TY - BOOK T1 - Fast Facts - Vascular Surgery Highlights 2005 - 2006 A1 - Davies AH Y1 - 2006/// PB - Health Press Limited N2 - - ER - TY - BOOK T1 - Vascular Surgery (International Surgical Practice) A1 - Davies A H Y1 - 2005/// PB - Springer Verlag N2 - - ER - TY - BOOK T1 - A Guide to the MRCP Part 2 Written Paper A1 - Warrens, A N A1 - Persey, M A1 - Fertleman, M A1 - Powis, S H A1 - Zumla, A Y1 - 2005/// VL - Second Edition PB - Hodder Arnold CY - London SN - 0-340-80658-3 N2 - - ER - TY - BOOK T1 - Fast Facts - Vascular Surgery Highlights 2004 -2005 A1 - Davies A H Y1 - 2005/// PB - Health Press Limited N2 - - ER - TY - BOOK T1 - Towards Vascular and Endovascular Consensus A1 - Greenhalgh RM ED - Greenhalgh RM Y1 - 2005/// PB - Biba Medical CY - London N2 - - ER - TY - BOOK T1 - Surgical EMQ's A1 - Fliglestone L Y1 - 2004/// PB - TFM Press Limited N2 - - ER - TY - BOOK T1 - Fast Facts - Vascular Surgery Highlights 2003 - 2004 A1 - Davies A H Y1 - 2004/// PB - Health Press Limited N2 - - ER - TY - BOOK T1 - Gastroenterology Update A1 - Ghosh S A1 - Watts D A1 - Kinnear M ED - Mayberry J Y1 - 2004/// PB - Radcliffe Publishing Ltd CY - Oxon OX14 1AA SN - 1 85775 631 2 SP - 75 EP - 100 N2 - - ER - TY - BOOK T1 - Venous Disease Simplified A1 - Davies A H Y1 - 2004/// PB - TFM Press Limited N2 - - ER - TY - BOOK T1 - Management of Chronic Viral Hepatitis A1 - Foster A1 - Goldin RD ED - Foster; Goldin Y1 - 2004/// PB - Dunitz N2 - - ER - TY - BOOK T1 - Vascular and Endovascular Challenges A1 - Greenhalgh RM ED - Greenhalgh RM Y1 - 2004/// PB - Biba Medical CY - London N2 - - ER - TY - BOOK T1 - PCR Technology: Current Innovations A1 - Various ED - T. Weissensteiner, H. G. Griffin, A. M. Griffin Y1 - 2003/11/13/ VL - 2 IS - 1 PB - Taylor and Franceis CY - Baton Rouge SN - 0849311845 SP - 1 EP - 416 N2 - - UR - http://www.crcpress.co.uk/shopping_cart/products/product_reviews.asp?id=&parent_id=&sku=1184&pc= L1 - http://www.biosciencenetbase.com/ejournals/books/book_summary/features.asp?id=4747 ER - TY - BOOK T1 - Aging of Organs and Systems A1 - Aspinall R ED - Aspinall R Y1 - 2003/// IS - 3 PB - Kluwer Academic Publishers CY - Dordrecht/Boston/London SN - 1-4020-1743-X N2 - - ER - TY - BOOK T1 - Fast Facts - Vascualr Surgery Highlights 2002 - 2003 A1 - Davies AH Y1 - 2003/// PB - Health Press Limited N2 - - ER - TY - BOOK T1 - Infection and Immunity A1 - Lightstone EB ED - Friedland JS; Lightstone EB Y1 - 2003/// PB - Martin Dunitz CY - 11 New Fetter Lane, London EC4P 4EE SN - 1 84184 373 3 N2 - - UR - http://www.dunitz.co.uk ER - TY - BOOK T1 - Vascular and Endovascular Controversies A1 - Greenhalgh RM ED - Greenhalgh RM Y1 - 2003/// PB - Biba Medical CY - London N2 - - ER - TY - BOOK T1 - Vascular surgery. Cases, questions and answers A1 - Geroulakos G ED - Geroulakos G; van Urk H; Hobson W II; Caligaro K Y1 - 2003/// PB - Springer Verlag N2 - - ER - TY - BOOK T1 - Leg Ulcers A1 - Moneta G A1 - Davies A H Y1 - 2003/// PB - Health Press Limited N2 - - ER - TY - BOOK T1 - Renal Access A1 - Davies A H Y1 - 2003/// PB - TFM Press Limited N2 - - ER - TY - BOOK T1 - The year in rheumatic disorders 2002: special issue: rheumatoid arthritis A1 - Cope AP Y1 - 2002/// SN - 0-9537-3399-8 N2 - - ER - TY - BOOK T1 - Diseases of the visceral circulation A1 - Geroulakos G ED - Geroulakos G; Cherry K Y1 - 2002/// PB - Arnold CY - London N2 - - ER - TY - BOOK T1 - Diseases of the visceral circulation A1 - Geroulakos G A1 - Cherry KJ Y1 - 2002/// SN - 0-3408-0722-9 N2 - - ER - TY - BOOK T1 - Preventing kidney disease: the ethnic challenge in Brent A1 - Lightstone L A1 - Woolnough L Y1 - 2002/// PB - National Kidney Research Fund SN - 1-9042-2704-X N2 - - ER - TY - BOOK T1 - Fast Facts - Vascular Surgery Highlights 2001 - 2002 A1 - Davies AH Y1 - 2002/// PB - Health Press Limited N2 - - ER - TY - BOOK T1 - The Evidence for Vascular and Endovascular Reconstruction A1 - Greenhalgh RM ED - Greenhalgh RM Y1 - 2002/// PB - W M Saunders CY - London, Philadelphia N2 - - ER - TY - BOOK T1 - An Atlas of Endovascular and Vascular Surgery A1 - Davies A H A1 - Greenhalgh RM A1 - Mitchell A Y1 - 2001/// PB - Saunders W. B. N2 - - ER - TY - BOOK T1 - Fast Facts - Vascular Surgery Highlights 2000 - 2001 A1 - Davies A H Y1 - 2001/// PB - Health Press Limited N2 - - ER - TY - BOOK T1 - Vascular and Endovascular Surgical Techniques (4th Edition Atlas) A1 - Greenhalgh RM ED - Greenhalgh RM Y1 - 2001/// PB - W B Saunders CY - London, Philadelphia N2 - - ER - TY - BOOK T1 - Preventing kidney disease: the ethnic challenge A1 - Lightstone E Y1 - 2001/// PB - National Kidney Research Fund CY - Peterborough, England SN - 1-9042-2700-7 N2 - - ER - TY - BOOK T1 - The Complement Factsbook A1 - Morley, B J ED - Morley, B J and Walport, M J Y1 - 2000/// PB - Academic Press N2 - - ER - TY - BOOK T1 - Fast Facts - Vascular Surgery Highlights 1999 - 2000 A1 - Davies AH Y1 - 2000/// PB - Health Press Limited N2 - - ER - TY - BOOK T1 - Essential Postgraduate Surgery A1 - Fliglestone L A1 - Davies A H Y1 - 2000/// PB - Churchill Livingstone N2 - - ER - TY - BOOK T1 - Pocket Reference to TNF alpha antagonism and rheumatoid arthritis A1 - Maini RN A1 - Feldmann M Y1 - 2000/// PB - Science Press Ltd CY - London N2 - - ER - TY - BOOK T1 - HLA in Health and Disease A1 - Warrens AN ED - Lechler RI ; Warrens AN Y1 - 2000/// PB - Academic Press CY - London SN - 0-12-440315-8 N2 - - ER - TY - BOOK T1 - Essential Vascular Surgery A1 - Davies AH A1 - Beard JN A1 - Wyatt M Y1 - 1999/// PB - W. B. Saunders N2 - - ER - TY - BOOK T1 - Fast Facts - Vascular Surgery Highlights 1998 - 1999 A1 - Davies AH Y1 - 1999/// PB - Helath Press Limited N2 - - ER - TY - CHAP T1 - Choroideremia A1 - MacDonald I A1 - Meltzer MR A1 - Smaoui N T2 - GeneReviews at GeneTests: Medical Genetics Information Resource [database online] 1997-2007 Y1 - 2007/04// N2 - - UR - http://www.genetests.org ER - TY - CHAP T1 - Internal standards in differentiating embryonic stem cells in vitro. A1 - Murphy, CL T2 - Methods in Molecular Biology Y1 - 2006/07/19/ M2 - 329 PB - Humana Press CY - United States SP - 101 EP - 112 N2 - - UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Display&DB=pubmed ER - TY - CHAP T1 - Immunosuppressive drugs in renal transplantation - 2006 A1 - Warrens, A N ED - Haskard, D O T2 - Horizons in Medicine - 17 Y1 - 2006/// PB - Royal College of Physicians of London SN - 1-86016-253-3 SP - 71 EP - 77 N2 - - ER - TY - CHAP T1 - Quality of life in patients wiht varicose veins A1 - Davies AH ED - Davies AH Lees T Lane I T2 - Venous Disease Simplified Y1 - 2006/// CY - TFM Publishing N2 - - ER - TY - CHAP T1 - The case against endoluminal treatment of varicose veins A1 - Aravind B A1 - Davies AH ED - Greenhalgh RM T2 - Vascular Disease Y1 - 2006/// PB - Biba Medical Publishing N2 - - ER - TY - CHAP T1 - Hypoxia Inducible Factor-1 and oxygen sensing. A1 - P. Maxwell. T2 - In Actualities Nephrologiques Jean Hamburger Hospital Necker 2006 Y1 - 2006/// SN - 2257108213 N2 - - ER - TY - CHAP T1 - Quality of life in patiens with venous ulcers A1 - Sharp BM ED - Davies AH Lees T Lane I T2 - Venous Disease Simplified Y1 - 2006/// PB - TFM Publishing N2 - - ER - TY - CHAP T1 - Handbook “Disorders of iron homeostasis, erythrocytes, erythropoiesis A1 - Maxwell PH A1 - Pugh CW ED - Beaumont C. Beuzard Y. Beris P. & Brugnara C. T2 - Regulation of oxygen sensing and erythropoietin production. Y1 - 2006/// VL - First PB - European School of Haematology CY - Paris, France SP - 13 EP - 36 N2 - - ER - TY - CHAP T1 - Management of the ischaemic complication of renal access. A1 - Brooks M ED - Davies AH T2 - Fast Facts - Vascular Highlights 2005-2006 Y1 - 2006/// PB - Health Press Limited N2 - - ER - TY - CHAP T1 - Quality of life in venous disease A1 - Davies M A1 - Tsange F ED - Stansby G Labrapoulos N Y1 - 2005/// N2 - - ER - TY - CHAP T1 - Gastrointestinal Diseases A1 - Chaudhary R A1 - Ghosh S ED - Lakhani m, Charlton R T2 - Recent Advances in Primary Care Y1 - 2005/// PB - Royal College of General Practitioners CY - London SP - 197 EP - 222 N2 - - ER - TY - CHAP T1 - Vascular Trauma A1 - Ozsvath KJ A1 - Darling RC A1 - Tabatabai L A1 - Hamdani S, Davies AH ED - Davies AH Brophy C T2 - Vascular Surgery Y1 - 2005/// PB - Springer Verlag SP - 125 EP - 132 N2 - - ER - TY - CHAP T1 - Management of a Ruptured AAA. A1 - Davis M A1 - Davies A H ED - Greenhalgh RM Y1 - 2005/// PB - Biba Medical N2 - - ER - TY - CHAP T1 - Lower lImi Ischaemia A1 - Sarakar R ED - Davies AH Brophy C T2 - Vascular Surgery Y1 - 2005/// PB - Springer Verlag SP - 91 EP - 104 N2 - - ER - TY - CHAP T1 - Statins in vascular disease A1 - Rodd C A1 - Davies A H ED - Davies AH T2 - Fast Facts - Vascular Highlights 2004-2005 Y1 - 2005/// PB - Health Press Limited N2 - - ER - TY - CHAP T1 - Quantitative Profiling of Protein-DNA Binding on Microarrays A1 - Ragoussis J A1 - Field S A1 - Udalova IA ED - Bina M T2 - Methods in Molecular Biology, vol. 338: Gene Mapping, Discovery, and Expression: Methods and Protocols Y1 - 2005/// PB - Humana Press Inc CY - USA N2 - - ER - TY - CHAP T1 - Non-atherosclerotic Vascular Disease A1 - Hutt JRB ED - Davies AH Brophy C T2 - Vascular Surgery Y1 - 2005/// PB - Springer Verlag SP - 73 EP - 90 N2 - - ER - TY - CHAP T1 - BCL-6: rearrangement and mutation in lymphoma. A1 - Wagner, S D A1 - Kaeda, J S T2 - Methods Mol Med. Y1 - 2005/// M2 - 115 SP - 251 EP - 270 N2 - - ER - TY - CHAP T1 - Loutcome measures in Vascular Disease A1 - Kwolek CJ ED - Davies AH Brophy C T2 - Vascular Surgery Y1 - 2005/// PB - Springer Verlag SP - 149 EP - 154 N2 - - ER - TY - CHAP T1 - IN VITRO ASSAYS FOR IMMUNE-MONITORING IN TRANSPLANTATION A1 - Hernandez-Fuentes M ED - Hornick PI, Rose ML. T2 - Transplant Immunology Y1 - 2005/// PB - Humana Press CY - New Jersey N2 - - ER - TY - CHAP T1 - How to manage renal disease in pregnancy A1 - Lightstone L ED - Jayne Franklyn T2 - Horizons in Medicine 16 Updates on major clinical advances Y1 - 2004/08// PB - Royal College of Physicians of London CY - London SN - 1 86016 233 9 SP - 261 EP - 270 N2 - - ER - TY - CHAP T1 - Arterial Disease A1 - Fligelstone LJ T2 - EMQ's for Surgery Y1 - 2004/// PB - TFM Publishers Limited SP - 1 EP - 21 N2 - - ER - TY - CHAP T1 - The Road to Transplantation Tolerance A1 - Salama AD A1 - MH Sayegh ED - M Weir T2 - Medical management of Kidney Transplantation Y1 - 2004/// PB - Lippincott, Williams and Wilkins N2 - - ER - TY - CHAP T1 - Basic Surgical Knowledge A1 - Davies AH A1 - Fligelstone LJ T2 - EMQ's for Surgery Y1 - 2004/// PB - TFM Publishers Limited SP - 1 EP - 21 N2 - - ER - TY - CHAP T1 - The von Hippel-Lindau Protein: a key player in oxygen homeostasis and matrix assembly. A1 - Esteban M A1 - Mandriota S A1 - Maxwell P ED - Matsuzawa Y, Kita T, Nagai R & Teramoto T. T2 - Atherosclerosis XIII. Y1 - 2004/// VL - First Edition SN - 0444514481 SP - 450 EP - 453 N2 - - ER - TY - CHAP T1 - Vein graft surveillance is a waste of time? A1 - Wales L A1 - Hawdon A Y1 - 2004/// PB - Minerva N2 - - ER - TY - CHAP T1 - Biological Therapies in Inflammatory Bowel Disease A1 - Ghosh S ED - Bianchi Porro G, Ardizzone S, Colombo E T2 - IBD Year Book 2004 Y1 - 2004/// PB - Nomos Edizioni CY - Milano SP - 107 EP - 127 N2 - - ER - TY - CHAP T1 - Venous Disease A1 - Davies A H T2 - EMQ's for Surgery Y1 - 2004/// PB - TFM Press Limited SP - 77 EP - 88 N2 - - ER - TY - CHAP T1 - The transfer of a laboratory based hypothesis to a clinically useful therapy: the development of anti-TNF therapy of rheumatoid arthritis. A1 - Feldmann M A1 - Brennan FM A1 - WIlliams RO A1 - Woody JN A1 - Maini RN ED - L. Klareskog and S. Lindblad T2 - Scientific Basis of Rheumatology: Best Practice & Research, Clinical Rheumatology Y1 - 2004/// M2 - 18 (1) PB - Bailliere Tindall SP - 59 EP - 80 N2 - - ER - TY - CHAP T1 - Management of Hyperhidrosis A1 - Ashwin C A1 - Naughton-Morgan N ED - Davies AH T2 - Fast Facts - Vascular Highlights 2003-2004 Y1 - 2004/// PB - Health Press Limited N2 - - ER - TY - CHAP T1 - The role of tumour necrosis factor in rheumatoid arthritis A1 - Maini RN ED - van den Berg WB; Miossec P T2 - Cytokines and Injury in Progress in Inflammation Research Y1 - 2004/// PB - Birkhauser Verlag CY - Basel SN - 3-7643-7001-7 SP - 1 EP - 28 N2 - - ER - TY - CHAP T1 - Immunopathogenesis of rheumatoid arthritis A1 - Maini RN A1 - Feldmann M ED - Isenberg DA; Maddison PJ; Woo P; Glass D; Breedveld FC T2 - Oxford Textbook of Rheumatology Y1 - 2004/// M2 - 4th Ed PB - Oxford University Press CY - Oxford SN - 0 19 850948 0 SP - 677 EP - 697 N2 - - ER - TY - CHAP T1 - Optimizing PCR with the Aid of Experimental Design A1 - Weissensteiner, T ED - T. Weissensteiner, H. G. Griffin, A. M. Griffin T2 - PCR Technology: Current Innovations Y1 - 2003/11/13/ VL - 2 M2 - 1 PB - Taylor and Francis CY - Baton Rouge SN - 0849311845 SP - 1 EP - 416 N2 - - UR - http://www.crcpress.com/shopping_cart/products/product_detail.asp?sku=1184&isbn=0849311845&parent_id=&pc= L1 - http://www.biosciencenetbase.com/ejournals/books/book_summary/summary.asp?id=4747 ER - TY - CHAP T1 - Thoacoscopic Sympathectomy A1 - Clayton G ED - Lumley J T2 - Vascular Surgery Y1 - 2003/// N2 - - ER - TY - CHAP T1 - TNFalpha A1 - Feldmann M A1 - Maini RN. ED - J. Smolen and P. Lipsky T2 - Targeted Therapies in Rheumatology Y1 - 2003/// PB - Martin Dunitz Ltd. CY - London SP - 201 EP - 212 N2 - - ER - TY - CHAP T1 - Definition of TNFalpha as a therapeutic target for rheumatoid arthritis A1 - Feldmann M A1 - Brennan F A1 - Williams RO A1 - Maini RN ED - Moreland, Emery T2 - TNFalpha inhibition in the treatment of rheumatoid arthritis Y1 - 2003/// PB - Martin Dunitz CY - London SP - 1 EP - 22 N2 - - ER - TY - CHAP T1 - Medical management of varicose veins A1 - Gibbs R A1 - Soumian S ED - Hallett JW Mill JL Earnshaw JJ Reekers JA T2 - Comprehensive Vacular and Endovascular Surgery Y1 - 2003/// PB - Mosby N2 - - ER - TY - CHAP T1 - Infliximab therapy. A1 - Maini RN A1 - Feldmann M ED - L.W. Moreland and P. Emery T2 - TNFalpha inhibition in the treatment of rheumatoid arthritis. Y1 - 2003/// PB - Martin Dunitz CY - London SP - 23 EP - 45 N2 - - ER - TY - CHAP T1 - Definition of TNFalpha as a therapeutic target for rheumatoid arthritis. A1 - Feldmann M A1 - Brennan FM A1 - Williams RO A1 - Maini RN ED - L.W. Moreland and P. Emery T2 - TNFalpha inhibition in the treatment of rheumatoid arthritis. Y1 - 2003/// PB - Martin Dunitz CY - London SP - 1 EP - 22 N2 - - ER - TY - CHAP T1 - Crescentic glomerulonephritis A1 - Levy JB A1 - Pusey CD ED - Brady HR, Wilcox CS T2 - Therapy in Nephrology and Hypertension, 2nd Edition Y1 - 2003/// PB - WB Saunders CY - Philadelphia SP - 177 EP - 188 N2 - - ER - TY - CHAP T1 - Definition of TNFalpha as a therapeutic target for rheumatoid arthritis A1 - Feldmann M A1 - Brennan FM A1 - Williams RO A1 - Maini RN ED - Moreland LW; Emery P T2 - TNFalpha-inhibition in the treatment of rheumatoid arthritis Y1 - 2003/// PB - Martin Dunitz CY - London SN - 1-84184-156-0 SP - 1 EP - 22 N2 - - ER - TY - CHAP T1 - Anti-glomerular basement membrane disease A1 - Levy J A1 - Pusey CD ED - Warrell DA; Cox TM; Firth JD T2 - Oxford Textbook of Medicine, 4th Edition Y1 - 2003/// PB - Oxford University Press CY - Oxford SN - 0-19-852789-6 SP - 335 EP - 339 N2 - - ER - TY - CHAP T1 - Thrombolysis in Graft occlusions is overrated A1 - Davies A H A1 - Rodway A A1 - Gibbs R ED - Greenhalgh R M Y1 - 2003/// PB - BIBA Medical SP - 349 EP - 356 N2 - - ER - TY - CHAP T1 - The Future of Dialysis A1 - Davies A H ED - Davies A H Gibbons C P T2 - Renal Access Simplified Y1 - 2003/// PB - TFM Publishers SP - 183 EP - 189 N2 - - ER - TY - CHAP T1 - Ageing and the Immune Response A1 - S.M. Henson A1 - R. Aspinall ED - R. Aspinall T2 - Ageing of the Organs and Systems Y1 - 2003/// M2 - 3 PB - Kluwer Academic Publishers 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 - Plasma exchange A1 - Levy J A1 - Pusey CD ED - Johnson RJ, Feehally J T2 - Comprehensive Clinical Nephrology, 2nd Edition Y1 - 2003/// PB - Harcourt Publishers SN - 07234-31175 SP - 1035 EP - 1042 N2 - - ER - TY - CHAP T1 - Assessment of disease activity in rheumatoid arthritis A1 - Abrahams S A1 - Cope A A1 - Taylor PC ED - Scott D and Cope A T2 - The year in rheumatic disorders 2003 Y1 - 2003/// PB - Clinical Publishing Services CY - Oxford SN - 1 904392 09 1 SP - 103 EP - 126 N2 - - ER - TY - CHAP T1 - Surgery for venous ulcers A1 - Beresford T ED - Davies AH Nelson A Moneta G T2 - Fast Facts - Leg Ulcers Y1 - 2003/// PB - Health Press Limited N2 - - ER - TY - CHAP T1 - Mechanisms of allorecognition A1 - Dupont, P J A1 - Herbert, P E A1 - Warrens, A N ED - Lesavre, P Drueke, T Legendre, C Niaudet, P T2 - Actualites Nephrologiques Jean Hamburger: Hopital Necker Y1 - 2003/// PB - Flammarion Medicine-Sciences CY - Paris SN - 2-257-10815-9 N2 - - ER - TY - CHAP T1 - Rheumatoid Arthritis A1 - Maini RN ED - Warrell DA; Cox TM; Firth JD T2 - Oxford Textbook of Medicine Y1 - 2003/// M2 - 4th edition PB - Oxford University Press CY - Oxford SN - 0-19-262922-0 N2 - - ER - TY - CHAP T1 - The role of NF-kappaB in inflammatory diseases. A1 - Andreakos E A1 - Udalova IA A1 - Sacre S ED - Beyaert R T2 - Nuclear Factor kappaB. Regulation and Role in Disease. Y1 - 2003/// PB - Kluwer Academic Publishers CY - Netherlands SP - 297 EP - 325 N2 - - ER - TY - CHAP T1 - TNF alpha A1 - Feldmann M A1 - Maini RN ED - Smolen J; Lipsky P T2 - Targeted Therapies in Rheumatology Y1 - 2003/// PB - Martin Dunitz Ltd CY - London SN - 1-84184-157-9 SP - 201 EP - 212 N2 - - ER - TY - CHAP T1 - Mechanisms of allorecognition A1 - Dupont PJ A1 - Herbert PE A1 - Warrens AN ED - Lesavre P, Drueke T, Legendre C and Niaudet P T2 - Actualites Nephrologiques Jean Hamburger Y1 - 2003/// PB - Flammarion SN - 2-257-10815-9 SP - 285 EP - 298 N2 - - ER - TY - CHAP T1 - Autoimmunity and cytokines: pathogenesis and therapy. A1 - Andreakos E A1 - Feldmann M ED - A.W. Thomson and M.T. Lotze T2 - Cytokine Handbook, 4th Edition Y1 - 2003/// PB - Academic Press SP - 1189 EP - 1211 N2 - - ER - TY - CHAP T1 - Immunological Aspects of Multiple Sclerosis with Emphasis on the Potential Use of Autologous Hemopoietic Stem Cell Transplantation A1 - Muraro, P A A1 - McFarland, H F A1 - Martin, R ED - Burt R, Marmont A T2 - Stem Cell Therapy for Autoimmune Diseas Y1 - 2003/// PB - Landes Bioscience CY - Georgetown, TX SN - 1-58706-031-0 SP - 277 EP - 283 N2 - - UR - http://www.landesbioscience.com/books/special/id/812 ER - TY - CHAP T1 - Infliximab Therapy A1 - Feldmann M A1 - Maini RN ED - Moreland LW; Emery P T2 - TNFalpha-inhibition in the treatment of rheumatoid arthritis Y1 - 2003/// PB - Martin Dunitz CY - London SN - 1-84184-156-0 SP - 23 EP - 45 N2 - - ER - TY - CHAP T1 - Imaging A1 - Taylor P T2 - The year in rheumatic disorders 2002: special issue: rheumatoid arthritis Y1 - 2002/// SN - 0-9537-3399-8 SP - 159 EP - 177 N2 - - ER - TY - CHAP T1 - Management of acute visceral ischaemia A1 - Perko MJ A1 - Schroeder TV T2 - Diseases of the visceral circulation Y1 - 2002/// SN - 0-3408-0722-9 SP - 80 EP - 87 N2 - - ER - TY - CHAP T1 - Infections in multiple myeloma A1 - Kelleher P A1 - Chapel H T2 - Multiple Myeloma Y1 - 2002/// SN - 1-9018-6550-9 SP - 223 EP - 239 N2 - - ER - TY - CHAP T1 - Gene therapy approaches for rheumatoid arthritis A1 - Bondeson J A1 - Feldmann M A1 - Maini RN T2 - Gene Therapy: the use of DNA as a drug Y1 - 2002/// SN - 0-8536-9455-9 SP - 215 EP - 265 N2 - - ER - TY - CHAP T1 - Gene therapy approaches for rheumatoid arthritis A1 - Bondeson J A1 - Feldmann M A1 - Maini RN T2 - Gene Therapy: the use of DNA as a drug Y1 - 2002/// SN - 0-8536-9455-9 SP - 215 EP - 265 N2 - - ER - TY - CHAP T1 - Angiogenesis A1 - Paleolog EM T2 - The year in rheumatic disorders 2002: special issue: rheumatoid arthritis Y1 - 2002/// SN - 0-9537-3399-8 SP - 63 EP - 80 N2 - - ER - TY - CHAP T1 - Calcium, phosphate and magnesium disturbances A1 - Dorling A T2 - Acute renal failure in practice Y1 - 2002/// SN - 1-8609-4216-4 SP - 174 EP - 183 N2 - - ER - TY - CHAP T1 - Lymphocyte biology A1 - Cope A T2 - The Year in Rheumatic Disorders 2002: special issue: rheumatoid arthritis Y1 - 2002/// SN - 0-9537-3399-8 SP - 81 EP - 106 N2 - - ER - TY - CHAP T1 - Immunopathogenesis of viral infections in children A1 - Openshaw PJM A1 - Matthews S A1 - Pala P A1 - Hussell T A1 - Walzi G T2 - Textbook of respiratory cell and molecular biology Y1 - 2002/// SN - 9-0582-3178-X SP - 283 EP - 298 N2 - - ER - TY - CHAP T1 - Ischemic colitis A1 - Stansby G A1 - Thomas.H. A1 - Goldin R T2 - Diseases of the Visceral Circulation Y1 - 2002/// SN - 0-3408-0722-9 SP - 145 EP - 157 N2 - - ER - TY - CHAP T1 - Effect of exercise on patients with intermittent claudiation A1 - Cheetham D A1 - Davies A H ED - Davies A H T2 - Fast Facts - Vascular Highlights Y1 - 2002/// PB - Health Press Limited SP - 13 EP - 17 N2 - - ER - TY - CHAP T1 - The Renal Transplant Recipient A1 - Warrens AN ED - Glynne P, Allen A and Pusey C T2 - Acute Renal Failure in Practice Y1 - 2002/// PB - Imperial College Press SN - 1-86094-287-3 SP - 453 EP - 464 N2 - - ER - TY - CHAP T1 - Leg Ulcer Clinics A1 - Beresford T A1 - Williams A T2 - Care Pathways in Vascular Surgery Y1 - 2002/// PB - JVRG TFM Publishers SP - 63 EP - 70 N2 - - ER - TY - CHAP T1 - Bcl-6 uncouples B lymphocyte proliferation from differentiation. A1 - Fearon, D T A1 - Manders, P M A1 - Wagner, S D T2 - Adv Exp Med Biol. Y1 - 2002/// M2 - 512 SP - 21 EP - 28 N2 - - ER - TY - CHAP T1 - Imaging A1 - Taylor P T2 - The year in rheumatic disorders 2002: special issue: rheumatoid arthritis Y1 - 2002/// SN - 0-9537-3399-8 SP - 159 EP - 177 N2 - - ER - TY - CHAP T1 - Angiogenesis A1 - Paleolog EM T2 - The year in rheumatic disorders 2002: special issue: rheumatoid arthritis Y1 - 2002/// SN - 0-9537-3399-8 SP - 63 EP - 80 N2 - - ER - TY - CHAP T1 - HUS and TTP A1 - Salama AD ED - Glynne, Allen and Pusey T2 - Acute Renal Failure Y1 - 2002/// PB - Imperial College Press N2 - - ER - TY - CHAP T1 - Pulmonary renal syndrome A1 - Allen AR A1 - Pusey CD ED - Davison AM T2 - Nephrology Y1 - 2002/// PB - McGraw Hill SN - 0-0770-9525-1 SP - 205 EP - 211 N2 - - ER - TY - CHAP T1 - Graft Surveillance A1 - Beattie D A1 - Ellis M T2 - Care Pathways in Vascular Surgery Y1 - 2002/// PB - JVRG TFM Publishers SP - 107 EP - 116 N2 - - ER - TY - CHAP T1 - Rapidly progressive glomerulonephritis A1 - Gaskin G T2 - Acute renal failure in practice Y1 - 2002/// SN - 1-8609-4287-3 SP - 341 EP - 355 N2 - - ER - TY - CHAP T1 - Endovascular versus surgical reconstruction for the management of chronic visceral ischaemia; a comparative analysis A1 - Robless P A1 - Belli AM A1 - Geroulakos G T2 - Diseases of the visceral circulation Y1 - 2002/// SN - 0-3408-0722-9 SP - 108 EP - 118 N2 - - ER - TY - CHAP T1 - CHM (Choroideremia) Gene A1 - van den Hurk, J.A.J.M. A1 - Cremers, F.P.M. A1 - Seabra, M.C. T2 - Wiley Encylopedia of Molecular Medicine Y1 - 2002/// PB - John Wiley & Sons Inc. SP - 750 EP - 752 N2 - - ER - TY - CHAP T1 - Calcium, phosphate and magnesium disturbances A1 - Dorling A T2 - Acute renal failure in practice Y1 - 2002/// SN - 1-8609-4216-4 SP - 174 EP - 183 N2 - - ER - TY - CHAP T1 - Fetal somatic gene therapy - a preventive approach to the treatment of genetic disease: the case for A1 - Coutelle C A1 - Themis M A1 - Schneider H A1 - Cook HT Y1 - 2001/// SN - 3-5406-7701-1 SP - 99 EP - 114 N2 - - ER - TY - CHAP T1 - Goodpasture's syndrome and other anti-GBM disease A1 - Pusey CD Y1 - 2001/// M2 - 3rd SN - 0-1229-9100-1 SP - 172 EP - 175 N2 - - ER - TY - CHAP T1 - Thoracoscopic Sympathectomy A1 - Clayton G ED - Greenahalgh R M Mitchell A Davies AH T2 - An Atalas of Endovascular and Vascular Surgery Y1 - 2001/// PB - Saunders W B SP - 293 EP - 294 N2 - - ER - TY - CHAP T1 - Revascularization and or Debridement in Infection and Ischaemia A1 - Hafez H ED - Melini M T2 - Medicine & Hygiene Y1 - 2001/// PB - Geneva SP - 71 EP - 74 N2 - - ER - TY - CHAP T1 - Substrate specificity of MMPs A1 - Nagase H Y1 - 2001/// SN - 0-8960-3668-5 SP - 39 EP - 66 N2 - - ER - TY - CHAP T1 - The Investigation and assessment and Management of Varicose Veins A1 - Smith J ED - Davies A H T2 - Fast Facts - Vascular Highlights Y1 - 2001/// PB - Health Press Limited SP - 34 EP - 44 N2 - - ER - TY - CHAP T1 - The role of TNF? and IL-1 in rheumatoid arthritis A1 - Feldmann M A1 - Brennan FM A1 - Foxwell BMJ A1 - Maini RN Y1 - 2001/// SN - 3-8055-7120-8 SP - 188 EP - 199 N2 - - ER - TY - CHAP T1 - Inhibition of proteolytic enzymes A1 - Salvesen GS A1 - Nagase H Y1 - 2001/// M2 - 2nd SN - 0-1996-3662-1 SP - 105 EP - 130 N2 - - ER - TY - CHAP T1 - Donor lymphocyte infusions A1 - Dazzi F A1 - Stauss HJ Y1 - 2001/// SN - 1-8531-7890-X SP - 385 EP - 399 N2 - - ER - TY - CHAP T1 - Genetics and molecular medicine A1 - Vyse TJ Y1 - 2001/// SN - 0-6320-5859-5 SP - 3 EP - 24 N2 - - ER - TY - CHAP T1 - Pathology of vascular disease A1 - Cook HT A1 - Pusey CD Y1 - 2001/// SN - 0-8493-1335-X SP - 3 EP - 21 N2 - - ER - TY - CHAP T1 - TNF receptors A1 - Aggarwal BB A1 - Samanta A A1 - Feldmann M Y1 - 2001/// SN - 0-1225-2670-8 SP - 1619 EP - 1632 N2 - - ER - TY - CHAP T1 - Introduction to the role of cytokines in innate host defense and adaptive immunity A1 - Oppenheim JJ A1 - Feldmann M Y1 - 2001/// SN - 0-1225-2670-8 SP - 3 EP - 20 N2 - - ER - TY - CHAP T1 - Rheumatologic diseases associated with interstitial nephritis A1 - Salama AD A1 - Pusey CD Y1 - 2001/// SN - 0-1926-3178-0 SP - 465 EP - 484 N2 - - ER - TY - CHAP T1 - Peptic Ulcer Disease A1 - Kinnear M A1 - Ghosh S ED - R Walker, C Edwards T2 - Clinical Pharmacy and Therapeutics Y1 - 2001/// PB - Churchill Livingstone CY - Edinburgh SP - 135 N2 - - ER - TY - CHAP T1 - The role of TNF-Alpha and IL-1 in rheumatoid arthritis A1 - Feldmann M A1 - Brennan FM A1 - Foxwell BMJ A1 - Maini RN Y1 - 2001/// SN - 3-8055-7120-8 SP - 188 EP - 199 N2 - - ER - TY - CHAP T1 - TNF? A1 - Aggarwal BB A1 - Samanta A A1 - Feldmann M Y1 - 2001/// SN - 0-1225-2670-8 SP - 413 EP - 434 N2 - - ER - TY - CHAP T1 - Cytokines and disease A1 - Feldmann M A1 - Brennan FM Y1 - 2001/// SN - 0-1225-2670-8 SP - 35 EP - 51 N2 - - ER - TY - CHAP T1 - Plasmapheresis and immunoadsorption A1 - Griffin SV A1 - Lockwood CM A1 - Pusey CD Y1 - 2001/// M2 - 2nd SN - 0-6320-4359-8 SP - 597 EP - 611 N2 - - ER - TY - CHAP T1 - 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 - Vasculitis A1 - Gaskin G A1 - Pusey CD Y1 - 2001/// M2 - 4th SN - 0-6833-0488-7 SP - 792 EP - 804 N2 - - ER - TY - CHAP T1 - Proinflammatory cytokines A1 - Feldmann M A1 - Saklatvala J Y1 - 2001/// SN - 0-1225-2670-8 SP - 291 EP - 305 N2 - - ER - TY - CHAP T1 - Cytokines and disease A1 - Feldmann M A1 - Brennan FM Y1 - 2001/// SN - 0-1225-2670-8 SP - 35 EP - 51 N2 - - ER - TY - CHAP T1 - Finding, purification and characterization of natural protease inhibitors A1 - Nagase H A1 - Salvesen GS Y1 - 2001/// M2 - 2nd SN - 0-1996-3663-X SP - 131 EP - 147 N2 - - ER - TY - CHAP T1 - Pathology of vascular disease A1 - Cook HT A1 - Pusey CD Y1 - 2001/// SN - 0-8493-1335-X SP - 3 EP - 21 N2 - - ER - TY - CHAP T1 - Anti-TNFalpha therapy in rheumatoid arthritis and other diseases. A1 - Feldmann M A1 - Maini RN ED - Austen KF; Frank MM; Atkinson JP; Cantor H T2 - Samter's Immunologic Diseases (Sixth Edition) Y1 - 2001/// PB - Lippincott Williams & Wilkins SP - 1180 EP - 1198 N2 - - ER - TY - CHAP T1 - Metalloproteinases A1 - Nagase H Y1 - 2001/// SN - 0-4711-1184-8 SP - 21 EP - 21 N2 - - ER - TY - CHAP T1 - Vasculitis A1 - Gaskin G A1 - Pusey CD ED - Massry SG, Glassock RJ T2 - Massry and Glassock's Textbook of Nephrology, 4th Edition Y1 - 2001/// PB - Lippincott Williams and Wilkins CY - New York SN - 0-683-30488-7 SP - 792 EP - 804 N2 - - ER - TY - CHAP T1 - Xenotransplantation A1 - Dorling A A1 - Lechler RI Y1 - 2001/// SN - 0-632-03676-1 SP - 136 EP - 176 N2 - - ER - TY - CHAP T1 - The Role of Graft Surveillance A1 - Beattie D T2 - Emergency Vascular Surgery Y1 - 2001/// VL - 2nd N2 - - ER - TY - CHAP T1 - Exploring the pathogenesis of rheumatoid arthritis in transgenic and mutant mice A1 - Cope AP Y1 - 2001/// SN - 3-8055-7120-8 SP - 64 EP - 93 N2 - - ER - TY - CHAP T1 - Proinflammatory cytokines A1 - Feldmann M A1 - Saklatvala J Y1 - 2001/// SN - 0-1225-2670-8 SP - 291 EP - 305 N2 - - ER - TY - CHAP T1 - The role of TNF? and IL-1 in rheumatoid arthritis A1 - Feldmann M A1 - Brennan FM A1 - Foxwell BMJ A1 - Maini RN Y1 - 2001/// SN - 3-8055-7120-8 SP - 188 EP - 199 N2 - - ER - TY - CHAP T1 - Tubulointerstitial Nephritis in Rheumatologic Disease A1 - Salama AD A1 - Pusey CD ED - Adu, Madaio and Emery T2 - Rheumatology and the Kidney Y1 - 2001/// PB - Oxford University Press N2 - - ER - TY - CHAP T1 - The role of TNFalpha and IL-1 in rheumatoid arthritis A1 - Feldmann M A1 - Brennan FM A1 - Foxwell BMJ A1 - Maini RN Y1 - 2001/// SN - 3-8055-7120-8 SP - 188 EP - 199 N2 - - ER - TY - CHAP T1 - The analysis of genetic susceptibility A1 - Vyse, T J A1 - Morley, B J ED - Lechler, R and Warrens, A T2 - HLA in health and disease Y1 - 2000/// VL - 2nd PB - Academic press SP - 107 EP - 128 N2 - - ER - TY - CHAP T1 - Factor I A1 - Morley, B J ED - Morley, B J and Walport M J T2 - The Complement Factsbook Y1 - 2000/// PB - Academic Press SP - 83 EP - 86 N2 - - ER - TY - CHAP T1 - Biochemistry of Rab geranylgeranyl transferase A1 - Seabra, M.C. ED - Tamanoi, F. and Sigman, D. T2 - The Enzymes Y1 - 2000/// M2 - XXI PB - Academic Press CY - New York SP - 131 EP - 154 N2 - - ER - TY - CHAP T1 - The debut of anti-TNF therapy of rheumatoid arthritis in the clinic A1 - Maini RN ED - Higgs GA; Henderson B T2 - Progress in Inflammation Research Y1 - 2000/// PB - Birkhauser Verlag CY - Basel SP - 145 EP - 156 N2 - - ER - TY - CHAP T1 - The naïve and memory MBP-reactive CD4+ T cell repertoire A1 - Muraro, P A A1 - Bielekova, B ED - Gambi D, Muraro PA, Lugaresi A T2 - Advances in the Immunopathogenesis of Multiple Sclerosis Y1 - 1999/// PB - Springer-Verlag CY - Milan SN - 88-470-0067-X SP - 11 EP - 19 N2 - - UR - http://www.springer.de ER - TY - CHAP T1 - Overview of the Immune system A1 - R. Aspinall ED - J. C. Buckingham, G.E. Giles and A.M. Cowell T2 - Stress, Stress Hormones and the Immune System Y1 - 1997/// N2 - - ER - TY - CHAP T1 - Renal failure A1 - Warrens, A N ED - Hornick, P Lumley, J Grace, P T2 - Case presentations for the MRCS and AFRCS Y1 - 1997/// M2 - 2 PB - Butterworth Heinemann CY - London SN - 0-7506-3258-5 SP - 4 EP - 9 N2 - - ER - TY - CHAP T1 - Renal failure A1 - Warrens, A N ED - Hornick, P Lumley, J Grace, P T2 - Case presentations for the MRCS and AFRCS Y1 - 1997/// M2 - 1 PB - Butterworth Heinemann CY - London SN - 0-7506-3257-7 SP - 6 EP - 10 N2 - - ER - TY - CHAP T1 - Adhesion molecules in xenotransplantation A1 - Simon, A R A1 - Warrens, A N ED - Steinhoff, G T2 - Adhesion molecules in organ transplantation Y1 - 1997/// PB - Springer Verlag N2 - - ER - TY - CHAP T1 - Methods for monitoring immune function A1 - R. Aspinall ED - J. C. Buckingham, G.E. Giles and A.M. Cowell T2 - Stress, Stress Hormones and the Immune System Y1 - 1997/// PB - J.Wiley and sons N2 - - ER - TY - CONF T1 - Development of a hyperspectral fluorescence lifetime imaging microscope and its application to tissue imaging - art. no. 64411K A1 - Owen, DM A1 - Manning, HB A1 - de Beule, P A1 - Talbot, C A1 - Requejo-Isidro, J A1 - Dunsby, C A1 - McGinty, J A1 - Benninger, RKP A1 - Elson, DS A1 - Munro, I A1 - Galletly, NP A1 - Lever, MJ A1 - Stamp, GW A1 - Anand, P A1 - Neil, MAA A1 - French, PMW U1 - Conference on Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues V Y1 - 2007/// Y2 - // VL - 6441 SP - K4411 EP - K4411 N2 - - ER - TY - CONF T1 - A novel hyperspectral lifetime probe for autofluorescence - art. no. 643303 A1 - De Beule, PAA A1 - Dunsby, C A1 - Owen, DM A1 - Galletly, NP A1 - Anand, U A1 - Benham, CD A1 - Naylor, A A1 - Stamp, GW A1 - Anand, P A1 - French, PMW U1 - Conference on Optical Fibers and Sensors for Medical Diagnostics and Treatment Applications VII Y1 - 2007/// Y2 - // VL - 6433 SP - 43303 EP - 43303 N2 - - ER - TY - CONF T1 - Poly(ADP-ribose) polymerase-1 regulates Bcl-6 transcription A1 - Ambrose, HE A1 - Beswick, RW A1 - Wagner, SD A2 - Nicola Curtin U1 - PARP2005 AD - Newcastle J1 - Medical Science Monitor Y1 - 2005/10// Y2 - 2005/10/04/ VL - 11S1 PB - Medical Science International Ltd. CY - Warsaw SN - 1234-1010 N2 - - UR - http://www.MedSciMonit.com ER - TY - CONF T1 - Improved thymic function in exclusively breast-fed babies is associated with higher breast milk IL-7 A1 - Ngom, PT A1 - Collinson, AC A1 - Lopez, JP A1 - Henson, SM A1 - Prentice, AM A1 - Aspinall, R U1 - 12th Annual International Congress of Immunology and 4th Annual Conference of the Federation-of-Clinical-Immunology-Societies (FOCIS) Y1 - 2004/// Y2 - // SP - 309 EP - 313 N2 - - ER - TY - CONF T1 - Urinary levels of monocyte chemoattractant protein-1 (MCP-1) as a disease marker of disease activity in ANCA associated vasculitis A1 - Hammad TM A1 - Tam FWK A1 - Pusey CD A1 - Levy JB U1 - American Society of Nephrology 36th Meeting AD - San Diego Y1 - 2003/// Y2 - 2003/// VL - 14 PB - J Am Soc Nephrol N2 - - ER - TY - CONF T1 - Preventing Renal Disease: The NKRF ABLE project A1 - Lightstone L U1 - Ethnicity and Renal Failure: disparity or diversity? AD - British Library Y1 - 2003/// Y2 - 2003/10// PB - SouthWest Thames Renal Research Institute CY - St Helier Hospital, Carshalton, Surrey N2 - - ER - TY - CONF T1 - Urinary monocyte chemoattractant protein-1 is more useful than PDGF-BB or INF-? for monitoring activity of lupus nephritis A1 - Barhamein MY A1 - Tam FWK A1 - Lai P A1 - Chaudhry A A1 - Thompson M A1 - Pusey CD A1 - Lightstone L U1 - American Society of Nephrology 36th Meeting AD - San Diego Y1 - 2003/// Y2 - 2003/// VL - 14 PB - J Am Soc Nephrol N2 - - ER - TY - CONF T1 - Bench to Bedside: Anti-TNF a paradigm for biological targeted therapy A1 - Maini RN U1 - Therapeutic antibodies - 9th Annual Symposium - Ranbaxy Science Foundation AD - New Delhi Y1 - 2003/// Y2 - 2003/// PB - Ranbaxy Science Foundation SP - 13 EP - 24 N2 - - ER - TY - JFULL T1 - Anti-inflammatory functions of glucocorticoid-induced genes. A1 - Clark, AR J1 - Mol Cell Endocrinol Y1 - 2007/09/15/ VL - 275 SN - 0303-7207 SP - 79 EP - 97 N2 - There is a broad consensus that glucocorticoids (GCs) exert anti-inflammatory effects largely by inhibiting the function of nuclear factor kappaB (NFkappaB) and consequently the transcription of pro-inflammatory genes. In contrast, side effects are thought to be largely dependent on GC-induced gene expression. Biochemical and genetic evidence suggests that the positive and negative effects of GCs on transcription can be uncoupled from one another. Hence, novel GC-related drugs that mediate inhibition of NFkappaB but do not activate gene expression are predicted to retain therapeutic effects but cause fewer or less severe side effects. Here, we critically re-examine the evidence in favor of the consensus, binary model of GC action and discuss conflicting evidence, which suggests that anti-inflammatory actions of GCs depend on the induction of anti-inflammatory mediators. We propose an alternative model, in which GCs exert anti-inflammatory effects at both transcriptional and post-transcriptional levels, both by activating and inhibiting expression of target genes. The implications of such a model in the search for safer anti-inflammatory drugs are discussed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17561338&query_hl=1 ER - TY - JFULL T1 - Platelet-Derived Growth Factor Reorganizes the Actin Cytoskeleton through 3-Phosphoinositide-Dependent and 3-Phosphoinositide-Independent Mechanisms in Human Mesangial Cells. A1 - Harper, L A1 - Kashiwagi, Y A1 - Pusey, CD A1 - Hendry, BM A1 - Domin, J J1 - Nephron Physiol Y1 - 2007/09/05/ VL - 107 SN - 1660-2137 SP - p45 EP - p56 N2 - Background: Platelet-derived growth factor (PDGF) is a potent activator of mesangial cell proliferation and migration. Although phosphoinositide 3-kinase (PI3K) enzymes are important downstream targets of the PDGF receptor, the contribution made by their 3-phosphoinositide products in the reorganization of actin cytoskeleton and focal adhesions has been questioned. Methods and Results: Pharmacological inhibition of the PI3K activity blocks PDGF-induced migration of human primary mesangial cells using an in vitro scrape wound healing assay. Acute (<10 min) inhibition of the PI3K activity did not alter the effect of PDGF on either stress fibre dissolution or reorganization of focal adhesions. However, at later times (>30 min), PDGF-stimulated responses were inhibited. In contrast, PDGF-stimulated membrane ruffling remained insensitive to PI3K inhibitors throughout. Inhibition of protein kinase C and Erk also attenuated PDGF-stimulated mesangial cell migration; however, neither signaling pathway was responsible for the initial effects on filamentous actin and focal adhesions. Conclusions: We propose that following PDGF stimulation of mesangial cells, reorganization of the actin cytoskeleton occurs in a biphasic manner. The mechanism responsible for mesangial cell migration that occurs immediately following PDGF stimulation may serve to 'prime' for the subsequent 3-phosphoinositide-, protein-kinase-C-, and Erk-dependent migration. Copyright (c) 2007 S. Karger AG, Basel. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17804914&query_hl=1 ER - TY - JFULL T1 - A protein kinase Cepsilon /anti-apoptotic kinase signalling complex protects human vascular endothelial cells against apoptosis through induction of Bcl-2. A1 - Steinberg, R A1 - Harari, OA A1 - Lidington, EA A1 - Boyle, JJ A1 - Nohadani, M A1 - Samarel, AM A1 - Ohba, M A1 - Haskard, DO A1 - Mason, JC J1 - J Biol Chem Y1 - 2007/09/04/ SN - 0021-9258 N2 - Endothelial cell apoptosis is associated with vascular injury and predisposes to atherogenesis. EC express anti-apoptotic genes including Bcl-2, Bcl-X(L) and survivin, which also contribute to angiogenesis and vascular remodelling. We report a central role for PKCepsilon in the regulation of Bcl-2 expression and cytoprotection of human vascular endothelium against apoptosis. Using myristoylated inhibitory peptides, a predominant role for PKCepsilon in VEGF-mediated endothelial resistance to apoptosis was revealed. Immunoblotting of endothelial cells infected with an adenovirus expressing a constitutively-active form of PKCepsilon (Adv-PKCepsilon-CA) or control Adv-beta-gal demonstrated a 3-fold, PKCepsilon-dependent increase in Bcl-2 expression, with no significant change in Bcl-X(L), Bad, Bak or Bax. The induction of Bcl-2 inhibited apoptosis induced by serum starvation or etoposide, and PKCepsilon activation attenuated etoposide-induced caspase-3 cleavage. The functional role of Bcl-2 was confirmed with Bcl-2 antagonist HA-14-1. Inhibition of PI-3K attenuated VEGF-induced protection against apoptosis and this was rescued by over-expression of CA-PKCepsilon, suggesting PKCepsilon acts downstream of PI-3K. Co-immunoprecipitation studies demonstrated a physical interaction between PKCepsilon and Akt, which resulted in formation of a signaling complex, leading to optimal induction of Bcl-2. This study reveals a pivotal role for PKCepsilon in endothelial cell cytoprotection against apoptosis. We demonstrate that PKCepsilon forms a signalling complex and acts co-operatively with Akt to protect human vascular endothelial cells against apoptosis, through induction of the anti-apoptotic protein Bcl-2 and inhibition of caspase-3 cleavage. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17785460&query_hl=1 ER - TY - JFULL T1 - Reply to 'Splenectomy status of the patient may have impact on response to donor lymphocyte infusions' by Duygu Uckan-Cetinkaya et al. A1 - Dazzi, F A1 - Fozza, C J1 - Leukemia Y1 - 2007/09// VL - 21 SN - 0887-6924 SP - 2050 EP - 2051 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17597812&query_hl=1 ER - TY - JFULL T1 - The anti-allergic drug, N-(3',4'-dimethoxycinnamonyl) anthranilic acid, exhibits potent anti-inflammatory and analgesic properties in arthritis. A1 - Inglis, JJ A1 - Criado, G A1 - Andrews, M A1 - Feldmann, M A1 - Williams, RO A1 - Selley, ML J1 - Rheumatology (Oxford) Y1 - 2007/09// VL - 46 SN - 1462-0324 SP - 1428 EP - 1432 N2 - Objectives. The degradation of tryptophan by indoleamine 2,3-dioxygenase yields a number of immunomodulatory metabolites, including 3-hydroxyanthranilic acid, 3-hydroxykynurenic acid and quinolinic acid. N-(3',4'-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) is a synthetic anthranilic acid derivative that has been used therapeutically in Japan for many years as an anti-allergic drug and has recently been shown to be effective in a murine model of multiple sclerosis. Methods. In the present study, we tested the efficacy of 3,4-DAA in collagen-induced arthritis, a mouse model of rheumatoid arthritis, and analysed its mechanism of action. Results. Administration of 3,4-DAA after arthritis onset reduced clinical and histological severity of arthritis and reduced pain. It completely abrogated thermal and mechanical hyperalgesia. 3,4-DAA also suppressed Th1 cell activity in lymph node cell cultures and raised serum levels of IL-10. In vitro, 3,4-DAA suppressed IFNgamma production and proliferation of both T and B lymphocytes in a manner comparable with the endogenous tryptophan metabolite, 3-hydroxyanthranilic acid, suggesting similar mechanisms of action. Conclusion. It is concluded that 3,4-DAA has both anti-inflammatory and analgesic properties, and may therefore be useful in filling an unmet need, in the treatment of rheumatoid and other forms of arthritis, especially in the light of its analgesic properties. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17644821&query_hl=1 ER - TY - JFULL T1 - Mass Spectrometric Analysis of the Endogenous Type I Interleukin-1 (IL-1) Receptor Signaling Complex Formed after IL-1 Binding Identifies IL-1RAcP, MyD88, and IRAK-4 as the Stable Components. A1 - Brikos, C A1 - Wait, R A1 - Begum, S A1 - O'neill, LA A1 - Saklatvala, J J1 - Mol Cell Proteomics Y1 - 2007/09// VL - 6 SN - 1535-9476 SP - 1551 EP - 1559 N2 - We investigated the composition of the endogenous ligand-bound type I interleukin-1 (IL-1) receptor (IL-1RI) signaling complex using immunoprecipitation and tandem mass spectrometry. Three proteins with approximate molecular masses of 60 (p60), 36 (p36), and 90 kDa (p90) became phosphorylated after treatment with IL-1. Phosphorylation in vitro of p60 has been reported previously, but its identity was unknown. We showed using tandem mass spectrometry that p60 is identical to interleukin-1 receptor-associated kinase (IRAK)-4. MS also enabled detection of IL-1, IL-1RI, IL-1 receptor accessory protein (IL-1RAcP), and myeloid differentiation primary response protein 88 (MyD88) in the complex. The p60 protein (IRAK-4) was the earliest component of the complex to be phosphorylated. Phosphorylated IRAK-4 from the receptor complex migrated more slowly in SDS-PAGE than its unphosphorylated form as did recombinant IRAK-4 autophosphorylated in vitro. Phosphorylation was restricted to serine and threonine residues. IRAK-4, p36, IL-1RAcP, and MyD88 bound to the liganded receptor within 15 s of activation by IL-1 and remained associated upon prolonged activation, suggesting that the signaling complex is very stable. The p90 phosphoprotein was only transiently associated with the receptor. This behavior and its size were consistent with it being IRAK-1. Our work revealed that liganding of IL-1RI causes its strong and stable association with IL-1RAcP, MyD88, and the previously unidentified protein p60 (IRAK-4). The only component of the IL-1RI signaling complex that dissociated is IRAK-1. Our study is therefore the first detailed description of the endogenous IL-1RI complex. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17507369&query_hl=1 ER - TY - JFULL T1 - Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease. A1 - Tisato, V A1 - Naresh, K A1 - Girdlestone, J A1 - Navarrete, C A1 - Dazzi, F J1 - Leukemia Y1 - 2007/09// VL - 21 SN - 0887-6924 SP - 1992 EP - 1999 N2 - The immunosuppressive properties of mesenchymal stem cells (MSC) make them particularly attractive to manipulate graft-versus-host disease (GVHD). So far, the experience of using MSC to treat GVHD is limited to a few cases, controversial results come from preclinical models and several issues remain to be clarified. The present studies were designed to address these questions in a xenogenic model testing the ability of umbilical cord blood-derived MSC (UCB-MSC) to prevent and/or treat GVHD. Sublethally irradiatiated non-obese diabetic/severe combined immunodeficiency NOD/SCID mice transplanted with human peripheral blood mononuclear cells (huPBMC) showed extensive human T-cell proliferation in the peripheral blood, lymphoid and non-lymphoid tissues, which evolved in extensive GVHD (wasting, ruffled hair and hunched back). The mice treated with a single dose of UCB-MSC did not behave differently form the controls. However, when UCB-MSC were given at weekly intervals, there was a marked decrease in human T-cell proliferation and none of the mice developed GVHD. No therapeutic effect was obtained if UCB-MSC were administered at onset of GVHD. This work supports the clinical use of MSC in stem cell transplantation as a prophylaxis rather than treatment of GVHD.Leukemia (2007) 21, 1992-1999; doi:10.1038/sj.leu.2404847; published online 12 July 2007. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17625609&query_hl=1 ER - TY - JFULL T1 - Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. A1 - Lee-Kirsch, MA A1 - Gong, M A1 - Chowdhury, D A1 - Senenko, L A1 - Engel, K A1 - Lee, YA A1 - de Silva, U A1 - Bailey, SL A1 - Witte, T A1 - Vyse, TJ A1 - Kere, J A1 - Pfeiffer, C A1 - Harvey, S A1 - Wong, A A1 - Koskenmies, S A1 - Hummel, O A1 - Rohde, K A1 - Schmidt, RE A1 - Dominiczak, AF A1 - Gahr, M A1 - Hollis, T A1 - Perrino, FW A1 - Lieberman, J A1 - Hübner, N J1 - Nat Genet Y1 - 2007/09// VL - 39 SN - 1061-4036 SP - 1065 EP - 1067 N2 - TREX1 acts in concert with the SET complex in granzyme A-mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutières syndrome and familial chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3' UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 x 10(-7)). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17660818&query_hl=1 ER - TY - JFULL T1 - 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 - New approaches to the treatment of dense deposit disease. A1 - Smith, RJ A1 - Alexander, J A1 - Barlow, PN A1 - Botto, M A1 - Cassavant, TL A1 - Cook, HT A1 - de Córdoba, SR A1 - Hageman, GS A1 - Jokiranta, TS A1 - Kimberling, WJ A1 - Lambris, JD A1 - Lanning, LD A1 - Levidiotis, V A1 - Licht, C A1 - Lutz, HU A1 - Meri, S A1 - Pickering, MC A1 - Quigg, RJ A1 - Rops, AL A1 - Salant, DJ A1 - Sethi, S A1 - Thurman, JM A1 - Tully, HF A1 - Tully, SP A1 - van der Vlag, J A1 - Walker, PD A1 - Würzner, R A1 - Zipfel, PF A1 - Dense Deposit Disease Focus Group J1 - J Am Soc Nephrol Y1 - 2007/09// VL - 18 SN - 1046-6673 SP - 2447 EP - 2456 N2 - The development of clinical treatment protocols usually relies on evidence-based guidelines that focus on randomized, controlled trials. For rare renal diseases, such stringent requirements can represent a significant challenge. Dense deposit disease (DDD; also known as membranoproliferative glomerulonephritis type II) is a prototypical rare disease. It affects only two to three people per million and leads to renal failure within 10 yr in 50% of affected children. On the basis of pathophysiology, this article presents a diagnostic and treatment algorithm for patients with DDD. Diagnostic tests should assess the alternative pathway of complement for abnormalities. Treatment options include aggressive BP control and reduction of proteinuria, and on the basis of pathophysiology, animal data, and human studies, plasma infusion or exchange, rituximab, sulodexide, and eculizumab are additional options. Criteria for treatment success should be prevention of progression as determined by maintenance or improvement in renal function. A secondary criterion should be normalization of activity levels of the alternative complement pathway as measured by C3/C3d ratios and C3NeF levels. Outcomes should be reported to a central repository that is now accessible to all clinicians. As the understanding of DDD increases, novel therapies should be integrated into existing protocols for DDD and evaluated using an open-label Bayesian study design. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17675665&query_hl=1 ER - TY - JFULL T1 - The pathogenesis of vascular inflammation by anti-neutrophil cytoplasm antibodies A1 - Pusey, C J1 - PEDIATR NEPHROL Y1 - 2007/09// VL - 22 SN - 0931-041X SP - 1427 EP - 1427 ER - TY - JFULL T1 - Protein Sulfenation as a Redox Sensor: Proteomics Studies Using a Novel Biotinylated Dimedone Analogue. A1 - Charles, RL A1 - Schröder, E A1 - May, G A1 - Free, P A1 - Gaffney, PR A1 - Wait, R A1 - Begum, S A1 - Heads, RJ A1 - Eaton, P J1 - Mol Cell Proteomics Y1 - 2007/09// VL - 6 SN - 1535-9476 SP - 1473 EP - 1484 N2 - Protein sulfenic acids are reactive intermediates in the catalytic cycles of many enzymes as well as the in formation of other redox states. Sulfenic acid formation is a reversible post-translational modification with potential for protein regulation. Dimedone (5,5-dimethyl-1,3-cyclohexanedione) is commonly used in vitro to study sulfenation of purified proteins, selectively "tagging" them, allowing monitoring by mass spectrometry. However dimedone is of little use in complex protein mixtures because selective monitoring of labeling is not possible. To address this issue, we synthesized a novel biotinylated derivative of dimedone, keeping the dione cassette required for sulfenate reactivity but adding the functionality of a biotin tag. Biotin-amido(5-methyl-5-carboxamidocyclohexane 1,3-dione) tetragol (biotin dimedone) was prepared in six steps, combining 3,5-dimethoxybenzoic acid (Birch reduction, ultimately leading to the dimedone unit with a carboxylate functionality), 1-amino-11-azido-3,6,9-trioxaundecane (a differentially substituted tetragol spacer), and biotin. We loaded biotin dimedone (0.1 mm, 30 min) into rat ventricular myocytes, treated them with H(2)O(2) (0.1-10,000 mum, 5 min), and monitored derivatization on Western blots using streptavidin-horseradish peroxidase. There was a dose-dependent increase in labeling of multiple proteins that was maximal at 0.1 or 1 mm H(2)O(2) and declined sharply below basal with 10 mm treatment. Cell-wide labeling was observed in fixed cells probed with avidin-FITC using a confocal fluorescence microscope. Similar H(2)O(2)-induced labeling was observed in isolated rat hearts. Hearts loaded and subjected to hypoxia showed a striking loss of labeling, which returned when oxygen was resupplied, highlighting the protein sulfenates as oxygen sensors. Cardiac proteins that were sulfenated during oxidative stress were purified with avidin-agarose and identified by separation of tryptic digests by liquid chromatography with on-line analysis by mass spectrometry. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17569890&query_hl=1 ER - TY - JFULL T1 - Monocytosis in BXSB mice is due to epistasis between Yaa and the telomeric region of Chromosome 1 but does not drive the disease process. A1 - Rogers, NJ A1 - Gabriel, L A1 - Nunes, CT A1 - Rose, SJ A1 - Thiruudaian, V A1 - Boyle, J A1 - Morley, BJ J1 - Genes Immun Y1 - 2007/08/30/ SN - 1466-4879 N2 - The BXSB murine model of systemic lupus erythematosus is differentiated from other murine models of lupus by a severe monocytosis. The recently identified Y-linked autoimmune accelerator locus, Yaa, which is fundamental to accelerated disease in male BXSB mice, is required for the monocytic phenotype in BXSB. It has also recently been shown to induce monocytosis in combination with the Nba2 locus from NZB. To dissect the genetic basis and associated pathogenicity of BXSB-related monocytosis, a panel of existing congenic mice were studied and a novel sub-congenic mouse B10.Y(BXSB).BXSB-Bxs3 was generated. Monocytosis was found to be caused by an epistatic interaction between Yaa and the telomeric region of chromosome 1, an area of approximately 30 cM. Bxs3 and Yaa together were sufficient to generate monocytosis equivalent to that of BXSB. In contrast to the NZB model, however, where monocytosis tightly correlated with autoantibody production and lethal lupus nephritis, this was not the case in BXSB. While Yaa(+) mice bearing the Bxs3 locus drive monocytosis, glomerulonephritis and autoantibody production, both autoantibody production and nephritis are discreet events that occur in the absence of the Bxs3 locus. Yaa is a pre-requisite for monocytosis, demonstrating a novel synergistic interaction between Yaa and Bxs3.Genes and Immunity advance online publication, 30 August 2007; doi:10.1038/sj.gene.6364424. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17728791&query_hl=1 ER - TY - JFULL T1 - 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 - Immunotherapy with Antibody-Targeted HLA Class I Complexes: Results of in vivo Tumour Cell Killing and Therapeutic Vaccination. A1 - Savage, P A1 - Dyson, J A1 - Milrain, M A1 - Mathews, D A1 - King, B A1 - Chan, HT A1 - Barber, L A1 - Epenetos, A A1 - Ogg, G A1 - McMichael, A A1 - Glennie, MJ A1 - French, RR J1 - Tumour Biol Y1 - 2007/08/20/ VL - 28 SN - 1010-4283 SP - 205 EP - 211 N2 - Background: The delivery of antibody-targeted major histocompatibility complex (MHC) class I complexes containing immunogenic peptides to the surface of tumour cells allows cytotoxic T lymphocytes (CTLs) of non-tumour specificity to recognise and kill the tumour cell. Previous studies have demonstrated the activity of this system in vitro and in a simple pre-clinical model. This system has also been shown to be an effective method of expanding antigen-specific CTLs in vitro when used to target MHC class I complexes to the surface of B cells. Methods: Mice were immunised with ovalbumin and the survival of EL4Hu20 lymphoma cells targeted with H2-D(b)/Ova complexes and control MHC complexes was compared by FACS analysis. A tumour protection assay was performed where immunised mice were injected B16Hu20 melanoma cells targeted with H2-K(b)/Ova or control complexes. T cell expansion in vivo was examined by administering B cells targeted with MHC class I/peptide complexes and assessing T cell expansion by tetramer analysis. Results: In vivo killing of H2-D(b)/Ova-targeted lymphoma cells in the immunised mice was demonstrated with these cells present at only 12% of the level of the control cells. In contrast, in non-immunised mice the survival of H2-D(b)/Ova-targeted and control cells was comparable. In the tumour protection assay, injection of melanoma cells targeted with H2-K(b)/Ova complexes resulted in the development of only a solitary metastasis in each mouse. This compared to an average of 130 metastases in the control mice injected with B16Hu20 cells targeted with a control MHC peptide complex. In vivo CTL expansion was demonstrated after a single intravenous administration of Daudi B cells coated with H2-D(b)/Uty complexes produced an increase in the proportion of Uty-reactive CTLs from 3.3 to 21.5%. Conclusion: This study supports the development of antibody-delivered MHC complexes as a method of producing CTL-mediated lysis of cancer cells in vivo. As a therapeutic vaccine, the system may provide an effective approach for expanding oligoclonal T cell responses in vivo in the treatment of malignancy and infectious diseases. Copyright (c) 2007 S. Karger AG, Basel. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17709989&query_hl=1 ER - TY - JFULL T1 - Tuberculosis antigen-specific immune responses can be detected using enzyme-linked immunospot technology in human immunodeficiency virus (HIV)-1 patients with advanced disease. A1 - Clark, SA A1 - Martin, SL A1 - Pozniak, A A1 - Steel, A A1 - Ward, B A1 - Dunning, J A1 - Henderson, DC A1 - Nelson, M A1 - Gazzard, B A1 - Kelleher, P J1 - Clin Exp Immunol Y1 - 2007/08/02/ SN - 0009-9104 N2 - There are limited data on the efficacy of T cell-based assays to detect tuberculosis (TB) antigen-specific responses in immune-deficient human immunodeficiency virus (HIV) patients. The aim of this study is to determine whether TB antigen-specific immune responses can be detected in patients with HIV-1 infection, especially in those with advanced disease (CD4 T cell count < 300 cells/microl). An enzyme-linked immunospot (ELISPOT) assay, which detects interferon (IFN)-gamma secreted by T cells exposed to TB antigens, was used to assess specific immune responses in a prospective study of 201 HIV-1-infected patients with risk factors for TB infection, attending a single HIV unit. The performance of the ELISPOT assay to detect TB antigen-specific immune responses is independent of CD4 T cell counts in HIV-1 patients. The sensitivity and specificity of this assay for the diagnosis of active tuberculosis does not differ significantly from values obtained in immunocompetent subjects. The negative predictive value of the TB ELISPOT test is 98.2%. A positive predictive value of 86% for the diagnosis of active tuberculosis was found when the combined number of early secretory antigen target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) IFN-gamma spots to CD4 T cell count ratio was > 1.5. TB antigen-specific immune responses can be detected in HIV patients with low CD4 T cell counts using ELISPOT technology in a routine diagnostic laboratory and is a useful test to exclude TB infection in immune-deficient HIV-1 patients. A combination of TB antigen-specific IFN-gamma responses and CD4 T cell counts has the potential to distinguish active tuberculosis from latent infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17672869&query_hl=1 ER - TY - JFULL T1 - Separate cell culture conditions to promote proliferation or quiescent cell survival in chronic lymphocytic leukemia. A1 - Willimott, S A1 - Baou, M A1 - Huf, S A1 - Wagner, SD J1 - Leuk Lymphoma Y1 - 2007/08// VL - 48 SN - 1042-8194 SP - 1647 EP - 1650 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17701602&query_hl=1 ER - TY - JFULL T1 - In vivo evidence for apoptosis in the bone marrow in systemic lupus erythematosus. A1 - Hepburn, AL A1 - Lampert, IA A1 - Boyle, JJ A1 - Horncastle, D A1 - Ng, WF A1 - Layton, M A1 - Vyse, TJ A1 - Botto, M A1 - Mason, JC J1 - Ann Rheum Dis Y1 - 2007/08// VL - 66 SN - 0003-4967 SP - 1106 EP - 1109 N2 - An increase in leucocyte apoptosis and impaired clearance of apoptotic cells has been observed in patients with systemic lupus erythematosus (SLE). Apoptotic cells are likely to be a key source of autoantigens in SLE as they express many of the nuclear autoantigens (in surface blebs and apoptotic bodies) that are relevant to this disease. The clearance of apoptotic cells is usually a rapid process, such that few cells are usually seen in the extracellular environment in vivo. We report a case in which multiple apoptotic bodies were observed in the bone marrow of a patient with SLE that was complicated by an immune-mediated pancytopenia. We have subsequently examined the frequency of apoptotic cells, identified morphologically, and by caspase-3 staining in bone-marrow trephine samples taken from patients with SLE over a 10-year period of follow-up. A high proportion of bone marrows contained apoptotic debris. The novel demonstration of apoptotic bodies in vivo in patients with SLE is unusual and supports the notion that the marrow may be a target organ in the disease. Their abundance is also consistent with the hypothesis that normal clearance mechanisms are defective and/or overwhelmed in SLE. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17277002&query_hl=1 ER - TY - JFULL T1 - 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 - Implication of the satellite cell in dystrophic muscle fibrosis: a self-perpetuating mechanism of collagen overproduction. A1 - Alexakis, C A1 - Partridge, T A1 - Bou-Gharios, G J1 - Am J Physiol Cell Physiol Y1 - 2007/08// VL - 293 SN - 0363-6143 SP - C661 EP - C669 N2 - Because of its mechanical function, skeletal muscle is heavily influenced by the composition of its extracellular matrix (ECM). Fibrosis generated by chronic damage, such as occurs in muscular dystrophies, is thus particularly disastrous in this tissue. Here, we examined the interrelationship between the muscle satellite cell and the production of collagen type I, a major component of fibrotic ECM, by using both C2C12, a satellite cell-derived cell line, and primary muscle satellite cells. In C2C12 cells, we found that expression of collagen type I mRNA decreases substantially during skeletal muscle differentiation. On a single-cell level, collagen type I and myogenin became mutually exclusive after 3 days in differentiation medium, whereas addition of collagen markedly suppressed differentiation of C2C12 cells. Primary cultures of satellite cells associated with isolated single fibers of the young (4 wk old) mdx dystrophic mouse and of C57BL/10ScSn wild-type controls expressed collagen type I and type III mRNA and protein. This pattern persisted in wild-type mice at all ages. But, curiously, in older (18-mo-old) mdx mice, although the myogenic cells continued to express type III collagen, type I expression became restricted to nonmyogenic cells. These cells typically constituted part of a cellular sheet surrounding the old mdx fibers. This combination of features strongly suggests that the progression to fibrosis in dystrophic muscle involves changes in the mechanisms controlling matrix production, which generates positive feedback that results in a reprogramming of myoblasts to a profibrotic function. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17475662&query_hl=1 ER - TY - JFULL T1 - 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 - Cytokine inhibitors in rheumatoid arthritis and other autoimmune diseases. A1 - Williams, RO A1 - Paleolog, E A1 - Feldmann, M J1 - Curr Opin Pharmacol Y1 - 2007/08// VL - 7 SN - 1471-4892 SP - 412 EP - 417 N2 - The clinical success of TNFalpha blocking biologics in a growing number of immune-mediated pathologies, including rheumatoid arthritis, Crohn's disease, ankylosing spondylitis and psoriasis, confirms the importance of TNFalpha in driving chronic inflammation and represents an important step forward in the treatment of these conditions. TNFalpha blockade, however, is a treatment, rather than a cure, and is not effective in all patients or in all autoimmune diseases and further research is needed to get closer to a cure. Recently, the identification of a novel, IL-17 producing, T helper cell subset, that plays a dominant pathogenic role in animal models of autoimmunity, is a major advance on existing knowledge, although the role of these cells in human disease remains to be established. Cytokines driving angiogenesis are also important in disease chronicity and thus might be valid therapeutic targets. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17627887&query_hl=1 ER - TY - JFULL T1 - Regulation of fibroblast migration by tenascin-C. A1 - Trebaul, A A1 - Chan, EK A1 - Midwood, KS J1 - Biochem Soc Trans Y1 - 2007/08// VL - 35 SN - 0300-5127 SP - 695 EP - 697 N2 - Synthesis of new tissue by fibroblasts is required for tissue rebuilding in response to injury. Fibroblast migration from surrounding healthy tissue into the fibrin-fibronectin provisional matrix deposited upon injury is a key rate-limiting step of this stage of tissue repair. These events must be tightly regulated. Excessive deposition of scar tissue is the major hallmark of fibrotic disease. Tenascin-C is an extracellular matrix glycoprotein that is transiently expressed upon tissue injury, where it is specifically localized to the wound edge, and persistently up-regulated in fibrotic disease. We have shown that full-length tenascin-C promotes fibroblast migration within fibrin-fibronectin matrices and we have mapped the domains within the molecule critical for enhancing migration. We also demonstrated that specific fragments of tenascin-C inhibit fibroblast migration. These results suggest that transient expression of tenascin-C at the wound boundary is key to tissue repair: its induction recruits fibroblasts into the wound and fragments resulting from its breakdown prevent excessive fibroblast infiltration. Our results demonstrate how fibroblast migration in three-dimensional provisional matrices may be differentially regulated by proteolysis of matrix molecules and could explain how persistent expression of tenascin-C contributes to the progression of fibrotic disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17635125&query_hl=1 ER - TY - JFULL T1 - C1q deficiency promotes the production of transgenic-derived IgM and IgG3 autoantibodies in anti-DNA knock-in transgenic mice. A1 - Fossati-Jimack, L A1 - Cortes-Hernandez, J A1 - Norsworthy, PJ A1 - Walport, MJ A1 - Cook, HT A1 - Botto, M J1 - Mol Immunol Y1 - 2007/07/31/ SN - 0161-5890 N2 - C1q-deficient mice have been shown to develop a lupus-like disease and to display an impaired clearance of apoptotic cells that are enriched in lupus autoantigens. However, the role of C1q in the regulation of autoreactive B cells remains debatable. To explore this we crossed MRL/Mp C1q-deficient mice with knock-in transgenic (Tg) mice expressing an anti-ssDNA antibody (V(H)3H9R and V(H)3H9R/V(L)kappa8R). Analysis of the V(H)3H9R mice showed that in the absence of C1q higher titres of Tg-derived IgM and IgG(3) anti-ssDNA antibodies were detectable. In contrast, in the V(H)3H9R/V(L)kappa8R C1q-deficient animals no increase in Tg antibody levels was observed. In both models the lack of C1q induced a marked reduction of marginal zone B cells and this was paralleled by a significant increase in the percentage of plasmocytes. Thus, one could postulate that in the absence of C1q the failure to clear efficiently dying cells provides an additional stimulus to the autoreactive Tg B cells resulting in their emigration from the marginal zone B cell compartment with subsequent increase in plasmocytes. However, the lack of C1q led to an increased production of Tg IgM and IgG(3) antibodies only in V(H)3H9R mice indicating that additional genetic susceptibility factors are required to break self-tolerance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17675234&query_hl=1 ER - TY - JFULL T1 - A patient with suspected miscarriage is found to have hypertension, renal failure, and thrombocytopenia: case outcome. A1 - Laing, CM A1 - Roberts, R A1 - Lightstone, L A1 - Graham, A A1 - Cook, TH A1 - Summers, S A1 - Pusey, CD J1 - BMJ Y1 - 2007/07/28/ VL - 335 SN - 1468-5833 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17656546&query_hl=1 ER - TY - JFULL T1 - Key differences in TLR3/POLY I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems. A1 - Lundberg, AM A1 - Drexler, SK A1 - Monaco, C A1 - Williams, LM A1 - Sacre, SM A1 - Feldmann, M A1 - Foxwell, BM J1 - Blood Y1 - 2007/07/27/ SN - 0006-4971 N2 - TLR3 recognizes double-stranded RNA, a product associated with viral infections. Many details of TLR3-induced mechanisms have emerged from gene-targeted mice or inhibition studies in transformed cell lines. However, the pathways activated in human immune cells or cells from disease tissue are less well understood. We have investigated TLR3-induced mechanisms of human primary cells of the innate immune system, including dendritic cells (DC), macrophages (MØ), endothelial cells (EC) and synovial fibroblasts isolated from rheumatoid arthritis joint tissue (RA-SF). Here we report that while these cells all express TLR3 they differ substantially in their response to TLR3 stimulation. The key antiviral response chemokine IP-10 was produced by all cell types, while DC and MØ failed to produce the proinflammatory cytokines TNFalpha and IL-6. Unexpectedly, TNFalpha was found secreted by TLR3 stimulated RA-SF. Furthermore, TLR3 stimulation did not activate NFkappaB, MAPKs or IRF-3 in DC and MØ, but were able to do so in EC and RA-SF. These findings were specific for human cells thereby revealing a complexity not previously expected. This is the first report of such cell type and species-specific response for any TLR stimulation and helps understand important difficulties in correlating murine models of inflammatory diseases and human inflammation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17660379&query_hl=1 ER - TY - JFULL T1 - Alpha1,3-galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here? A1 - Cooper, DK A1 - Dorling, A A1 - Pierson, RN A1 - Rees, M A1 - Seebach, J A1 - Yazer, M A1 - Ohdan, H A1 - Awwad, M A1 - Ayares, D J1 - Transplantation Y1 - 2007/07/15/ VL - 84 SN - 0041-1337 SP - 1 EP - 7 N2 - The ability to genetically engineer pigs that no longer express the Galalpha1,3Gal (Gal) oligosaccharide has been a significant step toward the clinical applicability of xenotransplantation. Using a chronic immunosuppressive regimen based on costimulatory blockade, hearts from these pigs have survived from 2 to 6 months in baboons. Graft failure was predominantly from the development of a thrombotic microangiopathy. Potential contributing factors include the presence of preformed anti-nonGal antibodies or the development of low levels of elicited antibodies to nonGal antigens, natural killer (NK) cell or macrophage activity, and inherent coagulation dysregulation between pigs and primates. The breeding of pigs transgenic for an "anticoagulant" gene, such as human tissue factor pathway inhibitor, hirudin, or CD39, or lacking the gene for the prothrombinase, fibrinogen-like protein-2, is anticipated to inhibit the change in the endothelium to a procoagulant state that takes place in the pig organ after transplantation. The identification of the targets for anti-nonGal antibodies and/or human macrophages might allow further genetic modification of the pig, and xenogeneic NK cell recognition and activation may be inhibited by the transgenic expression of human leukocyte antigen molecules and/or by blocking the function of activating NK receptors. The ultimate goal of induction of T-cell tolerance may be possible only if these hurdles in the coagulation system and innate immunity can be overcome. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17627227&query_hl=1 ER - TY - JFULL T1 - 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 - A patient with suspected miscarriage is found to have hypertension, renal failure, and thrombocytopenia: case progression. A1 - Laing, CM A1 - Roberts, R A1 - Lightstone, L A1 - Graham, A A1 - Cook, TH A1 - Summers, S A1 - Pusey, CD J1 - BMJ Y1 - 2007/07/07/ VL - 335 SN - 1468-5833 SP - 44 N2 - L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17615226&query_hl=1 ER - TY - JFULL T1 - Disease progression after bone marrow transplantation in a model of multiple sclerosis is associated with chronic microglial and glial progenitor response. A1 - Cassiani-Ingoni, R A1 - Muraro, PA A1 - Magnus, T A1 - Reichert-Scrivner, S A1 - Schmidt, J A1 - Huh, J A1 - Quandt, JA A1 - Bratincsak, A A1 - Shahar, T A1 - Eusebi, F A1 - Sherman, LS A1 - Mattson, MP A1 - Martin, R A1 - Rao, MS J1 - J Neuropathol Exp Neurol Y1 - 2007/07// VL - 66 SN - 0022-3069 SP - 637 EP - 649 N2 - Multiple sclerosis (MS), the most common nontraumatic cause of neurologic disability in young adults in economically developed countries, is characterized by inflammation, gliosis, demyelination, and neuronal degeneration in the CNS. Bone marrow transplantation (BMT) can suppress inflammatory disease in a majority of patients with MS but retards clinical progression only in patients treated in the early stages of the disease. Here, we applied BMT in a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE), and investigated the kinetics of reconstitution of the immune system in the periphery and in the CNS using bone marrow cells isolated from syngeneic donors constitutively expressing green fluorescent protein. This approach allowed us to dissect the contribution of donor cells to the turnover of resident microglia and to the pathogenesis of observed disease relapses after BMT. BMT effectively blocked or delayed EAE development when mice were treated early in the course of the disease but was without effect in mice with chronic disease. We found that there is minimal overall replacement of host microglia with donor cells in the CNS and that newly transplanted cells do not appear to contribute to disease progression. In contrast, EAE relapses are accompanied by the robust activation of endogenous microglial and macroglial cells, which further involves the maturation of endogenous Olig2 glial progenitor cells into reactive astrocytes through the cytoplasmic translocation of Olig2 and the expression of CD44 on the cellular membrane. The observed maturation of large numbers of reactive astrocytes from glial progenitors and the chronic activation of host microglial cells have relevance for our understanding of the resident glial response to inflammatory injury in the CNS. Our data indicate that reactivation of a local inflammatory process after BMT is sustained predominantly by endogenous microglia/macrophages. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17620989&query_hl=1 ER - TY - JFULL T1 - Gene expression profiling of fibroblasts in response to applied bio-mechanical force A1 - Eastwood, M A1 - Shiwen, X A1 - Bou-Gharios, G A1 - Black, C A1 - Abraham, D J1 - TISSUE ENG Y1 - 2007/07// VL - 13 SN - 1076-3279 SP - 1699 EP - 1699 ER - TY - JFULL T1 - Natural killer cells, killer immunoglobulin-like receptors and human leucocyte antigen class I in disease. A1 - Boyton, RJ A1 - Altmann, DM J1 - Clin Exp Immunol Y1 - 2007/07// VL - 149 SN - 0009-9104 SP - 1 EP - 8 N2 - Natural killer cells constitute a potent, rapid part of the innate immune response to infection or transformation, and also generate a link to priming of adaptive immunity. Their function can encompass direct cytotoxicity as well as the release of cytokines and chemokines. In humans, a major component of natural killer (NK) cell target recognition depends mainly on the surveillance of human leucocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIR). Different KIR can transmit inhibitory or activatory signals to the cell, and effector function is considered to result from the balance of these contributing signals. The regulation of NK cell responses depends on a number of variables: KIR genotype, HLA genotype, heterozygosity versus homozygosity for these, whether there is cognate recognition between the HLA and KIR products carried by an individual, clonal variation between individual NK cells in KIR expression, and the specific modulation of HLA expression by infection, transformation or peptide binding. Different HLA/KIR genotypes can impart different thresholds of activation to the NK cell repertoire and such genotypic variation has been found to confer altered risk in a number of diseases including human immunodeficiency virus (HIV) susceptibility and progression, hepatitis C virus clearance, idiopathic bronchiectasis, autoimmunity and cancer. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17521317&query_hl=1 ER - TY - JFULL T1 - FGF-2 is bound to perlecan in the pericellular matrix of articular cartilage, where it acts as a chondrocyte mechanotransducer. A1 - Vincent, TL A1 - McLean, CJ A1 - Full, LE A1 - Peston, D A1 - Saklatvala, J J1 - Osteoarthritis Cartilage Y1 - 2007/07// VL - 15 SN - 1063-4584 SP - 752 EP - 763 N2 - OBJECTIVE: We have shown previously that cutting or loading articular cartilage resulted in a fibroblast growth factor-2 (FGF-2) dependent activation of the extracellularly regulated kinase (ERK), and induction of a number of chondrocyte regulatory proteins including tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases 1 and 3. An extracellular matrix-bound pool of FGF-2 was apparent, which could be liberated from the tissue by heparitinase (Vincent et al., Proc Natl Acad Sci U S A 2002;99(12):8259-64, Vincent et al., Arthritis Rheum 2004 Feb;50(2):526-33). Our objectives were to determine where FGF-2 was stored in articular cartilage, to which proteoglycan it was bound, and to elucidate its role in chondrocyte mechanotransduction. METHODS: Immunohistochemistry and confocal microscopy were used to localise FGF-2 in the tissue. In vitro binding studies were performed using IASYS surface plasmon resonance. To study the role of pericellular FGF-2 in mechanotransduction cartilage explants or articular chondrocytes encapsulated in alginate were loaded using an in house loading rig. The loading response was assessed by the activation of ERK, in the presence or absence of a specific FGFR inhibitor. RESULTS: Here we have identified perlecan as the heparan sulphate proteoglycan that sequesters FGF-2 in articular cartilage. Perlecan and FGF-2 co-localised within the type VI collagen-rich pericellular matrix of porcine and human articular cartilage. Chondrocytes encapsulated in alginate were able to accumulate pericellular perlecan and FGF-2 in culture, and deliver an FGF-dependent activation of ERK when loaded. CONCLUSION: Loading-induced ERK activation was dependent upon the presence and concentration of pericellular FGF-2, suggesting a functional role for this matrix-bound growth factor in chondrocyte mechanotransduction. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17368052&query_hl=1 ER - TY - JFULL T1 - Insertional polymorphisms: a new lease of life for endogenous retroviruses in human disease. A1 - Moyes, D A1 - Griffiths, DJ A1 - Venables, PJ J1 - Trends Genet Y1 - 2007/07// VL - 23 SN - 0168-9525 SP - 326 EP - 333 N2 - Human endogenous retroviruses (HERVs) result from ancestral infection by infectious viruses over millions of years of primate evolution. Some are transcriptionally active, express proteins and therefore have the potential to cause disease. Here we review the controversial attempts to link them with cancer and autoimmunity. The main difficulty is that most HERVs investigated to date are present at the same locus in 100% of the population. However, a new class of insertionally polymorphic HERV-K family members, present in a minority of individuals, has recently been described. We propose that insertionally polymorphic HERVs could be novel genetic risk factors and hence provide a new lease of life for research into HERVs and disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17524519&query_hl=1 ER - TY - JFULL T1 - Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. A1 - Jayne, DR A1 - Gaskin, G A1 - Rasmussen, N A1 - Abramowicz, D A1 - Ferrario, F A1 - Guillevin, L A1 - Mirapeix, E A1 - Savage, CO A1 - Sinico, RA A1 - Stegeman, CA A1 - Westman, KW A1 - van der Woude, FJ A1 - de Lind van Wijngaarden, RA A1 - Pusey, CD A1 - European Vasculitis Study Group J1 - J Am Soc Nephrol Y1 - 2007/07// VL - 18 SN - 1046-6673 SP - 2180 EP - 2188 N2 - Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17582159&query_hl=1 ER - TY - JFULL T1 - A patient with suspected miscarriage is found to have hypertension, renal failure, and thrombocytopenia: case presentation. A1 - Laing, CM A1 - Roberts, R A1 - Lightstone, L A1 - Graham, A A1 - Cook, TH A1 - Summers, S A1 - Pusey, CD J1 - BMJ Y1 - 2007/06/30/ VL - 334 SN - 1468-5833 SP - 1372 N2 - L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17600028&query_hl=1 ER - TY - JFULL T1 - Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. A1 - Gendron, C A1 - Kashiwagi, M A1 - Lim, NH A1 - Enghild, JJ A1 - Thøgersen, IB A1 - Hughes, C A1 - Caterson, B A1 - Nagase, H J1 - J Biol Chem Y1 - 2007/06/22/ VL - 282 SN - 0021-9258 SP - 18294 EP - 18306 N2 - Aggrecanases have been characterized as proteinases that cleave the Glu373-Ala374 bond of the aggrecan core protein, and they are multidomain metalloproteinases belonging to the ADAMTS (adamalysin with thrombospondin type 1 motifs) family. The first aggrecanases discovered were ADAMTS-4 (aggrecanase 1) and ADAMTS-5 (aggrecanase 2). They contain a zinc catalytic domain followed by non-catalytic ancillary domains, including a disintegrin domain, a thrombospondin domain, a cysteine-rich domain, and a spacer domain. In the case of ADAMTS-5, a second thrombospondin domain follows the spacer domain. We previously reported that the non-catalytic domains of ADAMTS-4 influence both its extracellular matrix interaction and proteolytic abilities. Here we report the effects of these domains of ADAMTS-5 on the extracellular matrix interaction and proteolytic activities and compare them with those of ADAMTS-4. Although the spacer domain was critical for ADAMTS-4 localization in the matrix, the cysteine-rich domain influenced ADAMTS-5 localization. Similar to previous reports of other ADAMTS family members, very little proteolytic activity was detected with the ADAMTS-5 catalytic domain alone. The sequential inclusion of each carboxyl-terminal domain enhanced its activity against aggrecan, carboxymethylated transferrin, fibromodulin, decorin, biglycan, and fibronectin. Both ADAMTS-4 and -5 had a broad optimal activity at pH 7.0-9.5. Aggrecanolytic activities were sensitive to the NaCl concentration, but activities on non-aggrecan substrates, e.g. carboxymethylated transferrin, were not affected. Although ADAMTS-4 and ADAMTS-5 had similar general proteolytic activities, the aggrecanase activity of ADAMTS-5 was at least 1,000-fold greater than that of ADAMTS-4 under physiological conditions. Our studies suggest that ADAMTS-5 is a major aggrecanase in cartilage metabolism and pathology. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17430884&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 - 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 - Results of endoscopic surgery and intralesional steroid therapy for airway compromise due to tracheobronchial Wegener's Granulomatosis. A1 - Nouraei, SA A1 - Obholzer, R A1 - Ind, PW A1 - Salama, AD A1 - Pusey, CD A1 - Porter, F A1 - Howard, DJ A1 - Sandhu, GS J1 - Thorax Y1 - 2007/06/15/ SN - 0040-6376 N2 - BACKGROUND: Upper airway compromise due to tracheobronchial stenosis commonly occurs in patients with Wegener's Granulomatosis (WG). There is at present no consensus on the optimal management of this life-threatening condition. OBJECTIVE: To assess the results of laryngo-tracheo-bronchoscopy, intralesional steroid therapy, laser surgery and dilatation in managing obstructive tracheobronchial WG. Methods Records of eighteen previously-untreated stridulous patients with obstructive tracheobronchial WG, treated between 2004 and 2006 were prospectively recorded on an airway database and retrospectively reviewed. Information about patient and lesion characteristics and treatment details were recorded. Treatment progress was illustrated using a timeline plot, and intervention-free intervals were calculated with actuarial analysis. RESULTS: There were nine males and the average age at presentation was 40 (16) years [range 13-74]. There were thirteen patients with tracheal, and five patients with tracheal and bronchial lesions. The average tracheal lesion height was 8 (3) mm, located 23 (9) mm below the glottis. There were 1, 10 and 7 Myer-Cotton grade I, II and III lesions respectively. Mean intervention-free interval following minimally-invasive treatment was 26 (2.8) months. Following endobronchial therapy the median intervention-free interval was 22 months (p>0.8 vs. tracheal lesions). No patient required a tracheostomy or endoluminal stenting. CONCLUSIONS: Intralesional steroid therapy and conservative endoluminal surgery is an effective strategy for treating airway compromise due to active tracheal and bronchial WG. It obviates the need for airway bypass or stenting. We recommend the combination of endotracheal dilatation, conservative laser surgery and steroid therapy as the standard of care for treating airway compromise due to obstructive tracheobronchial WG. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17573443&query_hl=1 ER - TY - JFULL T1 - Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. A1 - Pickering, MC A1 - de Jorge, EG A1 - Martinez-Barricarte, R A1 - Recalde, S A1 - Garcia-Layana, A A1 - Rose, KL A1 - Moss, J A1 - Walport, MJ A1 - Cook, HT A1 - de Córdoba, SR A1 - Botto, M J1 - J Exp Med Y1 - 2007/06/11/ VL - 204 SN - 0022-1007 SP - 1249 EP - 1256 N2 - Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype-phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17517971&query_hl=1 ER - TY - JFULL T1 - Disease relapse after haematopoietic stem cell transplantation: risk factors and treatment. A1 - Dazzi, F A1 - Fozza, C J1 - Best Pract Res Clin Haematol Y1 - 2007/06// VL - 20 SN - 1521-6926 SP - 311 EP - 327 N2 - Disease relapse is the commonest cause of treatment failure after allogeneic haematopoietic stem-cell transplantation. Adoptive immunotherapy based on donor lymphocyte infusions (DLI) has a prominent role in the management of disease recurrence. Although the highest remission rates are achieved in chronic myeloid leukaemia (CML), encouraging results have also been reported in chronic lymphoproliferative disorders. However, the experience of DLI in CML is not necessarily applicable to the management of lymphoproliferative diseases because of the heterogeneity of the conditioning regimens used in chronic lymphoid malignancies. We will review the role of DLI for different disease types in the context of conventional and reduced-intensity conditioning regimens. The factors influencing response and graft-versus-host disease as well as the optimal cell dose will be discussed. Finally, we will describe the main avenues currently being explored to improve the selectivity and efficacy of DLI. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17448964&query_hl=1 ER - TY - JFULL T1 - FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. A1 - Fanciulli, M A1 - Norsworthy, PJ A1 - Petretto, E A1 - Dong, R A1 - Harper, L A1 - Kamesh, L A1 - Heward, JM A1 - Gough, SC A1 - de Smith, A A1 - Blakemore, AI A1 - Froguel, P A1 - Owen, CJ A1 - Pearce, SH A1 - Teixeira, L A1 - Guillevin, L A1 - Graham, DS A1 - Pusey, CD A1 - Cook, HT A1 - Vyse, TJ A1 - Aitman, TJ J1 - Nat Genet Y1 - 2007/06// VL - 39 SN - 1061-4036 SP - 721 EP - 723 N2 - Naturally occurring variation in gene copy number is increasingly recognized as a heritable source of susceptibility to genetically complex diseases. Here we report strong association between FCGR3B copy number and risk of systemic lupus erythematosus (P = 2.7 x 10(-8)), microscopic polyangiitis (P = 2.9 x 10(-4)) and Wegener's granulomatosis in two independent cohorts from the UK (P = 3 x 10(-3)) and France (P = 1.1 x 10(-4)). We did not observe this association in the organ-specific Graves' disease or Addison's disease. Our findings suggest that low FCGR3B copy number, and in particular complete FCGR3B deficiency, has a key role in the development of systemic autoimmunity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17529978&query_hl=1 ER - TY - JFULL T1 - The anabolic effects of strontium increase the number of progenitor but not primitive haemopoietic stem cells A1 - Lymperi, S A1 - Horwood, N A1 - Cope, A A1 - Dazzi, F J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 122 EP - 122 ER - TY - JFULL T1 - Mesenchymal stem cell mediated immunosuppression is not confined to progenitor status A1 - Jones, F A1 - Horwood, N A1 - Cope, A A1 - Dazzi, F J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 316 EP - 316 ER - TY - JFULL T1 - Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families. A1 - Graham, DS A1 - Akil, M A1 - Vyse, TJ J1 - Rheumatology (Oxford) Y1 - 2007/06// VL - 46 SN - 1462-0324 SP - 927 EP - 930 N2 - OBJECTIVES: This is a family-based association study to investigate the genetic contribution of tyrosine kinase 2 (TYK2 ) to disease susceptibility in 380 UK systemic lupus erythematosus (SLE) families, consisting of parents and affected offspring. METHODS: Genotyping was performed using the Sequenom platform on DNA from affected individuals and their parents. Haplotypes were constructed using Haploview from the founders, and family-based association was conducted using GENEHUNTER-TDT and Family-Based Association Test. RESULTS: There are two associated haplotypes across TYK2, both carrying alleles with distorted inheritance. One SNP shows individual association to SLE. This is the under-transmitted rare A allele of TYK2 SNP 6 (P = 0.004), which tags the under-transmitted haplotype 2 (P = 0.055). A second SNP shows a trend for association. This is the A allele of TYK2 SNP 13, which is unique to the over-transmitted haplotype 1 (P = 0.014). We defined a 2.8 kb core association region in TYK2, between these two variants, which narrows down the 5.7 kb gap in the study by Sigurdsson et al. (Sigurdsson S, Nordmark G, Goring HH et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005;76:528-37). CONCLUSIONS: We have shown association to SLE from individual SNPs and haplotypes in TYK2. The strongest individual association, which is carried on the associated haplotype, is from TYK2 SNP 6. The variant is located close to an intron/exon boundary, suggesting a role for mis-splicing events in molecular pathogenesis. The associated haplotype also carries a missense mutation at TYK2. Therefore it is likely that the allelic contribution of TYK2 to SLE is complex, our data confirm previous findings and provide additional resolution regarding the causal polymorphisms in this gene. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17384181&query_hl=1 ER - TY - JFULL T1 - Mesangial immune complex glomerulonephritis due to complement factor D deficiency A1 - Abrera-Abeleda, MA A1 - Xu, Y A1 - Pickering, MC A1 - Smith, RJH A1 - Sethi, S J1 - KIDNEY INT Y1 - 2007/06// VL - 71 SN - 0085-2538 SP - 1142 EP - 1147 N2 - Complement factor D is a serine protease essential for the activation of the alternative pathway and is expressed in the kidney, adipocytes, and macrophages. Factor D is found at relatively high levels in glomeruli suggesting that this component of the complement cascade could influence renal pathophysiology. In this study, we utilize mice with a targeted deletion of the activating complement factor D gene and compare these results to mice with targeted deletion of the inhibitory complement factor H gene. Eight-month-old mice with a deleted factor D gene spontaneously develop albuminuria and have reduced creatinine clearance due to mesangial immune complex glomerulonephritis. These mesangial deposits contain C3 and IgM. In contrast to the mesangial location of the immune deposits in the factor D-deficient mice, age-matched factor H-deficient mice develop immune deposits along the glomerular capillary wall. Our observations suggest that complement factor D or alternative pathway activation is needed to prevent spontaneous accumulation of C3 and IgM deposits within the mesangium. Our studies show that the complement factor D gene knockout mice are a novel model of spontaneous mesangial immune complex glomerulonephritis. ER - TY - JFULL T1 - Lack of endothelial cell survivin causes embryonic defects in angiogenesis, cardiogenesis, and neural tube closure A1 - Zwerts, F A1 - Lupu, F A1 - De Vriese, A A1 - Pollefeyt, S A1 - Moons, L A1 - Altura, RA A1 - Jiang, YY A1 - Maxwell, PH A1 - Hill, P A1 - Oh, H A1 - Rieker, C A1 - Collen, D A1 - Conway, SJ A1 - Conway, EM J1 - BLOOD Y1 - 2007/06/01/ VL - 109 SN - 0006-4971 SP - 4742 EP - 4752 N2 - We explored the physiologic role of endothelial cell apoptosis during development by generating mouse embryos lacking the inhibitor of apoptosis protein (IAP) survivin in endothellum. This was accomplished by intercrossing survivin(lox/lox) mice with mice expressing cre recombinase under the control of the endothelial cell specific tiel promoter (tiel-cre mice). Lack of endothelial cell survivin resulted in embryonic lethality. Mutant embryos had prominent and diffuse hemorrhages from embryonic day 9.5 (E9.5) and died before E13.5. Heart development was strikingly abnormal. Survivin-null endocardial lineage cells could not support normal epithelial-mesenchymal transformation (EMT), resulting in hypoplastic endocardial cushions and in utero heart failure. In addition, 30% of mutant embryos had neural tube closure defects (NTDs) that were not caused by bleeding or growth retardation, but were likely due to alterations in the release of soluble factors from endothelial cells that otherwise support neural stem cell proliferation and neurulation. Thus, regulation of endothelial cell survival, and maintenance of vascular integrity by survivin are crucial for normal embryonic angiogenesis, cardiogenesis, and neurogenesis. ER - TY - JFULL T1 - Borrelia burgdorferi binding of host complement regulator factor H is not required for efficient mammalian infection. A1 - Woodman, ME A1 - Cooley, AE A1 - Miller, JC A1 - Lazarus, JJ A1 - Tucker, K A1 - Bykowski, T A1 - Botto, M A1 - Hellwage, J A1 - Wooten, RM A1 - Stevenson, B J1 - Infect Immun Y1 - 2007/06// VL - 75 SN - 0019-9567 SP - 3131 EP - 3139 N2 - The causative agent of Lyme disease, Borrelia burgdorferi, is naturally resistant to its host's alternative pathway of complement-mediated killing. Several different borrelial outer surface proteins have been identified as being able to bind host factor H, a regulator of the alternative pathway, leading to a hypothesis that such binding is important for borrelial resistance to complement. To test this hypothesis, the development of B. burgdorferi infection was compared between factor H-deficient and wild-type mice. Factor B- and C3-deficient mice were also studied to determine the relative roles of the alternative and classical/lectin pathways in B. burgdorferi survival during mammalian infection. While it was predicted that B. burgdorferi should be impaired in its ability to infect factor H-deficient animals, quantitative analyses of bacterial loads indicated that those mice were infected at levels similar to those of wild-type and factor B- and C3-deficient mice. Ticks fed on infected factor H-deficient or wild-type mice all acquired similar numbers of bacteria. Indirect immunofluorescence analysis of B. burgdorferi acquired by feeding ticks from the blood of infected mice indicated that none of the bacteria had detectable levels of factor H on their outer surfaces, even though such bacteria express high levels of surface proteins capable of binding factor H. These findings demonstrate that the acquisition of host factor H is not essential for mammalian infection by B. burgdorferi and indicate that additional mechanisms are employed by the Lyme disease spirochete to evade complement-mediated killing. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17420242&query_hl=1 ER - TY - JFULL T1 - Genes expressed by both mesangial cells and bone marrow-derived cells underlie genetic susceptibility to crescentic glomerulonephritis in the rat. A1 - Smith, J A1 - Lai, PC A1 - Behmoaras, J A1 - Roufosse, C A1 - Bhangal, G A1 - McDaid, JP A1 - Aitman, T A1 - Tam, FW A1 - Pusey, CD A1 - Cook, HT J1 - J Am Soc Nephrol Y1 - 2007/06// VL - 18 SN - 1046-6673 SP - 1816 EP - 1823 N2 - The Wistar-Kyoto (WKY) rat shows marked susceptibility to crescentic glomerulonephritis. In the model of nephrotoxic nephritis (NTN) that is induced by a small dose of nephrotoxic globulin, WKY rats developed crescents in 80 +/- 2% of glomeruli at day 10, whereas no crescents were seen in Lewis rats. This was associated with marked increase in monocyte chemoattractant protein-1 synthesis in WKY glomeruli. It was posited whether susceptibility depended on circulating cells or intrinsic renal cells. Bone marrow (BM) isografts from WKY to WKY or Lewis to Lewis did not affect susceptibility to NTN. When BM was transferred from WKY to Lewis rats, crescents developed in 35 +/- 9% of glomeruli 10 d after induction of NTN, indicating that susceptibility could be transferred by BM cells. However, crescents were also seen in WKY rats that were given Lewis marrow. For assessment of the contribution of intrinsic renal cells, kidneys from WKY or Lewis rats were transplanted into F1 animals. In NTN, the ratio of crescents in the transplanted kidney to the native kidney was significantly higher for WKY-to-F1 than for Lewis-to-F1 transplants, demonstrating that the kidney itself also influences susceptibility. Mesangial cell responses were then examined in the two strains. Mesangial cells that were derived from WKY rats synthesized significantly more monocyte chemoattractant protein-1 basally and after stimulation with heat-aggregated rabbit IgG or TNF-alpha. These results show that susceptibility to NTN in the WKY rat depends on both circulating and intrinsic renal cells and that there are genetic differences between the strains in mesangial responses to inflammatory stimuli. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17475818&query_hl=1 ER - TY - JFULL T1 - Do Tc-99m-diphosphonate bone scans have any place in the investigation of polyarthralgia? A1 - Fisher, BA A1 - Frank, JW A1 - Taylor, PC J1 - Rheumatology (Oxford) Y1 - 2007/06// VL - 46 SN - 1462-0324 SP - 1036 EP - 1037 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17449485&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 - 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 - Cord blood derived mesenchymal stem cells are effective at preventing graft-versus-host disease A1 - Tisato, V A1 - Naresh, K A1 - Girdlestone, J A1 - Navarrete, C A1 - Dazzi, F J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 317 EP - 317 ER - TY - JFULL T1 - NF-kappa B inhibition by blockade of IKK-2 and MYD88 in vein graft smooth muscle cells reduces the expression of key mediators of intimal hyperplasia A1 - Finch, J A1 - Navin, T A1 - Gregan, S A1 - Foxwell, B A1 - Haskard, D A1 - Monaco, C A1 - Hornick, P J1 - HEART Y1 - 2007/06// VL - 93 SN - 1355-6037 SP - A24 EP - A25 ER - TY - JFULL T1 - A new pathologic scoring system for renal calcineurin-inhibitor toxicity correlates with future graft function. A1 - Cook, T J1 - Nat Clin Pract Nephrol Y1 - 2007/06// VL - 3 SN - 1745-8331 SP - 316 EP - 317 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17471278&query_hl=1 ER - TY - JFULL T1 - 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 - Low intensity transplantat regimens facilitate recruitment of donor apecific regulatory T cell which promote heamatopoietic engraftment A1 - Weng, L A1 - Dyson, J A1 - Dazzi, F J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 379 EP - 379 ER - TY - JFULL T1 - A comparison of the behavior of C57BL/6 and C57BL/10 mice A1 - Deacon, RMJ A1 - Thomas, CL A1 - Rawlins, JNP A1 - Morley, BJ J1 - BEHAV BRAIN RES Y1 - 2007/05/16/ VL - 179 SN - 0166-4328 SP - 239 EP - 247 N2 - Selection of an appropriate animal model is a crucial first step in many research programs. The C57BL/6 (B6) mouse is the most widely used inbred mouse strain in biomedical research; this is particularly so in behavioral studies. However, there are several C57BL substrains, all derived from common ancestors. C57BL/10 (B10) mice are superficially almost identical to B6 mice in appearance and behavior and widely used in inflammation and immunology research, yet rarely in behavioral studies. The present study assessed the comparability of behavioral results from these two strains, to determine whether they could be used interchangeably in future behavioral experiments. The results showed that the behavior of B6 mice clearly differed from that of B10 mice: in tests of cognition, species-typical behaviors, and motor coordination the B6 strain performed better. Consequently, B6 mice will probably remain the preferred choice for behavioral studies. Interpretation of results derived from the B10 strain should take into account its particular behavioral characteristics. (c) 2007 Elsevier B.V. All rights reserved. ER - TY - JFULL T1 - The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita A1 - Mihai, S A1 - Chiriac, MT A1 - Takahashi, K A1 - Thurman, JM A1 - Holers, VM A1 - Zillikens, D A1 - Botto, M A1 - Sitaru, C J1 - J IMMUNOL Y1 - 2007/05/15/ VL - 178 SN - 0022-1767 SP - 6514 EP - 6521 N2 - Epidermolysis bullosa acquisita is a subepidermal blistering disease associated with tissue-bound and circulating autoantibodies against type VII collagen, a major constituent of the dermal-epidermal junction. The passive transfer of Abs against type VII collagen into mice induces a subepidermal blistering disease dependent upon activation of terminal complement components. To further dissect the role of the different complement activation pathways in this model, we injected C1qdeficient, mannan-binding lectin-deficient, and factor B-deficient mice with rabbit Abs against murine type VII collagen. The development and evolution of blistering had a similar pattern in mannan-binding lectin-deficient and control mice and was initially only marginally less extensive in Clq-deficient mice compared with controls. Importantly, factor B-deficient mice developed a delayed and significantly less severe blistering disease compared with factor B-sufficient mice. A significantly lower neutrophilic infiltration was observed in factor B-deficient mice compared with controls and local reconstitution with granulocytes restored the blistering disease in factor B-deficient mice. Our study provides the first direct evidence for the involvement of the alternative Pathway in an autoantibody-induced blistering disease and should facilitate the development of new therapeutic strategies for epidermolysis bullosa acquisita and related autoimmune diseases. The Journal of Immunology, 2007, 178: 6514-6521. ER - TY - JFULL T1 - TCRzetadim lymphocytes define populations of circulating effector cells that migrate to inflamed tissues. A1 - Zhang, Z A1 - Gorman, CL A1 - Vermi, AC A1 - Monaco, C A1 - Foey, A A1 - Owen, S A1 - Amjadi, P A1 - Vallance, A A1 - McClinton, C A1 - Marelli-Berg, F A1 - Isomäki, P A1 - Russell, A A1 - Dazzi, F A1 - Vyse, TJ A1 - Brennan, FM A1 - Cope, AP J1 - Blood Y1 - 2007/05/15/ VL - 109 SN - 0006-4971 SP - 4328 EP - 4335 N2 - The T-cell receptor zeta (TCRzeta) chain is a master sensor and regulator of lymphocyte responses. Loss of TCRzeta expression has been documented in infectious, inflammatory, and malignant diseases, suggesting that it may serve to limit T-cell reactivity and effector responses at sites of tissue damage. These observations prompted us to explore the relationship between TCRzeta expression and effector function in T cells. We report here that TCRzeta(dim) lymphocytes are enriched for antigen-experienced cells refractory to TCR-induced proliferation. Compared to their TCRzeta(bright) counterparts, TCRzeta(dim) cells share characteristics of differentiated effector T cells but use accessory pathways for transducing signals for inflammatory cytokine gene expression and cell contact-dependent pathways to activate monocytes. TCRzeta(dim) T cells accumulate in inflamed tissues in vivo and have intrinsic migratory activity in vitro. Whilst blocking leukocyte trafficking with anti-TNF therapy in vivo is associated with the accumulation of TCRzeta(dim) T cells in peripheral blood, this T-cell subset retains the capacity to migrate in vitro. Taken together, the functional properties of TCRzeta(dim) T cells make them promising cellular targets for the treatment of chronic inflammatory disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17255353&query_hl=1 ER - TY - JFULL T1 - Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment. A1 - Weng, L A1 - Dyson, J A1 - Dazzi, F J1 - Proc Natl Acad Sci U S A Y1 - 2007/05/15/ VL - 104 SN - 0027-8424 SP - 8415 EP - 8420 N2 - Low- or reduced-intensity conditioning regimens for allogeneic hemopoietic stem cell transplantation are effective at establishing donor hematopoietic engraftment and host-vs.-graft (HvG) tolerance. We investigated the mechanisms of HvG tolerance induction and maintenance in an animal model in which transplantation of sublethally irradiated female recipients with bone marrow (BM) from syngeneic male donors produces mixed chimerism. Splenocytes from chimeric mice inhibited HY-specific CD8(+) T cell responses both in vitro and in vivo, and their adoptive transfer facilitated donor hematopoietic engraftment. These properties were contained within the CD4(+)CD25(+) population. The conditioning protocol alone led to a proportional expansion of regulatory T cells (T(regs)), but the inhibitory activity was induced only if male BM was infused. The administration of anti-CD25-depleting antibodies to conditioned recipients at time of BM transplantation prevented donor-recipient chimerism but did not affect engraftment if performed after the establishment of chimerism, thus indicating that recipient T(regs) are required for the generation but not the maintenance of HvG tolerance. We conclude that donor-specific T(regs) of recipient origin are recruited when the donor antigens are present during reduced-intensity conditioning-induced T(reg) expansion. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17494756&query_hl=1 ER - TY - JFULL T1 - 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 - Hepatitis B virus core antigen epitopes presented by HLA-A2 single-chain trimers induce functional epitope-specific CD8(+) T-cell responses in HLA-A2.1/Kb transgenic mice A1 - Zhang, YX A1 - Li, S A1 - Shan, M A1 - Pan, XW A1 - Zhuang, K A1 - He, LH A1 - Gould, K A1 - Tien, P J1 - IMMUNOLOGY Y1 - 2007/05// VL - 121 SN - 0019-2805 SP - 105 EP - 112 N2 - The potency of CD8(+) cytotoxic T lymphocyte (CTL) responses toward core antigen has been shown to affect the outcomes of hepatitis B virus (HBV) infection. Since single-chain trimers (SCT) composed of peptide epitope beta(2)-microglobulin (beta(2)m) and major histocompatiblity complex (MHC) class I heavy chain covalently linked together in a single molecule have been shown to stimulate efficient CTL responses, we investigated the properties of human leucocyte antigen (HLA)-A2 SCTs encoding the HBV core antigen (HBcAg) epitopes C18-27 and C107-115. Transfection of NIH-3T3 cells with pcDNA3.0-SCT-C18-27 and SCT-C107-115 leads to stable presentation of HBcAg epitopes at the cell surface. HLA-A2.1/Kb transgenic mice vaccinated with the SCT constructs, either as a DNA vaccine alone or followed by a boost with recombinant vaccinia virus, were shown to generate HBcAg-specific CTL responses by enzyme-linked immunospot assay (ELISPOT) and in vitro interferon-gamma release experiments. HBcAg-specific CTLs from vaccinated HLA-A2.1/Kb transgenic mice were able to inhibit HBV surface and e antigen expression as indicated by HepG2.2.15 cells. Our data indicate that a DNA vaccine encoding a human HLA-A2 SCT with HBV epitopes can lead to stable, enhanced HBV core antigen presentation, and may be useful for the control of HBV infection in HLA-A2-positive HBV carriers. ER - TY - JFULL T1 - Monitoring peripheral blood regulatory T cells on clinically defined groups of kidney transplant recipients. A1 - Sagoo, P A1 - Sawitzki, B A1 - Hernandez-Fuentes, M A1 - Perucha, E A1 - Craciun, L A1 - Brouard, S A1 - Chaprnan, S A1 - Bradeau, C A1 - Peters, B A1 - Roberts, I A1 - Janssen, U A1 - Soulillou, JP A1 - Warrens, AN A1 - Wood, K A1 - Goldman, M A1 - Volk, HD A1 - Lechler, RI J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 340 EP - 340 ER - TY - JFULL T1 - NK cell and macrophage infiltration into organ xenografts is absolutely dependent on thrombin-mediated production of MCP-1 through protease activated receptor-1. A1 - Dorling, A A1 - Chen, D J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 224 EP - 224 ER - TY - JFULL T1 - Biomarkers of tolerance in kidney transplants. A1 - Hernandez-Fuentes, MP A1 - Sawitzki, B A1 - Sagoo, P A1 - Craciun, L A1 - Brouard, S A1 - Perucha, E A1 - Chapman, S A1 - Bradeau, C A1 - Peters, B A1 - Roberts, I A1 - Sergeant, R A1 - Janssen, U A1 - Warrens, A A1 - Wood, K A1 - Soulillou, JP A1 - Goldman, M A1 - Volk, HD A1 - Lechler, RI J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 337 EP - 337 ER - TY - JFULL T1 - The ternary Rab27a-Myrip-Myosin VIIa complex regulates melanosome motility in the retinal pigment epithelium. A1 - Lopes, VS A1 - Ramalho, JS A1 - Owen, DM A1 - Karl, MO A1 - Strauss, O A1 - Futter, CE A1 - Seabra, MC J1 - Traffic Y1 - 2007/05// VL - 8 SN - 1398-9219 SP - 486 EP - 499 N2 - The retinal pigment epithelium (RPE) contains melanosomes similar to those found in the skin melanocytes, which undergo dramatic light-dependent movements in fish and amphibians. In mammals, those movements are more subtle and appear to be regulated by the Rab27a GTPase and the unconventional myosin, Myosin VIIa (MyoVIIa). Here we address the hypothesis that a recently identified Rab27a- and MyoVIIa-interacting protein, Myrip, promotes the formation of a functional tripartite complex. In heterologous cultured cells, all three proteins co-immunoprecipitated following overexpression. Rab27a and Myrip localize to the peripheral membrane of RPE melanosomes as observed by immunofluorescence and immunoelectron microscopy. Melanosome dynamics were studied using live-cell imaging of mouse RPE primary cultures. Wild-type RPE melanosomes exhibited either stationary or slow movement interrupted by bursts of fast movement, with a peripheral directionality trend. Nocodazole treatment led to melanosome paralysis, suggesting that movement requires microtubule motors. Significant and similar alterations in melanosome dynamics were observed when any one of the three components of the complex was missing, as studied in ashen- (Rab27a defective) and shaker-1 (MyoVIIa mutant)-derived RPE cells, and in wild-type RPE cells transduced with adenovirus carrying specific sequences to knockdown Myrip expression. We observed a significant increase in the number of motile melanosomes, exhibiting more frequent and prolonged bursts of fast movement, and inversion of directionality. Similar alterations were observed upon cytochalasin D treatment, suggesting that the Rab27a-Myrip-MyoVIIa complex regulates tethering of melanosomes onto actin filaments, a process that ensures melanosome movement towards the cell periphery. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17451552&query_hl=1 ER - TY - JFULL T1 - Neutrophils as antigen-presenting cells: Bridging innate and adaptive immunity. A1 - Ambrose, LR A1 - Smith, LM A1 - Little, MAP A1 - Dupont, PJ A1 - Warrens, AN J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 412 EP - 412 ER - TY - JFULL T1 - Significant contribution by recipient platelets and monocytes to the enchanced thrombosis seen after xenotransplantation. A1 - Lin, CC A1 - Dorling, A J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 583 EP - 583 ER - TY - JFULL T1 - Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. A1 - Simula, MP A1 - Marktel, S A1 - Fozza, C A1 - Kaeda, J A1 - Szydlo, RM A1 - Nadal, E A1 - Bua, M A1 - Rahemtulla, A A1 - Kanfer, E A1 - Marin, D A1 - Olavarria, E A1 - Goldman, JM A1 - Apperley, JF A1 - Dazzi, F J1 - Leukemia Y1 - 2007/05// VL - 21 SN - 0887-6924 SP - 943 EP - 948 N2 - Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3(+) cell dose < or =10(7)/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17361226&query_hl=1 ER - TY - JFULL T1 - The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus. A1 - Hellquist, A A1 - Zucchelli, M A1 - Kivinen, K A1 - Saarialho-Kere, U A1 - Koskenmies, S A1 - Widen, E A1 - Julkunen, H A1 - Wong, A A1 - Karjalainen-Lindsberg, ML A1 - Skoog, T A1 - Vendelin, J A1 - Cunninghame-Graham, DS A1 - Vyse, TJ A1 - Kere, J A1 - Lindgren, CM J1 - J Med Genet Y1 - 2007/05// VL - 44 SN - 1468-6244 SP - 314 EP - 321 N2 - BACKGROUND: Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin-dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE). Material and METHODS: To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family-based SLE collections, containing more than 2000 samples. RESULT: A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 3' part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non-terminated mRNA for homozygous individuals (p<0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5-6 times, p<0.0001 for all tests). CONCLUSION: Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17220214&query_hl=1 ER - TY - JFULL T1 - Mechanisms of action of TRAIL in inhibiting immune response to alogeneic tissue. A1 - Kumar, R A1 - Herbert, PE A1 - Warrens, AN J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 148 EP - 148 ER - TY - JFULL T1 - Reversal of refractory c4d chronic allograft nephropathy with ritximab. A1 - Galliford, J A1 - Cook, T A1 - Brookes, P A1 - Chan, K A1 - Taube, D A1 - Dorling, A J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 526 EP - 526 ER - TY - JFULL T1 - Flow-PRA characterisarion of de novo Anti-HLA class I donor specific antibodies in patients with apparent 'transplant accommodation'. A1 - Dorling, A A1 - Hingley, S A1 - Clarke, HM J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 345 EP - 345 ER - TY - JFULL T1 - Proteomic analysis of proteins regulated by TRPS1 transcription factor in DU145 prostate cancer cells. A1 - Chang, GT A1 - Gamble, SC A1 - Jhamai, M A1 - Wait, R A1 - Bevan, CL A1 - Brinkmann, AO J1 - Biochim Biophys Acta Y1 - 2007/05// VL - 1774 SN - 0006-3002 SP - 575 EP - 582 N2 - The aim of the present study was to identify proteins differentially regulated by TRPS1 in human prostate cancer cells in order to better understand the role of TRPS1 in prostate cancer development. The proteomes of androgen-independent DU145 prostate cancer cells, that do not express TRPS1 and of genetically engineered DU145 cells that stable and inducible express recombinant TRPS1 protein, were compared. Using two-dimensional electrophoresis followed by mass spectrometric analysis, 13 proteins that were differentially expressed between these two cell lines were identified. These proteins represent a dominant reduction of expression of antioxidant proteins, including superoxide dismutase, protein disulfide isomerase A3 precursor, endoplasmin precursor and annexin A2. Furthermore, regulation was observed for mitochondrion-associated proteins, glycolytic enzymes, a cytoskeleton-associated protein, a nuclear protein and proteins involved in apoptosis. Our data indicate that overexpression of TRPS1 protein is correlated with reduced protein expression of certain antioxidants. This suggests a possible involvement of TRPS1 in oxidative stress, and possibly in apoptosis in androgen-independent DU145 prostate cancer cells. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17467349&query_hl=1 ER - TY - JFULL T1 - Modulation of dendritic cell function by tissue factor and coagulation proteases. A1 - Shrivastava, S A1 - Dorling, A J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 414 EP - 414 ER - TY - JFULL T1 - Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3. A1 - Villegas-Mendez, A A1 - Montes, R A1 - Ambrose, LR A1 - Warrens, AN A1 - Laffan, M A1 - Lane, DA J1 - J Thromb Haemost Y1 - 2007/05// VL - 5 SN - 1538-7933 SP - 980 EP - 988 N2 - BACKGROUND: The endothelial cell protein C receptor (EPCR) presents protein C to the thrombin:thrombomodulin complex on the endothelium of large vessels, and enhances the generation of activated protein C (APC) and activation of protease-activated receptor-1. A previous report has demonstrated binding of soluble (s) EPCR to activated neutrophils via surface proteinase 3 (PR3). METHODS: We now report further characterization of this interaction. Activated neutrophils and purified PR3 both decrease endothelial cell (EC) surface EPCR, suggestive of its proteolysis. RESULTS: When added to purified recombinant sEPCR, PR3 produced multiple cleavages, with early products including 20 kDa N-terminal and C-terminal (after Lys(176)) fragments. The binding of active site blocked PR3 to sEPCR was studied by surface plasmon resonance. Estimates of the K(D) of 18.5-102 nM were obtained with heterogeneous binding, suggestive of more than a single interaction site. CONCLUSIONS: This work demonstrates PR3 binding to and proteolysis of EPCR and suggests a mechanism by which anticoagulant and cell protective pathways can be down-regulated during inflammation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17459006&query_hl=1 ER - TY - JFULL T1 - Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation. A1 - Rowbotham, NJ A1 - Hager-Theodorides, AL A1 - Cebecauer, M A1 - Shah, DK A1 - Drakopoulou, E A1 - Dyson, J A1 - Outram, SV A1 - Crompton, T J1 - Blood Y1 - 2007/05/01/ VL - 109 SN - 0006-4971 SP - 3757 EP - 3766 N2 - TCR signal strength is involved in many cell fate decisions in the T-cell lineage. Here, we show that transcriptional events induced by Hedgehog (Hh) signaling reduced TCR signal strength in mice. Activation of Hh signaling in thymocytes in vivo by expression of a transgenic transcriptional-activator form of Gli2 (Gli2DeltaN(2)) changed the outcome of TCR ligation at many stages of thymocyte development, allowing self-reactive cells to escape clonal deletion; reducing transgenic TCR-mediated positive selection; reducing the ratio of CD4/CD8 single-positive (SP) cells; and reducing cell surface CD5 expression. In contrast, in the Shh(-/-) thymus the ratio of CD4/CD8 cells and both positive and negative selection of a transgenic TCR were increased, demonstrating that Shh does indeed influence TCR repertoire selection and the transition from double-positive (DP) to SP cell in a physiological situation. In peripheral T cells, Gli2DeltaN(2) expression attenuated T-cell activation and proliferation, by a mechanism upstream of ERK phosphorylation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17227833&query_hl=1 ER - TY - JFULL T1 - Metabolic modulation induced by chronic hypoxia in rats using a comparative proteomic analysis of skeletal muscle tissue. A1 - De Palma, S A1 - Ripamonti, M A1 - Vigano, A A1 - Moriggi, M A1 - Capitanio, D A1 - Samaja, M A1 - Milano, G A1 - Cerretelli, P A1 - Wait, R A1 - Gelfi, C J1 - J Proteome Res Y1 - 2007/05// VL - 6 SN - 1535-3893 SP - 1974 EP - 1984 N2 - Hypoxia-induced changes of rat skeletal muscle were investigated by two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry. The results indicated that proteins involved in the TCA cycle, ATP production, and electron transport are down-regulated, whereas glycolytic enzymes and deaminases involved in ATP and AMP production were up-regulated. Up-regulation of the hypoxia markers hypoxia inducible factor 1 (HIF-1alpha) and pyruvate dehydrogenase kinase 1 (PDK1) was also observed, suggesting that in vivo adaptation to hypoxia requires an active metabolic switch. The kinase protein, mammalian target of rapamycin (mTOR), which has been implicated in the regulation of protein synthesis in hypoxia, appears unchanged, suggesting that its activity, in this system, is not controlled by oxygen partial pressure. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17391017&query_hl=1 ER - TY - JFULL T1 - Peritonitis, peritoneal inflammation and membrane permeability: a longitudinal study of dialysate and serum MCP-1 in stable patients on peritoneal dialysis. A1 - Malik, AR A1 - Little, MA A1 - Henriksson, M A1 - Tam, FW A1 - Brown, EA J1 - J Nephrol Y1 - 2007/05// VL - 20 SN - 1121-8428 SP - 340 EP - 349 N2 - BACKGROUND: Increase in peritoneal membrane permeability (D/P) correlates with systemic and peritoneal markers of inflammation and neoangiogenesis. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is a potent chemoattractant and activator of monocytes/macrophages. We measured the serum (sMCP-1) and dialysate MCP-1 (dMCP-1) concentrations of stable peritoneal dialysis (PD) patients and studied various factors affecting MCP-1 production. We also looked at the correlation of dMCP-1 concentrations with change in D/P over 12 months. METHODS: Forty-five stable prevalent and 6 new PD patients (22 CAPD, 29 APD) were studied. Median PD duration was 21 months (range 1-114). D/P was measured by standardized peritoneal equilibration test (PET). Patients with recent peritonitis within 3 months of the start of study were excluded. MCP-1 concentrations were measured in serum, overnight dialysate and post-PET dialysate, both at baseline and at 12 months by ELISA. RESULTS: On univariate analysis, post-PET dMCP-1 concentrations positively correlated with sMCP-1 (p=0.0002), duration of PD (p=0.02), dialysate volume (p=0.001), peritoneal creatinine clearance (p=0.0002) and D/P (p=0.001). There was a negative correlation with residual renal function (p=0.001). dMCP-1 concentrations were higher in patients with past peritonitis (p=0.001). On multivariate analysis, factors independently associated with dMCP-1 were sMCP-1 (p=0.003) and past peritonitis (p=0.001). Thirty patients completed this study, and D/P rose by > 0.1 in 20% patients. dMCP-1 concentrations were higher in baseline and 12-month samples in patients with change in D/P >0.1. CONCLUSIONS: We conclude that dMCP-1 concentrations are related to past peritonitis and serum MCP-1. It is difficult to interpret the relationship of dMCP-1 with change in D/P over time due to the small number of patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17557268&query_hl=1 ER - TY - JFULL T1 - Prevalence of oesophageal eosinophils and eosinophilic oesophagitis in adults: the population-based Kalixanda study. A1 - Ronkainen, J A1 - Talley, NJ A1 - Aro, P A1 - Storskrubb, T A1 - Johansson, SE A1 - Lind, T A1 - Bolling-Sternevald, E A1 - Vieth, M A1 - Stolte, M A1 - Walker, MM A1 - Agréus, L J1 - Gut Y1 - 2007/05// VL - 56 SN - 0017-5749 SP - 615 EP - 620 N2 - BACKGROUND: Eosinophilic oesophagitis may be increasing but the prevalence in the general population remains unknown. Our aim was to assess this and the presence of eosinophils in the distal oesophageal epithelium in the community. METHODS: Oesophagogastroduodenoscopy was performed in a random sample (n = 1000) of the adult Swedish population (mean age 54 years, 49% men). Oesophageal biopsy samples were obtained from 2 cm above, and at, the Z-line. Any eosinophil infiltration of the epithelium was defined as "eosinophils present". Definite eosinophilic oesophagitis was defined as > or =20, probable as 15-19, and possible as 5-14 eosinophils/high-power field (HPF, at magnification x 40) in oesophageal biopsy specimens. RESULTS: Eosinophils were present in 48 subjects (4.8%, 95% CI 3.5 to 6.1%, mean age 54 years, 63% men), in 54% without troublesome reflux symptoms. Definite eosinophilic oesophagitis was present in four subjects (0.4%, 95% CI 0.01 to 0.8%, mean age 51 years, 75% men) and probable eosinophilic oesophagitis in seven subjects (0.7%, 95% CI 0.2 to 1.2%, mean age 58 years, 43% men). Erosive oesophagitis (OR = 2.99, 95% CI 1.58 to 5.66) and absence of dyspepsia (OR = 0.23, 95% CI 0.07 to 0.75) and Helicobacter pylori infection (OR = 0.41, 95% CI 0.19 to 0.92) were independent predictors for "eosinophils present". Definite eosinophilic oesophagitis was associated with dysphagia (2/66 vs 2/926, p = 0.025), and probable eosinophilic oesophagitis with narrowing of the oesophageal lumen (2/15 vs 5/978, p = 0.005). CONCLUSIONS: Oesophageal eosinophils were present in nearly 5% of the general population; approximately 1% had definite or probable eosinophilic oesophagitis. Oesophageal eosinophils may be a manifestation of reflux disease in adults, but the condition is as likely to be asymptomatic and go unrecognised. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17135307&query_hl=1 ER - TY - JFULL T1 - T cell responses to a non-glycosylated epitope predominate in type II collagen-immunised HLA-DRB1*0101 transgenic mice. A1 - von Delwig, A A1 - Altmann, DM A1 - Charlton, FG A1 - McKie, N A1 - Isaacs, JD A1 - Holmdahl, R A1 - Robinson, JH J1 - Ann Rheum Dis Y1 - 2007/05// VL - 66 SN - 0003-4967 SP - 599 EP - 604 N2 - AIM: To study collagen-induced arthritis in human leucocyte antigen (HLA)-DR1 transgenic mice lacking endogenous major histocompatibility complex class II molecules (MHC-II) and to determine T cell specificity against the arthritogenic CII(259-273) epitope of type II collagen either unmodified or post-translationally glycosylated at Lys(264). METHODS: Arthritis was induced by immunisation with human type II collagen in complete Freund's adjuvant and measured by footpad swelling, clinical score and histology. T cell responses were assessed by proliferation of spleen and lymph node cells and in antigen presentation assays, using T cell hybridomas specific for the glycosylated and non-glycosylated CII(259-273) epitope. RESULTS: The incidence of arthritis was 50% in DR1-transgenic mice lacking endogenous MHC-II molecules. Recall T cell responses in draining lymph nodes and spleen were consistently greater against the non-glycosylated epitope than to the glycosylated CII(259-273). Most of the T cell hybridomas generated from CII-immunised mice recognised the non-glycosylated CII epitope and this form of the epitope was also presented with 100-fold higher efficiency and 1 h faster kinetics by both macrophages and dendritic cells. CONCLUSION: This study shows that T cell responses to the non-glycosylated epitope of heterologous (human) CII are dominant in HLA-DR1 transgenic mice lacking MHC-II, which could contribute to the pathogenicity of autoimmune arthritis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17114189&query_hl=1 ER - TY - JFULL T1 - Identification of tolerant patients based on a combinational analysis of foxp3 and aMannosidase transcription. A1 - Sawitzki, BS A1 - Hernandez-Fuentes, M A1 - Sagoo, P A1 - Perucha, E A1 - Lemoine, A A1 - Brouard, S A1 - Chapman, S A1 - Peters, B A1 - Roberts, I A1 - Janssen, U A1 - Soulillou, JP A1 - Warrens, A A1 - Wood, K A1 - Goldman, M A1 - Lechler, R A1 - Volk, HD J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 488 EP - 488 ER - TY - JFULL T1 - Is it possible totissue type a kidney donor who is no longer available? A1 - Srikantha, M A1 - Sergeant, R A1 - Hernandez-Fuentes, M A1 - Lechler, RI A1 - Warrens, AN J1 - AM J TRANSPLANT Y1 - 2007/05// VL - 7 SN - 1600-6135 SP - 268 EP - 268 ER - TY - JFULL T1 - Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. A1 - Graham, RR A1 - Kyogoku, C A1 - Sigurdsson, S A1 - Vlasova, IA A1 - Davies, LR A1 - Baechler, EC A1 - Plenge, RM A1 - Koeuth, T A1 - Ortmann, WA A1 - Hom, G A1 - Bauer, JW A1 - Gillett, C A1 - Burtt, N A1 - Cunninghame Graham, DS A1 - Onofrio, R A1 - Petri, M A1 - Gunnarsson, I A1 - Svenungsson, E A1 - Rönnblom, L A1 - Nordmark, G A1 - Gregersen, PK A1 - Moser, K A1 - Gaffney, PM A1 - Criswell, LA A1 - Vyse, TJ A1 - Syvänen, AC A1 - Bohjanen, PR A1 - Daly, MJ A1 - Behrens, TW A1 - Altshuler, D J1 - Proc Natl Acad Sci U S A Y1 - 2007/04/17/ VL - 104 SN - 0027-8424 SP - 6758 EP - 6763 N2 - Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3' UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17412832&query_hl=1 ER - TY - JFULL T1 - Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. A1 - Crozat, K A1 - Hoebe, K A1 - Ugolini, S A1 - Hong, NA A1 - Janssen, E A1 - Rutschmann, S A1 - Mudd, S A1 - Sovath, S A1 - Vivier, E A1 - Beutler, B J1 - J Exp Med Y1 - 2007/04/16/ VL - 204 SN - 0022-1007 SP - 853 EP - 863 N2 - Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea-induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60-million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17420270&query_hl=1 ER - TY - JFULL T1 - IL-10 induces IL-10 in primary human monocyte-derived macrophages via the transcription factor Stat3. A1 - Staples, KJ A1 - Smallie, T A1 - Williams, LM A1 - Foey, A A1 - Burke, B A1 - Foxwell, BM A1 - Ziegler-Heitbrock, L J1 - J Immunol Y1 - 2007/04/15/ VL - 178 SN - 0022-1767 SP - 4779 EP - 4785 N2 - IL-10 is an important immunosuppressive cytokine that can down-regulate expression of other cytokines and has been shown to down-regulate itself. We show, in this study, that treatment of human monocyte-derived macrophages with IL-10 induces IL-10 mRNA in a dose- and time-dependent manner with an optimum induction at 100 ng/ml and at 6 h, whereas IL-10-induced IL-10 protein can be detected at 18 h. In the same cells, IL-10 can partially suppress IL-10 mRNA induced by LPS, but only down to the level of IL-10-induced IL-10. An adenoviral luciferase reporter construct driven by the -195 IL-10 promoter, which contains a Stat motif, was readily induced by both IL-10 and LPS. Mutation of this Stat motif ablated IL-10 activation of this promoter, but not the LPS activation. Finally, we show that overexpression of a dominant-negative Stat3 protein will prevent IL-10 induction, but not LPS induction, of IL-10 mRNA. These data show that IL-10 induces IL-10 in monocyte-derived macrophages in an autocrine manner via activation of the transcription factor Stat3. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17404258&query_hl=1 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 - Rab27b regulates number and secretion of platelet dense granules. A1 - Tolmachova, T A1 - Abrink, M A1 - Futter, CE A1 - Authi, KS A1 - Seabra, MC J1 - Proc Natl Acad Sci U S A Y1 - 2007/04/03/ VL - 104 SN - 0027-8424 SP - 5872 EP - 5877 N2 - The Rab27 GTPase subfamily consists of two closely related homologs, Rab27a and Rab27b. Rab27a has been shown previously to regulate organelle movement and regulated exocytosis in a wide variety of secretory cells. However, the role of the more restrictedly expressed Rab27b remains unclear. Here we describe the creation of Rab27b knockout (KO) strain that was subsequently crossed with the naturally occurring Rab27a KO line, ashen, to produce double KO (Rab27a(ash/ash) Rab27b(-/-)) mice. Rab27b KO (and double KO) exhibit significant hemorrhagic disease in contrast to ashen mice. In vitro assays demonstrated impaired aggregation with collagen and U46619 and reduced secretion of dense granules in both Rab27b and double KO strains. Additionally, we detected a 50% reduction in the number of dense granules per platelet and diminished platelet serotonin content, possibly due to a dense granule packaging defect into proplatelets during megakaryocyte maturation. The presence of Rab27a partially compensated for the secretory defect but not the reduced granule number. The morphology and function of platelet alpha-granules were unaffected. Our data suggest that Rab27b is a key regulator of dense granule secretion in platelets and thus a candidate gene for delta-storage pool deficiency in humans. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17384153&query_hl=1 ER - TY - JFULL T1 - Poly-(ADP-ribose) polymerase-1 (Parp-1) binds in a sequence-specific manner at the Bcl-6 locus and contributes to the regulation of Bcl-6 transcription. A1 - Ambrose, HE A1 - Papadopoulou, V A1 - Beswick, RW A1 - Wagner, SD J1 - Oncogene Y1 - 2007/04/02/ SN - 0950-9232 N2 - Bcl-6 is a transcription factor that is normally expressed in germinal centre B cells. It is essential for the formation of germinal centres and the production of high-affinity antibodies. Transcriptional downregulation of Bcl-6 occurs on terminal differentiation to plasma cells. Bcl-6 is highly expressed in B-cell non-Hodgkin's lymphoma and, in a subset of cases of diffuse large cell lymphoma, the mechanism of Bcl-6 overexpression involves interruption of normal transcriptional controls. Transcriptional control of Bcl-6 is, therefore, important for normal antibody responses and lymphomagenesis, but little is known of the cis-acting control elements. This report focuses on a region of mouse/human sequence homology in the first intron of Bcl-6, which is a candidate site for such a control element. We demonstrate that poly-(ADP-ribose) polymerase-1 (Parp-1) binds in vitro and in vivo to specific sequences in this region. We further show that PARP inhibitors, and Parp-1 knockdown by siRNA induce Bcl-6 mRNA expression in Bcl-6 expressing cell lines. We speculate that Parp-1 activation plays a role in switching off Bcl-6 transcription and subsequent B-cell exit from the germinal centre.Oncogene advance online publication, 2 April 2007; doi:10.1038/sj.onc.1210434. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17404575&query_hl=1 ER - TY - JFULL T1 - CD4+ CD25+ regulatory T-cells exhibit a higher T-cell receptor diversity than CD4+ CD25- conventional T-cells after allogeneic stem cell transplantation A1 - Fozza, C A1 - Nadal, E A1 - Longinotti, M A1 - Dazzi, F J1 - BONE MARROW TRANSPL Y1 - 2007/04// VL - 39 SN - 0268-3369 SP - S46 EP - S46 ER - TY - JFULL T1 - Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. A1 - Pollard, PJ A1 - Spencer-Dene, B A1 - Shukla, D A1 - Howarth, K A1 - Nye, E A1 - El-Bahrawy, M A1 - Deheragoda, M A1 - Joannou, M A1 - McDonald, S A1 - Martin, A A1 - Igarashi, P A1 - Varsani-Brown, S A1 - Rosewell, I A1 - Poulsom, R A1 - Maxwell, P A1 - Stamp, GW A1 - Tomlinson, IP J1 - Cancer Cell Y1 - 2007/04// VL - 11 SN - 1535-6108 SP - 311 EP - 319 N2 - Germline mutations in the fumarate hydratase (FH) tumor suppressor gene predispose to leiomyomatosis, renal cysts, and renal cell cancer (HLRCC). HLRCC tumors overexpress HIF1alpha and hypoxia pathway genes. We conditionally inactivated mouse Fh1 in the kidney. Fh1 mutants developed multiple clonal renal cysts that overexpressed Hif1alpha and Hif2alpha. Hif targets, such as Glut1 and Vegf, were upregulated. We found that Fh1-deficient murine embryonic stem cells and renal carcinomas from HLRCC showed similar overexpression of HIF and hypoxia pathway components to the mouse cysts. Our data have shown in vivo that pseudohypoxic drive, resulting from HIF1alpha (and HIF2alpha) overexpression, is a direct consequence of Fh1 inactivation. Our mouse may be useful for testing therapeutic interventions that target angiogenesis and HIF-prolyl hydroxylation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17418408&query_hl=1 ER - TY - JFULL T1 - The cellular origin and proliferative status of regenerating renal parenchyma after mercuric chloride damage and erythropoietin treatment A1 - Yen, TH A1 - Alison, MR A1 - Cook, HT A1 - Jeffery, R A1 - Otto, WR A1 - Wright, NA A1 - Poulsom, R J1 - CELL PROLIFERAT Y1 - 2007/04// VL - 40 SN - 0960-7722 SP - 143 EP - 156 N2 - Objectives: In this study, we have sought to establish the cellular origin and proliferative status of the renal parenchyma as it regenerates after damage induced by mercuric chloride, with or without erythropoietin treatments, that might alter the response. Materials and methods: Female mice were irradiated and male whole bone marrow was transplanted into them. Six weeks later recipient mice were assigned to one of four groups: control, mercuric chloride treated, erythropoietin treated and treated with mercuric chloride plus erythropoietin. Results: Tubular injury scores were high 3 days after mercuric chloride and had recovered partially after 14 days, in line with serum urea nitrogen levels. Confocal microscopy confirmed the tubular location of bone marrow-derived cells. A 'four-in-one' analytical technique (identifying cell origin, tubular phenotype, tubular basement membranes and S-phase status) revealed that tubular necrosis increased bone marrow derivation of renal tubular epithelium from a baseline of similar to 1.3% to similar to 4.0%. Erythropoietin increased the haematocrit, but no other effects were detected. Conclusion: As 1 in 12 proximal tubular cells in S-phase was derived from bone marrow, we conclude that in the kidney, the presence of bone marrow-derived cells makes a minor but important regenerative contribution after tubular necrosis. ER - TY - JFULL T1 - 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 - Immediate hemodynamic effect of the additional use of the SCD EXPRESS Compression System in patients with venous ulcers treated with the four-layer compression bandaging system. A1 - Kalodiki, E A1 - Ellis, M A1 - Kakkos, SK A1 - Williams, A A1 - Davies, AH A1 - Geroulakos, G J1 - Eur J Vasc Endovasc Surg Y1 - 2007/04// VL - 33 SN - 1078-5884 SP - 483 EP - 487 N2 - OBJECTIVES: To test the hypothesis that the SCD EXPRESS intermittent pneumatic compression applied in combination with a four-layer bandage in patients with venous ulcers increases popliteal vein volume flow and velocity. DESIGN: Twenty limbs of 18 patients with venous leg ulcers were studied, median age 76 years. The Total Volume Flow (TVF) and the Peak Systolic Velocity (PSV) were recorded in the popliteal vein using duplex ultrasonography. Measurements were made (i) without bandage, (ii) with four layer bandage and (iii) following the application of the SCD Compression System on top of a four-layer bandage for at least 15 minutes. RESULTS: The median VCSS was 17 (range, 12-22) while the median VSDS for reflux was 4.5 (range, 1-7.5). The median TVF was 71 mL/min (inter-quartile range 57-101) without bandage, 112 (IQR 89-148) with four-layer bandage and 291 (IQR 241-392) with the addition of the SCD System (P<.001, Wilcoxon signed ranks test). The median PSV was 8.4 cm/sec (IQR 6.8-14) without bandage, 13 (9.0-19) with four-layer bandage and 27 (21-31) with the addition of the SCD System (P<.001, Wilcoxon signed ranks test). Both TVF and PSV increased slightly with the addition of the four-layer bandage. However, with the addition of the SCD System these parameters increased three fold. CONCLUSIONS: The SCD EXPRESS Compression System accelerates venous flow in the legs of patients with venous ulcers already treated with a four-layer bandage. The combination of four-layer compression with the SCD System on healing venous ulcers needs to be tested by a clinical effectiveness study. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17224283&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 - Effect of anti-TNF antibodies on T lymphocyte cell cycle and relation to apoptosis A1 - Chaudhary, R A1 - Butler, M A1 - Ghosh, S J1 - GUT Y1 - 2007/04// VL - 56 SN - 0017-5749 SP - A108 EP - A108 ER - TY - JFULL T1 - Texture analysis of ultrasonic images of symptomatic carotid plaques can identify those plaques associated with ipsilateral embolic brain infarction. A1 - Kakkos, SK A1 - Stevens, JM A1 - Nicolaides, AN A1 - Kyriacou, E A1 - Pattichis, CS A1 - Geroulakos, G A1 - Thomas, D J1 - Eur J Vasc Endovasc Surg Y1 - 2007/04// VL - 33 SN - 1078-5884 SP - 422 EP - 429 N2 - OBJECTIVES: The aim of our study was to determine the association between objective, computerised texture analysis of carotid plaque ultrasonic images and embolic CT-brain infarction in patients presenting with hemispheric neurological symptoms. DESIGN: Cross-sectional study in patients with 50%-99% (ECST) carotid stenosis. PATIENTS AND METHODS: Carotid plaque ultrasonic images (n=54, 26 with TIAs and 28 with stroke) obtained during carotid ultrasound were normalised and standardised for resolution and subsequently assessed visually for the presence of discrete echogenic or juxtaluminal echolucent components and overall echogenicity (plaque type). Using computer software, 51 histogram/textural features of the plaque outlines were calculated. Factor analysis was subsequently applied to eliminate redundant variables. Small cortical, large cortical and discrete subcortical infarcts on CT-brain scan were considered as being embolic. RESULTS: Twenty-five cases (46%) had embolic infarcts. On logistic regression, grey-scale median (GSM), a measure of echolucency, spatial grey level dependence matrices (SGLDM) correlation and SGLDM information measure of correlation-1, measures of homogeneity were significant (p<0.05), but not grey level runlength statistics (RUNL) Run Percentage (RP), stenosis severity, type of symptoms or echolucent juxtaluminal components. Using ROC curves methodology, SGLDM information measure of correlation-1 improved the value of GSM in distinguishing embolic from non-embolic CT-brain infarction. CONCLUSION: Computerised texture analysis of ultrasonic images of symptomatic carotid plaques can identify those that are associated with brain infarction, improving the results achieved by GSM alone. This methodology could be applied to prospective natural history studies of symptomatic patients not operated on or randomised trials of patients undergoing carotid angioplasty and stenting in order to identify high-risk subgroups for cerebral infarction. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17161964&query_hl=1 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 - The Bxs6 locus of BXSB mice is sufficient for high-level expression of gp70 and the production of gp70 immune complexes. A1 - Rankin, J A1 - Boyle, JJ A1 - Rose, SJ A1 - Gabriel, L A1 - Lewis, M A1 - Thiruudaian, V A1 - Rogers, NJ A1 - Izui, S A1 - Morley, BJ J1 - J Immunol Y1 - 2007/04/01/ VL - 178 SN - 0022-1767 SP - 4395 EP - 4401 N2 - High levels of the retroviral envelope protein gp70 and gp70 immune complexes have been linked to a single locus on chromosome 13 (Bxs6) in the BXSB model, to which linkage of nephritis was also seen. Congenic lines containing the BXSB Bxs6 interval on a non-autoimmune C57BL/10 background were bred in the presence or absence of the BXSB Y chromosome autoimmune accelerator gene (Yaa), which accelerates disease in male mice. In these mice, we have shown that Bxs6 is sufficient to cause high-level expression of gp70 and the production of gp70 autoantibodies, independently of Yaa, with gp70 immune complex levels enhanced by Yaa. In the presence of Yaa, Bxs6 also causes mild nephritis, and interestingly the sporadic production of high levels of anti-DNA Abs in some mice. Fine mapping using rare recombinant mice suggested that Bxs6 lies between 59.7 and 74.8 megabases (Mb), although the interval of 0.6 Mb between 73.6 and 78.6 Mb on chromosome 13 cannot be excluded in this study. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17371996&query_hl=1 ER - TY - JFULL T1 - Rab27a regulates phagosomal pH and NADPH oxidase recruitment to dendritic cell phagosomes. A1 - Jancic, C A1 - Savina, A A1 - Wasmeier, C A1 - Tolmachova, T A1 - El-Benna, J A1 - Dang, PM A1 - Pascolo, S A1 - Gougerot-Pocidalo, MA A1 - Raposo, G A1 - Seabra, MC A1 - Amigorena, S J1 - Nat Cell Biol Y1 - 2007/04// VL - 9 SN - 1465-7392 SP - 367 EP - 378 N2 - To prevent excessive degradation of internalized antigens, which could destroy the peptides recognized by T lymphocytes, dendritic cells have developed several strategies that limit proteolytic activity in phagosomes. The recruitment of the NADPH oxidase NOX2 prevents acidification of phagosomes, limiting antigen degradation. Here, we show that dendritic cells derived from Rab27a-deficient ashen mice show increased phagosome acidification and antigen degradation, causing a defect in antigen cross-presentation. Enhanced acidification results from a delay in the recruitment to phagosomes of a subset of lysosome-related organelles containing the membrane subunits of NOX2. The Rab27a-dependent recruitment of these "inhibitory lysosome-related organelles" to phagosomes continuously limits acidification and degradation of ingested particles in dendritic cells, thus promoting antigen cross-presentation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17351642&query_hl=1 ER - TY - JFULL T1 - Missed upper gastrointestinal cancer within 3 years of previous endoscopy A1 - Milestone, AN A1 - Kent, AJ A1 - Goldin, RD A1 - Hoare, JM J1 - GASTROENTEROLOGY Y1 - 2007/04// VL - 132 SN - 0016-5085 SP - A312 EP - A313 ER - TY - JFULL T1 - Inhibition of p38 mitogen-activated protein kinase is effective in the treatment of experimental crescentic glomerulonephritis and suppresses monocyte chemoattractant protein-1 but not IL-1beta or IL-6. A1 - Sheryanna, A A1 - Bhangal, G A1 - McDaid, J A1 - Smith, J A1 - Manning, A A1 - Foxwell, BM A1 - Feldmann, M A1 - Cook, HT A1 - Pusey, CD A1 - Tam, FW J1 - J Am Soc Nephrol Y1 - 2007/04// VL - 18 SN - 1046-6673 SP - 1167 EP - 1179 N2 - Activation of p38 mitogen-activated protein kinase (MAPK) is known to be important in cytokine production and cell survival in inflammation. This study examined the effect of inhibiting p38 MAPK after onset of renal injury in an experimental model of crescentic glomerulonephritis. Furthermore, this study investigated whether p38 MAPK inhibition would cause widespread suppression of the cytokine network in vivo or uncontrolled apoptosis. In the in vivo studies, daily treatment with a p38 MAPKalpha/beta inhibitor was started 1 h (early treatment study) or 4 d (late treatment study) after induction of nephrotoxic nephritis in Wistar Kyoto rats. The treated rats remained healthy with normal weight gain during the study. Both early and late treatment with p38 MAPK inhibitor reduced renal monocyte chemoattractant protein-1 (MCP-1) levels, the number of glomerular macrophages, the severity of tissue injury, and proteinuria compared with the vehicle group. Unexpected, treatment with p38 MAPK inhibitor did not suppress renal levels of IL-1beta or IL-6. In the in vitro study, the p38 MAPKalpha/beta inhibitor reduced production of MCP-1 and IL-6 by TNF-alpha-or IL-1beta-stimulated mesangial cells without any effect on cell viability or apoptosis. In conclusion, p38 MAPK inhibition is effective in reducing the severity of crescentic glomerulonephritis even when treatment is started after onset of disease. The therapeutic effect is associated with selective suppression of MCP-1, without widespread suppression of cytokine production or increased apoptosis. Therefore, p38 MAPK therapeutic blockade is a promising strategy in the treatment of antibody-mediated glomerulonephritis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17314328&query_hl=1 ER - TY - JFULL T1 - Natalizumab maintains corticosteroid-free remission for 2 years in patients with moderately to severely active crohn's disease and in those with prior infliximab exposure: Results from an open-label extension study A1 - Ghosh, S A1 - Panaccione, R J1 - GUT Y1 - 2007/04// VL - 56 SN - 0017-5749 SP - A22 EP - A22 ER - TY - JFULL T1 - Hydrogen peroxide in exhaled breath condensate (EBC) vs eosinophil count in induced sputum (IS) in parenchymal vs airways lung diseases. A1 - Fireman, E A1 - Shtark, M A1 - Priel, IE A1 - Shiner, R A1 - Mor, R A1 - Kivity, S A1 - Fireman, Z J1 - Inflammation Y1 - 2007/04// VL - 30 SN - 0360-3997 SP - 44 EP - 51 N2 - We compared exhaled breath condensate (EBC) and induced sputum (IS) for assessing inflammation in pulmonary diseases in patients with obstructive lung disease (n = 20), persistent cough >6 months (n = 20), interstitial lung disease (n = 25) and controls (n = 10). EBC was collected by suspending a Teflon perfluoroalkoxy tube installed in an ice-filled container and connected to a polypropylene test tube. IS was recovered after 20' inhalation of 3% saline with an ultrasonic nebulizer, and 300 cells were differentially counted in cytospin Giemsa-stained slides. H(2)0(2) was measured by a method based on oxidation of phenolsulfonphthalein (phenol red) mediated by horseradish peroxidases and H(2)0(2). Pulmonary function tests were performed by conventional methods. H(2)0(2) levels in EBC and % eosinophils in IS were significantly different between groups. A positive and significant correlation was found between % eosinophils in IS and the levels of H(2)0(2) in EBC for each group and for all patients combined. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17372840&query_hl=1 ER - TY - JFULL T1 - Effects of anti-TNF antibodies in vitro on dendritic cell apoptosis and function A1 - Patel, V A1 - Butler, M A1 - Ghosh, S J1 - GUT Y1 - 2007/04// VL - 56 SN - 0017-5749 SP - A110 EP - A110 ER - TY - JFULL T1 - Peritoneal mesothelioma: an unusual cause of an acute phase response presenting to the rheumatologist. A1 - Hamdulay, SS A1 - Cook, HT A1 - Strickland, N A1 - Davies, KA A1 - Mason, JC J1 - Clin Rheumatol Y1 - 2007/04// VL - 26 SN - 0770-3198 SP - 584 EP - 586 N2 - The presence of an acute phase response may pre-date the eventual diagnosis of malignant disease by months or even years. We describe two patients referred to the rheumatology clinic, in which extensive investigation failed to identify an underlying cause to account for the presenting symptoms and an associated acute phase response. Several months later, repeated abdominal CT scans revealed an abnormality and subsequent laparoscopic biopsy confirmed a diagnosis of peritoneal mesothelioma. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16416032&query_hl=1 ER - TY - JFULL T1 - 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 - Increased trpv1 expressing nerve fibres in colonic biopsies from irritable bowel syndrome patients correlate with the degree of abdominal pain A1 - Akbar, A A1 - Yiangou, Y A1 - Facer, P A1 - Anand, P A1 - Ghosh, S J1 - GUT Y1 - 2007/04// VL - 56 SN - 0017-5749 SP - A19 EP - A19 ER - TY - JFULL T1 - Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28. A1 - Mirenda, V A1 - Jarmin, SJ A1 - David, R A1 - Dyson, J A1 - Scott, D A1 - Gu, Y A1 - Lechler, RI A1 - Okkenhaug, K A1 - Marelli-Berg, FM J1 - Blood Y1 - 2007/04/01/ VL - 109 SN - 0006-4971 SP - 2968 EP - 2977 N2 - Productive T-cell immunity requires both the activation and the migration of specific T cells to the antigenic tissue. The costimulatory molecule CD28 plays an essential role in the initiation of T-cell-mediated immunity. We investigated the possibility that CD28 may also regulate migration of primed T cells to target tissue. In vitro, CD28-mediated signals enhanced T-cell transendothelial migration, integrin clustering, and integrin-mediated migration. In vivo, T cells bearing a mutation in the CD28 cytoplasmic domain, which abrogates PI3K activation, displayed normal clonal expansion but defective localization to antigenic sites following antigenic rechallenge. Importantly, antibody-mediated CD28 stimulation led to unregulated memory T-cell migration to extra-lymphoid tissue, which occurred independently of T-cell receptor (TCR)-derived signals and homing-receptor expression. Finally, we provide evidence that CD28- and CTLA-4-mediated signals exert opposite effects on T-cell trafficking in vivo. These findings highlight a novel physiologic function of CD28 that has crucial implications for the therapeutic manipulation of this and other costimulatory molecules. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17119120&query_hl=1 ER - TY - JFULL T1 - Proteome changes associated with hippocampal MRI abnormalities in the lithium pilocarpine-induced model of convulsive status epilepticus. A1 - Greene, ND A1 - Bamidele, A A1 - Choy, M A1 - de Castro, SC A1 - Wait, R A1 - Leung, KY A1 - Begum, S A1 - Gadian, DG A1 - Scott, RC A1 - Lythgoe, MF J1 - Proteomics Y1 - 2007/04// VL - 7 SN - 1615-9853 SP - 1336 EP - 1344 N2 - Convulsive status epilepticus is associated with subsequent hippocampal damage and development of mesial temporal sclerosis in a subset of individuals. The lithium pilocarpine model of status epilepticus (SE) in the rat provides a model in which to investigate the molecular and pathogenic process leading to hippocampal damage. In this study, a 2-DE-based approach was used to detect proteome changes in the hippocampus, at an early stage (2 days) after SE, when increased T2 values were detectable by magnetic resonance imaging. Gel image analysis was followed by LC-MS/MS identification of protein species that differed in abundance between pilocarpine-treated and control rats. The most significantly up-regulated species in the experimental animals was identified as heat shock 27-kDa protein, in line with findings in humans and in other experimental models of epilepsy. Additional up-regulated species included dihydropyrimidinase-related protein-2, cytoskeletal proteins (alpha-tubulin and ezrin) and dihydropteridine reductase. In summary, the hippocampus of rats subject to pilocarpine-induced SE exhibits specific changes in protein abundance, which likely relate to pathogenic, neuroprotective and neurogenic responses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17366478&query_hl=1 ER - TY - JFULL T1 - The identification of surface proteins of Burkholderia pseudomallei. A1 - Harding, SV A1 - Sarkar-Tyson, M A1 - Smither, SJ A1 - Atkins, TP A1 - Oyston, PC A1 - Brown, KA A1 - Liu, Y A1 - Wait, R A1 - Titball, RW J1 - Vaccine Y1 - 2007/03/30/ VL - 25 SN - 0264-410X SP - 2664 EP - 2672 N2 - Burkholderia pseudomallei, the causative agent of the disease melioidosis is a human pathogen endemic in Northern Australia and South-East Asia. At present there is no available vaccine or effective treatment for this disease. Surface proteins play crucial roles in the host-pathogen interaction and have been exploited as vaccine candidates and diagnostic targets. Therefore, we wished to identify immunogenic surface proteins of B. pseudomallei. To this end we used two proteomic-based approaches in parallel: a biotinylation approach for the detection of surface located proteins identified 35 proteins, while screening with human sera identified 12 immunogenic proteins. Nine of these proteins were identified by both methods indicating that they may be both surface located and immunogenic: these proteins will be evaluated further as vaccine candidates and diagnostic targets. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17289218&query_hl=1 ER - TY - JFULL T1 - Reactivation of Snail genes in renal fibrosis and carcinomas - A process of reversed embryogenesis? A1 - Boutet, A A1 - Esteban, MA A1 - Maxwell, PH A1 - Nieto, MA J1 - CELL CYCLE Y1 - 2007/03/15/ VL - 6 SP - 638 EP - 642 N2 - While the activity of Snail genes is required during embryonic development for the formation of different tissues and organs, they must be repressed in the adult in order to maintain epithelial integrity and homeostasis. Indeed, pathological activation of Snail in epithelial tumors induces malignancy and the recurrence of tumors. Here we show that in dedifferentiated areas of human renal carcinomas, Snail undergoes a process of reactivation. In addition to tumor progression, renal fibrosis is also linked to the activity of Snail genes and indeed, reactivation of Snail in the adult kidney is sufficient to induce fibrosis. Thus, Snail genes illustrate a paradigm whereby reactivation of crucial embryonic genes in adult tissues provokes the onset of devastating diseases. ER - TY - JFULL T1 - Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation. A1 - Cunninghame Graham, DS A1 - Manku, H A1 - Wagner, S A1 - Reid, J A1 - Timms, K A1 - Gutin, A A1 - Lanchbury, JS A1 - Vyse, TJ J1 - Hum Mol Genet Y1 - 2007/03/15/ VL - 16 SN - 0964-6906 SP - 579 EP - 591 N2 - Results from two studies have implicated the interferon regulatory gene IRF5 as a susceptibility gene in systemic lupus erythematosus (SLE). In this study, we conducted a family-based association analysis in 380 UK SLE nuclear families. Using a higher density of markers than has hitherto been screened, we show that there is association with two SNPs in the first intron, rs2004640 (P = 3.4 x 10(-4)) and rs3807306 (P = 4.9 x 10(-4)), and the association extends into the 3'-untranslated region (UTR). There is a single haplotype block encompassing IRF5 and we show for the first time that the gene comprises two over-transmitted haplotypes and a single under-transmitted haplotype. The strongest association is with a TCTAACT haplotype (T:U = 1.92, P = 5.8 x 10(-5)), which carries all the over-transmitted alleles from this study. Haplotypes carrying the T alleles of rs2004640 and rs2280714 and the A allele of rs10954213 are over-transmitted in SLE families. The TAT haplotype shows a dose-dependent relationship with mRNA expression. A differential expression pattern was seen between two expression probes located each side of rs10954213 in the 3'-UTR. rs10954213 shows the strongest association with RNA expression levels (P = 1 x 10(-14)). The A allele of rs10954213 creates a functional polyadenylation site and the A genotype correlates with increased expression of a transcript variant containing a shorter 3'-UTR. Expression levels of transcript variants with the shorter or longer 3'-UTRs are inversely correlated. Our data support a new mechanism by which an IRF5 polymorphism controls the expression of alternate transcript variants which may have different effects on interferon signalling. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17189288&query_hl=1 ER - TY - JFULL T1 - Natural regulation of immunity to minor histocompatibility antigens. A1 - Robertson, NJ A1 - Chai, JG A1 - Millrain, M A1 - Scott, D A1 - Hashim, F A1 - Manktelow, E A1 - Lemonnier, F A1 - Simpson, E A1 - Dyson, J J1 - J Immunol Y1 - 2007/03/15/ VL - 178 SN - 0022-1767 SP - 3558 EP - 3565 N2 - MHC-matched hemopoietic stem cell transplantation is commonly used for the treatment of some forms of leukemia. Conditioning regimens before transplant act to reduce the burden of leukemic cells and the graft-vs-leukemia (GvL) effect can eliminate residual disease. The GvL effect results largely from the recognition of minor histocompatibility Ags by donor T cells on recipient tissues. These Ags are generally widely expressed and also provoke graft-vs-host (GvH) disease. Manipulation of immunity to promote GvL while curtailing GvH would greatly improve clinical outcome. To develop strategies that may achieve this, the parameters which control immunity to minor histocompatibility Ags need to be defined. In this study, we have analyzed responses to the mouse HY minor histocompatibility Ag using hemopoietic cell and skin grafts as surrogate GvL and GvH targets, respectively. We show that natural regulation of CD8 T cell responses to HY operates at multiple levels. First, CD4 T cell help is required for primary CD8 responses directed at hemopoietic cells. However, although CD4 T cells of H2(k) mouse strains recognize HY, they provide ineffective help associated with a proportion of recipients developing tolerance. This was further investigated using TCR-transgenic mice which revealed H2(k)-restricted HY-specific CD4 T cells are highly susceptible to regulation by CD25(+) regulatory T cells which expand in tolerant recipients. A second level of regulation, operating in the context of skin grafts, involves direct inhibition of CD8 T cell responses by CD94/NKG2 engagement of the nonclassical MHC class I molecule Qa1. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17339452&query_hl=1 ER - TY - JFULL T1 - 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 - Expression of constitutively active STAT3 can replicate the cytokine-suppressive activity of interleukin-10 in human primary macrophages. A1 - Williams, LM A1 - Sarma, U A1 - Willets, K A1 - Smallie, T A1 - Brennan, F A1 - Foxwell, BM J1 - J Biol Chem Y1 - 2007/03/09/ VL - 282 SN - 0021-9258 SP - 6965 EP - 6975 N2 - There is general agreement that signal transducer and activation of transcription 3 (STAT3) is required to mediate the anti-inflammatory activities of interleukin (IL)-10. However, STAT3 is activated by multiple factors that do not share the anti-inflammatory activity of IL-10. The question remains whether STAT3 is sufficient for the anti-inflammatory effects or whether there are other signals required, as had been suggested previously. We set out to map the human IL-10 receptor and to identify the key elements involved in transducing the cytokine-suppressive effects of IL-10. We were able to show an absolute requirement for both of the tyrosine residues found within the YXXQ-STAT3-docking site within the IL-10 receptor 1 and that no other signals appeared to be required. We used a constitutively active STAT3 to determine whether expression of this factor could suppress lipopolysaccharide-induced tumor necrosis factor and IL-6 production. Our data show that STAT3 activity can suppress both IL-6 and tumor necrosis factor production in lipopolysaccharide-stimulated macrophages. However, in synovial fibroblasts, STAT3 did not suppress IL-6 production, suggesting that the cellular environment plays an important role in dictating whether STAT3 drives a pro- or anti-inflammatory response. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17194701&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 - Heat shock protein 27 functions in inflammatory gene expression and transforming growth factor-beta-activated kinase-1 (TAK1)-mediated signaling. A1 - Alford, KA A1 - Glennie, S A1 - Turrell, BR A1 - Rawlinson, L A1 - Saklatvala, J A1 - Dean, JL J1 - J Biol Chem Y1 - 2007/03/02/ VL - 282 SN - 0021-9258 SP - 6232 EP - 6241 N2 - Heat shock protein (HSP) 27 has long been known to be a component of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. p38 MAPK has important functions in the inflammatory response, but the role of HSP27 in inflammation has remained unknown. We have used small interfering RNAs to suppress HSP27 expression in HeLa cells and fibroblasts and found that it is required for pro-inflammatory cell signaling and the expression of pro-inflammatory genes. HSP27 is needed for the activation by interleukin (IL)-1 of TAK1 and downstream signaling by p38 MAPK, JNK, and their activators (MKK-3, -4, -6, -7) and IKKbeta. IL-1-induced ERK activation appears to be independent of HSP27. HSP27 is required for both IL-1 and TNF-induced signaling pathways for which the most upstream common signaling protein is TAK1. HSP27 is also required for IL-1-induced expression of the pro-inflammatory mediators, cyclooxygenase-2, IL-6, and IL-8. HSP27 functions to drive cyclooxygenase-2 and IL-6 expression by augmenting the activation of the kinase downstream of p38 MAPK, MK2, resulting in stabilization of cyclooxygenase-2 and IL-6 mRNAs. The mechanism may not occur in cells of myeloid lineage because HSP27 protein was undetectable in human monocytes and murine macrophages. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17202147&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 - Tregs in peripheral blood of clinically defined groups of renal transplant recipients A1 - Hernandez-Fuentes, MP A1 - Sagoo, P A1 - Sawitzki, B A1 - Perucha, E A1 - Jimenez-Vera, E A1 - Craciun, L A1 - Brouard, S A1 - Chapman, S A1 - Jansen, U A1 - Warrens, AN A1 - Goldman, M A1 - Volk, HD A1 - Soulillou, JP A1 - Wood, K A1 - Lechler, RI J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 10 EP - 10 ER - TY - JFULL T1 - Proteomic analysis of white matter from the dorsolateral prefrontal cortex in schizophrenia demonstrated alterations in synaptic associated proteins A1 - English, J A1 - Dicker, P A1 - Wait, R A1 - O'Donoghue, N A1 - Pennington, S A1 - Dunn, M A1 - Cotter, D J1 - SCHIZOPHRENIA BULL Y1 - 2007/03// VL - 33 SN - 0586-7614 SP - 259 EP - 260 ER - TY - JFULL T1 - Transfer of tolerance to naive recipients by CD4+ and CD25+ T cells from donors with experimental autoimmune glomerulonephritis treated with an anti-ICOSL monoclonal antibody A1 - Reynolds, J A1 - Maine, C A1 - Sando, GS A1 - Salama, AD A1 - Pusey, CD J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 35 EP - 35 ER - TY - JFULL T1 - TCR-zeta dim T cells define a population of circulating effector cells that migrate to inflamed tissues A1 - Gorman, CL A1 - Zhang, Z A1 - Vermi, AC A1 - Monaco, C A1 - Marelli-Berg, F A1 - Dazzi, F A1 - Cope, AP J1 - ANN RHEUM DIS Y1 - 2007/03/01/ VL - 66 SN - 0003-4967 SP - A17 EP - A17 ER - TY - JFULL T1 - Factors for graft-versus-host disease after donor lymphocyte infusions with an escalating dose regimen: lack of association with cell dose. A1 - Fozza, C A1 - Szydlo, RM A1 - Abdel-Rehim, MM A1 - Nadal, E A1 - Goldman, JM A1 - Apperley, JF A1 - Dazzi, F J1 - Br J Haematol Y1 - 2007/03// VL - 136 SN - 0007-1048 SP - 833 EP - 836 N2 - We investigated the risk factors for graft-versus-host disease (GVHD) in 82 patients treated with donor lymphocyte infusions (DLI) using an escalating dose regimen for chronic myeloid leukaemia in relapse following conventional allografting. Two factors emerged as predictors of both acute and chronic GVHD: the infusion of male recipients with lymphocytes from a female donor and the interval between transplant and last DLI, but only the first remained significant at multivariate analysis. Surprisingly, lymphocyte dose did not influence the incidence of GVHD. Our results suggest that DLI can be given in large cell doses without increasing the risk of GVHD. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17341269&query_hl=1 ER - TY - JFULL T1 - Increased nitric oxide production regulates T cell function in rheumatoid arthritis A1 - Nagy, G A1 - Clark, JM A1 - Buzas, E A1 - Gorman, C A1 - Falus, A A1 - Cope, AP J1 - JOINT BONE SPINE Y1 - 2007/03// VL - 74 SN - 1297-319X SP - 215 EP - 216 ER - TY - JFULL T1 - Identification of target mRNAs regulated by both p38 MAPK and tristetraprolin in murine macrophages A1 - Tudor, C A1 - Hitti, E A1 - Blackshear, PJ A1 - Clark, AR A1 - Saklatvala, J A1 - Dean, JLE J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 16 EP - 16 ER - TY - JFULL T1 - Physiological and aberrant regulation of memory T cell trafficking by the co-stimulatory molecule CD28 A1 - Mirenda, V A1 - Jarmin, SJ A1 - David, R A1 - Dyson, J A1 - Scott, D A1 - Gu, Y A1 - Lechler, RI A1 - Okkenhaug, K A1 - Marelli-Berg, FM J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 31 EP - 31 ER - TY - JFULL T1 - BXSB/long-lived is a recombinant inbred strain containing powerful disease suppressor loci A1 - Gabriel, L A1 - Haywood, MEK A1 - Rose, SJ A1 - Rogers, NJ A1 - Izui, S A1 - Morley, BJ J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 72 EP - 72 ER - TY - JFULL T1 - Differential expression of CD40, OX40L & PDL2 on lung dendritic cells in polarised immune responses to Respiratory Syncytial Virus (RSV) A1 - Wythe, SE A1 - Dodd, JS A1 - Openshaw, PJ A1 - Schwarze, J J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 15 EP - 15 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 - Growth and protein profile changes in Lepidium sativum L. plantlets exposed to cadmium A1 - Gianazza, E A1 - Wait, R A1 - Sozzi, A A1 - Regondi, S A1 - Saco, D A1 - Labrac, M A1 - Agradi, E J1 - ENVIRON EXP BOT Y1 - 2007/03// VL - 59 SN - 0098-8472 SP - 179 EP - 187 N2 - Plant metabolic response to heavy metal stress is still to be clarified. The present investigation was undertaken to examine the influence of different concentrations of cadmium on the Lepidium sativum L. plantlets. Exposure of seedlings of L. sativum L. to increasing concentrations of cadmium results in the growth inhibition and in the accumulation of proteins in the 10-25 kDa range in cotyledons and hypocotyls of the plantlets. Most of these proteins are also found in extracts of L. sativum seeds. Analysis by ESI-MS after two-dimensional electrophoresis showed that these proteins exhibit sequences similar to those of storage proteins from various Cruciferae species. The response to metal exposure during germination and initial plantlet elongation thus involves inhibition of both storage protein catabolism and plant protein anabolism. In addition, two of the proteins present in higher amounts in plantlets exposed to cadmium heat-shock, in agreement with literature data, and jasmonate-like inducible protein are related to cellular stress and another two (LEAs or late embryogenesis abundant) are involved in embryogenesis. Changes in protein expression can be detected by two-dimensional electrophoresis after exposure to heavy metal concentrations lower than those at which morphometric changes become evident. Proteomics of germinating L. sativiun thus constitutes a very sensitive too] for evaluating environmental pollution. (c) 2006 Elsevier B.V. All rights reserved. ER - TY - JFULL T1 - Circulating endothelial progenitor cells as a link between synovial vascularity and cardiovascular mortality in rheumatoid arthritis. A1 - Akhavani, MA A1 - Larsen, H A1 - Paleolog, E J1 - Scand J Rheumatol Y1 - 2007/03// VL - 36 SN - 0300-9742 SP - 83 EP - 90 N2 - Cardiovascular disease refers to the class of diseases that involve the heart and/or blood vessels (arteries and veins). Most Western countries face high and ever-increasing rates of cardiovascular disease. Each year, more Americans are killed by heart disease than by cancer. Diseases of the heart alone cause 30% of all deaths, with other diseases of the cardiovascular system causing substantial further deaths and disability. Indeed, cardiovascular disease is the major cause of death and disability in the USA and most European countries. The development of the vascular systems requires an intricate interplay of molecules such as vascular endothelial growth factor and endothelial progenitor cells. A defective vascular repair/regeneration is thought to be responsible for propagation of atherosclerosis, a key feature of cardiovascular disease. This is partly attributed to a reduction in the circulating endothelial progenitor cells in peripheral blood. Patients with rheumatoid arthritis (RA) have a higher than average incidence of cardiovascular disease in comparison with the general population, with an increased risk of stroke and myocardial infarction, and an increased risk of fatality following myocardial infarction. This review focuses on the current evidence linking the role played by endothelial progenitor cells to the development of cardiovascular disease and why this might relate to the increased risk observed in RA patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17476612&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 - IL-21 depletion exacerbates augmented respiratory syncytial virus (RSV) disease by deregulating control of dendritic cell: CD4 T cell stimulation A1 - Dodd, JS A1 - Clark, D A1 - O'Brien, D A1 - Korpis, C A1 - Openshaw, PJM J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 14 EP - 14 ER - TY - JFULL T1 - Inhaled therapy in elderly COPD patients; time for re-evaluation? A1 - Jarvis, S A1 - Ind, PW A1 - Shiner, RJ J1 - Age Ageing Y1 - 2007/03// VL - 36 SN - 0002-0729 SP - 213 EP - 218 N2 - OBJECTIVE: chronic obstructive pulmonary disease (COPD) prevalence steadily increases with age. However, the effectiveness of inhaled therapy in the elderly COPD population has rarely been formally evaluated. We studied a group of elderly patients with COPD with a range of severity, selected from one General Practice register to measure peak inspiratory flow (PIF) and assess patient perceived benefit. METHODS: we recruited 53 randomly selected elderly patients with COPD (36 males) with a mean age of 73.5 years (range 65-89 years). The evaluation consisted of (i) information obtained from directed questions and (ii) objective measurements of the ability to generate adequate PIF for a variety of inhalers. Patients answered questions regarding ease of use, perceived benefit from and specific problems encountered with their inhaler. Three recordings of PIF were measured at varying inhaled resistances using the 'In-Check Dial'. RESULTS: thirty-five were classified as mild, 17 moderate and 1 severe COPD. All patients used a metered dose inhaler (pMDI), and 12 of the patients also used a dry powder inhaler (DPI). Forty six per cent of patients using a pMDI and 17% of those using a DPI rated their device difficult to use. No patient used a nebuliser. Thirty-one of the 53 patients using just a pMDI felt they were able to perceive benefit in comparison to 4 of the 12 DPI users. Even though most DPI users (10/12) had rated their inhaler as easy to use, 50% were 'unsure' as to whether they received any clinical benefit. Most patients were unable to generate sufficient inspiratory flow to use the higher resistance DPI's and patients with COPD who were able to generate adequate PIF were invariably mild. A significant negative correlation was found between age and the PIF achieved when assessed using the high resistance device setting (R = 0.84, P<0.0001). Multivariate analysis showed the effect of age on PIF was independent of the disease grade. CONCLUSIONS: elderly patients with COPD, even when in a stable clinical condition, may be unable to gain optimum benefit from their inhaler. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17267450&query_hl=1 ER - TY - JFULL T1 - Adenoviral gene transfer of the endogenous inhibitor IkappaBalpha into human osteoarthritis synovial fibroblasts demonstrates that several matrix metalloproteinases and aggrecanases are nuclear factor-kappaB-dependent. A1 - Bondeson, J A1 - Lauder, S A1 - Wainwright, S A1 - Amos, N A1 - Evans, A A1 - Hughes, C A1 - Feldmann, M A1 - Caterson, B J1 - J Rheumatol Y1 - 2007/03// VL - 34 SN - 0315-162X SP - 523 EP - 533 N2 - OBJECTIVE: To investigate the role of the transcription factor nuclear factor-kB (NF-kappaB) in promoting inflammatory and destructive responses in human osteoarthritis (OA) synovial fibroblasts, by assessing the effect of NF-kappaB blockade on the production of cytokines and destructive enzymes. METHODS: Infection with adenoviruses transferring the beta-galactosidase gene was used to ascertain that the OA fibroblasts could be infected (> 95%). Using an adenovirus transferring the inhibitory subunit IkappaBa, effective inhibition of NF-kappaB was achieved. The expression and production of several pro- and antiinflammatory cytokines and mediators, the major matrix metalloproteinases (MMP 1, 3, and 13), their main inhibitor tissue inhibitor of metalloproteinase-1 (TIMP-1), and the aggrecanases (ADAMTS4 and ADAMTS5) were measured by ELISA and/or reverse transcription-polymerase chain reaction, and their dependence on NF-kappaB evaluated. RESULTS: The production of interleukin 6 (IL-6), monocyte chemoattractant protein-1, and RANTES was potently inhibited by IkBa overexpression, irrespective of stimulus, but IL-8 was unaffected. The p55 soluble tumor necrosis factor (TNF) receptor was unaffected, but the p75 soluble TNF receptor was potently inhibited by IkBa overexpression. MMP-1, MMP-3, and MMP-13 were inhibited by IkappaBa overexpression, at both the mRNA and protein levels, whereas TIMP-1 was unaffected. The mRNA gene expression of ADAMTS4 was also inhibited by IkappaBa overexpression, particularly in IL-1-stimulated cells, but ADAMTS5 was unaffected. CONCLUSION: In OA synovial fibroblasts, inhibition of NF-kappaB has a beneficial effect on the balance between the expression of proinflammatory cytokines and antiinflammatory mediators. Inhibition of this transcription factor also results in the decreased expression of several destructive metalloproteinases and also the ADAMTS4 aggrecanase. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17295438&query_hl=1 ER - TY - JFULL T1 - Nasal administration of an immunodominant peptide from rat alpha 3(IV)NC1 in the treatment of established experimental autoimmune glomerulonephritis A1 - Reynolds, J A1 - Karegli, J A1 - Abbott, DA A1 - Haxby, J A1 - Pusey, CD J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 39 EP - 39 ER - TY - JFULL T1 - Altered expression and endocytic function of CD205 in human dendritic cells, and detection of a CD205-DCL-1 fusion protein upon dendritic cell maturation. A1 - Butler, M A1 - Morel, AS A1 - Jordan, WJ A1 - Eren, E A1 - Hue, S A1 - Shrimpton, RE A1 - Ritter, MA J1 - Immunology Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 362 EP - 371 N2 - CD205 (DEC-205) is a member of the macrophage mannose receptor family of C-type lectins. These molecules are known to mediate a wide variety of biological functions including the capture and internalization of ligands for subsequent processing and presentation by dendritic cells. Although its ligands await identification, the endocytic properties of CD205 make it an ideal target for those wishing to design vaccines and targeted immunotherapies. We present a detailed analysis of CD205 expression, distribution and endocytosis in human monocyte-derived dendritic cells undergoing lipopolysaccharide-induced maturation. Unlike other members of the macrophage mannose receptor family, CD205 was up-regulated upon dendritic cell maturation. This increase was a result of de novo synthesis as well as a redistribution of molecules from endocytic compartments to the cell surface. Furthermore, the endocytic capacity of CD205 was abrogated and small amounts of the recently identified CD205-DCL-1 fusion protein were detected in mature DC. Our results suggest that CD205 has two distinct functions -- one as an endocytic receptor on immature dendritic cells and a second as a non-endocytic molecule on mature dendritic cells -- and further highlight its potential as an immuno-modulatory target for vaccine and immunotherapy development. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17163964&query_hl=1 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 - Characterising pre and post-mortem factors influencing human post-mortem brain proteomic studies A1 - Cotter, D A1 - English, J A1 - Dicker, P A1 - Wait, R A1 - Dunn, M J1 - SCHIZOPHRENIA BULL Y1 - 2007/03// VL - 33 SN - 0586-7614 SP - 258 EP - 258 ER - TY - JFULL T1 - Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. A1 - Garín, MI A1 - Chu, CC A1 - Golshayan, D A1 - Cernuda-Morollón, E A1 - Wait, R A1 - Lechler, RI J1 - Blood Y1 - 2007/03/01/ VL - 109 SN - 0006-4971 SP - 2058 EP - 2065 N2 - The naturally occurring population of dedicated regulatory T cells that coexpress CD4 and CD25 is known to play a key role in the maintenance of peripheral T-cell tolerance; however, their mechanism of action has remained obscure. Here we report that a member of the family of beta-galactoside-binding proteins, galectin-1, is overexpressed in regulatory T cells, and that expression is increased after activation. Most importantly, blockade of galectin-1 binding significantly reduced the inhibitory effects of human and mouse CD4+CD25+ T cells. Reduced regulatory activity was observed in CD4+CD25+ T cells obtained from galectin-1-homozygous null mutant mice. These results suggest that galectin-1 is a key effector of the regulation mediated by these cells. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17110462&query_hl=1 ER - TY - JFULL T1 - Manipulation of the PD1/PDL1 negative T cell costimulatory pathway in treatment of established experimental autoimmune glomerulonephritis A1 - Reynolds, J A1 - Marsh, OB A1 - Sando, GS A1 - Salama, AD A1 - Pusey, CD J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 35 EP - 35 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 - Increased positive selection of B1 cells and reduced B cell tolerance to intracellular antigens in C1q-deficient mice A1 - Ferry, H A1 - Potter, PK A1 - Crockford, TL A1 - Nijnik, A A1 - Ehrenstein, MR A1 - Walport, MJ A1 - Botto, M A1 - Cornall, RJ J1 - J IMMUNOL Y1 - 2007/03/01/ VL - 178 SN - 0022-1767 SP - 2916 EP - 2922 N2 - Inherited deficiency of early components of the classical complement pathway is strongly associated with the targeting of intracellular self Ags in systemic lupus erythematosus, but the reasons for this association are debated. In this study, we show that C1q deficiency increases the positive selection of B1b B cells and IgM autoantibodies by an intracellular self Ag, which is exposed on dying cells, and decreases the negative selection of autoreactive conventional B cells by the same Ag. These effects are specific to intracellular Ag because C1q deficiency does not affect negative selection by extracellular self Ag or increase the positive selection of naive B cells. The B1-derived IgM autoantibody binds to the intracellular Ag when it is expressed on dying cells, leading to fixation of C1q and clearance of cells by phagocytosis. These findings suggest that the positive selection of autoreactive B1 cells by self Ags may contribute to the IgM and C1q-dependent clearance of dying cells in a feedback loop that limits exposure of conventional B cells to immunogenic self Ags. We show that exposure of intracellular Ag leads to the activation of conventional B cells, when there is a source of T cell help in vivo. ER - TY - JFULL T1 - Increased nitric oxide production regulates T cell function in rheumatoid arthritis A1 - Nagy, G A1 - Clark, JM A1 - Buzas, E A1 - Gorman, C A1 - Falus, A A1 - Cope, AP J1 - ANN RHEUM DIS Y1 - 2007/03/01/ VL - 66 SN - 0003-4967 SP - A69 EP - A69 ER - TY - JFULL T1 - Lymphoid tissue distribution of DC subtypes in a murine model of SLE A1 - Maniati, E A1 - Rogers, NJ A1 - Morley, BJ J1 - IMMUNOLOGY Y1 - 2007/03// VL - 120 SN - 0019-2805 SP - 73 EP - 73 ER - TY - JFULL T1 - Extraanatomic stents for transplant ureteric stenosis. A1 - Olsburgh, J A1 - Dorling, A A1 - Tait, P A1 - Williams, G J1 - Br J Radiol Y1 - 2007/03// VL - 80 SN - 1748-880X SP - 216 EP - 218 N2 - Surgical and standard endourology options are limited in transplant patients with severe ureteric stenosis, particularly when access to the transplant renal pelvis is limited. The use of a silicone-polytetrafluoroethelene (PTFE)-bonded extraanatomic urinary tract stent for urinary tract drainage is described in two patients. This technique of ureteric reconstruction in renal transplantation may be considered when standard approaches have failed. It appears to be safe when performed by radiologists and urologists with expertise in percutaneous renal access. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17092956&query_hl=1 ER - TY - JFULL T1 - Increased frequencies of CD4(+)CD25(high) T(regs) correlate with disease relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. A1 - Nadal, E A1 - Garin, M A1 - Kaeda, J A1 - Apperley, J A1 - Lechler, R A1 - Dazzi, F J1 - Leukemia Y1 - 2007/03// VL - 21 SN - 0887-6924 SP - 472 EP - 479 N2 - The therapeutic efficacy of allogeneic hemopoietic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) largely relies on the graft-versus-leukemia (GvL) effect exerted by donor T cells. CD4(+)CD25(high) regulatory T cells (T(regs)) have been shown to downregulate antitumor responses but their role on GvL has not been evaluated. We performed a cross-sectional study in which we enumerated and characterized CD4(+)CD25(high) T(regs) in the peripheral blood of CML patients undergoing allogeneic SCT. We documented higher frequencies of T(regs) in patients after transplant as compared to normal controls and newly diagnosed patients. The increment was particularly evident in patients who had received their SCT 18 months before. In vitro functional studies demonstrated that the T(regs) purified from SCT patients exhibited a more potent suppressive activity than T(regs) isolated from healthy volunteers. Patients in whom T(regs) numbers were higher than controls more than 18 months after SCT showed evidence of disease relapse. Although the increment in T(regs) might have an advantageous effect on graft rejection in the early phase post-transplant, our data suggest that T(regs) exert an inhibitory effect on GvL. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17215853&query_hl=1 ER - TY - JFULL T1 - The interface between coagulation and immunity. A1 - Shrivastava, S A1 - McVey, JH A1 - Dorling, A J1 - Am J Transplant Y1 - 2007/03// VL - 7 SN - 1600-6135 SP - 499 EP - 506 N2 - Coagulation proteases are involved in generating fibrin after vascular injury (hemostasis) but they also have multiple other effects, many of which are mediated independently of fibrin generation, via interactions with specific cell membrane-expressed "protease activated receptors". In inflammation, this family of proteins has a complex influence, the facets of which are still incompletely understood, though a common feature in different models appears to be amplification of innate signals that are initially generated by pathogenic elements or, in the context of transplantation, ischemia or anti-graft antibodies, for instance. There is increasing evidence that these proteases may also have specific effects on cells involved in adaptive immunity and on cells that mediate chronic inflammation and fibrosis. Understanding whether these effects are relevant in the responses generated against transplanted organs is important, as it could lead ultimately to the development of novel ways to promote long-term graft survival. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17229071&query_hl=1 ER - TY - JFULL T1 - Rab27a is a key component of the secretory machinery of azurophilic granules in granulocytes. A1 - Munafó, DB A1 - Johnson, JL A1 - Ellis, BA A1 - Rutschmann, S A1 - Beutler, B A1 - Catz, SD J1 - Biochem J Y1 - 2007/03/01/ VL - 402 SN - 1470-8728 SP - 229 EP - 239 N2 - Neutrophils kill micro-organisms using microbicidal products that they release into the phagosome or into the extracellular space. The secretory machinery utilized by neutrophils is poorly characterized. We show that the small GTPase Rab27a is an essential component of the secretory machinery of azurophilic granules in granulocytes. Rab27a-deficient mice have impaired secretion of MPO (myeloperoxidase) into the plasma in response to lipopolysaccharide. Cell fractionation analysis revealed that Rab27a and the Rab27a effector protein JFC1/Slp1 (synaptotagmin-like protein 1) are distributed principally in the low-density fraction containing a minor population of MPO-containing granules. By immunofluorescence microscopy, we detected Rab27a and JFC1/Slp1 in a minor subpopulation of MPO-containing granules. Interference with the JFC1/Slp1-Rab27a secretory machinery impaired secretion of MPO in permeabilized neutrophils. The expression of Rab27a was dramatically increased when promyelocytic HL-60 cells were differentiated into granulocytes but not when they were differentiated into monocytes. Down-regulation of Rab27a in HL-60 cells by RNA interference did not affect JFC1/Slp1 expression but significantly decreased the secretion of MPO. Neither Rab27a nor JFC1/Slp1 was integrated into the phagolysosome membrane during phagocytosis. Neutrophils from Rab27a-deficient mice efficiently phagocytose zymosan opsonized particles and deliver MPO to the phagosome. We conclude that Rab27a and JFC1/Slp1 permit MPO release into the surrounding milieu and constitute key components of the secretory machinery of azurophilic granules in granulocytes. Our results suggest that the granules implicated in cargo release towards the surrounding milieu are molecularly and mechanistically different from those involved in their release towards the phagolysosome. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17090228&query_hl=1 ER - TY - JFULL T1 - 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 - Synovial fibroblasts are important mediators of synovial angiogenesis in the hypoxic rheumatoid joint A1 - Larsen, H A1 - Feldmann, M A1 - Paleolog, E J1 - ANN RHEUM DIS Y1 - 2007/03/01/ VL - 66 SN - 0003-4967 SP - A61 EP - A61 ER - TY - JFULL T1 - Optimized clonotypic analysis of T-cell receptor repertoire in immune reconstitution. A1 - Packer, AN A1 - Muraro, PA J1 - Exp Hematol Y1 - 2007/03// VL - 35 SN - 0301-472X SP - 516 EP - 521 N2 - OBJECTIVE: In recent years, T-cell receptor (TCR) sequencing analysis has proven an effective technique for the identification of T-cell populations of interest in cancer and autoimmunity, as well as for the characterization of peripheral immune repertoire reconstitution after hematopoietic stem cell transplantation (HSCT). However, despite its increased utilization, to our knowledge no group has investigated the minimum number of sequences necessary to accurately and efficiently describe the composition of TCR repertoire. The primary aim of this study was to optimize a procedure for clonotypic analysis of the TCR repertoire in patients undergoing autologous HSCT. MATERIALS AND METHODS: TCR beta-chain diversity was analyzed by DNA sequencing and CDR3 spectratyping CD8(+) T cells isolated from three patients with multiple sclerosis undergoing autologous HSCT. Samples were collected at baseline and 1 or 2 years post-HSCT. RESULTS: Using DNA cloning and high throughput sequencing, we analyzed over 1500 in-frame TCR sequences, allowing us to evaluate how our measures of TCR repertoire diversity change with increasing numbers of sequences included in the analysis. Our findings show that by analyzing 75 to 100 in-frame sequences, we are able to estimate TCR diversity within 5.0% to 7.4% of the values obtained at endpoint analysis (213-312 sequences per sample). CONCLUSIONS: This study confirms the use of TCR sequencing as an effective technique for the characterization of immune renewal after autologous HSCT. In addition, we demonstrate for the first time convincing evidence to support the use of moderate sample sizes to accurately and efficiently evaluate TCR repertoire diversity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17309832&query_hl=1 ER - TY - JFULL T1 - Selective use of TRAM in lipopolysaccharide (LPS) and lipoteichoic acid (LTA) induced NF-kappaB activation and cytokine production in primary human cells: TRAM is an adaptor for LPS and LTA signaling. A1 - Sacre, SM A1 - Lundberg, AM A1 - Andreakos, E A1 - Taylor, C A1 - Feldmann, M A1 - Foxwell, BM J1 - J Immunol Y1 - 2007/02/15/ VL - 178 SN - 0022-1767 SP - 2148 EP - 2154 N2 - TLR signal via Toll-IL-1R (TIR) homology domain-containing adaptor proteins. One of these adaptors, Toll-IL-1R domain-containing adaptor inducing IFN-beta-related adaptor molecule (TRAM), has been shown to be essential for TLR4 signaling in TRAM(-/-) mice and cell lines. Previously, we showed that MyD88 or Mal dominant-negative constructs did not inhibit LPS induction of cytokines in primary human M-CSF-derived macrophages. A possible explanation was redundancy of the adaptors during LPS signaling. TRAM is a suitable candidate to compensate for these adaptors. To investigate a potential role for TRAM in LPS signaling in human M-CSF-derived macrophages, we engineered an adenoviral construct expressing dominant-negative TRAM-C117H (AdTRAMdn). Synovial fibroblasts (SF) and human umbilical endothelial cells (HUVECs) were used as a nonmyeloid comparison. AdTRAMdn inhibited LPS-induced signaling in SFs and HUVECs, reducing NF-kappaB activation and cytokine production, but did not inhibit LPS signaling in M-CSF-derived human macrophages. Further investigation of other TLR ligands showed that AdTRAMdn was also able to inhibit signaling initiated by lipoteichoic acid, a TLR2 ligand, in SFs and HUVECs and lipoteichoic acid and macrophage-activating lipopeptide 2 signaling was also inhibited in TRAM(-/-) murine embryonic fibroblasts. We conclude that TRAM is an adaptor protein for both TLR4 and TLR2/6 signaling in SFs, HUVECs, and murine embryonic fibroblasts, but cannot demonstrate a role in human macrophages. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17277119&query_hl=1 ER - TY - JFULL T1 - Genetic dissection of spontaneous autoimmunity driven by 129-derived chromosome 1 Loci when expressed on C57BL/6 mice. A1 - Carlucci, F A1 - Cortes-Hernandez, J A1 - Fossati-Jimack, L A1 - Bygrave, AE A1 - Walport, MJ A1 - Vyse, TJ A1 - Cook, HT A1 - Botto, M J1 - J Immunol Y1 - 2007/02/15/ VL - 178 SN - 0022-1767 SP - 2352 EP - 2360 N2 - Extensive evidence indicates that genetic predisposition is a central element in susceptibility to systemic lupus erythematosus both in humans and animals. We have previously shown that a congenic line carrying a 129-derived chromosome 1 interval on the C57BL/6 background developed humoral autoimmunity. To further dissect the contribution to autoimmunity of this 129 interval, we have created six subcongenic strains carrying fractions of the original 129 region and analyzed their serological and cellular phenotypes. At 1 year of age the congenic strain carrying a 129 interval between the microsatellites D1Mit15 (87.9 cM) and D1Mit115 (99.7 cM) (B6.129chr1b) had high levels of autoantibodies, while all the other congenic lines were not significantly different from the C57BL/6 controls. The B6.129chr1b strain displayed only mild proliferative glomerulonephritis despite high levels of IgG and C3 deposited in the kidneys. FACS analysis of the spleens revealed that the B6.129chr1b mice had a marked increase in the percentage of activated T cells associated with a significant reduction in the proportion of CD4(+)CD25(high) regulatory T cells. Moreover, this analysis showed a significantly reduced percentage of marginal zone B cells that preceded autoantibody production. Interestingly the 129chr1b-expressing bone marrow-derived macrophages displayed an impaired uptake of apoptotic cells in vitro. Collectively, our data indicate that the 129chr1b segment when recombined on the C57BL/6 genomic background is sufficient to induce loss of tolerance to nuclear Ags. These findings have important implication for the interpretation of the autoimmune phenotype associated with gene-targeted models. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17277141&query_hl=1 ER - TY - JFULL T1 - Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. A1 - Ramasamy, R A1 - Lam, EW A1 - Soeiro, I A1 - Tisato, V A1 - Bonnet, D A1 - Dazzi, F J1 - Leukemia Y1 - 2007/02// VL - 21 SN - 0887-6924 SP - 304 EP - 310 N2 - Mesenchymal stem cells (MSC) have received much attention in the field of hematopoietic stem cell transplantation because not only do they support hematopoiesis but also exhibit a profound immunosuppressive activity that can be exploited to prevent undesired alloreactivity. We have previously shown that their immunosuppressive activity is mainly exerted at the level of T-cell proliferation. Here, we show that MSC exhibit a similar antiproliferative activity on tumor cells of hematopoietic and non hematopoietic origin. In vitro, MSC produced the transient arrest of tumor cells in the G(1) phase of cell cycle; this was accompanied by a reduction in the apoptotic rate even when survival factors were limiting. However, when tumor cells were injected into non-obese diabetic-severe combined immunodeficient mice in conjunction with MSC, their growth was much faster as compared to the group receiving only tumor cells. To explain the discrepancy between the in vitro and in vivo behavior, we suggest that MSC have the ability to form a cancer stem cell niche in which tumor cells can preserve the potential to proliferate and sustain the malignant process. We conclude that the clinical use of MSC in conditions in which a malignant disease is involved should be handled with extreme caution. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17170725&query_hl=1 ER - TY - JFULL T1 - Complement C1q and C3 are critical for the innate immune response to Streptococcus pneumoniae in the central nervous system A1 - Rupprecht, TA A1 - Angele, B A1 - Klein, M A1 - Heesemann, J A1 - Pfister, HW A1 - Botto, M A1 - Koedel, U J1 - J IMMUNOL Y1 - 2007/02/01/ VL - 178 SN - 0022-1767 SP - 1861 EP - 1869 N2 - Previous studies suggest that the complement system can contribute to limiting pneumococcal outgrowth within the CNS. In this study, we evaluated the role of the complement system in the activation of the innate immune response and the development of the prognosis-relevant intracranial complications in a murine model of pneumococcal meningitis. Thereby, we used mice deficient in C1q, lacking only the classical pathway, and C3, lacking all three complement activation pathways. At 24 h after intracisternal infection, bacterial titers in the CNS were almost 12- and 20-fold higher in C1q- and C3-deficient-mice, respectively, than in wild-type mice. Mean CSF leukocyte counts were reduced by 47 and 73% in C1q- and O-deficient-mice, respectively. Intrathecal reconstitution with wild-type serum in C3-deficient mice restored both the ability of mice to combat pneumococcal infection of the CSF and the ability of leukocytes to egress into the CSF. The altered recruitment of leukocytes into the CSF of C3-deficient mice was paralleled by a strong reduction of the brain expression of cytokines and chemokines. The dampened immune response in C3-deficient mice was accompanied by a reduction of meningitis-induced intracranial complications, but, surprisingly, also with a worsening of short-term outcome. The latter seems to be due to more severe bacteremia (12- and 120-fold higher in C1q- and C3-deficient-mice, respectively) and, consecutively, more severe systemic complications. Thus, our study demonstrated for the first time that the complement system plays an integral role in mounting the intense host immune response to Streptococcus pneumoniae infection of the CNS. ER - TY - JFULL T1 - 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 - Enhanced depletion of alloreactive T cells using combined CD25/71 immunomagnetic selection A1 - Samarasinghe, S A1 - Karlsson, H A1 - Nawroly, N A1 - Openshaw, P A1 - Veys, P A1 - Amrolia, P J1 - BIOL BLOOD MARROW TR Y1 - 2007/02// VL - 13 SN - 1083-8791 SP - 21 EP - 21 ER - TY - JFULL T1 - Predicting the outcome of surgery for the proximal interphalangeal joint in Dupuytren's disease. A1 - Misra, A A1 - Jain, A A1 - Ghazanfar, R A1 - Johnston, T A1 - Nanchahal, J J1 - J Hand Surg [Am] Y1 - 2007/02// VL - 32 SN - 0363-5023 SP - 240 EP - 245 N2 - PURPOSE: We prospectively studied the outcome of limited Dupuytren's fasciectomy, in combination with joint release if necessary, for disease involving 49 proximal interphalangeal joints (PIPJs) to identify factors that predispose to recurrent PIPJ contracture. METHODS: Thirty-seven patients were treated over a 4-year period. The flexion contracture of the PIPJ was measured before surgery, immediately after surgery, and at more than 1 year after surgery. RESULTS: A mean preoperative flexion contracture of 67 degrees +/- 22 degrees was corrected to 6 degrees +/- 10 degrees at the time of surgery and 25 degrees +/- 25 degrees at the follow-up evaluation. There was a positive correlation between the severity of the preoperative flexion contracture and recurrent deformity, with a preoperative contracture greater than 60 degrees leading to significantly worse outcome. Incomplete correction of PIPJ flexion contracture during surgery and poor postoperative compliance with therapy were also associated with worse recurrent joint contractures. The digit involved and the necessity for joint release did not significantly affect outcome. CONCLUSIONS: In the absence of recurrent Dupuytren's disease, severe preoperative deformity, incomplete correction at surgery, and noncompliance with therapy predispose patients to worse PIPJ contracture. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17275601&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 - Placental pathology of recurrent spontaneous abortion: the role of histopathological examination of products of conception in routine clinical practice: a mini review. A1 - Jindal, P A1 - Regan, L A1 - Fourkala, EO A1 - Rai, R A1 - Moore, G A1 - Goldin, RD A1 - Sebire, NJ J1 - Hum Reprod Y1 - 2007/02// VL - 22 SN - 0268-1161 SP - 313 EP - 316 N2 - BACKGROUND: Histopathological examination of products of conception from miscarriages is part of routine clinical practice. The extent of additional clinically relevant information provided by this investigation in the setting of recurrent spontaneous abortion remains uncertain. METHODS: Review of the literature was performed to identify studies reporting on findings of histological examination of routinely obtained products of conception in the setting of recurrent spontaneous abortion. The initial search identified 312 potential references, but 300 were excluded on further examination due to lack of data on specific histopathological findings in routine products of conception specimens from patients with recurrent spontaneous abortion. The 12 included studies indicated that such examination may identify hydatidiform moles, villous dysmorphic features suggesting fetal aneuploidy, chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition and impaired trophoblast invasion. However, in most cases, morphological assessment cannot reliably determine the cause of the miscarriage or distinguish recurrent from sporadic miscarriage. Studies reporting on the use of additional immunohistochemical methods do not currently provide additional clinically useful diagnostic or prognostic information. CONCLUSION: Routine histological examination of products of conception in the setting of recurrent spontaneous abortion can provide important clinical information in a minority of cases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17008326&query_hl=1 ER - TY - JFULL T1 - Long-term effects of perinatal nutrition on T lymphocyte kinetics in young Gambian men A1 - Ghattas, H A1 - Wallace, DL A1 - Solon, JA A1 - Henson, SM A1 - Zhang, Y A1 - Ngom, PT A1 - Aspinall, R A1 - Morgan, G A1 - Griffin, GE A1 - Prentice, AM A1 - Macallan, DC J1 - AM J CLIN NUTR Y1 - 2007/02// VL - 85 SN - 0002-9165 SP - 480 EP - 487 N2 - Background: Nutritional status is highly dependent on season in countries such as The Gambia. In a rural Gambian setting, individuals born during periods of seasonal nutritional deprivation ("hungry seasons") are susceptible to mortality from infectious diseases in adult life.Objective: We investigated the hypothesis that impaired immunocompetence in those born in the hungry season results from an underlying defect in immunologic memory, similar to the immunosenescence of old age, which is likely to be reflected in the phenotype and kinetics of T lymphocytes in young adults.Design: T cell phenotype in terms of CD3, CD4, CD8, CD45RA, and CD45R0 expression and in vivo dynamics measured by stable isotope labeling of T cell subsets combined with gas chromatography-mass spectrometry and frequency of T cell receptor excision circles were measured in 25 young (18-24-y-old) Gambian men. Thirteen of these 25 men were exposed to perinatal malnutrition as defined by birth season and birth weight.Results: In persons born in the hungry season with low birth weight, no differences in the proportions of memory or naive T cells were found. Kinetic analysis showed higher proliferation rates in memory (CD45R0(+)) subsets of T cells than in nalve (CD45R0(-)) cells, which is consistent with previous studies, but no evidence was found for an effect of birth weight or season on T lymphocyte proliferation and disappearance rates. No significant correlations were found between in vivo T cell kinetics and frequency of T cell receptor excision circles. Only absolute numbers of granulocytes were elevated in those born in the nutritionally deprived season.Conclusion: In healthy young Gambian men, T lymphocyte homeostasis is extremely robust regardless of perinatal nutritional compromise. ER - TY - JFULL T1 - Management of severe open ankle injuries. A1 - Khan, U A1 - Smitham, P A1 - Pearse, M A1 - Nanchahal, J J1 - Plast Reconstr Surg Y1 - 2007/02// VL - 119 SN - 1529-4242 SP - 578 EP - 589 N2 - BACKGROUND: Functional outcome after reconstruction of open ankle injuries has not been well presented in the literature. The authors present the functional results of 24 patients who sustained complex ankle injuries. METHODS: Patients were assessed using three scoring systems (a modified A/O score, the Enneking score, and the AOFAS) and subdivided into two groups: those primarily treated at Charing Cross Hospital according to strict protocols combining orthopedic and plastic surgical techniques (group P) and those secondarily treated who were transferred to Charing Cross Hospital after initial management at a remote unit (group S). RESULTS: There were nine patients (37.5 percent) in group P and 15 (62.5 percent) in group S. Eighteen patients (75 percent) underwent free-tissue transfer. Sixteen patients (67 percent) were assessed (group P, n = 7; group S, n = 9) for return of function using the Enneking score. Mean time to assessment was 10.5 months for group P and 11.4 months for group S. Mean Enneking percentage score was 75 for group P and 72.2 for group S. There were no significant differences (p > 0.05) between these scores. The mean time to union was 19 weeks (n = 5) for group P and 24 weeks (n = 7) for group S. The mean AOFAS Ankle-Hindfoot Scores were comparable to the Enneking scores when independent observers undertook this assessment. Most patients in both groups reported difficulty with descent of stairs. CONCLUSIONS: Although the authors were able to achieve a similar return of function for both groups, group S patients needed at least one more operation. In cases of ankle fracture where there is significant soft-tissue injury (either closed or open), representing a complex injury, the authors recommend making no attempt to internally fix the fracture and instead referring the patient to a specialist center for combined orthoplastic attention. If this is not immediately at hand, screw fixation of the medial malleolus should be undertaken after open reduction. The lateral malleolus should not be internally fixed, but should it require control, external fixation is the preferred method of skeletal stabilization. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17230094&query_hl=1 ER - TY - JFULL T1 - Fluorescence lifetime imaging of unstained human atherosclerotic plaques A1 - Hegyi, L A1 - Talbot, C A1 - Monaco, C A1 - Sandison, A A1 - Davies, AH A1 - Peston, D A1 - Requejo-Isidro, J A1 - Elson, DS A1 - Dunsby, C A1 - Munro, I A1 - Neil, MA A1 - French, PM A1 - Stamp, GW A1 - Lever, MJ J1 - HEART Y1 - 2007/02// VL - 93 SN - 1355-6037 ER - TY - JFULL T1 - Increased expression of the pro-apoptotic ATP-sensitive P2X7 receptor in experimental and human glomerulonephritis. A1 - Turner, CM A1 - Tam, FW A1 - Lai, PC A1 - Tarzi, RM A1 - Burnstock, G A1 - Pusey, CD A1 - Cook, HT A1 - Unwin, RJ J1 - Nephrol Dial Transplant Y1 - 2007/02// VL - 22 SN - 0931-0509 SP - 386 EP - 395 N2 - BACKGROUND: The involvement of IL-1beta and other pro-inflammatory cytokines in most forms of glomerulonephritis is now well established. The P2X(7) receptor, an ATP-sensitive P2X receptor, functions not only as a non-selective cation channel, but it is also involved in the rapid processing and release of IL-1beta, apoptosis and necrotic cell death. Therefore, we wanted to investigate if expression of this receptor is altered in the glomeruli of rodent models of glomerulonephritis. METHODS: P2X(7) receptor protein expression was investigated using immunohistochemistry, and apoptosis was assessed using the TUNEL assay and caspase-3 immunostaining. Real-time PCR with gene-specific primers was used to detect P2X(7), IL-1beta, p53, bax and bcl-2 mRNA expression. RESULTS: Although the levels of the P2X(7) receptor protein in mouse kidney are normally very low, or undetectable, we detected an increase in glomerular expression of this receptor and an increase in glomerular apoptotic cells in a mouse model of accelerated nephrotoxic nephritis. We also observed increased glomerular and tubular expression of the P2X(7) receptor protein in renal biopsy tissue of patients with autoimmune-related glomerulonephritis. Furthermore, P2X(7) receptor mRNA increased in the kidneys of a rat model of proliferative glomerulonephritis and this coincided with the onset of proteinuria. We also observed increased mRNA expression of Il-1beta and the pro-apoptotic markers p53 and bax, but not of anti-apoptotic bcl-2. CONCLUSION: Although there is an association between expression of the pro-inflammatory and pro-apoptotic P2X(7) receptor and glomerulonephritis in these rodent models, and in at least one form of human glomerulonephritis, the underlying relationship and its functional significance remain to be explored. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17040997&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 - Inflammatory signaling in cartilage: MAPK and NF-kappaB pathways in chondrocytes and the use of inhibitors for research into pathogenesis and therapy of osteoarthritis. A1 - Saklatvala, J J1 - Curr Drug Targets Y1 - 2007/02// VL - 8 SN - 1873-5592 SP - 305 EP - 313 N2 - Osteoarthritis is characterised by degeneration of articular cartilage. It is thought to be primarily a disease of cartilage. Inflammatory response genes, such as proteinases, cyclooxygenase, and cytokines are implicated in its pathogenesis. The evidence for expression of these genes in articular cartilage in osteoarthritis is reviewed. The expression of inflammatory response genes is controlled by four major intracellular signalling pathways. These lead to activation of the three mitogen-activated protein kinases (MAPK) and the transcriptional regulator nuclear factor kappa (NFkappa)-B. The current state of knowledge of the structure of these pathways is summarized. Pharmacological inhibitors of the protein kinases of the pathways in current use are described, and insights into chondrocyte gene expression obtained with them are discussed. Very limited use of these inhibitors has yet been made in animal models of osteoarthritis. The main use of the inhibitors in the near future will be in investigation of pathogenetic mechanisms in osteoarthritis, both in experimental animals and in vitro, with a view to identifying therapeutic targets. Prospects for using signalling pathway inhibitors for therapy in osteoarthritis are distant. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17305508&query_hl=1 ER - TY - JFULL T1 - Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. A1 - Mahmood, A A1 - FitzGerald, AJ A1 - Marchbank, T A1 - Ntatsaki, E A1 - Murray, D A1 - Ghosh, S A1 - Playford, RJ J1 - Gut Y1 - 2007/02// VL - 56 SN - 0017-5749 SP - 168 EP - 175 N2 - BACKGROUND: Zinc carnosine (ZnC) is a health food product claimed to possess health-promoting and gastrointestinal supportive activity. Scientific evidence underlying these claims is, however, limited. AIM: To examine the effect of ZnC on various models of gut injury and repair, and in a clinical trial. METHODS: In vitro studies used pro-migratory (wounded monolayer) and proliferation ([(3)H]-thymidine incorporation) assays of human colonic (HT29), rat intestinal epithelial (RIE) and canine kidney (MDCK) epithelial cells. In vivo studies used a rat model of gastric damage (indomethacin/restraint) and a mouse model of small-intestinal (indomethacin) damage. Healthy volunteers (n = 10) undertook a randomised crossover trial comparing changes in gut permeability (lactulose:rhamnose ratios) before and after 5 days of indomethacin treatment (50 mg three times a day) with ZnC (37.5 mg twice daily) or placebo coadministration. RESULTS: ZnC stimulated migration and proliferation of cells in a dose-dependent manner (maximum effects in both assays at 100 micromol/l using HT29 cells), causing an approximate threefold increase in migration and proliferation (both p<0.01). Oral ZnC decreased gastric (75% reduction at 5 mg/ml) and small-intestinal injury (50% reduction in villus shortening at 40 mg/ml; both p<0.01). In volunteers, indomethacin caused a threefold increase in gut permeability in the control arm; lactulose:rhamnose ratios were (mean (standard error of mean)) 0.35 (0.035) before indomethacin treatment and 0.88 (0.11) after 5 days of indomethacin treatment (p<0.01), whereas no significant increase in permeability was seen when ZnC was coadministered. CONCLUSION: ZnC, at concentrations likely to be found in the gut lumen, stabilises gut mucosa. Further studies are warranted. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16777920&query_hl=1 ER - TY - JFULL T1 - Chronic exposure to Helicobacter pylori impairs dendritic cell function and inhibits Th1 development. A1 - Mitchell, P A1 - Germain, C A1 - Fiori, PL A1 - Khamri, W A1 - Foster, GR A1 - Ghosh, S A1 - Lechler, RI A1 - Bamford, KB A1 - Lombardi, G J1 - Infect Immun Y1 - 2007/02// VL - 75 SN - 0019-9567 SP - 810 EP - 819 N2 - Helicobacter pylori causes chronic gastric infection that affects the majority of the world's population. Despite generating an inflammatory response, the immune system usually fails to clear the infection. Since dendritic cells (DCs) play a pivotal role in shaping the immune response, we investigated the effects of H. pylori on DC function. We have demonstrated that H. pylori increased the expression of activation markers on DCs while upregulating the inhibitory B7 family molecule, PD-L1. Functionally, H. pylori-treated DCs resulted in the production of interleukin-10 (IL-10) and IL-23 but not of alpha interferon (IFN-alpha). While very little or no IL-12 was produced to H. pylori alone, simultaneous ligation of CD40 on DCs induced IL-12 release. We also demonstrated that DCs treated with H. pylori-induced IFN-gamma production by allogeneic naive T cells. However, stimulation of DCs with H. pylori for an extended period of time impaired their ability to produce cytokines after CD40 ligation and limited their ability to promote IFN-gamma release, suggesting that the DCs had become exhausted by the prolonged stimulation. The effect of chronic infection with H. pylori on DC function was further investigated by focusing on DC development. Demonstrating that monocytes differentiated into DCs in the presence of H. pylori exhibited an exhausted phenotype with an impaired ability to produce IL-12 and a downregulation of CD1a. Our results raise the possibility that in chronic H. pylori infection DCs become exhausted after prolonged antigen exposure leading to suboptimal Th1 development. This effect may contribute to persistence of H. pylori infection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17101659&query_hl=1 ER - TY - JFULL T1 - Mapping the 5-50-kDa fraction of human amniotic fluid proteins by 2-DE and ESI-MS A1 - Gianazza, E A1 - Wait, R A1 - Begum, S A1 - Eberini, I A1 - Campagnoli, M A1 - Labo, S A1 - Galliano, M J1 - PROTEOM CLIN APPL Y1 - 2007/02// VL - 1 SP - 167 EP - 175 N2 - This report presents a proteomic analysis and provides a reference map of the 5-50-kDa components of normal amniotic fluid collected in gestational weeks 16-18. Early amniocentesis samples were pooled and proteins with molecular mass lower than albumin were separated by gel filtration chromatography. The 2-DE protocol was optimized for the separation of the small proteins and peptides in the fraction of interest. A total of 132 Coomassie blue-stained protein spots were analyzed, following in-gel tryptic digestion, by ESI-MS/MS and 49 different gene products were identified. The treatment with alkaline phosphatase caused the shift of the phosphoisoforms of insulin-like growth factor-binding protein-1 and of the N-terminal osteopontin fragment. Of the 33 full-length proteins identified in the 2-DE profile, 23 had not been previously detected in the amniotic fluid and, of these, 22 are not present in the human plasma proteome under physiological conditions. Fragments of 16 larger proteins were identified and the sequence coverage data revealed that several correspond to autonomous domains that may have biological roles on their own. Several of the detected proteins and peptides appear to be involved in critical regulatory processes associated with placentation and early development, thus representing potential markers of various physiological or pathological conditions. ER - TY - JFULL T1 - T-cell receptor repertoire usage after allografting differs between CD4+CD25+ regulatory T cells and their CD4+CD25- counterpart. A1 - Fozza, C A1 - Nadal, E A1 - Longinotti, M A1 - Dazzi, F J1 - Haematologica Y1 - 2007/02// VL - 92 SN - 1592-8721 SP - 206 EP - 214 N2 - BACKGROUND AND OBJECTIVES: After allogeneic haematopoietic stem cell transplantation (SCT) the whole T-cell receptor (TCR) repertoire shows a markedly skewed pattern for 2-3 years. A small fraction of CD4+ T cells is represented by CD25+ regulatory lymphocytes (Treg), which play a crucial role in modulating peripheral tolerance. To investigate their ability to react to the massive antigenic stimulation generated in an allogeneic host, which could significantly affect their pattern of reconstitution, we analyzed the TCR repertoire of Treg after SCT, focusing on the degree of similarity to CD4+CD25- conventional T cells (Tconv). DESIGN AND METHODS: We assessed the TCR Vbeta repertoire of Treg in ten patients who had received allogeneic SCT, by using complementarity determining region 3 (CDR3) spectratyping. We developed a new similarity score for the analysis. This score expresses the proportion of Vbeta with similar profile between Treg and Tconv. RESULTS: For up to 3 years after SCT the repertoires of Treg and Tconv were characterized by several Vbeta with different profiles between the two cell subsets, while they were extremely similar in patients more than 3 years post-allografting (similarity score= 0.90 vs. 0.61). The differences observed early after SCT were mainly ascribable to Vbeta expressing an oligoclonal profile in Tconv but not in Treg. INTERPRETATION AND CONCLUSIONS: Our data show that the TCR repertoires of Treg and Tconv are significantly different early post-SCT, while they tend to become identical with full reconstitution. This difference could reflect either a discrepancy in the in vivo reactivity against common antigenic stimulations or be the result of different post-transplant ontogeny. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17296570&query_hl=1 ER - TY - JFULL T1 - Efficient clearance of opsonised apoptotic cells in the absence of PECAM-1. A1 - Potter, PK A1 - Larbi, KY A1 - Nourshargh, S A1 - Botto, M J1 - Mol Immunol Y1 - 2007/02// VL - 44 SN - 0161-5890 SP - 1135 EP - 1140 N2 - It is now accepted that the recognition and uptake of apoptotic cells by phagocytes is a complex process involving a large number of opsonins, receptors and ligands, however the relative contribution of all these molecules are still debated. Here we examined the role of CD31 (PECAM-1) in the recognition/uptake of apoptotic thymocytes by murine bone marrow-derived macrophages (BMDM) in vitro, and by resident peritoneal macrophages in vivo. In the absence of serum, CD31 deficiency, on either the phagocyte or the apoptotic cell, resulted in a reduction in the clearance of apoptotic thymocytes, when a high ratio of apoptotic cells to macrophages was applied. In the presence of serum however there was no discernible contribution of CD31 to the clearance of apoptotic cells by bone marrow-derived macrophages, irrespective of the ratio of cells used. In vivo peritoneal clearance experiments confirmed that in the presence of soluble opsonins CD31 deficiency had no effect on this process. These data suggest that the overall role played by CD31 in the ingestion of apoptotic cells is negligible and most likely overwhelmed by the effects of serum opsonins, such as complement components. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16911831&query_hl=1 ER - TY - JFULL T1 - 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 - Mesenchymal stem cells are effective at preventing but not at treating GvJD A1 - Tisato, V A1 - Naresh, K A1 - Navarrete, C A1 - Dazzi, F J1 - BIOL BLOOD MARROW TR Y1 - 2007/02// VL - 13 SN - 1083-8791 SP - 44 EP - 45 ER - TY - JFULL T1 - Etanercept plus sulfasalazine: added value in rheumatoid arthritis? A1 - Fisher, BA A1 - Taylor, PC J1 - Nat Clin Pract Rheumatol Y1 - 2007/02// VL - 3 SN - 1745-8382 SP - 70 EP - 71 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17228310&query_hl=1 ER - TY - JFULL T1 - Reduced intensity conditioning allografting induces the generation of antigen-specific regulatory T cells necessary for graft tolerance A1 - Weng, L A1 - Dyson, J A1 - Dazzi, F J1 - BIOL BLOOD MARROW TR Y1 - 2007/02// VL - 13 SN - 1083-8791 SP - 104 EP - 104 ER - TY - JFULL T1 - Increased CD4+CD25high+regulatory T-cell are associated with disease relapse after allogeneic stem cell transplantation (SCT) for chronic myeloid leukaemia (CML) A1 - Nadal, E A1 - Kaeda, J A1 - Apperley, JF A1 - Lechler, R A1 - Dazzi, F J1 - BIOL BLOOD MARROW TR Y1 - 2007/02// VL - 13 SN - 1083-8791 SP - 15 EP - 15 ER - TY - JFULL T1 - The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. A1 - Sacre, SM A1 - Andreakos, E A1 - Kiriakidis, S A1 - Amjadi, P A1 - Lundberg, A A1 - Giddins, G A1 - Feldmann, M A1 - Brennan, F A1 - Foxwell, BM J1 - Am J Pathol Y1 - 2007/02// VL - 170 SN - 0002-9440 SP - 518 EP - 525 N2 - The widespread distribution of Toll-like receptors (TLRs) and their ligands raises the question whether they contribute to the production of inflammatory and tissue destructive molecules in rheumatoid arthritis (RA). We examined the expression and function of TLR2 and TLR4 and their downstream signaling adaptors MyD88 and Mal/TIRAP in synovial membrane cultures from RA tissue. Both TLR2 and TLR4 were detected by flow cytometry, and stimulation with TLR2 and TLR4 ligands augmented the spontaneous production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, indicating that TLR2 and TLR4 are functional in these cultures. In addition, overexpression of dominant-negative forms of MyD88 and Mal/TIRAP significantly down-regulated the spontaneous production of cytokines tumor necrosis factor-alpha, IL-6, and vascular endothelial growth factor, and enzymes MMP-1, MMP-2, MMP-3, and MMP-13 in RA synovial membrane cell cultures. Because TLR2 and TLR4 require both MyD88 and Mal/TIRAP for signaling, this study suggests that TLR function may regulate the expression of these factors in the RA synovium. Conditioned media from synovial membrane cell cultures stimulated human macrophages in a MyD88- and Mal-dependent manner, suggesting the release of a TLR ligand(s) from these cells. Thus, TLRs not only protect against infection but may also promote the inflammatory and destructive process in RA. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17255320&query_hl=1 ER - TY - JFULL T1 - Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. A1 - Ramasamy, R A1 - Fazekasova, H A1 - Lam, EW A1 - Soeiro, I A1 - Lombardi, G A1 - Dazzi, F J1 - Transplantation Y1 - 2007/01/15/ VL - 83 SN - 0041-1337 SP - 71 EP - 76 N2 - BACKGROUND: Mesenchymal stem cells (MSCs) play a crucial role in hematopoietic development and have been shown to exert a powerful immunosuppressive effect. In this study, we investigated the effect of bone marrow MSC on the differentiation and function of peripheral blood monocytes into dendritic cells (DCs). METHODS: Human MSCs, generated from normal bone marrow, were added to peripheral blood monocytes stimulated in vitro with granulocyte-macrophage colony stimulating factor and interleukin-4 to become DCs. Monocytes were then examined for the expression of markers characteristic of DCs and their ability to stimulate allogeneic T cells. In addition, the effect of MSCs on the cell cycle of monocyte-derived DCs and the expression of various cell cycle proteins were analyzed by cytometric analysis and Western blotting with specific antibodies. RESULTS: MSCs blocked the differentiation of monocytes into DCs and impaired their antigen-presenting ability. This resulted from a block of monocytes from entering the G1 phase of the cell cycle with a progressive number of cells accumulating in the G0 phase. Cyclin D2 was downregulated. However, differently from what was observed in T-cells stimulated in the presence of MSCs, the expression of p27 was found decreased, suggesting the involvement of similar but not identical pathways. CONCLUSIONS: We conclude that MSCs impair monocyte differentiation and function by interfering with the cell cycle. These findings imply that MSC-induced immunosuppression might be a side product of a more general antiproliferative effect. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17220794&query_hl=1 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 - Rab GTPases containing a CAAX motif are processed post-geranylgeranylation by proteolysis and methylation. A1 - Leung, KF A1 - Baron, R A1 - Ali, BR A1 - Magee, AI A1 - Seabra, MC J1 - J Biol Chem Y1 - 2007/01/12/ VL - 282 SN - 0021-9258 SP - 1487 EP - 1497 N2 - Post-translational modification by protein prenylation is required for membrane targeting and biological function of monomeric GTPases. Ras and Rho proteins possess a C-terminal CAAX motif (C is cysteine, A is usually an aliphatic residue, and X is any amino acid), in which the cysteine is prenylated, followed by proteolytic cleavage of the AAX peptide and carboxyl methylation by the Rce1 CAAX protease and Icmt methyltransferase, respectively. Rab GTPases usually undergo double geranylgeranylation within CC or CXC motifs. However, very little is known about processing and membrane targeting of Rabs that naturally contain a CAAX motif. We show here that a variety of Rab-CAAX proteins undergo carboxyl methylation, both in vitro and in vivo, with one exception. Rab38(CAKS) is not methylated in vivo, presumably because of the inhibitory action of the lysine residue within the AAX motif for cleavage by Rce1. Unlike farnesylated Ras proteins, we observed no targeting defects of overexpressed Rab-CAAX proteins in cells deficient in Rce1 or Icmt, as reported for geranylgeranylated Rho proteins. However, endogenous geranylgeranylated non-methylated Rab-CAAX and Rab-CXC proteins were significantly redistributed to the cytosol at steady-state levels and redistribution correlates with higher affinity of RabGDI for non-methylated Rabs in Icmt-deficient cells. Our data suggest a role for methylation in Rab function by regulating the cycle of Rab membrane recruitment and retrieval. Our findings also imply that those Rabs that undergo post-prenylation processing follow an indirect targeting pathway requiring initial endoplasmic reticulum membrane association prior to specific organelle targeting. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17114793&query_hl=1 ER - TY - JFULL T1 - Substrate conformation modulates aggrecanase (ADAMTS-4) affinity and sequence specificity. Suggestion of a common topological specificity for functionally diverse proteases. A1 - Lauer-Fields, JL A1 - Minond, D A1 - Sritharan, T A1 - Kashiwagi, M A1 - Nagase, H A1 - Fields, GB J1 - J Biol Chem Y1 - 2007/01/05/ VL - 282 SN - 0021-9258 SP - 142 EP - 150 N2 - Protease-substrate interactions are governed by a variety of structural features. Although the substrate sequence specificities of numerous proteases have been established, "topological specificities," whereby proteases may be classified based on recognition of distinct three-dimensional structural motifs, have not. The aggrecanase members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family cleave a variety of proteins but do not seem to possess distinct sequence specificities. In the present study, the topological substrate specificity of ADAMTS-4 (aggrecanase-1) was examined using triple-helical or single-stranded poly(Pro) II helical peptides. Substrate topology modulated the affinity and sequence specificity of ADAMTS-4 with K(m) values indicating a preference for triple-helical structure. In turn, non-catalytic ADAMTS-4 domains were critical for hydrolysis of triple-helical and poly(Pro) II helical substrates. Comparison of ADAMTS-4 with MMP-1 (collagenase 1), MMP-13 (collagenase 3), trypsin, and thermolysin using triple-helical peptide (THP) and single-stranded peptide (SSP) substrates demonstrated that all five proteases possessed efficient "triple-helical peptidase" activity and fell into one of two categories: (k(cat)/K(m))(SSP) > (k(cat)/K(m))(THP) (thermolysin, trypsin, and MMP-13) or (k(cat)/K(m))(THP) > or = (k(cat)/K(m))(SSP) and (K(m))(SSP) > (K(m))(THP) (MMP-1 and ADAMTS-4). Overall these results suggest that topological specificity may be a guiding principle for protease behavior and can be utilized to design specific substrates and inhibitors. The triple-helical and single-stranded poly(Pro) II helical peptides represent the first synthetic substrates successfully designed for aggrecanases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17095512&query_hl=1 ER - TY - JFULL T1 - Combined C1q and C8 beta deficiency in a patient with recurrent childhood infections and adult-onset systemic lupus erythematosus A1 - Pickering, MC A1 - Fish, J A1 - Macor, P A1 - Durigutto, P A1 - Bossi, F A1 - Botto, M A1 - Tedesco, F J1 - MOL IMMUNOL Y1 - 2007/01// VL - 44 SN - 0161-5890 SP - 228 EP - 228 ER - TY - JFULL T1 - HIF-2alpha is Essential for Hypoxic Induction of the Human Articular Chondrocyte Phenotype A1 - Lafont, J A1 - Talma, S A1 - Murphy, CL J1 - Arthritis and Rheumatism Y1 - 2007/// ER - TY - JFULL T1 - Interpretation of renal biopsies in IgA nephropathy. A1 - Cook, HT J1 - Contrib Nephrol Y1 - 2007/// VL - 157 SN - 0302-5144 SP - 44 EP - 49 N2 - The renal biopsy is essential for the diagnosis of IgA nephropathy. It should also be possible to derive important information from the biopsy about prognosis and likely response to treatment. Biopsy features that are associated with progression to end-stage renal disease are glomerulosclerosis and tubulointerstitial scarring, marked crescent formation and marked arteriolar hyalinosis. However, with our present classification systems the renal biopsy adds little over and above clinical features in predicting outcome. It may be possible to improve the predictive value of the renal biopsy by adopting the following recommendations in developing new classifications: (1) looking at the ability of the biopsy to predict changes in renal function in the short term after biopsy rather than prediction of progression to end stage renal disease; (2) examining subgroups of patients where the biopsy is likely to be most informative; (3) distinguishing the effects of reversible and irreversible changes particularly with regard to response to treatment; (4) ensuring uniformity of definitions between pathologists, and (5) paying attention to small lesions and considering including additional biopsy features. The most important role for the renal biopsy in the future is likely to be in predicting response to therapy rather than predicting progression to end-stage renal disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17495436&query_hl=1 ER - TY - JFULL T1 - Cell therapy for autoimmune diseases. A1 - Dazzi, F A1 - van Laar, JM A1 - Cope, A A1 - Tyndall, A J1 - Arthritis Res Ther Y1 - 2007/// VL - 9 SN - 1478-6362 SP - 206 EP - 206 N2 - Cell therapy, pioneered for the treatment of malignancies in the form of bone marrow transplantation, has subsequently been tested and successfully employed in autoimmune diseases. Autologous haemopoietic stem cell transplantation (HSCT) has become a curative option for conditions with very poor prognosis such as severe forms of scleroderma, multiple sclerosis, and lupus, in which targeted therapies have little or no effect. The refinement of the conditioning regimens has virtually eliminated transplant-related mortality, thus making HSCT a relatively safe choice. Although HSCT remains a nonspecific approach, the knowledge gained in this field has led to the identification of new avenues. In fact, it has become evident that the therapeutic efficacy of HSCT cannot merely be the consequence of a high-dose immuno-suppression, but rather the result of a resetting of the abnormal immune regulation underlying autoimmune conditions. The identification of professional and nonprofessional immunosuppressive cells and their biological properties is generating a huge interest for their clinical exploitation. Regulatory T cells, found abnormal in several autoimmune diseases, have been proposed as central to achieve long-term remissions. Mesenchymal stem cells of bone marrow origin have more recently been shown not only to be able to differentiate into multiple tissues, but also to exert a potent antiproliferative effect that results in the inhibition of immune responses and prolonged survival of haemopoietic stem cells. All of these potential resources clearly need to be investigated at the preclinical level but support a great deal of enthusiasm for cell therapy of autoimmune diseases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17367542&query_hl=1 ER - TY - JFULL T1 - Rab27a and MyoVa are the primary Mlph interactors regulating melanosome transport in melanocytes. A1 - Hume, AN A1 - Ushakov, DS A1 - Tarafder, AK A1 - Ferenczi, MF A1 - Seabra, MC J1 - J Cell Sci Y1 - 2007/// VL - 120 SP - 3111 EP - 3122 N2 - Melanosome transport in melanocytes is a model system for the study of cytoskeletal regulation of intracellular transport. Melanophilin (Mlph) is a Rab27a- and myosin Va (MyoVa)-binding protein that regulates this process. Using yeast two-hybrid screening, we identified MT plus-end binding protein (EB1) as a melanocyte-expressed Mlph-interacting protein. To address the role of EB1 versus Rab27a and MyoVa interactions in Mlph targeting and function, we used siRNA and Mlph mutations to specifically disrupt each interaction in cultured melanocytes. Using the Mlph R35W mutant that blocks Mlph-Rab27a interaction and Rab27a siRNA we show this interaction is required for melanosome targeting and stability of Mlph. Mutants and siRNA that affect Mlph-MyoVa and Mlph-EB1 interactions reveal that while neither MyoVa nor EB1 affect Mlph targeting to melanosomes, MyoVa but not EB1 interaction is required for transport of melanosomes to peripheral dendrites. We propose that Mlph is targeted to and/or stabilised on melanosomes by Rab27a, and then recruits MyoVa, which provides additional stability to the complex and allows melanosomes to transfer from MT to actin-based transport and achieve peripheral distribution. EB1 appears to be non-essential to this process in cultured melanocytes, which suggests that it plays a redundant role and/or is required for melanocyte/keratinocyte contacts and melanosome transfer. ER - TY - JFULL T1 - Pulmonary infection with Cryptococcus neoformans in the face of underlying sarcoidosis. A1 - Boyton, RJ A1 - Altmann, DM A1 - Wright, A A1 - Kon, OM J1 - Respiration Y1 - 2007/// VL - 74 SN - 0025-7931 SP - 462 EP - 466 N2 - We present a case of limited pulmonary cryptococcal infection following exposure to pigeon excreta in a patient with sarcoidosis. The pathogenicity of Cryptococcus neoformans depends on the interplay between the immune status of the host and the virulence of the infecting strain. It can range from asymptomatic lung colonization in the immunocompetent host to rapidly progressive meningitis in immunocompromised patients. Immunological models of respiratory disease emphasize a distinction between infections associated with immune suppression on the one hand and diseases such as sarcoidosis believed to involve an excessive Th1-mediated immune response on the other. This case exemplifies the complex nature of immunological responses in the lung and highlights the importance of considering the possibility of co-existent fungal infection in individuals with sarcoidosis. Novel immunotherapeutic options for cryptococcal infection are discussed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16106116&query_hl=1 ER - TY - JFULL T1 - C1q can alter the levels of IgM autoantibody production in anti-DNA transgenic models A1 - Fossati-Jimack, L A1 - Cortes-Hernandez, J A1 - Norsworthy, P A1 - Cook, HT A1 - Botto, M J1 - MOL IMMUNOL Y1 - 2007/01// VL - 44 SN - 0161-5890 SP - 171 EP - 171 ER - TY - JFULL T1 - Increased susceptibility of heterozygous factor H deficient mice to accelerated serum nephrotoxic nephritis A1 - Pickering, MC A1 - Rose, KL A1 - Carlucci, F A1 - Howard, J A1 - Cook, HT A1 - Botto, M J1 - MOL IMMUNOL Y1 - 2007/01// VL - 44 SN - 0161-5890 SP - 228 EP - 228 ER - TY - JFULL T1 - Fas ligand exerts its pro-inflammatory effects via neutrophil recruitment but not activation. A1 - Dupont, PJ A1 - Warrens, AN J1 - Immunology Y1 - 2007/01// VL - 120 SN - 0019-2805 SP - 133 EP - 139 N2 - Fas ligand (FasL) expression induces apoptosis of activated T cells and has been suggested as a strategy to inhibit graft rejection. Unfortunately, the use of FasL to confer 'immune privilege' in this setting has been hampered by the finding that it may also provoke a destructive granulocytic response. While the Fas/FasL-mediated apoptotic pathways are well defined, the pro-inflammatory effects of FasL are poorly understood. Our aim in this study was to define in vitro the biological effects of FasL on neutrophil recruitment and activation. DAP-3 cells expressing human FasL on the cell membrane (mFasL) potently induced apoptosis in human neutrophils and in activated T lymphocytes. Recombinant human soluble FasL (sFasL), by contrast, was a very weak inducer of apoptosis, even at high concentrations. This latter observation suggests that cleavage of mFasL by naturally occurring matrix metalloproteinases may serve to down-regulate FasL activity in vivo. However, in the presence of a cross-linking antibody, the efficiency of apoptosis-induction by sFasL was greatly increased, suggesting that the lesser pro-apoptotic potency of sFasL reflects an inability to induce trimerization of the Fas receptor. With regard to pro-inflammatory effects, we found that sFasL is a potent neutrophil chemoattractant and, given that it induces little apoptosis, the dominance of sFasL over mFasL may mean that graft-infiltrating neutrophils will survive to mediate inflammation. Neither sFasL nor mFasL produced neutrophil activation as assessed by chemiluminescence assay. This suggests that neutrophils recruited to an inflammatory site by FasL will be activated by mechanisms other than Fas-FasL signalling. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17233740&query_hl=1 ER - TY - JFULL T1 - Dectin-1 is required for beta-glucan recognition and control of fungal infection A1 - Taylor, PR A1 - Tsoni, SV A1 - Willment, JA A1 - Dennehy, KM A1 - Rosas, M A1 - Findon, H A1 - Haynes, K A1 - Steele, C A1 - Botto, M A1 - Gordon, S A1 - Brown, GD J1 - NAT IMMUNOL Y1 - 2007/01// VL - 8 SN - 1529-2908 SP - 31 EP - 38 N2 - beta-Glucan is one of the most abundant polysaccharides in fungal pathogens, yet its importance in antifungal immunity is unclear. Here we show that deficiency of dectin-1, the myeloid receptor for beta-glucan, rendered mice susceptible to infection with Candida albicans. Dectin-1-deficient leukocytes demonstrated significantly impaired responses to fungi even in the presence of opsonins. Impaired leukocyte responses were manifested in vivo by reduced inflammatory cell recruitment after fungal infection, resulting in substantially increased fungal burdens and enhanced fungal dissemination. Our results establish a fundamental function for beta-glucan recognition by dectin-1 in antifungal immunity and demonstrate a signaling non-Toll-like pattern-recognition receptor required for the induction of protective immune responses. ER - TY - JFULL T1 - Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. A1 - Bailey, C A1 - Negus, R A1 - Morris, A A1 - Ziprin, P A1 - Goldin, R A1 - Allavena, P A1 - Peck, D A1 - Darzi, A J1 - Clin Exp Metastasis Y1 - 2007/// VL - 24 SN - 0262-0898 SP - 121 EP - 130 N2 - Chemokines promote tumour progression by enhancing proliferation and modifying the immune response. The purpose of this study was to test the hypothesis that CCL2 monocyte chemotactic protein-1 (MCP-1) contributes to the progression of colorectal cancer by influencing the number and distribution of tumour associated macrophages (TAMs). Chemokine expression was assessed in human colorectal adenocarcinomas by ribonuclease protection assay (RPA). Colonic adenocarcinoma cell lines were used to assess chemokine production by enzyme linked immunosorbant assay (ELISA), and Boyden microchemotaxis assays were performed to determine cell line supernatant monocyte chemotactic activity. CCL2 production was assessed in paraffin embedded tumour samples by immunohistochemistry. Finally, the number of macrophages and their distribution was determined in the same colorectal adenocarcinomas and compared with CCL2 expression and tumour stage. Results showed that CCL2 produced by cell lines induced monocyte chemoattraction, the expression of this chemokine in solid cancers increased with tumour stage (P < 0.05) and immunohistochemistry localized production to tumour cells. Analysis of the macrophage infiltrate showed that the accumulation was significantly greater in tumours than controls (P < 0.005) and within tumours it was greatest in necrotic regions (median 44,600 per mm(3)). Macrophage accumulation increased with tumour stage and correlated with CCL2 expression (r(s) = 0.8). CXCL8 interleukin 8 (IL-8), a potent angiogenic factor and growth factor, was expressed in all tumours and cell lines. It is concluded that CCL2 induces the accumulation of tumour promoting TAMs in human colorectal cancer and represents a therapeutic target to modify the macrophage response and direct immune mediated therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17390111&query_hl=1 ER - TY - JFULL T1 - The role of complement in innate, acquired and eosinophil-mediated immunity to the nematode Nippostrongylus brasiliensis A1 - Giacomin, P A1 - Gordon, D A1 - Botto, M A1 - Dent, L J1 - MOL IMMUNOL Y1 - 2007/01// VL - 44 SN - 0161-5890 SP - 176 EP - 177 ER - TY - JFULL T1 - Binding of Ras to Phosphoinositide 3-kinase p110α is required for Ras-driven tumorigenesis in mice A1 - Gupta, S. A1 - Ramjaun, A.R. A1 - Haiko, P., A1 - Haiko, P. A1 - Wang, Y. A1 - Warne, P.H. A1 - Nicke, B. A1 - Nye, E. A1 - Stamp, G. A1 - Alitalo, K. A1 - Downward, J. J1 - Cell Y1 - 2007/// IS - 5 VL - 129 SN - 0092-8674 SP - 957 EP - 968 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 - Spontaneous haemolytic uraemic syndrome (HUS) in factor H-deficient mice transgenic for murine factor H protein lacking the five C-terminal domains (FH Delta 16-20) A1 - Pickering, MC A1 - de Jorge, EG A1 - Rose, KL A1 - Moss, J A1 - Cook, HT A1 - de Cordoba, SR A1 - Botto, M J1 - MOL IMMUNOL Y1 - 2007/01// VL - 44 SN - 0161-5890 SP - 227 EP - 228 ER - TY - JFULL T1 - Collagen-induced arthritis in mice: a major role for tumor necrosis factor-alpha. A1 - Williams, RO J1 - Methods Mol Biol Y1 - 2007/// VL - 361 SN - 1064-3745 SP - 265 EP - 284 N2 - Collagen-induced arthritis is the most widely used animal model for the evaluation of novel therapeutic strategies for rheumatoid arthritis. The disease is induced by immunization of genetically susceptible strains of mice or rats with type II collagen in adjuvant. Susceptibility to collagen-induced arthritis is associated with major histocompatibility complex (MHC) class II genes, although non-MHC genes also play a role. Both B- and T-lymphocytes are important in the pathogenesis of collagen-induced arthritis, with the peak of the T-cell response occurring around the time of disease onset. Histopathological assessment of the joints of animals with collagen-induced arthritis reveal a proliferative synovitis with infiltration of polymorphonuclear and mononuclear cells, the formation of an erosive pannus, cartilage degradation, and fibrosis. As in human rheumatoid arthritis, a number of both pro- and anti-inflammatory cytokines are expressed in the joints of mice with collagen-induced arthritis, including tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-1beta, IL-6, IL-1Ra, IL-10, and transforming growth factor beta. The use transgenic and knockout strains of mice, as well as biological inhibitors, have revealed important pathological roles for multiple cytokines. Of these, TNFalpha emerged as a valid therapeutic target for rheumatoid arthritis and this led to the setting up of clinical trials of anti-TNFalpha antibody therapy. Three anti-TNFalpha biologics(infliximab, etanercept, and adalimumab) are now approved for use and TNFalpha blockade therefore represents an important advance in our ability to treat rheumatoid arthritis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17172717&query_hl=1 ER - TY - JFULL T1 - Apolipoprotein A-I breakdown is induced by thrombolysis in coronary patients. A1 - Eberini, I A1 - Gianazza, E A1 - Breghi, L A1 - Klugmann, S A1 - Calabresi, L A1 - Gomaraschi, M A1 - Mombelli, G A1 - Brusoni, B A1 - Wait, R A1 - Sirtori, CR J1 - Ann Med Y1 - 2007/// VL - 39 SN - 0785-3890 SP - 306 EP - 311 N2 - BACKGROUND: The outcome of percutaneous coronary intervention (PCI) is apparently worse in patients receiving a prior thrombolytic therapy ('facilitated PCI'). Recombinant tissue-type plasminogen activator (rt-PA) can degrade circulating high-density lipoproteins (HDL) bound apolipoprotein A-I (apoA-I), thus possibly reducing the vascular protective activity. There have never been reports of the detection of apolipoprotein breakdown products in the circulation. AIM: We studied the potential interactions between the protein components of HDL and tenecteplase, infused as thrombolytic therapy. METHODS: Sera from a total of 40 patients with acute myocardial infarction (AMI), unstable angina (UA), and dilative cardiomyopathy (controls) were investigated. AMI patients underwent either immediate PCI or were treated with tenecteplase thrombolysis. RESULTS: Products of extensive proteolysis of apoA-I were found in many acute coronary patients treated with tenecteplase, and in some AMI patients before starting the treatment (time 0). These were not detected in controls, UA patients as well as AMI patients undergoing immediate PCI. Small pre-beta-HDLs were selectively degraded. CONCLUSION: Significant apoA-I degradation occurs in AMI patients after thrombolytic treatment. This finding may provide a potential mechanism for the apparent reduction of benefit of facilitated versus nonfacilitated PCI. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17558602&query_hl=1 ER - TY - JFULL T1 - Molecular profile of peripheral blood mononuclear cells from patients with rheumatoid arthritis. A1 - Edwards, CJ A1 - Feldman, JL A1 - Beech, J A1 - Shields, KM A1 - Stover, JA A1 - Trepicchio, WL A1 - Larsen, G A1 - Foxwell, BM A1 - Brennan, FM A1 - Feldmann, M A1 - Pittman, DD J1 - Mol Med Y1 - 2007/01// VL - 13 SN - 1076-1551 SP - 40 EP - 58 N2 - Rheumatoid arthritis (RA) is a chronic inflammatory arthritis. Currently, diagnosis of RA may take several weeks, and factors used to predict a poor prognosis are not always reliable. Gene expression in RA may consist of a unique signature. Gene expression analysis has been applied to synovial tissue to define molecularly distinct forms of RA; however, expression analysis of tissue taken from a synovial joint is invasive and clinically impractical. Recent studies have demonstrated that unique gene expression changes can be identified in peripheral blood mononuclear cells (PBMCs) from patients with cancer, multiple sclerosis, and lupus. To identify RA disease-related genes, we performed a global gene expression analysis. RNA from PBMCs of 9 RA patients and 13 normal volunteers was analyzed on an oligonucleotide array. Compared with normal PBMCs, 330 transcripts were differentially expressed in RA. The differentially regulated genes belong to diverse functional classes and include genes involved in calcium binding, chaperones, cytokines, transcription, translation, signal transduction, extracellular matrix, integral to plasma membrane, integral to intracellular membrane, mitochondrial, ribosomal, structural, enzymes, and proteases. A k-nearest neighbor analysis identified 29 transcripts that were preferentially expressed in RA. Ten genes with increased expression in RA PBMCs compared with controls mapped to a RA susceptibility locus, 6p21.3. These results suggest that analysis of RA PBMCs at the molecular level may provide a set of candidate genes that could yield an easily accessible gene signature to aid in early diagnosis and treatment. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17515956&query_hl=1 ER - TY - JFULL T1 - Crystal-ball gazing - the future of immunological research viewed from the cutting edge A1 - Brent, L A1 - Cohen, IR A1 - Doherty, PC A1 - Feldmann, M A1 - Matzinger, P A1 - Holgate, ST A1 - Lachmann, P A1 - Mitchison, NA A1 - Nossal, G A1 - Rose, NR A1 - Zinkernagel, R A1 - Ghost Lab J1 - CLIN EXP IMMUNOL Y1 - 2007/01// VL - 147 SN - 0009-9104 SP - 1 EP - 10 ER - TY - JFULL T1 - The molecular basis by which polymorphism in the OX40L gene predisposes to SLE A1 - Manku, H A1 - Graham, DC A1 - Graham, RR A1 - Behrens, TW A1 - Behrens, TW A1 - Althshuler, D A1 - Vyse, TJ J1 - CLIN IMMUNOL Y1 - 2007/// VL - 123 SN - 1521-6616 SP - S134 EP - S134 ER - TY - JFULL T1 - Accuracy and reproducibility of protein-DNA microarray technology. A1 - Field, S A1 - Udalova, I A1 - Ragoussis, J J1 - Adv Biochem Eng Biotechnol Y1 - 2007/// VL - 104 SN - 0724-6145 SP - 87 EP - 110 N2 - Microarray-based methods for understanding protein-DNA interactions have been developed in the last 6 years due to the need to introduce high-throughput technologies in this field. Protein-DNA microarrays utilise chips upon which a large number of DNA sequences may be printed or synthesised. Any DNA-binding protein may then be interrogated by applying either purified sample or cellular/nuclear extracts, subject to availability of a suitable detection system. Protein is simply added to the microarray slide surface, which is then washed and subjected to at least one further incubation with a labelled molecule which binds specifically to the protein of interest. The signal obtained is proportional to the level of DNA-binding protein bound to each DNA feature, enabling relative affinities to be calculated. Key factors for reproducible and accurate quantification of protein binding are: microarray surface chemistry; length of oligonucleotides; position of the binding site sequence; quality of the protein and antibodies; and hybridisation conditions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17290820&query_hl=1 ER - TY - JFULL T1 - Varicose vein surgery and deep vein thrombosis prophylaxis A1 - Abbott, D A1 - Dharmarajah, B A1 - Davies, AH J1 - PHLEBOLOGY Y1 - 2007/// VL - 22 SN - 0268-3555 SP - 1 EP - 2 ER - TY - JFULL T1 - LACE-conditioned autologous stem cell transplantation for relapsed or refractory Hodgkin's lymphoma: treatment outcome and risk factor analysis in 67 patients from a single centre. A1 - Perz, JB A1 - Giles, C A1 - Szydlo, R A1 - O'Shea, D A1 - Sanz, J A1 - Chaidos, A A1 - Wagner, S A1 - Davis, J A1 - Loaiza, S A1 - Marin, D A1 - Apperley, J A1 - Olavarria, E A1 - Rahemtulla, A A1 - Lampert, I A1 - Naresh, K A1 - Samson, D A1 - MacDonald, D A1 - Kanfer, EJ J1 - Bone Marrow Transplant Y1 - 2007/01// VL - 39 SN - 0268-3369 SP - 41 EP - 47 N2 - High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a recognized treatment option for patients with relapsed Hodgkin's lymphoma. We have analysed 67 patients who underwent ASCT after LACE (lomustine (CCNU), cytarabine (Ara-C), cyclophosphamide, etoposide) conditioning for relapsed (n=61) or primary refractory (n=6) Hodgkin's lymphoma. The 100-day treatment-related mortality was 3%. With a median follow-up of 67 months (range 3.3-161.0) the probabilities of overall survival (OS) and progression-free survival (PFS) at 5 years were 68 and 64%, respectively. Probabilities for OS and PFS at 5 years for patients with chemosensitive relapse (n=40) were 81 and 78% versus 50 and 35%, respectively, for patients (n=27) with chemoresistant relapse (P=0.012 for OS, P=0.002 for PFS). In multivariate analysis mixed cellularity classical or lymphocyte-depleted classical histology subtype and haemoglobin level of 10 g/dl or less at the time of ASCT were identified as risk factors for worse OS, whereas stage III or IV disease at diagnosis and disease status at ASCT other than complete or partial remission predicted inferior PFS. LACE followed by ASCT is an effective treatment for the majority of patients with chemosensitive relapsed Hodgkin's lymphoma and a proportion of chemorefractory patients also benefit. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17115062&query_hl=1 ER - TY - JFULL T1 - Rab27b regulates mast cell granule dynamics and secretion. A1 - Mizuno, K A1 - Tolmachova, T A1 - Ushakov, DS A1 - Romao, M A1 - Abrink, M A1 - Ferenczi, MF A1 - Raposo, G A1 - Seabra, MC J1 - Traffic Y1 - 2007/// VL - 8 SP - 883 EP - 892 N2 - The Rab GTPase family regulates membrane domain organization and vesicular transport pathways. Recent studies indicate that one member of the family, Rab27a, regulates transport of lysosome-related organelles in specialized cells, such as melanosomes and lytic granules. Very little is known about the related isoform, Rab27b. Here we used genetically modified mice to study the involvement of the Rab27 proteins in mast cells, which play key roles in allergic responses. Both Rab27a and Rab27b isoforms are expressed in bone marrow-derived mast cells (BMMC) and localize to secretory granules. Nevertheless, secretory defects as measured by beta-hexosaminidase release in vitro and passive cutaneous anaphylaxis in vivo were found only in Rab27b and double Rab27 knockout (KO) mice. Immunofluorescence studies suggest that a subset of Rab27b and double Rab27-deficient BMMCs exhibit mild clustering of granules. Quantitative analysis of live-cell time-lapse imaging revealed that BMMCs derived from double Rab27 KO mice showed almost 10-fold increase in granules exhibiting fast movement (>1.5 microm/s), which could be disrupted by nocodazole. These results suggest that Rab27 proteins, particularly Rab27b, play a crucial role in mast cell degranulation and that their action regulates the transition from microtubule to actin-based motility. ER - TY - JFULL T1 - Genetic insights into the hypoxia-inducible factor (HIF) pathway. A1 - Kiriakidis, S A1 - Esteban, MA A1 - Maxwell, PH J1 - Adv Enzyme Regul Y1 - 2007/// VL - 47 SN - 0065-2571 SP - 288 EP - 306 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17335877&query_hl=1 ER - TY - JFULL T1 - Localization of a long-range cis-regulatory element of IL13 by allelic transcript ratio mapping. A1 - Forton, JT A1 - Udalova, IA A1 - Campino, S A1 - Rockett, KA A1 - Hull, J A1 - Kwiatkowski, DP J1 - Genome Res Y1 - 2007/01// VL - 17 SN - 1088-9051 SP - 82 EP - 87 N2 - It appears that, for many genes, the two alleles possessed by an individual may produce different amounts of transcript. When such allelic differences in transcription are observed for some individuals but not others, a plausible explanation is genetic variation in the cis-acting elements that regulate the gene in question. Here we describe a novel analytical approach that uses such observations, combined with genotyping data from the HapMap project, to define the genomic location of cis-acting regulatory elements. When applied to the human 5q31 chromosomal region, where complex regulatory mechanisms are known to exist, we demonstrate the sensitivity of this approach by locating a highly significant cis-regulatory element operating on IL13 at long range from a position 250 kb upstream from the gene (P = 2 x 10(-6)). As this method is unaffected by other sources of variation, such as environmental and trans-acting genetic factors, it provides a tractable approach for dissecting the complexities of genetic variation in gene regulation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17135570&query_hl=1 ER - TY - JFULL T1 - Family-based association analysis with ordered categorical phenotypes, covariates and interactions. A1 - Baksh, MF A1 - Balding, DJ A1 - Vyse, TJ A1 - Whittaker, JC J1 - Genet Epidemiol Y1 - 2007/01// VL - 31 SN - 0741-0395 SP - 1 EP - 8 N2 - Genetic association analyses of family-based studies with ordered categorical phenotypes are often conducted using methods either for quantitative or for binary traits, which can lead to suboptimal analyses. Here we present an alternative likelihood-based method of analysis for single nucleotide polymorphism (SNP) genotypes and ordered categorical phenotypes in nuclear families of any size. Our approach, which extends our previous work for binary phenotypes, permits straightforward inclusion of covariate, gene-gene and gene-covariate interaction terms in the likelihood, incorporates a simple model for ascertainment and allows for family-specific effects in the hypothesis test. Additionally, our method produces interpretable parameter estimates and valid confidence intervals. We assess the proposed method using simulated data, and apply it to a polymorphism in the c-reactive protein (CRP) gene typed in families collected to investigate human systemic lupus erythematosus. By including sex interactions in the analysis, we show that the polymorphism is associated with anti-nuclear autoantibody (ANA) production in females, while there appears to be no effect in males. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17096343&query_hl=1 ER - TY - JFULL T1 - The pitfalls in the development of biologic therapy. A1 - Maini, RN A1 - Feldmann, M J1 - Nat Clin Pract Rheumatol Y1 - 2007/01// VL - 3 SN - 1745-8382 SP - 1 EP - 1 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17202998&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 - Inhaled allergen-driven CD1c up-regulation and enhanced antigen uptake by activated human respiratory-tract dendritic cells in atopic asthma. A1 - McCarthy, NE A1 - Jones, HA A1 - Marks, NA A1 - Shiner, RJ A1 - Ind, PW A1 - Al-Hassi, HO A1 - English, NR A1 - Murray, CM A1 - Lambert, JR A1 - Knight, SC A1 - Stagg, AJ J1 - Clin Exp Allergy Y1 - 2007/01// VL - 37 SN - 0954-7894 SP - 72 EP - 82 N2 - BACKGROUND: Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory-tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis. OBJECTIVE: To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. METHODS: Sputum cells were induced from steroid-naïve, allergen-challenged and allergen-naïve subjects (atopic asthmatics, atopic non-asthmatics and non-atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. RESULTS: hRTDC stained HLA-DR(+) (negative for markers of other cell lineages) were predominantly myeloid and comprised approximately 0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4(+) naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC-dextran was enhanced in cells from asthmatics (P<0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P<0.05-P<0.001), CD1c, CD1d and langerin (P<0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P<0.05). CD11c(-)CD123(high) hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. CONCLUSION: Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17210044&query_hl=1 ER - TY - JFULL T1 - Expansion of CD8+ cytotoxic T cells in vitro and in vivo using MHC class I tetramers. A1 - Savage, P A1 - Millrain, M A1 - Dimakou, S A1 - Stebbing, J A1 - Dyson, J J1 - Tumour Biol Y1 - 2007/// VL - 28 SN - 1010-4283 SP - 70 EP - 76 N2 - BACKGROUND: The expansion of cytotoxic CD8+ T lymphocytes (CTLs) which recognize peptide epitopes of tumour or viral origin has been a major aim of immunotherapy research for the past decade. Alongside the established dendritic cell-based methods, more recent approaches using recombinant MHC class I peptide complexes have been developed. METHODS: In this study we have explored the potential of a simplified system using soluble streptavidin-linked MHC class I tetramers to expand antigen-specific CTLs in vitro and in vivo. RESULTS: In vitro tetramer-mediated expansion of CD8+ CTLs recognizing HLA-2/Melan-A and HLA-A2/Gag complexes was demonstrated with PBMCs from healthy donors or HIV+ donors, respectively. With 3 weekly rounds of tetramer stimulation, cell numbers expanded 100-fold from 0.05 to 5.0%. The lytic function of HLA-A2/Melan-A-expanded cells was demonstrated in 51Cr release assays by specific killing of T2 cells pulsed with Melan-A, but not other peptides. Similarly, murine CD8+ T cells specific for the HY epitope H2-Db/Uty could be expanded in vitro over a wide range of tetramer concentrations (0.008-1.0 microg/ml), with a single exposure producing substantial T cell expansion from 0.11 to 36%. Intraperitoneal administration of H2-Db/Uty tetramers to primed C57BL/6 mice produced over 5-fold expansion of Db/Uty-specific CTL in vivo. CONCLUSION: The results in this paper demonstrate that simple, multimeric MHC complexes may be of value in expanding CTLs in vitro for adoptive immunotherapy and also potentially in vivo. Further studies will be necessary to clarify the optimum protocols and schedules of administration for T cell expansion using recombinant MHC multimers. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17264539&query_hl=1 ER - TY - JFULL T1 - Differential regulation of cytokine release and leukocyte migration by lipopolysaccharide-stimulated primary human lung alveolar type II epithelial cells and macrophages. A1 - Thorley, AJ A1 - Ford, PA A1 - Giembycz, MA A1 - Goldstraw, P A1 - Young, A A1 - Tetley, TD J1 - J Immunol Y1 - 2007/01/01/ VL - 178 SN - 0022-1767 SP - 463 EP - 473 N2 - Bacterial colonization is a secondary feature of many lung disorders associated with elevated cytokine levels and increased leukocyte recruitment. We hypothesized that, alongside macrophages, the epithelium would be an important source of these mediators. We investigated the effect of LPS (0, 10, 100, and 1000 ng/ml LPS, up to 24 h) on primary human lung macrophages and alveolar type II epithelial cells (ATII; isolated from resected lung tissue). Although macrophages produced higher levels of the cytokines TNF-alpha and IL-1beta (p < 0.0001), ATII cells produced higher levels of chemokines MCP-1, IL-8, and growth-related oncogene alpha (p < 0.001), in a time- and concentration-dependent manner. Macrophage (but not ATII cell) responses to LPS required activation of ERK1/2 and p38 MAPK signaling cascades; phosphorylated ERK1/2 was constitutively up-regulated in ATII cells. Blocking Abs to TNF-alpha and IL-1beta during LPS exposure showed that ATII cell (not macrophage) MCP-1 release depended on the autocrine effects of IL-1beta and TNF-alpha (p < 0.003, 24 h). ATII cell release of IL-6 depended on autocrine effects of TNF-alpha (p < 0.006, 24 h). Macrophage IL-6 release was most effectively inhibited when both TNF-alpha and IL-1beta were blocked (p < 0.03, 24 h). Conditioned media from ATII cells stimulated more leukocyte migration in vitro than conditioned media from macrophages (p < 0.0002). These results show differential activation of cytokine and chemokine release by ATII cells and macrophages following LPS exposure. Activated alveolar epithelium is an important source of chemokines that orchestrate leukocyte migration to the peripheral lung; early release of TNF-alpha and IL-1beta by stimulated macrophages may contribute to alveolar epithelial cell activation and chemokine production. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17182585&query_hl=1 ER - TY - JFULL T1 - Long-term outcome of patients with severe ANCA associated vasculitis treated with plasmapheresis A1 - Salama, A A1 - Ryba, M A1 - Levy, J A1 - Gaskin, G A1 - Pusey, C J1 - CLIN EXP RHEUMATOL Y1 - 2007/01// VL - 25 SN - 0392-856X SP - S118 EP - S118 ER - TY - JFULL T1 - ABAVAS: A trial of CTLA4Ig in ANCA vasculitis A1 - Salama, A A1 - Pusey, C A1 - Jayne, D A1 - Mosley, K J1 - CLIN EXP RHEUMATOL Y1 - 2007/01// VL - 25 SN - 0392-856X SP - S114 EP - S114 ER - TY - JFULL T1 - Novel zinc-based fixative for high quality DNA, RNA and protein analysis. A1 - Lykidis, D A1 - Van Noorden, S A1 - Armstrong, A A1 - Spencer-Dene, B A1 - Li, J A1 - Zhuang, Z A1 - Stamp, GW J1 - Nucleic Acids Res Y1 - 2007/// VL - 35 SN - 1362-4962 SP - e85 EP - e85 N2 - We have developed a reliable, cost-effective and non-toxic fixative to meet the needs of contemporary molecular pathobiology research, particularly in respect of RNA and DNA integrity. The effects of 25 different fixative recipes on the fixed quality of tissues from C57BL/6 mice were investigated. Results from IHC, PCR, RT-PCR, RNA Agilent Bioanalyser and Real-Time PCR showed that a novel zinc-based fixative (Z7) containing zinc trifluoroacetate, zinc chloride and calcium acetate was significantly better than the standard zinc-based fixative (Z2) and neutral buffered formalin (NBF) for DNA, RNA and protein preservation. DNA sequences up to 2.4 kb in length and RNA fragments up to 361 bp in length were successfully amplified from Z7 fixed tissues, as demonstrated by PCR, RT-PCR and Real-Time PCR. Total protein analysis was achieved using 2-D gel electrophoresis. In addition, nucleic acids and proteins were very stable over a 6-14-month period. This improved, non-toxic and economical tissue fixative could be applied for routine use in pathology laboratories to permit subsequent genomic/proteomic studies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17576663&query_hl=1 ER - TY - JFULL T1 - Generation and expansion of human CD4+ CD25+ regulatory T cells with indirect allospecificity: Potential reagents to promote donor-specific transplantation tolerance. A1 - Jiang, S A1 - Tsang, J A1 - Game, DS A1 - Stevenson, S A1 - Lombardi, G A1 - Lechler, RI J1 - Transplantation Y1 - 2006/12/27/ VL - 82 SN - 0041-1337 SP - 1738 EP - 1743 N2 - BACKGROUND: Harnessing naturally arising CD4+ CD25+ regulatory T cells (Tregs) for potential adoptive cell therapy is hampered by their innate autoreactivity and their limited number. METHODS: CD4+ CD25+ Tregs were purified from peripheral blood of human leukocyte antigen (HLA) DR1*0101+ A2- individuals, and stimulated with autologous monocyte-derived dendritic cells (DCs). RESULTS: Here we show that CD4+ CD25+ Tregs specific for an HLA A2 (103-120) peptide can be selected from the peripheral blood CD4+ CD25+ T cell population of a healthy individual and detected using a tetramer comprised of HLA DRB1*0101 and the A2 peptide. The selected cells can be expanded substantially (i.e., a 1600-fold increase over a two-week period) by T-cell receptor (TCR) stimulation and high-doses of interleukin-2 (IL-2). The CD4+ CD25+Tregs with indirect allospecificity for the A2 peptide showed more potent antigen-specific suppression than polyclonal CD4+ CD25+ Tregs. CONCLUSIONS: These data may pave the way for clinical studies using CD4+ CD25+ Tregs with indirect allospecificity as therapeutic reagents for the induction of donor-specific transplantation tolerance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17198269&query_hl=1 ER - TY - JFULL T1 - Early events in the thymus affect the balance of effector and regulatory T cells A1 - Pennington, DJ A1 - Silva-Santos, B A1 - Silberzahn, T A1 - Escorcio-Correia, M A1 - Woodward, MJ A1 - Roberts, SJ A1 - Smith, AL A1 - Dyson, PJ A1 - Hayday, AC J1 - NATURE Y1 - 2006/12/21/ VL - 444 SN - 0028-0836 SP - 1073 EP - 1077 N2 - In cellular immunology the critical balance between effector and regulatory mechanisms is highlighted by serious immunopathologies attributable to mutations in Foxp3, a transcription factor required for a major subset of regulatory T (T-R) cells(1-3). Thus, many studies have focused on the developmental origin of T-R cells, with the prevailing view that they emerge in the thymus from late-stage T-cell progenitors whose T-cell receptors (TCRs) engage high affinity (agonist) ligands(4-6). This study questions the completeness of that interpretation. Here we show that without any obvious effect on TCR-mediated selection, the normal differentiation of mouse gamma delta T cells into potent cytolytic and interferon-gamma-secreting effector cells is switched towards an aggregate regulatory phenotype by limiting the capacity of CD4(+) CD8(+) T-cell progenitors to influence in trans early gamma delta cell progenitors. Unexpectedly, we found that the propensity of early TCR-alpha beta(+) progenitors to differentiate into Foxp3 1 T-R cells is also regulated in trans by CD4(+) CD8(+) T-cell progenitor cells, before agonist selection. ER - TY - JFULL T1 - Structurally distinct membrane nanotubes between human macrophages support long-distance vesicular traffic or surfing of bacteria. A1 - Onfelt, B A1 - Nedvetzki, S A1 - Benninger, RK A1 - Purbhoo, MA A1 - Sowinski, S A1 - Hume, AN A1 - Seabra, MC A1 - Neil, MA A1 - French, PM A1 - Davis, DM J1 - J Immunol Y1 - 2006/12/15/ VL - 177 SN - 0022-1767 SP - 8476 EP - 8483 N2 - We report that two classes of membrane nanotubes between human monocyte-derived macrophages can be distinguished by their cytoskeletal structure and their functional properties. Thin membrane nanotubes contained only F-actin, whereas thicker nanotubes, i.e., those > approximately 0.7 microm in diameter, contained both F-actin and microtubules. Bacteria could be trapped and surf along thin, but not thick, membrane nanotubes toward connected macrophage cell bodies. Once at the cell body, bacteria could then be phagocytosed. The movement of bacteria is aided by a constitutive flow of the nanotube surface because streptavidin-coated beads were similarly able to traffic along nanotubes between surface-biotinylated macrophages. Mitochondria and intracellular vesicles, including late endosomes and lysosomes, could be detected within thick, but not thin, membrane nanotubes. Analysis from kymographs demonstrated that vesicles moved in a stepwise, bidirectional manner at approximately 1 microm/s, consistent with their traffic being mediated by the microtubules found only in thick nanotubes. Vesicular traffic in thick nanotubes and surfing of beads along thin nanotubes were both stopped upon the addition of azide, demonstrating that both processes require ATP. However, microtubule destabilizing agents colchicine or nocodazole abrogated vesicular transport but not the flow of the nanotube surface, confirming that distinct cytoskeletal structures of nanotubes give rise to different functional properties. Thus, membrane nanotubes between macrophages are more complex than unvarying ubiquitous membrane tethers and facilitate several means for distal interactions between immune cells. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17142745&query_hl=1 ER - TY - JFULL T1 - The roles of substrate thermal stability and P-2 and P-1 ' subsite identity on matrix metalloproteinase triple-helical peptidase activity and collagen specificity A1 - Minond, D A1 - Lauer-Fields, JL A1 - Cudic, M A1 - Overall, CM A1 - Pei, DQ A1 - Brew, K A1 - Visse, R A1 - Nagase, H A1 - Fields, GB J1 - J BIOL CHEM Y1 - 2006/12/15/ VL - 281 SN - 0021-9258 SP - 38302 EP - 38313 N2 - The hydrolysis of collagen (collagenolysis) is one of the committed steps in extracellular matrix turnover. Within the matrix metalloproteinase (MMP) family distinct preferences for collagen types are seen. The substrate determinants that may guide these specificities are unknown. In this study, we have utilized 12 triple-helical substrates in combination with 10 MMPs to better define the contributions of substrate sequence and thermal stability toward triple helicase activity and collagen specificity. In general, MMP-13 was found to be distinct from MMP-8 and MT1-MMP(Delta 279-523), in that enhanced substrate thermal stability has only a modest effect on activity, regardless of sequence. This result correlates to the unique collagen specificity of MMP-13 compared with MMP-8 and MT1-MMP, in that MMP-13 hydrolyzes type II collagen efficiently, whereas MMP-8 and MT1-MMP are similar in their preference for type I collagen. In turn, MMP-1 was the least efficient of the collagenolytic MMPs at processing increasingly thermal stable triple helices and thus favors type III collagen, which has a relatively flexible cleavage site. Gelatinases (MMP-2 and MMP-9(Delta 444-707)) appear incapable of processing more stable helices and are thus mechanistically distinct from collagenolytic MMPs. The collagen specificity of MMPs appears to be based on a combination of substrate sequence and thermal stability. Analysis of the hydrolysis of triple-helical peptides by an MMP mutant indicated that Tyr(210) functions in triple helix binding and hydrolysis, but not in processing triple helices of increasing thermal stabilities. Further exploration of MMP active sites and exosites, in combination with substrate conformation, may prove valuable for additional dissection of collagenolysis and yield information useful in the design of more selective MMP inhibitors. 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 - Trichophyia and hypertrichosis: a side effect of foam sclerotherapy. A1 - Kalodiki, E A1 - Azzam, M A1 - Geroulakos, G J1 - J Vasc Surg Y1 - 2006/12// VL - 44 SN - 0741-5214 SP - 1377 EP - 1377 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17145449&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 - Strain susceptibility to active induction and passive transfer of experimental autoimmune glomerulonephritis in the rat. A1 - Reynolds, J A1 - Albouainain, A A1 - Duda, MA A1 - Evans, DJ A1 - Pusey, CD J1 - Nephrol Dial Transplant Y1 - 2006/12// VL - 21 SN - 0931-0509 SP - 3398 EP - 3408 N2 - BACKGROUND: Previous studies have shown that different inbred rat strains vary in their susceptibility to experimental autoimmune glomerulonephritis (EAG). The Wistar Kyoto (WKY) rat is highly susceptible and develops crescentic glomerulonephritis, while the Lewis (LEW) rat is resistant. When immunized with collagenase-solubilized rat glomerular basement membrane (GBM), both strains produce circulating autoantibodies reactive with rat GBM by enzyme-linked immunosorbent assay, but only the WKY rat shows strong linear deposits of IgG on the GBM. METHODS: We investigated the hypothesis that differences in the characteristics of the anti-GBM antibodies produced, or in the inflammatory response to antibody deposition, could account for susceptibility. RESULTS: We found that circulating anti-GBM antibodies from WKY rats immunized with GBM were present at a higher concentration than those from LEW rats. Antibodies from WKY rats also recognized the rat alpha3 chain of type IV collagen [alpha3(IV)NC1], whereas those from LEW rats did not. Antibody eluted from the kidneys of WKY rats with EAG induced by GBM showed a higher affinity for GBM and recombinant rat alpha3(IV)NC1 than circulating antibody. This eluted antibody bound strongly to normal kidney sections from both WKY and LEW rats. Passive transfer of eluted anti-GBM antibodies from WKY rats with EAG resulted in similar binding of IgG to the GBM of WKY and LEW rats at 24 h. However, only the WKY recipients went on to develop crescentic glomerulonephritis by 28 days. CONCLUSIONS: This study demonstrates that the characteristics of the anti-GBM antibodies induced in WKY rats contribute to their susceptibility to EAG. However, the passive transfer experiments reveal that factors related to the inflammatory response to antibody deposition are also important in determining susceptibility. A combination of these genetic influences could explain the variation in severity of human anti-GBM disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16998225&query_hl=1 ER - TY - JFULL T1 - Remote ischaemic preconditioning protect against experimental or induced inflammation in humans. A1 - Gordon, SE A1 - Griffiths, MJ J1 - CRIT CARE MED Y1 - 2006/12// VL - 34 SN - 0090-3493 SP - A111 EP - A111 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 - Mitochondrial reactive oxygen species are required for mechanical strain-induced interleukin-8 production by lung epithelial cells A1 - Pinhu, L A1 - Griffiths, MJD J1 - THORAX Y1 - 2006/12// VL - 61 SN - 0040-6376 SP - II52 EP - II52 ER - TY - JFULL T1 - Differential effects of immunosuppressive drugs on T-cell motility. A1 - Datta, A A1 - David, R A1 - Glennie, S A1 - Scott, D A1 - Cernuda-Morollon, E A1 - Lechler, RI A1 - Ridley, AJ A1 - Marelli-Berg, FM J1 - Am J Transplant Y1 - 2006/12// VL - 6 SN - 1600-6135 SP - 2871 EP - 2883 N2 - The best-characterized mechanism of the action of immunosuppressive drugs is to prevent T-cell clonal expansion, thus containing the magnitude of the ensuing immune response. As T-cell recruitment to the inflammatory site is another key step in the development of T-cell-mediated inflammation, we analyzed and compared the effects of two commonly used immunosuppressants, cyclosporin A (CsA) and the rapamycin-related compound SDZ-RAD, on the motility of human CD4+ T cells. We show that CsA, but not SDZ-RAD, inhibits T-cell transendothelial migration in vitro. CsA selectively impaired chemokine-induced T-cell chemotaxis while integrin-mediated migration was unaffected. The inhibition of T-cell chemotaxis correlated with reduced AKT/PKB but not ERK activation following exposure to the chemokine CXCL-12/SDF-1. In addition, CsA, but not SDZ-RAD, prevents some T-cell receptor-mediated effects on T-cell motility. Finally, we show that CsA, but not SDZ-RAD inhibits tissue infiltration by T cells in vivo. Our data suggest a prominent antiinflammatory role for CsA in T-cell-mediated tissue damage, by inhibiting T-cell trafficking into tissues in addition to containing clonal expansion. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17061998&query_hl=1 ER - TY - JFULL T1 - Platelet-derived growth factor-beta receptor activation is essential for fibroblast and pericyte recruitment during cutaneous wound healing A1 - Rajkumar, VS A1 - Xu, SW A1 - Bostrom, M A1 - Leoni, P A1 - Muddle, J A1 - Ivarsson, M A1 - Gerdin, B A1 - Denton, CP A1 - Bou-Gharios, G A1 - Black, CM A1 - Abraham, DJ J1 - AM J PATHOL Y1 - 2006/12// VL - 169 SN - 0002-9440 SP - 2254 EP - 2265 N2 - Connective tissue remodeling provides mammals with a rapid mechanism to repair wounds after injury. Inappropriate activation of this reparative process leads to scarring and fibrosis. Here, we studied the effects of platelet-derived growth factor receptor-beta blockade in vivo using the platelet-derived growth factor receptor (PDGFR)-beta inhibitor imatinib mesylate on tissue repair. After 7 days, healing of wounds was delayed with significantly reduced wound closure and concomitant reduction in myofibroblast frequency, expression of fibronectin ED-A, and collagen type I. Using a collagen type I transgenic reporter mouse, we showed that inhibiting PDGFR-beta activation restricted the distribution of collagen-synthesizing cells to wound margins and dramatically reduced cell proliferation in vivo. By 14 days, treated wounds were fully closed. Blocking PDGFR-beta signaling did not prevent the differentiation of myofibroblasts in vitro but potently inhibited fibroblast proliferation and migration. in addition, PDGFR-beta inhibition in vivo was accompanied by abnormal microvascular morphogenesis reminiscent of that observed in PDGFR-beta(-/-) mice with significantly reduced immunostaining; of the pericyte marker NG2. imatinib treatment also inhibited pericyte proliferation and migration in vitro. This study highlights the significance of PDGFR-beta signaling for the recruitment, proliferation, and functional activities of fibroblasts and pericytes during the early phases of wound healing. ER - TY - JFULL T1 - Dual-specificity phosphatase 1: a critical regulator of innate immune responses. A1 - Abraham, SM A1 - Clark, AR J1 - Biochem Soc Trans Y1 - 2006/12// VL - 34 SN - 0300-5127 SP - 1018 EP - 1023 N2 - Innate immune responses are critically dependent on MAPK (mitogen-activated protein kinase) signalling pathways, in particular JNK (c-Jun N-terminal kinase) and p38 MAPK. Both of these kinases are negatively regulated via their dephosphorylation by DUSP1 (dual--specificity phosphatase 1). Several pro- and anti-inflammatory stimuli converge to regulate the DUSP1 gene and to modulate the time course of its expression. In turn, the pattern of expression of DUSP1 dictates the kinetics of activation of JNK and p38 MAPK, and this influences the expression of several mediators of innate immunity. DUSP1 is therefore a central regulator of innate immunity, and its expression can profoundly affect the outcome of inflammatory challenges. We discuss possible implications for immune-mediated inflammatory diseases and their treatment. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17073741&query_hl=1 ER - TY - JFULL T1 - Urinary proteomic profiles distinguish between active and inactive lupus nephritis. A1 - Mosley, K A1 - Tam, FW A1 - Edwards, RJ A1 - Crozier, J A1 - Pusey, CD A1 - Lightstone, L J1 - Rheumatology (Oxford) Y1 - 2006/12// VL - 45 SN - 1462-0324 SP - 1497 EP - 1504 N2 - OBJECTIVES: Key aims of the treatment of lupus nephritis (LN) are to induce and maintain remission with minimal side effects. However, assessing ongoing renal inflammatory activity is poorly served by current diagnostic tests apart from renal biopsy, but frequent biopsies cannot be justified. Our long-term aim is to identify novel biomarkers from urinary protein profiles to improve diagnosis and monitoring of activity and response to therapy in LN. METHODS: We used surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to identify biomarkers able to discriminate between urine samples from patients with inactive (n= 49) and active (n= 26) LN. Discriminant function analysis was used to define the minimum number of proteins whose levels best distinguished between the two patient groups. Serial urines of six biopsied patients were studied prospectively, and multiple regression (MR) scores calculated. RESULTS: Proteins with masses of 3340 and 3980 distinguished active from inactive LN with 92% sensitivity and specificity of 92% each. The prospective study of the biopsied patients demonstrated that MR scores could predict both relapse and remission earlier than traditional clinical markers. CONCLUSIONS: SELDI-TOF MS identified potential biomarker profiles strongly associated with activity in LN. Identification of these proteins will allow us to devise specific assays to routinely monitor disease progression, and alter immunosuppressive drug regimens accordingly. These proteins may also play a critical role in the pathogenesis of glomerulonephritis, and could therefore provide targets for therapeutic intervention. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17046860&query_hl=1 ER - TY - JFULL T1 - Topographical variation in glycosaminoglycan content in human articular cartilage A1 - Rogers, BA A1 - Murphy, CL A1 - Cannon, SR A1 - Briggs, TWR J1 - J BONE JOINT SURG BR Y1 - 2006/12// VL - 88B SN - 0301-620X SP - 1670 EP - 1674 N2 - The weight-bearing status of articular cartilage has been shown to affect its biochemical composition. We have investigated the topographical variation of sulphated glycosaminoglycan (GAG) relative to the DNA content of the chondrocyte in human distal femoral articular cartilage.Paired specimens of distal femoral articular cartilage, from weight-bearing and non-weight-bearing regions, were obtained from 13 patients undergoing above-knee amputation. After papain enzyme digestion, spectrophotometric GAG and fluorometric DNA assays assessed the biochemical composition of the samples. The results were analysed using a paired t-test.Although there were no significant differences in cell density between the regions, the weight-bearing areas showed a significantly higher concentration of GAG relative to DNA when compared with non-weight-bearing areas (p = 0.02).We conclude that chondrocytes are sensitive to their mechanical environment, and that local loading conditions influence the metabolism of the cells and hence the biochemical structure of the tissue. ER - TY - JFULL T1 - Cell therapy for renal regeneration-time for some joined-up thinking? A1 - Poulsom, R A1 - Prodromidi, EI A1 - Pusey, CD A1 - Cook, HT J1 - NEPHROL DIAL TRANSPL Y1 - 2006/12// VL - 21 SN - 0931-0509 SP - 3349 EP - 3353 ER - TY - JFULL T1 - Cell surface collagenolysis requires homodimerization of the membrane-bound collagenase MT1-MMP. A1 - Itoh, Y A1 - Ito, N A1 - Nagase, H A1 - Evans, RD A1 - Bird, SA A1 - Seiki, M J1 - Mol Biol Cell Y1 - 2006/12// VL - 17 SN - 1059-1524 SP - 5390 EP - 5399 N2 - Pericellular degradation of interstitial collagens is a crucial event for cells to migrate through the dense connective tissue matrices, where collagens exist as insoluble fibers. A key proteinase that participates in this process is considered to be membrane-type 1 matrix metalloproteinase (MT1-MMP or MMP-14), but little is known about the mechanism by which it cleaves the insoluble collagen. Here we report that homodimerization of MT1-MMP through its hemopexin (Hpx) domain is essential for cleaving type I collagen fibers at the cell surface. When dimerization was blocked by coexpressing either a membrane-bound or a soluble form of the Hpx domain, cell surface collagenolytic activity was inhibited in a dose-dependent manner. When MMP-13, a soluble collagenase active as a monomer in solution, was expressed as a membrane-anchored form on the cell surface, homodimerization was also required to cleave collagen. Our results introduce a new concept in that pericellular collagenolysis is regulated by correct molecular assembly of the membrane-anchored collagenase, thereby governing the directionality of the cell to migrate in tissue. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17050733&query_hl=1 ER - TY - JFULL T1 - Multiple sclerosis conference synopsis and discussion: cellular therapy for treatment of autoimmune diseases (October 2005). A1 - Openshaw, H A1 - Atkins, HL A1 - Chen, JT A1 - de Bittencourt, PR A1 - Griffith, LM A1 - Kerr, DA A1 - Khoury, SA A1 - Muraro, PA A1 - Nash, RA A1 - Saccardi, R J1 - Mult Scler Y1 - 2006/12// VL - 12 SN - 1352-4585 SP - 824 EP - 825 N2 - At a conference held in October 2005, participants presented studies on high dose immunosuppression with hematopoietic cell transplant (HCT) for multiple sclerosis (MS), including neuroimmunological and magnetic resonance imaging (MRI) mechanistic approaches, clinical registry reports, and ongoing or newly-designed protocols. A discussion panel considered questions on how to define success, timing of controlled clinical trials, difficulty in patient recruitment, and future direction of high dose therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17263013&query_hl=1 ER - TY - JFULL T1 - Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney A1 - Boutet, A A1 - De Frutos, CA A1 - Maxwell, PH A1 - Mayol, MJ A1 - Romero, J A1 - Nieto, MA J1 - EMBO J Y1 - 2006/11/29/ VL - 25 SN - 0261-4189 SP - 5603 EP - 5613 N2 - During embryonic development, the kidney epithelium originates from cells that undergo a mesenchymal to epithelial transition (MET). The reverse process, epithelium to mesenchyme transition (EMT), has been implicated in epithelial tumor progression and in the fibrosis that leads to end-stage kidney failure. Snail transcription factors induce both natural and pathological EMT, but their implication in renal development and disease is still unclear. We show that Snail genes are downregulated during the MET that occurs during renal development and that this is correlated with Cadherin-16 expression. Snail suppresses Cadherin-16 via the direct repression of the kidney differentiation factor HNF-1 beta, a novel route by which Snail disrupts epithelial homeostasis. Indeed, Snail activation is sufficient to induce EMT and kidney fibrosis in adult transgenic mice. Significantly, Snail is also activated in patients with renal fibrosis. Thus, Snail expression is suppressed during renal development and it must remain silent in the mature kidney where its aberrant activation leads to fibrosis. ER - TY - JFULL T1 - Development of stable organic solvent nanofiltration membranes for membrane enhanced dynamic kinetic resolution A1 - Roengpithya, C A1 - Patterson, DA A1 - Taylor, PC A1 - Livingston, AG J1 - DESALINATION Y1 - 2006/11/20/ VL - 199 SN - 0011-9164 SP - 195 EP - 197 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 - All anti-HBc-positive, HBsAg-negative dialysis patients on the transplant waiting list should be regarded as at risk of hepatitis B reactivation post-renal transplantation--report of three cases from a single centre. A1 - Roberts, RC A1 - Lane, C A1 - Hatfield, P A1 - Clutterbuck, E A1 - Atkins, M A1 - Brown, A A1 - Dorling, A J1 - Nephrol Dial Transplant Y1 - 2006/11// VL - 21 SN - 0931-0509 SP - 3316 EP - 3319 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16954172&query_hl=1 ER - TY - JFULL T1 - The RNA binding protein Zfp36l1 is required for normal vascularisation and post-transcriptionally regulates VEGF expressiono A1 - Bell, SE A1 - Sanchez, MJ A1 - Spasic-Boskovic, O A1 - Santalucia, T A1 - Gambardella, L A1 - Burton, GJ A1 - Murphy, JJ A1 - Norton, JD A1 - Clark, AR A1 - Turner, M J1 - DEV DYNAM Y1 - 2006/11// VL - 235 SN - 1058-8388 SP - 3144 EP - 3155 N2 - The Zfp36l1 gene encodes a zinc finger-containing mRNA binding protein implicated in the posttranscriptional control of gene expression. Mouse embryos homozygous for a targeted mutation in the Zfp36l1 locus died mid-gestation and exhibited extraembryonic and intraembryonic vascular abnormalities and heart defects. In the developing placenta, there was a failure of the extraembryonic mesoderm to invaginate the trophoblast layer. The phenotype was associated with an elevated expression of vascular endothelial growth factor (VEGF)-A in the embryos and in embryonic fibroblasts cultured under conditions of both normoxia and hypoxia. VEGF-A overproduction by embryonic fibroblasts was not a consequence of changes in Vegf-a mRNA stability; instead, we observed enhanced association with polyribosomes, suggesting Zfp36l1 influences translational regulation. These data implicate Zfp36l1 as a negative regulator of Vegf-a gene activity during development. ER - TY - JFULL T1 - Case 31: Eosinophilia and pruritus. A1 - Jayakar, V A1 - Goldin, RD A1 - Bain, BJ J1 - Leuk Lymphoma Y1 - 2006/11// VL - 47 SN - 1042-8194 SP - 2404 EP - 2405 N2 - A 39-year-old man presented with a pruritic rash, abdominal pain, weight loss and eosinophilia. A subsequent emergency laparotomy disclosed the nature of his underlying illness and the cause of the eosinophilia. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17107916&query_hl=1 ER - TY - JFULL T1 - Transcriptional regulation of the human alpha2(I) collagen gene A1 - Antoniv, T A1 - Tanaka, S A1 - Ramirez, F A1 - Bou-Gharios, G J1 - MATRIX BIOL Y1 - 2006/11// VL - 25 SN - 0945-053X SP - S78 EP - S78 ER - TY - JFULL T1 - Bone marrow-derived cells contribute to podocyte regeneration and amelioration of renal disease in a mouse model of Alport syndrome. A1 - Prodromidi, EI A1 - Poulsom, R A1 - Jeffery, R A1 - Roufosse, CA A1 - Pollard, PJ A1 - Pusey, CD A1 - Cook, HT J1 - Stem Cells Y1 - 2006/11// VL - 24 SN - 1066-5099 SP - 2448 EP - 2455 N2 - In a model of autosomally recessive Alport syndrome, mice that lack the alpha3 chain of collagen IV (Col4alpha3(-/-)) develop progressive glomerular damage leading to renal failure. The proposed mechanism is that podocytes fail to synthesize normal glomerular basement membrane, so the collagen IV network is unstable and easily degraded. We used this model to study whether bone marrow (BM) transplantation can rectify this podocyte defect by correcting the deficiency in Col4alpha3. Female C57BL/6 Col4alpha3(-/-) (-/-) mice were transplanted with whole BM from male wild-type (+/+) mice. Control female -/- mice received BM from male -/- littermates. Serum urea and creatinine levels were significantly lower in recipients of +/+ BM compared with those of -/- BM 20 weeks post-transplant. Glomerular scarring and interstitial fibrosis were also significantly decreased. Donor-derived cells were detected by in situ hybridization (ISH) for the Y chromosome, and fluorescence and confocal microscopy indicated that some showed an apparent podocyte phenotype in mice transplanted with +/+ BM. Glomeruli of these mice showed small foci of staining for alpha3(IV) protein by immunofluorescence. alpha3(IV) mRNA was detectable by reverse transcription-polymerase chain reaction and ISH in some mice transplanted with +/+ BM but not -/- BM. However, a single injection of mesenchymal stem cells from +/+ mice to irradiated -/- recipients did not improve renal disease. Our data show that improved renal function in Col4alpha3(-/-) mice results from BM transplantation from wild-type donors, and the mechanism by which this occurs may in part involve generation of podocytes without the gene defect. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16873763&query_hl=1 ER - TY - JFULL T1 - CTGF overexpressing mice: a model for human scleroderma A1 - Sonnylal, S A1 - Bou-Gharios, G A1 - Abraham, D A1 - de Crombrugghe, B J1 - MATRIX BIOL Y1 - 2006/11// VL - 25 SN - 0945-053X SP - S32 EP - S33 ER - TY - JFULL T1 - Chain register shift in type I collagen alters MMP1 cleavage A1 - Kuznetsova, NV A1 - Makareeva, E A1 - Cabral, WA A1 - Visse, R A1 - Nagase, H A1 - Marini, JC A1 - Leikin, S J1 - MATRIX BIOL Y1 - 2006/11// VL - 25 SN - 0945-053X SP - S75 EP - S75 ER - TY - JFULL T1 - Remission of collagen-induced arthritis is associated with high levels of transforming growth factor-beta expression in the joint. A1 - Marinova-Mutafchieva, L A1 - Gabay, C A1 - Funa, K A1 - Williams, RO J1 - Clin Exp Immunol Y1 - 2006/11// VL - 146 SN - 0009-9104 SP - 287 EP - 293 N2 - Immunization of genetically susceptible strains of mice with heterologous type II collagen leads to the induction of a self-limiting polyarthritis that begins to subside around 10 days after onset of clinical disease. The aims of this study were to compare pro- and anti-inflammatory cytokine expression in the joints during the course of arthritis in order to identify cytokines involved in spontaneous remission of arthritis. DBA/1 mice were immunized with type II collagen and an immunohistochemical analysis of expression of proinflammatory cytokines [tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6] and anti-inflammatory cytokines [IL-10, IL-1ra, transforming growth factor (TGF)-beta1, TGF-beta2 and TGF-beta3] in joints was carried out over the course of the disease. Both pro- and anti-inflammatory cytokines were found to be expressed in early arthritis. However, around 10 days after onset of arthritis, the level of expression of proinflammatory cytokines declined while the level of expression of anti-inflammatory cytokines, particularly TGF-beta1 and TGF-beta2, increased. Surprisingly, TNF-alpha continued to be expressed at low levels during the period of disease remission (30 days after onset). Blockade of TNF-alpha during the period of disease remission had no effect on TGF-beta expression. This study confirms that the level of inflammation in arthritis correlates strongly with the balance of pro- and anti-inflammatory cytokine expression in the joints. Of the anti-inflammatory cytokines studied, TGF-beta1 and TGF-beta2 predominate during the time of disease remission, suggesting that these cytokines are involved in regulating disease activity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17034581&query_hl=1 ER - TY - JFULL T1 - A nephritogenic peptide induces intermolecular epitope spreading on collagen IV in experimental autoimmune glomerulonephritis. A1 - Chen, L A1 - Hellmark, T A1 - Pedchenko, V A1 - Hudson, BG A1 - Pusey, CD A1 - Fox, JW A1 - Bolton, WK J1 - J Am Soc Nephrol Y1 - 2006/11// VL - 17 SN - 1046-6673 SP - 3076 EP - 3081 N2 - This group previously identified a peptide p13 of alpha3(IV)NC1 domain of type IV collagen that induces experimental autoimmune glomerulonephritis (EAG) in rats with generation of antibodies to sites on alpha3(IV)NC1 external to the peptide as a result of intramolecular epitope spreading. It was hypothesized that intermolecular epitope spreading to other collagen IV chains also was induced. Rats were immunized with nephritogenic peptide that was derived from the amino terminal part of rat alpha3(IV)NC1 domain, and serum and kidney eluate were examined for antibodies to both native and recombinant NC1 domains of collagen IV. Peptide induced EAG with proteinuria and decreased renal function and glomerular basement membrane IgG deposits. Sera from these rats were examined by ELISA, which revealed reactivity not only to immunizing peptide but also to human and rat alpha3(IV)NC1 and to human alpha4(IV)NC1 domains. Kidney eluate that was depleted of alpha3(IV)NC1 antibodies still reacted to alpha4(IV)NC1, and alpha3(IV)NC1 column-bound antibody reacted with alpha3(IV)NC1. There was minimal reactivity to other collagen chains. Eluate that was adsorbed to NC1 hexamer from rat glomerular basement membrane lost all reactivity to glomerular constituents, and the eluted antibodies reacted to alpha3(IV)NC1 and alpha4(IV)NC1 domains. These studies show that a T cell epitope of alpha3(IV)NC1 induces EAG, intramolecular epitope spreading along alpha3(IV)NC1, and intermolecular epitope spreading to alpha4(IV)NC1 domain with minimal or no reactivity to other collagen chains or glomerular constituents. This is the first demonstration in EAG of intermolecular epitope spreading and identification of the spread epitopes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17005930&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 - Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus in a family-based study. A1 - Graham, DS A1 - Wong, AK A1 - McHugh, NJ A1 - Whittaker, JC A1 - Vyse, TJ J1 - Hum Mol Genet Y1 - 2006/11/01/ VL - 15 SN - 0964-6906 SP - 3195 EP - 3205 N2 - CD28, CTLA4 (cytotoxic T lymphocyte-associated protein 4) and ICOS (inducible T cell co-stimulator) are good candidate genes for systemic lupus erythematosus (SLE) because of their role in regulating T cell activation. CTLA4 inhibits CD28-mediated T cell activation. CTLA4 is expressed on CD4+ and CD8+ activated T cells, and also B cells, but CD28 and ICOS are largely restricted to T cells. An interval encompassing the CD28-CTLA4-ICOS locus on chromosome 2q33 was linked to lupus in two genome-wide linkage scans. This large family-based association study in 532 UK SLE families represents the first high-density genetic screen of 80 SNPs at this locus. There are seven haplotype blocks across the locus. In CTLA4, the strongest signal comes from two variants, located 2.1 kb downstream from the 3'-UTR. These polymorphisms, rs231726 (SNP 43) and rs231726 (SNP 44), are in complete linkage disequilibrium (LD) (r(2)=1) and are associated with SLE P=0.0008 (GH) and P=0.01 (family-based association test). There is also a signal in the distal 3' flanking region of CTLA4/ICOS promoter (P=0.003). There was no confirmation of published associations for SLE in the promoter or coding region of CTLA4. These SLE risk alleles are more distal than those identified in Graves' disease and are in LD with Graves' disease protective alleles identified in both of these regions of CTLA4 (Ueda et al. 2003). These factors suggest an SLE-specific pattern of association. The functional consequences of the associated polymorphisms are likely to influence CTLA4 expression, although it is possible that genetically modulated ICOS expression is involved in SLE susceptibility. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17000707&query_hl=1 ER - TY - JFULL T1 - Current pharmacotherapy for the treatment of crescentic glomerulonephritis. A1 - Tam, FW J1 - Expert Opin Investig Drugs Y1 - 2006/11// VL - 15 SN - 1744-7658 SP - 1353 EP - 1369 N2 - Glomerulonephritis is an important cause of end-stage renal disease. Crescentic glomerulonephritis is the most severe form of glomerulonephritis and, if untreated, patients will develop renal failure within days or weeks of diagnosis. Current immunotherapy consists of corticosteroids, cytotoxic drugs and plasma exchange. Challenges include minimising toxicity of therapy, preventing relapse in antineutrophil cytoplasmic antibodies-associated vasculitis and finding an effective treatment for crescentic IgA nephropathy. There are opportunities for more specific therapies using monoclonal antibodies to T cells (and their co-stimulatory receptors), B cells and cytokines, or pharmacological inhibitors of signal transduction. Their efficacy and safety remain to be established with controlled clinical trials. Recent development of urinary cytokine measurement provides a noninvasive biomarker of renal disease activity, which is useful in monitoring response to therapy and assessing prognosis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17040196&query_hl=1 ER - TY - JFULL T1 - The human prion protein residue 129 polymorphism lies within a cluster of epitopes for T cell recognition. A1 - Isaacs, JD A1 - Ingram, RJ A1 - Collinge, J A1 - Altmann, DM A1 - Jackson, GS J1 - J Neuropathol Exp Neurol Y1 - 2006/11// VL - 65 SN - 0022-3069 SP - 1059 EP - 1068 N2 - T cell immune responses to central nervous system-derived and other self-antigens are commonly described in both healthy and autoimmune individuals. However, in the case of the human prion protein (PrP), it has been argued that immunologic tolerance is uncommonly robust. Although development of an effective vaccine for prion disease requires breaking of tolerance to PrP, the extent of immune tolerance to PrP and the identity of immunodominant regions of the protein have not previously been determined in humans. We analyzed PrP T cell epitopes both by using a predictive algorithm and by measuring functional immune responses from healthy donors. Interestingly, clusters of epitopes were focused around the area of the polymorphic residue 129, previously identified as an indicator of susceptibility to prion disease, and in the C-terminal region. Moreover, responses were seen to PrP peptide 121-134 containing methionine at position 129, whereas PrP 121-134 [129V] was not immunogenic. The residue 129 polymorphism was also associated with distinct patterns of cytokine response: PrP 128-141 [129M] inducing IL-4 and IL-6 production, which was not seen in response to PrP 128-141 [129V]. Our data suggest that the immunogenic regions of human PrP lie between residue 107 and the C-terminus and that, like with many other central nervous system antigens, healthy individuals carry responses to PrP within the T cell repertoire and yet do not experience deleterious autoimmune reactions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17086102&query_hl=1 ER - TY - JFULL T1 - Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis. A1 - Walmsley, SR A1 - Cowburn, AS A1 - Clatworthy, MR A1 - Morrell, NW A1 - Roper, EC A1 - Singleton, V A1 - Maxwell, P A1 - Whyte, MK A1 - Chilvers, ER J1 - Blood Y1 - 2006/11/01/ VL - 108 SN - 0006-4971 SP - 3176 EP - 3178 N2 - Neutrophils are key mediators of the innate immune response and are required to function at sites of low oxygenation. We have shown that in hypoxia neutrophils are protected from apoptosis via a mechanism dependent on prolyl hydroxylase domain/hypoxia-inducible factor 1alpha (PHD/HIF-1alpha). This response would be predicted to involve the von Hippel Lindau protein (pVHL)-dependent ubiquitination and degradation of HIF-1alpha. Patients with VHL disease inherit a mutation in one VHL allele, which allows us to study the effects of heterozygous VHL expression in human neutrophils. Neutrophils exhibited a striking "partial hypoxic" pheno-type, with delayed rates of apoptosis and enhanced bacterial phagocytosis under normoxic conditions and preserved responses to low levels of oxygen. This provides direct evidence that the HIF-1alpha/VHL pathway regulates the innate immune response in humans. It also establishes that heterozygous VHL defects are sufficient to perturb normal responses and illustrates the potential to use this to address the role of HIF and VHL in human biology. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16809612&query_hl=1 ER - TY - JFULL T1 - Evolution of VHL tumourigenesis in nerve root tissue. A1 - Vortmeyer, AO A1 - Tran, MG A1 - Zeng, W A1 - Gläsker, S A1 - Riley, C A1 - Tsokos, M A1 - Ikejiri, B A1 - Merrill, MJ A1 - Raffeld, M A1 - Zhuang, Z A1 - Lonser, RR A1 - Maxwell, PH A1 - Oldfield, EH J1 - J Pathol Y1 - 2006/11// VL - 210 SN - 0022-3417 SP - 374 EP - 382 N2 - Haemangioblastomas are the key central nervous system manifestation of von Hippel-Lindau (VHL) disease, which is caused by germline mutation of the VHL gene. We have recently shown that 'tumour-free' spinal cord from patients with VHL disease contains microscopic, poorly differentiated cellular aggregates in nerve root tissue, which we descriptively designated 'mesenchymal tumourlets'. Here we have investigated spinal cord tissue affected by multiple tumours. We show that a small subset of mesenchymal tumourlets extends beyond the nerve root to form proliferative VHL-deficient mesenchyme and frank haemangioblastoma. We thus demonstrate that tumourlets present potential, but true precursor material for haemangioblastoma. We further show that intraradicular tumourlets consist of scattered VHL-deficient cells with activation of HIF-2alpha and HIF-dependent target proteins including CAIX and VEGF, and are associated with an extensive angiogenic response. In contrast, activation of HIF-1alpha was only observed in the later stages of tumour progression. In addition, ultrastructural examination reveals gradual transition from poorly differentiated VHL-deficient cells into vacuolated cells with a 'stromal' cell phenotype. The evolution of frank haemangioblastoma seems to involve multiple steps from a large pool of precursor lesions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16981244&query_hl=1 ER - TY - JFULL T1 - Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats. A1 - Thompson, EL A1 - Murphy, KG A1 - Patterson, M A1 - Bewick, GA A1 - Stamp, GW A1 - Curtis, AE A1 - Cooke, JH A1 - Jethwa, PH A1 - Todd, JF A1 - Ghatei, MA A1 - Bloom, SR J1 - Am J Physiol Endocrinol Metab Y1 - 2006/11// VL - 291 SN - 0193-1849 SP - E1074 EP - E1082 N2 - The kisspeptins are KiSS-1 gene-derived peptides that signal through the G protein-coupled receptor-54 (GPR54) and have recently been shown to be critical regulators of reproduction. Acute intracerebroventricular or peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis. This effect is thought to be mediated via the hypothalamic gonadotropin-releasing hormone (GnRH) system. Chronic administration of GnRH agonists paradoxically suppresses the HPG axis after an initial agonistic stimulation. We investigated the effects of continuous peripheral kisspeptin administration in male rats by use of Alzet minipumps. Initially we compared the effects of acute subcutaneous administration of kisspeptin-10, -14, and -54 on the HPG axis. Kisspeptin-54 produced the greatest increase in plasma LH and total testosterone at 60 min postinjection and was used in the subsequent continuous administration experiments. Chronic subcutaneous long-term administration of 50 nmol kisspeptin-54/day for 13 days decreased testicular weight. Histological examination showed degeneration of the seminiferous tubules associated with a significant decrease in the circulating levels of the testes-derived hormone, inhibin B. Plasma free and total testosterone were also lower, although these changes did not reach statistical significance. Further studies examined the effects of shorter periods of continuous kisspeptin administration. Subcutaneous administration of 50 nmol kisspeptin-54 for 1 day increased plasma LH and testosterone. This effect was lost after 2 days of administration, suggesting a downregulation of the HPG axis response to kisspeptin following continuous administration. These findings indicate that kisspeptin may provide a novel tool for the manipulation of the HPG axis and spermatogenesis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16787965&query_hl=1 ER - TY - JFULL T1 - A coiled-coil domain of melanophilin is essential for Myosin Va recruitment and melanosome transport in melanocytes. A1 - Hume, AN A1 - Tarafder, AK A1 - Ramalho, JS A1 - Sviderskaya, EV A1 - Seabra, MC J1 - Mol Biol Cell Y1 - 2006/11// VL - 17 SN - 1059-1524 SP - 4720 EP - 4735 N2 - Melanophilin (Mlph) regulates retention of melanosomes at the peripheral actin cytoskeleton of melanocytes, a process essential for normal mammalian pigmentation. Mlph is proposed to be a modular protein binding the melanosome-associated protein Rab27a, Myosin Va (MyoVa), actin, and microtubule end-binding protein (EB1), via distinct N-terminal Rab27a-binding domain (R27BD), medial MyoVa-binding domain (MBD), and C-terminal actin-binding domain (ABD), respectively. We developed a novel melanosome transport assay using a Mlph-null cell line to study formation of the active Rab27a:Mlph:MyoVa complex. Recruitment of MyoVa to melanosomes correlated with rescue of melanosome transport and required intact R27BD together with MBD exon F-binding region (EFBD) and unexpectedly a potential coiled-coil forming sequence within ABD. In vitro binding studies indicate that the coiled-coil region enhances binding of MyoVa by Mlph MBD. Other regions of Mlph reported to interact with MyoVa globular tail, actin, or EB1 are not essential for melanosome transport rescue. The strict correlation between melanosomal MyoVa recruitment and rescue of melanosome distribution suggests that stable interaction with Mlph and MyoVa activation are nondissociable events. Our results highlight the importance of the coiled-coil region together with R27BD and EFBD regions of Mlph in the formation of the active melanosomal Rab27a-Mlph-MyoVa complex. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16914517&query_hl=1 ER - TY - JFULL T1 - Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. A1 - Pollard, PJ A1 - El-Bahrawy, M A1 - Poulsom, R A1 - Elia, G A1 - Killick, P A1 - Kelly, G A1 - Hunt, T A1 - Jeffery, R A1 - Seedhar, P A1 - Barwell, J A1 - Latif, F A1 - Gleeson, MJ A1 - Hodgson, SV A1 - Stamp, GW A1 - Tomlinson, IP A1 - Maher, ER J1 - J Clin Endocrinol Metab Y1 - 2006/11// VL - 91 SN - 0021-972X SP - 4593 EP - 4598 N2 - CONTEXT: Activation of the hypoxia-inducible transcription factors HIF-1 and HIF-2 and a HIF-independent defect in developmental apoptosis have been implicated in the pathogenesis of pheochromocytoma (PCC) associated with VHL, SDHB, and SDHD mutations. OBJECTIVE: Our objective was to compare protein (HIF-1alpha, EPAS1, SDHB, JunB, CCND1, CD34, CLU) and gene (VEGF, BNIP3) expression patterns in VHL and SDHB/D associated tumors. RESULTS: Overexpression of HIF-2 was relatively more common in VHL than SDHB/D PCC (12 of 13 vs. 14 of 20, P = 0.02), whereas nuclear HIF-1 staining was relatively more frequent in SDHB/D PCC (19 of 20 vs. 13 of 16, P = 0.04). In addition, CCND1 and VEGF expression (HIF-2 target genes) was significantly higher in VHL than in SDHB/D PCC. These findings suggest that VHL inactivation leads to preferential HIF-2 activation and CCND1 expression as described previously in VHL-defective renal cell carcinoma cell lines but not in other cell types. These similarities between the downstream consequences of VHL inactivation and HIF dysregulation in renal cell carcinoma and PCC may explain how inactivation of the ubiquitously expressed VHL protein results in susceptibility to specific tumor types. Both VHL and SDHB/D PCC demonstrated reduced CLU and SDHB expression. SDHB PCC are associated with a high risk of malignancy, and expression of (proapototic) BNIP3 was significantly lower in SDHB than VHL PCC. CONCLUSION: Although inactivation of VHL and SDHB/D may disrupt similar HIF-dependent and HIF-independent signaling pathways, their effects on target gene expression are not identical, and this may explain the observed clinical differences in PCC and associated tumors seen with germline VHL and SDHB/D mutations. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16954163&query_hl=1 ER - TY - JFULL T1 - Immunotherapy with antibody targeted MHC complexes: Results of in vivo tumour cell killing and therapeutic vaccination A1 - Savage, P A1 - Dyson, J A1 - French, R A1 - Glennie, M J1 - J IMMUNOTHER Y1 - 2006/11// VL - 29 SN - 1524-9557 SP - 636 EP - 637 ER - TY - JFULL T1 - Bone marrow stem cells contribution to tissue fibrosis A1 - Bou-Gharios, G J1 - MATRIX BIOL Y1 - 2006/11// VL - 25 SN - 0945-053X SP - S23 EP - S24 ER - TY - JFULL T1 - Direct activation of type I protein kinase a (PKA) by oxidants independently of cAMP is mediated by RI subunit interprotein disulphide bond formation A1 - Brennan, JP A1 - Bardswell, SC A1 - Burgoyne, JR A1 - Fuller, W A1 - Schroder, E A1 - Wait, R A1 - Begum, S A1 - Kentish, JC A1 - Eaton, P J1 - CIRCULATION Y1 - 2006/10/31/ VL - 114 SN - 0009-7322 SP - 1 EP - 2 ER - TY - JFULL T1 - Increased infarct size and decreased vascular leakage following. transient focal cerebral ischemia in mice with inhibition of endothelial and leukocyte NF-kB A1 - Ahl, D A1 - Kim, HH A1 - Harari, OA A1 - Tejima, E A1 - Wang, HW A1 - Schmidt-Ullrich, R A1 - Moskowitz, MA A1 - Lo, EH A1 - Liao, JK J1 - CIRCULATION Y1 - 2006/10/31/ VL - 114 SN - 0009-7322 SP - 182 EP - 182 ER - TY - JFULL T1 - A role for Dicer in immune regulation. A1 - Cobb, BS A1 - Hertweck, A A1 - Smith, J A1 - O'Connor, E A1 - Graf, D A1 - Cook, T A1 - Smale, ST A1 - Sakaguchi, S A1 - Livesey, FJ A1 - Fisher, AG A1 - Merkenschlager, M J1 - J Exp Med Y1 - 2006/10/30/ VL - 203 SN - 0022-1007 SP - 2519 EP - 2527 N2 - Micro RNAs (miRNAs) regulate gene expression at the posttranscriptional level. Here we show that regulatory T (T reg) cells have a miRNA profile distinct from conventional CD4 T cells. A partial T reg cell-like miRNA profile is conferred by the enforced expression of Foxp3 and, surprisingly, by the activation of conventional CD4 T cells. Depleting miRNAs by eliminating Dicer, the RNAse III enzyme that generates functional miRNAs, reduces T reg cell numbers and results in immune pathology. Dicer facilitates, in a cell-autonomous fashion, the development of T reg cells in the thymus and the efficient induction of Foxp3 by transforming growth factor beta. These results suggest that T reg cell development involves Dicer-generated RNAs. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17060477&query_hl=1 ER - TY - JFULL T1 - Rab38 and Rab32 control post-Golgi trafficking of melanogenic enzymes. A1 - Wasmeier, C A1 - Romao, M A1 - Plowright, L A1 - Bennett, DC A1 - Raposo, G A1 - Seabra, MC J1 - J Cell Biol Y1 - 2006/10/23/ VL - 175 SN - 0021-9525 SP - 271 EP - 281 N2 - A mutation in the small GTPase Rab38 gives rise to the mouse coat color phenotype "chocolate" (cht), implicating Rab38 in the regulation of melanogenesis. However, its role remains poorly characterized. We report that cht Rab38(G19V) is inactive and that the nearly normal pigmentation in cht melanocytes results from functional compensation by the closely related Rab32. In cht cells treated with Rab32-specific small interfering RNA, a dramatic loss of pigmentation is observed. In addition to mature melanosomes, Rab38 and Rab32 localize to perinuclear vesicles carrying tyrosinase and tyrosinase-related protein 1, consistent with a role in the intracellular sorting of these proteins. In Rab38/Rab32-deficient cells, tyrosinase appears to be mistargeted and degraded after exit from the trans-Golgi network (TGN). This suggests that Rab38 and Rab32 regulate a critical step in the trafficking of melanogenic enzymes, in particular, tyrosinase, from the TGN to melanosomes. This work identifies a key role for the Rab38/Rab32 subfamily of Rab proteins in the biogenesis of melanosomes and potentially other lysosome-related organelles. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17043139&query_hl=1 ER - TY - JFULL T1 - New flow cytometric technique for the evaluation of circulating endothelial progenitor cell levels in various disease groups. A1 - Dulic-Sills, A A1 - Blunden, MJ A1 - Mawdsley, J A1 - Bastin, AJ A1 - McAuley, D A1 - Griffiths, M A1 - Rampton, DS A1 - Yaqoob, MM A1 - Macey, MG A1 - Agrawal, SG J1 - J Immunol Methods Y1 - 2006/10/20/ VL - 316 SN - 0022-1759 SP - 107 EP - 115 N2 - Circulating endothelial progenitor cells (EPC) localise to sites of ischaemia and play a role in vascular repair and re-endothelialisation of injured blood vessels. Low levels of EPCs are associated with cardiovascular disease (CVD) in the general population. It is not clear at present whether and how the numbers of circulating EPCs vary in diseases other than CVD. We have enumerated EPCs by the flow cytometric analysis of whole blood by using a novel cocktail of monoclonal antibodies. This consisted of CD2FITC, CD13FITC and CD22FITC to eliminate non-progenitor cells and VEGFR2PE and CD133-streptavidin-PeCy7 to include only EPCs. We analysed 250 patients with varying stages of uraemia, 36 patients with inflammatory bowel disease (IBD) and 9 patients with acute respiratory distress syndrome and compared this to 74 healthy controls. Using flow cytometry we were able to measure the circulating levels of EPCs, with a result available within hours of the sample being obtained. Circulating EPC numbers vary in different patient groups and healthy controls. In uraemic patients, irrespective of disease severity, there are lower numbers of circulating EPC numbers compared to normal controls (46.6+/-3.7 vs. 66.1+/-4.7; p=0.03). This new technique provides a means of monitoring patients and shows a reduction in circulating EPCs in uraemic patients; this abnormality may be a target of novel therapies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17027849&query_hl=1 ER - TY - JFULL T1 - Regulation of prostate cell growth and morphogenesis by Dickkopf-3. A1 - Kawano, Y A1 - Kitaoka, M A1 - Hamada, Y A1 - Walker, MM A1 - Waxman, J A1 - Kypta, RM J1 - Oncogene Y1 - 2006/10/19/ VL - 25 SN - 0950-9232 SP - 6528 EP - 6537 N2 - Wnt signalling plays a critical role in the development of cancer. Recent studies indicate that Wnt signalling is negatively regulated by secreted Wnt antagonists such as secreted frizzled related proteins (sFRPs) and Dickkopfs (Dkks). We compared Dkk family expression levels in normal prostate and prostate cancer cells and found a reduction in Dkk-3 expression in cancer cells. Ectopic expression of Dkk-3 inhibited colony formation in LNCaP and PC3 prostate cancer cell lines and inducible expression of Dkk-3 reduced LNCaP cell proliferation. Moreover, small interfering RNA-mediated downregulation of Dkk-3 enhanced cell cycle progression in untransformed RWPE-1 prostate epithelial cells. Immunohistochemical analysis revealed that Dkk-3 is expressed in a subset of normal prostate gland acini and that Dkk-3 expression is reduced in prostate tumours, particularly those with a high Gleason grade, suggesting a role for Dkk-3 in postmitotic differentiation. Consistent with this, depletion of Dkk-3 disrupted acinar morphogenesis of RWPE-1 cells in a three-dimensional cell culture model. Our results are consistent with the loss of Dkk-3 expression resulting in impairment of glandular structure and uncontrolled prostate epithelial cell (PrEC) proliferation, both of which are crucial for prostate cancer progression. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16751809&query_hl=1 ER - TY - JFULL T1 - Classical and non-classical ruthenium-based anticancer drugs: Towards targeted chemotherapy A1 - Ang, WH A1 - Dyson, PJ J1 - EUR J INORG CHEM Y1 - 2006/10/16/ SN - 1434-1948 SP - 4003 EP - 4018 N2 - Ruthenium-based anticancer chemotherapies are making significant advances in clinical trials. Until recently, the focus has been on coordination complexes, and mechanisms such as "activation by reduction" and "transferrin-targeted delivery" have been proposed to account for the excellent cytotoxicity and low general toxicity of these complexes. More recently organoruthenium compounds, which to some extent appear not to follow the established rules, have started to be investigated. Despite such differences, similar activities between certain coordination and organometallic compounds suggest similar modes of action are present. DNA, the classic target, is believed to be the dominant mechanism for cytotoxicity with certain ruthenium drugs, while with others, non-classical targets are thought to be more important. In this article we describe these features and show how both ruthenium coordination complexes and organoruthenium compounds represent an ideal scaffold for further drug design and optimisation. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006). ER - TY - JFULL T1 - A novel mechanism for complement activation at the surface of B cells following antigen binding A1 - Manderson, AP A1 - Quah, B A1 - Botto, M A1 - Goodnow, CC A1 - Walport, MJ A1 - Parish, CR J1 - J IMMUNOL Y1 - 2006/10/15/ VL - 177 SN - 0022-1767 SP - 5155 EP - 5162 N2 - Coligation of CD21 with BCR on the surface of B cells provides a costimulatory signal essential for efficient Ab responses to T-dependent Ags. To achieve this, Ag must be directly linked to C3 fragments, but how this occurs in vivo is not fully understood. Using BCR transgenic mice, we demonstrated that C3 was deposited on the surface of B cells following both high- and moderate-affinity Ag binding. This was dependent on the specific binding of IgM to the BCR-bound Ag and can occur independently of soluble immune complex formation. Based on these data, we propose a novel model in which immune complexes can form directly on the surface of the B cell following Ag binding. This model has implications for our understanding of B lymphocyte activation. ER - TY - JFULL T1 - 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 - Adenoviral gene transfer into osteoarthritis synovial cells using the endogenous inhibitor I kappa B alpha reveals that most, but not all, inflammatory and destructive mediators are NF kappa B dependent A1 - Amos, N A1 - Lauder, S A1 - Evans, A A1 - Feldmann, M A1 - Bondeson, J J1 - RHEUMATOLOGY Y1 - 2006/10// VL - 45 SN - 1462-0324 SP - 1201 EP - 1209 N2 - Objectives. Despite recent major advances in the understanding of the pathogenesis of rheumatoid arthritis, with tumour necrosis factor-alpha (TNF alpha) established as a major therapeutic target, comparatively little is known about the mediators involved in the destructive and inflammatory pathways in osteoarthritis (OA). Recently, it has become appreciated that an inflammatory synovitis contributes not only to the signs and symptoms of osteoarthritis, but also to disease progression. Here, we use high-efficiency adenoviral gene transfer to investigate the role of the transcription factor nuclear factor-kappa B (NF kappa B) in regulating inflammatory and destructive mediators in the late stage OA synovium.Methods. Infection with reporter adenoviruses transferring the beta-galactosidase or green fluorescent protein genes verified that OA synovial cells could be infected (> 95%). Adenovirus transferring the inhibitory subunit I kappa B alpha inhibited NF kappa B. The production of a whole array of pro-and anti-inflammatory cytokines and mediators, and several matrix metalloproteinases and their main inhibitor, was measured by enzyme-linked immunosorbent assay.Results. The spontaneous production of macrophage-produced pro-inflammatory cytokines varied: TNF alpha was modestly inhibited by I kappa B alpha overexpression, but interleukin (IL)-1 was unaffected. Both IL-6 and IL-8 were potently inhibited, as were granulocyte-macrophage colony stimulating factor and oncostatin M. Anti-inflammatory mediators like IL-10, the IL-1 receptor antagonist and the p55 soluble TNF receptor were unaffected. Matrix metalloproteinases 1, 3, 9 and 13 were potently inhibited by I kappa B alpha overexpression, but not their main inhibitor tissue inhibitor of metalloproteinase-1.Conclusions. The OA synovium is a highly inflammatory environment, with spontaneous production of many cytokines and matrix metalloproteinases. Inhibition of NF kappa B may have a beneficial effect on the balance between pro-inflammatory cytokines and anti-inflammatory mediators, and between destructive metalloproteinases and their main inhibitor. ER - TY - JFULL T1 - Postinjury vascular intimal hyperplasia in mice is completely inhibited by CD34+ bone marrow-derived progenitor cells expressing membrane-tethered anticoagulant fusion proteins. A1 - Chen, D A1 - Weber, M A1 - Shiels, PG A1 - Dong, R A1 - Webster, Z A1 - McVey, JH A1 - Kemball-Cook, G A1 - Tuddenham, EG A1 - Lechler, RI A1 - Dorling, A J1 - J Thromb Haemost Y1 - 2006/10// VL - 4 SN - 1538-7933 SP - 2191 EP - 2198 N2 - BACKGROUND: Coagulation proteins promote neointimal hyperplasia and vascular remodelling after vessel injury, but the precise mechanisms by which they act in vivo remain undetermined. OBJECTIVES: This study, using an injury model in which the neointima is derived from bone marrow (BM)-derived cells, compared inhibition of tissue factor or thrombin on either BM-derived or existing vascular smooth muscle cells. METHODS: Two transgenic (Tg) mouse strains expressing membrane-tethered tissue factor pathway inhibitor (TFPI) or hirudin (Hir) fusion proteins driven by an alpha smooth muscle actin (SMA) promoter were generated (alpha-TFPI-Tg and alpha-Hir-Tg) and the phenotype after wire-induced endovascular injury was compared with that in wild-type (WT) controls. Results: WT mice developed progressive neointimal expansion, whereas injury in either Tg was followed by repair back to a preinjured state. This was also seen when WT mice were reconstituted with BM from Tg mice but not when Tgs were reconstituted with WT BM, in which injury was followed by slowly progressive neointimal expansion. Injection of CD34+ cells from Tg mice into injured WT mice resulted in the accumulation of fusion protein-expressing cells from day 3 onwards and an absence of neointimal hyperplasia in those areas. CONCLUSIONS: Neointimal development after wire-induced endovascular injury in mice was completely inhibited when BM-derived cells infiltrating the damaged artery expressed membrane tethered anticoagulant fusion proteins under an alpha-SMA promoter. These findings enhance our understanding of the pathological role that coagulation proteins play in vascular inflammation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16803463&query_hl=1 ER - TY - JFULL T1 - Thymic output, ageing and zinc. A1 - Mitchell, WA A1 - Meng, I A1 - Nicholson, SA A1 - Aspinall, R J1 - Biogerontology Y1 - 2006/10// VL - 7 SN - 1389-5729 SP - 461 EP - 470 N2 - The role of the thymus is vital for orchestration of T-cell development and maturation. With increasing age the thymus undergoes a process of involution which results in a reduction in thymic size, function and output. Until relatively recent it was not feasible to accurately measure the magnitude of age-related loss of thymic function. With the discovery of T-cell receptor excision circles (TRECs), which are the stable by-products of the newly generated T-cells, it is now possible to quantitatively measure the extent of thymic output. This review examines the available data on immune function and zinc deficiency and places them in the context of the aims of the ZINCAGE project which include the evaluation of the role played by zinc in maintaining thymic output in healthy elderly individuals. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16964524&query_hl=1 ER - TY - JFULL T1 - Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus. A1 - Heidari, Y A1 - Bygrave, AE A1 - Rigby, RJ A1 - Rose, KL A1 - Walport, MJ A1 - Cook, HT A1 - Vyse, TJ A1 - Botto, M J1 - Genes Immun Y1 - 2006/10// VL - 7 SN - 1466-4879 SP - 592 EP - 599 N2 - Systemic lupus erythematosus is an autoimmune disease in which complex interactions between genes and environmental factors determine the disease phenotype. We have shown that genes from the non-autoimmune strains 129 and C57BL/6 (B6), commonly used for generating gene-targeted animals, can induce a lupus-like disease. Here, we conducted a genome-wide scan analysis of a cohort of (129 x B6)F2 C1q-deficient mice to identify loci outside the C1qa locus contributing to the autoimmune phenotype described in these mice. The results were then confirmed in a larger dataset obtained by combining the data from the C1q-deficient mice with data from previously reported wild-type mice. Both analyses showed that a 129-derived interval on distal chromosome 1 is strongly linked to autoantibody production. The B6 genome contributed to anti-nuclear autoantibody production with an interval on chromosome 3. Two regions were linked to glomerulonephritis: a 129 interval on proximal chromosome 7 and a B6 interval on chromosome 13. These findings demonstrate that interacting loci between 129 and B6 mice can cause the expression of an autoimmune phenotype in gene-targeted animals in the absence of any disrupted gene. They also indicate that some susceptibility genes can be inherited from the genome of non-autoimmune parental strains. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16943797&query_hl=1 ER - TY - JFULL T1 - MT1-MMP: a key regulator of cell migration in tissue. A1 - Itoh, Y J1 - IUBMB Life Y1 - 2006/10// VL - 58 SN - 1521-6543 SP - 589 EP - 596 N2 - Controlled cell migration is a fundamental and critical event in many physiological processes. However once control is lost, cell migration facilitates disease progression such as seen in cancer metastasis, atherosclerosis, and rheumatoid arthritis. One of the critical proteinases involved in cell migration is membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14). MT1-MMP degrades extracellular matrix to make a path for cells to migrate, sheds cell surface molecules to give migratory signals, and activates ERK (extracellular signal-regulated protein kinase) enhancing cell migration. For MT1-MMP to promote cell migration, it needs to act in co-ordination with other cell migration machinery. Understanding such regulatory links may provide insights into the development of novel disease therapies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17050376&query_hl=1 ER - TY - JFULL T1 - The role of the cellular prion protein in the immune system. A1 - Isaacs, JD A1 - Jackson, GS A1 - Altmann, DM J1 - Clin Exp Immunol Y1 - 2006/10// VL - 146 SN - 0009-9104 SP - 1 EP - 8 N2 - Prion protein (PrP) plays a key role in the pathogenesis of prion diseases. However, the normal function of the protein remains unclear. The cellular isoform (PrP(C)) is expressed widely in the immune system, in haematopoietic stem cells and mature lymphoid and myeloid compartments in addition to cells of the central nervous system. It is up-regulated in T cell activation and may be expressed at higher levels by specialized classes of lymphocyte. Furthermore, antibody cross-linking of surface PrP modulates T cell activation and leads to rearrangements of lipid raft constituents and increased phosphorylation of signalling proteins. These findings appear to indicate an important but, as yet, ill-defined role in T cell function. Although PrP(-/-) mice have been reported to have only minor alterations in immune function, recent work has suggested that PrP is required for self-renewal of haematopoietic stem cells. Here, we consider the evidence for a distinctive role for PrP(C) in the immune system and what the effects of anti-prion therapeutics may be on immune function. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16968391&query_hl=1 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 - Parallel protein and transcript profiles of FSHD patient muscles correlate to the D4Z4 arrangement and reveal a common impairment of slow to fast fibre differentiation and a general deregulation of MyoD-dependent genes. A1 - Celegato, B A1 - Capitanio, D A1 - Pescatori, M A1 - Romualdi, C A1 - Pacchioni, B A1 - Cagnin, S A1 - Viganò, A A1 - Colantoni, L A1 - Begum, S A1 - Ricci, E A1 - Wait, R A1 - Lanfranchi, G A1 - Gelfi, C J1 - Proteomics Y1 - 2006/10// VL - 6 SN - 1615-9853 SP - 5303 EP - 5321 N2 - Here, we present the first study of a human neuromuscular disorder at transcriptional and proteomic level. Autosomal dominant facio-scapulo-humeral muscular dystrophy (FSHD) is caused by a deletion of an integral number of 3.3-kb KpnI repeats inside the telomeric region D4Z4 at the 4q35 locus. We combined a muscle-specific cDNA microarray platform with a proteomic investigation to analyse muscle biopsies of patients carrying a variable number of KpnI repeats. Unsupervised cluster analysis divides patients into three classes, according to their KpnI repeat number. Expression data reveal a transition from fast-glycolytic to slow-oxidative phenotype in FSHD muscle, which is accompanied by a deficit of proteins involved in response to oxidative stress. Besides, FSHD individuals show a disruption in the MyoD-dependent gene network suggesting a coregulation at transcriptional level during myogenesis. We also discuss the hypothesis that D4Z4 contraction may affect in trans the expression of a set of genes involved in myogenesis, as well as in the regeneration pathway of satellite cells in adult tissue. Muscular wasting could result from the inability of satellite cells to successfully differentiate into mature fibres and from the accumulation of structural damages caused by a reactive oxygen species (ROS) imbalance induced by an increased oxidative metabolism in fibres. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17013991&query_hl=1 ER - TY - JFULL T1 - IFN gamma and CXCR-1 gene polymorphisms in idiopathic bronchiectasis. A1 - Boyton, RJ A1 - Reynolds, C A1 - Wahid, FN A1 - Jones, MG A1 - Ozerovitch, L A1 - Ahmad, T A1 - Chaudhry, A A1 - Jewell, DP A1 - Kon, OM A1 - Smith, J A1 - Rose, M A1 - Newman-Taylor, AJ A1 - Cole, P A1 - Wilson, R A1 - Altmann, DM J1 - Tissue Antigens Y1 - 2006/10// VL - 68 SN - 0001-2815 SP - 325 EP - 330 N2 - Idiopathic bronchiectasis is a disease of chronic, bacterial lung infection, unresolving inflammation and progressive lung damage. Bronchiectasis can be associated with autoimmune diseases including ulcerative colitis. Defects of both innate and adaptive immunity have been proposed. The airway inflammation is characterized by interleukin-8 (IL-8) expression and infiltration by neutrophils and T cells. Here we investigated two candidate gene polymorphisms that may contribute to disease susceptibility: a CXCR-1 (+2607 G/C) gene polymorphism that is implicated in IL-8 binding and neutrophil trafficking as well as the interferon-gamma (IFNgamma) (+874 T/A) polymorphism which is linked to levels of IFNgamma production. These polymorphisms were distributed similarly in the idiopathic bronchiectasis group and controls, suggesting that these two candidate gene polymorphisms are not associated with disease susceptibility. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17026468&query_hl=1 ER - TY - JFULL T1 - How effective is adalimumab for inducing remission in patients with moderate-to-severe Crohn's disease? A1 - Ghosh, S J1 - Nat Clin Pract Gastroenterol Hepatol Y1 - 2006/10// VL - 3 SN - 1743-4386 SP - 540 EP - 541 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17008921&query_hl=1 ER - TY - JFULL T1 - A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. A1 - de Bakker, PI A1 - McVean, G A1 - Sabeti, PC A1 - Miretti, MM A1 - Green, T A1 - Marchini, J A1 - Ke, X A1 - Monsuur, AJ A1 - Whittaker, P A1 - Delgado, M A1 - Morrison, J A1 - Richardson, A A1 - Walsh, EC A1 - Gao, X A1 - Galver, L A1 - Hart, J A1 - Hafler, DA A1 - Pericak-Vance, M A1 - Todd, JA A1 - Daly, MJ A1 - Trowsdale, J A1 - Wijmenga, C A1 - Vyse, TJ A1 - Beck, S A1 - Murray, SS A1 - Carrington, M A1 - Gregory, S A1 - Deloukas, P A1 - Rioux, JD J1 - Nat Genet Y1 - 2006/10// VL - 38 SN - 1061-4036 SP - 1166 EP - 1172 N2 - The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16998491&query_hl=1 ER - TY - JFULL T1 - Specific donor FasR and FasL genotypes may be associated with increased acute cellular rejection in renal transplant recipients A1 - Gjorgjimajkoska, O A1 - Sergeant, R A1 - Brookes, P A1 - Davey, N A1 - Warrens, A J1 - HUM IMMUNOL Y1 - 2006/10// VL - 67 SN - 0198-8859 SP - S104 EP - S104 ER - TY - JFULL T1 - Review on the value of graduated elastic compression stockings after deep vein thrombosis. A1 - Kakkos, SK A1 - Daskalopoulou, SS A1 - Daskalopoulos, ME A1 - Nicolaides, AN A1 - Geroulakos, G J1 - Thromb Haemost Y1 - 2006/10// VL - 96 SN - 0340-6245 SP - 441 EP - 445 N2 - Graduated elastic compression stockings (GECS) are commonly used in the primary prevention of deep vein thrombosis (DVT); however, their role in preventing recurrent DVT and also post-thrombotic syndrome is less well established. The aim of this review was to investigate the effect of GECS after DVT. A literature search was performed by two independent searchers in order to identify randomised controlled trials on the effect of GECS in preventing recurrent DVT and post-thrombotic syndrome. Four randomised trials, including 537 patients, were identified. Two of the studies demonstrated that below-knee GECS significantly reduced post-thrombotic syndrome during follow-up, while a smaller study showed equivocal results. GECS reduced the incidence of post-thrombotic syndrome from 54% to 25.2% [relative risk (RR) 0.47, 95% confidence interval (CI) 0.36-0.61] with the number needed to treat (NNT) being 4 (95% CI 2.7-5.0). The rate of recurrent asymptomatic DVT was also significantly reduced by GECS (RR 0.20, 95% CI 0.06-0.64; NNT 5); the reduction in symptomatic DVT was not significant (RR 0.79, 95% CI 0.50-1.26; NNT 34). In conclusion, there is level Ia evidence to suggest that GECS can significantly reduce the incidence of post-thrombotic syndrome (PTS) after DVT, and therefore these should be routinely prescribed. The evidence for recurrent DVT is less conclusive. Further research is needed towards standardising PTS diagnostic criteria and evaluating more effective preventive measures after DVT. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17003920&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 - 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 - Effect of nutritional counselling on hepatic, muscle and adipose tissue fat content and distribution in non-alcoholic fatty liver disease. A1 - Thomas, EL A1 - Brynes, AE A1 - Hamilton, G A1 - Patel, N A1 - Spong, A A1 - Goldin, RD A1 - Frost, G A1 - Bell, JD A1 - Taylor-Robinson, SD J1 - World J Gastroenterol Y1 - 2006/09/28/ VL - 12 SN - 1007-9327 SP - 5813 EP - 5819 N2 - AIM: To assess the effectiveness of the current UK clinical practice in reducing hepatic fat (IHCL). METHODS: Whole body MRI and (1)H MRS were obtained, before and after 6 mo nutritional counselling, from liver, soleus and tibialis muscles in 10 subjects with non-alcoholic fatty liver disease (NAFLD). RESULTS: A 500 Kcal-restricted diet resulted in an average weight loss of 4% (-3.4 kg,) accompanied by significant reductions in most adipose tissue (AT) depots, including subcutaneous (-9.9%), abdominal subcutaneous (-10.2%) and intra-abdominal-AT (-11.4%). Intramyocellular lipids (IMCL) were significantly reduced in the tibialis muscle (-28.2%). Decreases in both IHCL (-39.9%) and soleus IMCL (-12.2%) content were also observed, although these were not significant. Several individuals showed dramatic decreases in IHCL, while others paradoxically showed increases in IHCL content. Changes in body composition were accompanied by improvements in certain liver function tests: serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Significant correlations were found between decreases in IHCL and reductions in both intra-abdominal and abdominal subcutaneous AT. Improvements in liver function tests were associated with reductions in intra-abdominal AT, but not with changes in IHCL. CONCLUSION: This study shows that even a very modest reduction in body weight achieved through lifestyle modification can result in changes in body fat depots and improvements in LFTs. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17007047&query_hl=1 ER - TY - JFULL T1 - Activation of NF-kappaB by the intracellular expression of NF-kappaB-inducing kinase acts as a powerful vaccine adjuvant. A1 - Andreakos, E A1 - Williams, RO A1 - Wales, J A1 - Foxwell, BM A1 - Feldmann, M J1 - Proc Natl Acad Sci U S A Y1 - 2006/09/26/ VL - 103 SN - 0027-8424 SP - 14459 EP - 14464 N2 - There is a pressing need for adjuvants that will enhance the effectiveness of genetic vaccines. This is particularly important in cancer and infectious disease such as HIV and malaria for which successful vaccines are desperately needed. Here, we describe an approach to enhance immunogenicity that involves the activation of NF-kappaB by the transgenic expression of an intracellular signaling molecule, NF-kappaB-inducing kinase (NIK). In vitro, NIK increases dendritic cell antigen presentation in allogeneic and antigen-specific T cell proliferation assays by potently activating NF-kappaB and consequently up-regulating the expression of cytokines (TNF-alpha, IL-6, IL-12, IL-15, and IL-18), chemokines [IL-8, RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-1, and monocyte chemoattractant protein-3], MHC antigen-presenting molecules (class I and II), and costimulatory molecules (CD80 and CD86). In vivo, NIK enhances immune responses against a vector-encoded antigen and shifts them toward a T helper 1 immune response with increased IgG2a levels, T cell proliferation, IFN-gamma production, and cytotoxic T lymphocyte responses more potently than complete Freund's adjuvant, a very efficacious T helper 1-inducing adjuvant. These findings define NIK, and possibly other inducers of NF-kappaB activation, as a potent adjuvant strategy that offers great potential for genetic vaccine development. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16971487&query_hl=1 ER - TY - JFULL T1 - Free innervated sole of foot transfer for contralateral lower limb salvage. A1 - Irwin, MS A1 - Jain, A A1 - Anand, P A1 - Nanchahal, J J1 - Plast Reconstr Surg Y1 - 2006/09/15/ VL - 118 SN - 1529-4242 SP - 93e EP - 97e L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16980840&query_hl=1 ER - TY - JFULL T1 - Complement activation contributes to both glomerular and tubulointerstitial damage in adriamycin nephropathy in mice. A1 - Turnberg, D A1 - Lewis, M A1 - Moss, J A1 - Xu, Y A1 - Botto, M A1 - Cook, HT J1 - J Immunol Y1 - 2006/09/15/ VL - 177 SN - 0022-1767 SP - 4094 EP - 4102 N2 - Adriamycin nephropathy is a model of focal segmental glomerulosclerosis, characterized by proteinuria and progressive glomerulosclerosis and tubulointerstitial damage. In this study, we examined the role of complement in the etiology of adriamycin nephropathy in mice. We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls. C3 deposition occurred in the glomeruli of wild-type mice as early as 48 h following a single i.v. injection of adriamycin. C3-deficient mice developed significantly less proteinuria and less podocyte injury at day 3 postadriamycin than controls, suggesting that complement is important in mediating the early podocyte injury. At later time points, C3-deficient mice were protected from glomerulosclerosis, tubulointerstitial injury, and renal dysfunction. Factor D-deficient mice were also protected from renal disease, confirming the importance of alternative pathway activation in this model. In contrast, C1q-deficient mice developed similar disease to controls, indicating that the complement cascade was not activated via the classical pathway. CD59-deficient mice, which lack adequate control of C5b-9 formation, developed significantly worse histological and functional markers of renal disease than controls. Interestingly, although more C9 deposited in glomeruli of CD59-deficient mice than controls, in neither group was tubulointerstitial C9 staining apparent. We have demonstrated for the first time that alternative pathway activation of complement plays an important role in mediating the initial glomerular damage in this in vivo model of focal segmental glomerulosclerosis. Lack of CD59, which regulates the membrane attack complex, led to greater glomerular and tubulointerstitial injury. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16951374&query_hl=1 ER - TY - JFULL T1 - TIMP-3 inhibits the procollagen N-proteinase ADAMTS-2 A1 - Wang, WM A1 - Ge, GX A1 - Lim, NH A1 - Nagase, H A1 - Greenspan, DS J1 - BIOCHEM J Y1 - 2006/09/15/ VL - 398 SN - 0264-6021 SP - 515 EP - 519 N2 - ADAMTS-2 is an extracellular metalloproteinase responsible for cleaving the N-propeptides of procollagens I-III; an activity necessary for the formation of collagenous ECM (extracellular matrix). The four TIMPs (tissue inhibitors of metalloprotemases) regulate the activities of matrix metalloproteinases, which are involved in degrading ECM components. Here we delineate the abilities of the TIMPs to affect biosynthetic processing of procollagens. TIMP-1, -2 and -4 show no inhibitory activity towards ADAMTS-2, in addition none of the TIMPs showed inhibitory activity towards bone morphogenetic protein 1, which is responsible for cleaving procollagen C-propeptides. In contrast, TIMP-3 is demonstrated to inhibit ADAMTS-2 in vitro with apparent K-i values of 160 and 602 nM, in the presence of heparin or without respectively; and TIMP-3 is shown to inhibit procollagen processing by cells. ER - TY - JFULL T1 - Crystal structure of an active form of human MMP-1 A1 - Iyer, S A1 - Visse, R A1 - Nagase, H A1 - Acharya, KR J1 - J MOL BIOL Y1 - 2006/09/08/ VL - 362 SN - 0022-2836 SP - 78 EP - 88 N2 - The extracellular matrix is a dynamic environment that constantly undergoes remodelling and degradation during vital physiological processes such as angiogenesis, wound healing, and development. Unbalanced extracellular matrix breakdown is associated with many diseases such as arthritis, cancer and fibrosis. Interstitial collagen is degraded by matrix metalloproteinases with collagenolytic activity by MMP-1, MMP-8 and MMP-13, collectively known as the collagenases. Matrix metalloproteinase 1 (MMP-1) plays a pivotal role in degradation of interstitial collagen types I, II, and III. Here, we report the crystal structure of the active form of human MMP-1 at 2.67 angstrom resolution. This is the first MMP-1 structure that is free of inhibitor and a water molecule essential for peptide hydrolysis is observed coordinated with the active site zinc. Comparing this structure with the human proMMP-1 shows significant structural differences, mainly in the relative orientation of the hemopexin domain, between the pro form and active form of the human enzyme. (c) 2006 Elsevier Ltd. All rights reserved. ER - TY - JFULL T1 - TLR4-NOX4-AP-1 signaling mediates lipopolysaccharide-induced CXCR6 expression in human aortic smooth muscle cells. A1 - Patel, DN A1 - Bailey, SR A1 - Gresham, JK A1 - Schuchman, DB A1 - Shelhamer, JH A1 - Goldstein, BJ A1 - Foxwell, BM A1 - Stemerman, MB A1 - Maranchie, JK A1 - Valente, AJ A1 - Mummidi, S A1 - Chandrasekar, B J1 - Biochem Biophys Res Commun Y1 - 2006/09/08/ VL - 347 SN - 0006-291X SP - 1113 EP - 1120 N2 - CXCL16 is a transmembrane non-ELR CXC chemokine that signals via CXCR6 to induce aortic smooth muscle cell (ASMC) proliferation. While bacterial lipopolysaccharide (LPS) has been shown to stimulate CXCL16 expression in SMC, its effects on CXCR6 are not known. Here, we demonstrate that LPS upregulates CXCR6 mRNA, protein, and surface expression in human ASMC. Inhibition of TLR4 with neutralizing antibodies or specific siRNA interference blocked LPS-mediated CXCR6 expression. LPS stimulated both AP-1 (c-Fos, c-Jun) and NF-kappaB (p50 and p65) activation, but only inhibition of AP-1 attenuated LPS-induced CXCR6 expression. Using dominant negative expression vectors and siRNA interference, we demonstrate that LPS induces AP-1 activation via MyD88, TRAF6, ERK1/2, and JNK signaling pathways. Furthermore, the flavoprotein inhibitor diphenyleniodonium chloride significantly attenuated LPS-mediated AP-1-dependent CXCR6 expression, as did inhibition of NOX4 NADPH oxidase by siRNA. Finally, CXCR6 knockdown inhibited CXCL16-induced ASMC proliferation. These results demonstrate that LPS-TLR4-NOX4-AP-1 signaling can induce CXCR6 expression in ASMC, and suggest that the CXCL16-CXCR6 axis may be an important proinflammatory pathway in the pathogenesis of atherosclerosis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16870145&query_hl=1 ER - TY - JFULL T1 - Unique association signals in SLE at the CD28-CTLA4-ICOS locus. A1 - Cunninghame, DS A1 - Wong, GAK A1 - Vyse, TJ J1 - ARTHRITIS RHEUM Y1 - 2006/09// VL - 54 SN - 0004-3591 SP - S289 EP - S289 ER - TY - JFULL T1 - Immunohistochemical expression of hypoxic inducible factor (HIF) and vascular endothelial growth factor (VEGF) in colorectal cancer patients on statin therapy A1 - De Four, K A1 - Paleolog, E A1 - Sandison, A A1 - Dawson, P A1 - Cohen, P J1 - MODERN PATHOL Y1 - 2006/09// VL - 19 SN - 0893-3952 SP - 57 EP - 57 ER - TY - JFULL T1 - Optimal processing of bone marrow trephine biopsy: the Hammersmith Protocol. A1 - Naresh, KN A1 - Lampert, I A1 - Hasserjian, R A1 - Lykidis, D A1 - Elderfield, K A1 - Horncastle, D A1 - Smith, N A1 - Murray-Brown, W A1 - Stamp, GW J1 - J Clin Pathol Y1 - 2006/09// VL - 59 SN - 0021-9746 SP - 903 EP - 911 N2 - Specimens of bone marrow trephine biopsy (BMT) are transported and fixed in acetic acid-zinc-formalin fixative, decalcified in 10% formic acid-5% formaldehyde and processed with other specimens to paraffin-wax embedding. Sections, 1-microm-thick, are cut by experienced histotechnologists and used for haematoxylin and eosin, Giemsa, reticulin silver and other histological stains. Further, all immunohistochemical procedures used in the laboratory, including double immunostaining, can be used on these sections with no or minimal modifications. About 10,000 BMT specimens have been analysed using this procedure since 1997 and diseases involving the bone marrow have been classified successfully. More recently, standardised polymerase chain reaction-based analysis and mRNA in situ hybridisation studies have been conducted. Excellent morphology with good antigen, DNA and RNA preservation is offered by the Hammersmith Protocol. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16935969&query_hl=1 ER - TY - JFULL T1 - Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. A1 - Maini, RN A1 - Taylor, PC A1 - Szechinski, J A1 - Pavelka, K A1 - Bröll, J A1 - Balint, G A1 - Emery, P A1 - Raemen, F A1 - Petersen, J A1 - Smolen, J A1 - Thomson, D A1 - Kishimoto, T A1 - CHARISMA Study Group J1 - Arthritis Rheum Y1 - 2006/09// VL - 54 SN - 0004-3591 SP - 2817 EP - 2829 N2 - OBJECTIVE: To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti-interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA). METHODS: The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo. RESULTS: A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX. CONCLUSION: These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16947782&query_hl=1 ER - TY - JFULL T1 - Infliximab inhibits radiographic progression regardless of disease activity at baseline and following treatment in patients with early active rheumatoid arthritis. A1 - Smolen, JS A1 - Han, C A1 - van der Heijde, D A1 - Emery, P A1 - Bathon, JM A1 - Keystone, E A1 - Maini, RN A1 - Kalden, JR A1 - Aletaha, D A1 - Baker, D A1 - Han, J A1 - Bala, M A1 - Clair, EW J1 - ARTHRITIS RHEUM Y1 - 2006/09// VL - 54 SN - 0004-3591 SP - S231 EP - S231 ER - TY - JFULL T1 - Structural features of the reprolysin atrolysin C and tissue inhibitors of metalloproteinases (TIMPs) interaction A1 - Pinto, AFM A1 - Terra, RMS A1 - Guimaraes, JA A1 - Kashiwagi, M A1 - Nagase, H A1 - Serrano, SMT A1 - Fox, JW J1 - BIOCHEM BIOPH RES CO Y1 - 2006/09/01/ VL - 347 SN - 0006-291X SP - 641 EP - 648 N2 - Atrolysin C is a P-I snake venom metalloproteinase (SVMP) from Crotalus atrox venom, which efficiently degrades capillary basement membranes, extracellular matrix, and cell surface proteins to produce hemorrhage. The tissue inhibitors of metalloproteinases (TIMPs) are effective inhibitors of matrix metalloproteinases which share some structural similarity with the SVMPs. In this work, we evaluated the inhibitory profile of TIMP-1, TIMP-2, and the N-terminal domain of TIMP-3 (N-TIMP-3) on the proteolytic activity of atrolysin C and analyzed the structural requirements and molecular basis of inhibitor-enzyme interaction using molecular modeling. While TIMP-1 and TIMP-2 had no inhibitory activity upon atrolysin C, the N-terminal domain of TIMP-3 (N-TIMP-3) was a potent inhibitor with a K-i value of approximately 150 nM. The predicted docking structures of atrolysin C and TIMPs were submitted to molecular dynamics simulations and the complex atrolysin C/N-TIMP-3 was the only one that maintained the inhibitory conformation. This study is the first to shed light on the structural determinants required for the interaction between a SVMP and a TIMP, and suggests a structural basis for TIMP-3 inhibitory action and related proteins such as the ADAMs. (c) 2006 Elsevier Inc. All rights reserved. ER - TY - JFULL T1 - Modulation of Cell-Fibronectin Matrix Interactions during Tissue Repair. A1 - Midwood, KS A1 - Mao, Y A1 - Hsia, HC A1 - Valenick, LV A1 - Schwarzbauer, JE J1 - J Invest Dermatol Y1 - 2006/09// VL - 126 Suppl SN - 0022-202X SP - 73 EP - 78 N2 - Environmental signals from the extracellular matrix (ECM) are transmitted by cell surface receptors that connect to the actin cytoskeleton and to multiple intracellular signaling pathways. To dissect how the ECM regulates cell functions, we are using a three-dimensional (3D) fibrin-fibronectin matrix, resembling the wound provisional matrix. Fibroblasts adhere to fibronectin in this matrix via concomitant engagement of alpha5beta1 integrin receptors and syndecan-4, a transmembrane proteoglycan. An adhesive phenotype is developed with actin stress fibers and activation of focal adhesion kinase (FAK) and Rho GTPase. Lack of syndecan-4 engagement, as occurs in the presence of the ECM protein tenascin-C, promotes a motile phenotype; FAK and Rho signaling are downregulated and filopodia are extended. Fibronectin matrices have distinct effects on two other receptors: alpha4beta1 and alphavbeta3 integrins. Although alpha4beta1 does not naturally support strong cell interactions with a fibrin-fibronectin matrix, binding is dramatically enhanced by proteolytic cleavage of fibronectin. Conversely, activity of alphavbeta3 is stimulated by multimeric fibronectin fibrils showing that the organization of fibronectin differentially affects integrin functions. Thus, deposition of additional ECM components, expression of co-receptors for ECM, cleavage of adhesive proteins, and the architecture of the ECM microenvironment are different mechanisms for modulating cell responses to fibronectin matrix.Journal of Investigative Dermatology Symposium Proceedings (2006) 11, 73-78. doi:10.1038/sj.jidsymp.5650005. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16983359&query_hl=1 ER - TY - JFULL T1 - The VHL tumor suppressor gene and oxygen sensing A1 - Maxwell, PH J1 - J MED GENET Y1 - 2006/09// VL - 43 SN - 0022-2593 SP - S21 EP - S21 ER - TY - JFULL T1 - Mice, humans and haplotypes--the hunt for disease genes in SLE. A1 - Rigby, RJ A1 - Fernando, MM A1 - Vyse, TJ J1 - Rheumatology (Oxford) Y1 - 2006/09// VL - 45 SN - 1462-0324 SP - 1062 EP - 1067 N2 - Defining the polymorphisms that contribute to the development of complex genetic disease traits is a challenging, although increasingly tractable problem. Historically, the technical difficulties in conducting association studies across the entire human genome are such that murine models have been used to generate candidate genes for analysis in human complex diseases, such as SLE. In this article we discuss the advantages and disadvantages of this approach and specifically address some assumptions made in the transition from studying one species to another, using lupus as an example. These issues include differences in genetic structure and genetic organisation which are a reflection on the population history. Clearly there are major differences in the histories of the human population and inbred laboratory strains of mice. Both human and murine genomes do exhibit structure at the genetic level. That is to say, they comprise haplotypes which are genomic regions that carry runs of polymorphisms that are not independently inherited. Haplotypes therefore reduce the number of combinations of the polymorphisms in the DNA in that region and facilitate the identification of disease susceptibility genes in both mice and humans. There are now novel means of generating candidate genes in SLE using mutagenesis (with ENU) in mice and identifying mice that generate antinuclear autoimmunity. In addition, murine models still provide a valuable means of exploring the functional consequences of genetic variation. However, advances in technology are such that human geneticists can now screen large fractions of the human genome for disease associations using microchip technologies that provide information on upwards of 100,000 different polymorphisms. These approaches are aimed at identifying haplotypes that carry disease susceptibility mutations and rely less on the generation of candidate genes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16769771&query_hl=1 ER - TY - JFULL T1 - Effect of L-carnitine administration on erythrocyte survival in haemodialysis patients. A1 - Arduini, A A1 - Bonomini, M A1 - Clutterbuck, EJ A1 - Laffan, MA A1 - Pusey, CD J1 - Nephrol Dial Transplant Y1 - 2006/09// VL - 21 SN - 0931-0509 SP - 2671 EP - 2672 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16611680&query_hl=1 ER - TY - JFULL T1 - Effects of mouse and human lipocalin homologues 24p3/lcn2 and neutrophil gelatinase-associated lipocalin on gastrointestinal mucosal integrity and repair A1 - Playford, RJ A1 - Belo, A A1 - Poulsom, R A1 - Fitzgerald, AJ A1 - Harris, K A1 - Pawluczyk, I A1 - Ryon, J A1 - Darby, T A1 - Nilsen-Hamilton, M A1 - Ghosh, S A1 - Marchbank, T J1 - GASTROENTEROLOGY Y1 - 2006/09// VL - 131 SN - 0016-5085 SP - 809 EP - 817 N2 - Background & Aims: The lipocalin superfamily, including the mouse and human homologues 24p3/lcn2 and neutrophil gelatinase-associated lipocalin, show great functional diversity including roles in olfaction, transportation, and prostaglandin synthesis in mammals. Their potential role in maintaining gastrointestinal mucosal integrity and repair is, however, unclear. Methods: Changes in 24p3/lcn2 expression in the mouse gut in response to various noxious agents were examined using Northern blot, in situ hybridization, and immunohistochemistry. Effects of recombinant 24p3/lcn2 on proliferation ([H-3]-thymidine uptake), and restitution (cell-wounding migration) were assessed using human colonic HT29 and HCT116 cells. In addition, the effects of recombinant 24p3/lcn2 on the amount of gastric damage were assessed in rats treated with indomethacin (20 mg/kg) and restraint. Results: Marked up-regulation of expression of 24p3/lcn2 was seen throughout the gut in response to indomethacin or dextran sodium sulfate treatment. Expression was increased particularly in the surface epithelial cells and infiltrating inflammatory cells. Proliferation and restitution assays in the presence of recombinant wild-type sequence neutrophil gelatinase-associated lipocalin, wild-type cys(98)-24p3/lcn2, and mutant ala(98)-24p3/lcn2 showed that all 3 peptides caused a 3- to 4-fold increase in promigratory activity (P < .01 vs control) but did not influence proliferation. The administration of wild-type cys(98)-, or mutant ala(98)-24p3/lcn2 (25 and 50 mu g/kg/h, respectively), given via the subcutaneous route, both caused similar reductions in the rat gastric damage model (60% reduction at highest dose, P < .01 vs control), although oral administration was ineffective. Conclusions: 24p3/lcn2 facilitates mucosal regeneration by promoting cell migration. ER - TY - JFULL T1 - Epididymal cystadenomas and epithelial tumourlets: effects of VHL deficiency on the human epididymis. A1 - Gläsker, S A1 - Tran, MG A1 - Shively, SB A1 - Ikejiri, B A1 - Lonser, RR A1 - Maxwell, PH A1 - Zhuang, Z A1 - Oldfield, EH A1 - Vortmeyer, AO J1 - J Pathol Y1 - 2006/09// VL - 210 SN - 0022-3417 SP - 32 EP - 41 N2 - Although epididymal cystadenomas (ECAs) are among the most frequent VHL disease-associated tumours, fundamental questions about their pathogenesis have remained unanswered. Classification of ECAs is controversial, and the cell of origin is unknown. It is also unknown whether ECAs-like other VHL disease-associated tumours-arise as a result of VHL gene inactivation, and whether ECAs exhibit subsequent activation of hypoxia-inducible factor HIF. Moreover, the morphological spectrum of earliest ECA formation is unknown. In a detailed molecular pathological analysis of a series of epididymides collected from VHL patients at autopsy, we found that ECAs are true neoplasms that arise secondary to inactivation of the wild-type copy of the VHL gene, followed by early and simultaneous activation of HIF1 and HIF2 associated with up-regulation of downstream targets, including CAIX and GLUT-1. The observations also indicate that ECA formation evolves from a variety of microscopic epithelial tumourlets, and that these tumourlets are confined to the efferent ductular system. Although genetic and immunohistochemical analysis of precursor structures consistently revealed VHL gene inactivation and activation of HIF in the precursor lesions, only a small subset appears to progress into frank cystadenoma. Thus, ECA tumorigenesis in VHL disease shares fundamental principles with tumorigenesis in other affected organ systems. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16841375&query_hl=1 ER - TY - JFULL T1 - The synovial fluid: a site for citrullinated autoantigen generation in RA. A1 - Kinloch, A A1 - Lundberg, K A1 - Begum, S A1 - Peirce, MJ A1 - Wait, R A1 - Venables, PJ J1 - ARTHRITIS RHEUM Y1 - 2006/09// VL - 54 SN - 0004-3591 SP - S566 EP - S567 ER - TY - JFULL T1 - Harmful waste products as novel immune modulators for treating inflammatory arthritis? A1 - Cope, AP J1 - PLoS Med Y1 - 2006/09// VL - 3 SN - 1549-1676 SP - e385 EP - e385 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16968131&query_hl=1 ER - TY - JFULL T1 - Development of a novel 2D proteomics approach for the identification of proteins secreted by primary chondrocytes after stimulation by IL-1 and oncostatin M. A1 - Catterall, JB A1 - Rowan, AD A1 - Sarsfield, S A1 - Saklatvala, J A1 - Wait, R A1 - Cawston, TE J1 - Rheumatology (Oxford) Y1 - 2006/09// VL - 45 SN - 1462-0324 SP - 1101 EP - 1109 N2 - OBJECTIVES: To develop a proteomics approach to study changes in the secreted protein levels of primary human chondrocytes after stimulation by the pro-inflammatory cytokines interleukin-1 and oncostatin M. METHODS: Using both the primary human articular and bovine nasal chondrocyte-conditioned mediums, methods were investigated to enable the separation of proteins by two-dimensional (2D) gel electrophoresis. Differentially regulated proteins were identified using tandem electrospray mass spectrometery. RESULTS: We discovered that proteoglycans and glycosylaminoglycans (GAGs) secreted by chondrocytes significantly interfered with 2D gel focusing. Several different methods for GAG removal were attempted including enzymic digestion, cetyl pyridinium chloride precipitation and anion exchange in high salt. The anion exchange proved to be the most effective. Even from these initial gels, we were able to identify eight proteins produced by human chondrocytes: matrix metalloproteinase (MMP)-1, MMP-3, YKL40, cyclophilin A, beta2-microglobulin, transthyretin, S100A11, peroxidine 1 and cofilin. MMP-1, MMP-3, YKL40 and cyclophilin A were all identified as processed, smaller peptide fragments. CONCLUSIONS: We were able to develop a novel sample preparation protocol to allow the reproducible sample preparation of secreted proteins from human chondrocytes. From the initial data, we were able to show that at least some of the proteins produced were cleaved to smaller fragments as a result of proteolysis. Therefore, this technique provides valuable information about protein processing which gene-based arrays do not. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16567360&query_hl=1 ER - TY - JFULL T1 - Febrile temperatures enhance antigen processing of type II collagen for presentation to CD4 T cells. A1 - von Delwig, A A1 - Wilson, A A1 - Altmann, DM A1 - Holmdahl, R A1 - Harding, CV A1 - McKie, N A1 - Isaacs, JD A1 - Lakey, JH A1 - Robinson, JH J1 - ARTHRITIS RHEUM Y1 - 2006/09// VL - 54 SN - 0004-3591 SP - S37 EP - S37 ER - TY - JFULL T1 - Bone marrow contributes to podocyte regeneration and amelioration of renal disease in Alport's syndrome A1 - Prodromidi, EI A1 - Poulsom, R A1 - Jeffery, R A1 - Roufosse, CA A1 - Hunt, T A1 - Pusey, CD A1 - Cook, HT J1 - J PATHOL Y1 - 2006/09// VL - 210 SN - 0022-3417 SP - 60 EP - 60 ER - TY - JFULL T1 - Effective immune depletion following novel lymphoablative regimen for autologous hematopoietic stem cell transplantation (AutoHSCT) in systemic lupus erythematosus (SLE). A1 - Nikolov, NP A1 - Illei, GG A1 - Yarboro, C A1 - Hakim, F A1 - Leitman, S A1 - Read, E A1 - Khuu, H A1 - Gramrner, A A1 - Fischer, R A1 - Balow, J A1 - Austin, H A1 - Gea-Banacloche, J A1 - Muraro, P A1 - Babb, R A1 - Krumlauf, M A1 - Sportes, C A1 - Lipsky, P A1 - Gress, R A1 - Pavletic, S J1 - ARTHRITIS RHEUM Y1 - 2006/09// VL - 54 SN - 0004-3591 SP - S790 EP - S790 ER - TY - JFULL T1 - Febrile temperatures enhance antigen processing of type II collagen for presentation to CD4 T cells. A1 - von Delwig, A A1 - Wilson, AJ A1 - Altmann, DM A1 - Holmdahl, R A1 - Harding, CV A1 - Mckie, N A1 - Isaacs, JD A1 - Lakey, JH A1 - Robinson, JH J1 - ARTHRITIS RHEUM Y1 - 2006/09// VL - 54 SN - 0004-3591 SP - S639 EP - S639 ER - TY - JFULL T1 - Review article: mode of action and delivery of 5-aminosalicylic acid - new evidence A1 - Desreumaux, P A1 - Ghosh, S J1 - ALIMENT PHARM THERAP Y1 - 2006/09// VL - 24 SN - 0269-2813 SP - 2 EP - 9 N2 - The effectiveness of sulfasalazine depends on the splitting of the diazo bond in the molecule by the action of bacteria in the large bowel, releasing the pharmacologically active moiety, 5-aminosalicylic acid. The development of pH-dependent, delayed-release formulations of 5-aminosalicylic acid abolished the toxicity associated with the sulfapyridine part of sulfasalazine.5-aminosalicylic acid is now believed to act by activating a class of nuclear receptors involved in the control of inflammation, cell proliferation, apoptosis and metabolic function, the gamma form of peroxisome proliferator-activated receptors. These receptors are expressed at particularly high levels in colon epithelial cells, where their expression appears to be at least in part stimulated by gut bacteria. Other drugs known to act via peroxisome proliferator-activated receptor-gamma, such as rosiglitazone and the selective peroxisome proliferator-activated receptor-gamma ligand GW1929, can be displaced from their binding sites on the peroxisome proliferator-activated receptor-gamma molecule by 5-aminosalicylic acid at concentrations of 5-aminosalicylic acid that correspond with the concentrations found in the lumen of ulcerative colitis patients taking oral mesalazine.Genetically engineered heterozygous knockout mice (peroxisome proliferator-activated receptor-gamma +/-) are particularly susceptible to colonic inflammation, and inflammation is more severe in these mice, in response to chemicals that induce experimental colonic ulcers. In these experimental models, 5-aminosalicylic acid is ineffective in peroxisome proliferator-activated receptor-gamma +/- mice. This new insight provides a mechanistic foundation for the possibility that long-term treatment with 5-aminosalicylic acid can reduce the risk of colorectal cancer in patients with ulcerative colitis. ER - TY - JFULL T1 - NK-cell-dependent acute xenograft rejection in the mouse heart-to-rat model. A1 - Chen, D A1 - Weber, M A1 - Lechler, R A1 - Dorling, A J1 - Xenotransplantation Y1 - 2006/09// VL - 13 SN - 0908-665X SP - 408 EP - 414 N2 - BACKGROUND: Acute humoral xenograft rejection is characterized by widespread intravascular thrombosis with a significant NK-cell and macrophage infiltrate. Although in vitro and ex vivo data have shown that NK cells are capable of killing xenogeneic tissue, the precise role they play in vivo is still not certain. Consequently, there are few tested strategies for dealing with NK-cell-mediated rejection, should this prove to be a problem. One reason for this has been the lack of a relevant rodent model in which rejection by these cells can be easily studied. METHODS: Prior to transplantation of mouse hearts, we depleted rat recipients of fibrinogen using a snake venom, ANCROD, from the Malayan pit viper. Graft survival was examined by manual palpation and the rejected hearts were examined by histology. Levels of circulating interferon gamma (IFN-gamma), used as a surrogate marker for NK-cell activation, were determined by an enzyme-linked immunosorbent assay. RESULTS: Depletion of fibrinogen to approximately 5% of normal allowed surgery without a significant increase in the technical failure rates and prolonged graft survival compared with that seen in unmanipulated rats. Rejected hearts showed no evidence of intravascular thrombosis but did show significant antibody and complement deposition. There was little T-cell infiltration and cyclosporin had no influence on survival. Instead, hearts were infiltrated with NK cells and macrophages and rejection was associated with significant IFN-gamma production. Depletion of NK cells with anti-asialo-GM-1 from ANCROD-treated recipients led to a further significant prolongation of graft survival. CONCLUSIONS: Inhibition of intravascular thrombosis by fibrinogen depletion, in the absence of any other manipulation, unmasks NK-cell-dependent acute xenograft rejection in the mouse-to-rat heart transplantation model. This relatively simple model is expected to be useful to investigate the mechanisms of NK-cell-mediated rejection and to provide insight into the types of graft manipulation that could modify this process. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16925664&query_hl=1 ER - TY - JFULL T1 - TCR-alpha CDR3 loop audition regulates positive selection. A1 - Ferreira, C A1 - Furmanski, A A1 - Millrain, M A1 - Bartok, I A1 - Guillaume, P A1 - Lees, R A1 - Simpson, E A1 - MacDonald, HR A1 - Dyson, J J1 - J Immunol Y1 - 2006/08/15/ VL - 177 SN - 0022-1767 SP - 2477 EP - 2485 N2 - How positive selection molds the T cell repertoire has been difficult to examine. In this study, we use TCR-beta-transgenic mice in which MHC shapes TCR-alpha use. Differential AV segment use is directly related to the constraints placed on the composition of the CDR3 loops. Where these constraints are low, efficient selection of alphabeta pairs follows. This mode of selection preferentially uses favored AV-AJ rearrangements and promotes diversity. Increased constraint on the alpha CDR3 loops leads to inefficient selection associated with uncommon recombination events and limited diversity. Further, the two modes of selection favor alternate sets of AJ segments. We discuss the relevance of these findings to the imprint of self-MHC restriction and peripheral T cell activation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16888009&query_hl=1 ER - TY - JFULL T1 - Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. A1 - Abraham, SM A1 - Lawrence, T A1 - Kleiman, A A1 - Warden, P A1 - Medghalchi, M A1 - Tuckermann, J A1 - Saklatvala, J A1 - Clark, AR J1 - J Exp Med Y1 - 2006/08/07/ VL - 203 SN - 0022-1007 SP - 1883 EP - 1889 N2 - Glucocorticoids (GCs), which are used in the treatment of immune-mediated inflammatory diseases, inhibit the expression of many inflammatory mediators. They can also induce the expression of dual specificity phosphatase 1 (DUSP1; otherwise known as mitogen-activated protein kinase [MAPK] phosphatase 1), which dephosphorylates and inactivates MAPKs. We investigated the role of DUSP1 in the antiinflammatory action of the GC dexamethasone (Dex). Dex-mediated inhibition of c-Jun N-terminal kinase and p38 MAPK was abrogated in DUSP1-/- mouse macrophages. Dex-mediated suppression of several proinflammatory genes (including tumor necrosis factor, cyclooxygenase 2, and interleukin 1alpha and 1beta) was impaired in DUSP1-/- mouse macrophages, whereas other proinflammatory genes were inhibited by Dex in a DUSP1-independent manner. In vivo antiinflammatory effects of Dex on zymosan-induced inflammation were impaired in DUSP1-/- mice. Therefore, the expression of DUSP1 is required for the inhibition of proinflammatory signaling pathways by Dex in mouse macrophages. Furthermore, DUSP1 contributes to the antiinflammatory effects of Dex in vitro and in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16880258&query_hl=1 ER - TY - JFULL T1 - Oxidant-induced activation of type I protein kinase A is mediated by RI subunit interprotein disulfide bond formation. A1 - Brennan, JP A1 - Bardswell, SC A1 - Burgoyne, JR A1 - Fuller, W A1 - Schröder, E A1 - Wait, R A1 - Begum, S A1 - Kentish, JC A1 - Eaton, P J1 - J Biol Chem Y1 - 2006/08/04/ VL - 281 SN - 0021-9258 SP - 21827 EP - 21836 N2 - Here we demonstrate that type I protein kinase A is redoxactive, forming an interprotein disulfide bond between its two regulatory RI subunits in response to cellular hydrogen peroxide. This oxidative disulfide formation causes a subcellular translocation and activation of the kinase, resulting in phosphorylation of established substrate proteins. The translocation is mediated at least in part by the oxidized form of the kinase having an enhanced affinity for alpha-myosin heavy chain, which serves as a protein kinase A (PKA) anchor protein and localizes the PKA to its myofilament substrates troponin I and myosin binding protein C. The functional consequence of these events in cardiac myocytes is that hydrogen peroxide increases contractility independently of beta-adrenergic stimulation and elevations of cAMP. The oxidant-induced phosphorylation of substrate proteins and increased contractility is blocked by the kinase inhibitor H89, indicating that these events involve PKA activation. In essence, type I PKA contains protein thiols that operate as redox sensors, and their oxidation by hydrogen peroxide directly activates the kinase. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16754666&query_hl=1 ER - TY - JFULL T1 - The alternative pathway of complement activation is critical for the induction of experimental epidermolysis bullosa acquisita A1 - Mihai, S A1 - Chiriac, MT A1 - Takahashi, K A1 - Thurman, JM A1 - Holers, VM A1 - Botto, M A1 - Zillikens, D A1 - Sitaru, C J1 - J INVEST DERMATOL Y1 - 2006/08// VL - 126 SN - 0022-202X SP - 21 EP - 21 ER - TY - JFULL T1 - Expansion of zeta-dim CD4+ T-cells and zeta-dim natural-killer (NK)-cells correlates with C-reactive protein (CRP) in patients with acute coronary syndromes (ACS) A1 - Ammirati, E A1 - Banfi, M A1 - Cianflone, D A1 - Cope, AP A1 - Godino, C A1 - Mussardo, M A1 - Maseri, A A1 - Monaco, C J1 - EUR HEART J Y1 - 2006/08// VL - 27 SN - 0195-668X SP - 971 EP - 971 ER - TY - JFULL T1 - Genetic and structural analyses suggest that a novel SPG3A mutation causes severe phenotypes of hereditary spastic paraplegia A1 - Chen, SQ A1 - Zhou, Y A1 - Li, XH A1 - Labu A1 - Huang, S A1 - Huang, WJ A1 - Zhou, CL A1 - Maxwell, PH A1 - Wang, YM J1 - CHINESE SCI BULL Y1 - 2006/08// VL - 51 SN - 1001-6538 SP - 2038 EP - 2040 N2 - Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structural predictions could not detect gross changes in the mutant protein. However, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G > A (p.G410R), in a Tibetan kindred. The mutation occurred at the highly conserved nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan mutation occurred at the linking part between the guanylate-binding protein domain (GB, the ball region) and the transmembrane helices (TM, the rod region) at the start point of an a-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembrane region of the molecule. Our results indicate that severe phenotypes can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domain and the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides potential evidence for a possible correlation between the severity of the phenotypes of HSP with the extension of the changes in the protein structures of atlastin. ER - TY - JFULL T1 - Aberrations of early trophoblast differentiation predispose to pregnancy failure: lessons from the anti-phospholipid syndrome. A1 - Bose, P A1 - Kadyrov, M A1 - Goldin, R A1 - Hahn, S A1 - Backos, M A1 - Regan, L A1 - Huppertz, B J1 - Placenta Y1 - 2006/08// VL - 27 SN - 0143-4004 SP - 869 EP - 875 N2 - OBJECTIVES: The epithelium of the human placenta comprises an inner cytotrophoblast (CT) which proliferates and fuses with the outer differentiated syncytiotrophoblast (ST). Turnover has been studied focussing on second and third trimester placentas but with a paucity of data describing the normal first trimester trophoblast. The aim of this study was to compare the nuclear CT:ST ratio in normal and pathological pregnancy and thus establish the relationship between cytotrophoblast and syncytiotrophoblast nuclear number during early gestation. METHODS: Archival first trimester material from placentas from healthy pregnancy and recurrent miscarriage (anti-phospholipid syndrome) was stained with H&E, cytokeratin-7 and Mib-1. The area of trophoblast as a fraction of total villous area was calculated and the number of sectioned cytotrophoblast and syncytiotrophoblast nuclei as well as the number of proliferating cytotrophoblast was evaluated. RESULTS: Normal features of trophoblast development during the first trimester (rise in trophoblast area, increase in number of syncytiotrophoblast nuclei, increase in number of proliferating cytotrophoblast, decrease in the nuclear CT:ST ratio) are absent/reversed in tissues from recurrent miscarriage (decreasing trophoblast area, constant number of syncytiotrophoblast nuclei, decreasing number of proliferating trophoblast, constant nuclear CT:ST ratio). CONCLUSIONS: Proliferation of cytotrophoblast in early gestation provides a pool of trophoblast stem cells critical for ongoing placental development. Premature cytotrophoblast differentiation in favour of syncytial fusion results in deficiencies of cytotrophoblast and rarification of villous trophoblast. Abnormal trophoblast differentiation in early gestation may be due to a premature onset of maternal perfusion of the placenta and may be a likely antecedent for conditions associated with failure of placentation such as recurrent miscarriage. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16289730&query_hl=1 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 - Transcriptional regulation of the human alpha 2(I) collagen gene (COL1A2), an informative model system to study fibrotic diseases A1 - Ramirez, F A1 - Tanaka, S A1 - Bou-Gharios, G J1 - MATRIX BIOL Y1 - 2006/08// VL - 25 SN - 0945-053X SP - 365 EP - 372 N2 - During the past two decades, the human pro-alpha 2(1) collagen gene (COL1A2) has emerged as an informative model in which to study the general principles that govern the transcriptional control of extracellular matrix deposition in normal and fibrotic conditions. Multiple studies have in fact delineated the genomic regions, cis-acting elements and trans-acting factors implicated in constitutive, cytokine-modulated and tissue-specific expression of COL1A2. These functional components are integrated into a regulatory network that consists of the proximal promoter, far-upstream enhancer and downstream repressor, and which operates according to two mechanisms. The first mechanism is one in which combinatorial interactions among promoter-bound proteins determine transcriptional outcome in different cellular and experimental contexts. The other mechanism is one whereby cooperative assembly of protein complexes at distantly located DNA elements directs spatiotemporal specificity. These transcriptional studies have also an additional value in translational research, in that they are providing the conceptual means to develop new animal models of and therapeutic strategies for fibrotic diseases. (c) 2006 Elsevier B.V./Intemational Society of Matrix Biology. All rights reserved. ER - TY - JFULL T1 - TF ligation by factor VIIa induces pro-inflammatory cytokine production in atheroma smooth muscle cells A1 - Persson, L A1 - Navin, T A1 - Gregan, S A1 - Davies, AH A1 - Feldmann, M A1 - Monaco, C J1 - EUR HEART J Y1 - 2006/08// VL - 27 SN - 0195-668X SP - 455 EP - 455 ER - TY - JFULL T1 - Survey on the perioperative use of TNFalpha inhibitors in rheumatoid hand surgery. A1 - Jain, A A1 - Harley, O A1 - Patel, RM A1 - Nanchahal, J J1 - J Hand Surg [Br] Y1 - 2006/08// VL - 31 SN - 0266-7681 SP - 463 EP - 464 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16716465&query_hl=1 ER - TY - JFULL T1 - Interfering with interferons in inflammatory bowel disease. A1 - Ghosh, S A1 - Chaudhary, R A1 - Carpani, M A1 - Playford, R J1 - Gut Y1 - 2006/08// VL - 55 SN - 0017-5749 SP - 1071 EP - 1073 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16849343&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 - 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 - Cytokines for myocardial ischaemia: a echocardiographic study A1 - Raisakis, K A1 - Monaco, C A1 - Stamatelopoulos, K A1 - Desforges, L A1 - Liodakis, E A1 - Nihoyannopoulos, P J1 - EUR HEART J Y1 - 2006/08// VL - 27 SN - 0195-668X SP - 561 EP - 561 ER - TY - JFULL T1 - Typing of absent renal donors A1 - Sergeant, R A1 - Khan, T A1 - Hernandez, M A1 - Davey, N A1 - Warrens, A J1 - INT J IMMUNOGENET Y1 - 2006/08// VL - 33 SN - 1744-3121 SP - 326 EP - 326 ER - TY - JFULL T1 - Early immunological development and mortality from infectious disease in later life A1 - Moore, SE A1 - Collinson, AC A1 - N'Gom, PT A1 - Aspinall, R A1 - Prentice, AM J1 - P NUTR SOC Y1 - 2006/08// VL - 65 SN - 0029-6651 SP - 311 EP - 318 N2 - In rural Gambia the risk of mainly infection-related mortality is 10-fold higher for adults born in the nutritionally-debilitating 'hungry' season, suggesting that immune function may be compromised by events early in life. The current programme of research focuses on the biological mechanisms underlying this hypothesis, exploring early-life environmental influences on immune development and the long-term functional consequences these influences may have. Results obtained to date show that thymus development during infancy is critically sensitive to environmental exposures, with smaller thymuses observed in the hungry season. Measurement of the frequency of T-cell receptor excision circles indicate that thymus function is also sensitive to seasonal influences, with further studies implicating variations in breast-milk IL-7 as a possible mediator of these effects. Studies in adults have shown that size at birth is positively correlated with antibody responses to vaccination with polysaccharide antigens, thus providing evidence for long-term functional deficits. The present paper will review progress made to date within this field of research. ER - TY - JFULL T1 - Complement deficiencies in humans and animals: links to autoimmunity. A1 - Lewis, MJ A1 - Botto, M J1 - Autoimmunity Y1 - 2006/08// VL - 39 SN - 0891-6934 SP - 367 EP - 378 N2 - Complement is involved in the pathogenesis of systemic lupus erythematosus (SLE) in multiple ways and may act as both friend and foe. Inherited homozygous deficiency of one of the earliest components of the classical pathway is strongly associated with susceptibility to the development of SLE. However, complement is also implicated in the effector inflammatory phase of the autoimmune response that characterizes the disease. A further paradox in the links between complement and SLE is the observation that autoantibodies to some complement proteins, especially to C1q, develop as part of the autoantibody response. In this chapter, the role of the complement system in SLE is reviewed and hypotheses advanced to explain the complex relationships between complement and lupus. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16923536&query_hl=1 ER - TY - JFULL T1 - Management of patients presenting with Sjogren's syndrome. A1 - Venables, PJ J1 - Best Pract Res Clin Rheumatol Y1 - 2006/08// VL - 20 SN - 1521-6942 SP - 791 EP - 807 N2 - Sjogren's syndrome is an autoimmune exocrinopathy that predominantly affects salivary and lachrymal glands, leading to dry eyes and mouth. The most common clinical problems faced by the rheumatologist are those of dry eyes and mouth, parotid swelling, fatigue and extraglandular manifestations. The first stage in management is to make an accurate diagnosis based on the American/European consensus criteria. The most frequent differential diagnoses are dry eyes and mouth symptoms, a variant of chronic fatigue syndrome and fibromyalgia, and sialosis, which causes a non-inflammatory enlargement of the parotid glands. The mainstay of treatment for the sicca symptoms is local therapy, and that for the milder systemic symptoms is hydroxychloroquine. Steroids and immunosuppressive drugs are reserved for more severe extraglandular disease. In spite of intensive research in other systemic treatments including biologic therapies, there is limited evidence to support their use in routine clinical practice. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16979538&query_hl=1 ER - TY - JFULL T1 - A rapid method for labelling CD4+ T cells with ultrasmall paramagnetic iron oxide nanoparticles for magnetic resonance imaging that preserves proliferative, regulatory and migratory behaviour in vitro. A1 - Garden, OA A1 - Reynolds, PR A1 - Yates, J A1 - Larkman, DJ A1 - Marelli-Berg, FM A1 - Haskard, DO A1 - Edwards, AD A1 - George, AJ J1 - J Immunol Methods Y1 - 2006/07/31/ VL - 314 SN - 0022-1759 SP - 123 EP - 133 N2 - A number of techniques have been developed to track the migration of T cells in vivo, but they all suffer significant shortcomings, including the examination of selected organs rather than the organism as a whole--thus precluding longitudinal studies--or limitations imposed by poor spatial resolution and the application of ionizing radiation. By conjugating the HIV tat peptide to ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles in a reaction yielding a mean valence of 45, a magnetic resonance (MR) contrast agent was synthesised that allowed T cells to be efficiently labelled within just 5 min. The USPIO nanoparticles were incorporated into both the cytoplasm and nucleus of labelled cells, which retained normal in vitro proliferative responses to a polyclonal stimulus; suppressive responses mediated by labelled CD4(+) CD25(+) regulatory T cells; chemotactic responses to the chemokine CXCL-12; and transmigration of an activated endothelial monolayer. We believe that this rapid, efficient and essentially non-toxic approach to labelling both murine and human T cells for MRI holds considerable promise, paving the way for the wider immunological application of this exciting technology. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16860821&query_hl=1 ER - TY - JFULL T1 - The mammalian chitinase-like lectin, YKL-40, binds specifically to type I collagen and modulates the rate of type I collagen fibril formation. A1 - Bigg, HF A1 - Wait, R A1 - Rowan, AD A1 - Cawston, TE J1 - J Biol Chem Y1 - 2006/07/28/ VL - 281 SN - 0021-9258 SP - 21082 EP - 21095 N2 - YKL-40 is expressed in arthritic cartilage and produced in large amounts by cultured chondrocytes, but its exact role is unclear, and the identities of its physiological ligands remain unknown. Purification of YKL-40 from resorbing bovine nasal cartilage and chondrocyte monolayers demonstrated the existence of three isoforms, a major and minor form from resorbing cartilage and a third species from chondrocytes. Affinity chromatography experiments with purified YKL-40 demonstrated specific binding of all three forms to collagen types I, II, and III, thus identifying collagens as potential YKL-40 ligands. Binding to immobilized type I collagen was inhibited by soluble native ligand, but not heat-denatured ligand, confirming a specific interaction. Binding of the chondrocyte-derived species to type I collagen was also demonstrated by surface plasmon resonance analysis, and the dissociation rate constant was calculated (3.42 x 10(-3) to 4.50 x 10(-3) s(-1)). The chondrocyte-derived species was found to prevent collagenolytic cleavage of type I collagen and to stimulate the rate of type I collagen fibril formation in a concentration-dependent manner. By contrast, the cartilage major form had an inhibitory effect on type I collagen fibrillogenesis. Digestion with N-glycosidase F, endoglycosidase H and lectin blotting did not reveal any difference in the carbohydrate component of these two YKL-40 species, indicating that this does not account for the opposing effects on fibril formation rate. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16704970&query_hl=1 ER - TY - JFULL T1 - Bronchiolitis. A1 - Smyth, RL A1 - Openshaw, PJ J1 - Lancet Y1 - 2006/07/22/ VL - 368 SN - 1474-547X SP - 312 EP - 322 N2 - Bronchiolitis is a distressing, potentially life-threatening respiratory condition that affects young babies. Around 2-3% of all infants younger than 1 year are admitted to hospital with bronchiolitis, usually during the seasonal epidemic. The majority of these infants are infected with respiratory syncytial virus and all have an intense inflammatory response in their airways. Although most infants recover, they have an increased risk of recurrent wheezing. Although bronchiolitis is common, little is known about what causes infants to be susceptible. Diagnostic interventions have little effect on clinical outcome, and apart from supportive measures, there is no specific treatment. Bronchiolitis therefore presents an intriguing clinical conundrum and a major challenge to researchers. High quality clinical studies are needed to clarify assessment of disease severity and criteria for hospital admission, particularly the use of pulse oximetry and chest radiography. Careful mapping of the inflammatory pathways in the pathogenesis of bronchiolitis should lead to development of new therapies to alleviate symptoms. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16860701&query_hl=1 ER - TY - JFULL T1 - Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. A1 - Jiang, Z A1 - Georgel, P A1 - Li, C A1 - Choe, J A1 - Crozat, K A1 - Rutschmann, S A1 - Du, X A1 - Bigby, T A1 - Mudd, S A1 - Sovath, S A1 - Wilson, IA A1 - Olson, A A1 - Beutler, B J1 - Proc Natl Acad Sci U S A Y1 - 2006/07/18/ VL - 103 SN - 0027-8424 SP - 10961 EP - 10966 N2 - The immunovariant N-ethyl-N-nitrosourea-induced mutations Pococurante (Poc) and Lackadaisical were found to alter MyD88, creating striking receptor-selective effects. Poc, in particular, prevented sensing of all MyD88-dependent Toll-like receptor (TLR) ligands except diacyl lipopeptides. Furthermore, Poc-site and classical BB loop mutations caused equivalent phenotypes when engrafted into any TLR/IL-1 receptor/resistance (TIR) domain. These observations, complemented by data from docking studies and site-directed mutagenesis, revealed that BB loops and Poc sites interact homotypically across the receptor:adapter signaling interface, whereas the C-terminal alpha(E)-helices support adapter:adapter and receptor:receptor oligomerization. We have thus defined the TIR domain surface that mediates association between TLRs and MyD88 and the surface required for MyD88 or TLR oligomerization. Moreover, MyD88 engages individual TLRs differently, suggesting the feasibility of selective pharmacologic TIR domain receptor blockade. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16832055&query_hl=1 ER - TY - JFULL T1 - Role of immunoproteasomes in cross-presentation A1 - Palmowski, MJ A1 - Gileadi, U A1 - Salio, M A1 - Gallimore, A A1 - Millrain, M A1 - James, E A1 - Addey, C A1 - Scott, D A1 - Dyson, J A1 - Simpson, E A1 - Cerundolo, V J1 - J IMMUNOL Y1 - 2006/07/15/ VL - 177 SN - 0022-1767 SP - 983 EP - 990 N2 - The evidence that proteasomes are involved in the processing of cross-presented proteins is indirect and based on the in vitro use of proteasome inhibitors. It remains, therefore, unclear whether cross-presentation of MHC class I peptide epitopes can occur entirely within phagolysosomes or whether it requires proteasome degradation. To address this question, we studied in vivo cross-presentation of an immunoproteasome-dependent epitope. First, we demonstrated that generation of the immunodominant HY Uty(246-254) epitope is LMP7 dependent, resulting in the lack of rejection of male LMP7-deficient (LMP7(-/-)) skin grafts by female LMP7(-/-) mice. Second, we ruled out an altered Uty(246-254)-specific T cell repertoire in LMP7(-/-) female mice and demonstrated efficient Uty(246-254) presentation by re-expressing LMP7 in male LMP7(-/-) cells. Finally, we observed that LMP7 expression significantly enhanced cross-priming of Uty(246-254)-specific T cells in vivo. The observations that male skin grafts are not rejected by LMP7(-/-) female mice and that presentation of a proteasome-dependent peptide is not efficiently rescued by alternative cross-presentation pathways provide strong evidence that proteasomes play an important role in cross-priming events. ER - TY - JFULL T1 - NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. A1 - Savina, A A1 - Jancic, C A1 - Hugues, S A1 - Guermonprez, P A1 - Vargas, P A1 - Moura, IC A1 - Lennon-Duménil, AM A1 - Seabra, MC A1 - Raposo, G A1 - Amigorena, S J1 - Cell Y1 - 2006/07/14/ VL - 126 SN - 0092-8674 SP - 205 EP - 218 N2 - To initiate adaptative cytotoxic immune responses, proteolytic peptides derived from phagocytosed antigens are presented by dendritic cells (DCs) to CD8+ T lymphocytes through a process called antigen "crosspresentation." The partial degradation of antigens mediated by lysosomal proteases in an acidic environment must be tightly controlled to prevent destruction of potential peptides for T cell recognition. We now describe a specialization of the phagocytic pathway of DCs that allows a fine control of antigen processing. The NADPH oxidase NOX2 is recruited to the DC's early phagosomes and mediates the sustained production of low levels of reactive oxygen species, causing active and maintained alkalinization of the phagosomal lumen. DCs lacking NOX2 show enhanced phagosomal acidification and increased antigen degradation, resulting in impaired crosspresentation. Therefore, NOX2 plays a critical role in conferring DCs the ability to function as specialized phagocytes adapted to process antigens rather than kill pathogens. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16839887&query_hl=1 ER - TY - JFULL T1 - Low oxygen stimulates the intellect - Symposium on hypoxia and development, physiology and disease A1 - Koumenis, C A1 - Maxwell, PH J1 - EMBO REP Y1 - 2006/07// VL - 7 SN - 1469-221X SP - 679 EP - 684 ER - TY - JFULL T1 - The potassium channel opener levcromakalim causes expansive remodelling of experimental vein grafts. A1 - Wales, L A1 - Gosling, M A1 - Taylor, GW A1 - Davies, AH A1 - Powell, JT J1 - J Vasc Surg Y1 - 2006/07// VL - 44 SN - 0741-5214 SP - 159 EP - 165 N2 - BACKGROUND: Maintenance of luminal area is essential for the optimal performance of venous bypass grafts. However, injury and response to the arterial circulation evoke vascular remodelling that favors intimal hyperplasia, with luminal encroachment and inward remodelling. Potassium channel-opening drugs reduce tissue workload and peripheral vascular resistance and through these mechanisms could favor outward or expansive remodelling of vein grafts. We tested the hypothesis that levcromakalim, a potassium channel opener, would enhance expansive remodelling in vein grafts. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in 33 rats with vena cava-to-aorta bypass grafts. Drugs were administered via osmotic pump for 7 days after surgery. Half the cohort had bromodeoxyuridine (BrdU) infused at day 6. Morphometric analysis was conducted of pressure perfusion-fixed grafts harvested at 1 week and 4 weeks. RESULTS: At 1 week, lumen area was similar in both groups (1.82 +/- 0.39 mm(2) placebo vs 1.85 +/- 0.36 mm(2) levcromakalim), although medial cell density and BrdU staining were significantly increased in the placebo group. At 4 weeks, lumen area was unchanged in the placebo group (1.88 +/- 0.51 mm(2)) but had increased to 2.32 +/- 0.46 mm(2) in the levcromakalim group (P = .039 vs 1 week), with a very significant reduction in the intimal area (levcromakalim, 0.06 +/- 0.02 mm(2) vs placebo, 0.33 +/- 0.17 mm(2); P = .001). CONCLUSIONS: Early, short-term treatment with levcromakalim favors expansive remodelling of experimental vein grafts to mimic the effect of external stenting. This expansive remodelling was associated with a reduction in medial cell proliferation at 1 week. CLINICAL RELEVANCE: Critical limb ischemia can be treated by bypass surgery or angioplasty, but inward remodelling with restenosis is a common problem. There has been little previous experimental work to identify treatments associated with expansive remodelling, which would increase the chances of vessel patency. Here, in a randomized trial, we show that short-term treatment with a potassium channel opener (a class of drug that can be used to treat hypertension) results in strong, expansive remodelling, with increases the lumen area and graft size of experimental vein grafts by >25%. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16828441&query_hl=1 ER - TY - JFULL T1 - Clinically applicable procedure for gene delivery to fetal gut by ultrasound-guided gastric injection: Toward prenatal prevention of early-onset intestinal diseases A1 - David, AL A1 - Peebles, DM A1 - Gregory, L A1 - Waddington, SN A1 - Themis, M A1 - Weisz, B A1 - Ruthe, A A1 - Lawrence, L A1 - Cook, T A1 - Rodeck, CH A1 - Coutelle, C J1 - HUM GENE THER Y1 - 2006/07// VL - 17 SN - 1043-0342 SP - 767 EP - 779 N2 - Targeting gene therapy vectors to the fetal intestinal tract could provide a novel means toward prevention of the early postnatal intestinal pathology of cystic fibrosis and other conditions, such as congenital enteropathy, that cause intestinal failure. Among these conditions, cystic fibrosis is by far the most common lethal genetic disease. It is caused by a functional absence or deficiency of the cystic fibrosis transmembrane conductance regulator and manifests in the gut as meconium ileus. Prenatal treatment of genetic disease may avoid early-onset tissue damage and immune sensitization, and may target cells that are less accessible in the adult. We investigated gene transfer to the fetal gut, using a minimally invasive injection technique. First-generation replication-deficient adenoviral vectors encoding the beta-galactosidase gene and transduction-enhancing agents were injected into the stomach of early-gestation fetal sheep (n=8, 60 days of gestation; term, 145 days) under ultrasound guidance. Reporter gene expression was observed 2 days after injection in the villi of the gastrointestinal epithelia after 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining and beta-galactosidase immunohistochemistry of fetal tissues. Expression of beta-galactosidase, as measured by enzyme-linked immunosorbent assay, was enhanced after pretreatment of the fetal gut with sodium caprate, which opens tight junctions, and after adenovirus complexation with DEAE-dextran, which confers a positive charge to the virus. Instillation of the fluorocarbon perflubron after virus delivery resulted in tissue transduction from the fetal stomach to the colon. Using a clinically relevant technique, we have demonstrated widespread gene transfer to the fetal gastrointestinal epithelia. ER - TY - JFULL T1 - Interleukin-11 suppressed fibrotic processes in nephrotoxic nephritis in Wistar Kyoto Rats A1 - Stangou, M A1 - Bhangal, G A1 - Lai, PC A1 - Smith, J A1 - Keith, J A1 - Boyle, J A1 - Pusey, C A1 - Cook, T A1 - Tam, F J1 - NEPHROL DIAL TRANSPL Y1 - 2006/07// VL - 21 SN - 0931-0509 SP - 36 EP - 37 ER - TY - JFULL T1 - The generation of thymus-independent germinal centers depends on CD40 but not on CD154, the T cell-derived CD40-ligand A1 - Gaspal, FMC A1 - McConnell, FM A1 - Kim, MY A1 - Gray, D A1 - Kosco-Vilbois, MH A1 - Raykundalia, CR A1 - Botto, M A1 - Lane, PJL J1 - EUR J IMMUNOL Y1 - 2006/07// VL - 36 SN - 0014-2980 SP - 1665 EP - 1673 N2 - In this report, we show that the formation of germinal center (GC)-like structures to thymus-independent type 2 antigens in mice depends on intact signals through CD40, but does not depend on T cell-derived CD40-ligand (CD 154). In addition, we show that follicular dendritic cells (FDC) are also critical to thymus-independent GC formation, as their depletion by blockade of lymphotoxin-P receptor signals abrogated GC development unless the responding B cells bound antigen with high affinity. Further evidence that immune complexes drove this CD40-dependent B cell proliferation was provided by the observation that an antibody that detects immune complexes containing complement component 4 on FDC also inhibited thymus-independent GC formation when injected in vivo at the time of immunization. Finally, we show that thymus-independent B cell proliferation was associated with class switching to IgG3, as IgG3(+) antigen-specific switched B cells could be visualized directly in GC, suggesting that immune complexes can provide the signals for class switching within GC in the absence of CD154. ER - TY - JFULL T1 - Neutrophils as antigen-presenting cells in transplantation: Bridging innate and adaptive immunity A1 - Ambrose, L A1 - Smith, L A1 - Little, M A1 - Dupont, P A1 - Williams, G A1 - Warrens, A J1 - NEPHROL DIAL TRANSPL Y1 - 2006/07// VL - 21 SN - 0931-0509 SP - 549 EP - 549 ER - TY - JFULL T1 - Re: Mehta T, Venkata Subramaniam A, Chetter I, McCollum P. Assessing the validity and responsiveness of disease-specific quality of life instruments in intermittent claudication. Eur J Vasc Endovasc Surg 2006;31:46-52. A1 - Chong, PF A1 - Garratt, AM A1 - Greenhalgh, RM A1 - Davies, AH J1 - Eur J Vasc Endovasc Surg Y1 - 2006/07// VL - 32 SN - 1078-5884 SP - 110 EP - 111 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16584901&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 - Detection of muramyl dipeptide-sensing pathway defects in patients with Crohn's disease. A1 - van Heel, DA A1 - Hunt, KA A1 - King, K A1 - Ghosh, S A1 - Gabe, SM A1 - Mathew, CG A1 - Forbes, A A1 - Playford, RJ J1 - Inflamm Bowel Dis Y1 - 2006/07// VL - 12 SN - 1078-0998 SP - 598 EP - 605 N2 - BACKGROUND AND AIMS: Crohn's disease is strongly associated with double mutations in NOD2/CARD15. Three common mutations (Arg702Trp, Gly908Arg, Leu1007fs) impair innate immune responses to bacterial muramyl dipeptide. Rare NOD2 variants occur, but it is difficult to both identify them and assess their functional effect. We assessed the true frequency of defective muramyl dipeptide sensing in Crohn's disease and developed a rapid diagnostic assay. MATERIALS AND METHODS: An ex vivo assay was established and validated based on muramyl dipeptide stimulation of peripheral blood mononuclear cell cytokine production. Muramyl dipeptide-induced enhancement of interleukin (IL)-8 secretion and synergistic increase in lipopolysaccharide-induced IL-1beta secretion were studied. Assay results were compared with NOD2 genotype status (3 common mutations and rare variants) in 91 individuals including a prospective cohort of 49 patients with Crohn's disease. RESULTS: The assay was highly sensitive and specific for detection of profound defects in muramyl dipeptide sensing caused by double NOD2 mutations (IL-8 P = 0.0002; IL-1beta P = 0.0002). Disease state, active inflammation, or concurrent use of immunosuppressive medication did not influence results. Healthy NOD2 heterozygotes had modest impairment of muramyl dipeptide induced IL-8 secretion (P = 0.003). Only 1 of 7 patients with Crohn's disease with both a common mutation and a rare variant had a profound muramyl dipeptide-sensing defect. CONCLUSIONS: Profound defects in muramyl dipeptide sensing were found in 10% of patients with Crohn's disease. Defects were caused exclusively by inherited mutations in NOD2. The ex vivo assay has multiple potential applications as a clinical diagnostic tool to distinguish patients with muramyl dipeptide-sensing defects and for research investigation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16804397&query_hl=1 ER - TY - JFULL T1 - Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein. A1 - Esteban, MA A1 - Harten, SK A1 - Tran, MG A1 - Maxwell, PH J1 - J Am Soc Nephrol Y1 - 2006/07// VL - 17 SN - 1046-6673 SP - 1801 EP - 1806 N2 - Growing evidence points to defects in the primary cilium as a critical mechanism underlying renal cyst development. Inactivation of the VHL gene is responsible for the autosomal dominant condition von Hippel-Lindau (VHL) disease and is implicated in most sporadic clear cell renal carcinomas. Manifestations of VHL disease include cysts in several organs, particularly in the kidney. Here it is shown that VHL inactivation is associated with abrogation of the primary cilium in renal cysts of patients with VHL disease and in VHL-defective cell lines. Complementation of VHL-defective clear cell renal carcinoma cell lines with wild-type VHL restored primary cilia. Moreover, it is shown that the effects of VHL on the primary cilium are mediated substantially via hypoxia-inducible factor. The effect of VHL status on the primary cilium provides a potential mechanism for renal cyst development in VHL disease and may help in the understanding of how VHL acts as a tumor suppressor. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16775032&query_hl=1 ER - TY - JFULL T1 - Ultrasound-guided injection and occlusion of the trachea in fetal sheep A1 - David, AL A1 - Weisz, B A1 - Gregory, L A1 - Themis, M A1 - Cook, T A1 - Roubliova, X A1 - Deprest, J A1 - Coutelle, C A1 - Rodeck, CH A1 - Peebles, DM J1 - ULTRASOUND OBST GYN Y1 - 2006/07// VL - 28 SN - 0960-7692 SP - 82 EP - 88 N2 - Objectives To access the fetal sheep trachea by ultrasound-guided transthoracic injection in order to deliver gene therapy vectors or occlude the trachea with a detachable balloon.Methods Fetal sheep were operated on at a mean gestational age of 102 (range, 81-116) days (term 145 days). Under ultrasound guidance, either a 20-G spinal (for vector delivery) or a 16-G Kellett (for placement of an occlusive balloon) needle was inserted via the fetal thorax into the fetal trachea.Results Using the 20-G spinal needle the trachea was accessed successfully in 33/36 fetuses, with 97% survival. Failure to inject was related to fetal Position and gestational age. Blood vessel damage causing significant morbidity occurred in two fetuses (6%). Tracheal occlusion was achieved by puncturing the trachea with the 16-G needle and advancing an endoluminal balloon in three out of five attempts in a mean time of 17 (range, 16-19) min, with 100% survival. In one case, the balloon became sited within the accessory lobe bronchus and was not inflated. At postmortem examination 21 days later, all balloons remained inflated and occluded the trachea, and the lung-to-body weight ratio and airways morphometric indices were consistent with relative pulmonary hyperplasia in the obstructed lungs.Conclusions Ultrasound-guided transthoracic tracheal puncture is a reliable technique in fetal sheep, with low morbidity and mortality. Using this technique, a detachable endotracheal balloon can be placed to provoke pulmonary growth. Advances in needle design and balloon size may improve the success rate. Copyright (c) 2006 ISUOG. Published by John Wiley & Sons, Ltd. ER - TY - JFULL T1 - Haematopoietic lineage-committed marrow cells, but not cloned cultured mesenchymal stem cells, contribute to regeneration after acute tubular necrosis A1 - Fang, TC A1 - Poulsom, R A1 - Alison, MR A1 - Cook, HT A1 - Otto, WR A1 - Rao, J A1 - Jeffery, R A1 - Hunt, T A1 - Wright, NA J1 - NEPHROL DIAL TRANSPL Y1 - 2006/07// VL - 21 SN - 0931-0509 SP - 319 EP - 320 ER - TY - JFULL T1 - Characterization and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor. A1 - Gordon, MY A1 - Levicar, N A1 - Pai, M A1 - Bachellier, P A1 - Dimarakis, I A1 - Al-Allaf, F A1 - M'Hamdi, H A1 - Thalji, T A1 - Welsh, JP A1 - Marley, SB A1 - Davies, J A1 - Dazzi, F A1 - Marelli-Berg, F A1 - Tait, P A1 - Playford, R A1 - Jiao, L A1 - Jensen, S A1 - Nicholls, JP A1 - Ayav, A A1 - Nohandani, M A1 - Farzaneh, F A1 - Gaken, J A1 - Dodge, R A1 - Alison, M A1 - Apperley, JF A1 - Lechler, R A1 - Habib, NA J1 - Stem Cells Y1 - 2006/07// VL - 24 SN - 1066-5099 SP - 1822 EP - 1830 N2 - A phase I study was performed to determine the safety and tolerability of injecting autologous CD34(+) cells into five patients with liver insufficiency. The study was based on the hypothesis that the CD34(+) cell population in granulocyte colony-stimulating factor (G-CSF)-mobilized blood contains a subpopulation of cells with the potential for regenerating damaged tissue. We separated a candidate CD34(+) stem cell population from the majority of the CD34(+) cells (99%) by adherence to tissue culture plastic. The adherent and nonadherent CD34(+) cells were distinct in morphology, immunophenotype, and gene expression profile. Reverse transcription-polymerase chain reaction-based gene expression analysis indicated that the adherent CD34(+) cells had the potential to express determinants consistent with liver, pancreas, heart, muscle, and nerve cell differentiation as well as hematopoiesis. Overall, the characteristics of the adherent CD34(+) cells identify them as a separate putative stem/progenitor cell population. In culture, they produced a population of cells exhibiting diverse morphologies and expressing genes corresponding to multiple tissue types. Encouraged by this evidence that the CD34(+) cell population contains cells with the potential to form hepatocyte-like cells, we gave G-CSF to five patients with liver insufficiency to mobilize their stem cells for collection by leukapheresis. Between 1 x 10(6) and 2 x 10(8) CD34(+) cells were injected into the portal vein (three patients) or hepatic artery (two patients). No complications or specific side effects related to the procedure were observed. Three of the five patients showed improvement in serum bilirubin and four of five in serum albumin. These observations warrant further clinical trials. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16556705&query_hl=1 ER - TY - JFULL T1 - Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary physiology. A1 - Smith, TG A1 - Brooks, JT A1 - Balanos, GM A1 - Lappin, TR A1 - Layton, DM A1 - Leedham, DL A1 - Liu, C A1 - Maxwell, PH A1 - McMullin, MF A1 - McNamara, CJ A1 - Percy, MJ A1 - Pugh, CW A1 - Ratcliffe, PJ A1 - Talbot, NP A1 - Treacy, M A1 - Robbins, PA J1 - PLoS Med Y1 - 2006/07// VL - 3 SN - 1549-1676 SP - e290 EP - e290 N2 - BACKGROUND: The von Hippel-Lindau tumour suppressor protein-hypoxia-inducible factor (VHL-HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL-HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL-HIF pathway in systemic human cardiopulmonary physiology. METHODS AND FINDINGS: Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. CONCLUSIONS: The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16768548&query_hl=1 ER - TY - JFULL T1 - Expression and distribution of hypoxia inducible transcription factors in mouse liver, heart and kidney A1 - Bernhardt, WM A1 - Cramer, T A1 - Rohwer, N A1 - Klanke, B A1 - Wiesener, MS A1 - Maxwell, PH A1 - Eckardt, KU J1 - NEPHROL DIAL TRANSPL Y1 - 2006/07// VL - 21 SN - 0931-0509 SP - 17 EP - 17 ER - TY - JFULL T1 - Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice. A1 - Pickering, MC A1 - Warren, J A1 - Rose, KL A1 - Carlucci, F A1 - Wang, Y A1 - Walport, MJ A1 - Cook, HT A1 - Botto, M J1 - Proc Natl Acad Sci U S A Y1 - 2006/06/20/ VL - 103 SN - 0027-8424 SP - 9649 EP - 9654 N2 - Membranoproliferative glomerulonephritis (MPGN) type II (dense deposit disease) is an inflammatory renal disease characterized by electron-dense deposits and complement C3 on the glomerular basement membrane. There is no effective therapy. We investigated the role of C5 activation in a model of MPGN that develops spontaneously in complement factor H-deficient mice (Cfh(-/-)). At 12 months there was a significant reduction in mortality, glomerular cellularity, neutrophil numbers, and serum creatinine levels in Cfh(-/-) mice deficient in C5. Excessive glomerular neutrophil numbers, frequently seen in patients with MPGN during disease flares, were also observed in Cfh(-/-) mice after the administration of an antiglomerular basement membrane antibody. This exaggerated injurious phenotype was absent in Cfh(-/-) mice deficient in C5 but not in Cfh(-/-) mice deficient in C6, indicating a key role for C5 activation in the induction of renal lesions. Importantly, the renal injury was completely reversed in Cfh(-/-) mice pretreated with an anti-murine C5 antibody. These results demonstrate an important role for C5 in both spontaneous MPGN and experimentally induced nephritis in factor H-deficient mice and provide preliminary evidence that C5 inhibition therapy might be useful in human MPGN type II. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16769899&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