controls) at 120 h. Fibroblasts strongly expressed CXCL8 in vivo in human TB granulomas. Inhibition of TNF-alpha or IL-1 in CoMTb abrogated the induction of CXCL8 at a pretranscriptional level. CXCL8 secretion was NF-kappaB, C/EBP, and JNK dependent. Sustained NF-kappaB activation was demonstrated beyond 24 h in response to CoMTb. Exogenous CXCL8 reduced the survival of Mtb within macrophages, and inhibition of CXCL8 was associated with intracellular mycobacterial proliferation. These data show that fibroblasts have a previously unrecognized role in modulating inflammation in TB by their CXCL8-dependent contribution to cell recruitment and mycobacterial killing within the granuloma. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17339475&query_hl=1 ER - TY - JFULL T1 - Discovery of a vaccine antigen that protects mice from Chlamydia pneumoniae infection. A1 - Thorpe, C A1 - Edwards, L A1 - Snelgrove, R A1 - Finco, O A1 - Rae, A A1 - Grandi, G A1 - Guilio, R A1 - Hussell, T J1 - Vaccine Y1 - 2007/03/08/ VL - 25 SN - 0264-410X SP - 2252 EP - 2260 N2 - Chlamydiae are atypical intracellular bacteria that infect via mucosal surfaces causing, for example, trachoma, pneumonia, cervicitis, urethritis and infertility. Existing antibiotics are only partially effective and no vaccines are available. Using surface expressed or secreted proteins previously identified by genomics and proteomics we tested five as vaccines against intranasal challenge with Chlamydia pneumoniae. One antigen, LcrE, induced CD4+ and CD8+ T cell activation, type 1 cytokine secretion and neutralising antibodies and was completely effective in eliminating infection. Such antigens are highly conserved and essential to all Chlamydial species. The discovery of an effective vaccine for Chlamydiae pneumoniae has potential wide benefits for human health. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17275142&query_hl=1 ER - TY - JFULL T1 - Dissecting signalling pathways regulating tissue destruction in pulmonary tuberculosis A1 - Rand, L A1 - Green, JA A1 - Elkington, PTG A1 - Friedland, JS J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 48 EP - 48 ER - TY - JFULL T1 - Upregulation of OX40 and OX40 ligand during respiratory virus infection A1 - Cavanagh, MM A1 - Gwyer, E A1 - Snelgrove, RJ A1 - Hussell, T J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 27 EP - 27 ER - TY - JFULL T1 - AP endonuclease paralogues with distinct activities in DNA repair and bacterial pathogenesis A1 - Carpenter E A1 - Corbett A A1 - Thomson H A1 - Adacha J A1 - Jensen K A1 - Bergeron J A1 - Kasampalidis I A1 - Exley R A1 - Winterbotham M A1 - Tang C A1 - Baldwin GS A1 - Freemont P J1 - EMBO Journal Y1 - 2007/03// IS - 5 VL - 26 SN - 0261-4189 SP - 1363 EP - 1372 ER - TY - JFULL T1 - Impact of L-arginine deprivation on macrophage effector functions A1 - Choi, BS A1 - Clara-Martinez-Fal, I A1 - Corset, C A1 - Muller, I A1 - Kropf, P J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 83 EP - 83 ER - TY - JFULL T1 - Laboratory development and assay standardization for the evaluation of HIV vaccines in Africa and India A1 - Gilmour, J A1 - Stevens, G A1 - Gill, D A1 - Tarragona, T A1 - Seamons, L A1 - Birungi, J A1 - Kato, PK A1 - Semaganda, A A1 - Anzala, O A1 - Farah, B A1 - Ogola, S A1 - Indangasi, J A1 - Mhlanga, P A1 - Ndzamela, N A1 - Thakar, M A1 - Pujari, A A1 - Purandare, B A1 - Mishra, S A1 - Goonetilleke, N A1 - Moore, S A1 - Mahmoud, A A1 - Gotch, F A1 - Styles, T A1 - Stout, J A1 - Dally, L A1 - Boaz, MJ A1 - Hayes, P J1 - CYTOM PART B-CLIN CY Y1 - 2007/03// VL - 72B SN - 1552-4949 SP - 120 EP - 120 ER - TY - JFULL T1 - Mapping of citrullinated alpha-enolase antibodies to an immunodominant epitope with high sequence similarity to bacterial enolase A1 - Lundberg, K A1 - Kinloch, A A1 - Allison, H A1 - Sriskandan, S A1 - Moyes, D A1 - Venables, P J1 - ANN RHEUM DIS Y1 - 2007/03/01/ VL - 66 SN - 0003-4967 SP - A18 EP - A19 ER - TY - JFULL T1 - Long-term alteration of innate immunity at mucosal surfaces after recovery from viral infection A1 - Didierlaurent, A A1 - Snelgrove, R A1 - Low, L A1 - Sirard, JC A1 - Hussell, T J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 25 EP - 25 ER - TY - JFULL T1 - Leishmania transmission from the sand fly vector: parasite secretory gel A1 - Rogers, M A1 - Ilg, T A1 - Sizova, O A1 - Nikolaev, A A1 - Ferguson, M A1 - Muller, I A1 - Bates, P J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 63 EP - 63 ER - TY - JFULL T1 - Effect of HIV-1 infection on T-Cell-based and skin test detection of tuberculosis infection. A1 - Rangaka, MX A1 - Wilkinson, KA A1 - Seldon, R A1 - Van Cutsem, G A1 - Meintjes, GA A1 - Morroni, C A1 - Mouton, P A1 - Diwakar, L A1 - Connell, TG A1 - Maartens, G A1 - Wilkinson, RJ J1 - Am J Respir Crit Care Med Y1 - 2007/03/01/ VL - 175 SN - 1073-449X SP - 514 EP - 520 N2 - RATIONALE: Two forms of the IFN-gamma release assay (IFNGRA) to detect tuberculosis infection are available, but neither has been evaluated in comparable HIV-infected and uninfected persons in a high tuberculosis incidence environment. OBJECTIVE: To compare the ability of the T-SPOT.TB (Oxford Immunotec, Abingdon, UK), QuantiFERON-TB Gold (Cellestis, Melbourne, Australia), and Mantoux tests to identify latent tuberculosis in HIV-infected and uninfected persons. METHODS: A cross-sectional study of 160 healthy adults without active tuberculosis attending a voluntary counseling and testing center for HIV infection in Khayelitsha, a deprived urban South African community with an HIV antenatal seroprevalence of 33% and a tuberculosis incidence of 1,612 per 100,000. MEASUREMENTS AND MAIN RESULTS: One hundred and sixty (74 HIV(+) and 86 HIV(-)) persons were enrolled. A lower proportion of Mantoux results was positive in HIV-infected subjects compared with HIV-uninfected subjects (p < 0.01). By contrast, the proportion of positive IFNGRAs was not significantly different in HIV-infected persons for the T-SPOT.TB test (52 vs. 59%; p = 0.41) or the QuantiFERON-TB Gold test (43 and 46%; p = 0.89). Fair agreement between the Mantoux test (5- and 10-mm cutoffs) and the IFNGRA was seen in HIV-infected people (kappa = 0.52-0.6). By contrast, poor agreement between the Mantoux and QuantiFERON-TB Gold tests was observed in the HIV-uninfected group (kappa = 0.07-0.30, depending on the Mantoux cutoff). The pattern was similar for T-SPOT.TB (kappa = 0.18-0.24). Interpretation: IFNGRA sensitivity appears relatively unimpaired by moderately advanced HIV infection. However, agreement between the tests and with the Mantoux test varied from poor to fair. This highlights the need for prospective studies to determine which test may predict the subsequent risk of tuberculosis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17158278&query_hl=1 ER - TY - JFULL T1 - Old rhesus macaques treated with interleukin-7 show increased TREC levels and respond well to influenza vaccination. A1 - Aspinall, R A1 - Pido-Lopez, J A1 - Imami, N A1 - Henson, SM A1 - Ngom, PT A1 - Morre, M A1 - Niphuis, H A1 - Remarque, E A1 - Rosenwirth, B A1 - Heeney, JL J1 - Rejuvenation Res Y1 - 2007/03// VL - 10 SN - 1549-1684 SP - 5 EP - 17 N2 - Old age is accompanied by an increased incidence of infection and poorer responses to vaccination. In this proof of principle study, old female rhesus macaques (aged 18.5 to 23.9 years) were treated with recombinant simian interleukin-7 (IL-7) or saline, according to a two-phase regime. Treatment was not associated with bone loss as judged by plasma carboxy terminal telopeptide of type I collagen (ICTP) levels, nor with neutropenia. IL-7-treated animals showed an increase in the number of blood CD4(+) CD3(+) and CD8(+) CD3(+) T cells after both phases of treatment and a transient increase in the number of naïve (CD62L(+) CD45RA(+)) T cells for both CD4(+) and CD8(+) subsets after only the first treatment. Increases in TREC levels per T cell followed both phases of treatment, but were more prolonged after the second phase. Following vaccination with inactivated influenza strain A/PR/8/34, hemagglutination inhibition assays showed that half of the IL-7-treated animals showed a greater than eight-fold increase in antibody titer following the first challenge with the vaccine. In addition IL-7-treated animals showed higher numbers of central memory CD8(+) T cells compared to pretreatment levels with numbers greater than in the saline-treated group. Animals with the highest hemagglutination inhibition titers and the best proliferation against flu antigen were among those with the highest TREC per T cell levels after the second phase of treatment. Treatment of the elderly with IL-7 may provide an effective therapy to improve the immune system. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17378748&query_hl=1 ER - TY - JFULL T1 - Lactate acquisition promotes successful colonization of the murine genital tract by Neisseria gonorrhoeae. A1 - Exley, RM A1 - Wu, H A1 - Shaw, J A1 - Schneider, MC A1 - Smith, H A1 - Jerse, AE A1 - Tang, CM J1 - Infect Immun Y1 - 2007/03// VL - 75 SN - 0019-9567 SP - 1318 EP - 1324 N2 - Previous studies on Neisseria gonorrhoeae have demonstrated that metabolism of lactate in the presence of glucose increases the growth rate of the bacterium and enhances its resistance to complement-mediated killing. Although these findings in vitro suggest that the acquisition of lactate promotes gonococcal colonization, the significance of this carbon source to the survival of the gonococcus in vivo remains unknown. To investigate the importance of lactate utilization during Neisseria gonorrhoeae genital tract infection, we identified the gene lctP, which encodes the gonococcal lactate permease. A mutant that lacks a functional copy of lctP was unable to take up exogenous lactate and did not grow in defined medium with lactate as the sole carbon source, in contrast to the wild-type and complemented strains; the mutant strain exhibited no growth defect in defined medium containing glucose. In defined medium containing physiological concentrations of lactate and glucose, the lctP mutant demonstrated reduced early growth and increased sensitivity to complement-mediated killing compared with the wild-type strain; the enhanced susceptibility to complement was associated with a reduction in lipopolysaccharide sialylation of the lctP mutant. The importance of lactate utilization during colonization was evaluated in the murine model of lower genital tract infection. The lctP mutant was significantly attenuated in its ability to colonize and survive in the genital tract, while the complemented mutant exhibited no defect for colonization. Lactate is a micronutrient in the genital tract that contributes to the survival of the gonococcus. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17158905&query_hl=1 ER - TY - JFULL T1 - Suppressive valacyclovir therapy: impact on the population spread of HSV-2 infection. A1 - Williams, JR A1 - Jordan, JC A1 - Davis, EA A1 - Garnett, GP J1 - Sex Transm Dis Y1 - 2007/03// VL - 34 SN - 0148-5717 SP - 123 EP - 131 N2 - OBJECTIVES: Recent trial results demonstrate that the transmission probability of HSV-2 in monogamous couples is nearly halved by the use of valacyclovir as suppressive therapy. GOAL: The goal of this study is to understand the potential impact of suppressive valacyclovir therapy on the transmission of HSV-2 within a population. STUDY DESIGN: A mathematical model of HSV-2 epidemiology was developed which included suppressive therapy with the efficacy observed in the clinical trial. The model represented HSV-2 spread in an age and sexual activity stratified population where rates of viral shedding declined based on time since infection. The model tested the impact of a range of suppression coverage levels. RESULTS: Suppressive therapy reduces the population incidence of HSV-2. With coverage rates of 3.2%, the incidence of HSV-2 would be reduced by between 1.8% and 2.8%. Higher coverage rates were estimated to reduce the incidence of new cases up to 13%. Starting suppression closer to the time of infection also reduces the incidence of new cases. CONCLUSION: The impact of suppressive therapy on the HSV-2 epidemic is modest at current coverage levels but could be substantially increased with higher rates of diagnosis and a focus on coverage soon after infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17325600&query_hl=1 ER - TY - JFULL T1 - mda-5, but not RIG-I, is a common target for paramyxovirus V proteins A1 - Childs, K A1 - Stock, N A1 - Ross, C A1 - Andrejeva, J A1 - Hilton, L A1 - Skinner, M A1 - Randall, R A1 - Goodbourn, S J1 - VIROLOGY Y1 - 2007/03/01/ VL - 359 SN - 0042-6822 SP - 190 EP - 200 N2 - The induction of IFN-beta by the paramyxovirus PIV5 (formerly known as SV5) is limited by the action of the viral V protein that targets the cellular RNA helicase mda-5. Here we show that 12 other paramyxoviruses also target mda-5 by a direct interaction between the conserved cysteine-rich C-terminus of their V proteins and the helicase domain of mda-5. The inhibition of IFN-beta induction is not species-restricted, being observed in a range of mammalian cells as well as in avian cells, and we show that the inhibition of mda-5 function is also not restricted to mammalian cells. In contrast, the V proteins do not bind to the related RNA helicase RIG-I and do not inhibit its activity. The relative contributions of mda-5 and RIG-I to IFN-beta induction are discussed. (c) 2006 Elsevier Inc. All rights reserved. ER - TY - JFULL T1 - Networks regulate differential microglial MMP and TIMP expression in CNS tuberculosis A1 - Green, JA A1 - Elkington, PTG A1 - Rand, L A1 - Fry, J A1 - Dholakia, S A1 - Graeber, M A1 - Friedland, JS J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 31 EP - 31 ER - TY - JFULL T1 - Vitamin D in the treatment of pulmonary tuberculosis. A1 - Martineau, AR A1 - Honecker, FU A1 - Wilkinson, RJ A1 - Griffiths, CJ J1 - J Steroid Biochem Mol Biol Y1 - 2007/03// VL - 103 SN - 0960-0760 SP - 793 EP - 798 N2 - Vitamin D was used to treat tuberculosis in the pre-antibiotic era. New insights into the immunomodulatory properties of 1alpha,25-dihydroxy-vitamin D have rekindled interest in vitamin D as an adjunct to antituberculous therapy. We describe the historical use of vitamin D in tuberculosis treatment; discuss the mechanisms by which it may modulate host response to infection with Mycobacterium tuberculosis; and review three clinical trials and ten case series in which vitamin D has been used in the treatment of pulmonary tuberculosis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17223549&query_hl=1 ER - TY - JFULL T1 - The V beta specific response to bacterial superantigens is determined by concentration and HLA class II A1 - Llewelyn, M A1 - Sriskandan, S A1 - Terrazzini, N A1 - Cohen, J A1 - Altmann, DM J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 77 EP - 77 ER - TY - JFULL T1 - Predictors of CD4 count change over 8 months of follow up in HIV-1-infected patients with a CD4 count >= 300 cells/mu L who were assigned to 7.5 MIU interleukin-2 A1 - Fox, Z A1 - Antunes, F A1 - Davey, R A1 - Gazzard, B A1 - Klimas, N A1 - Labriola, A A1 - Losso, M A1 - Neaton, JD A1 - Phillips, AN A1 - Ruxrungtham, K A1 - Staszewski, S A1 - Weiss, L A1 - Lundgren, JD A1 - Abrams, DI A1 - Cooper, DA A1 - Abrams, DI A1 - Cooper, DA A1 - Darbyshire, JH A1 - Duncan, WR A1 - Emery, S A1 - Lane, HC A1 - Lehrman, S A1 - Lundgren, JD A1 - Neaton, JD A1 - Aguilar, L A1 - Angel, EB A1 - Aquilia, S A1 - Belloso, W A1 - Benetucci, J A1 - Bittar, V A1 - Cahn, P A1 - Casiro, A A1 - Contarelli, J A1 - Corral, J A1 - Daciuk, L A1 - David, D A1 - Ferrari, I A1 - Fridman, D A1 - Galache, V A1 - Guaragna, G A1 - Ivalo, S A1 - Laplume, H A1 - Lanusse, I A1 - Lasala, MB A1 - Lattes, R A1 - Lasovsky, J A1 - Lopardo, G A1 - Losso, M A1 - Lourtau, L A1 - Lupo, S A1 - Maranzana, A A1 - Marson, C A1 - Massera, L A1 - Sanchez, MD A1 - Somenzini, C A1 - Tocci, M A1 - Algar, S A1 - Anderson, J A1 - Baker, D A1 - Blavius, K A1 - Bloch, M A1 - Boyle, M A1 - Bradford, D A1 - Britton, P A1 - Carrall, L A1 - Carr, A A1 - Chuah, J A1 - Curry, M A1 - D'Arcy-Evans, C A1 - Dobson, P A1 - Doong, N A1 - Egan, C A1 - Ferguson, W A1 - Finlayson, R A1 - French, M A1 - Frater, A A1 - Gold, J A1 - Habel, P A1 - Haig, K A1 - Holland, R A1 - Hyland, N A1 - Hoy, J A1 - Hudson, J A1 - James, R A1 - Leung, J A1 - Lowe, K A1 - MacRae, K A1 - McMurchie, M A1 - Medland, N A1 - Miller, S A1 - Murray, J A1 - Newman, R A1 - Orth, D A1 - Patching, J A1 - Primrose, R A1 - Ree, H A1 - Richardson, R A1 - Rogers, G A1 - Roney, J A1 - Roth, N A1 - Sarangapany, J A1 - Shaw, D A1 - Silberberg, C A1 - Skett, J A1 - Williams, L A1 - Soo, TM A1 - Sowden, D A1 - Street, A A1 - Vale, R A1 - Villella, C A1 - Walker, A A1 - Watson, A A1 - Wendt, N A1 - Wood, H A1 - Youds, D A1 - Aichelburg, A A1 - Rieger, A A1 - Vetter, N A1 - Clumeck, N A1 - De Wit, S A1 - Kabeya, K A1 - O'Doherty, E A1 - Amorim, CD A1 - Basso, CR A1 - Lewi, DS A1 - Pereira, LC A1 - da Silva, M A1 - Souza, TNL A1 - Angel, J A1 - Bouchard, PR A1 - Clark, F A1 - Cohen, J A1 - Dambreville, M A1 - Ellis, M A1 - Fiset, S A1 - Foster, A A1 - Fraser, C A1 - Gagnon, S A1 - Gilmour, J A1 - Guenette, R A1 - Haldane, H A1 - Hawley-Foss, N A1 - Hyndman, S A1 - Johnston, L A1 - Jubinville, N A1 - Juneau, F A1 - Kelleher, L A1 - LaPointe, L A1 - Latendre-Paquette, J A1 - Lindemulder, A A1 - Mashinter, L A1 - Lefebvre, E A1 - McFarland, N A1 - Morisseau, C A1 - O'Neill, R A1 - Piche, A A1 - Ralph, E A1 - Rouleau, D A1 - Routy, JP A1 - Sandre, R A1 - Schmidt, S A1 - Shafran, S A1 - Smaill, F A1 - Stromberg, D A1 - Trepanier, JM A1 - Trottier, S A1 - Veal, S A1 - Walmsley, S A1 - Weiss, K A1 - Williams, K A1 - Young, M A1 - Zaleschuk, B A1 - Zarowny, D A1 - Baadegaard, B A1 - Black, F A1 - Boedker, K A1 - Gerstoft, J A1 - Jensen, L A1 - Mathiesen, L A1 - Nielsen, H A1 - Pedersen, C A1 - Petersen, D A1 - Aboulker, JP A1 - Baakili, A A1 - Bengrait, N A1 - Bensalem, M A1 - Berthe, H A1 - Bloche, M A1 - Bazin, C A1 - Boue, F A1 - Bouvet, E A1 - Brancon, C A1 - Capitant, C A1 - Ceppi, C A1 - Cheneau, C A1 - Coutellier, A A1 - Chennebault, JM A1 - Coquet, F A1 - De Truchis, P A1 - Delavalle, AM A1 - Frixon-Marin, V A1 - Gastaut, JA A1 - Delfraissy, F A1 - Eliaszeicz, M A1 - Gallais, H A1 - Gataut, JA A1 - Gilquin, J A1 - Gonzalez-Canali, G A1 - Gaudebout, C A1 - Goujard, C A1 - Hoen, B A1 - Honore, P A1 - Jarousse, B A1 - Lang, JM A1 - Lefebvre, B A1 - Levy, Y A1 - Loison, J A1 - Maignan, A A1 - Meynard, JL A1 - Michon, C A1 - Mole, M A1 - Marsal, L A1 - Matheron, S A1 - Mortier, E A1 - Oksenhendler, E A1 - Poirier, S A1 - Picard-Dahan, C A1 - Ravaux, I A1 - Raffi, F A1 - Raguin, G A1 - Reynes, J A1 - Rozenbaum, W A1 - Salmon, D A1 - Simon, A A1 - Spiridon, G A1 - Viard, JP A1 - Vidal, M A1 - Weiss, L A1 - Zucman, D A1 - Bergmann, F A1 - Brockmeyer, N A1 - Faetkenheuer, G A1 - Fenske, S A1 - Gey, D A1 - Goebel, FD A1 - Goetsch, M A1 - Hartmann, M A1 - Klinker, H A1 - Kremer, G A1 - Mantzsch, K A1 - Mauss, S A1 - Rockstroh, J A1 - Rotty, J A1 - Rund, E A1 - Schneider, K A1 - Schuermann, D A1 - Staszweski, S A1 - Tilmann, K A1 - Vogel, M A1 - Bentwich, Z A1 - Drora, G A1 - Kedem, E A1 - Lang, R A1 - Levi, I A1 - Maayan, S A1 - Magen, E A1 - Mamorsky, M A1 - Pilpul, A A1 - Pollack, S A1 - Sthoeger, Z A1 - Vered, H A1 - Yust, I A1 - Lyons, F A1 - Mulcahy, F A1 - Rochford, A A1 - Auiti, F A1 - Angarano, G A1 - Bertelli, D A1 - Bini, T A1 - Bruno, R A1 - Cadeo, GP A1 - Carosi, G A1 - Monforte, AD A1 - Del Giacco, S A1 - Di Pietro, M A1 - Esposito, R A1 - Filice, G A1 - Gavazzeni, G A1 - Guaraldi, G A1 - Indiveri, F A1 - Lazzarin, A A1 - Mazzotta, F A1 - Minolli, L A1 - Montroni, M A1 - Moroni, M A1 - Nozza, S A1 - Pastor, G A1 - Poli, G A1 - Raise, E A1 - Romagnani, S A1 - Rusconi, V A1 - Sacchi, P A1 - Suter, F A1 - Tambussi, G A1 - Tirelli, U A1 - Fraser, H A1 - Iwamoto, A A1 - Kikuchi, Y A1 - Mori, M A1 - Nakamura, T A1 - Odawara, T A1 - Oka, S A1 - Shirasaka, T A1 - Takano, M A1 - To, J A1 - Ueta, C A1 - El Filali, K A1 - Erradey, I A1 - Himmich, H A1 - Blok, W A1 - Borleffs, J A1 - Bravenboer, B A1 - Bronveld, W A1 - Claessen, F A1 - Duurvoort, M A1 - Ferwerda, J A1 - Frissen, P A1 - Hulshoff, N A1 - Juttman, J A1 - Kauffmann, R A1 - Koopmans, P A1 - Kroon, F A1 - Lowe, S A1 - Leemhuis, M A1 - Meenhorst, P A1 - de Boer, LP A1 - Reiss, P A1 - Reinders-Folmer, S A1 - Richter, C A1 - Santegoets, R A1 - Schoemaker, M A1 - Schrey, G A1 - Sprenger, H A1 - Ten Veen, J A1 - Tessalaar, J A1 - van der Ende, M A1 - van der Vall, H A1 - van Eeden, A A1 - van Leeuwen, R A1 - Vermeulen, J A1 - ten Kate, RW A1 - van Boxtel, R A1 - van Eden, A A1 - van de Ven, B A1 - van der Meulen, P A1 - ten Napei, C A1 - Vriesendrop, R A1 - Bruun, J A1 - Bakowska, E A1 - Beniowski, M A1 - Boron-Kaczmarska, A A1 - Gasiorowski, J A1 - Gxadysz, A A1 - Horban, A A1 - Knysz, B A1 - Mularska, E A1 - Pynka, M A1 - Szymczak, A A1 - Aldir, I A1 - Antunes, F A1 - Doroana, M A1 - Duque, L A1 - Mansinho, K A1 - Pinto, I A1 - Valadas, E A1 - Vera, J A1 - Foo, E A1 - Panchalingham, A A1 - Lim, PL A1 - Paton, N A1 - Peperstraete, B A1 - Quek, A A1 - Alcazar-Caballero, R A1 - Arrizabalaga, J A1 - Bouza, E A1 - Cepeda, C A1 - de Barron, X A1 - Jimenez, MC A1 - Clotet, B A1 - Cortes, L A1 - Domingo, P A1 - Fernandez, P A1 - Fernandez-Cruz, E A1 - Fuster, M A1 - Gatell, J A1 - Gijon, P A1 - Gil, I A1 - Gonzales-Lahoz, J A1 - Gonzalez, A A1 - Hernandez, M A1 - Iribarren, J A1 - Jimenez, M A1 - Knobel, H A1 - Leon, A A1 - Lopez, JC A1 - Lozano, A A1 - Lopez, P A1 - Moreno, J A1 - Munoz, R A1 - Padilla, B A1 - Parras, A A1 - Pastor, A A1 - Pedreira, J A1 - Pristo, J A1 - Pena, J A1 - Roca, V A1 - Rubio, R A1 - de Rivera, JS A1 - Sanz, J A1 - Tamargo, L A1 - Torres, R A1 - Pehrson, PO A1 - Sandstrom, E A1 - Bernasconi, E A1 - Gurtner, V A1 - Magenta, L A1 - Ampunpong, U A1 - Bowonwatnuwong, C A1 - Chanchai, P A1 - Chetchotisakd, P A1 - Chuenyam, T A1 - Duncombe, C A1 - Horsakulthai, M A1 - Kantipong, P A1 - Liddy, J A1 - Phanuphak, P A1 - Pongsurachet, V A1 - Ruxrungtham, K A1 - Seekaew, S A1 - Sonjai, A A1 - Subsri, N A1 - Suwanagool, S A1 - Techasathit, W A1 - Wankoon, J A1 - Adebiyi, A A1 - Aldam, D A1 - Alexander, I A1 - Angus, B A1 - Barber, T A1 - Bonnington, S A1 - Care, C A1 - Carroll, A A1 - Cornforth, D A1 - Donaldson, O A1 - Druiff, L A1 - Easterbrook, P A1 - Edwards, B A1 - Ellis, C A1 - Erradey, I A1 - El Filali, K A1 - Fisher, M A1 - Fox, R A1 - Gazzard, B A1 - Harrison, A A1 - Herman, S A1 - Heald, L A1 - Higgs, C A1 - Himmich, H A1 - Jendrulek, I A1 - Johnson, M A1 - Judges, L A1 - Karim, F A1 - Kinghorn, G A1 - Laurenti, J A1 - Lee, C A1 - Leen, C A1 - Legg, K A1 - Lyons, F A1 - Maw, R A1 - MacConachie, A A1 - McKernan, S A1 - McLean, L A1 - McMillan, A A1 - Mguni, S A1 - Morris, S A1 - Mulchay, F A1 - Mullan, D A1 - Mullaney, S A1 - Murphy, M A1 - Nunn, A A1 - Ong, E A1 - Owen, M A1 - Palfreeman, A A1 - Perry, N A1 - Peters, B A1 - Pozniak, A A1 - Rochford, A A1 - Ronan, A A1 - Skinner, C A1 - Stroud, C A1 - Takawira, M A1 - Tamm, N A1 - Thomas, R A1 - Yee, TT A1 - Vanthuyne, A A1 - Wansborough-Jones, M A1 - Weber, J A1 - White, D A1 - Wilkins, E A1 - Wiselka, M A1 - Williams, I A1 - Waugh, M A1 - Wotherspoon, J A1 - Youle, M A1 - Doyle, M A1 - Goodwin, E A1 - Luskin-Hawk, R A1 - Sullivan, J A1 - Verheggen, R A1 - Abrams, D A1 - Baxter, J A1 - Besch, CL A1 - Child, C A1 - Cohn, D A1 - Cooper, P A1 - El-Sadr, W A1 - Farrough, M A1 - Fisher, E A1 - Fuentes, L A1 - Goodwin, E A1 - Gordin, F A1 - Graeber, C A1 - Kelly, ME A1 - Kostman, J A1 - Labriola, A A1 - Lattanzi, K A1 - MacArthur, R A1 - Makohon, L A1 - Markowitz, NP A1 - Martinez, N A1 - Mastro-Polak, D A1 - Mitchell, V A1 - Mushatt, D A1 - Patterson, K A1 - Perez, G A1 - Rosmarin, C A1 - Rouff, JR A1 - Saldanha, J A1 - Sampson, J A1 - Sawyer, R A1 - Standridge, B A1 - Sullivan, J A1 - Sweeton, B A1 - Tedaldi, E A1 - Thompson, M A1 - Valencia, P A1 - Verlinghieri, G A1 - Walker, J A1 - Watson, V A1 - Williams, B A1 - Armstrong, A A1 - Banks, S A1 - Blazes, D A1 - Barile, A A1 - Coelho, L A1 - Dennis, M A1 - Flaks, H A1 - Gilcrest, J A1 - Gittens, K A1 - Hopper, S A1 - Humphries, MJ A1 - Spooner, K A1 - Tamminga, CL A1 - Vita, J A1 - Wegner, SA A1 - Wortmann, G A1 - Bisby, N A1 - Blake, W A1 - Brown, S A1 - Chilliade, P A1 - Cole, T A1 - Elliot, K A1 - Geisler, C A1 - Goetz, M A1 - Gomez-Perez, E A1 - Gordin, F A1 - Helman, J A1 - Klimas, N A1 - Labriola, A A1 - Nahass, R A1 - LeFlore, D A1 - Marston, B A1 - Obregon, M A1 - Petrolati, J A1 - Pitrak, DL A1 - Roland, R A1 - Rosa, C A1 - Rossman, B A1 - Wirtz, SS A1 - Schuck, S A1 - Scretchings, T A1 - Simon, G A1 - Smith, M A1 - Standridge, B A1 - Summers, K A1 - Werhane, MJ A1 - Arduino, R A1 - Bell, B A1 - Breaux, K A1 - Cuervo, H A1 - Hale, C A1 - Lewis, S A1 - Mall, M A1 - Mora, F A1 - Diez, MM A1 - Okhuysen, P A1 - Rodriguez-Barradas, M A1 - Schrader, SR A1 - Healy, L A1 - Kaszubski, C A1 - Kolber, M A1 - Tanner, T A1 - Armstrong, J A1 - Dahlke, J A1 - Johnson, L A1 - Kaminski, P A1 - Rhame, F A1 - Shoden, C A1 - Temesgen, Z A1 - Urbanich, M A1 - Valenti, S A1 - Zervos, M A1 - Davey, R A1 - Barrick, B A1 - Chaitt, D A1 - Hahn, B A1 - Lane, C A1 - Martell, D A1 - McNay, L A1 - Metcalf, J A1 - Powers, A A1 - Tavel, JA A1 - Loveless, K A1 - Martinez, N A1 - Peterson, S A1 - Sampson, J A1 - Sweek, S A1 - Abrams, D A1 - Albrecht, H A1 - Antoine, N A1 - Kelly, ME A1 - Pell, P A1 - Belloso, W A1 - Gatell, JM A1 - Hoy, J A1 - Lifson, A A1 - Pederson, C A1 - Rhame, F A1 - El-Sadr, W A1 - Borup, L A1 - Dragsted, UB A1 - Greve, AF A1 - Jensen, K A1 - Lundgren, J A1 - Mollerup, D A1 - Pearson, M A1 - Phillips, A A1 - Aboulhab, J A1 - Angus, B A1 - Babiker, A A1 - Cordwell, B A1 - Darbyshire, J A1 - Hack, L A1 - Hooker, M A1 - Moraes, Y A1 - Newberry, D A1 - Nuwagaba-Biribonwoha, H A1 - van Hooff, F A1 - Denning, E A1 - Klemme, LH A1 - Carey, C A1 - Chan, F A1 - Cooper, D A1 - Courtney-Rodgers, D A1 - Drummond, F A1 - Emery, S A1 - Jacoby, S A1 - Law, M A1 - Stewart, M A1 - Pett, S A1 - Alloo, Z A1 - Bebchuk, J A1 - Bollenbeck, P A1 - DuChene, AG A1 - Fosdick, L A1 - Harrison, M A1 - Krum, E A1 - Larson, G A1 - Lifson, A A1 - Meger, S A1 - Neaton, J A1 - Nelson, R A1 - Quan, SFL A1 - Schultz, T A1 - Telke, S A1 - Thackeray, L A1 - Thompson, G A1 - Wentworth, D A1 - Wyman, N A1 - Duncan, W A1 - Ferguson, E A1 - Fox, L A1 - Gettinger, N A1 - Herrera, J A1 - Lehrman, S A1 - Luzar, MA A1 - Maeshiro, M A1 - Martinez, A A1 - Oseekey, K A1 - Baigent, G A1 - Capra, W A1 - Duliege, AM A1 - Fitzgerald, L A1 - Kwakkelstein, M A1 - Maral, J A1 - O'Hara, M A1 - Sahner, D A1 - Weber, C A1 - Adam-Perchec, C A1 - Barron, N A1 - Bell, ML A1 - Dolan, S A1 - Eckstrand, J A1 - Hicks, S A1 - McAuley, G A1 - Beck, S A1 - Brown, S A1 - Rupert, A A1 - ESPRIT Res Grp J1 - HIV MED Y1 - 2007/03// VL - 8 SP - 112 EP - 123 N2 - Background ESPRIT is a randomized trial comparing the clinical impact of interleukin (IL)-2 plus antiretrovirals vs antiretrovirals alone. Identification of factors that influence the relationship between IL-2 and CD4 count recovery will enable better personalization of treatment with IL-2 in HIV-1-positive individuals. The IL-2 induction phase consists of three dosing cycles over 6-8 months (7.5 MIU twice a day, for 5 days every 8 weeks).Methods We included patients initiating IL-2 at the 7.5 MIU dose with an 8-month CD4 count, measured at least 30 days after their last cycle. We identified baseline predictors of CD4 count changes over 8 months using linear regression.Results Of 2090 patients assigned IL-2, 1673 (80%) were included in the analysis. The median (interquartile range) baseline CD4 count was 461 (370, 587) cells/mu L with a median increase of 233 (90, 411) cells/mu L at month 8. After adjustments, significant predictors of CD4 count change included CD4 nadir (29.8 cells/mu L greater increase per 100 cells/mu L higher; P < 0.0001), last CD4 count before baseline (mean 36.0 cells/mu L greater increase per 100 cells/mu L higher; P < 0.0001), time from antiretroviral start to baseline (8.3 cells/mu L smaller increase per year longer; P=0.001), age (11.7 cells/mu L smaller increase per 5 years older; P=0.005) and race (79.7 cells/mu L greater increase for black patients vs white patients; P=0.003). A linear relationship existed between total IL-2 dose in the first cycle and CD4 count change (73.1 cells/mu L greater increase per 15 MIU higher; P < 0.0001).Conclusions Prior nadir and current CD4 counts, age and IL-2 dose are major determinants of CD4 increases induced by with intermittent administration of IL-2 in HIV-1-positive individuals on antiretrovirals. The clinical function of these induced CD4 cells is under study. 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 - Innate and adaptive immune interactions during respiratory infection A1 - Hussell, T J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 24 EP - 24 ER - TY - JFULL T1 - A gateway to disease: migration of HTLV-1-infected lymphocytes across human brain endothelial cells A1 - Barnard, AL A1 - Taylor, GP A1 - Tanaka, Y A1 - Bangham, CRM J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 32 EP - 32 ER - TY - JFULL T1 - SseL, a Salmonella deubiquitinase required for macrophage killing and virulence. A1 - Rytkönen, A A1 - Poh, J A1 - Garmendia, J A1 - Boyle, C A1 - Thompson, A A1 - Liu, M A1 - Freemont, P A1 - Hinton, JC A1 - Holden, DW J1 - Proc Natl Acad Sci U S A Y1 - 2007/02/27/ VL - 104 SN - 0027-8424 SP - 3502 EP - 3507 N2 - Expression of the Salmonella enterica serovar Typhimurium pathogenicity island 2 (SPI-2) type III secretion system is controlled by the two-component regulatory system SsrA-SsrB. We used a transcriptomic approach to help define the SsrA-SsrB regulon. We identified a gene encoding an uncharacterized effector (SseL) whose translocation into host cells depends on the SPI-2 secretion system. SseL has similarities to cysteine proteases with deubiquitinating activity. A GST-SseL fusion protein specifically hydrolyzed mono- and polyubiquitin substrates in vitro with a preference for K63-linked ubiquitin chains. Ubiquitin-modified proteins accumulated in macrophages infected with Salmonella sseL mutant strains but to a lesser extent when infected with bacteria expressing active protein, demonstrating that SseL functions as a deubiquitinase in vivo. Salmonella sseL mutant strains did not show a replication defect or induce altered levels of cytokine production upon infection of macrophages but were defective for a delayed cytotoxic effect and were attenuated for virulence in mice. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17360673&query_hl=1 ER - TY - JFULL T1 - Kaposi sarcoma herpesvirus-encoded vFLIP and vIRF1 regulate antigen presentation in lymphatic endothelial cells. A1 - Lagos, D A1 - Trotter, MW A1 - Vart, RJ A1 - Wang, HW A1 - Matthews, NC A1 - Hansen, A A1 - Flore, O A1 - Gotch, F A1 - Boshoff, C J1 - Blood Y1 - 2007/02/15/ VL - 109 SN - 0006-4971 SP - 1550 EP - 1558 N2 - Kaposi sarcoma-associated herpesvirus (KSHV) is etiologically linked to Kaposi sarcoma (KS), a tumor genetically akin to lymphatic endothelial cells (LECs). We obtained the immune transcriptional signature of KS and used KSHV-infected LECs (KLECs) as an in vitro model to determine the effects of KSHV on transcription and expression of genes involved in immunity. The antigen presentation, interferon (IFN) response, and cytokine transcriptomes of KLECs resemble those of KS. Transcription of genes involved in class I presentation is increased in KS and after infection of LECs, but MHC-I and ICAM-1 surface expression are down-regulated in KLECs. Inhibition of IFN induction of MHC-I transcription indicates that KSHV regulates MHC-I transcription. We show that MHC-I transcription is regulated by the KSHV-encoded viral FLICE inhibitory protein (vFLIP) and by viral IFN regulatory factor 1 (vIRF1). vFLIP up-regulates MHC-I and ICAM-1 through activation of NF-kappaB and stimulates T-cell proliferation, revealing a mechanism to prevent uncontrolled viral dissemination. In contrast, vIRF1 inhibits basal and IFN- and vFLIP-induced MHC-I transcription and surface expression through its interaction with the transcriptional coactivator p300, contributing to immune evasion. We propose that regulation of MHC-I by vFLIP and vIRF1 plays a crucial role in the host-pathogen equilibrium. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17047149&query_hl=1 ER - TY - JFULL T1 - Improving the treatment of hepatitis C infection in the UK. A1 - Cooke, GS A1 - Main, J J1 - Expert Opin Pharmacother Y1 - 2007/02// VL - 8 SN - 1744-7666 SP - 183 EP - 191 N2 - The UK lags behind its European neighbours in the identification and treatment of hepatitis C virus infection. Having recognised this problem, national guidelines are evolving based on detailed examination of clinical evidence. This article reviews recommended treatments for hepatitis C virus infection in the UK, recent advances in the understanding of how to use these treatments and new developments. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17257088&query_hl=1 ER - TY - JFULL T1 - Altered monocyte cyclooxygenase response to lipopolysaccharlde in type 1 diabetes.(vol 55, pg 3439, 2006) A1 - Beyan, H A1 - Goodier, MR A1 - Nawroly, NS A1 - Hawa, MI A1 - Bustin, SA A1 - Ogunkolade, WB A1 - Londei, M A1 - Yousaf, N A1 - Leslie, RDG J1 - DIABETES Y1 - 2007/02// VL - 56 SN - 0012-1797 SP - 549 EP - 549 ER - TY - JFULL T1 - Swine cysticercosis hotspots surrounding Taenia solium tapeworm carriers. A1 - Lescano, AG A1 - Garcia, HH A1 - Gilman, RH A1 - Guezala, MC A1 - Tsang, VC A1 - Gavidia, CM A1 - Rodriguez, S A1 - Moulton, LH A1 - Green, JA A1 - Gonzalez, AE A1 - Cysticercosis Working Group in Peru J1 - Am J Trop Med Hyg Y1 - 2007/02// VL - 76 SN - 0002-9637 SP - 376 EP - 383 N2 - We estimated the Taenia solium swine cysticercosis risk gradient surrounding tapeworm carriers in seven rural communities in Peru. At baseline, the prevalences of taeniasis by microscopy and swine cysticercosis by serology were 1.2% (11 of 898) and 30.8% (280 of 908), respectively. The four-month cumulative seroincidence was 9.8% (30 of 307). The unadjusted swine seroprevalence and seroincidence rates increased exponentially by 12.0% (95% confidence [CI] = 9.7-14.3%) and 32.8% (95% CI = 25.0-41.0%), respectively when distance to carriers decreased by half. Swine seroprevalence was 18.4% at > 500 meters from a carrier, 36.5% between 51 and 500 meters, and 68.9% within 50 meters (P < 0.001). Swine seroincidence also displayed a strong gradient near tapeworm carriers (3.8%, 12.2%, and 44.0%; P < 0.001). Within 50 meters, swine seroprevalence appeared unaffected if the owners harbored tapeworms, although pigs owned by a tapeworm carrier had a four times higher seroincidence compared with other pigs (P = 0.005). In rural areas, swine cysticercosis occurs in high-risk hotspots around carriers where control interventions could be delivered. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17297051&query_hl=1 ER - TY - JFULL T1 - IL-1 beta stimulates divergent upper and lower airway epithelial cell CCL5 secretion. A1 - Thomas, LH A1 - Wickremasinghe, MI A1 - Friedland, JS J1 - Clin Immunol Y1 - 2007/02// VL - 122 SN - 1521-6616 SP - 229 EP - 238 N2 - Direct infection of respiratory epithelium induces chemokine secretion and upregulates cytokine networks, which are central in regulating inflammation. IL-1beta may have a pivotal role in such networks. Differential control of chemokine secretion within specific airway regions, which have distinct roles in immunity, is not well characterized. We investigated IL-1beta-induced CXCL8 and CCL5 secretion from primary normal human bronchial and small airway epithelial cells, and the alveolar cell line A549. CXCL8 was secreted by all cells, but only lower airway cells secreted CCL5. IL-1beta induced nuclear translocation of NF-kappaB (p50, p65 and c-Rel subunits), NF-IL-6 and AP-1, each with distinct kinetics. This was associated with high level CCL5 promoter activation, via transcription factor binding to multiple regions, including NF-kappaB, AP-1 and NF-IL-6 sites. The IL-1-related cytokine IL-18 did not drive or modulate IL-1beta-induced CXCL8 or CCL5 secretion. In summary, IL-1beta, but not IL-18, induces transcription-dependent lower airway epithelial cell-specific CCL5 secretion. Differential chemokine secretion may have profound effects on local leukocyte influx within upper or lower airways exposed to airway infection or environmental stimuli, which might then require different anti-inflammatory strategies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17126080&query_hl=1 ER - TY - JFULL T1 - Monocytes infected with Mycobacterium tuberculosis regulate MAP kinase-dependent astrocyte MMP-9 secretion. A1 - Harris, JE A1 - Green, JA A1 - Elkington, PT A1 - Friedland, JS J1 - J Leukoc Biol Y1 - 2007/02// VL - 81 SN - 0741-5400 SP - 548 EP - 556 N2 - Tuberculosis (TB) of the CNS (CNS-TB) carries a high mortality. Disease pathology is characterized by widespread destruction of CNS tissues. Matrix metalloproteinase-9 (MMP-9) is able to catabolyze specific components of the CNS tissue matrix and blood-brain barrier. Increased cerebrospinal fluid MMP-9 concentrations are associated with tissue damage, leukocyte infiltration, and death in CNS-TB. Using zymography, Western analysis, and transcription factor assays, we investigated mechanisms regulating MMP-9 activity in CNS-TB. We demonstrate that conditioned media from monocytes infected with Mycobacterium tuberculosis (CoMTB) induce MMP-9 secretion from astrocytes (U373-MG). IL-1beta and TNF-alpha are necessary but not sufficient for such induction of astrocyte MMP-9 secretion. CoMTB up-regulates AP-1 DNA-binding activity, and the c-Jun, FosB, and JunB subunits are particularly increased. MMP-9 secretion from CoMTB-stimulated astrocytes is dependent on the activity of p38, Erk, and Jnk MAPKs. Phosphorylation of p38, Erk, and Jnk is activated rapidly, peaking 30 min poststimulation with CoMTB. Inhibition of IL-1beta but not TNF-alpha in CoMTB decreases p38, Erk, and Jnk activity in astrocytes. Consistently, IL-1beta signals through the MAPK cascade at physiological levels, whereas TNF-alpha, IL-6, IL-10, CCL-2, CCL-5, and CXCL-8 (all present in CoMTB) do not. In summary, the data suggest that monocyte-dependent cytokine networks may play a key role in the development of a matrix-degrading environment during CNS-TB. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17079649&query_hl=1 ER - TY - JFULL T1 - Precise identification of a human immunodeficiency virus type 1 antigen processing mutant. A1 - Zimbwa, P A1 - Milicic, A A1 - Frater, J A1 - Scriba, TJ A1 - Willis, A A1 - Goulder, PJ A1 - Pillay, T A1 - Gunthard, H A1 - Weber, JN A1 - Zhang, HT A1 - Phillips, RE J1 - J Virol Y1 - 2007/02// VL - 81 SN - 0022-538X SP - 2031 EP - 2038 N2 - Human immunodeficiency virus type 1 (HIV-1) evokes a strong immune response, but the virus persists. Polymorphisms within known antigenic sites result in loss of immune recognition and can be positively selected. Amino acid variation outside known HLA class I restricted epitopes can also enable immune escape by interfering with the processing of the optimal peptide antigen. However, the lack of precise rules dictating epitope generation and the enormous genetic diversity of HIV make prediction of processing mutants very difficult. Polymorphism E169D in HIV-1 reverse transcriptase (RT) is significantly associated with HLA-B*0702 in HIV-1-infected individuals. This polymorphism does not map within a known HLA-B*0702 epitope; instead, it is located five residues downstream of a HLA-B*0702-restricted epitope SPAIFQSSM (SM9). Here we investigate the association between E169D and HLA-B*0702 for immune escape via the SM9 epitope. We show that this single amino acid variation prevents the immune recognition of the flanked SM9 epitope by cytotoxic T cells through lack of generation of the epitope, which is a result of aberrant proteasomal cleavage. The E169D polymorphism also maps within and abrogates the recognition of an HLA-A*03-restricted RT epitope MR9. This study highlights the potential for using known statistical associations as indicators for viral escape but also the complexity involved in interpreting the immunological consequences of amino acid changes in HIV sequences. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17108020&query_hl=1 ER - TY - JFULL T1 - IFNgamma synergizes with IL-1beta to up-regulate MMP-9 secretion in a cellular model of central nervous system tuberculosis. A1 - Harris, JE A1 - Fernandez-Vilaseca, M A1 - Elkington, PT A1 - Horncastle, DE A1 - Graeber, MB A1 - Friedland, JS J1 - FASEB J Y1 - 2007/02// VL - 21 SN - 1530-6860 SP - 356 EP - 365 N2 - Matrix metalloproteinase-9 (MMP-9) activity is implicated in pathogenesis of central nervous system tuberculosis (CNS-TB). IFNgamma, a key cytokine in TB, usually inhibits MMP-9 secretion. Addition of IFNgamma to conditioned media from M. tb-infected monocytes (CoMTB) resulted in a 7-fold increase in MMP-9 activity detected by gelatin zymography (P<0.01). In contrast, tissue inhibitor of metalloproteinase (TIMP)-1 and -2 secretion, measured by ELISA, was suppressed. Dexamethasone abolished the synergistic increase in MMP-9 activity. Interleukin (IL)-1beta in CoMTB is a critical mediator of synergy with IFNgamma, and IL-1beta alone synergizes with IFNgamma to increase MMP-9 secretion from 51 +/- 31 to 762 +/- 136 U. IL-1beta activity is dependent on p38 mitogen-activated protein (MAPK) kinase, which was found to be phosphorylated in tissue specimens from patients with CNS-TB. Extracellular signal regulated kinase (Erk) and p38 MAPK activation did not affect IFNgamma signaling pathways. Inhibition of janus-activated kinase (JAK)-2 by 50 microM AG540 decreased MMP-9 secretion to 124 +/- 11.1 from 651 +/- 229 U of activity (P<0.01). However, signal transducer and activator of transcription (STAT)-3 but not STAT-1 phosphorylation was synergistically up-regulated by IFNgamma and CoMTB. In summary, synergy between IL-1beta and STAT-3 dependent IFNgamma signaling is key in control of up-regulation of MMP-9 activity in CNS-TB and may be a significant mechanism of brain tissue destruction. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17158965&query_hl=1 ER - TY - JFULL T1 - A new inhibitor of apoptosis from vaccinia virus and eukaryotes. A1 - Gubser, C A1 - Bergamaschi, D A1 - Hollinshead, M A1 - Lu, X A1 - van Kuppeveld, FJ A1 - Smith, GL J1 - PLoS Pathog Y1 - 2007/02// VL - 3 SN - 1553-7374 SP - e17 EP - e17 N2 - A new apoptosis inhibitor is described from vaccinia virus, camelpox virus, and eukaryotic cells. The inhibitor is a hydrophobic, multiple transmembrane protein that is resident in the Golgi and is named GAAP (Golgi anti-apoptotic protein). Stable expression of both viral GAAP (v-GAAP) and human GAAP (h-GAAP), which is expressed in all human tissues tested, inhibited apoptosis induced by intrinsic and extrinsic apoptotic stimuli. Conversely, knockout of h-GAAP by siRNA induced cell death by apoptosis. v-GAAP and h-GAAP display overlapping functions as shown by the ability of v-GAAP to complement for the loss of h-GAAP. Lastly, deletion of the v-GAAP gene from vaccinia virus did not affect virus replication in cell culture, but affected virus virulence in a murine infection model. This study identifies a new regulator of cell death that is highly conserved in evolution from plants to insects, amphibians, mammals, and poxviruses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17319741&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 - Biomarker discovery in infectious diseases using SELDI. A1 - Hodgetts, A A1 - Levin, M A1 - Kroll, JS A1 - Langford, PR J1 - Future Microbiol Y1 - 2007/02// VL - 2 SN - 1746-0921 SP - 35 EP - 49 N2 - Surface enhanced laser desorption ionization-time of flight is a mass spectrometric-based method that requires a minimal amount of sample for analysis and can be used for high-throughput screening. It has been used to discover serum or tissue protein signatures and biomarkers for infectious diseases in the fields of virology (hepatitis B and C viruses, severe acute respiratory syndrome, HIV-1, human T-cell leukemia virus-1 and BK virus), parasitology (trypanosomiasis) and bacteriology (intra-amniotic inflammation, tuberculosis and bacterial endocarditis). The protein signatures, or biomarkers, can be used to diagnose infection, predict disease states and to inform on disease processes. Careful attention to experimental design, sample handling and storage, and the use of appropriate internal controls is crucial to success. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17661674&query_hl=1 ER - TY - JFULL T1 - Molecular dynamics simulations of proteins with chemically modified disulfide bonds A1 - Godwin, A A1 - Choi, JW A1 - Pedone, E A1 - Balan, S A1 - Jumnah, R A1 - Shaunak, S A1 - Brocchini, S A1 - Zloh, M J1 - THEOR CHEM ACC Y1 - 2007/02// VL - 117 SN - 1432-881X SP - 259 EP - 265 N2 - Proteins that are used as therapeutic drugs act in the extracellular microenvironment. They usually have a small number of intramolecular disulfide bonds to help maintain their tertiary structure in the vascular circulation. In general, most cysteine residues are part of a disulfide bond with free sulfhydrals being uncommon. We have studied whether the site-specific chemical reduction of disulfides and the incorporation of a 3-carbon methylene bridge between the cysteines in interferon-alpha 2a would change the structure of this protein. Bridging of both of the disulfide bonds of interferon-alpha 2a was studied using two different molecular simulation protocols: (1) molecular dynamics, and (2) stochastic dynamics. We have shown that the disulfide bonds in interferon-alpha 2a can be reduced and chemically modified without significantly altering the tertiary structure of the protein. This offers the novel possibility of chemically modifying therapeutically important proteins without affecting their biological properties. ER - TY - JFULL T1 - Current research priorities in chronic fatigue syndrome/myalgic encephalomyelitis: disease mechanisms, a diagnostic test and specific treatments A1 - Kerr, JR A1 - Christian, P A1 - Hodgetts, A A1 - Langford, PR A1 - D Devanur, L A1 - Petty, R A1 - Burke, B A1 - Sinclair, LI A1 - Richards, SCM A1 - Montgomery, J A1 - McDermott, CR A1 - Harrison, TJ A1 - Kellam, P A1 - Nutt, DJ A1 - Holgate, ST A1 - Clinical Study Grp J1 - J CLIN PATHOL Y1 - 2007/02// VL - 60 SN - 0021-9746 SP - 113 EP - 116 N2 - Chronic fatigue syndrome (CFS) is an illness characterised by disabling fatigue of at least 6 months duration, which is accompanied by various rheumatological, infectious and neuropsychiatric symptoms. A collaborative study group has been formed to deal with the current areas for development in CFS research - namely, to develop an understanding of the molecular pathogenesis of CFS, to develop a diagnostic test and to develop specific and curative treatments. Various groups have studied the gene expression in peripheral blood of patients with CFS, and from those studies that have been confirmed using polymerase chain reaction (PCR), clearly, the most predominant functional theme is that of immunity and defence. However, we do not yet know the precise gene signature and metabolic pathways involved. Currently, this is being dealt with using a microarray representing 47 000 human genes and variants, massive parallel signature sequencing and real-time PCR. It will be important to ensure that once a gene signature has been identified, it is specific to CFS and does not occur in other diseases and infections. A diagnostic test is being developed using surface-enhanced, laser-desorption and ionisation-time-of-flight mass spectrometry based on a pilot study in which putative biomarkers were identified. Finally, clinical trials are being planned; novel treatments that we believe are important to trial in patients with CFS are interferonb and one of the anti-tumour necrosis factor-alpha drugs. ER - TY - JFULL T1 - Natural ventilation for the prevention of airborne contagion. A1 - Escombe, AR A1 - Oeser, CC A1 - Gilman, RH A1 - Navincopa, M A1 - Ticona, E A1 - Pan, W A1 - Martínez, C A1 - Chacaltana, J A1 - Rodríguez, R A1 - Moore, DA A1 - Friedland, JS A1 - Evans, CA J1 - PLoS Med Y1 - 2007/02// VL - 4 SN - 1549-1676 SP - e68 EP - e68 N2 - BACKGROUND: Institutional transmission of airborne infections such as tuberculosis (TB) is an important public health problem, especially in resource-limited settings where protective measures such as negative-pressure isolation rooms are difficult to implement. Natural ventilation may offer a low-cost alternative. Our objective was to investigate the rates, determinants, and effects of natural ventilation in health care settings. METHODS AND FINDINGS: The study was carried out in eight hospitals in Lima, Peru; five were hospitals of "old-fashioned" design built pre-1950, and three of "modern" design, built 1970-1990. In these hospitals 70 naturally ventilated clinical rooms where infectious patients are likely to be encountered were studied. These included respiratory isolation rooms, TB wards, respiratory wards, general medical wards, outpatient consulting rooms, waiting rooms, and emergency departments. These rooms were compared with 12 mechanically ventilated negative-pressure respiratory isolation rooms built post-2000. Ventilation was measured using a carbon dioxide tracer gas technique in 368 experiments. Architectural and environmental variables were measured. For each experiment, infection risk was estimated for TB exposure using the Wells-Riley model of airborne infection. We found that opening windows and doors provided median ventilation of 28 air changes/hour (ACH), more than double that of mechanically ventilated negative-pressure rooms ventilated at the 12 ACH recommended for high-risk areas, and 18 times that with windows and doors closed (p < 0.001). Facilities built more than 50 years ago, characterised by large windows and high ceilings, had greater ventilation than modern naturally ventilated rooms (40 versus 17 ACH; p < 0.001). Even within the lowest quartile of wind speeds, natural ventilation exceeded mechanical (p < 0.001). The Wells-Riley airborne infection model predicted that in mechanically ventilated rooms 39% of susceptible individuals would become infected following 24 h of exposure to untreated TB patients of infectiousness characterised in a well-documented outbreak. This infection rate compared with 33% in modern and 11% in pre-1950 naturally ventilated facilities with windows and doors open. CONCLUSIONS: Opening windows and doors maximises natural ventilation so that the risk of airborne contagion is much lower than with costly, maintenance-requiring mechanical ventilation systems. Old-fashioned clinical areas with high ceilings and large windows provide greatest protection. Natural ventilation costs little and is maintenance free, and is particularly suited to limited-resource settings and tropical climates, where the burden of TB and institutional TB transmission is highest. In settings where respiratory isolation is difficult and climate permits, windows and doors should be opened to reduce the risk of airborne contagion. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17326709&query_hl=1 ER - TY - JFULL T1 - Early acquisition of cytolytic function and transcriptional changes in a primary CD8+ T-cell response in vivo. A1 - Chiu, C A1 - Heaps, AG A1 - Cerundolo, V A1 - McMichael, AJ A1 - Bangham, CR A1 - Callan, MF J1 - Blood Y1 - 2007/02/01/ VL - 109 SN - 0006-4971 SP - 1086 EP - 1094 N2 - Functional studies show that programming of CD8+ T cells occurs early after initial antigen encounter within as little as 2 hours. To define the molecular basis of these events, we transferred TCR transgenic T cells from F5 Rag-/- mice into naive recipients and stimulated them with recombinant vaccinia expressing the immunodominant influenza epitope NP366-374. Transcription in epitope-specific cytotoxic T lymphocytes (CTLs) was analyzed using Affymetrix 430 2.0 GeneChips and quantitative polymerase chain reaction (PCR). We demonstrated an early transcriptional burst with the greatest number of genes reaching peak expression 12 hours after stimulation. Using in vivo cytotoxicity assays we demonstrated that early up-regulation of cytolytic genes was accompanied by acquisition of killing capacity within 24 hours of stimulation. However, T-cell proliferation was not observed until 48 hours. We therefore conclude that clonal expansion rather than acquisition of effector function is the rate-limiting step in the development of a primary CTL response. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16990607&query_hl=1 ER - TY - JFULL T1 - Dynamin is required for F-actin assembly and pedestal formation by enteropathogenic Escherichia coli (EPEC). A1 - Unsworth, KE A1 - Mazurkiewicz, P A1 - Senf, F A1 - Zettl, M A1 - McNiven, M A1 - Way, M A1 - Holden, DW J1 - Cell Microbiol Y1 - 2007/02// VL - 9 SN - 1462-5814 SP - 438 EP - 449 N2 - After attaching to human intestinal epithelial cells, enteropathogenic Escherichia coli (EPEC) induces the formation of an actin-rich pedestal-like structure. The signalling pathway leading to pedestal formation is initiated by the bacterial protein Tir, which is inserted into the host cell plasma membrane. The domain exposed on the cell surface binds to another bacterial protein, intimin, while one of the cytoplasmic domains binds the adaptor protein Nck. This leads to recruitment of other cytoskeletal proteins including neural Wiskott-Aldrich syndrome protein (N-WASP) and Arp2/3, resulting in focused actin polymerization at the site of bacterial attachment. In this study we investigated the role of the large GTPase dynamin 2 (Dyn2) in pedestal formation. We found that in HeLa cells, both endogenous and overexpressed Dyn2 were recruited to sites of EPEC attachment. Recruitment of endogenous Dyn2 required the presence of Tir, Nck and N-WASP but was independent of cortactin and Arp2/3. Knock-down of Dyn2 expression by RNA interference reduced actin polymerization and pedestal formation. Overexpression of dominant-negative mutants of Dyn2 also reduced pedestal formation and prevented recruitment of N-WASP, Arp3 and cortactin, but not Nck. Together, our results indicate that Dyn2 is an integral component of the signalling cascade leading to actin polymerization in EPEC pedestals. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16965516&query_hl=1 ER - TY - JFULL T1 - A girl with fever after a visit to Africa A1 - Pasvol, G J1 - NEW ENGL J MED Y1 - 2007/02/01/ VL - 356 SN - 0028-4793 SP - 528 EP - 528 ER - TY - JFULL T1 - UK malaria treatment guidelines A1 - Lalloo, DG A1 - Shingadia, D A1 - Pasvol, G A1 - Chiodini, PL A1 - Whitty, CJ A1 - Beeching, NJ A1 - Hill, DR A1 - Warrell, DA A1 - Bannister, BA A1 - HPA Advisory Comm Malaria Prev UK J1 - J INFECTION Y1 - 2007/02// VL - 54 SN - 0163-4453 SP - 111 EP - 121 N2 - Malaria is the tropical disease most commonly imported into the UK, with 15002000 cases reported each year, and 10-20 deaths. Approximately three-quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other two species of Plasmodium: Plasmodium ovale or Plasmodium malariae. Mixed infections with more than 1 species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria.Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until 3 blood specimens have been examined by an experienced microscopist. There are no typical clinical features of malaria, even fever is not invariably present. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial. parasites; A falciparum malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens or enzymes, although RDTs for other Plasmodium species are not as reliable.The treatment of choice for non-falciparum malaria is a 3-day course of oral chloroquine, to which only a limited proportion of A vivax strains have gained resistance. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovate infection: the only currently effective drug for eradication of hypnozoites is primaquine. This must be avoided or given with caution under expert supervision in patients with gtucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis. Uncomplicated P. falciparum malaria can be treated orally with quinine, atovaquone plus proguanil (Malarone(R)) or co-artemether (Riamet(R)); quinine is highly effective but poorly tolerated in prolonged dosage and is always supplemented by additional treatment, usually with oral doxycycline. ALL patients treated for P. falciparum malaria should be admitted to hospital for at least 24 h, since patients can deteriorate suddenly, especially early in the course of treatment.Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized), should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. In the UK, the treatment of choice for severe or complicated malaria is currently an infusion of intravenous quinine. This may exacerbate hypoglycaemia that can occur in malaria; patients treated with intravenous quinine therefore require careful monitoring. Intravenous artesunate reduces high parasite loads more rapidly than quinine and is more effective in treating severe malaria in selected situations. It can also be used in patients with contra-indications to quinine. Intravenous artesunate is unlicensed in the EU. Assistance in obtaining artesunate may be sought from specialist tropical medicine centres, on consultation, for named patients. Patients with severe or complicated malaria should be managed in a high dependency or intensive care environment. They may require haemodynamic support and management of acute respiratory distress syndrome, disseminated intravascular coagulation, renal impairment/failure, seizures, and severe intercurrent infections including gram-negative bacteraemia/septicaemia.Falciparum malaria in pregnancy is more likely to be severe and complicated: the placenta contains high levels of parasites. Stillbirth or early delivery may occur and diagnosis can be difficult if parasites are concentrated in the placenta and scanty in the blood. The treatment of choice for falciparum malaria in pregnancy is quinine; doxycycline is contraindicated in pregnancy but clindamycin can be substituted for it, and is equally effective. Primaquine (for eradication of P. vivax or A ovate hypnozoites) is contraindicated in pregnancy; after treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery when hypnozoite eradication can be considered.Children are over-represented in the incidence of malaria in the UK, probably because completely susceptible UK-born children accompany their overseas-born parents on visits to family and friends in endemic areas. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints; the diagnosis must always be sought in a feverish or very sick child who has visited malaria-endemic areas. Children can be treated with most of the antimatarial regimens which are effective in adults, with appropriate dosage adjustment. Doxycycline plus quinine should not be given to children under 12 years as doxycycline is contraindicated in this age group, but clindamycin can be substituted for doxycycline, and pyrimethamine-sulfadoxine (Fansidar(R)) may also be an effective substitute. An acute attack of malaria does not confer protection from future attacks: individuals who have had malaria should take effective anti-mosquito precautions and chemoprophylaxis during future visits to endemic areas. (C) 2006 The British Infection Society. Published by Elsevier Ltd. All rights reserved. ER - TY - JFULL T1 - Specificity of anti-human leukocyte antigen antibody responses after immunization with Remune, an inactivated HIV-1 vaccine. A1 - Page, M A1 - Ojugo, A A1 - Imami, N A1 - Hardy, G A1 - Gotch, F A1 - Almond, N J1 - AIDS Y1 - 2007/01/30/ VL - 21 SN - 0269-9370 SP - 375 EP - 377 N2 - Antibody responses against human leukocyte antigen (HLA) classes I and II were detected in HIV-1 infected individuals who received a fixed inactivated HIV-1 (Remune) immunotherapy. The response was specific for HLA-B62 and HLA-DR4 concordant with the host cell line, HUT-78, used in vaccine production. These responses were not detected in HLA-B62 and HLA-DR4-positive individuals indicating that immunotherapy did not break tolerance to self-antigens. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17255748&query_hl=1 ER - TY - JFULL T1 - Recombination and the nature of bacterial speciation. A1 - Fraser, C A1 - Hanage, WP A1 - Spratt, BG J1 - Science Y1 - 2007/01/26/ VL - 315 SN - 1095-9203 SP - 476 EP - 480 N2 - Genetic surveys reveal the diversity of bacteria and lead to the questioning of species concepts used to categorize bacteria. One difficulty in defining bacterial species arises from the high rates of recombination that results in the transfer of DNA between relatively distantly related bacteria. Barriers to this process, which could be used to define species naturally, are not apparent. Here, we review conceptual models of bacterial speciation and describe our computer simulations of speciation. Our findings suggest that the rate of recombination and its relation to genetic divergence have a strong influence on outcomes. We propose that a distinction be made between clonal divergence and sexual speciation. Hence, to make sense of bacterial diversity, we need data not only from genetic surveys but also from experimental determination of selection pressures and recombination rates and from theoretical models. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17255503&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 - Monocyte-astrocyte networks regulate matrix metalloproteinase gene expression and secretion in central nervous system tuberculosis in vitro and in vivo. A1 - Harris, JE A1 - Nuttall, RK A1 - Elkington, PT A1 - Green, JA A1 - Horncastle, DE A1 - Graeber, MB A1 - Edwards, DR A1 - Friedland, JS J1 - J Immunol Y1 - 2007/01/15/ VL - 178 SN - 0022-1767 SP - 1199 EP - 1207 N2 - CNS tuberculosis (CNS-TB) is the most deadly form of tuberculous disease accounting for 10% of clinical cases. CNS-TB is characterized by extensive tissue destruction, in which matrix metalloproteinases (MMPs) may play a critical role. We investigated the hypothesis that Mycobacterium tuberculosis activates monocyte-astrocyte networks increasing the activity of key MMPs. We examined the expression of all human MMPs and the tissue inhibitors of metalloproteinases (TIMPs) in human astrocytes stimulated by conditioned medium from M. tuberculosis-infected monocytes (CoMTB). Real-time RT-PCR showed that gene expression of MMP-1, -2, -3, -7, and -9 was increased (p < 0.05). MMP-9 secretion was significantly up-regulated at 24 h and increased over 120 h (p < 0.01). MMP-1, -3, and -7 secretion was not detected. Secretion of MMP-2 was constitutive and unaffected by CoMTB. Astrocyte gene expression and secretion of TIMP-1 was not affected by CoMTB although TIMP-2 secretion increased 3-fold at 120 h. Immunohistochemical analysis of human brain biopsies confirmed that astrocyte MMP-9 secretion is a predominant feature in CNS-TB in vivo. Dexamethasone inhibited astrocyte MMP-9, but not TIMP-1/2 secretion in response to CoMTB. CoMTB stimulated the nuclear translocation of NF-kappaB, inducing a 6-fold increase in nuclear p65 and a 2-fold increase in nuclear p50. This was associated with degradation of IkappaBalpha and beta within 30 min, persisting for 24 h. In summary, networks active between monocytes and astrocytes regulate MMP-9 activity in tuberculosis and astrocytes are a major source of MMP-9 in CNS-TB. Astrocytes may contribute to a matrix degrading environment within the CNS and subsequent morbidity and mortality. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17202385&query_hl=1 ER - TY - JFULL T1 - MODS assay for the diagnosis of TB - Reply A1 - Moore, DAJ A1 - Gilman, RH A1 - Friedland, JS J1 - NEW ENGL J MED Y1 - 2007/01/11/ VL - 356 SN - 0028-4793 SP - 189 EP - 189 ER - TY - JFULL T1 - Prevalence of primary genotypic resistance in a UK centre: Comparison of primary HIV-1 and newly diagnosed treatment-naive individuals. A1 - Fox, J A1 - Hill, S A1 - Kaye, S A1 - Dustan, S A1 - McClure, M A1 - Fidler, S A1 - Mackie, NE J1 - AIDS Y1 - 2007/01/11/ VL - 21 SN - 0269-9370 SP - 237 EP - 239 N2 - The worrying finding that up to 19% of newly diagnosed HIV-1 cases in the UK have genotypic evidence of transmitted drug-resistant HIV-1 (TrDR-HIV-1) does not concur with levels observed in one London centre. A study of the prevalence of resistance in primary HIV infection and newly diagnosed antiretroviral-naive individuals demonstrated significantly lower levels of TrDR-HIV-1 than previously reported. Variations in the prevalence of TrDR-HIV-1 may reflect the heterogeneity of methodologies and definitions used for resistance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17197816&query_hl=1 ER - TY - JFULL T1 - MODS assay for the diagnosis of TB. A1 - Palomino, JC A1 - Martin, A A1 - Portaels, F J1 - N Engl J Med Y1 - 2007/01/11/ VL - 356 SN - 1533-4406 SP - 188; author reply 189 EP - 188; author reply 189 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17215539&query_hl=1 ER - TY - JFULL T1 - Structure-based mutagenesis of the integrase-LEDGF/p75 interface uncouples a strict correlation between in vitro protein binding and HIV-1 fitness. A1 - Rahman, S A1 - Lu, R A1 - Vandegraaff, N A1 - Cherepanov, P A1 - Engelman, A J1 - Virology Y1 - 2007/01/05/ VL - 357 SN - 0042-6822 SP - 79 EP - 90 N2 - LEDGF/p75 binding-defective IN mutant viruses were previously characterized as replication-defective, yet RNAi did not reveal an essential role for the host factor in HIV-1 replication. Correlative analyses of protein binding and viral fitness were expanded here by targeting 12 residues at the IN-LEDGF/p75 binding interface. Whereas many of the resultant viruses were defective, the majority of the INs displayed wild-type in vitro integration activities. Though an overall trend of parallel loss of LEDGF/p75 binding and HIV-1 infectivity was observed, a strict correlation was not. His-tagged IN(A128Q), derived from a phenotypically wild-type virus, failed to pull-down LEDGF/p75, but IN(A128Q) was effectively recovered in a reciprocal GST pull-down assay. Under these conditions, IN(H171A), also derived from a phenotypically wild-type virus, interacted less efficiently than a previously described interaction-defective mutant, IN(Q168A). Thus, the relative affinity of the in vitro IN-LEDGF/p75 interaction is not a universal predictor of IN mutant viral fitness. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16959283&query_hl=1 ER - TY - JFULL T1 - Estimating individual and household reproduction numbers in an emerging epidemic. A1 - Fraser, C J1 - PLoS ONE Y1 - 2007/// VL - 2 SN - 1932-6203 SP - e758 EP - e758 N2 - Reproduction numbers, defined as averages of the number of people infected by a typical case, play a central role in tracking infectious disease outbreaks. The aim of this paper is to develop methods for estimating reproduction numbers which are simple enough that they could be applied with limited data or in real time during an outbreak. I present a new estimator for the individual reproduction number, which describes the state of the epidemic at a point in time rather than tracking individuals over time, and discuss some potential benefits. Then, to capture more of the detail that micro-simulations have shown is important in outbreak dynamics, I analyse a model of transmission within and between households, and develop a method to estimate the household reproduction number, defined as the number of households infected by each infected household. This method is validated by numerical simulations of the spread of influenza and measles using historical data, and estimates are obtained for would-be emerging epidemics of these viruses. I argue that the household reproduction number is useful in assessing the impact of measures that target the household for isolation, quarantine, vaccination or prophylactic treatment, and measures such as social distancing and school or workplace closures which limit between-household transmission, all of which play a key role in current thinking on future infectious disease mitigation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17712406&query_hl=1 ER - TY - JFULL T1 - The contribution of cytomegalovirus to changes in NK cell receptor expression in HIV-1-infected individuals. A1 - Mela, CM A1 - Goodier, MR J1 - J Infect Dis Y1 - 2007/01/01/ VL - 195 SN - 0022-1899 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17152020&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 - A phase I, randomized study of combined IL-2 and therapeutic immunisation with antiretroviral therapy. A1 - Hardy, GA A1 - Imami, N A1 - Nelson, MR A1 - Sullivan, AK A1 - Moss, R A1 - Aasa-Chapman, MM A1 - Gazzard, B A1 - Gotch, FM J1 - J Immune Based Ther Vaccines Y1 - 2007/// VL - 5 SN - 1476-8518 SP - 6 EP - 6 N2 - BACKGROUND: Fully functional HIV-1-specific CD8 and CD4 effector T-cell responses are vital to the containment of viral activity and disease progression. These responses are lacking in HIV-1-infected patients with progressive disease. We attempted to augment fully functional HIV-1-specific CD8 and CD4 effector T-cell responses in patients with advanced chronic HIV-1 infection. DESIGN: Chronically infected patients with low CD4 counts T-cell counts who commenced antiretroviral therapy (ART) were subsequently treated with combined interleukin-2 and therapeutic vaccination. METHODS: Thirty six anti-retroviral naive patients were recruited and initiated on combination ART for 17 weeks before randomization to: A) ongoing ART alone; B) ART with IL-2 twice daily for 5 days every four weeks starting at week 17 for 3 cycles; C) ART with IL-2 as in group B and Remune HIV-1 vaccine administered once every 3 months, starting at week 17; and D) ART with Remune vaccine as in group C. Patients were studied for 65 weeks following commencement of ART, with an additional prior 6 week lead-in observation period. CD4 and CD8 T-cell counts, evaluations of HIV-1 RNA levels and proliferative responses to recall and HIV-1 antigens were complemented with assessment of IL-4-secretion alongside quantification of anti-HIV-1 CD8 T-cell responses and neutralizing antibody titres. RESULTS: Neither IL-2 nor Remune vaccination induced sustained HIV-1-specific T-cell responses. However, we report an inverse relationship between HIV-1-specific proliferative responses and IL-4 production which continuously increased in patients receiving immunotherapy, but not patients receiving ART alone. CONCLUSION: Induction of HIV-1-specific cell-mediated responses is a major challenge in chronically HIV-1-infected patients even when combining immunisation with IL-2 therapy. An antigen-specific IL-4-associated suppressive response may play a role in attenuating HIV-specific responses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17428345&query_hl=1 ER - TY - JFULL T1 - Diagnosis and management of meningococcal disease: the need for centralized care. A1 - Nadel, S A1 - Kroll, JS J1 - FEMS Microbiol Rev Y1 - 2007/01// VL - 31 SN - 0168-6445 SP - 71 EP - 83 N2 - Meningococcal infection remains a significant health problem in children, with a significant mortality and morbidity. Prompt recognition and aggressive early treatment are the only effective measures against invasive disease. This requires immediate administration of antibiotic therapy, and the recognition and treatment of patients who may have complications of meningococcal infection such as shock, raised intracranial pressure (ICP) or both. Encouragingly, its mortality has fallen in recent years. This is the result of several factors such as the centralization of care of seriously ill children in paediatric intensive care units (PICUs), the establishment of specialized mobile intensive care teams, the development of protocols for the treatment of meningococcal infection, and the dissemination by national bodies and charities of guidance about early recognition and management. We will review the pathophysiology and management of the different presentations of meningococcal disease and examine the possible role of adjunctive therapies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17233636&query_hl=1 ER - TY - JFULL T1 - PAR-1 knockout bone marrow stem cells can confer an anti-fibrotic phenotype to the injured liver A1 - Kallis, YN A1 - Scotton, CJ A1 - Goldin, RD A1 - Russo, FP A1 - Chambers, RC A1 - Thomas, HC A1 - Forbes, SJ J1 - J HEPATOL Y1 - 2007/01// VL - 46 SN - 0168-8278 SP - S129 EP - S129 ER - TY - JFULL T1 - Immunoepidemiology of Wuchereria bancrofti infection: the dynamic relationship between parasite transmission intensity and age-profiles of filarial-specific antibody isotypes in two East African communities A1 - Jaoko, W G A1 - Michael, E A1 - Meyrowitsch, D W A1 - Estambale, B B A A1 - Malecela, M N A1 - Simonsen, P E J1 - Infection and immunity Y1 - 2007/// VL - in press ER - TY - JFULL T1 - Bancroftian filariasis: house-to-house variation in the vectors and transmission - and the relationship to human infection - in an endemic community of coastal Tanzania A1 - Rwegoshora, RT A1 - Simonsen, PE A1 - Meyrowitsch, DW A1 - Malecela-Lazaro, MN A1 - Michael, E A1 - Pedersen, EM J1 - ANN TROP MED PARASIT Y1 - 2007/01// VL - 101 SN - 0003-4983 SP - 51 EP - 60 N2 - The house-to-house variation in Wuchereria bancrofti vector abundance and transmission intensity, and the relationship of these parameters to human infection, were investigated in an endemic community in coastal Tanzania. Vector mosquitoes were collected in light traps set up in 50 randomly selected households once weekly for 1 year. They were identified, dissected and checked for filarial larvae. Vector densities and transmission potentials varied markedly between households, both for all vectors combined and for the individual vector species (Anopheles gambiae s.l., An. funestus and Culex quinquefasciatus), even between households located close to each other. The variation in vector abundance was probably mainly attributable to differences in the distance to breeding sites, to specific household features likely to ease mosquito entry and hiding, and to the number of household inhabitants. Household annual biting rates (ABR) correlated positively with household annual transmission potentials (ATP), indicating that intense vector biting led to a high transmission intensity. Intriguingly, however, the human filarial-infection status (as indicated by microfilaraemia or circulating filarial antigenemia) did not differ significantly between households with relatively high and lower ABR or ATP. Possible reasons for this result include the long time required for W. bancrofti infection to establish in humans, human behaviour affecting exposure, the sharing of mosquito populations between households, and differential susceptibility of humans to infection. The marked heterogeneity in exposure between households, and the lack of immediate relationship between transmission and detectable human infection at household level, should be taken into account when considering the transmission pattern of lymphatic filariasis. ER - TY - JFULL T1 - Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection. A1 - Lucas, M A1 - Ulsenheimer, A A1 - Pfafferot, K A1 - Heeg, MH A1 - Gaudieri, S A1 - Grüner, N A1 - Rauch, A A1 - Gerlach, JT A1 - Jung, MC A1 - Zachoval, R A1 - Pape, GR A1 - Schraut, W A1 - Santantonio, T A1 - Nitschko, H A1 - Obermeier, M A1 - Phillips, R A1 - Scriba, TJ A1 - Semmo, N A1 - Day, C A1 - Weber, JN A1 - Fidler, S A1 - Thimme, R A1 - Haberstroh, A A1 - Baumert, TF A1 - Klenerman, P A1 - Diepolder, HM J1 - PLoS ONE Y1 - 2007/// VL - 2 SN - 1932-6203 SP - e649 EP - e649 N2 - BACKGROUND: CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays. METHODOLOGY/PRINCIPAL FINDINGS: Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C. CONCLUSIONS/SIGNIFICANCE: During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17653276&query_hl=1 ER - TY - JFULL T1 - Epidemiological modelling for monitoring and evaluation of lymphatic filariasis control A1 - Michael, E A1 - Malecela, M N A1 - Kazura, J W J1 - Advances in Parasitology Y1 - 2007/// VL - in press ER - TY - JFULL T1 - Three-year immune reconstitution in PI-sparing and PI-containing antiretroviral regimens in advanced HIV-1 disease. A1 - Samri, A A1 - Goodall, R A1 - Burton, C A1 - Imami, N A1 - Pantaleo, G A1 - Kelleher, A A1 - Poli, G A1 - Gotch, F A1 - Autran, B J1 - Antivir Ther Y1 - 2007/// VL - 12 SN - 1359-6535 SP - 553 EP - 558 N2 - BACKGROUND: The long-term immunological benefit of protease inhibitor (PI)-sparing antiretroviral therapy (ART) using non-nucleoside reverse transcriptase inhibitors (NNRTIs) remains poorly investigated. METHODS: A total of 120 ART-naive, HIV-1-infected participants were included in the immunology substudy of INITIO, an international randomized trial comparing two NRTIs (didanosine + stavudine) combined with either: one NNRTI (efavirenz; EFV), one non-boosted PI (nelfinavir; NFV), or one NNRTI + one PI (EFV/NFV). CD4+ T-cell counts, HIV-1 plasma RNA load (VL), T-cell phenotype, T-cell proliferation and IFN-gamma production against opportunistic/recall and HIV-1 antigens/peptides were compared at baseline and at week (W) 96 and W156. RESULTS: Participants (37 EFV, 44 NFV, 39 EFV/NFV) had similar baseline VL; median CD4+ T-cell counts/mm3 were: 144 (64-303) EFV, 212 (42-313) NFV and 257 (86-331) EFV/NFV. At W156, the proportion of patients with VL < or =50 copies/ml was not different between the arms (P=0.3). From baseline to W156 there was a significant increase in CD4+ T-cell counts (P<0.001) and in naive CD4+ T cells (P<0.001), with no difference between arms and percentages of total and activated CD8+ T cells decreased significantly (P<0.001) in all arms. The decrease in activated memory CD4+ T-cells was significantly greater in the EFV arm at W96 (P=0.03) and W156 (P=0.01), but did not persist after adjusting for baseline CD4+ T-cell counts. During follow-up, responses to opportunistic pathogens increased in all patients while specific T-cell responses to HIV-1-p24 and gp160 recombinant proteins or to Gag and Nef peptides were not restored. CONCLUSION: Regimens using/sparing PIs provide similar levels of long-term immune reconstitution even in patients with low CD4+ T-cell counts. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17668564&query_hl=1 ER - TY - JFULL T1 - Systems biology and its impact on anti-infective drug development. A1 - Stumpf, MP A1 - Robertson, BD A1 - Duncan, K A1 - Young, DB J1 - Prog Drug Res Y1 - 2007/// VL - 64 SN - 0071-786X SP - 1, 3 EP - 20, 3 N2 - Systems biology offers the potential for more effective selection of novel targets for anti-infective drugs. In contrast to conventional reductionist biology, a systems approach allows targets to be viewed in a wider context of the entire physiology of the cell, with the potential to identify key susceptible nodes and to predict synergistic effects of blocking multiple pathways. In addition to the holistic perspective provided by systems biology, the emphasis on quantitative analysis is likely to add further rigour to the process of target selection. Systems biology also offers the potential to incorporate different levels of information into the selection process. Consideration of data from microbial population biology may be important in the context of predicting future drug-resistance profiles associated with targeting a particular pathway, for example. This chapter provides an overview of major themes in the developing field of systems biology, summarising the core technologies and the strategies used to translate datasets into useful quantitative models capable of predicting complex biological behaviour. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17195469&query_hl=1 ER - TY - JFULL T1 - Microarray analysis demonstrates insulin resistance is central to NASH pathogenesis in the IGT/6 model and suggests a role for CEACAM-1 in disease pathogenesis A1 - Anstee, QM A1 - Goldsworthy, M A1 - Goldin, R A1 - Thomas, HC A1 - Cox, R A1 - Thursz, M J1 - J HEPATOL Y1 - 2007/01// VL - 46 SN - 0168-8278 SP - S261 EP - S262 ER - TY - JFULL T1 - Cell dynamics and immune response to BLV infection: a unifying model. A1 - Florins, A A1 - Gillet, N A1 - Asquith, B A1 - Boxus, M A1 - Burteau, C A1 - Twizere, JC A1 - Urbain, P A1 - Vandermeers, F A1 - Debacq, C A1 - Sanchez-Alcaraz, MT A1 - Schwartz-Cornil, I A1 - Kerkhofs, P A1 - Jean, G A1 - Théwis, A A1 - Hay, J A1 - Mortreux, F A1 - Wattel, E A1 - Reichert, M A1 - Burny, A A1 - Kettmann, R A1 - Bangham, C A1 - Willems, L J1 - Front Biosci Y1 - 2007/// VL - 12 SN - 1093-4715 SP - 1520 EP - 1531 N2 - Bovine Leukemia virus (BLV) is the natural etiological agent of a lymphoproliferative disease in cattle. BLV can also be transmitted experimentally to a related ruminant species, sheep, in which the pathogenesis is more acute. Although both susceptible species develop a strong anti-viral immune response, the virus persists indefinitely throughout life, apparently at a transcriptionally silent stage, at least in a proportion of infected cells. Soon after infection, these humoral and cytotoxic activities very efficiently abolish the viral replicative cycle, permitting only mitotic expansion of provirus-carrying cells. Short term cultures of these infected cells initially indicated that viral expression protects against spontaneous apoptosis, suggesting that leukemia is a process of accumulation of long-lived cells. This conclusion was recently reconsidered following in vivo dynamic studies based on perfusions of nucleoside (bromodeoxyuridine) or fluorescent protein markers (CFSE). In sheep, the turnover rate of infected cells is increased, suggesting that a permanent clearance process is exerted by the immune system. Lymphocyte trafficking from and to the secondary lymphoid organs is a key component in the maintenance of cell homeostasis. The net outcome of the immune selective pressure is that only cells in which the virus is transcriptionally silenced survive and accumulate, ultimately leading to lymphocytosis. Activation of viral and/or cellular expression in this silent reservoir with deacetylase inhibitors causes the collapse of the proviral loads. In other words, modulation of viral expression appears to be curative in lymphocytic sheep, an approach that might also be efficient in patients infected with the related Human T-lymphotropic virus type 1. In summary, a dynamic interplay between BLV and the host immune response modulates a complex equilibrium between (i) viral expression driving (or) favoring proliferation and (ii) viral silencing preventing apoptosis. As conclusion, we propose a hypothetical model unifying all these mechanisms. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17127399&query_hl=1 ER - TY - JFULL T1 - Streptococcus pyogenes: Insight into the function of the streptococcal superantigens. A1 - Sriskandan, S A1 - Faulkner, L A1 - Hopkins, P J1 - Int J Biochem Cell Biol Y1 - 2007/// VL - 39 SN - 1357-2725 SP - 12 EP - 19 N2 - The group A streptococcus produces a number of highly potent exoproteins that act as superantigens. The cascade of pro-inflammatory events that follow invasive streptococcal infection is greatly enhanced by production of such toxins, leading to profound hypotension and multi-organ failure in some cases. Superantigens such as streptococcal mitogenic exotoxin Z (SMEZ) interact with host MHC class II and the T cell receptor, leading to activation events in both cells. In vitro, these interactions lead to expansion and cytokine production by specified T cell subsets. Studies using humanized HLA class II transgenic mice and isogenic streptococcal strains have characterised the in vivo responses to superantigens produced in the context of live infection. Notwithstanding the obvious deleterious role of superantigens in toxic shock, the evolutionary advantage conferred by these toxins remains a subject of speculation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17029999&query_hl=1 ER - TY - JFULL T1 - NKG2C+ NK cells are enriched in AIDS patients with advanced-stage Kaposi's sarcoma. A1 - Goodier, MR A1 - Mela, CM A1 - Steel, A A1 - Gazzard, B A1 - Bower, M A1 - Gotch, F J1 - J Virol Y1 - 2007/01// VL - 81 SN - 0022-538X SP - 430 EP - 433 N2 - Kaposi's sarcoma (KS) is an AIDS-defining condition in individuals with human immunodeficiency virus type 1 infection. We investigated the phenotype and function of the NKG2C+ NK cell population in individuals with AIDS and Kaposi's sarcoma. The staging of AIDS KS patients according to the AIDS Clinical Trial Group criteria revealed that patients with the S1 disease stage have a significantly higher proportion of NKG2C+ cells than those with the S0 disease stage. NKG2C+ cells from S1-stage patients are highly enriched for the expression of KIR3DL1, are depleted of NKp46, and respond poorly to major histocompatibility complex class I-positive target cells. These data demonstrate a link between NK cell phenotype and function and disease prognosis in AIDS. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17035308&query_hl=1 ER - TY - JFULL T1 - A kinetic model of calcium mass balance during dialysis therapy. A1 - Gotch, F A1 - Kotanko, P A1 - Handelman, G A1 - Levin, N J1 - Blood Purif Y1 - 2007/// VL - 25 SN - 0253-5068 SP - 139 EP - 149 N2 - A kinetic model of Ca mass balance during dialysis has been developed. It is a single-compartment, variable-volume model to compute Ca mass balance during dialysis in its volume of distribution, the extracellular fluid. The model was used to analyze literature data which were suitable for the assessment of Ca mass balance over the course of dialysis. The modeled analyses predicted the serial plasma Ca concentrations very well. The mass balance analyses revealed a pool of rapidly diffusible Ca beyond the extracellular fluid distribution volume where Ca could be mobilized (M+(Ca)) or sequestered (M-(Ca)) very rapidly at rate equal but opposite in sign to dialyzer flux and thus effectively maintain near constant plasma Ca in the face of dialyzer Ca concentration gradients. This pool is likely the large pool of diffusible (miscible) Ca in connective tissue and on bone surfaces. Analysis of net Ca flux during dialysis with Cdi(Ca) = 2.50 mEq/l suggests that 80% of patients are in positive Ca balance during dialysis. Further studies are required to verify the model and to develop a model of interdialytic Ca mass balance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17170552&query_hl=1 ER - TY - JFULL T1 - Safety of nevirapine in pregnancy A1 - Natarajan, U A1 - Pym, A A1 - McDonald, C A1 - Velisetty, P A1 - Edwards, SG A1 - Hay, P A1 - Welch, J A1 - de Ruiter, A A1 - Taylor, GP A1 - Anderson, J J1 - HIV MED Y1 - 2007/01// VL - 8 SP - 64 EP - 69 N2 - Background Nevirapine has been widely used in pregnancy for its efficacy, low pill burden, bioavailability and rapid transplacental transfer. Concern about nevirapine toxicity during pregnancy has emerged over recent years.Objectives The aims of the study were to document the frequency of cutaneous and hepatic toxicity secondary to nevirapine use during pregnancy and to compare rates in women starting nevirapine during the current pregnancy with those in women who had commenced nevirapine prior to the current pregnancy.Design This was a retrospective, comparative, five-centre study carried out in London, UK, in 1997-2003.Methods All HIV-1-infected women who received nevirapine as part of combination antiretroviral therapy (ART) during pregnancy were included in the study. Data on demographics, HIV infection risk, Centers for Disease Control and Prevention (CDC) status, surrogate markers at initiation of therapy, other medications hepatitis B and C virus coinfection and clinical data relating to potential toxicity were collated and analysed.Results Fifteen of 235 eligible women (6.4%) developed rash and eight (3.4%) developed hepatotoxicity, including four with coexistent rash, giving a combined incidence of 19 potential cases of nevirapine toxicity during pregnancy (8.1%). Alternative causes of rash/hepatotoxicity were suspected in seven cases and only 10 mothers (5.8%) discontinued nevirapine. Of the 170 women who commenced nevirapine during this pregnancy, 13 (7.6%) developed rash and eight (4.7%) hepatotoxicity, a combined incidence of 10%. Only two of 65 women with nevirapine exposure prior to this pregnancy developed rash (3.1%).Conclusions Nevirapine-containing ART was well tolerated in this cohort of pregnant women. Although pregnancy did not appear to increase the risk of nevirapine-associated toxicity compared to published adult data, CD4 count may be less predictive of toxicity in pregnancy. ER - TY - JFULL T1 - Size matters: body composition and outcomes in maintenance hemodialysis patients. A1 - Kotanko, P A1 - Thijssen, S A1 - Kitzler, T A1 - Wystrychowski, G A1 - Sarkar, SR A1 - Zhu, F A1 - Gotch, F A1 - Levin, NW J1 - Blood Purif Y1 - 2007/// VL - 25 SN - 0253-5068 SP - 27 EP - 30 N2 - In hemodialysis patients a low body mass index (BMI) is correlated with an unfavorable clinical outcome, a phenomenon known as "reverse epidemiology". Mechanisms underlying this observation are unclear. We propose the following: uremic toxin generation occurs predominantly in visceral organs and the mass of key uremiogenic viscera (gut, liver) relative to body weight is higher in small people. Consequently, the rate of uremic toxin generation per unit of BMI is higher in patients with a low BMI. Body water, mainly determined by muscle mass, serves as a dilution compartment for uremic toxins. Therefore, the concentration of uremic toxins is higher in small subjects. Uremic toxins are taken up by adipose and muscle tissues, subsequently metabolized and stored. Thus, the larger the ratio of fat and muscle mass to visceral mass, the lower the concentration of uremic toxins and the better the survival. To test this hypothesis, studies on uremic toxin kinetics in relation to body composition are needed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17170533&query_hl=1 ER - TY - JFULL T1 - The basic, quantifiable parameter of dialysis prescription is Kt/V urea; treatment time is determined by the ultrafiltration requirement; all three parameters are of equal importance. A1 - Gotch, F J1 - Blood Purif Y1 - 2007/// VL - 25 SN - 0253-5068 SP - 18 EP - 26 N2 - There have only been two randomized controlled trials studying outcome as a function of dose in hemodialysis (HD). The first was the National Cooperative Dialysis Study which showed that adequate dialysis was achieved with spKt/V >1.00. The second study was HEMO which was originally designed to study spKt/V 1.2 compared to spKt/V 1.45. Unfortunately by the time HEMO was started, observational studies (OS) had convinced the nephrology community that the minimum adequate dose of spKt/V was 1.40, so the lower target was increased to 1.4 and the upper target to 1.7. The study showed no difference in outcome, although OS have now demonstrated that outcome improves up to spKt/v 2.00. Analysis of HEMO as treated showed that there is a fundamental flaw in dose-targeted OS in that the optimal dose always, but spuriously, increases as the studied dose increases due to dose-targeting bias. Similar flaws exist in the association of treatment time to outcome. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17170532&query_hl=1 ER - TY - JFULL T1 - Exhaustion of virus specific CD4+T cells during acute hepatitis C A1 - Ulsenheimer, A A1 - Lucas, M A1 - Pfaffero, K A1 - Heeg, MH A1 - Gaudieri, S A1 - Gruener, N A1 - Rauch, A A1 - Gerlach, T A1 - Jung, MC A1 - Zachoval, R A1 - Pape, GR A1 - Santantonio, T A1 - Nitschko, H A1 - Baumertlo, TF A1 - Thimme, R A1 - Weber, JN A1 - Klenerman, P A1 - Diepolder, HM J1 - J HEPATOL Y1 - 2007/01// VL - 46 SN - 0168-8278 SP - S295 EP - S295 ER - TY - JFULL T1 - Impact on and use of an inner-city London Infectious Diseases Department by international migrants: a questionnaire survey. A1 - Cooke, G A1 - Hargreaves, S A1 - Natkunarajah, J A1 - Sandhu, G A1 - Dhasmana, D A1 - Eliahoo, J A1 - Holmes, A A1 - Friedland, JS J1 - BMC Health Serv Res Y1 - 2007/// VL - 7 SN - 1472-6963 SP - 113 EP - 113 N2 - BACKGROUND: The UK has witnessed a considerable increase in immigration in the past decade. Migrant may face barriers to accessing appropriate health care on arrival and the current focus on screening certain migrants for tuberculosis on arrival is considered inadequate. We assessed the implications for an inner-city London Infectious Diseases Department in a high migrant area. METHODS: We administered an anonymous 20-point questionnaire survey to all admitted patients during a 6 week period. Questions related to sociodemographic characteristics and clinical presentation. Analysis was by migration status (UK born vs overseas born). RESULTS: 111 of 133 patients completed the survey (response rate 83.4%). 58 (52.2%) were born in the UK; 53 (47.7%) of the cohort were overseas born. Overseas-born were over-represented in comparison to Census data for this survey site (47.7% vs 33.6%; proportional difference 0.142 [95% CI 0.049-0.235]; p = 0.002): overseas born reported 33 different countries of birth, most (73.6%) of whom arrived in the UK pre-1975 and self-reported their nationality as British. A smaller number (26.4%) were new migrants to the UK (< or =10 years), mostly refugees/asylum seekers. Overseas-born patients presented with a broad range and more severe spectrum of infections, differing from the UK-born population, resulting in two deaths in this group only. Presentation with a primary infection was associated with refugee/asylum status (n = 8; OR 6.35 [95% CI 1.28-31.50]; p = 0.023), being a new migrant (12; 10.62 [2.24-50.23]; p = 0.003), and being overseas born (31; 3.69 [1.67-8.18]; p = 0.001). Not having registered with a primary-care physician was associated with being overseas born, being a refugee/asylum seeker, being a new migrant, not having English as a first language, and being in the UK for < or =5 years. No significant differences were found between groups in terms of duration of illness prior to presentation or duration of hospitalisation (mean 11.74 days [SD 12.69]). CONCLUSION: Migrants presented with a range of more severe infections, which suggests they face barriers to accessing appropriate health care and screening both on arrival and once settled through primary care services. A more organised and holistic approach to migrant health care is required. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17659074&query_hl=1 ER - TY - JFULL T1 - Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation--author's response. A1 - Sriskandan, S J1 - J Antimicrob Chemother Y1 - 2007/01// VL - 59 SN - 0305-7453 SP - 159 EP - 160 N2 - L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17142817&query_hl=1 ER - TY - JFULL T1 - Site-specific PEGylation of protein disulfide bonds using a three-carbon bridge. A1 - Balan, S A1 - Choi, JW A1 - Godwin, A A1 - Teo, I A1 - Laborde, CM A1 - Heidelberger, S A1 - Zloh, M A1 - Shaunak, S A1 - Brocchini, S J1 - Bioconjug Chem Y1 - 2007/01// VL - 18 SN - 1043-1802 SP - 61 EP - 76 N2 - The covalent conjugation of a functionalized poly(ethylene glycol) (PEG) to multiple nucleophilic amine residues results in a heterogeneous mixture of PEG positional isomers. Their physicochemical, biological, and pharmaceutical properties vary with the site of conjugation of PEG. Yields are low because of inefficient conjugation chemistry and production costs high because of complex purification procedures. Our solution to these fundamental problems in PEGylating proteins has been to exploit the latent conjugation selectivity of the two sulfur atoms that are derived from the ubiquitous disulfide bonds of proteins. This approach to PEGylation involves two steps: (1) disulfide reduction to release the two cysteine thiols and (2) re-forming the disulfide by bis-alkylation via a three-carbon bridge to which PEG was covalently attached. During this process, irreversible denaturation of the protein did not occur. Mechanistically, the conjugation is conducted by a sequential, interactive bis-alkylation using alpha,beta-unsaturated beta'-monosulfone functionalized PEG reagents. The combination of (a) maintaining the protein's tertiary structure after disulfide reduction, (b) the mechanism for bis-thiol selectivity of the PEG reagent, and (c) the steric shielding of PEG ensure that only one PEG molecule is conjugated at each disulfide bond. PEG was site-specifically conjugated via a three-carbon bridge to 2 equiv of the tripeptide glutathione, the cyclic peptide hormone somatostatin, the tetrameric protein l-asparaginase, and to the disulfides in interferon alpha-2b (IFN). SDS-PAGE, mass spectral, and NMR analyses were used to confirm conjugation, thiol selectivity, and connectivity. The biological activity of the l-asparaginase did not change after the attachment of four PEG molecules. In the case of IFN, a small reduction in biological activity was seen with the single-bridged IFN (without PEG attached). A significantly larger reduction in biological activity was seen with the three-carbon disulfide single-bridged PEG-IFNs and with the double-bridged IFN (without PEG attached). The reduction of the PEG-IFN's in vitro biological activity was a consequence of the steric shielding caused by PEG, and it was comparable to that seen with all other forms of PEG-IFNs reported. However, when a three-carbon bridge was used to attach PEG, our PEG-IFN's biological activity was found to be independent of the length of the PEG. This property has not previously been described for PEG-IFNs. Our studies therefore suggest that peptides, proteins, enzymes, and antibody fragments can be site-specifically PEGylated across a native disulfide bond using three-carbon bridges without destroying their tertiary structure or abolishing their biological activity. The stoichiometric efficiency of this approach also enables recycling of any unreacted protein. It therefore offers the potential to make PEGylated biopharmaceuticals as cost-effective medicines for global use. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17226958&query_hl=1 ER - TY - JFULL T1 - LEDGF/p75 interacts with divergent lentiviral integrases and modulates their enzymatic activity in vitro. A1 - Cherepanov, P J1 - Nucleic Acids Res Y1 - 2007/// VL - 35 SN - 1362-4962 SP - 113 EP - 124 N2 - Transcriptional co-activator LEDGF/p75 is the major cellular interactor of HIV-1 integrase (IN), critical to efficient viral replication. In this work, a series of INs from the Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Spumavirus and Lentivirus retroviral genera were tested for interaction with the host factor. None of the non-lentiviral INs possessed detectable affinity for LEDGF in either pull-down or yeast two-hybrid assays. In contrast, all lentiviral INs examined, including those from bovine immunodeficiency virus (BIV), maedi-visna virus (MVV) and equine infectious anemia virus (EIAV) readily interacted with LEDGF. Mutation of Asp-366 to Asn in LEDGF ablated the interaction, suggesting a common mechanism of the host factor recognition by the INs. LEDGF potently stimulated strand transfer activity of divergent lentiviral INs in vitro. Unprecedentedly, in the presence of the host factor, EIAV IN almost exclusively catalyzed concerted integration, whereas HIV-1 IN promoted predominantly half-site integration, and BIV IN was equally active in both types of strand transfer. Concerted BIV and EIAV integration resulted in 5 bp duplications of the target DNA sequences. These results confirm that the interaction with LEDGF is conserved within and limited to Lentivirus and strongly argue that the host factor is intimately involved in the catalysis of lentiviral DNA integration. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17158150&query_hl=1 ER - TY - JFULL T1 - Buttermouse: The effect of high fat feeding on a new mouse model of insulin resistance and steatohepatitis A1 - Matthews, HC A1 - Absalom, N A1 - Goldsworthy, M A1 - Thomas, HC A1 - Goldin, R A1 - Thursz, MR A1 - Cox, R J1 - J HEPATOL Y1 - 2007/01// VL - 46 SN - 0168-8278 SP - S276 EP - S276 ER - TY - JFULL T1 - Elucidation of toll-like receptor and adapter protein signaling in vascular dysfunction induced by gram-positive Staphylococcus aureus or gram-negative Escherichia coli. A1 - Cartwright, N A1 - McMaster, SK A1 - Sorrentino, R A1 - Paul-Clark, M A1 - Sriskandan, S A1 - Ryffel, B A1 - Quesniaux, VF A1 - Evans, TW A1 - Mitchell, JA J1 - Shock Y1 - 2007/01// VL - 27 SN - 1073-2322 SP - 40 EP - 47 N2 - Pathogens contain specific pathogen-associated molecular patterns, which activate pattern recognition receptors of the innate immune system such as Toll-like receptors (TLRs). Although there is a clear evidence of how macrophages sense pathogens, we know less about such processes in vessels. This is critical to understand because activation of vascular cells and the subsequent induction of inflammatory genes by bacteria are crucial events in the development of septic shock. In the current study we have used genetically modified mice to investigate the role of TLRs, adapter proteins, tumor necrosis factor alpha (TNFalpha), and nitric oxide synthase II (NOSII) in vascular dysfunction induced by Gram-positive (Staphylococcus aureus) or Gram-negative (Escherichia coli) bacteria. Our data show that Gram-positive S. aureus or Gram-negative E. coli causes vascular dysfunction via the induction of NOSII. For S. aureus, this process requires TLR2, TLR6, myeloid differentiation factor 88 (MyD88) adapter-like, MyD88, and TNF, but not TLR4 or TLR1. Vascular dysfunction induced by E. coli requires TLR4 but has no requirement for TLR2, TLR1, TLR6, or TNF, and a partial but incomplete requirement of MyD88 and TIR domain-containing adapter inducing interferon-beta. Staphylococcus aureus induced NOSII protein expression in vascular smooth muscle cells but not in macrophages, whereas E. coli induced NOSII in both cell types. Our data are the first to establish the definitive roles of specific TLRs in the sensing of Gram-positive and Gram-negative bacteria by vessels and demonstrate that macrophages and blood vessels may differ in their response to pathogens. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17172979&query_hl=1 ER - TY - JFULL T1 - Integrated health information systems in Tanzania: experience and challenges A1 - Smith, M A1 - Madon, S A1 - Anifalaje, A A1 - Lazarro-Malecela, M A1 - Michael, E J1 - The Electronic Journal on Information Systems in Developing Countries Y1 - 2007/// VL - 32 SP - 1 EP - 21 ER - TY - JFULL T1 - Can disease progression in non-alcoholic fatty liver disease be predicted by metabolic biomarkers of lipid accumulation and peroxidation? A1 - Cobbold, JF A1 - Anstee, QM A1 - Goldin, RD A1 - Cox, RD A1 - Thursz, MR A1 - Thomas, HC A1 - Taylor-Robinson, SD A1 - Cox, IJ J1 - J HEPATOL Y1 - 2007/01// VL - 46 SN - 0168-8278 SP - S265 EP - S265 ER - TY - JFULL T1 - Early risk assessment for viral haemorrhagic fever: experience at the Hospital for Tropical Diseases, London, UK. A1 - Woodrow, CJ A1 - Eziefula, AC A1 - Agranoff, D A1 - Scott, GM A1 - Watson, J A1 - Chiodini, PL A1 - Lockwood, DN A1 - Grant, AD J1 - J Infect Y1 - 2007/01// VL - 54 SN - 0163-4453 SP - 6 EP - 11 N2 - OBJECTIVES: To implement a policy of systematic screening for viral haemorrhagic fever (VHF) among travellers returning from African countries with fever, commencing at initial clinical contact. METHODS: A protocol based on UK Advisory Committee on Dangerous Pathogens guidance was developed collaboratively by medical, nursing and laboratory staff. Audit was carried out to quantify resource demands and effects on time to diagnose malaria, the main differential diagnosis. RESULTS: A protocol is now implemented for all patients presenting to HTD with fever, with clear guidelines for interaction with clinical and laboratory staff at each stage. The protocol required moderate amounts of clinical and laboratory staff time and resulted in some additional hospital admissions. The time to a diagnosis of malaria increased from a median of 90 (range 50-125) min in patients without VHF risk to a median of 140 (range 101-225) min (p=0.0025) in those assessed as at risk. CONCLUSIONS: Although all acute medical services need to have robust procedures for early detection of patients with serious transmissible conditions, few implement such a policy. Our protocol requires increased human and other resources but has no important impact on the rapidity of diagnosis of malaria, and is now embedded in local practice. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16549203&query_hl=1 ER - TY - JFULL T1 - Epstein-barr virus-induced resistance to drugs that activate the mitotic spindle assembly checkpoint in Burkitt's lymphoma cells. A1 - Leao, M A1 - Anderton, E A1 - Wade, M A1 - Meekings, K A1 - Allday, MJ J1 - J Virol Y1 - 2007/01// VL - 81 SN - 0022-538X SP - 248 EP - 260 N2 - Epstein-Barr virus (EBV) is associated with a number of human cancers, and latent EBV gene expression has been reported to interfere with cell cycle checkpoints and cell death pathways. Here we show that latent EBV can compromise the mitotic spindle assembly checkpoint and rescue Burkitt's lymphoma (BL)-derived cells from caspase-dependent cell death initiated in aberrant mitosis. This leads to unscheduled mitotic progression, resulting in polyploidy and multi- and/or micronucleation. The EBV latent genes responsible for this phenotype are expressed from the P3HR1 strain of virus and several viruses with similar genomic deletions that remove the EBNA2 gene. Although EBNA2 and the latent membrane proteins are not expressed, the EBNA3 proteins are present in these BL cells. Survival of the EBV-positive cells is not consistently associated with EBV lytic gene expression or with the genes that are expressed in EBV latency I BL cells (i.e., EBNA1, EBERs, and BARTs) but correlates with reduced expression of the cellular proapoptotic BH3-only protein Bim. These data suggest that a subset of latent EBV gene products may increase the likelihood of damaged DNA being inherited because of the impaired checkpoint and enhanced survival capacity. This could lead to greater genetic diversity in progeny cells and contribute to tumorigenesis. Furthermore, since it appears that this restricted latent EBV expression interferes with the responses of Burkitt's lymphoma-derived cells to cytotoxic drugs, the results of this study may have important therapeutic implications in the treatment of some BL. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17035311&query_hl=1 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 - Spleen-dependent turnover of CD11b peripheral blood B lymphocytes in bovine leukemia virus-infected sheep. A1 - Florins, A A1 - Gillet, N A1 - Asquith, B A1 - Debacq, C A1 - Jean, G A1 - Schwartz-Cornil, I A1 - Bonneau, M A1 - Burny, A A1 - Reichert, M A1 - Kettmann, R A1 - Willems, L J1 - J Virol Y1 - 2006/12// VL - 80 SN - 0022-538X SP - 11998 EP - 12008 N2 - Lymphocyte homeostasis is determined by a critical balance between cell proliferation and death, an equilibrium which is deregulated in bovine leukemia virus (BLV)-infected sheep. We have previously shown that an excess of proliferation occurs in lymphoid tissues and that the peripheral blood population is prone to increased cell death. To further understand the mechanisms involved, we evaluated the physiological role of the spleen in this accelerated turnover. To this end, B lymphocytes were labeled in vivo using a fluorescent marker (carboxyfluorescein diacetate succinimidyl ester), and the cell kinetic parameters (proliferation and death rates) of animals before and after splenectomy were compared. We show that the enhanced cell death observed in BLV-infected sheep is abrogated after splenectomy, revealing a key role of the spleen in B-lymphocyte dynamics. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17035334&query_hl=1 ER - TY - JFULL T1 - The therapeutic potential of positive and negative immune cell co-stimulation during inflammation. A1 - Gwyer, E A1 - Snelgrove, R A1 - Hussell, T J1 - Biochem Soc Trans Y1 - 2006/12// VL - 34 SN - 0300-5127 SP - 1032 EP - 1036 N2 - Inflammatory cascades are initiated in response to alarm signals that may result from infection, malignant transformation or trauma. Immunity, however, must be controlled; otherwise damage may occur to otherwise healthy tissue within the same microenvironment. Similarly, peripheral tolerance mechanisms must ensure that autoreactive thymic or bone marrow emigrants do not respond upon encounter with the autoantigen. Organized lymphoid structures such as lymph nodes, spleen and Peyer's patches appear to regulate inflammation successfully, displaying controlled expansion and contraction. However, when immune cells flood into effector sites, the organization of T- and B-lymphocytes is lacking. What controls inflammatory cascades in lymph nodes but rarely in effector sites is not clear. We believe the difference lies in the Toll-like receptor ligand load, which is high in effector sites and drives uncontrolled inflammation. Similarly, we believe that initiation of autoimmune inflammation is initiated by the liberation of inflammatory signals due to infection or trauma. In this review, we highlight some of the molecules responsible for maintaining an activated T-cell phenotype, strategies to interrupt these therapeutically and the impact of ligating inhibitory receptors on antigen-presenting cells. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17073744&query_hl=1 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 - Histone deacetylase inhibitors increase virus gene expression but decrease CD8+ cell antiviral function in HTLV-1 infection. A1 - Mosley, AJ A1 - Meekings, KN A1 - McCarthy, C A1 - Shepherd, D A1 - Cerundolo, V A1 - Mazitschek, R A1 - Tanaka, Y A1 - Taylor, GP A1 - Bangham, CR J1 - Blood Y1 - 2006/12/01/ VL - 108 SN - 0006-4971 SP - 3801 EP - 3807 N2 - The dynamics of human T-lymphotropic virus type-1 (HTLV-1) provirus expression in vivo are unknown. There is much evidence to suggest that HTLV-1 gene expression is restricted: this restricted gene expression may contribute to HTLV-1 persistence by limiting the ability of the HTLV-1-specific CD8(+) cell immune response to clear infected cells. In this study, we tested the hypothesis that derepression of HTLV-1 gene expression would allow an increase in CD8(+) cell-mediated lysis of HTLV-1-infected cells. Using histone deacetylase enzyme inhibitors (HDIs) to hyperacetylate histones and increase HTLV-1 gene expression, we found that HDIs doubled Tax expression in naturally infected lymphocytes after overnight culture. However, the rate of CD8(+) cell-mediated lysis of Tax-expressing cells ex vivo was halved. HDIs appeared to inhibit the CD8(+) cell-mediated lytic process itself, indicating a role for the microtubule-associated HDAC6 enzyme. These observations indicate that HDIs may reduce the efficiency of cytotoxic T-cell (CTL) surveillance of HTLV-1 in vivo. The impact of HDIs on HTLV-1 proviral load in vivo cannot be accurately predicted because of the widespread effects of these drugs on cellular processes; we therefore recommend caution in the use of HDIs in nonmalignant cases of HTLV-1 infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16912225&query_hl=1 ER - TY - JFULL T1 - Neutrophil-mediated immunity to mycobacterium tuberculosis infection: Role of lipocalin 2 A1 - Martineau, AR A1 - Wilkinson, KA A1 - Kampmann, B A1 - Newton, SM A1 - White, JH A1 - Wang, TT A1 - Hall, BM A1 - Nawroly, N A1 - Packe, GE A1 - Davidson, RN A1 - Maunsell, Z A1 - Rainbow, S A1 - Griffiths, CJ A1 - Wilkinson, RJ J1 - THORAX Y1 - 2006/12// VL - 61 SN - 0040-6376 SP - II25 EP - II26 ER - TY - JFULL T1 - Signature-tagged mutagenesis: barcoding mutants for genome-wide screens. A1 - Mazurkiewicz, P A1 - Tang, CM A1 - Boone, C A1 - Holden, DW J1 - Nat Rev Genet Y1 - 2006/12// VL - 7 SN - 1471-0056 SP - 929 EP - 939 N2 - DNA signature tags (molecular barcodes) facilitate functional screens by identifying mutants in mixed populations that have a reduced or increased adaptation to a particular environment. Many innovative adaptations and refinements in the technology have been described since its original use with Salmonella; they have yielded a wealth of information on a broad range of biological processes--mainly in bacteria, but also in yeast and other fungi, viruses, parasites and, most recently, in mammalian cells. By combining whole-genome microarrays and comprehensive ordered libraries of mutants, high-throughput functional screens can now be achieved on a genomic scale. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17139324&query_hl=1 ER - TY - JFULL T1 - A hepatitis C virus (HCV) NS3/4A protease-dependent strategy for the identification and purification of HCV-infected cells A1 - Breiman A A1 - Vitour D A1 - Vilasco M A1 - Ottone C A1 - Molina S A1 - Pichard L A1 - Fournier C A1 - Delgrange D A1 - Charneau P A1 - Duverlie G A1 - Wychowski C A1 - Maurel P A1 - Meurs EF J1 - Journal of General Virology Y1 - 2006/12// VL - 87 SP - 3587 EP - 3598 ER - TY - JFULL T1 - The translocated Salmonella effector proteins SseF and SseG interact and are required to establish an intracellular replication niche. A1 - Deiwick, J A1 - Salcedo, SP A1 - Boucrot, E A1 - Gilliland, SM A1 - Henry, T A1 - Petermann, N A1 - Waterman, SR A1 - Gorvel, JP A1 - Holden, DW A1 - Méresse, S J1 - Infect Immun Y1 - 2006/12// VL - 74 SN - 0019-9567 SP - 6965 EP - 6972 N2 - The facultative intracellular pathogen Salmonella enterica causes a variety of diseases, including gastroenteritis and typhoid fever. Inside epithelial cells, Salmonella replicates in vacuoles, which localize in the perinuclear area in close proximity to the Golgi apparatus. Among the effector proteins translocated by the Salmonella pathogenicity island 2-encoded type III secretion system, SifA and SseG have been shown necessary but not sufficient to ensure the intracellular positioning of Salmonella vacuoles. Hence, we have investigated the involvement of other secreted effector proteins in this process. Here we show that SseF interacts functionally and physically with SseG but not SifA and is also required for the perinuclear localization of Salmonella vacuoles. The observations show that the intracellular positioning of Salmonella vacuoles is a complex phenomenon resulting from the combined action of several effector proteins. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17015457&query_hl=1 ER - TY - JFULL T1 - Altered monocyte cyclooxygenase response to lipopolysaccharide in type 1 diabetes. A1 - Beyan, H A1 - Goodier, MR A1 - Nawroly, NS A1 - Hawa, MI A1 - Bustin, SA A1 - Ogunkolade, WB A1 - Londei, M A1 - Yousaf, N A1 - Leslie, RD J1 - Diabetes Y1 - 2006/12// VL - 55 SN - 0012-1797 SP - 3439 EP - 3445 N2 - Type 1 diabetes is caused by adaptive immune responses, but innate immunity is important because monocytes infiltrate islets. Activated monocytes express cyclooxygenase (COX)-2, promoting prostaglandin-E(2) (PGE(2)) secretion, whereas COX-1 expression is constitutive. We aimed to define monocyte COX expression in type 1 diabetes basally and after lipopolysaccharide (LPS) stimulation. Isolated CD14(+) monocytes were analyzed for COX mRNA and protein expression from identical twins (discordant for type 1 diabetes) and control subjects. Basal monocyte COX mRNA, protein expression, and PGE(2) secretion were normal in type 1 diabetic subjects. After LPS, twins and control subjects showed a COX mRNA isoform switch with decreased COX-1 mRNA (P < 0.01), increased COX-2 mRNA (P < 0.01), and increased COX-2 protein expression (P < 0.01). Compared with control subjects, both diabetic and nondiabetic twins showed greater LPS-induced downregulation of monocyte COX-1 mRNA (P = 0.02), reduced upregulation of COX-2 mRNA and protein (P < 0.03), and greater inhibition by the COX-2 inhibitor di-isopropylfluorophosphate (DFP) of monocyte PGE(2) (P < 0.007). We demonstrate an alteration in monocyte COX mRNA expression as well as monocyte COX-2 and PGE(2) production after LPS in type 1 diabetic patients and their nondiabetic twins. Because COX-2 response to LPS is proinflammatory, an inherited reduced response would predispose to chronic inflammatory diseases such as type 1 diabetes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17130490&query_hl=1 ER - TY - JFULL T1 - Epstein-Barr virus selectively deregulates DNA damage responses in normal B cells but has no detectable effect on regulation of the tumor suppressor p53. A1 - O'Nions, J A1 - Turner, A A1 - Craig, R A1 - Allday, MJ J1 - J Virol Y1 - 2006/12// VL - 80 SN - 0022-538X SP - 12408 EP - 12413 N2 - To determine whether latent Epstein-Barr virus (EBV) modifies DNA damage responses in B lymphocytes, cells were treated with agents either producing DNA cross-links and adducts or generating double-strand breaks. The cyclin-dependent kinase inhibitor p21(WAF1) accumulated in mitogen-stimulated primary B cells following exposure to all genotoxins tested. In contrast, when proliferation was EBV driven, p21(WAF1) failed to accumulate after treatment with the DNA adduct-producing agents. The tumor suppressor p53 was stabilized and phosphorylated after all treatments, irrespective of whether latent EBV was present. This suggests that regulatory pathways upstream of p53 are unaffected by latent EBV but downstream effectors are altered if DNA adducts or distortions are involved. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16987979&query_hl=1 ER - TY - JFULL T1 - Tuberculosis mortality, drug resistance, and infectiousness in patients with and without HIV infection in Peru. A1 - Kawai, V A1 - Soto, G A1 - Gilman, RH A1 - Bautista, CT A1 - Caviedes, L A1 - Huaroto, L A1 - Ticona, E A1 - Ortiz, J A1 - Tovar, M A1 - Chavez, V A1 - Rodriguez, R A1 - Escombe, AR A1 - Evans, CA J1 - Am J Trop Med Hyg Y1 - 2006/12// VL - 75 SN - 0002-9637 SP - 1027 EP - 1033 N2 - The effects of HIV co-infection and multi-drug resistant tuberculosis (MDRTB) on tuberculosis prognosis are poorly defined. Therefore, we studied infectiousness and mortality of 287 tuberculosis patients treated with standard, directly observed, short-course therapy in the Peruvian community. During 6-17 months of treatment, 49 (18%) of patients died, of whom 48 (98%) had AIDS and 28 (57%) had MDRTB; 17/31 (55%) of MDRTB-patients with AIDS died within 2 months of diagnosis, before traditional susceptibility testing would have identified their MDRTB. Most non-MDRTB became smear- and culture-negative within 6 weeks of therapy, whereas most MDRTB remained sputum-culture-positive until death or treatment completion. HIV-negative patients with non-MDRTB had good outcomes. However, MDRTB was associated with prolonged infectiousness and HIV co-infection with early mortality, indicating a need for greater access to anti-retroviral therapy. Furthermore, early and rapid tuberculosis drug-susceptibility testing and infection control are required so that MDRTB can be appropriately treated early enough to reduce mortality and transmission. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17172361&query_hl=1 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 - Retention of 1.2 kbp of 'novel' genomic sequence in two European field isolates and some vaccine strains of Fowlpox virus extends open reading frame fpv241. A1 - Jarmin, SA A1 - Manvell, R A1 - Gough, RE A1 - Laidlaw, SM A1 - Skinner, MA J1 - J Gen Virol Y1 - 2006/12// VL - 87 SN - 0022-1317 SP - 3545 EP - 3549 N2 - The emergence of variant fowlpox viruses (FWPVs) and increasing field use of recombinants against avian influenza H5N1 emphasize the need to monitor vaccines and to distinguish them from field strains. Five commercial vaccines, two laboratory viruses and two European field isolates were characterized by PCR and sequencing at 18 loci differing between attenuated FP9 and its pathogenic progenitor. PCR failed to discriminate between the viruses and sequence determination revealed no significant differences at any locus, except for a polymorphic locus encompassed by deletion 24 (9.3 kbp) in FP9. Surprisingly, 'novel' previously unreported sequence (spanning 1.2 kbp) was found in both European field isolates and three of the vaccines. It was absent from the other two vaccines, removed by a 1.2 kbp deletion identical to that surprisingly also observed in the completely sequenced genome of FPV USDA. This locus (H9) adds a potentially useful tool for discriminating between FWPV field isolates and vaccines. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17098969&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 - Sequences, sequence clusters and bacterial species. A1 - Hanage, WP A1 - Fraser, C A1 - Spratt, BG J1 - Philos Trans R Soc Lond B Biol Sci Y1 - 2006/11/29/ VL - 361 SN - 0962-8436 SP - 1917 EP - 1927 N2 - Whatever else they should share, strains of bacteria assigned to the same species should have house-keeping genes that are similar in sequence. Single gene sequences (or rRNA gene sequences) have very few informative sites to resolve the strains of closely related species, and relationships among similar species may be confounded by interspecies recombination. A more promising approach (multilocus sequence analysis, MLSA) is to concatenate the sequences of multiple house-keeping loci and to observe the patterns of clustering among large populations of strains of closely related named bacterial species. Recent studies have shown that large populations can be resolved into non-overlapping sequence clusters that agree well with species assigned by the standard microbiological methods. The use of clustering patterns to inform the division of closely related populations into species has many advantages for poorly studied bacteria (or to re-evaluate well-studied species), as it provides a way of recognizing natural discontinuities in the distribution of similar genotypes. Clustering patterns can be used by expert groups as the basis of a pragmatic approach to assigning species, taking into account whatever additional data are available (e.g. similarities in ecology, phenotype and gene content). The development of large MLSA Internet databases provides the ability to assign new strains to previously defined species clusters and an electronic taxonomy. The advantages and problems in using sequence clusters as the basis of species assignments are discussed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17062411&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 - New strategies for the elimination of polio from India. A1 - Grassly, NC A1 - Fraser, C A1 - Wenger, J A1 - Deshpande, JM A1 - Sutter, RW A1 - Heymann, DL A1 - Aylward, RB J1 - Science Y1 - 2006/11/17/ VL - 314 SN - 1095-9203 SP - 1150 EP - 1153 N2 - The feasibility of global polio eradication is being questioned as a result of continued transmission in a few localities that act as sources for outbreaks elsewhere. Perhaps the greatest challenge is in India, where transmission has persisted in Uttar Pradesh and Bihar despite high coverage with multiple doses of vaccine. We estimate key parameters governing the seasonal epidemics in these areas and show that high population density and poor sanitation cause persistence by not only facilitating transmission of poliovirus but also severely compromising the efficacy of the trivalent vaccine. We analyze strategies to counteract this and show that switching to monovalent vaccine may finally interrupt virus transmission. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17110580&query_hl=1 ER - TY - JFULL T1 - Reduced rates of B cell proliferation in chronic lymphocytic leukemia. A1 - Defoiche, J A1 - Debacq, C A1 - Asquith, B A1 - Zhang, Y A1 - Burny, A A1 - Bron, D A1 - Lagneaux, L A1 - Macallan, D A1 - Willems, L J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 798A EP - 798A ER - TY - JFULL T1 - Histological response to pegIFNalpha-2a (40KD) plus ribavirin in HIV-hepatitis C virus co-infection. A1 - Lissen, E A1 - Clumeck, N A1 - Sola, R A1 - Mendes-Correa, M A1 - Montaner, J A1 - Nelson, M A1 - DePamphilis, J A1 - Pessôa, M A1 - Buggisch, P A1 - Main, J A1 - Dieterich, D J1 - AIDS Y1 - 2006/11/14/ VL - 20 SN - 0269-9370 SP - 2175 EP - 2181 N2 - OBJECTIVE: Paired liver biopsies from patients enrolled in the multinational AIDS PEGASYS Ribavirin International Co-infection Trial were analysed to investigate a possible correlation between virological and histological responses. DESIGN AND METHODS: A total of 860 HIV-hepatitis C virus (HCV)-co-infected patients were randomly assigned to receive pegIFNalpha-2a (40KD) 180 microg/week plus 800 mg daily ribavirin, pegIFNalpha-2a (40KD) plus placebo or conventional IFNalpha-2a 3 MIU three times a week plus ribavirin for 48 weeks. Paired biopsies were obtained from 401 patients and scored locally using the Ishak-modified histological activity index (HAI). The second biopsy was obtained, on average, 26 weeks or more after the end of treatment. Histological response was defined as a 2-point or greater reduction in the HAI score. RESULTS: The histological response rate was significantly higher in patients receiving pegIFNalpha-2a (40KD) plus ribavirin (57%) than in patients receiving pegIFNalpha-2a (40KD) plus placebo (39%; P < 0.017) or IFNalpha-2a plus ribavirin (41%; P = 0.04). Histological response was correlated with virological response, with the histological response rate ranging from 62 to 74% in patients who achieved a sustained virological response (SVR). Histological response was also seen in 32-43% of patients not achieving an SVR. A higher total HAI score was the only prognostic factor for achieving histological response. CONCLUSION: The histological response rate was significantly higher in HIV-HCV-co-infected patients who received pegIFNalpha-2a (40KD) plus ribavirin than in those receiving pegIFNalpha-2a (40KD) plus placebo or IFNalpha-2a plus ribavirin. Histological response was correlated with virological response, although a substantial proportion of patients who did not achieve an SVR experienced histological improvement. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17086057&query_hl=1 ER - TY - JFULL T1 - Mathematical models and lymphatic filariasis control: monitoring and evaluating interventions. A1 - Michael, E A1 - Malecela-Lazaro, MN A1 - Maegga, BT A1 - Fischer, P A1 - Kazura, JW J1 - Trends Parasitol Y1 - 2006/11// VL - 22 SN - 1471-4922 SP - 529 EP - 535 N2 - Monitoring and evaluation are crucially important to the scientific management of any mass parasite control programme. Monitoring enables the effectiveness of implemented actions to be assessed and necessary adaptations to be identified; it also determines when management objectives are achieved. Parasite transmission models can provide a scientific template for informing the optimal design of such monitoring programmes. Here, we illustrate the usefulness of using a model-based approach for monitoring and evaluating anti-parasite interventions and discuss issues that need addressing. We focus on the use of such an approach for the control and/or elimination of the vector-borne parasitic disease, lymphatic filariasis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16971182&query_hl=1 ER - TY - JFULL T1 - The role of Epstein-Barr virus in cancer. A1 - Pattle, SB A1 - Farrell, PJ J1 - Expert Opin Biol Ther Y1 - 2006/11// VL - 6 SN - 1744-7682 SP - 1193 EP - 1205 N2 - Epstein-Barr virus (EBV), discovered > 40 years ago from a Burkitt's lymphoma biopsy, was the first virus to be directly associated with human cancer. EBV has two distinct life cycles in the human host; a lytic form of infection that produces new infectious virions, and a latent form of infection that allows the virus to persist in a dormant state for the lifetime of the host. EBV has evolved a life cycle that mimics the natural differentiation pathway of antigen-activated B cells, giving the virus access to its site of latent infection, the resting memory B cell. By steering infected cells through the various stages of lymphocyte differentiation, EBV is able to enter a cell type suitable for long-term latent persistence and periodic reactivation. However, its presence in various stages of B-cell development, and its ability to infect certain epithelial cells, can have pathogenic consequences, and can contribute to the development of a diverse group of lymphomas and carcinomas. The presence of EBV in the tumour cells of EBV-associated cancers might provide a basis for specific therapy. This article focuses on the contributions that the virus may play in different types of human cancer, particularly Burkitt's lymphoma, Hodgkin's lymphoma, lymphomas and lymphoproliferative diseases in the immunocompromised, and nasopharyngeal and gastric carcinoma. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17049016&query_hl=1 ER - TY - JFULL T1 - Using treatment failure to screen for MDR TB is associated with recurrence, death and transmission A1 - Sherman, JM A1 - Tovar, M A1 - Gilman, RH A1 - Soto, G A1 - Caviedes, L A1 - Cabrera, L A1 - Zimic, M A1 - Bernabe, A A1 - Ortiz, J A1 - Rodriguez, R A1 - Ticona, E A1 - Friedland, JS A1 - Evans, CA J1 - AM J TROP MED HYG Y1 - 2006/11// VL - 75 SN - 0002-9637 SP - 312 EP - 313 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 - Immune reconstitution disease associated with parasitic infections following antiretroviral treatment A1 - Lawn, SD A1 - Wilkinson, RJ J1 - PARASITE IMMUNOL Y1 - 2006/11// VL - 28 SN - 0141-9838 SP - 625 EP - 633 N2 - HIV-associated immune reconstitution disease (IRD) is the clinical presentation or deterioration of opportunistic infections that results from enhancement of pathogen-specific immune responses among patients responding to antiretroviral treatment (ART). The vast majority of reported cases of IRD have been associated with mycobacterial, chronic viral and invasive fungal infections; such cases result from dysregulated augmentation of cell-mediated type 1 cytokine-secreting host immune responses. However, the spectrum of infections now recognized as associated with IRD is expanding and includes a number of parasitic infections, which may be mediated by different immunopathological mechanisms. These include leishmaniasis (visceral, cutaneous, mucosal and post kala azar dermal leishmaniasis), schistosomiasis and strongyloidiasis. Since the major burden of HIV lies in resource-limited countries where access to ART is now rapidly expanding, increased awareness and knowledge of these phenomena is important. Here we review the clinical spectrum and pathogenesis of IRD associated with parasitic infections. ER - TY - JFULL T1 - Feline calicivirus replication: requirement for polypyrimidine tract-binding protein is temperature-dependent. A1 - Karakasiliotis, I A1 - Chaudhry, Y A1 - Roberts, LO A1 - Goodfellow, IG J1 - J Gen Virol Y1 - 2006/11// VL - 87 SN - 0022-1317 SP - 3339 EP - 3347 N2 - The interaction of host-cell nucleic acid-binding proteins with the genomes of positive-stranded RNA viruses is known to play a role in the translation and replication of many viruses. To date, however, the characterization of similar interactions with the genomes of members of the family Caliciviridae has been limited to in vitro binding analysis. In this study, Feline calicivirus (FCV) has been used as a model system to identify and characterize the role of host-cell factors that interact with the viral RNA. It was demonstrated that polypyrimidine tract-binding protein (PTB) interacts specifically with the 5' sequences of the FCV genomic and subgenomic RNAs. Using RNA interference it was shown that PTB is required for efficient FCV replication in a temperature-dependent manner. siRNA-mediated knockdown of PTB resulted in a 15- to 100-fold reduction in virus titre, as well as a concomitant reduction in viral RNA and protein synthesis at 32 degrees C. In addition, virus-induced cytopathic effect was significantly delayed as a result of an siRNA-mediated reduction in PTB levels. A role for PTB in the calicivirus life cycle was more apparent at temperatures above and below 37 degrees C, fitting with the hypothesis that PTB functions as an RNA chaperone, potentially aiding the folding of RNA into functional structures. This is the first functional demonstration of a host-cell protein interacting with a calicivirus RNA. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17030868&query_hl=1 ER - TY - JFULL T1 - Quantification of antibody responses against multiple antigens of the two infectious forms of Vaccinia virus provides a benchmark for smallpox vaccination. A1 - Pütz, MM A1 - Midgley, CM A1 - Law, M A1 - Smith, GL J1 - Nat Med Y1 - 2006/11// VL - 12 SN - 1078-8956 SP - 1310 EP - 1315 N2 - Smallpox was eradicated without an adequate understanding of how vaccination induced protection. In response to possible bioterrorism with smallpox, the UK government vaccinated approximately 300 health care workers with vaccinia virus (VACV) strain Lister. Antibody responses were analyzed using ELISA for multiple surface antigens of the extracellular enveloped virus (EEV) and the intracellular mature virus (IMV), plaque reduction neutralization and a fluorescence-based flow cytometric neutralization assay. Antibody depletion experiments showed that the EEV surface protein B5 is the only target responsible for EEV neutralization in vaccinated humans, whereas multiple IMV surface proteins, including A27 and H3, are targets for IMV-neutralizing antibodies. These data suggest that it would be unwise to exclude the B5 protein from a future smallpox vaccine. Repeated vaccination provided significantly higher B5-specific and thus EEV-neutralizing antibody responses. These data provide a benchmark against which new, safer smallpox vaccines and residual immunity can be compared. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17086190&query_hl=1 ER - TY - JFULL T1 - Immunization with live Neisseria lactamica protects mice against meningococcal challenge and can elicit serum bactericidal antibodies. A1 - Li, Y A1 - Zhang, Q A1 - Winterbotham, M A1 - Mowe, E A1 - Gorringe, A A1 - Tang, CM J1 - Infect Immun Y1 - 2006/11// VL - 74 SN - 0019-9567 SP - 6348 EP - 6355 N2 - Natural immunity against Neisseria meningitidis is thought to develop following nasopharyngeal colonization with this bacterium or other microbes expressing cross-reactive antigens. Neisseria lactamica is a commensal of the upper respiratory tract which is often carried by infants and young children; epidemiological evidence indicates that colonization with this bacterium can elicit serum bactericidal activity (SBA) against Neisseria meningitidis, the most validated correlate of protective immunity. Here we demonstrate experimentally that immunization of mice with live N. lactamica protects animals against lethal meningococcal challenge and that some, but not all, strains of N. lactamica elicit detectable SBA in immunized animals regardless of the serogroup of N. meningitidis. While it is unlikely that immunization with live N. lactamica will be implemented as a vaccine against meningococcal disease, understanding the basis for the induction of cross-protective immunity and SBA should be valuable in the design of subunit vaccines for the prevention of this important human infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16966413&query_hl=1 ER - TY - JFULL T1 - Lentiviral vector expressing retinoic acid receptor beta2 promotes recovery of function after corticospinal tract injury in the adult rat spinal cord. A1 - Yip, PK A1 - Wong, LF A1 - Pattinson, D A1 - Battaglia, A A1 - Grist, J A1 - Bradbury, EJ A1 - Maden, M A1 - McMahon, SB A1 - Mazarakis, ND J1 - Hum Mol Genet Y1 - 2006/11/01/ VL - 15 SN - 0964-6906 SP - 3107 EP - 3118 N2 - Spinal cord injury often results in permanent and devastating neurological deficits and disability. This is due to the limited regenerative capacity of neurones in the central nervous system (CNS). We recently demonstrated that a transcription factor retinoic acid receptor beta2 (RARbeta2) promoted axonal regeneration in adult sensory neurones located peripherally. However, it is not known if RARbeta2 can promote axonal regeneration in cortical neurones of the CNS. Here, we demonstrate that delivery of RARbeta2 via a lentiviral vector to adult dissociated cortical neurones significantly enhances neurite outgrowth on adult cortical cryosections, which normally provide an unfavourable substrate for growth. We also show that lentiviral-mediated transduction of corticospinal neurones resulted in robust transgene expression in layer V corticospinal neurones and their axonal projections in the corticospinal tract (CST) of the spinal cord. Expression of RARbeta2 in these neurones enhanced regeneration of the descending CST fibres after injury to these axons in the mid-cervical spinal cord. Furthermore, we observed functional recovery in sensory and locomotor behavioural tests in RARbeta2-treated animals. These results suggest that a direct and selective delivery of RARbeta2 to the corticospinal neurones promotes long-distance functional regeneration of axons in the spinal cord and may thus offer new therapeutic gene strategy for the treatment of human spinal cord injuries. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16984961&query_hl=1 ER - TY - JFULL T1 - A critical role for ICOS co-stimulation in immune containment of pulmonary influenza virus infection. A1 - Humphreys, IR A1 - Edwards, L A1 - Snelgrove, RJ A1 - Rae, AJ A1 - Coyle, AJ A1 - Hussell, T J1 - Eur J Immunol Y1 - 2006/11// VL - 36 SN - 0014-2980 SP - 2928 EP - 2938 N2 - Lung pathology observed during influenza infection is due to direct damage resulting from viral replication and bystander damage caused by overly exuberant antiviral immune mechanisms. In the absence of universally effective vaccines and antiviral therapies, knowledge of the cellular components required for immune containment of influenza is essential. ICOS is a late co-stimulatory molecule expressed by T cells 12-24 h after activation. We show for the first time that inhibition of ICOS with a monoclonal antibody reduces pulmonary T cell inflammation and associated cytokine expression. Surprisingly however, this reduction in T cells was not accompanied by an alleviation of weight loss and illness. Furthermore, lung viral titres were elevated following anti-ICOS treatment, suggesting that the beneficial outcome of reducing T cell pathology was masked by enhanced virus-induced damage and innate inflammation. This study demonstrates the delicate balance that exists between pathogen burden and pulmonary T cell inflammation during influenza infection and highlights the critical role of ICOS in this response. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17039567&query_hl=1 ER - TY - JFULL T1 - Nonsense-mediated mRNA decay mutation in Aspergillus nidulans. A1 - Morozov, IY A1 - Negrete-Urtasun, S A1 - Tilburn, J A1 - Jansen, CA A1 - Caddick, MX A1 - Arst, HN J1 - Eukaryot Cell Y1 - 2006/11// VL - 5 SN - 1535-9778 SP - 1838 EP - 1846 N2 - An Aspergillus nidulans mutation, designated nmdA1, has been selected as a partial suppressor of a frameshift mutation and shown to truncate the homologue of the Saccharomyces cerevisiae nonsense-mediated mRNA decay (NMD) surveillance component Nmd2p/Upf2p. nmdA1 elevates steady-state levels of premature termination codon-containing transcripts, as demonstrated using mutations in genes encoding xanthine dehydrogenase (hxA), urate oxidase (uaZ), the transcription factor mediating regulation of gene expression by ambient pH (pacC), and a protease involved in pH signal transduction (palB). nmdA1 can also stabilize pre-mRNA (unspliced) and wild-type transcripts of certain genes. Certain premature termination codon-containing transcripts which escape NMD are relatively stable, a feature more in common with certain nonsense codon-containing mammalian transcripts than with those in S. cerevisiae. As in S. cerevisiae, 5' nonsense codons are more effective at triggering NMD than 3' nonsense codons. Unlike the mammalian situation but in common with S. cerevisiae and other lower eukaryotes, A. nidulans is apparently impervious to the position of premature termination codons with respect to the 3' exon-exon junction. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16963627&query_hl=1 ER - TY - JFULL T1 - Presence of copper- and zinc-containing superoxide dismutase in commensal Haemophilus haemolyticus isolates can be used as a marker to discriminate them from nontypeable H. influenzae isolates. A1 - Fung, WW A1 - O'Dwyer, CA A1 - Sinha, S A1 - Brauer, AL A1 - Murphy, TF A1 - Kroll, JS A1 - Langford, PR J1 - J Clin Microbiol Y1 - 2006/11// VL - 44 SN - 0095-1137 SP - 4222 EP - 4226 N2 - Respiratory isolates of Haemophilus haemolyticus are regularly misclassified as nontypeable (NT) Haemophilus influenzae due to an aberrant hemolytic reaction on blood agar, with implications for treatment. The presence of sodC or its cognate protein, copper-zinc superoxide dismutase, can distinguish respiratory isolates of H. haemolyticus from NT H. influenzae with 100% accuracy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16988021&query_hl=1 ER - TY - JFULL T1 - Effect of mass drug administration on transmission of lymphatic filariasis in Madang province of Papua New Guinea A1 - Bockarie, MJ A1 - Weil, GJ A1 - Kastens, W A1 - Susapu, M A1 - Dagoro, H A1 - Tarongka, N A1 - Baisor, M A1 - Michael, E A1 - King, C A1 - Kazura, JW J1 - AM J TROP MED HYG Y1 - 2006/11// VL - 75 SN - 0002-9637 SP - 298 EP - 298 ER - TY - JFULL T1 - Non-invasive evaluation of hepatic fibrosis using magnetic resonance and ultrasound techniques. A1 - Cobbold, JF A1 - Wylezinska, M A1 - Cunningham, C A1 - Crossey, ME A1 - Thomas, HC A1 - Cox, IJ A1 - Patel, N A1 - Taylor-Robinson, SD J1 - Gut Y1 - 2006/11// VL - 55 SN - 0017-5749 SP - 1670; author reply 1670 EP - 1670; author reply 1670 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17047120&query_hl=1 ER - TY - JFULL T1 - Susceptibility of healthcare workers in Kenya to hepatitis B: new strategies for facilitating vaccination uptake. A1 - Suckling, RM A1 - Taegtmeyer, M A1 - Nguku, PM A1 - Al-Abri, SS A1 - Kibaru, J A1 - Chakaya, JM A1 - Tukei, PM A1 - Gilks, CF J1 - J Hosp Infect Y1 - 2006/11// VL - 64 SN - 0195-6701 SP - 271 EP - 277 N2 - Hepatitis B virus (HBV) infection is preventable, yet many healthcare workers (HCWs) in resource-poor countries remain at risk. The aims of this study were to evaluate the susceptibility of HCWs in a Kenyan district to HBV infection, and the feasibility of expanding the Extended Programme of Immunization (EPI) for infants to incorporate hepatitis B vaccination of HCWs. HCWs in Thika district, Kenya were invited to complete an interviewer-administered questionnaire about their immunization status and exposure to blood or body fluids. Participants were asked to provide a blood sample to assess natural or vaccine-induced protection against HBV. All non-immune HCWs were offered hepatitis B vaccination. Thirty percent (168/554) of HCWs reported one or more needlestick injuries (NSIs) in the previous year, with an annual incidence of 0.97 NSIs/HCW/year. Only 12.8% (71/554) of HCWs had received vaccination previously and none had been screened for immunity or for hepatitis B surface antigen. In total, 407 staff provided blood samples; 41% were HBV core antibody, 4% expressed hepatitis B surface antibody from previous vaccination, and 55% were unprotected. Two hundred and twenty-two staff were eligible for vaccine delivered through the EPI infrastructure. Self-motivated uptake of a full course of vaccine was 92% in the smaller health centres and 44% in the district hospital. This study demonstrates the importance of hepatitis B vaccination of HCWs in parts of Africa where high exposure rates are combined with low levels of vaccine coverage. High rates of vaccination can be achieved using childhood immunization systems for the distribution of vaccine to HCWs. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16926061&query_hl=1 ER - TY - JFULL T1 - Human cell-mediated immunity against Mycobacterium tuberculosis antigens is augmented by treating intestinal helminths A1 - Zevallos, K A1 - Vergara, KC A1 - Gilman, RH A1 - Kosek, M A1 - Yori, P A1 - Banda, C A1 - Herrera, B A1 - Valencia, T A1 - Vidal, C A1 - Meza, G A1 - Friedland, JS A1 - Sandhu, GS A1 - Evans, CA J1 - AM J TROP MED HYG Y1 - 2006/11// VL - 75 SN - 0002-9637 SP - 313 EP - 313 ER - TY - JFULL T1 - Safety and immunogenicity of the malaria candidate vaccines FP9 CS and MVA CS in adult Gambian men. A1 - Imoukhuede, EB A1 - Berthoud, T A1 - Milligan, P A1 - Bojang, K A1 - Ismaili, J A1 - Keating, S A1 - Nwakanma, D A1 - Keita, S A1 - Njie, F A1 - Sowe, M A1 - Todryk, S A1 - Laidlaw, SM A1 - Skinner, MA A1 - Lang, T A1 - Gilbert, S A1 - Greenwood, BM A1 - Hill, AV J1 - Vaccine Y1 - 2006/10/30/ VL - 24 SN - 0264-410X SP - 6526 EP - 6533 N2 - We assessed the safety and immunogenicity of prime-boost vectors encoding the Plasmodium falciparum circumsporozoite (CS) protein expressed either in the attenuated fowl-pox virus (FP9) or modified vaccinia virus Ankara (MVA). Thirty-two adult Gambians in groups of four to eight received one, two or three doses of FP9 CS and/or MVA CS. No serious adverse event was observed following vaccination. The most immunogenic regimen was two doses of FP9 followed by a single dose of MVA 4 weeks later (an average of 1000 IFN-gamma spot forming units/million PBMCs). This level of effector T-cell responses appears higher than that seen in previously reported studies of CS-based candidate malaria vaccines. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16842888&query_hl=1 ER - TY - JFULL T1 - Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5 A1 - Floto, RA A1 - MacAry, PA A1 - Boname, JM A1 - Mien, TS A1 - Kampmann, B A1 - Hair, JR A1 - Huey, OS A1 - Houben, ENG A1 - Pieters, J A1 - Day, C A1 - Oehlmann, W A1 - Singh, M A1 - Smith, KGC A1 - Lehner, PJ J1 - SCIENCE Y1 - 2006/10/20/ VL - 314 SN - 0036-8075 SP - 454 EP - 458 N2 - An effective host immune response to mycobacterial infection must control pathogen dissemination without inducing immunopathology. Constitutive overexpression of mycobacterial heat shock protein (myHsp70) is associated with impaired bacterial persistence, but the immune-mediated mechanisms are unknown. We found that myHsp70, in addition to enhancing antigen delivery to human dendritic cells, signaled through the CCR5 chemokine receptor, promoting dendritic cell aggregation, immune synapse formation between dendritic cells and T cells, and the generation of effector immune responses. Thus, CCR5 acts as a pattern-recognition receptor for myHsp70, which may have implications for both the pathophysiology of tuberculosis and the use of myHsps in tumor-directed immunotherapy. ER - TY - JFULL T1 - A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion. A1 - Newton, SM A1 - Smith, RJ A1 - Wilkinson, KA A1 - Nicol, MP A1 - Garton, NJ A1 - Staples, KJ A1 - Stewart, GR A1 - Wain, JR A1 - Martineau, AR A1 - Fandrich, S A1 - Smallie, T A1 - Foxwell, B A1 - Al-Obaidi, A A1 - Shafi, J A1 - Rajakumar, K A1 - Kampmann, B A1 - Andrew, PW A1 - Ziegler-Heitbrock, L A1 - Barer, MR A1 - Wilkinson, RJ J1 - Proc Natl Acad Sci U S A Y1 - 2006/10/17/ VL - 103 SN - 0027-8424 SP - 15594 EP - 15598 N2 - Six major lineages of Mycobacterium tuberculosis appear preferentially transmitted amongst distinct ethnic groups. We identified a deletion affecting Rv1519 in CH, a strain isolated from a large outbreak in Leicester U.K., that coincidentally defines the East African-Indian lineage matching a major ethnic group in this city. In broth media, CH grew less rapidly and was less acidic and H2O2-tolerant than reference sequenced strains (CDC1551 and H37Rv). Nevertheless, CH was not impaired in its ability to grow in human monocyte-derived macrophages. When compared with CDC1551 and H37Rv, CH induced less protective IL-12p40 and more antiinflammatory IL-10 and IL-6 gene transcription and secretion from monocyte-derived macrophages. It thus appears that CH compensates microbiological attenuation by skewing the innate response toward phagocyte deactivation. Complementation of Rv1519, but none of nine additional genes absent from CH compared with the type strain, H37Rv, reversed the capacity of CH to elicit antiinflammatory IL-10 production by macrophages. The Rv1519 polymorphism in M. tuberculosis confers an immune subverting phenotype that contributes to the persistence and outbreak potential of this lineage. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17028173&query_hl=1 ER - TY - JFULL T1 - In the absence of reactive oxygen species, T cells default to a Th1 phenotype and mediate protection against pulmonary Cryptococcus neoformans infection. A1 - Snelgrove, RJ A1 - Edwards, L A1 - Williams, AE A1 - Rae, AJ A1 - Hussell, T J1 - J Immunol Y1 - 2006/10/15/ VL - 177 SN - 0022-1767 SP - 5509 EP - 5516 N2 - In recent years, the prevalence of invasive fungal infections has increased, attributed mostly to the rising population of immunocompromised individuals. Cryptococcus neoformans has been one of the most devastating, with an estimated 6-8% of AIDS-infected patients succumbing to Cryptococcus-associated meningitis. Reactive oxygen species (ROS) are potent antimicrobial agents but also play a significant role in regulating immune cell phenotype, but cause immunopathology when produced in excess. We now show that mice lacking phagocyte NADPH oxidase have heightened macrophage and Th1 responses and improved pathogen containment within pulmonary granulomatous lesions. Consequently, dissemination of this fungus to the brain is diminished, an effect that is independent of IL-12. Similar results are described using the metalloporphyrin antioxidant manganese(III) tetrakis(N-ethyl pyridinium-2-yl)porphyrin, which also promoted a protective Th1 response and reduced dissemination to the brain. These findings are in sharp contrast to the protective potential of ROS against other fungal pathogens, and highlight the pivotal role that ROS can fulfill in shaping the profile of the host's immune response. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17015737&query_hl=1 ER - TY - JFULL T1 - Evolution of competence and DNA uptake specificity in the Pasteurellaceae A1 - Redfield, RJ A1 - Findlay, WA A1 - Bosse, J A1 - Kroll, JS A1 - Cameron, ADS A1 - Nash, JHE J1 - BMC EVOL BIOL Y1 - 2006/10/12/ VL - 6 SN - 1471-2148 N2 - Background: Many bacteria can take up DNA, but the evolutionary history and function of natural competence and transformation remain obscure. The sporadic distribution of competence suggests it is frequently lost and/or gained, but this has not been examined in an explicitly phylogenetic context. Additional insight may come from the sequence specificity of uptake by species such as Haemophilus influenzae, where a 9 bp uptake signal sequence (USS) repeat is both highly overrepresented in the genome and needed for efficient DNA uptake. We used the distribution of competence genes and DNA uptake specificity in H. influenzae's family, the Pasteurellaceae, to examine the ancestry of competence.Results: A phylogeny of the Pasteurellaceae based on 12 protein coding genes from species with sequenced genomes shows two strongly supported subclades: the Hin subclade (H. influenzae, Actinobacillus actinomycetemcomitans, Pasteurella multocida, Mannheimia succiniciproducens, and H. somnus), and the Apl subclade (A. pleuropneumoniae, M. haemolytica, and H. ducreyi). All species contained homologues of all known H. influenzae competence genes, consistent with an ancestral origin of competence. Competence gene defects were identified in three species (H. somnus, H. ducreyi and M. haemolytica); each appeared to be of recent origin.The assumption that USS arise by mutation rather than copying was first confirmed using alignments of H. influenzae proteins with distant homologues. Abundant USS-like repeats were found in all eight Pasteurellacean genomes; the repeat consensuses of species in the Hin subclade were identical to that of H. influenzae (A (AGT) under bar GCGGT), whereas members of the Apl subclade shared the consensus A (CAA) under bar GCGGT. All species' USSs had the strong consensus and flanking AT-rich repeats of H. influenzae USSs. DNA uptake and competition experiments demonstrated that the Apl-type repeat is a true USS distinct from the Hin-type USS: A. pleuropneumoniae preferentially takes up DNA fragments containing the Apl-type USS over both H. influenzae and unrelated DNAs, and H. influenzae prefers its own USS over the Apl type.Conclusion: Competence and DNA uptake specificity are ancestral properties of the Pasteurellaceae, with divergent USSs and uptake specificity distinguishing only the two major subclades. The conservation of most competence genes over the similar to 350 million year history of the family suggests that lineages that lose competence may be evolutionary dead ends. ER - TY - JFULL T1 - Microscopic-observation drug-susceptibility assay for the diagnosis of TB. A1 - Moore, DA A1 - Evans, CA A1 - Gilman, RH A1 - Caviedes, L A1 - Coronel, J A1 - Vivar, A A1 - Sanchez, E A1 - Piñedo, Y A1 - Saravia, JC A1 - Salazar, C A1 - Oberhelman, R A1 - Hollm-Delgado, MG A1 - LaChira, D A1 - Escombe, AR A1 - Friedland, JS J1 - N Engl J Med Y1 - 2006/10/12/ VL - 355 SN - 1533-4406 SP - 1539 EP - 1550 N2 - BACKGROUND: New diagnostic tools are urgently needed to interrupt the transmission of tuberculosis and multidrug-resistant tuberculosis. Rapid, sensitive detection of tuberculosis and multidrug-resistant tuberculosis in sputum has been demonstrated in proof-of-principle studies of the microscopic-observation drug-susceptibility (MODS) assay, in which broth cultures are examined microscopically to detect characteristic growth. METHODS: In an operational setting in Peru, we investigated the performance of the MODS assay for culture and drug-susceptibility testing in three target groups: unselected patients with suspected tuberculosis, prescreened patients at high risk for tuberculosis or multidrug-resistant tuberculosis, and unselected hospitalized patients infected with the human immunodeficiency virus. We compared the MODS assay head-to-head with two reference methods: automated mycobacterial culture and culture on Löwenstein-Jensen medium with the proportion method. RESULTS: Of 3760 sputum samples, 401 (10.7%) yielded cultures positive for Mycobacterium tuberculosis. Sensitivity of detection was 97.8% for MODS culture, 89.0% for automated mycobacterial culture, and 84.0% for Löwenstein-Jensen culture (P<0.001); the median time to culture positivity was 7 days, 13 days, and 26 days, respectively (P<0.001), and the median time to the results of susceptibility tests was 7 days, 22 days, and 68 days, respectively. The incremental benefit of a second MODS culture was minimal, particularly in patients at high risk for tuberculosis or multidrug-resistant tuberculosis. Agreement between MODS and the reference standard for susceptibility was 100% for rifampin, 97% for isoniazid, 99% for rifampin and isoniazid (combined results for multidrug resistance), 95% for ethambutol, and 92% for streptomycin (kappa values, 1.0, 0.89, 0.93, 0.71, and 0.72, respectively). CONCLUSIONS: A single MODS culture of a sputum sample offers more rapid and sensitive detection of tuberculosis and multidrug-resistant tuberculosis than the existing gold-standard methods used. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17035648&query_hl=1 ER - TY - JFULL T1 - Seasonal infectious disease epidemiology. A1 - Grassly, NC A1 - Fraser, C J1 - Proc Biol Sci Y1 - 2006/10/07/ VL - 273 SN - 0962-8452 SP - 2541 EP - 2550 N2 - Seasonal change in the incidence of infectious diseases is a common phenomenon in both temperate and tropical climates. However, the mechanisms responsible for seasonal disease incidence, and the epidemiological consequences of seasonality, are poorly understood with rare exception. Standard epidemiological theory and concepts such as the basic reproductive number R0 no longer apply, and the implications for interventions that themselves may be periodic, such as pulse vaccination, have not been formally examined. This paper examines the causes and consequences of seasonality, and in so doing derives several new results concerning vaccination strategy and the interpretation of disease outbreak data. It begins with a brief review of published scientific studies in support of different causes of seasonality in infectious diseases of humans, identifying four principal mechanisms and their association with different routes of transmission. It then describes the consequences of seasonality for R0, disease outbreaks, endemic dynamics and persistence. Finally, a mathematical analysis of routine and pulse vaccination programmes for seasonal infections is presented. The synthesis of seasonal infectious disease epidemiology attempted by this paper highlights the need for further empirical and theoretical work. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16959647&query_hl=1 ER - TY - JFULL T1 - Meningococcal adhesion suppresses proapoptotic gene expression and promotes expression of genes supporting early embryonic and cytoprotective signaling of human endothelial cells. A1 - Linhartova, I A1 - Basler, M A1 - Ichikawa, J A1 - Pelicic, V A1 - Osicka, R A1 - Lory, S A1 - Nassif, X A1 - Sebo, P J1 - FEMS Microbiol Lett Y1 - 2006/10// VL - 263 SN - 0378-1097 SP - 109 EP - 118 N2 - Neisseria meningitidis colonizes the human nasopharynx and occasionally causes lethal or damaging septicemia and meningitis. Here, we examined the adherence-mediated signaling of meningococci to human cells by comparing gene expression profiles of human umbilical vein endothelial cells (HUVEC) infected by adherent wild-type, frpC-deficient mutant, or the nonadherent (DeltapilD) N. meningitidis. Pili-mediated adhesion of meningococci resulted in alterations of expression levels of human genes known to regulate apoptosis, cell proliferation, inflammatory response, adhesion and genes for signaling pathway proteins such as TGF-beta/Smad, Wnt/beta-catenin and Notch/Jagged. This reveals that adhering piliated meningocci manipulate host signaling pathways controlling cell proliferation while establishing a commensal relationship. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16958858&query_hl=1 ER - TY - JFULL T1 - Role of RNA structure and RNA binding activity of foot-and-mouth disease virus 3C protein in VPg uridylylation and virus replication A1 - Nayak, A A1 - Goodfellow, IG A1 - Woolaway, KE A1 - Birtley, J A1 - Curry, S A1 - Belsham, GJ J1 - J VIROL Y1 - 2006/10// VL - 80 SN - 0022-538X SP - 9865 EP - 9875 N2 - The uridylylation of the VPg peptide primer is the first stage in the replication of picornavirus RNA. This process can be achieved in vitro using purified components, including 3B (VPg) with the RNA dependent RNA polymerase (3D(pol)), the precursor 3CD, and an RNA template containing the cre/bus. We show that certain RNA sequences within the foot-and-mouth disease virus (FMDV) 5' untranslated region but outside of the cre/bus can enhance VPg uridylylation activity. Furthermore, we have shown that the FMDV X protein alone can substitute for 3CD, albeit less efficiently. In addition, the VPg precursors, 3B(3)3C and 3B(123)3C, can function as substrates for uridylylation in the absence of added 3C or 3CD. Residues within the FMDV 3C protein involved in interaction with the cre/bus RNA have been identified and are located on the face of the protein opposite from the catalytic site. These residues within 3C are also essential for VPg uridylylation activity and efficient virus replication. ER - TY - JFULL T1 - Transmitted drug-resistant HIV-1 in primary HIV-1 infection; incidence, evolution and impact on response to antiretroviral therapy. A1 - Fox, J A1 - Dustan, S A1 - McClure, M A1 - Weber, J A1 - Fidler, S J1 - HIV Med Y1 - 2006/10// VL - 7 SN - 1464-2662 SP - 477 EP - 483 N2 - OBJECTIVES: The aim of the study was to determine the incidence and persistence of transmitted drug-resistant HIV-1 in an incident cohort between 2000 and 2004, and to investigate the impact of transmitted drug-resistant HIV-1 on the response to antiretroviral therapy (ART). METHODS: A prospective, nonrandomized study was carried out on 140 individuals identified with primary HIV-1 infection (PHI). PHI was defined as an HIV-positive antibody test with an HIV antibody-negative result in the prior 6 months (n = 69); positive HIV DNA in the absence of antibody (n = 30); an evolving titre positive HIV antibody test (n = 23), or an incident 'detuned' assay (B clade viruses only) (n = 18). Genotypic resistance testing was performed at baseline, following ART and annually over a 4-year period. RESULTS: The prevalence of transmitted drug-resistant HIV-1 infection between January 2000 and June 2004 was nine in 140 (6.0%) and the annual incidence was stable. Seven of these nine patients had a single point mutation conferring single-class drug resistance and the other two patients had multiple mutations conferring multiclass drug resistance (MDR). In eight of the nine cases, mutations conferring drug resistance persisted for more than 12 months off therapy. In contrast to transmitted MDR HIV-1, the virological response to initial ART and CD4 decline were comparable in those with wild-type virus, virus with 'polymorphisms' (secondary mutations) and virus with single drug-resistance mutations. CONCLUSIONS: The incidence of transmitted drug-resistant HIV remained stable and low over a 4-year period. Although MDR remains rare, its presence significantly affects the response to first-line ART, predisposes towards the accumulation of new resistance mutations and is associated with a more rapid CD4 decline. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16925735&query_hl=1 ER - TY - JFULL T1 - How safe is safer sex? High levels of HSV-1 and HSV-2 in female sex workers in London. A1 - Fox, J A1 - Taylor, GP A1 - Day, S A1 - Parry, J A1 - Ward, H J1 - Epidemiol Infect Y1 - 2006/10// VL - 134 SN - 0950-2688 SP - 1114 EP - 1119 N2 - Female sex workers in Europe have low levels of sexually transmitted infections, attributable to condom use. The aim of this paper is to describe the seroepidemiology of HSV-1 and HSV-2 in female sex workers in London by using a 15-year prospective study of 453 sex workers. The seroprevalence of HSV-1 was 74.4% and independently associated with birth in a 'transitional country' (OR 5.4, 95% CI 1.61-18.20). The seroprevalence of HSV-2 was 60% and declined over time; it was also independently associated with time in sex work (OR 2.12, 95% CI 1.23-3.65) and birth in a 'developing country' (OR 2.95, 95% CI 1.34-6.48). We show that a cohort of sex workers with extensive condom use and little known sexually transmitted infection have high levels of HSV-1 and HSV-2 infection, suggesting that condoms may not be universally protective. Sex workers are candidates for HSV vaccine efficacy or intervention studies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16569273&query_hl=1 ER - TY - JFULL T1 - What is the achievable effectiveness of the India AIDS Initiative intervention among female sex workers under target coverage? Model projections from southern India. A1 - Williams, JR A1 - Foss, AM A1 - Vickerman, P A1 - Watts, C A1 - Ramesh, BM A1 - Reza-Paul, S A1 - Washington, RG A1 - Moses, S A1 - Blanchard, J A1 - Lowndes, CM A1 - Alary, M A1 - Boily, MC J1 - Sex Transm Infect Y1 - 2006/10// VL - 82 SN - 1368-4973 SP - 372 EP - 380 N2 - BACKGROUND: The India AIDS Initiative (Avahan) prevention programme funded by the Bill and Melinda Gates Foundation aims to reduce HIV prevalence in high risk groups such as female and male sex workers and their clients, to limit HIV transmission in the general population. OBJECTIVES: To assess the potential effectiveness of the Avahan intervention at the level of coverage targeted, in different epidemiological settings in India. METHODS: A deterministic compartmental model of the transmission dynamics of HIV and two sexually transmitted infections, and sensitivity analysis techniques, were used, in combination with available behavioural and epidemiological data from Mysore and Bagalkot districts in the Indian state of Karnataka, to evaluate the syndromic sexually transmitted infection (STI) management (STI treatment), periodic presumptive treatment of STI (PPT), and condom components of the Avahan intervention targeted to female sex workers (FSW). RESULTS: If all components of the intervention reach target coverage (that is, PPT, STI treatment and condom use), the intervention is expected to prevent 22-35% of all new HIV infections in FSW and in the total population over 5 years in a low transmission setting like Mysore, and to be half as effective in high transmission settings such as Bagalkot. The results were sensitive to small variations in intervention coverage. The condom component alone is expected to prevent around 20% of all new HIV infections over 5 years in Mysore and around 6% for the STI component alone; compared with 7%-14% for the PPT component alone. Multivariate sensitivity analyses suggested that interventions may be more effective in settings with low FSW HIV prevalence and small FSW populations, whereas HIV prevalence was most influenced by sexual behaviour and condom use parameters for FSW. CONCLUSION: The Avahan intervention is expected to be effective. However, to be able to demonstrate effectiveness empirically in the different settings, it is important to achieve target coverage or higher, which in the case of PPT could take a number of years to achieve. These preliminary model predictions need to be validated with more detailed mathematical models, as better data on sexual behaviour, condom use, STI and HIV trends over time, and intervention coverage data accumulate over the course of the programme. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17012512&query_hl=1 ER - TY - JFULL T1 - Pregnant women with HIV infection can expect healthy survival: three-year follow-up. A1 - Martin, F A1 - Navaratne, L A1 - Khan, W A1 - Sarner, L A1 - Mercey, D A1 - Anderson, J A1 - Noble, H A1 - Fakoya, A A1 - Hawkins, DA A1 - De Ruiter, A A1 - Taylor, GP J1 - J Acquir Immune Defic Syndr Y1 - 2006/10/01/ VL - 43 SN - 1525-4135 SP - 186 EP - 192 N2 - OBJECTIVES: To document postpartum disease-free survival of HIV-infected women taking antiretroviral therapy (ART) during pregnancy. METHODS: Laboratory and clinical data were collected on all HIV-infected pregnant women delivering from 1998 to 2002 and followed up until September 2004 at 6 hospitals in London. Mothers were grouped according to receipt of zidovudine monotherapy (ZDVm), highly active antiretroviral therapy (HAART) given during and continued after pregnancy (cHAART), and short-term HAART given during pregnancy and discontinued on delivery (START). RESULTS: Eight-five women took ZDVm, 155 took cHAART, and 71 took START. The mean follow-up for all mothers was 33 months, with a total of 847 person-years. At the first antenatal clinic (ANC) visit, 72% of women were in Centers for Disease Control and Prevention (CDC) stage A, 85% were treatment naive, and the ZDVm group had a median HIV viral load (VL) 10-fold less than those mothers who started HAART during pregnancy. At last follow-up, 1 patient had died and 6 (1.9%) had progressed to CDC stage C; 62% of all women, including a quarter of the ZDVm group, were receiving HAART for their own health; and 83% of all mothers had a VL <50 HIV RNA copies/mL of plasma regardless of whether they were on treatment or not. CONCLUSIONS: The median-term postpartum prognosis of HIV-infected pregnant women with access to HAART is good. Exposure to short-course ZDVm or START during pregnancy did not jeopardize their response to subsequent therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16940856&query_hl=1 ER - TY - JFULL T1 - Heliox-driven CPAP may be more effective than conventional CPAP in reducing work of breathing and improving tidal volumes in infant respiratory distress A1 - Chowdhury M M M A1 - Reus E A1 - Habibi P J1 - CHEST Y1 - 2006/10// ER - TY - JFULL T1 - Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) A1 - De Castro-Costa, CM A1 - Araujo, AQC A1 - Barreto, MM A1 - Takayanagui, OM A1 - Sohler, MP A1 - Da Silva, ELM A1 - De Paula, SMB A1 - Ishak, R A1 - Ribas, JGR A1 - Rovirosa, LC A1 - Carton, H A1 - Gotuzzo, E A1 - Hall, WW A1 - Montano, S A1 - Murphy, EL A1 - Oger, J A1 - Remondegui, C A1 - Taylor, GP J1 - AIDS RES HUM RETROV Y1 - 2006/10// VL - 22 SN - 0889-2229 SP - 931 EP - 935 N2 - After the first description of TSP/HAM in 1985 and the elaboration of WHO's diagnostic criteria in 1988, the experience of the professionals in this field has increased so that a critical reappraisal of these diagnostic guidelines was considered timely. Brazilian neurologists and observers from other countries met recently to discuss and propose a modified model for diagnosing TSP/HAM with levels of ascertainment as definite, probable, and possible, according to myelopathic symptoms, serological findings, and/or detection of HTLV-I DNA and exclusion of other disorders. ER - TY - JFULL T1 - The TCR Vbeta signature of bacterial superantigens spreads with stimulus strength. A1 - Llewelyn, M A1 - Sriskandan, S A1 - Terrazzini, N A1 - Cohen, J A1 - Altmann, DM J1 - Int Immunol Y1 - 2006/10// VL - 18 SN - 0953-8178 SP - 1433 EP - 1441 N2 - Superantigens (Sags) induce large-scale stimulation of T lymphocytes by a mechanism distinct from conventional antigen presentation, involving direct MHC binding and stimulation of TCR families based on Vbeta gene usage. The specific Vbeta targets of a given Sag have, since the earliest studies in murine models, been considered a hallmark of that toxin. Bacterial Sags are implicated in the aetiology of a wide range of human diseases, although their role has been most clearly defined in toxic shock syndrome. While Sags have been defined by the Vbeta-specific changes in T cell repertoire they induce, human studies of in vitro stimulation or analysis of cells from infected patients have produced inconsistent findings. Here we have evaluated the contribution of HLA allelic polymorphisms and strength of stimulus to this response. We show that there are differences in binding and presentation of the staphylococcal Sag, staphylococcal enterotoxin A (SEA), by different HLA-DR alleles. We also show that the TCR Vbeta response, previously thought to be a fixed property defining a given Sag, varies with stimulus strength such that a broader repertoire of response is seen at higher concentrations or following presentation by high-binding class II types. Responses of human Vbeta8 and Vbeta1 to SEA, Vbeta5 to SEB and of Vbeta12 and Vbeta13 to streptococcal pyrogenic exotoxin A are absolutely dependent on stimulus strength. These findings have important implications for heterogeneity in the response to Sags and the consequent differences in susceptibility to severe toxic shock. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16893924&query_hl=1 ER - TY - JFULL T1 - Differential roles of the co-stimulatory molecules GITR and CTLA-4 in the immune response to Trichinella spiralis. A1 - Furze, RC A1 - Culley, FJ A1 - Selkirk, ME J1 - Microbes Infect Y1 - 2006/10// VL - 8 SN - 1286-4579 SP - 2803 EP - 2810 N2 - We investigated the roles of the regulatory molecules glucocorticoid-induced TNF receptor family-related protein (GITR) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in murine infection with the nematode parasite Trichinella spiralis. Expression of GITR and CTLA-4 was rapidly upregulated on cells in the mesenteric lymph nodes and spleen, with approximately 80% of CD4+ lymphocytes expressing GITR by day 7 post-infection, coinciding with release and dissemination of newborn larvae. As the infection progressed to the chronic muscle phase, expression of GITR returned to normal, whereas CTLA-4 was sustained as late as day 60. Mice treated with anti-GITR antibodies rapidly developed higher titres of parasite-specific IgG1, IgG2a, IgG2b and IgM than controls. This was accompanied by elevated background lymphocyte proliferation, but parasite establishment in the intestine or the muscle was unaffected. In contrast, treatment with anti-CTLA-4 antibody resulted in elevated serum IgE, enhanced production of interleukin-4 and interleukin-10, and lower numbers of parasites recovered from skeletal muscle. These results reveal different temporal and regulatory roles for CTLA-4 and GITR in immune responses to helminth infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17045510&query_hl=1 ER - TY - JFULL T1 - Interactions between retinoic acid, nerve growth factor and sonic hedgehog signalling pathways in neurite outgrowth. A1 - So, PL A1 - Yip, PK A1 - Bunting, S A1 - Wong, LF A1 - Mazarakis, ND A1 - Hall, S A1 - McMahon, S A1 - Maden, M A1 - Corcoran, JP J1 - Dev Biol Y1 - 2006/10/01/ VL - 298 SN - 0012-1606 SP - 167 EP - 175 N2 - Many studies have shown a role of retinoid signalling in neurite outgrowth in vitro, and that the retinoic acid receptor (RAR) beta2 is critical for this process. We show here that RARbeta2 is expressed predominantly in dorsal root ganglia (DRG) neuronal subtypes that express neurofilament (NF) 200 and calcitonin gene-related peptide (CGRP), and that these neurons extend neurites in response to RA. We demonstrate that retinoid signalling has a role in neurite outgrowth in vivo, by showing that in a peripheral nerve crush model there is less neurite outgrowth from RARbeta null DRG compared to wild-type. We identify sonic hedgehog (Shh) as a downstream target of the RARbeta2 signalling pathway as it is expressed in the injured DRG of wild-type but not RARbeta null mice. This regulation is direct as when RARbeta2 is overexpressed in adult motoneurons Shh is induced in them. Finally we show that Shh alone cannot induce neurite outgrowth but potentiates RARbeta2 signalling in this process. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16860305&query_hl=1 ER - TY - JFULL T1 - Microarray principal components analysis demonstrates expression of vanin-1 is a strong determinant of NASH pathogenesis in the IGT/6 model A1 - Anstee, QM A1 - Goldsworthy, M A1 - Goldin, R A1 - Thomas, HC A1 - Cox, RD A1 - Thursz, M J1 - HEPATOLOGY Y1 - 2006/10// VL - 44 SN - 0270-9139 SP - 243A EP - 244A ER - TY - JFULL T1 - Tuberculous pericardial effusion after coronary artery bypass graft. A1 - Tuladhar, SM A1 - Noursadeghi, M A1 - Boyle, JJ A1 - Friedland, JS A1 - Hornick, P J1 - Ann Thorac Surg Y1 - 2006/10// VL - 82 SN - 1552-6259 SP - 1519 EP - 1521 N2 - We describe a case of a recurrent pericardial effusion after coronary artery bypass grafting. This was initially considered to be due to post-pericardiotomy syndrome, but was later treated empirically as tuberculosis. After definitive surgery for this condition, pericardial histology and immunohistochemistry confirmed the diagnosis of tubercular pericarditis. At 4-months follow-up, while continuing anti-tuberculous therapy and corticosteroids, the patient showed consistent improvement without further recurrence of his pericardial effusion. Local reactivation of tuberculosis after pericardiotomy has not been previously reported and merits careful consideration in population groups in which tuberculosis is highly endemic. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16996972&query_hl=1 ER - TY - JFULL T1 - Differential selection pressure exerted on HIV by CTL targeting identical epitopes but restricted by distinct HLA alleles from the same HLA supertype. A1 - Leslie, A A1 - Price, DA A1 - Mkhize, P A1 - Bishop, K A1 - Rathod, A A1 - Day, C A1 - Crawford, H A1 - Honeyborne, I A1 - Asher, TE A1 - Luzzi, G A1 - Edwards, A A1 - Rousseau, CM A1 - Rosseau, CM A1 - Mullins, JI A1 - Tudor-Williams, G A1 - Novelli, V A1 - Brander, C A1 - Douek, DC A1 - Kiepiela, P A1 - Walker, BD A1 - Goulder, PJ J1 - J Immunol Y1 - 2006/10/01/ VL - 177 SN - 0022-1767 SP - 4699 EP - 4708 N2 - HLA diversity is seen as a major challenge to CTL vaccines against HIV. One current approach focuses on "promiscuous" epitopes, presented by multiple HLA alleles from within the same HLA supertype. However, the effectiveness of such supertype vaccines depends upon the functional equivalence of CTL targeting a particular epitope, irrespective of the restricting HLA. In this study, we describe the promiscuous HIV-specific CTL epitopes presented by alleles within the B7 supertype. Substantial differences were observed in the ability of CTL to select for escape mutation when targeting the same epitope but restricted by different HLA. This observation was common to all six promiscuous B7 epitopes identified. Moreover, with one exception, there were no significant differences in the frequency, magnitude, or immunodominance of the CTL responses restricted by different HLA alleles to explain these discrepancies. This suggests that the unique peptide/MHC complexes generated by even closely related HLA induce CTL responses that are qualitatively different. This hypothesis is supported by additional differences observed between CTL targeting identical epitopes but restricted by different HLA: first, the occurrence of distinct, HLA-specific escape mutation; second, the recruitment of distinct TCR repertoires by particular peptide/MHC complexes; and, third, significant differences in the functional avidity of CTL. Taken together, these data indicate that significant functional differences exist between CTL targeting identical epitopes but restricted by different, albeit closely related HLA. These findings are of relevance to vaccine approaches that seek to exploit HLA supertypes to overcome the problem of HLA diversity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16982909&query_hl=1 ER - TY - JFULL T1 - Peripheral blood B-cell death compensates for excessive proliferation in lymphoid tissues and maintains homeostasis in bovine leukemia virus-infected sheep. A1 - Debacq, C A1 - Gillet, N A1 - Asquith, B A1 - Sanchez-Alcaraz, MT A1 - Florins, A A1 - Boxus, M A1 - Schwartz-Cornil, I A1 - Bonneau, M A1 - Jean, G A1 - Kerkhofs, P A1 - Hay, J A1 - Théwis, A A1 - Kettmann, R A1 - Willems, L J1 - J Virol Y1 - 2006/10// VL - 80 SN - 0022-538X SP - 9710 EP - 9719 N2 - The size of a lymphocyte population is primarily determined by a dynamic equilibrium between cell proliferation and death. Hence, lymphocyte recirculation between the peripheral blood and lymphoid tissues is a key determinant in the maintenance of cell homeostasis. Insights into these mechanisms can be gathered from large-animal models, where lymphatic cannulation from individual lymph nodes is possible. In this study, we assessed in vivo lymphocyte trafficking in bovine leukemia virus (BLV)-infected sheep. With a carboxyfluorescein diacetate succinimidyl ester labeling technique, we demonstrate that the dynamics of lymphocyte recirculation is unaltered but that accelerated proliferation in the lymphoid tissues is compensated for by increased death in the peripheral blood cell population. Lymphocyte homeostasis is thus maintained by biphasic kinetics in two distinct tissues, emphasizing a very dynamic process during BLV infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16973575&query_hl=1 ER - TY - JFULL T1 - Cell target genes of Epstein-Barr virus transcription factor EBNA-2: induction of the p55alpha regulatory subunit of PI3-kinase and its role in survival of EREB2.5 cells. A1 - Spender, LC A1 - Lucchesi, W A1 - Bodelon, G A1 - Bilancio, A A1 - Karstegl, CE A1 - Asano, T A1 - Dittrich-Breiholz, O A1 - Kracht, M A1 - Vanhaesebroeck, B A1 - Farrell, PJ J1 - J Gen Virol Y1 - 2006/10// VL - 87 SN - 0022-1317 SP - 2859 EP - 2867 N2 - Microarray analysis covering most of the annotated RNAs in the human genome identified a panel of genes induced by the Epstein-Barr virus (EBV) EBNA-2 transcription factor in the EREB2.5 human B-lymphoblastoid cell line without the need for any intermediate protein synthesis. Previous data indicating that PIK3R1 RNA (the alpha regulatory subunit of PI3-kinase) was induced were confirmed, but it is now shown that it is the p55alpha regulatory subunit that is induced. Several EBV-immortalized lymphoblastoid cell lines were shown to express p55alpha. Expression of PI3-kinase p85 regulatory and p110 catalytic subunits was not regulated by EBNA-2. Proliferation of EREB2.5 lymphoblastoid cells was inhibited by RNAi knock-down of p55alpha protein expression, loss of p55alpha being accompanied by an increase in apoptosis. p55alpha is thus a functional target of EBNA2 in EREB2.5 cells and the specific regulation of p55alpha by EBV will provide an opportunity to investigate the physiological function of p55alpha in this human cell line. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16963743&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 - Identification of diagnostic markers for tuberculosis by proteomic fingerprinting of serum. A1 - Agranoff, D A1 - Fernandez-Reyes, D A1 - Papadopoulos, MC A1 - Rojas, SA A1 - Herbster, M A1 - Loosemore, A A1 - Tarelli, E A1 - Sheldon, J A1 - Schwenk, A A1 - Pollok, R A1 - Rayner, CF A1 - Krishna, S J1 - Lancet Y1 - 2006/09/16/ VL - 368 SN - 1474-547X SP - 1012 EP - 1021 N2 - BACKGROUND: We investigated the potential of proteomic fingerprinting with mass spectrometric serum profiling, coupled with pattern recognition methods, to identify biomarkers that could improve diagnosis of tuberculosis. METHODS: We obtained serum proteomic profiles from patients with active tuberculosis and controls by surface-enhanced laser desorption ionisation time of flight mass spectrometry. A supervised machine-learning approach based on the support vector machine (SVM) was used to obtain a classifier that distinguished between the groups in two independent test sets. We used k-fold cross validation and random sampling of the SVM classifier to assess the classifier further. Relevant mass peaks were selected by correlational analysis and assessed with SVM. We tested the diagnostic potential of candidate biomarkers, identified by peptide mass fingerprinting, by conventional immunoassays and SVM classifiers trained on these data. FINDINGS: Our SVM classifier discriminated the proteomic profile of patients with active tuberculosis from that of controls with overlapping clinical features. Diagnostic accuracy was 94% (sensitivity 93.5%, specificity 94.9%) for patients with tuberculosis and was unaffected by HIV status. A classifier trained on the 20 most informative peaks achieved diagnostic accuracy of 90%. From these peaks, two peptides (serum amyloid A protein and transthyretin) were identified and quantitated by immunoassay. Because these peptides reflect inflammatory states, we also quantitated neopterin and C reactive protein. Application of an SVM classifier using combinations of these values gave diagnostic accuracies of up to 84% for tuberculosis. Validation on a second, prospectively collected testing set gave similar accuracies using the whole proteomic signature and the 20 selected peaks. Using combinations of the four biomarkers, we achieved diagnostic accuracies of up to 78%. INTERPRETATION: The potential biomarkers for tuberculosis that we identified through proteomic fingerprinting and pattern recognition have a plausible biological connection with the disease and could be used to develop new diagnostic tests. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16980117&query_hl=1 ER - TY - JFULL T1 - A systematic genetic analysis in Neisseria meningitidis defines the Pil proteins required for assembly, functionality, stabilization and export of type IV pili. A1 - Carbonnelle, E A1 - Helaine, S A1 - Nassif, X A1 - Pelicic, V J1 - Mol Microbiol Y1 - 2006/09// VL - 61 SN - 0950-382X SP - 1510 EP - 1522 N2 - Although type IV pili (Tfp) are among the commonest virulence factors in bacteria, their biogenesis by complex machineries of 12-15 proteins, and thereby their function remains poorly understood. Interestingly, some of these proteins were reported to merely antagonize the retraction of the fibres powered by PilT, because piliation could be restored in their absence by a mutation in the pilT gene. The recent identification of the 15 Pil proteins dedicated to Tfp biogenesis in Neisseria meningitidis offered us the unprecedented possibility to define their exact contribution in this process. We therefore systematically introduced a pilT mutation into the corresponding non-piliated mutants and characterized them for the rescue of Tfp and Tfp-mediated virulence phenotypes. We found that in addition to the pilin, the main constituent of Tfp, only six Pil proteins were required for the actual assembly of the fibres, because apparently normal fibres were restored in the remaining mutants. Restored fibres were surface-exposed, except in the pilQ/T mutant in which they were trapped in the periplasm, suggesting that the PilQ secretin was the sole Pil component necessary for their emergence on the surface. Importantly, although in most mutants the restored Tfp were not functional, the pilG/T and pilH/T mutants could form bacterial aggregates and adhere to human cells efficiently, suggesting that Tfp stabilization and functional maturation are two discrete steps. These findings have numerous implications for understanding Tfp biogenesis/function and provide a useful groundwork for the characterization of the precise function of each Pil protein in this process. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16968224&query_hl=1 ER - TY - JFULL T1 - High-throughput identification of conditionally essential genes in bacteria: from STM to TSM. A1 - Bossé, JT A1 - Zhou, L A1 - Kroll, JS A1 - Langford, PR J1 - Infect Disord Drug Targets Y1 - 2006/09// VL - 6 SN - 1871-5265 SP - 241 EP - 262 N2 - Signature-tagged mutagenesis (STM) provided the first widely applicable high-throughput method for detecting conditionally essential genes in bacteria by using negative selection to screen large pools of transposon (Tn) mutants. STM requires no prior knowledge of the bacterium's genome sequence, and has been used to study a large number of Gram-positive and Gram-negative species, greatly expanding the repertoires of known virulence factors for these organisms. Originally, hybridization of radiolabelled probes to colony or dot blots was used to detect differences in populations of tagged mutants before and after growth under a selective condition. Modifications of the tag detection method involving polymerase chain reaction (PCR) amplification and visualisation by gel electrophoresis have been developed and can be automated through the use of robotics. Genetic footprinting is another negative selection technique that uses PCR amplification to detect loss of mutants from a pool. Unlike PCR-STM, this technique allows direct amplification of Tn-flanking sequences. However, it requires the bacterium's whole genome sequence in order to design specific primers for every gene of interest. More recently, a number of techniques have been described that combine the negative-selection principle of STM and genetic footprinting with the genome-wide screening power of DNA microarrays. These techniques, although also requiring whole genome sequences, use either a form of linker-mediated or semi-random PCR to amplify and label Tn-flanking regions for hybridization to microarrays. The superior sensitivity microarray detection allows greater numbers of mutants to be screened per pool, as well as determination of the coverage/distribution of insertions in the library prior to screening, two significant advantages over STM. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16918485&query_hl=1 ER - TY - JFULL T1 - Heliox in ventilatory support. What does it mean for the future of infant care? A1 - Chowdhury M M M A1 - Reus E A1 - Brown M K A1 - Habibi P J1 - Infant Y1 - 2006/09// ER - TY - JFULL T1 - Infrequent MODS TB culture cross-contamination in a high-burden resource-poor setting. A1 - Moore, DA A1 - Caviedes, L A1 - Gilman, RH A1 - Coronel, J A1 - Arenas, F A1 - LaChira, D A1 - Salazar, C A1 - Carlos Saravia, J A1 - Oberhelman, RA A1 - Hollm-Delgado, MG A1 - Escombe, AR A1 - Evans, CA A1 - Friedland, JS J1 - Diagn Microbiol Infect Dis Y1 - 2006/09// VL - 56 SN - 0732-8893 SP - 35 EP - 43 N2 - One obstacle to wider use of rapid liquid culture-based tuberculosis diagnostics such as the microscopic observation drug susceptibility (MODS) assay is concern about cross-contamination. We investigated the rate of laboratory cross-contamination in MODS, automated MBBacT, and Lowenstein-Jensen (LJ) cultures performed in parallel, through triangulation of microbiologic (reculturing stored samples), molecular (spoligotype/RFLP), and clinical epidemiologic data. At least 1 culture was positive for Mycobacterium tuberculosis for 362 (11%) of 3416 samples; 53 were regarded as potential cross-contamination suspects. Cross-contamination accounted for 17 false-positive cultures from 14 samples representing 0.41% (14/3416) and 0.17% (17/10248) of samples and cultures, respectively. Positive predictive values for MODS, MBBacT (bioMérieux, Durham, NC), and LJ were 99.1%, 98.7%, and 99.7%, and specificity was 99.9% for all 3. Low rates of cross-contamination are achievable in mycobacterial laboratories in resource-poor settings even when a large proportion of samples are infectious and highly sensitive liquid culture-based diagnostics such as MODS are used. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16678991&query_hl=1 ER - TY - JFULL T1 - A polymorphism that reduces RANTES expression is associated with protection from death in HIV-seropositive Ugandans with advanced disease. A1 - Cooke, GS A1 - Tosh, K A1 - Ramaley, PA A1 - Kaleebu, P A1 - Zhuang, J A1 - Nakiyingi, JS A1 - Watera, C A1 - Gilks, CF A1 - French, N A1 - Whitworth, JA A1 - Hill, AV J1 - J Infect Dis Y1 - 2006/09/01/ VL - 194 SN - 0022-1899 SP - 666 EP - 669 N2 - We investigated the effect of RANTES polymorphisms on human immunodeficiency virus type 1 (HIV-1) disease progression in an urban population of Uganda. HIV-positive individuals homozygous for the INT1.1C polymorphism, which had been associated previously with low RANTES expression, were less likely to die than were those with other genotypes (hazard ratio, 0.53 [95% confidence interval, 0.33-0.83]; P=.007). This report of a non-human leukocyte antigen genetic association with HIV-1 and/or acquired immunodeficiency syndrome disease progression in an African population reveals a genetic effect different from that reported elsewhere for African Americans and may impact therapeutic strategies targeting the RANTES pathway in HIV infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16897666&query_hl=1 ER - TY - JFULL T1 - Identical twins discordant for type 1 diabetes show a different pattern of in vitro CD56+ cell activation. A1 - Goodier, MR A1 - Nawroly, N A1 - Beyan, H A1 - Hawa, M A1 - Leslie, RD A1 - Londei, M J1 - Diabetes Metab Res Rev Y1 - 2006/09// VL - 22 SN - 1520-7552 SP - 367 EP - 375 N2 - BACKGROUND: Recent studies in animal models indicate a role for natural killer (NK) cells in the protection against type 1 diabetes. In humans, a reduction of NK cell numbers has been reported in identical twins discordant for type 1 diabetes, irrespective of whether they have the disease. Here we have tested whether the activation and expansion of human NK cells with lipopolysaccharide (LPS) reveals differences between these twins. METHODS: Proportions of CD56(+) NK cells and T-cells and Va24Vb11(+) NK-T cells from diabetic and non-diabetic twins was assessed before and after activation using flow cytometry. NK receptor usage was monitored by PCR and flow cytometry. RESULTS: The profile of the expressed Killer Cell immunoglobulin-like receptor (KIR) repertoire (using mRNA) in freshly isolated NK cells was identical in pairs of identical twins, despite marked variation among individual twins as well as controls. Basal numbers of CD56(+) and CD94(+) (CD3(-) and CD3(+)) cells and Valpha24(+)Vbeta11(+) NK-T cells were similarly strongly correlated between identical twins (p < 0.006 for all correlations). Following LPS stimulation, the pattern of KIR mRNA expression remained unaltered in twins and the proportion of NK cells and Valpha24(+)Vbeta11(+) NK-T cells remained correlated between pairs of twins. However, there was a significant reduction in the proportion of CD56(+) cells and CD94(+) cells (whether defined as CD3(-) or CD3(+)) responding to LPS in the diabetic compared to the non-diabetic twin (p = 0.031 and 0.025, respectively). CONCLUSION: This reduction in NK cell expansion in response to LPS in patients with type 1 diabetes is consistent with a non-genetically determined alteration in the innate immune response either predisposing to or resulting from the disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16572491&query_hl=1 ER - TY - JFULL T1 - Hepatitis B virus reactivation in patients receiving chemotherapy for malignancies: role of precore stop-codon and basic core promoter mutations A1 - Alexopoulou, A A1 - Theodorou, M A1 - Dourakis, SP A1 - Karayiannis, P A1 - Sagkana, E A1 - Papanikolopoulos, K A1 - Archimandritis, AJ J1 - J VIRAL HEPATITIS Y1 - 2006/09// VL - 13 SN - 1352-0504 SP - 591 EP - 596 N2 - Hepatitis B virus (HBV) strains carrying the precore stop-codon mutation (A1896) have been considered among the predisposing factors for reactivation during chemotherapy for malignancies. The role of the T1762/A1764 basic core promoter (BCP) mutations has not been fully evaluated. We aimed to record any changes in HBV serological markers after reactivation, detect the presence of A1896 and BCP mutations and evaluate the type of cytotoxic drugs involved. We retrospectively screened eight patients presenting with HBV reactivation following chemotherapy for malignancies. The chemotherapy regimens used included corticosteroids (CSs), fludarabine and cyclophosphamide/adriamycine. The INNO-LiPA HBV PreCore kit was used for the detection of the A1896 and BCP mutations. Six patients who were hepatitis B surface antigen (HBsAg)-(+)/hepatitis B e antigen (HBeAg)-(-) before chemotherapy, had disease reactivation following a mean of four cycles of chemotherapy. Four survived and two died of hepatic failure. At the time of reactivation, all six patients carried the A1896 and five of them the BCP mutations. The remaining two patients were HBsAg-(-)/anti-HBs-(+)/anti-hepatitis B core (HBc)-(+)/HBeAg-(-) before chemotherapy. One of them reverted to HBeAg-(+) status but remained HBsAg-(-), while the other became HBsAg-(+)/HBeAg-(+), following three and eight cycles of fludarabine treatment, respectively. The former carried the A1896 and the latter the wild-type virus. Both died from causes associated with their haematological disease. All but one of our patients with HBV reactivation during chemotherapy carried the precore stop-codon and BCP mutations. Whether this occurs more frequently in such patients than those carrying the wild-type virus needs further investigation. Fludarabine should be added to the list of drugs inducing HBV reactivation. HBV reactivation following fludarabine treatment occurred in HBsAg-(-) patients who had been anti-HBs-(+). ER - TY - JFULL T1 - Factors associated with the development of opportunistic infections in HIV-1-infected adults with high CD4+ cell counts: a EuroSIDA study. A1 - Podlekareva, D A1 - Mocroft, A A1 - Dragsted, UB A1 - Ledergerber, B A1 - Beniowski, M A1 - Lazzarin, A A1 - Weber, J A1 - Clumeck, N A1 - Vetter, N A1 - Phillips, A A1 - Lundgren, JD A1 - EuroSIDA study group J1 - J Infect Dis Y1 - 2006/09/01/ VL - 194 SN - 0022-1899 SP - 633 EP - 641 N2 - BACKGROUND: Limited data exist on factors predicting the development of opportunistic infections (OIs) at higher-than-expected CD4(+) cell counts in human immunodeficiency virus (HIV) type 1-infected adults. METHODS: Multivariate Poisson regression models were used to determine factors related to the development of groups of OIs above their respective traditional upper CD4(+) cell count thresholds: group 1 (>or=100 cells/ microL), OIs caused by cytomegalovirus, Mycobacterium avium complex, and Toxoplasma gondii; group 2 (>or=200 cells/ microL), Pneumocystis pneumonia and esophageal candidiasis; and group 3 (>or=300 cells/ microL), pulmonary and extrapulmonary tuberculosis. RESULTS: In groups 1, 2, and 3, 71 of 9,219, 125 of 7,934, and 36 of 7,838 patients, respectively, developed >or=1 intragroup OI. The strongest predictor of an OI in groups 1 and 2 was current CD4(+) cell count (for group 1, incidence rate ratio [IRR] per 50% lower CD4(+) cell count, 5.37 [95% confidence interval {CI}, 3.71-7.77]; for group 2, 4.28 [95% CI, 2.98-6.14]). Injection drug use but not current CD4(+) cell count predicted risk in group 3. Use of antiretroviral treatment was associated with a lower incidence of OIs in all groups, likely by reducing HIV-1 RNA levels (IRR per 1-log(10) copies/mL higher HIV-1 RNA levels for group 1, 1.50 [95% CI, 1.15-1.95]; for group 2, 1.68 [95% CI, 1.40-2.02]; and for group 3, 1.89 [95% CI, 1.40-2.54]). CONCLUSION: Although the absolute incidence is low, the current CD4(+) cell count and HIV-1 RNA level are strong predictors of most OIs in patients with high CD4(+) cell counts. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16897662&query_hl=1 ER - TY - JFULL T1 - Suppression of T-cell functions by human granulocyte arginase A1 - Munder, M A1 - Schneider, H A1 - Luckner, C A1 - Giese, T A1 - Langhans, CD A1 - Fuentes, JM A1 - Kropf, P A1 - Mueller, I A1 - Kolb, A A1 - Modolell, M A1 - Ho, AD J1 - BLOOD Y1 - 2006/09/01/ VL - 108 SN - 0006-4971 SP - 1627 EP - 1634 N2 - Chronic inflammation is accompanied by impaired T-cell immunity. In the mouse, myeloid cell-associated arginase accounts for the suppression of immune reactivity in various models of tumor growth and chronic infections. Here we show that arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions. Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. This T-cell phenotype is due to arginase-mediated depletion of arginine in the T-cell environment, which leads to CD3 zeta chain down-regulation but does not alter T-cell viability. Our study therefore demonstrates that human granulocytes possess a previously unanticipated immunosuppressive effector function. Human granulocyte arginase is a promising pharmacologic target to reverse unwanted immunosuppression. ER - TY - JFULL T1 - Caliciviruses differ in their functional requirements for eIF4F components. A1 - Chaudhry, Y A1 - Nayak, A A1 - Bordeleau, ME A1 - Tanaka, J A1 - Pelletier, J A1 - Belsham, GJ A1 - Roberts, LO A1 - Goodfellow, IG J1 - J Biol Chem Y1 - 2006/09/01/ VL - 281 SN - 0021-9258 SP - 25315 EP - 25325 N2 - Two classes of viruses, namely members of the Potyviridae and Caliciviridae, use a novel mechanism for the initiation of protein synthesis that involves the interaction of translation initiation factors with a viral protein covalently linked to the viral RNA, known as VPg. The calicivirus VPg proteins can interact directly with the initiation factors eIF4E and eIF3. Translation initiation on feline calicivirus (FCV) RNA requires eIF4E because it is inhibited by recombinant 4E-BP1. However, to date, there have been no functional studies carried out with respect to norovirus translation initiation, because of a lack of a suitable source of VPg-linked viral RNA. We have now used the recently identified murine norovirus (MNV) as a model system for norovirus translation and have extended our previous studies with FCV RNA to examine the role of the other eIF4F components in translation initiation. We now demonstrate that, as with FCV, MNV VPg interacts directly with eIF4E, although, unlike FCV RNA, translation of MNV RNA is not sensitive to 4E-BP1, eIF4E depletion, or foot-and-mouth disease virus Lb protease-mediated cleavage of eIF4G. We also demonstrate that both FCV and MNV RNA translation require the RNA helicase component of the eIF4F complex, namely eIF4A, because translation was sensitive (albeit to different degrees) to a dominant negative form and to a small molecule inhibitor of eIF4A (hippuristanol). These results suggest that calicivirus RNAs differ with respect to their requirements for the components of the eIF4F translation initiation complex. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16835235&query_hl=1 ER - TY - JFULL T1 - Suppression of T-cell functions by human granulocyte arginase. A1 - Munder, M A1 - Schneider, H A1 - Luckner, C A1 - Giese, T A1 - Langhans, CD A1 - Fuentes, JM A1 - Kropf, P A1 - Mueller, I A1 - Kolb, A A1 - Modolell, M A1 - Ho, AD J1 - Blood Y1 - 2006/09/01/ VL - 108 SN - 0006-4971 SP - 1627 EP - 1634 N2 - Chronic inflammation is accompanied by impaired T-cell immunity. In the mouse, myeloid cell-associated arginase accounts for the suppression of immune reactivity in various models of tumor growth and chronic infections. Here we show that arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions. Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. This T-cell phenotype is due to arginase-mediated depletion of arginine in the T-cell environment, which leads to CD3zeta chain down-regulation but does not alter T-cell viability. Our study therefore demonstrates that human granulocytes possess a previously unanticipated immunosuppressive effector function. Human granulocyte arginase is a promising pharmacologic target to reverse unwanted immunosuppression. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16709924&query_hl=1 ER - TY - JFULL T1 - QuantiFERON-TB Gold: state of the art for the diagnosis of tuberculosis infection? A1 - Connell, TG A1 - Rangaka, MX A1 - Curtis, N A1 - Wilkinson, RJ J1 - EXPERT REV MOL DIAGN Y1 - 2006/09// VL - 6 SN - 1473-7159 SP - 663 EP - 677 N2 - Tuberculosis (TB) remains a major threat to global health. The recently launched Global Plan to Stop Tuberculosis 2006-2015 highlights the need for accurate, simple and low-cost diagnostic tests for the detection of TB infection. For the first time in decades, new diagnostic tools have emerged that may facilitate this goal. The discovery of Mycobacterium tuberculosis-specific immunodominant antigens has led to the development of interferon gamma-release assays that have been shown to have high sensitivity and specificity for TB disease. This review focuses on the QuantiFERON-TB Gold tests and addresses the potential strengths and limitations of the current assays, summarizes the available evidence for their use and identifies areas of future research and development. Although representing an advance in TB diagnostics, with the potential to have a significant impact on global TB control, many issues remain unanswered. The cost of the tests and laboratory requirements may limit their use in developing countries. Most importantly, additional studies are needed in TB-endemic regions, particularly in high-risk persons such as children and individuals who are also co-infected with HIV. ER - TY - JFULL T1 - Transmission dynamics of lymphatic filariasis: vector-specific density dependence in the development of Wuchereria bancrofti infective larvae in mosquitoes. A1 - Snow, LC A1 - Bockarie, MJ A1 - Michael, E J1 - Med Vet Entomol Y1 - 2006/09// VL - 20 SN - 0269-283X SP - 261 EP - 272 N2 - The principles of meta-analysis developed in a previous study were extended to investigate the process of Wuchereria bancrofti (Cobbold) (Filarioidea: Onchocercidae) infection in mosquito (Diptera: Culicidae) hosts, focusing specifically on the functional forms and strength of density dependence in the development of ingested microfilariae (mf) to infective (third instar) larvae (L3). Mathematical models describing observed mf-L3 functional responses for each of the major three parasite-transmitting vector genera, Aedes, Culex and Anopheles mosquitoes, were fitted to paired mf-L3 data collated from all available studies in the published literature. Model parameters were estimated and compared by deriving and applying a data synthetic framework, based on applying a non-linear weighted regression model for fitting mathematical models to multistudy data. The results confirm previous findings of the existence of significant between-genera differences in the mf-L3 development relationship, particularly with regard to the occurrence of limitation in Culex mosquitoes and facilitation in Aedes and Anopheles mosquitoes. New and unexpected findings regarding L3 development from ingested mf were discovered as follows: (1) for Culex, overcompensation in L3 development at higher intensities of mf (or a peaked mf-L3 functional response) was detected; (2) for Aedes mosquitoes, facilitation (with an apparent asymptotic constraint on L3 development at high mf densities) was shown to be the major process governing L3 development, and (3) for Anopheles, a stronger facilitation type of response with no apparent saturation in L3 development appears to govern L3 output from ingested mf. These results yield major new insights regarding filarial vector infection dynamics and their potential impacts on parasite control, and demonstrate the efficacy of employing a data synthetic approach to reveal and estimate parasitic infection processes in host populations. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17044876&query_hl=1 ER - TY - JFULL T1 - Reducing the impact of the next influenza pandemic using household-based public health interventions. A1 - Wu, JT A1 - Riley, S A1 - Fraser, C A1 - Leung, GM J1 - PLoS Med Y1 - 2006/09// VL - 3 SN - 1549-1676 SP - e361 EP - e361 N2 - BACKGROUND: The outbreak of highly pathogenic H5N1 influenza in domestic poultry and wild birds has caused global concern over the possible evolution of a novel human strain [1]. If such a strain emerges, and is not controlled at source [2,3], a pandemic is likely to result. Health policy in most countries will then be focused on reducing morbidity and mortality. METHODS AND FINDINGS: We estimate the expected reduction in primary attack rates for different household-based interventions using a mathematical model of influenza transmission within and between households. We show that, for lower transmissibility strains [2,4], the combination of household-based quarantine, isolation of cases outside the household, and targeted prophylactic use of anti-virals will be highly effective and likely feasible across a range of plausible transmission scenarios. For example, for a basic reproductive number (the average number of people infected by a typically infectious individual in an otherwise susceptible population) of 1.8, assuming only 50% compliance, this combination could reduce the infection (symptomatic) attack rate from 74% (49%) to 40% (27%), requiring peak quarantine and isolation levels of 6.2% and 0.8% of the population, respectively, and an overall anti-viral stockpile of 3.9 doses per member of the population. Although contact tracing may be additionally effective, the resources required make it impractical in most scenarios. CONCLUSIONS: National influenza pandemic preparedness plans currently focus on reducing the impact associated with a constant attack rate, rather than on reducing transmission. Our findings suggest that the additional benefits and resource requirements of household-based interventions in reducing average levels of transmission should also be considered, even when expected levels of compliance are only moderate. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16881729&query_hl=1 ER - TY - JFULL T1 - An anniversary without celebration? A1 - Imami, N A1 - Kebba, A A1 - Gotch, F J1 - Nat Immunol Y1 - 2006/09// VL - 7 SN - 1529-2908 SP - 893 EP - 893 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16924247&query_hl=1 ER - TY - JFULL T1 - Different consequences of ACE2 and SWI5 gene disruptions for virulence of pathogenic and nonpathogenic yeasts. A1 - MacCallum, DM A1 - Findon, H A1 - Kenny, CC A1 - Butler, G A1 - Haynes, K A1 - Odds, FC J1 - Infect Immun Y1 - 2006/09// VL - 74 SN - 0019-9567 SP - 5244 EP - 5248 N2 - Mutants of Candida albicans, Candida glabrata, and Saccharomyces cerevisiae with disruptions in the ACE2 gene and C. glabrata and S. cerevisiae swi5 disruption mutants were tested for virulence in a murine challenge model of disseminated yeast infection. All mutants showed a clumping phenotype, but clumping was minimized in challenge inocula by inclusion of chitinase in the growth medium. In animals rendered temporarily neutropenic by cyclophosphamide treatment, the C. glabrata ace2 null mutant was confirmed as hypervirulent: it led to early terminal illness and kidney, brain, and lung fungal burdens substantially and significantly larger than those in controls. The C. glabrata swi5 null mutant did not lead to terminal illness but generated significantly larger brain and lung burdens than those in controls. The C. albicans ace2 null mutant was very slightly attenuated and the S. cerevisiae ace2 and swi5 null mutants were substantially attenuated relative to their parental control strains. The phenotype of aggressive hypervirulence, unique to disruption of the C. glabrata ACE2 gene among the strains tested, was not seen when the C. glabrata ace2 strain was tested in immunologically intact mice. The different effects seen with these mutants rule out the clumping phenotype as the explanation for hypervirulence in the C. glabrata ace2 mutant. The absence of C. glabrata ace2 hypervirulence in healthy mice may be a tool for definitive future study of host-parasite cross talk in microbial opportunism. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16926418&query_hl=1 ER - TY - JFULL T1 - Cost effectiveness of interferon or peginterferon with ribavirin for histologically mild chronic hepatitis C A1 - Grieve, R A1 - Roberts, J A1 - Wright, M A1 - Sweeting, M A1 - DeAngelis, D A1 - Rosenberg, W A1 - Bassendine, M A1 - Main, J A1 - Thomas, H J1 - GUT Y1 - 2006/09// VL - 55 SN - 0017-5749 SP - 1332 EP - 1338 N2 - Background: For patients with mild chronic hepatitis C the cost effectiveness of antiviral therapy is unknown. Aims: To assess whether antiviral therapy (either interferon alpha or peginterferon alpha combined with ribavirin) is cost effective at a mild stage compared with waiting and only treating those cases who progress to moderate disease.Patients: Cases with mild chronic hepatitis C.Methods: A cost effectiveness model which estimates long term costs and outcomes for patients with mild chronic hepatitis C. The model uses effectiveness and cost data from the UK mild hepatitis C randomised controlled trial, combined with estimates of disease progression and cost from observational studies.Results: Antiviral treatment at a mild rather than a moderate stage improved outcomes measured by quality adjusted life years (QALYS) gained. The mean cost per QALY gained from antiviral treatment with interferon alpha-2b and ribavirin, compared with no treatment at a mild stage, was 4535 pound ($7108) for patients with genotype non-1 and 25 pound 188 ($ 39 480) for patients with genotype 1. Providing peginterferon -2b pound and ribavirin at a mild rather than a moderate stage was also associated with a gain in QALYS; the costs per QALY gained were 7821 pound ($12 259) for patients with genotype non-1 and 28 pound 409 ($ 44 528) for patients with genotype 1.Conclusions: For patients with chronic hepatitis C, it is generally more cost effective to provide antiviral treatment at a mild rather than a moderate disease stage. For older patients (aged 65 years or over) with genotype 1, antiviral treatment at a mild stage is not cost effective. ER - TY - JFULL T1 - Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS). A1 - Lobito, AA A1 - Kimberley, FC A1 - Muppidi, JR A1 - Komarow, H A1 - Jackson, AJ A1 - Hull, KM A1 - Kastner, DL A1 - Screaton, GR A1 - Siegel, RM J1 - Blood Y1 - 2006/08/15/ VL - 108 SN - 0006-4971 SP - 1320 EP - 1327 N2 - Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease associated with heterozygous mutations in TNF receptor 1 (TNFR1). Here we examined the structural and functional alterations caused by 9 distinct TRAPS-associated TNFR1 mutations in transfected cells and a mouse "knock-in" model of TRAPS. We found that these TNFR1 mutants did not generate soluble versions of the receptor, either through membrane cleavage or in exosomes. Mutant receptors did not bind TNF and failed to function as dominant-negative inhibitors of TNFR1-induced apoptosis. Instead, TRAPS mutant TNFR1 formed abnormal disulfide-linked oligomers that failed to interact with wild-type TNFR1 molecules through the preligand assembly domain (PLAD) that normally governs receptor self-association. TRAPS mutant TNFR1 molecules were retained intracellularly and colocalized with endoplasmic reticulum (ER) markers. The capacity of mutant receptors to spontaneously induce both apoptosis and nuclear factor kappaB (NF-kappaB) activity was reduced. In contrast, the R92Q variant of TNFR1 behaved like the wild-type receptor in all of these assays. The inflammatory phenotype of TRAPS may be due to consequences of mutant TNFR1 protein misfolding and ER retention. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16684962&query_hl=1 ER - TY - JFULL T1 - Current and future applications of in vitro magnetic resonance spectroscopy in hepatobiliary disease. A1 - Cox, IJ A1 - Sharif, A A1 - Cobbold, JF A1 - Thomas, HC A1 - Taylor-Robinson, SD J1 - World J Gastroenterol Y1 - 2006/08/14/ VL - 12 SN - 1007-9327 SP - 4773 EP - 4783 N2 - Nuclear magnetic resonance spectroscopy allows the study of cellular biochemistry and metabolism, both in the whole body in vivo and at higher magnetic field strengths in vitro. Since the technique is non-invasive and non-selective, magnetic resonance spectroscopy methodologies have been widely applied in biochemistry and medicine. In vitro magnetic resonance spectroscopy studies of cells, body fluids and tissues have been used in medical biochemistry to investigate pathophysiological processes and more recently, the technique has been used by physicians to determine disease abnormalities in vivo. This highlighted topic illustrates the potential of in vitro magnetic resonance spectroscopy in studying the hepatobiliary system. The role of in vitro proton and phosphorus magnetic resonance spectroscopy in the study of malignant and non-malignant liver disease and bile composition studies are discussed, particularly with reference to correlative in vivo whole-body magnetic resonance spectroscopy applications. In summary, magnetic resonance spectroscopy techniques can provide non-invasive biochemical information on disease severity and pointers to underlying pathophysiological processes. Magnetic resonance spectroscopy holds potential promise as a screening tool for disease biomarkers, as well as assessing therapeutic response. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16937457&query_hl=1 ER - TY - JFULL T1 - Current and future applications of in vitro magnetic resonance spectroscopy in hepatobiliary disease A1 - Cox, IJ A1 - Sharif, A A1 - Cobbold, JFL A1 - Thomas, HC A1 - Taylor-Robinson, SD J1 - WORLD J GASTROENTERO Y1 - 2006/08/14/ VL - 12 SN - 1007-9327 SP - 4773 EP - 4783 N2 -

Nuclear magnetic resonance spectroscopy allows the study of cellular biochemistry and metabolism, both in the whole body in vivo and at higher magnetic field strengths in vitro. Since the technique is non-invasive and non-selective, magnetic resonance spectroscopy methodologies have been widely applied in biochemistry and medicine. In vitro magnetic resonance spectroscopy studies of cells, body fluids and tissues have been used in medical biochemistry to investigate pathophysiological processes and more recently, the technique has been used by physicians to determine disease abnormalities in vivo. This highlighted topic illustrates the potential of in vitro magnetic resonance spectroscopy in studying the hepatobiliary system. The role of in vitro proton and phosphorus magnetic resonance spectroscopy in the study of malignant and non-malignant liver disease and bile composition studies are discussed, particularly with reference to correlative in vivo whole-body magnetic resonance spectroscopy applications. In summary, magnetic resonance spectroscopy techniques can provide non-invasive biochemical information on disease severity and pointers to underlying pathophysiological processes. Magnetic resonance spectroscopy holds potential promise as a screening tool for disease biomarkers, as well as assessing therapeutic response. (C) 2006 The WIG Press. All rights reserved.

ER - TY - JFULL T1 - Genome sequence diversity and clues to the evolution of variola (smallpox) virus A1 - Esposito, JJ A1 - Sammons, SA A1 - Frace, AM A1 - Osborne, JD A1 - Olsen-Rasmussen, M A1 - Zhang, M A1 - Govil, D A1 - Damon, IK A1 - Kline, R A1 - Laker, M A1 - Li, Y A1 - Smith, GL A1 - Meyer, H A1 - LeDuc, JW A1 - Wohlhueter, RM J1 - SCIENCE Y1 - 2006/08/11/ VL - 313 SN - 0036-8075 SP - 807 EP - 812 N2 - Comparative genomics of 45 epidemiologically varied variola virus isolates from the past 30 years of the smallpox era indicate low sequence diversity, suggesting that there is probably little difference in the isolates' functional gene content. Phylogenetic clustering inferred three clades coincident with their geographical origin and case-fatality rate; the latter implicated putative proteins that mediate viral virulence differences. Analysis of the viral linear DNA genome suggests that its evolution involved direct descent and DNA end-region recombination events. Knowing the sequences will help understand the viral proteome and improve diagnostic test precision, therapeutics, and systems for their assessment. ER - TY - JFULL T1 - The WHO public-health approach to antiretroviral treatment against HIV in resource-limited settings. A1 - Gilks, CF A1 - Crowley, S A1 - Ekpini, R A1 - Gove, S A1 - Perriens, J A1 - Souteyrand, Y A1 - Sutherland, D A1 - Vitoria, M A1 - Guerma, T A1 - De Cock, K J1 - Lancet Y1 - 2006/08/05/ VL - 368 SN - 1474-547X SP - 505 EP - 510 N2 - WHO has proposed a public-health approach to antiretroviral therapy (ART) to enable scaling-up access to treatment for HIV-positive people in developing countries, recognising that the western model of specialist physician management and advanced laboratory monitoring is not feasible in resource-poor settings. In this approach, standardised simplified treatment protocols and decentralised service delivery enable treatment to be delivered to large numbers of HIV-positive adults and children through the public and private sector. Simplified tools and approaches to clinical decision-making, centred on the "four Ss"--when to: start drug treatment; substitute for toxicity; switch after treatment failure; and stop--enable lower level health-care workers to deliver care. Simple limited formularies have driven large-scale production of fixed-dose combinations for first-line treatment for adults and lowered prices, but to ensure access to ART in the poorest countries, the care and drugs should be given free at point of service delivery. Population-based surveillance for acquired and transmitted resistance is needed to address concerns that switching regimens on the basis of clinical criteria for failure alone could lead to widespread emergence of drug-resistant virus strains. The integrated management of adult or childhood illness (IMAI/IMCI) facilitates decentralised implementation that is integrated within existing health systems. Simplified operational guidelines, tools, and training materials enable clinical teams in primary-care and second-level facilities to deliver HIV prevention, HIV care, and ART, and to use a standardised patient-tracking system. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16890837&query_hl=1 ER - TY - JFULL T1 - Human bancroftian filariasis: immunological markers of morbidity and infection A1 - Satapathy, AK A1 - Sartono, E A1 - Sahoo, PK A1 - Dentener, MA A1 - Michael, E A1 - Yazdanbakhsh, M A1 - Ravindran, B J1 - MICROBES INFECT Y1 - 2006/08// VL - 8 SN - 1286-4579 SP - 2414 EP - 2423 N2 - Induction of host cytokines plays a critical role in infection as well as disease in human filariasis. Measurements of such molecules in plasma could be used as windows of markers both for understanding the pathogenesis of the disease and for identifying markers of morbidity. Eight inflammatory and non-inflammatory host molecules in circulation were quantified in 207 subjects in filariasis endemic area of Orissa, India. IL-6, IL-8, IL-10, TNF-alpha, TNFR-I, TNFR-II, LBP and sICAM-1 were quantified by immunoassays and were analyzed by multivariate exploratory data analysis methods followed by multivariate analysis of variance. Raised levels of IL-6 and IL-8 emerged as markers of acute as well as chronic disease, while increased TNF-alpha was a feature found only in acute filariasis. Decreased sICAM-1 was a feature found only in asymptomatic subjects with filarial infection. There was a dichotomy in plasma levels of two TNF receptors between infected subjects and patients with filarial disease. Since plasma levels of these cytokines are often determined by host genetics, studies on cytokine genetic polymorphisms could offer new insights into the relationship between infection and disease in human lymphatic filariasis. (c) 2006 Elsevier SAS. All rights reserved. ER - TY - JFULL T1 - Avipoxvirus phylogenetics: identification of a PCR length polymorphism that discriminates between the two major clades. A1 - Jarmin, S A1 - Manvell, R A1 - Gough, RE A1 - Laidlaw, SM A1 - Skinner, MA J1 - J Gen Virol Y1 - 2006/08// VL - 87 SN - 0022-1317 SP - 2191 EP - 2201 N2 - Avipoxvirus infections have been observed in an extensive range of wild, captive and domesticated avian hosts, yet little is known about the genome diversity and host-range specificity of the causative agent(s). Genome-sequence data are largely restricted to Fowlpox virus (FWPV) and Canarypox virus (CNPV), which have been sequenced completely, showing considerable divergence between them. It is therefore proving difficult, by empirical approaches, to identify pan-genus, avipoxvirus-specific oligonucleotide probes for PCR and sequencing to support phylogenetic studies. A previous preliminary study used the fpv167 locus, which encodes orthologues of vaccinia virus core protein P4b (A3). PCR per se did not discriminate between viruses, but restriction-enzyme or sequence analysis indicated that the avipoxviruses clustered either with FWPV or with CNPV. Here, further study of the P4b locus demonstrated a third cluster, from psittacine birds. A newly identified locus, flanking fpv140 (orthologue of vaccinia virus H3L), confirms the taxonomic structure. This locus is particularly useful in that viruses from the fowlpox-like and canarypox-like clusters can be discriminated by PCR on the basis of fragment size, whilst sequence comparison allows discrimination for the first time between Pigeonpox virus and Turkeypox virus. Except within the psittacines, virus and avian host taxonomies do not show tight correlation, with viruses from the same species located in very different clades. Nor are all the existing recognized avipoxvirus species, defined primarily by avian host species (such as CNPV and Sparrowpox virus), resolved within the present structure. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16847115&query_hl=1 ER - TY - JFULL T1 - Detection of a hepatitis B surface antigen variant emerging in a patient with chronic lymphocytic leukaemia treated with fludarabine A1 - Alexopoulou, A A1 - Dourakis, SP A1 - Pandelidaki, H A1 - Archimandritis, AJ A1 - Karayiannis, P J1 - J MED VIROL Y1 - 2006/08// VL - 78 SN - 0146-6615 SP - 1043 EP - 1046 N2 - Fludarabine is used widely for the treatment of chronic lymphocytic leukaemia, but not as yet implicated in the emergence of hepatitis B surface antigen (HBsAg) variants following hepatitis B virus (HBV) reactivation. Such a variant was detected in a 78-year-old female who was HBsAg(-)/anti-HBc(+)/anti-HBs(+)/anti-HBe(+), and with normal ALT levels, who developed HBV reactivation after fludarabine treatment. She had high HBV-DNA levels, and became positive for HBeAg, in the absence of detectable HBsAg. HBV-DNA was extracted from serum and the HBsAg encoding region of the genome was amplified by PCR, followed by cloning and sequencing. The HBV strain appeared to be subtype adw, but had higher nucleotide homology with ayw than adw isolates, supported further by phylogenetic tree analysis. Amino-acid sequence comparisons over the alpha determinant region revealed the following substitutions: C124N, G130R, and N146S. There were also unique substitutions outside the alpha determinant. All these mutations appeared to have a profound effect on the antigenicity of this region, which resulted in failure to detect HBsAg by commercially available diagnostic assays. It is concluded that a surface variant emerged in an HBsAg(-)/anti-HBs(+) patient with chronic lymphocytic leukaemia following fludarabine treatment, with an unprecedented number of amino-acid substitutions in the alpha determinant region of HBsAg, including a subtype switch. ER - TY - JFULL T1 - No change to HIV-1 latency with valproate therapy. A1 - Steel, A A1 - Clark, S A1 - Teo, I A1 - Shaunak, S A1 - Nelson, M A1 - Gazzard, B A1 - Kelleher, P J1 - AIDS Y1 - 2006/08/01/ VL - 20 SN - 0269-9370 SP - 1681 EP - 1682 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16868456&query_hl=1 ER - TY - JFULL T1 - Primary HIV. A1 - Fox, J A1 - Weber, J A1 - Fidler, S J1 - Sex Transm Infect Y1 - 2006/08// VL - 82 SN - 1368-4973 SP - 267 EP - 268 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16877570&query_hl=1 ER - TY - JFULL T1 - Neurodevelopmental outcomes in children with HIV infection under 3 years of age. A1 - Foster, CJ A1 - Biggs, RL A1 - Melvin, D A1 - Walters, MD A1 - Tudor-Williams, G A1 - Lyall, EG J1 - Dev Med Child Neurol Y1 - 2006/08// VL - 48 SN - 0012-1622 SP - 677 EP - 682 N2 - Following the introduction of combination antiretroviral therapy, children vertically infected with the human immunodeficiency virus (HIV-1) living in the developed world are surviving into adult life. This paper reviews the neurodevelopmental outcomes of 62 consecutively-presenting children with HIV-1 infection diagnosed before 3 years of age (32 males, 30 females; median age at presentation 6 mo). Neurological and developmental data are presented with immunological and virological responses to antiretroviral therapy. Fourteen children (22%) had abnormal neurological signs and 25 (40%) demonstrated significant developmental delay on standardized developmental assessments. Children presenting with more severe HIV-1 disease and immune compromise had significantly more abnormal neurological signs and developmental delays than children presenting with milder HIV-1 symptomatology. Immune function, control of HIV-1 viral replication, and growth parameters improved with antiretroviral therapy (median age at last follow-up 7 y 3 mo); however, abnormal neurological signs and significant gross motor difficulties persisted. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16836781&query_hl=1 ER - TY - JFULL T1 - Differential effects of Gram-positive versus Gram-negative bacteria on NOSII and TNFalpha in macrophages: role of TLRs in synergy between the two. A1 - Paul-Clark, MJ A1 - McMaster, SK A1 - Belcher, E A1 - Sorrentino, R A1 - Anandarajah, J A1 - Fleet, M A1 - Sriskandan, S A1 - Mitchell, JA J1 - Br J Pharmacol Y1 - 2006/08// VL - 148 SN - 0007-1188 SP - 1067 EP - 1075 N2 - 1. Gram-negative and Gram-positive bacteria are sensed by Toll-like receptor (TLR)4 and TLR2, respectively. TLR4 recruits MyD88 and TRIF, whereas TLR2 recruits MyD88 without TRIF. NOSII and TNFalpha are central genes in innate immunity and are thought to be differentially regulated by the MyD88 versus TRIF signalling pathways. Here, we have used Gram-positive Staphylococcus aureus, Gram-negative Escherichia coli and highly selective TLR ligands to establish the precise relationship between TLR2, TLR1, TLR6 and TLR4 for NOSII versus TNFalpha induction. 2. In murine macrophages at 24 h, E. coli or LPS (TLR4) induced NO and TNFalpha release. In contrast, S. aureus (TLR2/TLR1/TLR6) or Pam(3)CSK4 (TLR2/TLR1), or FSL-1 and LTA (TLR2/TLR6) induced TNFalpha without an effect on NO. 3. At later time points (48-72 h), S. aureus induced NO release. The ability of S. aureus, but not E. coli or LPS, to induce NO release was inhibited by anti-TNFalpha-binding antibodies. 4. At 24 h, LPS synergised with TLR2 ligands to induce NO release and NOSII protein expression. LPS also induced the expression of TLR2 gene expression without affecting levels of TLR4. 5. Using cells from TLR2(-/-) or TLR4(-/-) mice, the ability of LPS to synergise with S. aureus or Pam(3)CSK4 was found to be dependent on both TLR2 and TLR4. 6. These observations are the first to clearly delineate the role of separately activating TLR2 and TLR4 in the induction of NOSII and TNFalpha genes compared with their coinduction when both receptor pathways are activated. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16783405&query_hl=1 ER - TY - JFULL T1 - Role of CCL5 (RANTES) in viral lung disease. A1 - Culley, FJ A1 - Pennycook, AM A1 - Tregoning, JS A1 - Dodd, JS A1 - Walzl, G A1 - Wells, TN A1 - Hussell, T A1 - Openshaw, PJ J1 - J Virol Y1 - 2006/08// VL - 80 SN - 0022-538X SP - 8151 EP - 8157 N2 - CCL5/RANTES is a key proinflammatory chemokine produced by virus-infected epithelial cells and present in respiratory secretions of asthmatics. To examine the role of CCL5 in viral lung disease, we measured its production during primary respiratory syncytial virus (RSV) infection and during secondary infection after sensitizing vaccination that induces Th2-mediated eosinophilia. A first peak of CCL5 mRNA and protein production was seen at 18 to 24 h of RSV infection, before significant lymphocyte recruitment occurred. Treatment in vivo with Met-RANTES (a competitive chemokine receptor blocker) throughout primary infection decreased CD4+ and CD8+ cell recruitment and increased viral replication. In RSV-infected, sensitized mice with eosinophilic disease, CCL5 production was further augmented; Met-RANTES treatment again reduced inflammatory cell recruitment and local cytokine production. A second wave of CCL5 production occurred on day 7, attributable to newly recruited T cells. Paradoxically, mice treated with Met-RANTES during primary infection demonstrated increased cellular infiltration during reinfection. We therefore show that RSV induces CCL5 production in the lung and this causes the recruitment of RSV-specific cells, including those making additional CCL5. If this action is blocked with Met-RANTES, inflammation decreases and viral clearance is delayed. However, the exact effects of chemokine modulation depend critically on time of administration, a factor that may potentially complicate the use of chemokine blockers in inflammatory diseases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16873271&query_hl=1 ER - TY - JFULL T1 - p27Kip1 and p130 cooperate to regulate hematopoietic cell proliferation in vivo. A1 - Soeiro, I A1 - Mohamedali, A A1 - Romanska, HM A1 - Lea, NC A1 - Child, ES A1 - Glassford, J A1 - Orr, SJ A1 - Roberts, C A1 - Naresh, KN A1 - Lalani, el-N A1 - Mann, DJ A1 - Watson, RJ A1 - Thomas, NS A1 - Lam, EW J1 - Mol Cell Biol Y1 - 2006/08// VL - 26 SN - 0270-7306 SP - 6170 EP - 6184 N2 - To investigate the potential functional cooperation between p27Kip1 and p130 in vivo, we generated mice deficient for both p27Kip1 and p130. In p27Kip1-/-; p130-/- mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27Kip1-/- counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27Kip1-/-; p130-/- animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1-/- splenocytes. The finding that the p27Kip1-/-; p130-/- splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27Kip1 to regulate hematopoietic cell proliferation in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16880527&query_hl=1 ER - TY - JFULL T1 - Interferon-alpha therapy in HBeAg-negative chronic hepatitis B: a long-term prospective study from north-western Greece A1 - Baltayiannis, G A1 - Katsanos, K A1 - Karayiannis, P A1 - Tsianos, EV J1 - ALIMENT PHARM THERAP Y1 - 2006/08/01/ VL - 24 SN - 0269-2813 SP - 525 EP - 533 N2 - To determine the long-term response to interferon-alpha therapy in patients with hepatitis B e antigen-negative chronic hepatitis B, and the factors independently associated with response and survival.Sixty-three patients with documented hepatitis B e antigen-negative chronic hepatitis B treated with interferon-alpha for a year were followed-up for a period of 6 years.Sustained biochemical and virological response was seen in 34.91% and 33.33% of patients at 6 and 12 months of follow-up, respectively, and histological improvement in 54.5% of sustained responders compared with non-responders (7.1%, P = 0.004, chi-squared test), at 6 months of follow-up. Multivariate analysis showed that patients with hepatitis B virus-DNA levels at 6 months of treatment < 10 000 copies/mL had a low probability of relapse, compared with those with levels > 10 000 copies/mL (P = 0.032). Age (> 65 years) and hepatitis B virus-DNA level at 6 months of treatment (> 10 000 copies/mL) were the independent factors for disease progression and survival (P = 0.041 and P = 0.044 respectively). At 6 years, a sustained response was still present in 19.04% of patients and 4.8% of them had developed anti-HBs.Hepatitis B virus-DNA monitoring by quantitative polymerase chain reaction at 6 months of treatment may allow for early prediction of response to interferon-alpha, and may serve as an indicator of disease progression in the future. ER - TY - JFULL T1 - A potential molecular mechanism for hypersensitivity caused by formalin-inactivated vaccines. A1 - Moghaddam, A A1 - Olszewska, W A1 - Wang, B A1 - Tregoning, JS A1 - Helson, R A1 - Sattentau, QJ A1 - Openshaw, PJ J1 - Nat Med Y1 - 2006/08// VL - 12 SN - 1078-8956 SP - 905 EP - 907 N2 - Heat, oxidation and exposure to aldehydes create reactive carbonyl groups on proteins, targeting antigens to scavenger receptors. Formaldehyde is widely used in making vaccines, but has been associated with atypical enhanced disease during subsequent infection with paramyxoviruses. We show that carbonyl groups on formaldehyde-treated vaccine antigens boost T helper type 2 (T(H)2) responses and enhance respiratory syncytial virus (RSV) disease in mice, an effect partially reversible by chemical reduction of carbonyl groups. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16862151&query_hl=1 ER - TY - JFULL T1 - Primary HIV A1 - Fox J A1 - Weber J J1 - Sex Transm Infect Y1 - 2006/08// ER - TY - JFULL T1 - Proton MR spectroscopy in neonates with perinatal cerebral hypoxic-ischemic injury: Metabolite peak-area ratios, relaxation times, and absolute concentrations A1 - Cheong, JLY A1 - Cady, EB A1 - Penrice, J A1 - Wyatt, JS A1 - Cox, IJ A1 - Robertson, NJ J1 - AM J NEURORADIOL Y1 - 2006/08// VL - 27 SN - 0195-6108 SP - 1546 EP - 1554 N2 - BACKGROUND: Results from cerebral proton H-1-MR spectroscopy studies of neonates with perinatal hypoxic-ischemic injury have generally been presented as metabolite peak-area ratios, which are T1 and T2-weighted, rather than absolute metabolite concentrations. We hypothesized that compared with 1H-MR spectroscopy peak-area ratios, calculation of absolute metabolite concentrations and relaxation times measured within the first 4 days after birth (1) would improve prognostic accuracy and (2) enhance the understanding of underlying neurochemical changes in neonates with neonatal encephalopathy.METHODS: Seventeen term infants with neonatal encephalopathy and 10 healthy controls were studied at 2.4T at 1 (1-3) and 2 (2-4) (median [interquartile range]) days afterbirth, respectively. Infants with neonatal encephalopathy were classified into 2 outcome groups (normal/mild and severe/fatal), according to neurodevelopmental assessments at 1 year. The MR spectroscopy peak-area ratios, relaxation times, absolute concentrations, and concentration ratios of lactate (Lac), creatine plus phosphocreatine (Cr), N-acetylaspartate (NAA), and choline-containing compounds (Cho) from a voxel centered on the thalami were analyzed according to outcome group.RESULTS: Comparing the severe/fatal group with the controls (significance assumed with P < 0.05), we found that Lac/NAA, Lac/Cho, and Lac/Cr peak-area ratios increased and NAA/Cr and NAA/Cho decreased; Lac, NAA, and Cr T2s were increased; [Lac] was increased and [Cho], [Cr], and [NAA] decreased; and among the concentration ratios, only [Lac]/[NAA] was increased. Comparison of the normal/mild group with controls revealed no differences in peak-area ratios, relaxation times, or concentration ratios but decreased [NAA], [Cho], and [Cr] were observed in the infants with normal/mild outcome. Comparison of the normal/mild and severe/fatal groups showed increased Lac/NAA and Lac/Cho and decreased NAA/Cr and NAA/Cho peak-area ratios, reduced [NAA], and increased Lac T2 in the infants with the worse outcome.CONCLUSIONS: Metabolite concentrations, in particular [NAA], enhance the prognostic accuracy of cerebral H-1-MR spectroscopy-[NAA] was the only measurable to discriminate among all (control, normal/mild, and severe/fatal outcome) groups. However, peak-area ratios are more useful prognostic indicators than concentration ratios because they depend on metabolite concentrations and T2s, both of which are pathologically modulated. Concentration ratios depend only on the concentrations of the constituent metabolites. Increased Cr T2 may provide an indirect marker of impaired cellular energetics, and similarly, NAA T2 may constitute an index of exclusively neuronal energy status. Our recommendation is to collect data that enable calculation of brain metabolite concentrations. However, if time constraints make this impossible, metabolite peak-area ratios provide the next best method of assigning early prognosis in neonatal encephalopathy. ER - TY - JFULL T1 - Strategies for mitigating an influenza pandemic. A1 - Ferguson, NM A1 - Cummings, DA A1 - Fraser, C A1 - Cajka, JC A1 - Cooley, PC A1 - Burke, DS J1 - Nature Y1 - 2006/07/27/ VL - 442 SN - 1476-4687 SP - 448 EP - 452 N2 - Development of strategies for mitigating the severity of a new influenza pandemic is now a top global public health priority. Influenza prevention and containment strategies can be considered under the broad categories of antiviral, vaccine and non-pharmaceutical (case isolation, household quarantine, school or workplace closure, restrictions on travel) measures. Mathematical models are powerful tools for exploring this complex landscape of intervention strategies and quantifying the potential costs and benefits of different options. Here we use a large-scale epidemic simulation to examine intervention options should initial containment of a novel influenza outbreak fail, using Great Britain and the United States as examples. We find that border restrictions and/or internal travel restrictions are unlikely to delay spread by more than 2-3 weeks unless more than 99% effective. School closure during the peak of a pandemic can reduce peak attack rates by up to 40%, but has little impact on overall attack rates, whereas case isolation or household quarantine could have a significant impact, if feasible. Treatment of clinical cases can reduce transmission, but only if antivirals are given within a day of symptoms starting. Given enough drugs for 50% of the population, household-based prophylaxis coupled with reactive school closure could reduce clinical attack rates by 40-50%. More widespread prophylaxis would be even more logistically challenging but might reduce attack rates by over 75%. Vaccine stockpiled in advance of a pandemic could significantly reduce attack rates even if of low efficacy. Estimates of policy effectiveness will change if the characteristics of a future pandemic strain differ substantially from those seen in past pandemics. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16642006&query_hl=1 ER - TY - JFULL T1 - Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial. A1 - INITIO Trial International Co-ordinating Committee A1 - Yeni, P A1 - Cooper, DA A1 - Aboulker, JP A1 - Babiker, AG A1 - Carey, D A1 - Darbyshire, JH A1 - Floridia, M A1 - Girard, PM A1 - Goodall, RL A1 - Hooker, MH A1 - Mijch, A A1 - Meiffredy, V A1 - Salzberger, B J1 - Lancet Y1 - 2006/07/22/ VL - 368 SN - 1474-547X SP - 287 EP - 298 N2 - BACKGROUND: Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well defined. METHODS: In INITIO, a large international randomised trial, we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received antiretroviral drugs. Primary outcomes were proportion with undetectable HIV RNA in plasma, and change in CD4 count from baseline at 3 years. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN44582462. FINDINGS: We followed up 911 participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262-316) for NFV, and 274x10(6) cells per L (231-291) for EFV/NFV (p=0.1). Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days (p=0.005). Participants in the EFV/NFV group had shorter time to stopping the initial regimen (p<0.0001) and to a treatment modifying adverse event (p=0.04) than those in the other groups. INTERPRETATION: Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen. The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16860698&query_hl=1 ER - TY - JFULL T1 - Blood tests for diagnosis of tuberculosis A1 - Kampmann, B A1 - Tena-Coki, G A1 - Anderson, S J1 - LANCET Y1 - 2006/07/22/ VL - 368 SN - 0140-6736 SP - 282 EP - 282 ER - TY - JFULL T1 - Parvovirus infection, malaria, and anemia in the tropics--a new hidden enemy? A1 - Pasvol, G J1 - J Infect Dis Y1 - 2006/07/15/ VL - 194 SN - 0022-1899 SP - 141 EP - 142 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16779717&query_hl=1 ER - TY - JFULL T1 - A case of multidrug resistant primary HIV infection with delayed CD4 T-cell count decline despite low viral load, treated with interleukin-2. A1 - Pao, D A1 - Smit, E A1 - Imami, N A1 - Fisher, M J1 - AIDS Y1 - 2006/07/13/ VL - 20 SN - 0269-9370 SP - 1564 EP - 1565 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16847417&query_hl=1 ER - TY - JFULL T1 - National adult antiretroviral therapy guidelines in resource-limited countries: concordance with 2003 WHO guidelines? A1 - Beck, EJ A1 - Vitoria, M A1 - Mandalia, S A1 - Crowley, S A1 - Gilks, CF A1 - Souteyrand, Y J1 - AIDS Y1 - 2006/07/13/ VL - 20 SN - 0269-9370 SP - 1497 EP - 1502 N2 - AIMS: To investigate the existence of national adult antiretroviral therapy (ART) guidelines in 43 World Health Organization (WHO) '3 by 5' focus countries and compare their content with the 2003 WHO ART guidelines. METHODS: Questionnaires covered initiation of ART, selection of first or second-line ART, monitoring treatment response and toxicity and dissemination of national guidelines. Weighted concordance scores were created and country scores correlated with national indicators and WHO recommendations. RESULTS: Thirty-nine (91%) countries returned questionnaires, three of which had no national ART guidelines. Of the 36, 16 (44%) recommended to start ART based on WHO clinical staging criteria and CD4 cell count or T-lymphocyte count, 12 (33%) WHO clinical staging criteria and CD4 cell count, four (11%) only CD4 cell counts. 35 (97%) recommended a standard first-line regimen and 24 (67%) preferred stavudine + lamivudine + nevirapine; 33 (92%) recommended second-line regimens, and 24 (60%) preferred abacavir + didanosine + lopinavir/ritonavir. Thirty-one (94%) recommended CD4 cell count, possibly combined with other indicators, to monitor ART. Concordance scores were higher in countries with lower health expenditure per capita (P = 0.009) and lower GDP per capita (P < 0.03). Median concordance scores for starting ART was 100 [interquartile range (IQR), 67 to 100]; first line therapy, 70 (IQR, 60 to 80); second-line regimens, 45 (IQR, 27 to 55) and for laboratory investigations, 80 (IQR, 80 to 100). CONCLUSIONS: Most countries had developed national ART guidelines as part of a comprehensive national HIV program. Concordance with WHO recommendations was strong on starting first-line ART regimens and routine monitoring but lower for second-line recommendations. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16847404&query_hl=1 ER - TY - JFULL T1 - Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation. A1 - Sriskandan, S A1 - Ferguson, M A1 - Elliot, V A1 - Faulkner, L A1 - Cohen, J J1 - J Antimicrob Chemother Y1 - 2006/07// VL - 58 SN - 0305-7453 SP - 117 EP - 124 N2 - OBJECTIVES: Polyclonal human intravenous immunoglobulin (IVIG) has been advocated as an adjunct to therapy in severe invasive streptococcal toxic shock because of its ability to neutralize superantigen toxins. The aim of this study was to assess IVIG therapeutic efficacy in an experimental model of streptococcal toxic shock. METHODS: To confirm the in vitro activity of IVIG against the Streptococcus pyogenes strain used in the study, IVIG was tested for superantigen neutralizing and bacterial opsonizing activity prior to in vivo studies. To evaluate the in vivo effects of IVIG in terms of microbiological outcome and disease severity in a superantigen-sensitive transgenic model of streptococcal shock, HLA-DQ transgenic mice were treated with IVIG either at the time of infection or after infection with S. pyogenes. Antibiotics were included in some studies. RESULTS: The IVIG preparation neutralized superantigenicity of S. pyogenes in vitro and enhanced bacterial killing in a whole blood assay. When given to mice at the time of S. pyogenes infection, IVIG neutralized circulating superantigens and reduced systemic inflammatory response. Remarkably, IVIG-enhanced systemic clearance of bacteria and enhanced neutrophil infiltrate into the infected tissues. However, when used in combination with penicillin and clindamycin in a delayed treatment setting, IVIG did not confer additional therapeutic benefit, in terms of inflammatory response, bacterial clearance or survival. CONCLUSIONS: IVIG monotherapy can confer benefit in experimental streptococcal shock, but extension of these findings to the clinical situation will require further evaluation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16670109&query_hl=1 ER - TY - JFULL T1 - Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation. A1 - Wright, M A1 - Grieve, R A1 - Roberts, J A1 - Main, J A1 - Thomas, HC A1 - UK Mild Hepatitis C Trial Investigators J1 - Health Technol Assess Y1 - 2006/07// VL - 10 SN - 1366-5278 SP - 1 EP - 113 N2 - OBJECTIVES: To determine whether combined therapy with interferon-alpha and ribavirin was more effective and cost-effective than no treatment for patients with mild chronic hepatitis C. DESIGN: A multicentre, randomised, controlled, non-blinded trial assessed the efficacy of combination therapy. A Markov model used these efficacy data combined with data on transition probabilities, costs and health-related quality of life (HRQoL) to assess the lifetime cost-effectiveness of the intervention. SETTING: A multicentre NHS setting. PARTICIPANTS: Treatment-naive, adult patients with histologically mild chronic hepatitis C (Ishak necroinflammatory scores <4 and fibrosis scores <3 on liver biopsy). INTERVENTIONS: Patients were randomised to receive interferon-alpha and ribavirin for 48 weeks or no treatment (control). MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of patients having a sustained virological response (SVR), measured at 6 months after cessation of therapy. Secondary outcome measures were: the ability of early phase kinetics to predict the eventual outcome of treating mild disease; HRQoL measured using the Short Form 36 and EuroQol (5 Dimensions) questionnaires, and the cost per quality-adjusted life-year (QALY) of interferon-alpha and ribavirin for mild disease compared with no treatment. RESULTS: In the treatment group, 32 out of 98 patients (33%) achieved an SVR. Patients infected with genotype 1 had a lower SVR than those infected with genotype non-1 (18% versus 49%, p = 0.02). No patients who failed to achieve a 2-log drop in viral load at 12 weeks achieved an SVR. HRQoL fell during treatment and rose with treatment cessation. For patients having an SVR there were modest improvements in HRQoL at 6 months post-treatment. The mean cost per QALY gained was 4535 pounds sterling for 40-year-old patients with genotype non-1 and 25,188 pounds sterling for patients with genotype 1. For patients with genotype 1 aged 65, providing interferon-alpha and ribavirin for mild disease led to fewer QALYs gained, and a mean cost per QALY of 53,017 pounds sterling. The model using efficacy estimates from the literature, showed that the cost per QALY gained from providing pegylated interferon alpha-2b and ribavirin at a mild stage rather than a moderate stage was 7821 pounds sterling for patients with genotype non-1 and 28,409 pounds sterling for patients with genotype 1. CONCLUSIONS: Based on the evidence collected in this study, interferon-alpha and ribavirin treatment for mild chronic hepatitis C patients is in general cost-effective at the 30,000 pounds sterling per QALY threshold previously used by policy-makers in the NHS. For patients with chronic hepatitis C aged 65 or over with genotype 1, antiviral treatment at a mild stage does not appear cost-effective. Further research is required on the cost-effectiveness of pegylated interferon and ribavirin, in particular the intervention's long-term impact on HRQoL and health service costs requires further evaluation. Further research is also needed to develop predictive tests, based on pharmacogenomics, that can identify those cases most likely to respond to antiviral therapy. Liver biopsy before treatment no longer appears justified apart from for older patients (aged 65 or over) with genotype 1. However, further research should monitor the impact this strategy would have on costs and outcomes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16750059&query_hl=1 ER - TY - JFULL T1 - Improved recovery of Mycobacterium tuberculosis from children using the microscopic observation drug susceptibility method A1 - Oberhelman, RA A1 - Soto-Castellares, G A1 - Caviedes, L A1 - Castillo, ME A1 - Kissinger, P A1 - Moore, DAJ A1 - Evans, C A1 - Gilman, RH J1 - PEDIATRICS Y1 - 2006/07// VL - 118 SN - 0031-4005 SP - E100 EP - E106 N2 - OBJECTIVE. The diagnosis of pulmonary tuberculosis presents challenges in children, because symptoms are nonspecific, sputa are not accessible, and Mycobacterium tuberculosis cultures and smears often are negative. The Microscopic Observation Drug Susceptibility technique is a simple, inexpensive method for Mycobacterium tuberculosis isolation with superior speed and sensitivity over Lowenstein-Jensen culture in studies of adults with pulmonary tuberculosis. The objective of this study was to determine whether Microscopic Observation Drug Susceptibility culture can improve the sensitivity and the speed of Mycobacterium tuberculosis recovery among Peruvian children with symptoms suggestive of pulmonary tuberculosis. METHODS. Two specimens of each type (gastric aspirate, nasopharyngeal aspirate, and stool specimens) were collected from each patient, examined by auramine stain, and cultured by Microscopic Observation Drug Susceptibility and Lowenstein-Jensen techniques. Patients (n = 165) were enrolled between April 2002 and February 2004 at the Instituto de Salud del Nino, the major pediatric hospital in Lima, Peru. Inclusion criteria were age <= 12 years, Stegen-Toledo clinical score >= 5 points, and absence of antituberculous therapy. The main outcome measurements were (1) proportion of specimens that were culture positive by Microscopic Observation Drug Susceptibility versus Lowenstein-Jensen and (2) days required for positive culture result, stratified by specimen type and auramine stain result. RESULTS. Fifteen (9%) patients had at least 1 positive Mycobacterium tuberculosis culture (from stool in 3 cases, nasopharyngeal aspirate in 8 cases, and gastric aspirate in 15 cases). Thirty-eight culture-positive specimens were obtained (22 gastric aspirate, 12 nasopharyngeal aspirates, and 4 stools). Microscopic Observation Drug Susceptibility provided significantly more positive cultures than Lowenstein-Jensen (33 of 38 specimens culture positive by Microscopic Observation Drug Susceptibility vs 21 of 38 by Lowenstein-Jensen). This was attributed to enhanced recovery of Mycobacterium tuberculosis from auramine-negative specimens (19 of 23 by Microscopic Observation Drug Susceptibility vs 9 of 23 by Lowenstein-Jensen), in contrast to similar detection rates for the 2 tests with auramine-positive samples. Similar results were found for analyses that were limited to gastric aspirates. Isolation was faster by Microscopic Observation Drug Susceptibility than Lowenstein-Jensen. CONCLUSIONS. Isolation of Mycobacterium tuberculosis from children with suspected pulmonary tuberculosis by Microscopic Observation Drug Susceptibility demonstrated greater yield and faster recovery than by Lowenstein-Jensen method, significantly improving local capabilities to detect pediatric tuberculosis in resource-poor settings. ER - TY - JFULL T1 - Hepatitis C virus (HCV) internal ribosome entry site (IRES) variants from serum, liver and PBMCs and their translational efficiency in different cell lines A1 - Hsieh, F A1 - Forton, D A1 - Thomas, HC A1 - Karayiannis, R J1 - J CLIN VIROL Y1 - 2006/07// VL - 36 SN - 1386-6532 SP - S116 EP - S116 ER - TY - JFULL T1 - Different levels of immunogenicity of two strains of Fowlpox virus as recombinant vaccine vectors eliciting T-cell responses in heterologous prime-boost vaccination strategies. A1 - Cottingham, MG A1 - van Maurik, A A1 - Zago, M A1 - Newton, AT A1 - Anderson, RJ A1 - Howard, MK A1 - Schneider, J A1 - Skinner, MA J1 - Clin Vaccine Immunol Y1 - 2006/07// VL - 13 SN - 1556-6811 SP - 747 EP - 757 N2 - The FP9 strain of F has been described as a more immunogenic recombinant vaccine vector than the Webster FPV-M (FPW) strain (R. J. Anderson et al., J. Immunol. 172:3094-3100, 2004). This study expands the comparison to include two separate recombinant antigens and multiple, rather than single, independent viral clones derived from the two strains. Dual-poxvirus heterologous prime-boost vaccination regimens using individual clones of recombinant FP9 or FPW in combination with recombinant modified V Ankara expressing the same antigen were evaluated for their ability to elicit T-cell responses against recombinant antigens from Plasmodium berghei (circumsporozoite protein) or human immunodeficiency virus type 1 (a Gag-Pol-Nef fusion protein). Gamma interferon enzyme-linked immunospot assay and fluorescence-activated cell sorting assays of the responses to specific epitopes confirmed the approximately twofold-greater cellular immunogenicity of FP9 compared to FPW, when given as the priming or boosting immunization. Equality of transgene expression in mouse cells infected with the two strains in vitro was verified by Western blotting. Directed partial sequence analysis and PCR analysis of FPW and comparison to available whole-genome sequences revealed that many loci that are mutated in the highly attenuated and culture-adapted FP9 strain are wild type in FPW, including the seven multikilobase deletions. These "passage-specific" alterations are hypothesized to be involved in determining the immunogenicity of fowlpox virus as a recombinant vaccine vector. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16829611&query_hl=1 ER - TY - JFULL T1 - Replication efficiency of hepatitis B virus infectious clones bearing core promoter, pre-core and surface gene mutations, in a common genetic background A1 - Jammeh, S A1 - Thomas, HC A1 - Karayiannis, P J1 - J CLIN VIROL Y1 - 2006/07// VL - 36 SN - 1386-6532 SP - S52 EP - S52 ER - TY - JFULL T1 - Passive sexual transmission of human immunodeficiency virus type 1 variants and adaptation in new hosts. A1 - Frater, AJ A1 - Edwards, CT A1 - McCarthy, N A1 - Fox, J A1 - Brown, H A1 - Milicic, A A1 - Mackie, N A1 - Pillay, T A1 - Drijfhout, JW A1 - Dustan, S A1 - Clarke, JR A1 - Holmes, EC A1 - Zhang, HT A1 - Pfafferott, K A1 - Goulder, PJ A1 - McClure, MO A1 - Weber, J A1 - Phillips, RE A1 - Fidler, S J1 - J Virol Y1 - 2006/07// VL - 80 SN - 0022-538X SP - 7226 EP - 7234 N2 - Human immunodeficiency virus type 1 (HIV-1) genetic diversity is a major obstacle for the design of a successful vaccine. Certain viral polymorphisms encode human leukocyte antigen (HLA)-associated immune escape, potentially overcoming limited vaccine protection. Although transmission of immune escape variants has been reported, the overall extent to which this phenomenon occurs in populations and the degree to which it contributes to HIV-1 viral evolution are unknown. Selection on the HIV-1 env gene at transmission favors neutralization-sensitive variants, but it is not known to what degree selection acts on the internal HIV-1 proteins to restrict or enhance the transmission of immune escape variants. Studies have suggested that HLA class I may determine susceptibility to HIV-1 infection, but a definitive role for HLA at transmission remains unproven. Comparing populations of acute seroconverters and chronically infected patients, we found no evidence of selection acting to restrict transmission of HIV-1 variants. We found that statistical associations previously reported in chronic infection between viral polymorphisms and HLA class I alleles are not present in acute infection, suggesting that the majority of viral polymorphisms in these patients are the result of transmission rather than de novo adaptation. Using four episodes of HIV-1 transmission in which the donors and recipients were both sampled very close to the time of infection we found that, despite a transmission bottleneck, genetic variants of HIV-1 infection are transmitted in a frequency-dependent manner. As HIV-1 infections are seeded by unique donor-adapted viral variants, each episode is a highly individual antigenic challenge. Host-specific, idiosyncratic HIV-1 antigenic diversity will seriously tax the efficacy of immunization based on consensus sequences. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16809328&query_hl=1 ER - TY - JFULL T1 - Hepatic vein transit time of SonoVue: a comparative study with Levovist. A1 - Lim, AK A1 - Patel, N A1 - Eckersley, RJ A1 - Goldin, RD A1 - Thomas, HC A1 - Cosgrove, DO A1 - Taylor-Robinson, SD A1 - Blomley, MJ J1 - Radiology Y1 - 2006/07// VL - 240 SN - 0033-8419 SP - 130 EP - 135 N2 - PURPOSE: To prospectively compare transit times of Levovist and SonoVue in healthy volunteers and patients with biopsy-proved hepatitis C-related liver disease. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Forty patients and 25 healthy volunteers were examined. Subjects fasted, a bolus of SonoVue (0.6 mL) was injected into a cubital fossa vein, and hepatic venous time-intensity profiles were measured with spectral Doppler tracing. This was repeated with two injections of Levovist (2 g) and another injection of SonoVue. Time-intensity curves of spectral Doppler signals of right and middle hepatic veins were analyzed. A sustained signal intensity increase of 10% above baseline levels indicated hepatic vein transit time (HVTT). Carotid artery audio intensity was measured in volunteers. Analysis of variance and t tests were used for statistical analysis. RESULTS: Twelve patients had mild hepatitis; 18, moderate or severe hepatitis; and 10, cirrhosis. Mean HVTTs in control, mild hepatitis, moderate or severe hepatitis, and cirrhosis groups were 38.3 seconds +/- 2.4 (standard error), 47.5 seconds +/- 6.5, 29.5 seconds +/- 10.8, and 17.6 seconds +/- 5.0, respectively, with Levovist (P < .001) and 29.4 seconds +/- 6.9, 27.4 seconds +/- 9.3, 22.9 seconds +/- 4.7, and 16.4 seconds +/- 4.9, respectively, with SonoVue (P < .001). HVTT decreased as severity increased at imaging with both contrast agents. There was no significant difference in HVTT between mild and moderate hepatitis groups with SonoVue; however, there were significant differences in HVTT between all patient groups with Levovist. HVTT of SonoVue was shorter than that of Levovist in all groups (P < .001) except the cirrhosis group; in this group, HVTT of the two contrast agents was similar (P = .05). No difference was observed in mean cardiopulmonary transit time for SonoVue or Levovist (9.1 seconds +/- 2.4 [standard error] and 8.4 seconds +/- 2.5, respectively, P = .18). CONCLUSION: HVTT was significantly shorter with SonoVue than with Levovist; there was no significant difference in cardiopulmonary transit time. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16720867&query_hl=1 ER - TY - JFULL T1 - Frequency and implications of pyrazinamide resistance in managing previously treated tuberculosis patients A1 - Louw, GE A1 - Warren, RM A1 - Donald, PR A1 - Murray, MB A1 - Bosman, M A1 - Van Heiden, PD A1 - Young, DB A1 - Victor, TC J1 - INT J TUBERC LUNG D Y1 - 2006/07// VL - 10 SN - 1027-3719 SP - 802 EP - 807 N2 - OBJECTIVE: To determine the extent of pyrazinamide (PZA) resistance in isolates from previously treated patients from the Western Cape, South Africa.DESIGN: Drug-resistant isolates, isolates resistant to one or more drugs other than PZA (PZA resistance is not routinely determined) (n = 127), and drug-susceptible (n = 47) clinical isolates of Mycobacterium tuberculosis from previously treated patients from the Western Cape were phenotypically (BACTEC MGIT 960) and genotypically (pncA gene sequencing) analysed for PZA resistance.RESULTS: MGIT analysis found that 68 of the 127 drug-resistant isolates were PZA-resistant. Nearly all (63/68) PZA-resistant isolates had diverse nucleotide changes scattered throughout the pncA gene, and five PZA-resistant isolates had no pncA mutations. Of the 47 phenotypi-cally susceptible isolates, 46 were susceptible to PZA, while one isolate was PZA-monoresistant (OR = 53.0, 95%Cl = 7.1-396.5). A pncA polymorphism (Thr(114)Met) that did not confer PZA resistance was also identified. PZA resistance was strongly associated with multidrugresistant tuberculosis (MDR-TB).CONCLUSION: An alarmingly high proportion of South African drug-resistant M. tuberculosis isolates are PZA resistant, indicating that PZA should not be relied upon in managing patients with MDR-TB in the Western Cape. A method for the rapid detection of PZA resistance would be beneficial in managing patients with suspected drug resistance. ER - TY - JFULL T1 - Filarial-specific antibody response in east African Bancroftian filariasis: Effects of host infection, clinical disease, and filarial endemicity A1 - Jaoko, WG A1 - Simonsen, PE A1 - Meyrowitsch, DW A1 - Estambale, BBA A1 - Malecela-Lazaro, MN A1 - Michael, E J1 - AM J TROP MED HYG Y1 - 2006/07// VL - 75 SN - 0002-9637 SP - 97 EP - 107 N2 - The effect of host infection, chronic clinical disease, and transmission intensity on the patterns of specific antibody responses in Bancroftian filariasis was assessed by analyzing specific IgG1, IgG2, IgG3, IgG4, and IgE profiles among adults from two communities with high and low Wuchereria bancrofti endemicity. In the high endemicity community, intensities of the measured antibodies were significantly associated with infection status. IgG1, IgG2, and IgE were negatively associated with microfilaria (MF) status, IgG3 was negatively associated with circulating filarial antigen (CFA) status, and IgG4 was positively associated with CFA status. None of the associations were significantly influenced by chronic lymphatic disease status. In contrast, IgG1, IgG2, and IgG4 responses were less vigorous in the low endemicity community and, except for IgG4, did not show any significant associations with MF or CFA status. The IgG3 responses were considerably more vigorous in the low endemicity community than in the high endemicity one. Only IgG4 responses exhibited a rather similar pattern in the two communities, being significantly positively associated with CFA status in both communities. The IgG4:IgE ratios were higher in infection-positive individuals than in infection-negative ones, and higher in the high endemicity community than in the low endemicity one. Overall, these results indicate that specific antibody responses in Bancroftian filariasis are more related to infection status than to chronic lymphatic disease status. They also suggest that community transmission intensity play a dominant but subtle role in shaping the observed response patterns. ER - TY - JFULL T1 - The effects of APOBEC3G on HBV replication A1 - Mohammed, E A1 - Navaratnam, N A1 - Hoare, JM A1 - McGarvey, MJ J1 - J CLIN VIROL Y1 - 2006/07// VL - 36 SN - 1386-6532 SP - S67 EP - S67 ER - TY - JFULL T1 - Elimination of lymphatic filariasis A1 - Michael, E A1 - Malecela-Lazaro, MN A1 - Kazura, JW J1 - LANCET Y1 - 2006/07// VL - 368 SN - 0140-6736 SP - 362 EP - 363 ER - TY - JFULL T1 - Multinucleate giant cells and the control of chemokine secretion in response to Mycobacterium tuberculosis. A1 - Zhu, XW A1 - Friedland, JS J1 - Clin Immunol Y1 - 2006/07// VL - 120 SN - 1521-6616 SP - 10 EP - 20 N2 - Multinucleate giant cells (MGC) are characteristic of tuberculous granulomas, but their function is not well understood. In a comparative study, we investigated regulation of chemokine secretion by MGC generated using 5 microg/ml ConA and 1000 IU/ml IFN-gamma. After 72-h differentiation of MGC cultures, CXCL8, CCL2 and CCL3 concentrations were 9540+/-110 pg/ml, 11190+/-2210 pg/ml and 19440+/-440 pg/ml respectively all significantly higher than in MDM (P<0.01). There was associated increased chemokine gene expression. M.tb stimulation of MGC, MDM and monocytes increased CXCL8 secretion. M.tb increased monocyte CCL2 secretion, whereas MGC and MDM secreted CCL2 constitutively. CXCL10 secretion was induced in M.tb-stimulated MDM and constitutive in MGC. All cell types responded to M.tb with CCL3 secretion. Monocyte chemokine secretion was associated with increased gene expression, whereas M.tb-stimulated MGC principally upregulated CCL3 gene expression. In summary, differentiating MGC express genes for and secrete chemokines which regulate cell influx to sites of infection. Established MGC will contribute to cell recruitment to granuloma, but this may not depend on exposure to the pathogen. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16504587&query_hl=1 ER - TY - JFULL T1 - Comparative investigation of the pathogenicity of three Mycobacterium tuberculosis mutants defective in the synthesis of p-hydroxybenzoic acid derivatives A1 - Stadthagen, G A1 - Jackson, M A1 - Charles, P A1 - Boudou, F A1 - Barilone, N A1 - Huerre, M A1 - Constant, P A1 - Liav, A A1 - Bottova, I A1 - Nigou, J A1 - Brando, T A1 - Puzo, G A1 - Daffe, M A1 - Benjamin, P A1 - Coade, S A1 - Buxton, RS A1 - Tascon, RE A1 - Rae, A A1 - Robertson, BD A1 - Lowrie, DB A1 - Young, DB A1 - Gicquel, B A1 - Griffin, R J1 - MICROBES INFECT Y1 - 2006/07// VL - 8 SN - 1286-4579 SP - 2245 EP - 2253 N2 - p-Hydroxybenzoic acid derivatives (p-HBADs) are glycoconjugates secreted by all Mycobacterium tuberculosis isolates whose contribution to pathogenicity remains to be determined. The pathogenicity of three transposon mutants of M. tuberculosis deficient in the biosynthesis of some or all forms of p-HBADs was studied. Whilst the mutants grew similarly to the wild-type strain in macrophages and C57BL/6 mice, two of the mutants induced a more severe and diffuse inflammation in the lungs. The lack of production of some or all forms of p-HBADs in these two mutants also correlated with an increased secretion of the pro-inflammatory cytokines tumour-necrosis factor alpha, interleukin 6 and interleukin 12 in vivo. We propose that the loss of production of p-HBADs by tubercle bacilli results in their diminished ability to suppress the pro-inflammatory response to infection and that this ultimately provokes extensive pulmonary lesions in the C5713L/6 model of tuberculosis infection. (c) 2006 Elsevier SAS. All rights reserved. ER - TY - JFULL T1 - Distal renal tubular acidosis in association with HIV infection and AIDS (vol 21, pg 1420, 2006) A1 - Laing, CM A1 - Roberts, R A1 - Summers, S A1 - Friedland, JS A1 - Lighstone, L A1 - Unwin, RJ J1 - NEPHROL DIAL TRANSPL Y1 - 2006/07// VL - 21 SN - 0931-0509 SP - 2044 EP - 2044 ER - TY - JFULL T1 - F-18 FDG PET in the diagnosis and monitoring of salmonella vertebral osteomyelitis: a comparison with MRI. A1 - Win, Z A1 - O'Flynn, E A1 - O'Rourke, EJ A1 - Singh, A A1 - Cooke, GS A1 - Friedland, JS A1 - Al-Nahhas, A J1 - Clin Nucl Med Y1 - 2006/07// VL - 31 SN - 0363-9762 SP - 437 EP - 440 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16785821&query_hl=1 ER - TY - JFULL T1 - Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers. A1 - Winston, A A1 - Back, D A1 - Fletcher, C A1 - Robinson, L A1 - Unsworth, J A1 - Tolowinska, I A1 - Schutz, M A1 - Pozniak, AL A1 - Gazzard, B A1 - Boffito, M J1 - AIDS Y1 - 2006/06/26/ VL - 20 SN - 0269-9370 SP - 1401 EP - 1406 N2 - INTRODUCTION: Recent studies have described reduced absorption of certain protease inhibitors when administered with agents known to increase gastric pH. No clinically significant interactions between saquinavir absorption and gastric pH have previously been shown. We evaluated the effect of omeprazole, a proton-pump-inhibitor, on the pharmacokinetics of the recently developed saquinavir-500 mg formulation co-administered with ritonavir. METHODS: Eighteen healthy subjects (n = 6 women and 12 men) received 1000/100 mg saquinavir/ritonavir twice daily in an open-label study for 15 days. On days 11-15, subjects were administered omeprazole 40 mg daily with the morning dose. Serial plasma samples were collected for 12-h pharmacokinetic profiles of saquinavir and ritonavir on days 10 and 15 and safety analysis on days 1, 4, 10, 15 and 29. RESULTS: The geometric mean and 95% confidence interval (CI), for the area under time-concentration curve (AUC; ng h/ml), trough plasma concentration (C trough; ng/ml) and maximum observed plasma concentration (Cmax; ng/ml) of saquinavir were 20599 (14396-29360) and 37511 (28733-48970); 737 (482-1127) and 1521 (1039-2227); 3227 (2370-4393) and 5611 (4507-7710) on days 10 and 15, respectively, with geometric mean ratios of 1.82, 2.06 and 1.75. No significant changes were observed in saquinavir elimination half life, ritonavir pharmacokinetic parameters or in safety laboratory tests. No unexpected adverse events attributed to study medication were noted. CONCLUSIONS: In the presence of omeprazole, total saquinavir plasma exposure is significantly increased (82% increase in AUC). The mechanism of this interaction requires elucidation. Despite the significant increase in saquinavir exposure, no short term toxicities were observed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16791014&query_hl=1 ER - TY - JFULL T1 - Reducing dialysis associated bacteraemia, and recommendations for surveillance in the United Kingdom: prospective study. A1 - George, A A1 - Tokars, JI A1 - Clutterbuck, EJ A1 - Bamford, KB A1 - Pusey, C A1 - Holmes, AH J1 - BMJ Y1 - 2006/06/17/ VL - 332 SN - 1468-5833 SP - 1435 EP - 1435 N2 - PROBLEM: Bacteraemia in dialysis units accounts for major morbidity, mortality, and antibiotic usage. Risk is much greater when lines rather than fistulas are used for haemodialysis. Surveillance is critical for infection control, but no standardised surveillance scheme exists in the United Kingdom. DESIGN: Prospective study in a London dialysis unit of the implementation and applicability of a dialysis associated bacteraemia surveillance scheme developed in the United States and its effect on bacteraemia, antibiotic usage, and admission. SETTING: Hammersmith Hospital dialysis unit, London, where 112 outpatients receive dialysis three times weekly. Between June 2002 and December 2004, 3418 patient months of data were collected. KEY MEASURES FOR IMPROVEMENT: Successful adoption of the scheme and reductions in bacteraemia rates, antibiotic usage, and admission to hospital. Strategy for improvement Embedding the surveillance scheme in the unit's clinical activity. EFFECTS OF CHANGE: Raised awareness of bacteraemia prevention, prudent antibiotic prescribing, and the need for improved provision of vascular access. The scheme required two hours a month of consultant time. Significant downward trends were seen in bacteraemia rates and antibiotic usage: mean rate ratios from quarter to quarter 0.90 (95% confidence interval 0.85 to 0.94) and 0.91 (0.87 to 0.96), respectively. The rate of admission to hospital also showed a significant downward trend, with admissions directly connected to access related infection declining more rapidly: mean rate ratio of successive quarters 0.90 (0.84 to 0.96). The overall proportion of patients dialysed through catheters was significantly higher than in US outpatient centres (62.3% v 29.4%, P < 0.01). Study data were successfully used in a business case to improve access provision. LESSONS LEARNT: Dialysis specific surveillance of bacteraemia is critical to infection control in dialysis units and improving quality of care. Such a scheme could be adopted across the United Kingdom. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16777887&query_hl=1 ER - TY - JFULL T1 - Quality improvement report - Reducing dialysis associated bacteraemia, and recommendations for surveillance in the United Kingdom: prospective study A1 - George, A A1 - Tokars, JI A1 - Clutterbuck, EJ A1 - Bamford, KB A1 - Pusey, C A1 - Holmes, AH J1 - BRIT MED J Y1 - 2006/06/17/ VL - 332 SN - 0959-8146 SP - 1435 EP - 1437 N2 - Problem Bacteraemia in dialysis units accounts for major morbidity, mortality and antibiotic usage. Risk is much greater when lines rather than fistulas are used for haemodialysis. Surveillance is critical for infection control, but no standardised surveillance scheme exists in die United Kingdom.Design Prospective study in a London dialysis unit of the implementation and applicability of a dialysis associated bacteraemia surveillance scheme developed in the United States and its effect on bacteraemia, antibiotic usage, and admission.Setting Hammersmith Hospital dialysis unit, London, where 112 outpatients receive dialysis three times weekly. Between June 2002 and December 2004, 3418 patient months of data were collected.Key measures for improvement Successful adoption of the scheme and reductions in bacteraemia rates, antibiotic usage, and admission to hospital.Strategy for improvement Embedding the surveillance scheme in the unit's clinical activity.Effects of change Raised awareness of bacteraemia prevention, prudent antibiotic prescribing, and the need for improved provision of vascular access. The scheme required two hours a month of consultant time. Significant downward trends were seen in bacteraemia rates and antibiotic usage: mean rate ratios from quarter to quarter 0.90 (95% confidence interval 0.85 to 0.94) and 0.91 (0.87 to 0.96), respectively The rate of admission to hospital also showed a significant downward trend, with admissions directly connected to access related infection declining more rapidly: mean rate ratio Of Successive quarters 0.90 (0.84 to 0.96).The overall proportion of patients dialysed through catheters was significantly higher than in US outpatient centres (62.3% v 29.4%, P < 0.01). Study data were successfully, used in a business case to improve access provision.Lessons learnt Dialysis specific surveillance of bacteraemia is critical to infection control in dialysis units and improving quality of care. Such a scheme could be adopted across the United Kingdom. ER - TY - JFULL T1 - Functional significance of factor H binding to Neisseria meningitidis. A1 - Schneider, MC A1 - Exley, RM A1 - Chan, H A1 - Feavers, I A1 - Kang, YH A1 - Sim, RB A1 - Tang, CM J1 - J Immunol Y1 - 2006/06/15/ VL - 176 SN - 0022-1767 SP - 7566 EP - 7575 N2 - Neisseria meningitidis is an important cause of septicemia and meningitis. To cause disease, the bacterium must successfully survive in the bloodstream where it has to avoid being killed by host innate immune mechanisms, particularly the complement system. A number of pathogenic microbes bind factor H (fH), the negative regulator of the alternative pathway of complement activation, to promote their survival in vivo. In this study, we show that N. meningitidis binds fH to its surface. Binding to serogroups A, B, and C N. meningitidis strains was detected by FACS and Far Western blot analysis, and occurred in the absence of other serum factors such as C3b. Unlike Neisseria gonorrhoeae, binding of fH to N. meningitidis was independent of sialic acid on the bacterium, either as a component of its LPS or its capsule. Characterization of the major fH binding partner demonstrated that it is a 33-kDa protein; examination of insertion mutants showed that porins A and B, outer membrane porins expressed by N. meningitidis, do not contribute significantly to fH binding. We examined the physiological consequences of fH bound to the bacterial surface. We found that fH retains its activity as a cofactor of factor I when bound to the bacterium and contributes to the ability of N. meningitidis to avoid complement-mediated killing in the presence of human serum. Therefore, the recruitment of fH provides another mechanism by which this important human pathogen evades host innate immunity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16751403&query_hl=1 ER - TY - JFULL T1 - Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin. A1 - Maertens, GN A1 - Cherepanov, P A1 - Engelman, A J1 - J Cell Sci Y1 - 2006/06/15/ VL - 119 SN - 0021-9533 SP - 2563 EP - 2571 N2 - Transcriptional co-activator p75 is implicated in human cancer, autoimmunity and replication of human immunodeficiency virus type 1 (HIV-1) as a dominant integrase-interacting protein. Although characterized as chromatin associated, the normal biological role(s) of p75 remains fairly unclear. To gain insight into p75 function, we have characterized its cellular binding partners and report that JPO2, a recently identified Myc-binding protein, associates with p75 in vitro and in vivo. The pseudo HEAT repeat analogous topology (PHAT) domain of p75, which mediates its interaction with integrase, also mediates the interaction with JPO2, and recombinant integrase protein competes with JPO2 protein for binding to p75 in vitro. JPO2 binds p75 through a 61-residue (amino acids 58-119) region that is distinct from its Myc-interacting domain. In cells, JPO2 and p75 co-localize throughout the cell cycle, and both proteins concentrate on condensed chromosomes during mitosis. Strikingly, the association of JPO2 with chromatin strictly depends upon p75, similar to that of ectopically expressed integrase. Also similar to its effect on integrase, p75 stabilizes intracellular steady-state levels of JPO2 protein. Our results suggest a role for p75 in the Myc regulatory network, and indicate that p75 is a general adaptor protein tethering divergent factors to chromatin through its versatile integrase-binding domain. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16735438&query_hl=1 ER - TY - JFULL T1 - Role of microbubble ultrasound contrast agents in the non-invasive assessment of chronic hepatitis C-related liver disease. A1 - Grier, S A1 - Lim, AK A1 - Patel, N A1 - Cobbold, JF A1 - Thomas, HC A1 - Cox, IJ A1 - Taylor-Robinson, SD J1 - World J Gastroenterol Y1 - 2006/06/14/ VL - 12 SN - 1007-9327 SP - 3461 EP - 3465 N2 - Patients who are chronically infected with the hepatitis C virus often develop chronic liver disease and assessment of the severity of liver injury is required prior to considering viral eradication therapy. This article examines the various assessment methods currently available from gold standard liver biopsy to serological markers and imaging. Ultrasound is one of the most widely used imaging modalities in clinical practice and is already a first-line diagnostic tool for liver disease. Microbubble ultrasound contrast agents allow higher resolution images to be obtained and functional assessments of microvascular change to be carried out. The role of these agents in quantifying the state of hepatic injury is discussed as a viable method of determining the stage and grade of liver disease in patients with hepatitis C. Although currently confined to specialist centres, the availability of microbubble contrast-enhanced ultrasound will inevitably increase in the clinical setting. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16773702&query_hl=1 ER - TY - JFULL T1 - Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence. A1 - Frodsham, AJ A1 - Zhang, L A1 - Dumpis, U A1 - Taib, NA A1 - Best, S A1 - Durham, A A1 - Hennig, BJ A1 - Hellier, S A1 - Knapp, S A1 - Wright, M A1 - Chiaramonte, M A1 - Bell, JI A1 - Graves, M A1 - Whittle, HC A1 - Thomas, HC A1 - Thursz, MR A1 - Hill, AV J1 - Proc Natl Acad Sci U S A Y1 - 2006/06/13/ VL - 103 SN - 0027-8424 SP - 9148 EP - 9153 N2 - Persistent hepatitis B virus infection is a major risk factor for hepatocellular carcinoma, the most frequent cancer in some developing countries. Up to 95% of those infected at birth and 15% of those infected after the neonatal period fail to clear hepatitis B virus, together resulting in approximately 350 million persistent carriers worldwide. Via a whole genome scan in Gambian families, we have identified a major susceptibility locus as a cluster of class II cytokine receptor genes on chromosome 21q22. Coding changes in two of these genes, the type I IFN receptor gene, IFN-AR2, and the IL-10RB gene that encodes a receptor chain for IL-10-related cytokines including the IFN-lambdas, are associated with viral clearance (haplotype P value = 0.0003), and in vitro assays support functional roles for these variants in receptor signaling. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16757563&query_hl=1 ER - TY - JFULL T1 - Can patient delivered partner therapy help us regain control of sexually transmitted infections in the UK? A1 - White, PJ A1 - Golden, MR A1 - Turner, KM A1 - Mercer, CH A1 - Cassell, JA A1 - Ward, H A1 - Garnett, GP J1 - SEX TRANSM INFECT Y1 - 2006/06// VL - 82 SN - 1368-4973 SP - A2 EP - A2 ER - TY - JFULL T1 - Expression of indoleamine 2,3-dioxygenase (IDO) by endothelial cells: implications for the control of alloresponses. A1 - Beutelspacher, SC A1 - Tan, PH A1 - McClure, MO A1 - Larkin, DF A1 - Lechler, RI A1 - George, AJ J1 - Am J Transplant Y1 - 2006/06// VL - 6 SN - 1600-6135 SP - 1320 EP - 1330 N2 - Indoleamine 2,3-dioxygenase (IDO) is an important enzyme in the regulation of immune responses; cells that express IDO can suppress T-cell responses and promote tolerance. Because of the critical role of endothelial cells in graft rejection, we have investigated the role of IDO expression by vascular endothelial cells and its consequence on immunoregulation. We compared the expression of IDO by primary human umbilical vein endothelial cells (HUVECs), human saphenous vein endothelial cells (HSVECs) and arterially derived endothelial cells using reverse transcriptase PCR, Western blotting and assays for enzymatic activity. In HUVECs IDO is upregulated by incubation with cytokines or in mycoplasma-infected cells. On the other hand HSVECs and arterially derived endothelial cells express little IDO, which is poorly upregulated upon activation (except by mycoplasma). Inhibition of IDO activity improved the ability of HUVECs to stimulate allogeneic T-cell responses. If either HUVECs or HSVECs are transfected with the gene encoding IDO, then they are incapable of stimulating allogeneic T-cell responses and induce anergy in allospecific T cells (which can also act as regulatory cells). The variable expression of IDO in different endothelial cells is important not only in understanding the role of endothelial cells in the regulation of graft rejection, but also as a potential therapeutic strategy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16686756&query_hl=1 ER - TY - JFULL T1 - Vaccinia virus strain Western Reserve protein B14 is an intracellular virulence factor. A1 - Chen, RA A1 - Jacobs, N A1 - Smith, GL J1 - J Gen Virol Y1 - 2006/06// VL - 87 SN - 0022-1317 SP - 1451 EP - 1458 N2 - A characterization of the B14R gene from Vaccinia virus (VACV) strain Western Reserve (WR) is presented. Computational analyses of the B14R gene indicated high conservation in orthopoxviruses but no orthologues outside the Poxviridae. To characterize the B14 protein, the B14R gene was expressed in Escherichia coli and recombinant protein was purified and used to generate a rabbit polyclonal antiserum. This antiserum recognized a 15 kDa cytoplasmic protein in mammalian cells that were transfected with the B14R gene or infected with VACV WR, but not from cells infected with a VACV mutant (vdeltaB14) from which the B14R gene was deleted. Compared to wild-type and revertant virus controls, vdeltaB14 had normal growth kinetics in cell culture. The virulence of vdeltaB14 was assessed in two in vivo models. Mice infected intranasally with vdeltaB14 had similar weight loss compared to the controls, but in C57BL/6 mice infected intradermally vdeltaB14 induced a smaller lesion size compared with controls. Moreover, intradermal infection with vdeltaB14 caused an increased infiltration of cells into the infected lesion despite the smaller lesion size. Therefore, B14 is an intracellular protein that is non-essential for virus replication in cell culture but contributes to virus virulence in vivo and affects the host response to infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16690909&query_hl=1 ER - TY - JFULL T1 - Magnetic resonance and ultrasound techniques for the evaluation of hepatic fibrosis. A1 - Cobbold, J A1 - Lim A A1 - Wylezinska M A1 - Cunningham C A1 - Crossey M A1 - Thomas H A1 - Patel N A1 - Cox J A1 - Taylor-Robinson J1 - Hepatology Y1 - 2006/06// IS - 6 VL - 43 SP - 1401 EP - 1402 UR - http://www3.interscience.wiley.com/cgi-bin/fulltext/112636849/PDFSTART ER - TY - JFULL T1 - Vaccinia virus kelch protein A55 is a 64 kDa intracellular factor that affects virus-induced cytopathic effect and the outcome of infection in a murine intradermal model. A1 - Beard, PM A1 - Froggatt, GC A1 - Smith, GL J1 - J Gen Virol Y1 - 2006/06// VL - 87 SN - 0022-1317 SP - 1521 EP - 1529 N2 - The vaccinia virus (VACV) protein A55 is a BTB/kelch protein with a broad-complex, tramtrack and bric-a-brac (BTB) domain in the N-terminal region and five kelch repeats in the C-terminal half. The BTB/kelch subgroup of the kelch superfamily of proteins has been associated with a wide variety of functions including regulation of the cytoskeleton. VACV contains three genes predicted to encode BTB/kelch proteins: A55R, F3L and C2L. The A55R gene product has been identified as an intracellular protein of 64 kDa that is expressed late in infection. A VACV strain lacking 93.6% of the A55R open reading frame (vdeltaA55) was constructed and found to have an unaltered growth rate in vivo but a different plaque morphology and cytopathic effect, as well as reduced development of VACV-induced Ca2+-independent cell/extracellular matrix adhesion. In a murine intradermal model of VACV infection, a virus lacking the A55R gene induced larger lesions than wild-type and revertant control viruses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16690916&query_hl=1 ER - TY - JFULL T1 - Site-specific PEGylation of native disulfide bonds in therapeutic proteins. A1 - Shaunak, S A1 - Godwin, A A1 - Choi, JW A1 - Balan, S A1 - Pedone, E A1 - Vijayarangam, D A1 - Heidelberger, S A1 - Teo, I A1 - Zloh, M A1 - Brocchini, S J1 - Nat Chem Biol Y1 - 2006/06// VL - 2 SN - 1552-4450 SP - 312 EP - 313 N2 - Native disulfide bonds in therapeutic proteins are crucial for tertiary structure and biological activity and are therefore considered unsuitable for chemical modification. We show that native disulfides in human interferon alpha-2b and in a fragment of an antibody to CD4(+) can be modified by site-specific bisalkylation of the two cysteine sulfur atoms to form a three-carbon PEGylated bridge. The yield of PEGylated protein is high, and tertiary structure and biological activity are retained. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16633351&query_hl=1 ER - TY - JFULL T1 - Reversal of neurochemical changes and pain-related behavior in a model of neuropathic pain using modified lentiviral vectors expressing GDNF. A1 - Pezet, S A1 - Krzyzanowska, A A1 - Wong, LF A1 - Grist, J A1 - Mazarakis, ND A1 - Georgievska, B A1 - McMahon, SB J1 - Mol Ther Y1 - 2006/06// VL - 13 SN - 1525-0016 SP - 1101 EP - 1109 N2 - In this study, we evaluated the possible use of lentiviral vectors in the treatment of neuropathic pain. We chose to administer GDNF-expressing vectors because of the known beneficial effect of this trophic factor in alleviation of neuropathic pain in adult rodents. Lentiviral vectors expressing either GDNF or control, green fluorescent protein or beta-galactosidase, were injected unilaterally into the spinal dorsal horn 5 weeks before a spinal nerve ligation was induced (or sham surgery for the controls). We observed that intraspinally administered lentiviral vectors resulted in a large and sustained expression of transgenes in both neurons and glial cells. Injection of GDNF-expressing viral vectors induced a significant reduction of ATF-3 up-regulation and IB4 down-regulation in damaged DRG neurons. In addition, it produced a partial but significant reversal of thermal and mechanical hyperalgesia observed following the spinal nerve ligation. In conclusion, our study suggests that lentiviral vectors are efficient tools to induce a marked and sustained expression of trophic factors in specific areas of the CNS and can, even if with some limitations, be efficient in the treatment of neuropathic pain. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16504588&query_hl=1 ER - TY - JFULL T1 - Neurocysticercal antigens stimulate chemokine secretion from human monocytes via an NF-kappaB-dependent pathway. A1 - Uddin, J A1 - Gonzalez, AE A1 - Gilman, RH A1 - Garcia, HH A1 - Verastegui, M A1 - Moore, LJ A1 - Evans, CA A1 - Read, RC A1 - Friedland, JS J1 - Microbes Infect Y1 - 2006/06// VL - 8 SN - 1286-4579 SP - 1732 EP - 1740 N2 - Neurocysticercosis, infection with larval Taenia solium, is a common, serious neuroparasitic infection. Larval degeneration results in inflammatory cell influx and granuloma formation which leads to clinical symptomatology. The role of chemokines in such cell influx is unknown. We demonstrate that monocyte stimulation by T. solium larval antigen (TsAg) results in a differential profile of CXCL8/IL-8 (146.5+/-8.5ng/ml after 24h), CCL2/MCP-1 (267+/-4 ng/ml after 48 h) and CCL3/MIP-1alpha (1.72+/-0.43 ng/ml after 8 h) secretion. There was coordinate mRNA accumulation reaching maximum at 1h for CCL3 and 2 h for CXCL8 and CCL2. TsAg induced maximal nuclear binding of p65, p50 and c-rel subunits of the transcriptional regulator NF-kappaB by 2 h. IkappaBalpha but not IkappaBbeta was degraded within 10 min before resynthesis by 2 h. Pre-treatment with the broad-spectrum NF-kappaB inhibitor pyrrolidine dithiocarbamate caused complete abrogation of TsAg-induced CCL2 secretion (p=0.005) and 91% reduction of CXCL8 secretion (p=0.0003). TsAg was unable to induce CXCL8 promoter activity in Toll-like receptor (TLR)-2 or TLR-4/MD-2 transfected HeLa cells in the absence of lectins or other adaptor molecules. In summary, our data demonstrate that TsAg induces chemokine secretion via specific pathways dependent on NF-kappaB but not TLR-4/TLR-2, and indicate a potential mechanism whereby larval degeneration results in brain inflammation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16815071&query_hl=1 ER - TY - JFULL T1 - An absence of reactive oxygen species improves the resolution of lung influenza infection. A1 - Snelgrove, RJ A1 - Edwards, L A1 - Rae, AJ A1 - Hussell, T J1 - Eur J Immunol Y1 - 2006/06// VL - 36 SN - 0014-2980 SP - 1364 EP - 1373 N2 - Three influenza virus pandemics occurred in the last century, in 1918 killing 40-50 million people. In the absence of strain-specific vaccines, with potential resistance to antivirals and the threat of an imminent pandemic, strategies that alleviate symptoms are a priority. Reactive oxygen species are potent antimicrobial agents but cause immunopathology when produced in excess. Mice lacking a functional phagocyte NADPH oxidase (Cybb tm1 mice) or treated with the metalloporphyrin antioxidant manganese (III) tetrakis (N-ethyl pyridinium-2-yl) porpyhrin (MnTE-2-PyP) show heightened inflammatory infiltrates in their airways in response to pulmonary influenza infection, with augmented macrophage populations and a Th1-skewed T cell infiltrate. Underlying this exuberant macrophage response was a significant reduction in apoptosis and down-regulation of the myeloid inhibitory molecule CD200. Both, Cybb tm1 and MnTE-2-PyP-treated mice exhibited a reduced influenza titer in the lung parenchyma. Inflammatory infiltrate into the lung parenchyma was markedly reduced and lung function significantly improved. Manipulation of the homeostatic control of myeloid cells by inflammatory mediators therefore represents a novel therapeutic strategy in the treatment of influenza virus infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16703568&query_hl=1 ER - TY - JFULL T1 - Commentary. A1 - Adams, EJ A1 - Turner, KM J1 - Sex Transm Infect Y1 - 2006/06// VL - 82 SN - 1368-4973 SP - 201 N2 - L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16731667&query_hl=1 ER - TY - JFULL T1 - Deep-seated resistance in relapsed paratyphoid fever. A1 - Cooke, GS A1 - Cooke, FJ A1 - Stone, M A1 - Turner, K A1 - Al-Nahhas, A A1 - Win, Z A1 - Wain, J A1 - Rogers, TR A1 - Friedland, JS A1 - Bamford, KB J1 - Clin Infect Dis Y1 - 2006/06/01/ VL - 42 SN - 1537-6591 SP - e92 EP - e94 N2 - We describe a case of relapsed paratyphoid fever in which the isolate had reduced susceptibility to ciprofloxacin due to a rare mutation within the gyrA gene. 18fluorodeoxyglucose positron emission tomography scanning identified deep-seated infection including unsuspected aortitis and highlights the utility of novel imaging techniques to improve our understanding and treatment of this disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16652303&query_hl=1 ER - TY - JFULL T1 - The clinical pharmacology of antiretrovirals in development. A1 - Winston, A A1 - Mallon, PW A1 - Boffito, M J1 - Expert Opin Drug Metab Toxicol Y1 - 2006/06// VL - 2 SN - 1742-5255 SP - 447 EP - 458 N2 - Drugs in development for the management of HIV type 1 (HIV-1) infection include agents in existing classes and agents of novel classes. Of existing classes, new protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors are in development. Novel therapeutic approaches include the development of chemokine receptor (CCR)5 antagonists, integrase inhibitors and maturation inhibitors. CCR5 antagonists are thought to inhibit HIV-1 entry into host cells by occupying a specific site on the CCR5 receptor, preventing attachment of the HIV-1 envelope protein gp120. Integrase inhibitors are small synthetically prepared molecules that block RNA/DNA interactions and modify protein or enzyme synthesis. Data on the pharmacokinetics and pharmacodynamics of these new antiretroviral agents continue to generate interest. This review reports the known data on the pharmacokinetics of experimental antiretrovirals, and describe the main drug-drug interactions studied so far. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16863445&query_hl=1 ER - TY - JFULL T1 - The clinical implications of antiretroviral pharmacogenomics. A1 - Fox, J A1 - Boffito, M A1 - Winston, A J1 - Pharmacogenomics Y1 - 2006/06// VL - 7 SN - 1462-2416 SP - 587 EP - 596 N2 - Heterogeneity exists in the effectiveness and toxic effects of antiretroviral agents between individuals and populations. Although patient-related clinical variables such as age, sex and ethnic origin have been associated with drug response, inherited predispositions may have a significant effect on treatment outcome. The role of host and pathogen pharmacogenomics is gaining increasing interest in the field of both antiretrovirals in development, such as the chemokine (C-C motif) receptor 5 (CCR5) inhibitors, and in established therapies where toxicity and efficacy may be predicted. Despite numerous studies available in the literature, the interpretation of the relationship between genetic polymorphisms and clinical outcomes is often posed with many confounding variables, making clinical interpretations of these results difficult. This review summarizes the key findings in the growing knowledge between human genetics and response to antiretroviral drugs and how these findings may be effectively applied in a clinical context. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16753006&query_hl=1 ER - TY - JFULL T1 - Clinical Effects of Heliox Administration for Acute Bronchiolitis in Young Infants (eLetter). A1 - Chowdhury M M M A1 - Reus E A1 - Habibi P J1 - Chest Y1 - 2006/05/23/ ER - TY - JFULL T1 - Current and future applications of magnetic resonance imaging and spectroscopy of the brain in hepatic encephalopathy. A1 - Grover, VP A1 - Dresner, MA A1 - Forton, DM A1 - Counsell, S A1 - Larkman, DJ A1 - Patel, N A1 - Thomas, HC A1 - Taylor-Robinson, SD J1 - World J Gastroenterol Y1 - 2006/05/21/ VL - 12 SN - 1007-9327 SP - 2969 EP - 2978 N2 - Hepatic encephalopathy (HE) is a common neuro-psychiatric abnormality, which complicates the course of patients with liver disease and results from hepatocellular failure and/or portosystemic shunting. The manifestations of HE are widely variable and involve a spectrum from mild subclinical disturbance to deep coma. Research interest has focused on the role of circulating gut-derived toxins, particularly ammonia, the development of brain swelling and changes in cerebral neurotransmitter systems that lead to global CNS depression and disordered function. Until recently the direct investigation of cerebral function has been difficult in man. However, new magnetic resonance imaging (MRI) techniques provide a non-invasive means of assessment of changes in brain volume (coregistered MRI) and impaired brain function (fMRI), while proton magnetic resonance spectroscopy (1H MRS) detects changes in brain biochemistry, including direct measurement of cerebral osmolytes, such as myoinositol, glutamate and glutamine which govern processes intrinsic to cellular homeostasis, including the accumulation of intracellular water. The concentrations of these intracellular osmolytes alter with hyperammonaemia. MRS-detected metabolite abnormalities correlate with the severity of neuropsychiatric impairment and since MR spectra return towards normal after treatment, the technique may be of use in objective patient monitoring and in assessing the effectiveness of various treatment regimens. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16718775&query_hl=1 ER - TY - JFULL T1 - Underdosing of antiretrovirals in UK and Irish children with HIV ias an example of problems in presrcibing medicines to children, 1997-2005: cohort study A1 - Menson, EN A1 - Walker, AS A1 - Sharland, M A1 - Wells, C A1 - Tudor-Williams, G A1 - Riordan, FA A1 - Lyall, EG A1 - Gibb, DM A1 - Collaborative HIV Paediatric Study Steering Committee J1 - Brit Med J Y1 - 2006/05/20/ IS - 7551 VL - 332 SN - 0959-535X SP - 1183 EP - 1187 ER - TY - JFULL T1 - Sex work practices and condom use in female sex workers in Sydney. A1 - J Fox A1 - Tideman RL A1 - Gilmour S A1 - Marks C A1 - van Beek I J1 - Int J STD AIDS Y1 - 2006/05/17/ ER - TY - JFULL T1 - Roles of the alternative complement pathway and C1q during innate immunity to Streptococcus pyogenes. A1 - Yuste, J A1 - Ali, S A1 - Sriskandan, S A1 - Hyams, C A1 - Botto, M A1 - Brown, JS J1 - J Immunol Y1 - 2006/05/15/ VL - 176 SN - 0022-1767 SP - 6112 EP - 6120 N2 - Complement is important for innate immunity to the common bacterial pathogen Streptococcus pyogenes, but the relative importance of the alternative and classical pathways has not been investigated. Using mice and human serum deficient in either C1q, the first component of the classical pathway, or factor B, an important component of the alternative pathway, we have investigated the role of both pathways for innate immunity to S. pyogenes. C3b deposition on four different strains of S. pyogenes was mainly dependent on factor B. As a consequence opsonophagocytosis of S. pyogenes was reduced in serum from factor B-deficient mice, and these mice were very susceptible to S. pyogenes infection. In contrast, C3b deposition was not dependent on C1q for two of the strains investigated, H372 and H305, yet opsonophagocytosis of all four S. pyogenes strains was impaired in serum deficient in C1q. Furthermore, infection in C1q-deficient mice with strain H372 resulted in a rapidly progressive disease associated with large numbers of bacteria in target organs. These results demonstrate the important role of the alternative pathway and C1q for innate immunity to S. pyogenes and suggest that C1q-mediated innate immunity to at least some strains of S. pyogenes may involve mechanisms that are independent of C3b on the bacteria. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16670320&query_hl=1 ER - TY - JFULL T1 - Quantifying lymphocyte kinetics in vivo using carboxyfluorescein diacetate succinimidyl ester (CFSE). A1 - Asquith, B A1 - Debacq, C A1 - Florins, A A1 - Gillet, N A1 - Sanchez-Alcaraz, T A1 - Mosley, A A1 - Willems, L J1 - Proc Biol Sci Y1 - 2006/05/07/ VL - 273 SN - 0962-8452 SP - 1165 EP - 1171 N2 - The cytoplasmic dye carboxyfluorescein diacetate succinimidyl ester (CFSE) is used to quantify cell kinetics. It is particularly important in studies of lymphocyte homeostasis where its labelling of cells irrespective of their stage in the cell cycle makes it preferable to deuterated glucose and BrdU, which only label dividing cells and thus produce unrepresentative results. In the past, experiments have been limited by the need to obtain a clear separation of CFSE peaks forcing scientists to adopt a strategy of in vitro labelling of cells followed by their injection into the host. Here we develop a framework for analysis of in vivo CFSE labelling data. This enables us to estimate the rate of proliferation and death of lymphocytes in situ, and thus represents a considerable advance over current procedures. We illustrate this approach using in vivo CFSE labelling of B lymphocytes in sheep. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16600897&query_hl=1 ER - TY - JFULL T1 - The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. 1986. A1 - Townsend, AR A1 - Rothbard, J A1 - Gotch, FM A1 - Bahadur, G A1 - Wraith, D A1 - McMichael, AJ J1 - J Immunol Y1 - 2006/05/01/ VL - 176 SN - 0022-1767 SP - 5141 EP - 5150 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16621977&query_hl=1 ER - TY - JFULL T1 - Intradermal immune response after infection with Vaccinia virus. A1 - Jacobs, N A1 - Chen, RA A1 - Gubser, C A1 - Najarro, P A1 - Smith, GL J1 - J Gen Virol Y1 - 2006/05// VL - 87 SN - 0022-1317 SP - 1157 EP - 1161 N2 - Although Vaccinia virus (VACV) was used to eradicate smallpox by dermal vaccination, there is little information available about the immune response induced at the vaccination site. Previously, an intradermal murine model that mimics smallpox vaccination was established. Here, this model was used to investigate which leukocytes are recruited to the infected lesion and what are the kinetics of recruitment. Data presented show that VACV infection induced the infiltration of macrophages, followed by granulocytes and lymphocytes. Up to 4 days post-infection, the major lymphocyte population was TCRgammadelta T cells, but thereafter, there was a large recruitment of CD4(+) and CD8(+) T cells. Interestingly, the majority of T cells expressed the natural killer-cell marker DX5. This report is the first to characterize the local immune response sequence to VACV infection and represents a benchmark against which the responses induced by genetically modified VACVs may be compared. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16603516&query_hl=1 ER - TY - JFULL T1 - Does alpha+-thalassaemia protect against malaria? A1 - Pasvol, G J1 - PLoS Med Y1 - 2006/05// VL - 3 SN - 1549-1676 SP - e235 EP - e235 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16646635&query_hl=1 ER - TY - JFULL T1 - Distal renal tubular acidosis in association with HIV infection and AIDS. A1 - Laing, CM A1 - Roberts, R A1 - Summers, S A1 - Friedland, JS A1 - Lightstone, L A1 - Lighstone, L A1 - Unwin, RJ J1 - Nephrol Dial Transplant Y1 - 2006/05// VL - 21 SN - 0931-0509 SP - 1420 EP - 1422 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16449292&query_hl=1 ER - TY - JFULL T1 - Invasive disease and toxic shock due to zoonotic Streptococcus suis: an emerging infection in the East? A1 - Sriskandan, S A1 - Slater, JD J1 - PLoS Med Y1 - 2006/05// VL - 3 SN - 1549-1676 SP - e187 EP - e187 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16594733&query_hl=1 ER - TY - JFULL T1 - Transmission of Mycobacterium tuberculosis undetected by tuberculin skin testing. A1 - Anderson, ST A1 - Williams, AJ A1 - Brown, JR A1 - Newton, SM A1 - Simsova, M A1 - Nicol, MP A1 - Sebo, P A1 - Levin, M A1 - Wilkinson, RJ A1 - Wilkinson, KA J1 - Am J Respir Crit Care Med Y1 - 2006/05/01/ VL - 173 SN - 1073-449X SP - 1038 EP - 1042 N2 - RATIONALE: The development of tuberculin skin test (TST) positivity following infection by Mycobacterium tuberculosis is not invariable and may depend on bacillary as well as host factors. OBJECTIVES: First, to compare the diagnostic performance of the TST and a form of in vitro IFN-gamma release assay (IFNGRA) in the circumstances of a contact investigation prompted by an unusually severe index case of infectious pulmonary tuberculosis. Second, to investigate the ability of the strain of M. tuberculosis responsible to induce cytokine secretion from monocytes in vitro. METHODS: A routine TST-based tuberculosis-contact screening procedure supplemented by the use of an "in house" IFNGRA that assays the T-cell response to the M. tuberculosis-specific antigens ESAT-6, CFP-10 (presented as a fusion protein within the inactivated adenylate cyclase of Bordetella pertussis), and purified protein derivative of M. tuberculosis. Isolation and genetic typing of the strain of M. tuberculosis responsible, and investigation of its ability to induce cytokine secretion from monocytes in vitro. MEASUREMENTS AND MAIN RESULTS: TST screening suggested a low rate of transmission with just 2/75 unequivocally positive responses. By contrast, the IFNGRA suggested an infection rate of 16/75 (22%). When compared with two reference strains of M. tuberculosis (H37Rv and CDC1551), the outbreak strain induced lower levels of tumor necrosis factor-alpha and interleukin-12p40 (p < 0.04), cytokines associated with the development of delayed-type hypersensitivity. CONCLUSIONS: These data suggest that infection by M. tuberculosis can be undetected by TST, and that this may partially relate to strain differences in immunogenicity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16456140&query_hl=1 ER - TY - JFULL T1 - Differential chemokine expression following respiratory virus infection reflects Th1- or Th2-biased immunopathology. A1 - Culley, FJ A1 - Pennycook, AM A1 - Tregoning, JS A1 - Hussell, T A1 - Openshaw, PJ J1 - J Virol Y1 - 2006/05// VL - 80 SN - 0022-538X SP - 4521 EP - 4527 N2 - Respiratory syncytial virus (RSV) is a major viral pathogen of infants that also reinfects adults. During RSV infection, inflammatory host cell recruitment to the lung plays a central role in determining disease outcome. Chemokines mediate cell recruitment to sites of inflammation and are influenced by, and influence, the production of cytokines. We therefore compared chemokine production in a mouse model of immunopathogenic RSV infection in which either Th1 or Th2 immunopathology is induced by prior sensitization to individual RSV proteins. Chemokine expression profiles were profoundly affected by the nature of the pulmonary immunopathology: "Th2" immunopathology in BALB/c mice was associated with increased and prolonged expression of CCL2 (MCP-1), CXCL10 (IP-10), and CCL11 (eotaxin) starting within 24 h of challenge. C57BL/6 mice with "Th2" pathology (enabled by a deficiency of CD8+ cells) also showed increased CCL2 production. No differences in chemokine receptor expression were detected. Chemokine blockers may therefore be of use for children with bronchiolitis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16611912&query_hl=1 ER - TY - JFULL T1 - The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides (reprinted from Cell, vol. 44, pg. 959-968, yr. 1986) A1 - Townsend, ARM A1 - Rothbard, J A1 - Gotch, FM A1 - Bahadur, G A1 - Wraith, D A1 - McMichael, AJ J1 - J IMMUNOL Y1 - 2006/05/01/ VL - 176 SN - 0022-1767 SP - 5141 EP - 5150 N2 - A proportion of cytotoxic T lymphocytes (CTL) responding to infection by influenza recognize target cells that express the viral nucleoprotein. Recent work showed that CTL can recognize short overlapping regions of large nucleoprotein fragments expressed in transfected L cells. This led to the suggestion that CTL recognize segmental epitopes of denatured or degraded proteins in a similar way to helper T cells. One corollary of this idea Is that CTL should recognize appropriate short peptides on the target cell surface. We demonstrate that the epitopes of nucleoprotein recognized by CTL in association with class I molecules of the major histocompatibility complex in both mouse and man can be defined with short synthetic peptides derived from the nucleoprotein sequence. ER - TY - JFULL T1 - Analysis of p53 mutations for a mutational signature in human intrahepatic cholangiocarcinoma. A1 - Khan, SA A1 - Taylor-Robinson, SD A1 - Carmichael, PL A1 - Habib, N A1 - Lemoine, NR A1 - Thomas, HC J1 - Int J Oncol Y1 - 2006/05// VL - 28 SN - 1019-6439 SP - 1269 EP - 1277 N2 - Cholangiocarcinoma development may be related to cholangiocyte DNA damage from genotoxic compounds in bile. We have previously shown that human biliary tissue is exposed to genotoxic agents, as evidenced by the presence of DNA adducts. Establishing the presence of a 'mutational signature' in tumour suppressor genes from tumour tissue provides a means of linking cause and effect in human cancer. Inactivation of p53, known to have 'hot-spots' for particular chemical carcinogens, has previously been linked to human cholangiocarcinoma. However, previous p53 studies have focused on exons 5-8, potentially missing gene alterations at other sites. This study examined the putative link between environmental carcinogens and intrahepatic cholangiocarcinoma by analysing DNA from 31 patients for complete p53 mutational signatures, using single strand conformational polymorphism and polymerase chain reaction. All mutations found were compared to known p53 mutations in cholangiocarcinoma and to mutations induced by environmental mutagens, as described in p53 databases. Five non-silent p53 mutations were found, including three new frameshift mutations and two new intron mutations which have not previously been reported in cholangiocarcinoma. Two frameshifts were due to deletions and the third due to an insertion in exon 5. There was no predominant mutational spectrum amongst the set of cholangiocarcinoma samples studied, or on combining these mutations with the dataset of known p53 mutations in cholangiocarcinoma. Several reasons may explain this, including lack of data outside exons 5-8, bias in mutation reporting, the involvement of mutations in non-coding regions or genes other than p53, or the possibility that there is no carcinogenic specific agent and therefore no signature. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16596244&query_hl=1 ER - TY - JFULL T1 - Mathematical models and lymphatic filariasis control: endpoints and optimal interventions. A1 - Michael, E A1 - Malecela-Lazaro, MN A1 - Kabali, C A1 - Snow, LC A1 - Kazura, JW J1 - Trends Parasitol Y1 - 2006/05// VL - 22 SN - 1471-4922 SP - 226 EP - 233 N2 - The current global initiative to eliminate lymphatic filariasis is a major renewed commitment to reduce or eliminate the burden of one of the major helminth infections from resource-poor communities of the world. Mathematical models of filariasis transmission can serve as an effective tool for guiding the scientific development and management of successful community-level intervention programmes by acting as analytical frameworks for integrating knowledge regarding parasite transmission dynamics with programmatic factors. However, the power of these tools for supporting control interventions will be realized fully only if researchers address the current uncertainties and gaps in data and knowledge of filarial population dynamics and the effectiveness of currently proposed filariasis intervention options. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16564745&query_hl=1 ER - TY - JFULL T1 - Epstein-Barr virus origin of lytic replication mediates association of replicating episomes with promyelocytic leukaemia protein nuclear bodies and replication compartments. A1 - Amon, W A1 - White, RE A1 - Farrell, PJ J1 - J Gen Virol Y1 - 2006/05// VL - 87 SN - 0022-1317 SP - 1133 EP - 1137 N2 - Epstein-Barr virus (EBV) establishes a latent persistence from which it can be reactivated to undergo lytic replication. Late lytic-cycle gene expression is linked to lytic DNA replication, as it is sensitive to the same inhibitors that block lytic replication, and it has recently been shown that the viral origin of lytic replication (ori lyt) is required in cis for late-gene expression. During the lytic cycle, the viral genome forms replication compartments, which are usually adjacent to promyelocytic leukaemia protein (PML) nuclear bodies. A tetracycline repressor DNA-binding domain-enhanced green fluorescent protein fusion was used to visualize replicating plasmids carrying a tetracycline operator sequence array. ori lyt mediated the production of plasmid replication compartments that were associated with PML nuclear bodies. Plasmids carrying ori lyt and EBV itself were visualized in the same cells and replicated in similar regions of the nucleus, further supporting the validity of the plasmids for studying late-gene regulation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16603513&query_hl=1 ER - TY - JFULL T1 - Direct measurement of in-vivo vaginal microbicide levels of PRO 2000 achieved in a human safety study. A1 - Lacey, CJ A1 - Wright, A A1 - Weber, JN A1 - Profy, AT J1 - AIDS Y1 - 2006/04/24/ VL - 20 SN - 0269-9370 SP - 1027 EP - 1030 N2 - OBJECTIVES: To directly measure the cervico-vaginal lavage (CVL) and plasma PRO 2000 concentrations achieved by vaginal dosing. DESIGN: A sub-study of a prospective randomized, double-blind phase 1 trial of a candidate vaginal microbicide, PRO 2000 gel. METHODS: Thirty-six sexually abstinent women self-administered 4% PRO 2000 gel, 0.5% PRO 2000 gel or placebo gel twice on day 0 and then once daily for a further 12 days. RESULTS: There was no evidence of systemic absorption of PRO 2000. PRO 2000 concentrations in CVL exceeded 25 microg/ml in all women in both the 4 and 0.5% groups at 2 h post-first dose, and in 10 of 12 of the women in the 4% gel group compared with five of 12 of women in the 0.5% group at 12 h post-seventh dose. Single use of both 4 and 0.5% PRO 2000 gels was therefore associated with levels of PRO 2000 in CVL that would be capable of preventing HIV infection in vitro, although the 4% gel gave a greater margin of excess. Levels substantially in excess of the target concentration were present 12 h after repeated dosing in twice as many 4% gel recipients compared with 0.5% gel recipients. CONCLUSIONS: Both PRO 2000 gel strengths provided satisfactory in-vivo HIV inhibitory concentrations. However, our observations show that higher concentrations of PRO 2000 are likely to provide a greater margin of potential efficacy in the context of sexual intercourse provided safety issues are equivalent for differing concentrations of the agent. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16603855&query_hl=1 ER - TY - JFULL T1 - Reconstitution of antimycobacterial immune responses in HIV-infected children receiving HAART. A1 - Kampmann, B A1 - Tena-Coki, GN A1 - Nicol, MP A1 - Levin, M A1 - Eley, B J1 - AIDS Y1 - 2006/04/24/ VL - 20 SN - 0269-9370 SP - 1011 EP - 1018 N2 - OBJECTIVE: Recent epidemiological studies in adults suggest that HAART can prevent the development of tuberculosis in HIV-infected individuals, but the mechanisms are incompletely understood and no data exist in children. We