TY - BOOK T1 - What can primary care do to improve health outcomes in diabetes and cardiovascular disease for ethnic minority groups in the UK? A1 - Misra T A1 - Saxena S A1 - Car J A1 - Smith R Y1 - 2006/// PB - Report for United Health Europe CY - London N2 - - ER - TY - CHAP T1 - Susceptibility to infectious diseases A1 - Walley, A A1 - Hill, A ED - Alan Wright and Nick Hastie T2 - Genes and Common Diseases: Genetics in Modern Medicine Y1 - 2007/08// VL - First PB - Cambridge University Press SN - 052154100X N2 - - ER - TY - CHAP T1 - Sex-specific aspects of dyslipidaemia and atherosclerosis A1 - Godsland, I F ED - Packard, C J T2 - The Year in Lipid Disorders Y1 - 2007/// M2 - 1 PB - Clinical Publishing CY - Oxford N2 - - ER - TY - CHAP T1 - Clinical Prospects of NF-κB Inhibitors to Further Target Therapies in Rheumatology A1 - Drexler, S A1 - Turner, JJO A1 - Foxwell, BMJ T2 - Further Targeted Therapy in Rheumatology. Y1 - 2007/// N2 - - ER - TY - CHAP T1 - Screening for Type 2 diabetes A1 - Johnston DG A1 - Alberti KGMM A1 - Godsland IF A1 - Pierce M A1 - Shepperd S ED - Marmot M, Elliott P T2 - Coronary Heart Disease Epidemiology Y1 - 2005/// VL - 2nd Edition PB - OUP CY - Oxford SP - 714 EP - 750 N2 - - ER - TY - CHAP T1 - Screening for type 2 diabetes A1 - Johnston, DG A1 - Alberti, KGMM A1 - Godsland, IF A1 - Pierce, M A1 - Shepperd, S ED - Marmot M, Elliott P T2 - Coronary Heart Disease Epidemiology: from aetiology to public health Y1 - 2005/// VL - 2nd PB - Oxford University Press CY - Oxford SN - 0-19-852573-7 N2 - - ER - TY - CHAP T1 - Carcinoid Syndrome A1 - Jayasena C A1 - Dhillo WS ED - Dhillo WS & Meeran K T2 - MEDICINE Y1 - 2005/// VL - 12 M2 - 33 SP - 47 EP - 48 N2 - - ER - TY - CHAP T1 - Estrogen deprivation and hormone replacement therapy: effects on glucose and insulin metabolism and the metabolic syndrome A1 - Godsland, IF ED - Lauritzen C, Studd J T2 - Current Management of the Menopause Y1 - 2005/// VL - 1st PB - Dunitz CY - London SN - 1-84184-232-X N2 - - ER - TY - CHAP T1 - HRT and SERMs. A1 - Stevenson JC ED - Woolf AD, Akesson K, Adami S. T2 - The Year Book in Osteoporosis. Y1 - 2004/// PB - Clinical Publishing CY - Oxford SP - 225 EP - 246 N2 - - ER - TY - CHAP T1 - Endocrine Tumors of the Gastrointestinal Tract A1 - Barakat MT A1 - Lynn JA A1 - Bloom SR ED - AE Schwartz, D Pertsemlidis & M Gagner T2 - Endocrine Surgery Y1 - 2003/// PB - Marcel Dekker CY - New York SP - 643 EP - 658 N2 - - ER - TY - CHAP T1 - Hirsutism & Virilization A1 - Gilling-Smith C A1 - Franks S ED - Shaw RW, Soutter WP & Stanton SL T2 - In Gynaecology Y1 - 2003/// PB - Churchill Livingstone CY - Edinburgh SP - 387 EP - 399 N2 - - ER - TY - CHAP T1 - Pituitary adenomas A1 - Kearney T A1 - Johnston DG T2 - Endocrinology: specialist handbook Y1 - 2002/// SN - 1-8418-4158-7 SP - 1 EP - 19 N2 - - ER - TY - CHAP T1 - Vasoactive intestinal peptide (VIP) A1 - Taheri S A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 3344 EP - 3346 N2 - - ER - TY - CHAP T1 - Ovary A1 - Gilling-Smith C A1 - Franks S T2 - Comprehensive Clinical Endocrinology Y1 - 2002/// M2 - 3rd SN - 0-7234-3185-X SP - 375 EP - 393 N2 - - ER - TY - CHAP T1 - Pancreatic polypeptide A1 - Stanley SA A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 2381 EP - 2384 N2 - - ER - TY - CHAP T1 - Hirsutism A1 - Gilling-Smith C A1 - Franks S T2 - Oxford Textbook of Endocrinology and Diabetes Y1 - 2002/// SN - 0-1926-3045-8 SP - 1148 EP - 1159 N2 - - ER - TY - CHAP T1 - Low-dose gonadotrophin treatment in polycystic ovary syndrome:the 'step-up' protocol A1 - Franks S A1 - White DM T2 - Ovulation Induction (Series-European practice in gynaecology and obstetrics,3) Y1 - 2002/// SN - 2-8429-9316-0 N2 - - ER - TY - CHAP T1 - Orexins (Hypocretins) A1 - Taheri S A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 2328 EP - 2331 N2 - - ER - TY - CHAP T1 - Androgenic modulation of the immune response A1 - Reed MJ A1 - Purohit A A1 - Singh A T2 - Menopause: the state of the art Y1 - 2002/// SN - 1-8421-4160-0 SP - 23 EP - 27 N2 - - ER - TY - CHAP T1 - Glucagon- and proglucagon-derived peptides A1 - Bloom SR A1 - Ghatei MA A1 - Taheri S T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 1430 EP - 1434 N2 - - ER - TY - CHAP T1 - Secretin A1 - Seal LJ A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 2871 EP - 2874 N2 - - ER - TY - CHAP T1 - Hormone replacement therapy and carbohydrate metabolism A1 - Stevenson JC T2 - Hormone replacement therapy and the menopause Y1 - 2002/// SN - 1-8531-7691-5 SP - 101 EP - 113 N2 - - ER - TY - CHAP T1 - Mastocytosis A1 - O'Shea D A1 - Dhillo WS T2 - Oxford Textbook of Endocrinology and Diabetes Y1 - 2002/// SN - 0-1926-3045-8 SP - 937 EP - 940 N2 - - ER - TY - CHAP T1 - Insulinomas and hypoglycaemia A1 - Todd JF A1 - Bloom SR T2 - Oxford Textbook of Endocrinology and Diabetes Y1 - 2002/// SN - 0-1926-3045-8 SP - 883 EP - 888 N2 - - ER - TY - CHAP T1 - Cholecystokinin (CCK) A1 - Taheri S A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encylopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 752 EP - 754 N2 - - ER - TY - CHAP T1 - Cholecystokinin (CCK) A1 - Taheri S A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encylopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 752 EP - 754 N2 - - ER - TY - CHAP T1 - Pancreatic polypeptide A1 - Stanley SA A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 2381 EP - 2384 N2 - - ER - TY - CHAP T1 - Female endocrinology A1 - Franks S T2 - Oxford textbook of endocrinology and diabetes Y1 - 2002/// SN - 0-1926-3045-8 SP - 1063 EP - 1226 N2 - - ER - TY - CHAP T1 - Secretin A1 - Seal LJ A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 2871 EP - 2874 N2 - - ER - TY - CHAP T1 - Gastrinoma A1 - Calam J A1 - Taheri S A1 - Bloom SR T2 - Oxford Textbook of Endocrinology and Diabetes Y1 - 2002/// SN - 0-1926-3045-8 SP - 877 EP - 882 N2 - - ER - TY - CHAP T1 - Role of genes encoding steroidogenic enzymes in polycystic ovary syndrome A1 - Franks S A1 - Gharani N A1 - McCarthy M T2 - Polycystic Ovary Syndrome Y1 - 2002/// SN - 0-8247-0746-X SP - 247 EP - 259 N2 - - ER - TY - CHAP T1 - Bombesin A1 - Howard JK A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 381 EP - 383 N2 - - ER - TY - CHAP T1 - Hypopituitarism in adults A1 - Johnston DG A1 - Al Mrayat M A1 - Kearney T T2 - Conn's current therapy Y1 - 2002/// SN - 0-7216-8744-X SP - 637 EP - 643 N2 - - ER - TY - CHAP T1 - Endocrinology of the gastrointestinal tract A1 - Taheri S A1 - Ghatei MA A1 - Bloom SR T2 - Comprehensive Clinical Endocrinology Y1 - 2002/// M2 - 3rd SN - 0-7234-3185-X SP - 453 EP - 469 N2 - - ER - TY - CHAP T1 - Steroid sulfatase A1 - Newman SP A1 - Purohit A A1 - Reed MJ A1 - Potter BVL T2 - Wiley encyclopedia of molecular medicine Y1 - 2002/// SN - 0-4712-0306-8 SP - 3012 EP - 3013 N2 - - ER - TY - CHAP T1 - Orexins (Hypocretins) A1 - Taheri S A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 2328 EP - 2331 N2 - - ER - TY - CHAP T1 - Bombesin A1 - Howard JK A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 381 EP - 383 N2 - - ER - TY - CHAP T1 - Glucagon- and proglucagon-derived peptides A1 - Bloom SR A1 - Ghatei MA A1 - Taheri S T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 1430 EP - 1434 N2 - - ER - TY - CHAP T1 - Polycystic ovary syndrome:candidate genes for hyperandrogenism and hyperinsulinaemia A1 - Franks S A1 - Cela E A1 - Gharani N A1 - Waterworth D A1 - McCarthy M T2 - Genetics in Endocrinology Y1 - 2002/// SN - 0-7817-1496-6 SP - 267 EP - 273 N2 - - ER - TY - CHAP T1 - Changes in metabolic, inflammatory and endothelial indices of cardiovascular risk A1 - Godsland I T2 - Textbook of men's health Y1 - 2002/// SN - 1-8421-4011-6 SP - 317 EP - 335 N2 - - ER - TY - CHAP T1 - Ovary A1 - Gilling-Smith C A1 - Franks S ED - Thorner MO, Besser GM T2 - In Comprehensive Clinical Endocrinology Y1 - 2002/// PB - Mosby CY - London SP - 375 EP - 393 N2 - - ER - TY - CHAP T1 - Glucagonoma A1 - Frankton S A1 - Bloom SR T2 - Oxford Textbook of Endocrinology and Diabetes Y1 - 2002/// SN - 0-1926-3045-8 SP - 889 EP - 894 N2 - - ER - TY - CHAP T1 - VIPomas A1 - Howard JK A1 - Bloom SR T2 - Oxford Textbook of Endocrinology and Diabetes Y1 - 2002/// SN - 0-1926-3045-8 SP - 895 EP - 899 N2 - - ER - TY - CHAP T1 - The breast A1 - Webber LJ A1 - Franks S T2 - Oxford Textbook of Endocrinology and Diabetes Y1 - 2002/// SN - 0-1926-3045-8 SP - 1202 EP - 1213 N2 - - ER - TY - CHAP T1 - Pancreatic polypeptide A1 - Stanley SA A1 - Ghatei MA A1 - Bloom SR T2 - Wiley Encyclopedia of Molecular Medicine Y1 - 2002/// SN - 0-4713-7494-6 SP - 2381 EP - 2384 N2 - - UR - NULL ER - TY - CHAP T1 - Thyroid disease and osteoporosis A1 - Williams GR T2 - Oxford textbook of endocrinology and diabetes Y1 - 2002/// SN - 0-1926-3045-8 SP - 677 EP - 683 N2 - - ER - TY - CHAP T1 - Hormone replacement therapy and the postmenopausal cardiovascular system: metabolic basis and clinical implications A1 - Stevenson JC T2 - The effective management of the menopause Y1 - 2002/// SN - 1-9030-4424-3 SP - 23 EP - 25 N2 - - ER - TY - CHAP T1 - Endocrinology of the gastrointestinal tract A1 - Taheri S A1 - Ghatei MA A1 - Bloom SR T2 - Comprehensive Clinical Endocrinology Y1 - 2002/// M2 - 3rd SN - 0-7234-3185-X SP - 453 EP - 469 N2 - - ER - TY - CHAP T1 - The orexins/hypocretins - novel hypothalamic neuropeptides with multiple functions A1 - Taheri S A1 - Ghatei MA A1 - Bloom SR Y1 - 2001/// SP - 121 EP - 133 N2 - - ER - TY - CHAP T1 - Bone metabolism A1 - Colston KW A1 - Stevenson JC Y1 - 2001/// M2 - 2nd SN - 0-3337-2306-6 SP - 529 EP - 540 N2 - - ER - TY - CHAP T1 - The orexins/hypocretins - novel hypothalamic neuropeptides with multiple functions A1 - Taheri S A1 - Ghatei MA A1 - Bloom SR Y1 - 2001/// SP - 121 EP - 133 N2 - - ER - TY - CHAP T1 - Genetics of Asthma A1 - Walley AJ A1 - Cookson WOCM ED - R.A. Stockley T2 - Molecular Biology Of The Lung Volume II: Asthma and Cancer Y1 - 1999/// PB - Birkhaüser Verlag CY - Basel, Switzerland SN - 0-8176-5968-4 SP - 23 EP - 39 N2 - - ER - TY - CONF T1 - The central role of thrombin in hemostasis A1 - Crawley, JTB A1 - Zanardelli, S A1 - Chion, CKNK A1 - Lane, DA U1 - 22nd Congress of the International-Society-on Thrombosis-and-Haemostasis Y1 - 2007/07// Y2 - // VL - 5 SP - 95 EP - 101 N2 - - ER - TY - CONF T1 - Androgenic modulation of the immune response A1 - Reed, MJ A1 - Purohit, A A1 - Singh, A A1 - Chander, SK U1 - 10th World Congress on the Menopause Y1 - 2003/// Y2 - // SP - 23 EP - 27 N2 - - ER - TY - CONF T1 - Mechanisms of estrogen action on the cardiovascular system A1 - Stevenson, JC U1 - 3rd International Symposium on Hormonal Carcinogenesis Y1 - 2001/// Y2 - // SP - 365 EP - 371 N2 - - ER - TY - CONF T1 - Regulation of aromatase in normal and malignant breast tissues: The role of the immune system A1 - Singh, A A1 - Purohit, A A1 - Ghilchik, MW A1 - Reed, MJ U1 - 3rd International Symposium on Hormonal Carcinogenesis Y1 - 2001/// Y2 - // SP - 277 EP - 284 N2 - - ER - TY - CONF T1 - Identification of the zinc binding protein in a child with hyperzincaemia as calprotectin (MRP8/MRP14) A1 - Sampson, B A1 - Richmond, P A1 - Golden, BE A1 - Fagerhol, MK A1 - Beattie, JH A1 - Kovar, IZ U1 - 10th International Symposium on Trace Elements in Man and Animals Y1 - 2000/// Y2 - // SP - 1031 EP - 1034 N2 - - ER - TY - CONF T1 - Metallothionein, calmodulin, and trace elements in healing skin wounds A1 - Sampson, B A1 - Lansdown, A A1 - Rowe, A U1 - 10th International Symposium on Trace Elements in Man and Animals Y1 - 2000/// Y2 - // SP - 1038 EP - 1038 N2 - - ER - TY - CONF T1 - Leptin, starvation and the mouse gut A1 - Chaudhary, M A1 - FitzGerald, AJ A1 - Mandir, N A1 - Howard, JK A1 - Lord, GM A1 - Ghatei, MA A1 - Bloom, SR A1 - Goodlad, RA U1 - 3rd Conference on Food and Cancer Prevention Y1 - 2000/// Y2 - // SP - 314 EP - 319 N2 - - ER - TY - CONF T1 - Glucagon like peptide-1 (GLP-1), Neuropeptide Y (NPY) and Melanin Concentrating Hormone (MCH) in the hypothalamic regulation of food intake A1 - Small, CJ A1 - Rossi, M A1 - Bloom, SR U1 - 8th International Congress on Obesity Y1 - 1999/// Y2 - // SP - 279 EP - 288 N2 - - ER - TY - CONF T1 - Action of specific estrogens on vascular cells A1 - Wingrove, CS A1 - Stevenson, JC U1 - 3rd International Symposium on Womens Health and Menopause Y1 - 1999/// Y2 - // VL - 13 SP - 53 EP - 58 N2 - - ER - TY - CONF T1 - Investigations in a child with hyperzincaemia: Partial characterisation of an abnormal zinc binding protein, kinetics and studies of liver pathology A1 - Sampson, B A1 - Kovar, IZ A1 - Beattie, JH A1 - McArdle, HJ A1 - Rauscher, A A1 - Fairweather-Tait, SJ A1 - Jasani, B U1 - 9th International Symposium on Trace Elements in Man and Animals (TEMA 9) Y1 - 1997/// Y2 - // SP - 484 EP - 486 N2 - - ER - TY - CONF T1 - HRT and the secondary prevention of coronary heart disease A1 - Stevenson, JC U1 - 2nd International Symposium on Womens Health in Menopause - Risk Reduction Strategies Y1 - 1997/// Y2 - // VL - 11 SP - 125 EP - 128 N2 - - ER - TY - CONF T1 - Hormone replacement therapy in diabetes A1 - Stevenson, JC A1 - Godsland, IF U1 - 8th International Congress on the Menopause Y1 - 1997/// Y2 - // SP - 315 EP - 322 N2 - - ER - TY - JFULL T1 - ENPP1 K121Q polymorphism and obesity, hyperglycaemia and type 2 diabetes in the prospective DESIR Study. A1 - Meyre, D A1 - Bouatia-Naji, N A1 - Vatin, V A1 - Veslot, J A1 - Samson, C A1 - Tichet, J A1 - Marre, M A1 - Balkau, B A1 - Froguel, P J1 - Diabetologia Y1 - 2007/10// VL - 50 SN - 0012-186X SP - 2090 EP - 2096 N2 - AIMS/HYPOTHESIS: We assessed the predictive value of ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1) SNPs with regard to the risk of developing obesity and/or type 2 diabetes in a large French general population. METHODS: We genotyped the ENPP1 SNPs K121Q (rs1044498), IVS20delT-11 (rs1799774) and A/G+1044TGA (rs7754561) in 5,153 middle-aged participants of the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. RESULTS: At baseline, the K121Q polymorphism was not associated either with BMI (p = 0.98) or with class I obesity (odds ratio [OR] 0.99, p = 0.81), but showed a borderline association with class II obesity (OR 1.65, p = 0.02). The K121Q variant was not associated with any trait during the 9-year follow-up. Pooled analyses both at baseline and at follow-up failed to show any association with hyperglycaemia (OR 1.08, p = 0.28) or type 2 diabetes (OR 1.15, p = 0.38). However, we did show an association of the Q121 allele with the risk of hyperglycaemia (OR 1.45, p = 0.001; n = 265) and type 2 diabetes (OR 1.65, p = 0.01; n = 103) in participants reporting a family history of type 2 diabetes. These results did not remain significant after a Bonferroni correction. The IVS20delT-11 and A/G+1044TGA polymorphisms and the three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA [QdelTG]) were not associated with any trait, either at baseline or at follow-up. CONCLUSIONS/INTERPRETATION: In a general French population we did not find an association of the QdelTG risk haplotype with adult obesity and type 2 diabetes. We detected nominal evidence of association between the K121Q polymorphism and both severe adult obesity at baseline and the risk of hyperglycaemia or type 2 diabetes in participants with a family history of type 2 diabetes in pooled analyses both at baseline and follow-up. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17704904&query_hl=1 ER - TY - JFULL T1 - 3,17-Disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol Derivatives: Synthesis, In Vitro and In Vivo Anticancer Activity. A1 - Bubert, C A1 - Leese, MP A1 - Mahon, MF A1 - Ferrandis, E A1 - Regis-Lydi, S A1 - Kasprzyk, PG A1 - Newman, SP A1 - Ho, YT A1 - Purohit, A A1 - Reed, MJ A1 - Potter, BV J1 - J Med Chem Y1 - 2007/09/06/ VL - 50 SN - 0022-2623 SP - 4431 EP - 4443 N2 - Estradiol-3,17-O,O-bis-sulfamates inhibit steroid sulfatase (STS), carbonic anhydrase (CA), and, when substituted at C-2, cancer cell proliferation and angiogenesis. C-2 Substitution and 17-sulfamate replacement of the estradiol-3,17-O,O-bis-sulfamates were explored with efficient and practical syntheses developed. Evaluation against human cancer cell lines revealed the 2-methyl derivative 27 (DU145 GI50 = 0.38 muM) as the most active novel bis-sulfamate, while 2-ethyl-17-carbamate derivative 52 (GI50 = 0.22 muM) proved most active of its series (cf. 2-ethylestradiol-3,17-O,O-bis-sulfamate 4 GI50 = 0.21 muM). Larger C-2 substituents were deleterious to activity. 2-Methoxy-17-carbamate 50 was studied by X-ray crystallography and was surprisingly 13-fold weaker as an STS inhibitor compared to parent bis-sulfamate 3. The potential of 4 as an orally dosed anti-tumor agent is confirmed using breast and prostate cancer xenografts. In the MDA-MB-231 model, dramatic reduction in tumor growth or regression was observed, with effects sustained after cessation of treatment. 3-O-Sulfamoylated 2-alkylestradiol-17-O-carbamates and sulfamates have considerable potential as anticancer agents. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17696419&query_hl=1 ER - TY - JFULL T1 - The dexamethasone-suppressed corticotropin-releasing hormone stimulation test and the desmopressin test to distinguish Cushing's syndrome from pseudo-Cushing's states. A1 - Martin, NM A1 - Dhillo, WS A1 - Meeran, K J1 - Clin Endocrinol (Oxf) Y1 - 2007/09// VL - 67 SN - 0300-0664 SP - 476 EP - 476 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17581261&query_hl=1 ER - TY - JFULL T1 - Ethnicity and quality of diabetes care in a health system with universal coverage: population-based cross-sectional survey in primary care. A1 - Gray, J A1 - Millett, C A1 - Saxena, S A1 - Netuveli, G A1 - Khunti, K A1 - Majeed, A J1 - J Gen Intern Med Y1 - 2007/09// VL - 22 SN - 1525-1497 SP - 1317 EP - 1320 N2 - BACKGROUND: The UK has a universal health care system that is free at the point of access. Over the past decade, the UK government has implemented an ambitious agenda of quality improvement initiatives in chronic disease management. OBJECTIVE: To assess the quality of diabetes care and intermediate clinical outcomes within a multiethnic population after a sustained period of investment in quality improvement. DESIGN: Population based cross-sectional survey, using electronic general practice records, carried out between November 2005 and January 2006. PATIENTS: Seven thousand six hundred five adults (>or=18 years) with diabetes registered with 32 primary care practices. MEASUREMENTS: Percentage achievement by ethnic group (black, south Asian, or white) of the quality indicators for diabetes in a new pay-for performance contract. RESULTS: There were only modest variations in recording of process measures of care between ethnic groups, with no significant differences in recent measurement of blood pressure, HbA1c, cholesterol, micro-albuminuria, creatinine, or retinopathy screening attendance. Blacks and south Asians were significantly less likely to meet all three national treatment targets for diabetes (HbA1c /= 20 years old, self-reported as US White, US Black, Mexican American, English White, English Black, Bangladeshi, Pakistani, Indian or Chinese the presence of diabetes, defined as self-report of doctor diagnosis or glycated haemoglobin (HbA(1c)) > 6.1%, was ascertained. Comparisons of proportions were made using chi(2)-tests. Receiver operating characteristic (ROC) curves were calculated for BMI, WC and WHR predicting diabetes. Results Other ethnic groups had a higher prevalence of diagnosed diabetes than English Whites. The crude prevalence of diabetes in English Whites of normal weight (BMI < 25 kg/m(2)) was 3.4%. Higher prevalences were seen in other ethnic groups (5.0-10.9%). Based on ROC curves, both WC and WHR had better discriminating ability for diabetes than BMI for both genders and some ethnic groups. Conclusions Ethnic differences exist in the crude prevalence of diabetes, even in those characterized as normal weight by BMI. Thus, clinicians need to exercise caution in interpreting diabetes risk associated with a normal BMI. The use of other anthropometric measures, such as WC or WHR, may improve risk determination across different ethnic groups. More research is needed to determine the thresholds for different anthropometric measures that improve diabetes risk determination. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17725630&query_hl=1 ER - TY - JFULL T1 - Positive replication and linkage disequilibrium mapping of the chromosome 21q22.1 malaria susceptibility locus. A1 - Khor, CC A1 - Vannberg, FO A1 - Chapman, SJ A1 - Walley, A A1 - Aucan, C A1 - Loke, H A1 - White, NJ A1 - Peto, T A1 - Khor, LK A1 - Kwiatkowski, D A1 - Day, N A1 - Scott, A A1 - Berkley, JA A1 - Marsh, K A1 - Peshu, N A1 - Maitland, K A1 - Williams, TN A1 - Hill, AV J1 - Genes Immun Y1 - 2007/08/16/ SN - 1466-4879 N2 - Four cytokine receptor genes are located on Chr21q22.11, encoding the alpha and beta subunits of the interferon-alpha receptor (IFNAR1 and IFNAR2), the beta subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-gamma receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44 kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/12 controls). Within the IFNAR1 gene, a newly studied C --> G single-nucleotide polymorphism (IFNAR1 272354c-g) at position -576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case-control studies. When all three studies were combined, using the Mantel-Haenszel test, the presence of IFNAR1 -576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95% CI: 1.17-1.64; P=1.7 x 10(-4)). This study builds on previous work to further highlight the importance of the type-I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations.Genes and Immunity advance online publication, 16 August 2007; doi:10.1038/sj.gene.6364417. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17703179&query_hl=1 ER - TY - JFULL T1 - Abnormal Preantral Folliculogenesis in Polycystic Ovaries is Associated with Increased Granulosa Cell Division. A1 - Stubbs, SA A1 - Stark, J A1 - Dilworth, SM A1 - Franks, S A1 - Hardy, K J1 - J Clin Endocrinol Metab Y1 - 2007/08/14/ SN - 0021-972X N2 - Context: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women but its etiology remains obscure. Recent data suggest that an intrinsic abnormality of early follicle development in the ovary is key to the pathogenesis of PCOS. We have recently found that in PCOS the proportion of primordial follicles is decreased with a reciprocal increase in the proportion of primary follicles. Objective: To examine whether the accelerated transition of follicles from primordial to primary stages in polycystic ovaries is due to increased granulosa cell (GC) division. Design: Comparison of expression of minichromosome maintenance protein 2 (MCM2; present in the nuclei of cells which are licensed to divide) in archive tissue from normal and polycystic ovaries. Setting: Laboratory-based study. Patients: 16 women with regular cycles (6 with normal and 10 with polycystic ovaries) and 5 anovulatory women with polycystic ovaries (anovPCO), classified histologically, with reference to menstrual history and ultrasound. Main outcome measure: Presence of MCM2 expression in GCs of 1371 follicles. Results: GC proliferation was increased in anovPCO compared with both normal and ovPCO, with an increased proportion of preantral follicles with MCM2-positive GCs (P 4) (67.0%, p=0.003). The A76A at risk T allele was also associated with overeating during meal (p=0.02) in an additional group of 102 non-obese children. None of MCHR2 variants, including the A76A SNP, showed association with adult severe obesity, although a trend for association of the T allele of this variant with food disinhibition (p=0.06) and higher hunger (p=0.09) was found. This variant was not associated with childhood obesity in an independent case-control study including 1,573 subjects (p=0.98). Moreover, the A76A SNP did not explain the linkage on the 6q locus. Conclusions: Our results altogether suggest that MCHR2 is not a major contributor to polygenic obesity and support a modest effect of the A76A SNP on food intake abnormalities in childhood. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17698913&query_hl=1 ER - TY - JFULL T1 - Comorbidity, health care utilisation and process of care measures in patients with congenital heart disease in the UK: cross-sectional population-based study with case control analysis. A1 - Billett, J A1 - Cowie, MR A1 - Gatzoulis, MA A1 - Vonder Muhll, IF A1 - Majeed, A J1 - Heart Y1 - 2007/08/07/ SN - 1468-201X N2 - Background Relatively little is known about the prevalence of comorbidities, patterns of health care utilisation and primary care recording of clinical indicators in patients with congenital heart disease. Methods We conducted a population-based case control study using data from general practices across the UK contributing data to the QRESEARCH primary care database. The subjects were 9952 cases of congenital heart disease and 29837 matched controls. Outcome measures were: Prevalence (%) of selected comorbidities; adjusted odds ratios (OR) for risk of comorbidities, health care utilisation and clinical indicator recording. Results The overall crude prevalence of congenital heart disease was 3.05 per 1000 patients (95% CI 2.90 to 3.11). Prevalence of key comorbidities in congenital heart disease patients ranged from 2.4% (95% CI 2.1 to 2.7) for epilepsy to 9.3% (95% CI 8.8 to 9.9) for hypertension. After adjusting for smoking and deprivation, cases were significantly more likely than controls to have each of the cardiovascular comorbidities e.g. adjusted odds ratio for atrial fibrillation 7.6 (6.1 to 9.3), and also had an increased risk of diabetes, epilepsy and renal disease. Patients with congenital heart disease were heavier users of primary care than controls. congenital heart disease patients were also more likely than controls to have lifestyle and risk factor measurements recorded in primary care e.g. adjusted odds ratio for BMI recording in cases versus controls 1.23 (95% CI 1.16 to 1.31), although overall levels of recording were low. Conclusions There is a significant burden of comorbidity associated with congenital heart disease, and levels of primary care utilisation and referral to secondary care are high in this patient population. The predicted future expansion in the numbers of adults with congenital heart disease owing to improvements in survival will have implications for primary and secondary care, and not just tertiary centres offering specialist care. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17646191&query_hl=1 ER - TY - JFULL T1 - Trends in hospital admissions, in-hospital case fatality and population mortality from congenital heart disease in England, 1994 to 2004. A1 - Billett, J A1 - Majeed, A A1 - Gatzoulis, MA A1 - Cowie, M J1 - Heart Y1 - 2007/08/07/ SN - 1468-201X N2 - Objective To ascertain time trends in rates of hospital admission, operations, in- hospital case fatality and general mortality for congenital heart disease (CHD) in England and Wales. Design Retrospective analysis of Hospital Episodes Statistics for England (April 1995-March 2004) and mortality statistics for England and Wales (1994-2003). Population All NHS patients admitted with a primary diagnosis of CHD to hospitals in England, and all deaths in England and Wales with an underlying cause of CHD. Main outcome measures Age standardised hospital admission rates, case fatality rates and death rates from congenital heart disease. Results Between 1995/96 and 2003/04 the age standardised hospital admission rate for CHD increased from 30.7 per 100,000 (95% CI 29.9-31.4) to 35.5 per 100,000 (95% CI 34.7-36.4) in males and from 28.2 per 100,000 (95% CI 27.4-28.9) to 32.8 per 100,000 (95% CI 32.0-33.6) in females. Between 1997/98 and 2003/04 in-hospital case fatality rates fell from 2.10% (95% CI 1.97-2.22) to 0.83% (95% CI 0.74-0.92). Population mortality fell steadily over the decade 1994 to 2003 in men and women, with the largest proportionate decrease in the 1-4 year age group. Conclusion Admission rates for CHD have increased over the past decade, particularly amongst patients in older age groups. There has also been a significant decrease in both in-hospital case fatality rates and in general population mortality rates. These trends are consistent with improvements in the quality of care for these patients, improvements in survival and the predicted expansion in the number of adults living with CHD. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17646196&query_hl=1 ER - TY - JFULL T1 - Ethnic inequalities in the management and outcome of diabetes in three English Primary Care Trusts. A1 - Soljak, M A1 - Majeed, A A1 - Eliahoo, J A1 - Dornhorst, A J1 - Int J Equity Health Y1 - 2007/08/02/ VL - 6 SN - 1475-9276 SP - 8 EP - 8 N2 - ABSTRACT: BACKGROUND: Although the prevalence of diabetes is three to five times higher in UK South Asians than Whites, there are no reports of the extent of ethnicity recording in routine general practice, and few population-based published studies of the effect of South Asian ethnicity on diabetes care and outcomes. We aimed to determine the effect of ethnicity and healthcare factors in an English population. METHODS: Data was obtained in 2002 on all 21,343 diabetic patients registered in 99% of all computerised general practitioner (GP) practices in three NW London Primary Care Trusts (PCTs), covering a total registered population of 720,000. Previously practices had been provided with training, data entry support and feedback. Treatment and outcome measures included drug treatment and blood pressure (BP), total cholesterol and haemoglobin A1c (HbA1c) levels. RESULTS: Seventy per cent of diabetic patients had a valid ethnicity code. In the relatively older White population, we expected a smaller proportion with a normal BP, but BP differences between the groups were small, suggesting poorer control in non-White ethnic groups. There were also significant differences between ethnic groups in the proportions of insulin-treated patients, with a smaller proportion of South Asians- 4.7% compared to 7.1% of Whites- receiving insulin, although the proportion with a satisfactory HbA1c was smaller- 25.6% compared to 37.9%. CONCLUSIONS: Recording the ethnicity of existing primary care patients is feasible, beginning with patients with established diseases such as diabetes. We have shown that the lower proportion of South Asian patients with good diabetes control, and who are receiving insulin, is at least partly due to poorer standards of care in South Asians, although biological factors could also contribute. This study highlights the need to capture ethnicity data in clinical trials and in routine care, to specifically investigate the reasons for these ethnic differences, and to consider more intensive management of diabetes and education about the disease in South Asian patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17678547&query_hl=1 ER - TY - JFULL T1 - Combined proteomic and metabonomic studies in three genetic forms of the renal Fanconi syndrome. A1 - Vilasi, A A1 - Cutillas, PR A1 - Maher, AD A1 - Zirah, SF A1 - Capasso, G A1 - Norden, AW A1 - Holmes, E A1 - Nicholson, JK A1 - Unwin, RJ J1 - Am J Physiol Renal Physiol Y1 - 2007/08// VL - 293 SN - 0363-6127 SP - F456 EP - F467 N2 - The renal Fanconi syndrome is a defect of proximal tubular function causing aminoaciduria and low-molecular-weight proteinuria. Dent's disease and Lowe syndrome are defined X-linked forms of Fanconi syndrome; there is also an autosomal dominant idiopathic form (ADIF), phenotypically similar to Dent's disease though its gene defect is still unknown. To assess whether their respective gene products are ultimately involved in a common reabsorptive pathway for proteins and low-molecular-mass endogenous metabolites, we compared renal Fanconi urinary proteomes and metabonomes with normal (control) urine using mass spectrometry and (1)H-NMR spectroscopy, respectively. Urine from patients with low-molecular-weight proteinuria secondary to ifosfamide treatment (tubular proteinuria; TP) was also analyzed for comparison. All four of the disorders studied had characteristic proteomic and metabonomic profiles. Uromodulin was the most abundant protein in normal urine, whereas Fanconi urine was dominated by albumin. (1)H-NMR spectroscopic data showed differences in the metabolic profiles of Fanconi urine vs. normal urine, due mainly to aminoaciduria. There were differences in the urinary metabolite and protein compositions between the three genetic forms of Fanconi syndrome: cluster analysis grouped the Lowe and Dent's urinary proteomes and metabonomes together, whereas ADIF and TP clustered together separately. Our findings demonstrate a distinctive "polypeptide and metabolite fingerprint" that can characterize the renal Fanconi syndrome; they also suggest that more subtle and cause-specific differences may exist between the different forms of Fanconi syndrome that might provide novel insights into the underlying mechanisms and cellular pathways affected. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17494094&query_hl=1 ER - TY - JFULL T1 - Thyroid status during skeletal development determines adult bone structure and mineralization. A1 - Bassett, JH A1 - Nordström, K A1 - Boyde, A A1 - Howell, PG A1 - Kelly, S A1 - Vennström, B A1 - Williams, GR J1 - Mol Endocrinol Y1 - 2007/08// VL - 21 SN - 0888-8809 SP - 1893 EP - 1904 N2 - Childhood hypothyroidism delays ossification and bone mineralization, whereas adult thyrotoxicosis causes osteoporosis. To determine how effects of thyroid hormone (T3) during development manifest in adult bone, we characterized TRalpha1(+/m)beta(+/-) mice, which express a mutant T3 receptor (TR) alpha1 with dominant-negative properties due to reduced ligand-binding affinity. Remarkably, adult TRalpha1(+/m)beta(+/-) mice had osteosclerosis with increased bone mineralization even though juveniles had delayed ossification. This phenotype was partially normalized by transient T3 treatment of juveniles and fully reversed in compound TRalpha1(+/m)beta(-/-) mutant mice due to 10-fold elevated hormone levels that allow the mutant TRalpha1 to bind T3. By contrast, deletion of TRbeta in TRalpha1(+/+)beta(-/ -) mice, which causes a 3-fold increase of hormone levels, led to osteoporosis in adults but advanced ossification in juveniles. T3-target gene analysis revealed skeletal hypothyroidism in TRalpha1(m/+)beta(+/-) mice, thyrotoxicosis in TRalpha1(+/+)beta(-/-) mice, and euthyroidism in TRalpha1(+/)beta(-/-) double mutants. Thus, TRalpha1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17488972&query_hl=1 ER - TY - JFULL T1 - Detailed analysis of variation at and around mitochondrial position 16189 in a large Finnish cohort reveals no significant associations with early growth or metabolic phenotypes at age 31 years. A1 - Das, S A1 - Bennett, AJ A1 - Sovio, U A1 - Ruokonen, A A1 - Martikainen, H A1 - Pouta, A A1 - Hartikainen, AL A1 - Franks, S A1 - Elliott, P A1 - Poulton, J A1 - Järvelin, MR A1 - McCarthy, MI J1 - J Clin Endocrinol Metab Y1 - 2007/08// VL - 92 SN - 0021-972X SP - 3219 EP - 3223 N2 - CONTEXT: Mitochondrial dysfunction is increasingly implicated in pathogenesis of adult metabolic disease. Rare mitochondrial (mt) DNA mutations impair glucose homeostasis, but the contribution of common variants is unclear. In small studies, variation within the OriB origin of replication (at mt16189 in particular) has been associated with both early growth and adult metabolic phenotypes and may contribute to life-course relationships between the two. OBJECTIVE: The aim was to study a large well-characterized cohort to determine whether previously reported small-scale associations between OriB sequence variation and early growth and adult metabolic phenotypes are robust. DESIGN/SETTING/PARTICIPANTS: This was a genetic association study of 5470 individuals from the population-based Northern Finland Birth Cohort of 1966, followed prospectively from pregnancy to age 31 yr. MAIN OUTCOME MEASURES: We measured indices of early growth (including birth weight, placental weight, and ponderal index) and adult metabolic homeostasis (including body mass index, fasting glucose and insulin, indices of insulin action and secretion) and their relationship to variation in the OriB region. RESULTS: Previously reported associations could not be confirmed. There were no significant (P < 0.01, uncorrected) associations between OriB sequence variation and measures of early growth including birth weight (P = 0.52, comparing individuals with mt16189T to those with a homopolymeric C-tract) and placental weight (P = 0.49). There were no significant associations with adult metabolic phenotypes including fasting glucose (P = 0.07), fasting insulin (P = 0.42), and homeostatic model assessment-derived measures of insulin sensitivity or secretion (P = 0.45 and P = 0.56, respectively). CONCLUSION: Despite substantial power to detect previously reported effects, mtDNA variations around OriB are not major contributors to variation in early growth and metabolic phenotypes during early adulthood. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17535991&query_hl=1 ER - TY - JFULL T1 - Management of cardiovascular risk in the peri-menopausal woman: a consensus statement of European cardiologists and gynaecologists. A1 - Collins, P A1 - Rosano, G A1 - Casey, C A1 - Daly, C A1 - Gambacciani, M A1 - Hadji, P A1 - Kaaja, R A1 - Mikkola, T A1 - Palacios, S A1 - Preston, R A1 - Simon, T A1 - Stevenson, J A1 - Stramba-Badiale, M J1 - Eur Heart J Y1 - 2007/08// VL - 28 SN - 0195-668X SP - 2028 EP - 2040 N2 - Cardiovascular risk is poorly managed in women, especially during the menopausal transition when susceptibility to cardiovascular events increases. Clear gender differences exist in the epidemiology, symptoms, diagnosis, progression, prognosis, and management of cardiovascular risk. Key risk factors that need to be controlled in the peri-menopausal woman are hypertension, dyslipidaemia, obesity, and other components of the metabolic syndrome, with the avoidance and careful control of diabetes. Hypertension is a particularly powerful risk factor and lowering of blood pressure is pivotal. Hormone replacement therapy is acknowledged as the gold standard for the alleviation of the distressing vasomotor symptoms of the menopause, but the findings of the Women's Health Initiative (WHI) study generated concern for the detrimental effect on cardiovascular events. Thus, hormone replacement therapy cannot be recommended for the prevention of cardiovascular disease. Whether the findings of WHI in older post-menopausal women can be applied to younger peri-menopausal women is unknown. It is increasingly recognized that hormone therapy is inappropriate for older post-menopausal women no longer displaying menopausal symptoms. Both gynaecologists and cardiovascular physicians have an important role to play in identifying peri-menopausal women at risk of cardiovascular morbidity and mortality and should work as a team to identify and manage risk factors such as hypertension. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17644507&query_hl=1 ER - TY - JFULL T1 - Statistical correlation and projection methods for improved information recovery from diffusion-edited NMR spectra of biological samples. A1 - Smith, LM A1 - Maher, AD A1 - Cloarec, O A1 - Rantalainen, M A1 - Tang, H A1 - Elliott, P A1 - Stamler, J A1 - Lindon, JC A1 - Holmes, E A1 - Nicholson, JK J1 - Anal Chem Y1 - 2007/08/01/ VL - 79 SN - 0003-2700 SP - 5682 EP - 5689 N2 - Although NMR spectroscopic techniques coupled with multivariate statistics can yield much useful information for classifying biological samples based on metabolic profiles, biomarker identification remains a time-consuming and complex procedure involving separation methods, two-dimensional NMR, and other spectroscopic tools. We present a new approach to aid complex biomixture analysis that combines diffusion ordered (DO) NMR spectroscopy with statistical total correlation spectroscopy (STOCSY) and demonstrate its application in the characterization of urinary biomarkers and enhanced information recovery from plasma NMR spectra. This method relies on calculation and display of the covariance of signal intensities from the various nuclei on the same molecule across a series of spectra collected under different pulsed field gradient conditions that differentially attenuate the signal intensities according to translational molecular diffusion rates. We term this statistical diffusion-ordered spectroscopy (S-DOSY). We also have developed a new visualization tool in which the apparent diffusion coefficients from DO spectra are projected onto a 1D NMR spectrum (diffusion-ordered projection spectroscopy, DOPY). Both methods either alone or in combination have the potential for general applications to any complex mixture analysis where the sample contains compounds with a range of diffusion coefficients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17585837&query_hl=1 ER - TY - JFULL T1 - Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. A1 - Stutzmann, F A1 - Vatin, V A1 - Cauchi, S A1 - Morandi, A A1 - Jouret, B A1 - Landt, O A1 - Tounian, P A1 - Levy-Marchal, C A1 - Buzzetti, R A1 - Pinelli, L A1 - Balkau, B A1 - Horber, F A1 - Bougnères, P A1 - Froguel, P A1 - Meyre, D J1 - Hum Mol Genet Y1 - 2007/08/01/ VL - 16 SN - 0964-6906 SP - 1837 EP - 1844 N2 - The melanocortin-4 receptor (MC4R) gene pathogenic mutations are the most prevalent forms of monogenic obesity, responsible for approximately 2% of obesity cases, but its role in common obesity is still elusive. We analyzed the contribution of non-synonymous mutations V103I (rs2229616, c.307G > A) and I251L (no rs, c.751A > C) to obesity in 16 797 individuals of European origin from nine independent case-control, population-based and familial cohorts. We observed a consistent negative association of I251L variant (prevalence ranging 0.41-1.21%) with both childhood and adult class III obesity [odds ratio (OR) ranging from 0.25 to 0.76, 0.001 < P-value < 0.05] and with modulation of body mass index (BMI) in general populations, in eight out of nine studies, whereas only one study showed an association between V103I and BMI. Meta-analyses of previous published data with the current ones provided strong evidence of the protective effect of I251L toward obesity (OR = 0.52, P = 3.58 10-5), together with a modest negative association between V103I and obesity (OR = 0.80, P = 0.002). Taken together, gain-of-function mutations I251L and V103I may be responsible for a preventive fraction of obesity of 2%, which mirrors the prevalence of monogenic obesity due to MC4R haploinsufficiency. These results also emphasize the importance of the MC4R signalling tonus to prevent obesity, even in the context of our current obesogenic environment. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17519222&query_hl=1 ER - TY - JFULL T1 - Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases. A1 - Smith, AJ A1 - Tsalenko, A A1 - Sampas, N A1 - Scheffer, A A1 - Yamada, NA A1 - Tsang, P A1 - Ben-Dor, A A1 - Yakhini, Z A1 - Ellis, RJ A1 - Bruhn, L A1 - Laderman, S A1 - Froguel, P A1 - Blakemore, AI J1 - Hum Mol Genet Y1 - 2007/07/31/ SN - 0964-6906 N2 - The discovery of copy number variation in healthy individuals is far from complete, and due to the resolution of detection systems used, the majority of loci reported so far are relatively large ( approximately 65% > 10kb). Applying a two-stage high-resolution array CGH approach to analyse 50 healthy Caucasian males from northern France, we discovered 2208 copy number variants (CNVs) detected by more than one consecutive probe. These clustered into 1469 copy number variant regions (CNVRs), of which 721 are thought to be novel. The majority of these are small (median size 4.4kb) and most have common boundaries, with a coefficient of variation less than 0.1 for 83% of end-points in those observed in multiple samples. Only 6% of the CNVRs analysed showed evidence of both copy number losses and gains at the same site. A further 6089 variants were detected by single probes: 48% of these were observed in more than one individual. In total, 2570 genes were seen to intersect variants: 1284 in novel loci. Genes involved in differentiation and development were significantly overrepresented, and approximately half the genes identified feature in the OMIM database. The biological importance of many of the genes affected, along with the well-conserved nature of the majority of the copy number variants, suggests they could have important implications for phenotype and, thus, be useful for association studies of complex diseases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17666407&query_hl=1 ER - TY - JFULL T1 - Rate of change and instability in body mass index, insulin resistance and lipid metabolism as predictors of atherosclerotic vascular disease. A1 - Christen, A A1 - Efstathiadou, Z A1 - Laspa, E A1 - Johnston, DG A1 - Godsland, IF J1 - J Clin Endocrinol Metab Y1 - 2007/07/31/ SN - 0021-972X N2 - Context: By definition, levels of metabolic risk factors predict atherosclerotic vascular disease (AVD), but the effects of long-term adverse change and instability remain under-researched. Objective: To quantify long-term rates of change and instability in risk factors and relate these measures to clinical AVD outcomes. Design: Prospective cohort study with unmatched and age- and follow-up-matched control analyses. Setting: Teaching hospital day ward. Participants: Four-hundred and sixty-five predominantly healthy white males in an occupational cohort, who had undergone repeated metabolic risk factor measurements (mean observation period 11.6 years, range 2-28), 62 of whom developed clinical AVD. Main outcome measures: Rate of change and instability in metabolic risk factor levels were quantified in each individual by linear regression with time and evaluated as predictors of AVD and coronary and cerebrovascular disease separately. Results: As expected, baseline and/or mean follow-up measures of established risk-factors relating to blood pressure, lipid metabolism and sub-clinical inflammation were significant predictors. Predictors independent of baseline and mean follow-up levels, confirmed in matched and unmatched analyses, were: i) AVD: instability in weight (cases vs controls:2.9% vs +2.5%); ii) coronary heart disease: instability in body mass index (3.0% vs +2.3%), a decline (-0.041 vs -0.011 per decade) and instability (19.1% v 14.6%) in the HDL / non-HDL cholesterol ratio, declining ESR and increasing uric acid; iii) cerebrovascular disease: a decline in insulin sensitivity (-0.394 vs 0.324 per decade). Conclusions: Within an individual, long-term change in metabolic risk factors, as well as their absolute levels, can be important in AVD. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17666474&query_hl=1 ER - TY - JFULL T1 - Dual aromatase-steroid sulfatase inhibitors. A1 - Woo, LW A1 - Bubert, C A1 - Sutcliffe, OB A1 - Smith, A A1 - Chander, SK A1 - Mahon, MF A1 - Purohit, A A1 - Reed, MJ A1 - Potter, BV J1 - J Med Chem Y1 - 2007/07/26/ VL - 50 SN - 0022-2623 SP - 3540 EP - 3560 N2 - By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17580845&query_hl=1 ER - TY - JFULL T1 - Kisspeptin-54 Stimulates Gonadotrophin Release Most Potently During The Preovulatory Phase Of The Menstrual Cycle In Women. A1 - Dhillo, WS A1 - Chaudhri, OB A1 - Thompson, EL A1 - Murphy, KG A1 - Patterson, M A1 - Ramachandran, R A1 - Nijher, GK A1 - Amber, V A1 - Kokkinos, A A1 - Donaldson, M A1 - Ghatei, MA A1 - Bloom, SR J1 - J Clin Endocrinol Metab Y1 - 2007/07/17/ SN - 0021-972X N2 - Context: Kisspeptin, the endogenous ligand of the GPR54 receptor, is a key regulator of the hypothalamo-pituitary-gonadal (HPG) axis. GPR54-null mice exhibit reproductive dysfunction and exogenous kisspeptin potently stimulates the HPG axis in rodents, primates and human males. The effects of kisspeptin administration to human females are unknown. Objective: To investigate the effects of kisspeptin on LH release during the menstrual cycle in female volunteers. Design: Bolus subcutaneous (sc) kisspeptin-54 to female volunteers and measurement of plasma gonadotrophins. Setting: Hospital clinical research facility. Volunteers: Healthy female volunteers with regular menstrual cycles. Intervention: (i) Volunteers received a sc bolus injection of kisspeptin-54 (0, 0.2, 0.4, 0.8, 1.6, 3.2 and 6.4 nmol/kg, n=3-4 per dose) in the follicular phase. (ii) Volunteers (n=8) received a sc bolus injection of either kisspeptin-54 (0.4 nmol/kg) or saline in random order during each phase of the menstrual cycle. Main outcome measures: plasma gonadotrophins. Results: (i) Kisspeptin-54 caused a dose-dependent increase in mean LH over time at doses from 0.2-6.4 nmol/kg. (ii) Kisspeptin-54 increased plasma LH compared to saline injection in all phases of the cycle. The effect of kisspeptin was greatest in the preovulatory phase and least in the follicular phase of the cycle [mean increase in LH over baseline (IU/L)+/-S.E.M.: follicular phase: 0.12+/-0.17; preovulatory phase: 20.64+/-2.91 (P<0.001 vs follicular phase); luteal phase: 2.17+/-0.79 (P<0.01 vs follicular phase)]. Conclusion: Elevation of plasma kisspeptin in human females potently stimulates LH release in the preovulatory phase and provides a novel mechanism for manipulation of the HPG axis in women. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17635940&query_hl=1 ER - TY - JFULL T1 - Experimental and analytical variation in human urine in 1H NMR spectroscopy-based metabolic phenotyping studies. A1 - Maher, AD A1 - Zirah, SF A1 - Holmes, E A1 - Nicholson, JK J1 - Anal Chem Y1 - 2007/07/15/ VL - 79 SN - 0003-2700 SP - 5204 EP - 5211 N2 - 1H NMR spectroscopy potentially provides a robust approach for high-throughput metabolic screening of biofluids such as urine and plasma, but sample handling and preparation need careful optimization to ensure that spectra accurately report biological status or disease state. We have investigated the effects of storage temperature and time on the 1H NMR spectral profiles of human urine from two participants, collected three times a day on four different days. These were analyzed using modern chemometric methods. Analytical and preparation variation (tested between -40 degrees C and room temperature) and time of storage (to 24 h) were found to be much less influential than biological variation in sample classification. Statistical total correlation spectroscopy and discriminant function methods were used to identify the specific metabolites that were hypervariable due to preparation and biology. Significant intraindividual variation in metabolite profiles were observed even for urine collected on the same day and after at least 6 h fasting. The effect of long-term storage at different temperatures was also investigated, showing urine is stable if frozen for at least 3 months and that storage at room temperature for long periods (1-3 months) results in a metabolic profile explained by bacterial activity. Presampling (e.g., previous day) intake of food and medicine can also strongly influence the urinary metabolic profiles indicating that collective detailed participant historical meta data are important for interpretation of metabolic phenotypes and for avoiding false biomarker discovery. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17555297&query_hl=1 ER - TY - JFULL T1 - IkappaB genetic polymorphisms and invasive pneumococcal disease. A1 - Chapman, SJ A1 - Khor, CC A1 - Vannberg, FO A1 - Frodsham, A A1 - Walley, A A1 - Maskell, NA A1 - Davies, CW A1 - Segal, S A1 - Moore, CE A1 - Gillespie, SH A1 - Denny, P A1 - Day, NP A1 - Crook, DW A1 - Davies, RJ A1 - Hill, AV J1 - Am J Respir Crit Care Med Y1 - 2007/07/15/ VL - 176 SN - 1073-449X SP - 181 EP - 187 N2 - RATIONALE: Increasing evidence supports a key role for the transcription factor nuclear factor (NF)-kappaB in the host response to pneumococcal infection. Control of NF-kappaB activity is achieved through interactions with the IkappaB family of inhibitors, encoded by the genes NFKBIA, NFKBIB, and NFKBIE. Rare NFKBIA mutations cause immunodeficiency with severe bacterial infection, raising the possibility that common IkappaB gene polymorphisms confer susceptibility to common bacterial disease. OBJECTIVES: To determine whether polymorphisms in NFKBIA, NFKBIB, and NFKBIE associate with susceptibility to invasive pneumococcal disease (IPD) and thoracic empyema. METHODS: We studied the frequencies of 62 single-nucleotide polymorphisms (SNPs) across NFKBIA, NFKBIB, and NFKBIE in individuals with IPD and control subjects (n=1,060). Significantly associated SNPs were then studied in a group of individuals with thoracic empyema and a second control group (n=632). MEASUREMENTS AND MAIN RESULTS: Two SNPs in the NFKBIA promoter region were associated with protection from IPD in both the initial study group and the pneumococcal empyema subgroup. Significant protection from IPD was observed for carriage of mutant alleles at these two loci on combining the groups (SNP rs3138053: Mantel-Haenszel 2x2 chi2=13.030, p=0.0003; odds ratio [OR], 0.60; 95% confidence interval [CI], 0.45-0.79; rs2233406: Mantel-Haenszel 2x2 chi2=18.927, p=0.00001; OR, 0.55; 95% CI, 0.42-0.72). An NFKBIE SNP associated with susceptibility to IPD but not pneumococcal empyema. None of the NFKBIB SNPs associated with IPD susceptibility. CONCLUSIONS: NFKBIA polymorphisms associate with susceptibility to IPD. Genetic variation in an inhibitor of NF-kappaB therefore not only causes a very rare immunodeficiency state but may also influence the development of common infectious disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17463416&query_hl=1 ER - TY - JFULL T1 - Synthesis of a novel 'smart' bifunctional chelating agent 1-(2-[beta,D-galactopyranosyloxy]ethyl)-7-(1-carboxy-3-[4-aminophenyl]propyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane (Gal-PA-DO3A-NH2) and its Gd(III) complex. A1 - Wardle, NJ A1 - Herlihy, AH A1 - So, PW A1 - Bell, JD A1 - Bligh, SW J1 - Bioorg Med Chem Y1 - 2007/07/15/ VL - 15 SN - 0968-0896 SP - 4714 EP - 4721 N2 - A new synthetic pathway to 1-(2-[beta,D-galactopyranosyloxy]ethyl)-7-(1-carboxy-3-[4-aminophenyl]propyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane (Gal-PA-DO3A-NH2) and 1-(2-[beta,D-galactopyranosyloxy]ethyl)-4,7,10-tris(carboxymethyl)-1, 4,7,10-tetraazacyclododecane (Gal-DO3A) chelating agents was developed involving full hydroxyl- and carboxyl-group protection in precursors to product. Two sequences of cyclen-N-functionalisation were subsequently investigated, one successfully, towards synthesis of the novel 'smart' bifunctional Gal-PA-DO3A-NH2 chelate. The longitudinal proton relaxivities of the neutral [Gd-(Gal-PA-DO3A-NH2)] and [Gd-(Gal-DO3A)] complexes were increased by 28% and 37% in the presence of beta-galactosidase, respectively. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17512738&query_hl=1 ER - TY - JFULL T1 - Nanopipet delivery of individual molecules to cellular compartments for single molecule fluorescence tracking. A1 - Bruckbauer, A A1 - James, P A1 - Zhou, D A1 - Yoon, JW A1 - Excell, D A1 - Korchev, Y A1 - Jones, R A1 - Klenerman, D J1 - Biophys J Y1 - 2007/07/13/ SN - 0006-3495 N2 - We have developed a new method, using a nanopipet, for controlled voltage-driven delivery of individual fluorescently labeled probe molecules to the plasma membrane which we used for single molecule fluorescence tracking (SMT). The advantages of the method are: application of the probe to predefined regions on the membrane; release of only one or a few molecules onto the cell surface; combined with total internal reflection fluorescence (TIRF) microscopy there is very low background due to unbound molecules; the experiment can first be optimized and then repeated on the same cell. We validated the method by performing a SMT study of the diffusion of individual membrane glycoproteins labeled with Atto 647-wheat germ agglutin (WGA) in different surface domains of boar spermatozoa. We found little deviation from Brownian diffusion with a mean diffusion coefficient of 0.79 +/- 0.04 microm(2)/s in the acrosomal region and 0.10 +/- 0.02 microm(2)/s in the postacrosomal region; this difference probably reflects different membrane structure. We also showed that we can analyze diffusional properties of different sub-regions of the cell membrane and probe for the presence of diffusion barriers. This new method should be straightforward to extend to other probes and cells and can be used as a new tool to investigate the cell membrane. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17631532&query_hl=1 ER - TY - JFULL T1 - Measurement of estrone sulfate in postmenopausal women: comparison of direct RIA and GC-MS/MS methods for monitoring response to endocrine therapy in women with breast cancer. A1 - Stanway, SJ A1 - Purohit, A A1 - Reed, MJ J1 - Anticancer Res Y1 - 2007/07// VL - 27 SN - 0250-7005 SP - 2765 EP - 2767 N2 - BACKGROUND: High concentrations of estrone sulfate (EIS) are present in serum of pre- and postmenopausal women. Most assays for this estrogen conjugate involve enzyme hydrolysis and chromatographic purification prior to RIA. We have compared concentrations of serum EIS in postmenopausal women measured by direct RIA or GC-MS/MS methods. PATIENTS AND METHODS: We analysed serum EIS concentrations using a direct 'ultrasensitive' RIA. Serum EIS concentrations were also measured by GC-MS/MS in which estrone conjugates are isolated using a solid-phase technique after which enzyme hydrolysis is employed to liberate estrone prior to GC-MS/MS analysis. RESULTS: We analysed 32 serum samples collected from 8 postmenopausal women participating in a Phase I trial of the steroid sulfatase inhibitor 667 COUMA TE. Concentrations of E1S were 998+/-86 pmol/l (mean +/- sem) and 912+/-114 pmol/l as measured by direct RIA and GC-MS/MS methods respectively. There was a highly significant correlation (r=0.96, p<0.001) between concentrations of EIS measured by the different methods. CONCLUSION: We conclude that the direct 'ultrasensitive' RIA for the measurement of serum EIS provides a reliable method for assaying serum concentrations of this estrogen conjugate and should be useful in monitoring the response to endocrine therapy in postmenopausal women with hormone-dependent breast cancer. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17695445&query_hl=1 ER - TY - JFULL T1 - TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. A1 - Cauchi, S A1 - El Achhab, Y A1 - Choquet, H A1 - Dina, C A1 - Krempler, F A1 - Weitgasser, R A1 - Nejjari, C A1 - Patsch, W A1 - Chikri, M A1 - Meyre, D A1 - Froguel, P J1 - J Mol Med Y1 - 2007/07// VL - 85 SN - 0946-2716 SP - 777 EP - 782 N2 - TCF7L2 variants have been consistently associated with type 2 diabetes (T2D) in populations of different ethnic descent. Among them, the rs7903146 T allele is probably the best proxy to evaluate the effect of this gene on T2D risk in additional ethnic groups. In the present study, we investigated the association between the TCF7L2 rs7903146 polymorphism and T2D in Moroccans (406 normoglycemic individuals and 504 T2D subjects) and in white Austrians (1,075 normoglycemic individuals and 486 T2D subjects). Then, we systematically reviewed the association of this single nucleotide polymorphism (SNP) with T2D risk in a meta-analysis, combining our data with data from previous studies. The allelic odds ratios (ORs) for T2D were 1.56 [1.29-1.89] (p = 2.9 x 10(-6)) and 1.52 [1.29-1.78] (p = 3.0 x 10(-7)) in Moroccans and Austrians, respectively. No heterogeneity was found between these two different populations by Woolf test (chi (2) = 0.04, df = 1, p = 0.84). We found 28 original published association studies dealing with the TCF7L2 rs7903146 polymorphism in T2D. A meta-analysis was then performed on 29,195 control subjects and 17,202 cases. No heterogeneity in genotypic distribution was found (Woolf test: chi (2) = 31.5, df = 26, p = 0.21; Higgins statistic: I2 = 14.1%). A Mantel-Haenszel procedure was then performed to provide a pooled odds ratio (OR) of 1.46 [1.42-1.51] (p = 5.4 x 10(-140)). No publication bias was detected, using the conservative Egger's regression asymmetry test (t = -1.6, df = 25, p = 0.11). Compared to any other gene variants previously confirmed by meta-analysis, TCF7L2 can be distinguished by its tremendous reproducibility of association with T2D and its OR twice as high. In the near future, large-scale genome-wide association studies will fully extend the genome coverage, potentially delivering other common diabetes-susceptibility genes like TCF7L2. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17476472&query_hl=1 ER - TY - JFULL T1 - Systematic review of primary healthcare interventions to improve diabetes outcomes in minority ethnic groups. A1 - Saxena, S A1 - Misra, T A1 - Car, J A1 - Netuveli, G A1 - Smith, R A1 - Majeed, A J1 - J Ambul Care Manage Y1 - 2007/07// VL - 30 SN - 0148-9917 SP - 218 EP - 230 N2 - OBJECTIVES: To systematically review the effectiveness of primary care interventions on glycaemic control and cardiovascular risk factors in minority ethnic groups with diabetes. RESEARCH DESIGN AND METHODS: We searched electronic databases, the Cochrane Library, and research registers to December 2006, using multiple search terms related to ethnicity and diabetes. We examined bibliographies of retrieved articles and corresponded with authors. We included randomized controlled trials, controlled clinical trials, and cohort studies. Two reviewers independently assessed study eligibility and quality. RESULTS: Nine studies including 2565 patients met our inclusion criteria. Two main models of care were identified: (1) case management, with specialist diabetes nurses and community health workers and (2) the use of the services of link workers from minority ethnic groups to guide people with diabetes. Heterogeneity of the studies prevented us from carrying out a meta-analysis. Case management improved glycaemic control (reduction in HbA1c range -0.5% to -1.75%). Small but statistically significant reductions in other cardiovascular risk factors were reported with both models. CONCLUSIONS: In minority ethnic groups with diabetes, case management improves glycaemic control and cardiovascular risk factors and link workers improve cardiovascular risk factor control. However, their relative effectiveness, cost, and sustainability of changes over time warrant further evaluation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17581434&query_hl=1 ER - TY - JFULL T1 - Mechanisms of disease: lessons from ethnicity in the role of triglyceride metabolism in ischemic heart disease. A1 - Godsland, IF A1 - Johnston, DG A1 - Chaturvedi, N J1 - Nat Clin Pract Endocrinol Metab Y1 - 2007/07// VL - 3 SN - 1745-8374 SP - 530 EP - 538 N2 - Mean risk factor levels in various ethnic groups illustrate the potential importance of triglyceride metabolism in the risk for ischemic heart disease (IHD). Serum triglyceride concentrations are a surrogate for a range of potentially atherogenic disturbances in lipoprotein species, including increased concentrations of remnants of VLDL and chylomicron metabolism, increased small, dense LDL concentrations and reduced HDL concentrations. Differences between at-risk groups in lipoprotein profiles reflect alterations in the metabolism of triglycerides that might be greater than differences observed when only circulating triglyceride concentrations are measured. This atherogenic lipoprotein profile is typically found in association with increased visceral fat, insulin resistance and type 2 diabetes and might be a characteristic of Asian Indian ethnicity. By contrast, despite being relatively insulin resistant, Afro-Caribbean men in the UK have a low risk of IHD and lack the adverse lipoprotein profile. This could result from secretion of relatively large proportions of their VLDL as small, triglyceride-poor particles, levels of which are not augmented in response to loss of insulin action. These considerations re-endorse the potential importance of triglyceride metabolism in IHD and present opportunities for identifying useful areas in which drug targets for reducing IHD risk can be sought. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17581622&query_hl=1 ER - TY - JFULL T1 - The central role of thrombin in hemostasis. A1 - Crawley, JT A1 - Zanardelli, S A1 - Chion, CK A1 - Lane, DA J1 - J Thromb Haemost Y1 - 2007/07// VL - 5 Suppl 1 SN - 1538-7933 SP - 95 EP - 101 N2 - Following vascular injury, blood loss is controlled by the mechanisms of hemostasis. During this process, the serine proteinase, thrombin, is generated both locally and rapidly at sites of vessel damage. It plays a pivotal role in clot promotion and inhibition, and cell signaling, as well as additional processes that influence fibrinolysis and inflammation. These functions involve numerous cleavage reactions, which must be tightly coordinated. Failure to do so can lead to either bleeding or thrombosis. The crystal structures of thrombin, in combination with biochemical analyses of thrombin mutants, have provided insight into the ways in which thrombin functions, and how its different activities are modulated. Many of the interactions of thrombin are facilitated by exosites on its surface that bind to its substrates and/or cofactors. The use of cofactors not only extends the range of thrombin specificity, but also enhances its catalytic efficiency for different substrates. This explains a paradox (i.e. thrombin is a specific proteinase, and yet one that has multiple, and sometimes opposing, substrate reactions). In this review, we describe the context in which thrombin acts during hemostasis and explain the roles that its exosites and cofactors play in directing thrombin function. Thereafter, we develop the concept of cofactor competition as a means by which the activities of thrombin are controlled. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17635715&query_hl=1 ER - TY - JFULL T1 - Continuity in clinical education. A1 - Noimark, DJ A1 - Meeran, K J1 - N Engl J Med Y1 - 2007/06/21/ VL - 356 SN - 1533-4406 SP - 2650 EP - 2650 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17600894&query_hl=1 ER - TY - JFULL T1 - Diagnostic scope of and exposure to primary care physicians in Australia, New Zealand, and the United States: cross sectional analysis of results from three national surveys. A1 - Bindman, AB A1 - Forrest, CB A1 - Britt, H A1 - Crampton, P A1 - Majeed, A J1 - BMJ Y1 - 2007/06/16/ VL - 334 SN - 1468-5833 SP - 1261 EP - 1261 N2 - OBJECTIVES: To compare mix of patients, scope of practice, and duration of visit in primary care physicians in Australia, New Zealand, and the United States. DESIGN: Comparison of three comparable cross sectional surveys performed in 2001-2. Physicians completed a questionnaire on patients' demographics, diagnoses, and duration of visit. SETTING: Primary care practice. PARTICIPANTS: 79,790 office visits in Australia, 10,064 in New Zealand, and 25,838 in the US. MAIN OUTCOME MEASURES: Diagnostic codes were mapped to the Johns Hopkins expanded diagnostic clusters. Scope of practice was defined as the number of expanded diagnostic clusters accounting for 75% of all managed problems related to morbidity. Exposure to primary care was calculated from duration of visits recorded by the physician, and reports on rates of visits to primary care for each country. RESULTS: In each country, primary care physicians managed an average of 1.4 morbidity related problems per visit. In the US, 46 expanded diagnostic clusters accounted for 75% of problems managed compared with 52 in Australia, and 57 in New Zealand. Correlations in the frequencies of managed health problems between countries were high (0.87-0.97 for pairwise comparisons). Though primary care visits were longer in the US than in New Zealand and Australia, the per capita annual exposure to primary care physicians in the US (29.7 minutes) was about half of that in New Zealand (55.5 minutes) and about a third of that in Australia (83.4 minutes) because of higher rates of visits to primary care in these countries. CONCLUSIONS: Despite differences in the supply and financing of primary care across countries, many aspects of the clinical practice of primary care physicians are remarkably similar in Australia, New Zealand, and the US. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17504790&query_hl=1 ER - TY - JFULL T1 - Impact of a pay-for-performance incentive on support for smoking cessation and on smoking prevalence among people with diabetes. A1 - Millett, C A1 - Gray, J A1 - Saxena, S A1 - Netuveli, G A1 - Majeed, A J1 - CMAJ Y1 - 2007/06/05/ VL - 176 SN - 1488-2329 SP - 1705 EP - 1710 N2 - BACKGROUND: Many people with diabetes continue to smoke despite being at high risk of cardiovascular disease. We examined the impact of a pay-for-performance incentive in the United Kingdom introduced in 2004 as part of the new general practitioner contract to improve support for smoking cessation and to reduce the prevalence of smoking among people with chronic diseases such as diabetes. METHODS: We performed a population-based longitudinal study of the recorded delivery of cessation advice and the prevalence of smoking using electronic records of patients with diabetes obtained from participating general practices. The survey was carried out in an ethnically diverse part of southwest London before (June-October 2003) and after (November 2005-January 2006) the introduction of a pay-for-performance incentive. RESULTS: Significantly more patients with diabetes had their smoking status ever recorded in 2005 than in 2003 (98.8% v. 90.0%, p <0.001). The proportion of patients with documented smoking cessation advice also increased significantly over this period, from 48.0% to 83.5% (p < 0.001). The prevalence of smoking decreased significantly from 20.0% to 16.2% (p < 0.001). The reduction over the study period was lower among women (adjusted odds ratio 0.71, 95% confidence interval 0.53-0.95) but was not significantly different in the most and least affluent groups. In 2005, smoking rates continued to differ significantly with age (10.6%-25.1%), sex (women, 11.5%; men, 20.6%) and ethnic background (4.9%-24.9%). INTERPRETATION: The introduction of a pay-for-performance incentive in the United Kingdom increased the provision of support for smoking cessation and was associated with a reduction in smoking prevalence among patients with diabetes in primary health care settings. Health care planners in other countries may wish to consider introducing similar incentive schemes for primary care physicians. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17548383&query_hl=1 ER - TY - JFULL T1 - Role of central nervous system and ovarian insulin receptor substrate 2 signaling in female reproductive function in the mouse. A1 - Neganova, I A1 - Al-Qassab, H A1 - Heffron, H A1 - Selman, C A1 - Choudhury, AI A1 - Lingard, SJ A1 - Diakonov, I A1 - Patterson, M A1 - Ghatei, M A1 - Bloom, SR A1 - Franks, S A1 - Huhtaniemi, I A1 - Hardy, K A1 - Withers, DJ J1 - Biol Reprod Y1 - 2007/06// VL - 76 SN - 0006-3363 SP - 1045 EP - 1053 N2 - Insulin receptor signaling regulates female reproductive function acting in the central nervous system and ovary. Female mice that globally lack insulin receptor substrate (IRS) 2, which is a key mediator of insulin receptor action, are infertile with defects in hypothalamic and ovarian functions. To unravel the tissue-specific roles of IRS2, we examined reproductive function in female mice that lack Irs2 only in the neurons. Surprisingly, these animals had minimal defects in pituitary and ovarian hormone levels, ovarian anatomy and function, and breeding performance, which indicates that the central nervous system IRS2 is not an obligatory signaling component for the regulation of reproductive function. Therefore, we undertook a detailed analysis of ovarian function in a novel Irs2 global null mouse line. Comparative morphometric analysis showed reduced follicle size, increased numbers of atretic follicles, as well as impaired oocyte growth and antral cavity development in Irs2 null ovaries. Granulosa cell proliferation was also defective in the Irs2 null ovaries. Furthermore, the insulin- and eCG-stimulated phosphoinositide-3-OH kinase signaling events, which included phosphorylation of Akt/protein kinase B and glycogen synthase kinase 3-beta, were impaired, whereas mitogen-activated protein kinase signaling was preserved in Irs2 null ovaries. These abnormalities were associated with reduced expression of cyclin D2 and increased CDKN1B levels, which indicates dysregulation of key components of the cell cycle apparatus implicated in ovarian function. Our data suggest that ovarian rather than central nervous system IRS2 signaling is important in the regulation of female reproductive function. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17329594&query_hl=1 ER - TY - JFULL T1 - New ABCC8 mutations in relapsing neonatal diabetes and clinical features. A1 - Vaxillaire, M A1 - Dechaume, A A1 - Busiah, K A1 - Cavé, H A1 - Pereira, S A1 - Scharfmann, R A1 - de Nanclares, GP A1 - Castano, L A1 - Froguel, P A1 - Polak, M A1 - SUR1-Neonatal Diabetes Study Group J1 - Diabetes Y1 - 2007/06// VL - 56 SN - 0012-1797 SP - 1737 EP - 1741 N2 - Activating mutations in the ABCC8 gene that encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the pancreatic islet ATP-sensitive K(+) channel (K(ATP) channel) cause both permanent and transient neonatal diabetes. Recently, we have described the novel mechanism where basal Mg-nucleotide-dependent stimulatory action of SUR1 on the Kir6.2 pore is increased. In our present study, we identified six new heterozygous ABCC8 mutations, mainly in patients presenting the transient form of neonatal diabetes (six of eight), with a median duration of initial insulin therapy of 17 months (range 0.5-38.0). Most of these mutations map to key functional domains of SUR1. Whereas Kir6.2 mutations are a common cause of permanent neonatal diabetes and in a few cases associate with the DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome, SUR1 mutations are more frequent in transient (52%) compared with permanent (14%) neonatal diabetes cases screened for ABCC8 in our series. Although ketoacidosis is frequent at presentation, SUR1 mutations associate mainly with transient hyperglycemia, with possible recurrence later in life. One-half of the SUR1 neonatal diabetic patients presented with de novo mutations. In some familial cases, diabetes is not always present in the adult carriers of SUR1 mutations, supporting variability in their clinical expressivity that remains to be fully explained. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17389331&query_hl=1 ER - TY - JFULL T1 - Coexistence in the same family of both focal and diffuse forms of hyperinsulinism A1 - Valayannopoulos, V A1 - Vaxillaire, M A1 - Aigrain, Y A1 - Jaubert, F A1 - Bellanne-Chantelot, C A1 - Ribeiro, MJ A1 - Brunelle, F A1 - Froguel, P A1 - Robert, JJ A1 - Polak, M A1 - Nihoul-Fekete, C A1 - de Lonlay, P J1 - DIABETES CARE Y1 - 2007/06// VL - 30 SN - 0149-5992 SP - 1590 EP - 1592 ER - TY - JFULL T1 - National trends in the use and costs of anti-obesity medications in England 1998-2005. A1 - Srishanmuganathan, J A1 - Patel, H A1 - Car, J A1 - Majeed, A J1 - J Public Health (Oxf) Y1 - 2007/06// VL - 29 SN - 1741-3842 SP - 199 EP - 202 N2 - BACKGROUND: To report the trends in the use and costs of anti-obesity medications in England from 1998 to 2005. METHODS: We analysed data on all community anti-obesity drug prescriptions in England collated by the prescription cost analysis system. RESULTS: Between 1998 and 2005, Orlistat prescriptions rose 36-fold from 17,880 to 646,700 and total cost increased by over 35-fold. Sibutramine prescriptions rose from 2001 to 2005 from 53,393 to 227,000, a 4-fold increase. Although prescriptions of Orlistat and Sibutramine have increased substantially since they were first introduced, the rate of growth decreased substantially in recent years until 2005, when a significant increase in the number and cost of prescriptions for orlistat occurred yet again. CONCLUSIONS: We found a large increase in the use and costs of anti-obesity prescriptions, consistent with the increased awareness of obesity amongst health care professionals and the public. Despite this large increase, there are still no head-to-head studies at a national level that directly compare all anti-obesity medication in use in the UK. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17494061&query_hl=1 ER - TY - JFULL T1 - Variation in FTO contributes to childhood obesity and severe adult obesity. A1 - Dina, C A1 - Meyre, D A1 - Gallina, S A1 - Durand, E A1 - Körner, A A1 - Jacobson, P A1 - Carlsson, LM A1 - Kiess, W A1 - Vatin, V A1 - Lecoeur, C A1 - Delplanque, J A1 - Vaillant, E A1 - Pattou, F A1 - Ruiz, J A1 - Weill, J A1 - Levy-Marchal, C A1 - Horber, F A1 - Potoczna, N A1 - Hercberg, S A1 - Le Stunff, C A1 - Bougnères, P A1 - Kovacs, P A1 - Marre, M A1 - Balkau, B A1 - Cauchi, S A1 - Chèvre, JC A1 - Froguel, P J1 - Nat Genet Y1 - 2007/06// VL - 39 SN - 1061-4036 SP - 724 EP - 726 N2 - We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17496892&query_hl=1 ER - TY - JFULL T1 - Predictors of progression of coronary artery calcium in type 2 diabetes: The predict study A1 - Elkeles, RS A1 - Rubens, M A1 - Godsland, IF A1 - Nugara, F A1 - Richmond, W A1 - Flather, MD J1 - ATHEROSCLEROSIS SUPP Y1 - 2007/06// VL - 8 SN - 1567-5688 SP - 8 EP - 8 ER - TY - JFULL T1 - Basolateral P2X4-like receptors regulate the extracellular ATP-stimulated epithelial Na+ channel activity in renal epithelia. A1 - Zhang, Y A1 - Sanchez, D A1 - Gorelik, J A1 - Klenerman, D A1 - Lab, M A1 - Edwards, C A1 - Korchev, Y J1 - Am J Physiol Renal Physiol Y1 - 2007/06// VL - 292 SN - 0363-6127 SP - F1734 EP - F1740 N2 - Extracellular ATP initiates potent effects on sodium transport across renal epithelia through membrane-associated purinergic receptors. Dependent on the location of these receptors, ATP either inhibits or stimulates sodium reabsorption. Using A6 cells, transepithelial electrical resistance measurements, and scanning ion conductance microscopy, we have identified the purinergic receptors involved in the stimulatory action on the epithelial cell basolateral plasma membrane. Addition of the potent P2X(4) receptor agonist 2-methylthio-ATP (2MeSATP) to the basolateral side of the A6 monolayer stimulated amiloride-sensitive sodium conductance and produced similar cell morphological changes to those found with ATPgammaS, aldosterone, or hypotonic stress. The agonist potency order determined by sodium conductance changes of the monolayer was: 2MeSATP >or= ATPgammaS > CTP, a similar agonist potency profile to that of cloned P2X(4) receptors but with higher sensitivity for beta, gamma-methylene-ATP and alpha,beta-methylene-ATP. We further demonstrated that the ATP effect on sodium transport was potentiated by ivermectin, not blocked by suramin and PPADS, enhanced by Zn(2+) but not by Cu(2+), and significantly reduced but not totally inhibited by brilliant blue G. These results led us to conclude that basolateral P2X(4)-like receptors were involved. We suggest that there is a reciprocal purinergic system acting both at a basolateral and apical location for control of Na(+) transport. This requires a mechanism within the cell that leads to either basolateral or apical ATP release to regulate renal tubular function. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17356127&query_hl=1 ER - TY - JFULL T1 - Ethnic disparities in diabetes management and pay-for-performance in the UK: the Wandsworth Prospective Diabetes Study. A1 - Millett, C A1 - Gray, J A1 - Saxena, S A1 - Netuveli, G A1 - Khunti, K A1 - Majeed, A J1 - PLoS Med Y1 - 2007/06// VL - 4 SN - 1549-1676 SP - e191 EP - e191 N2 - BACKGROUND: Pay-for-performance rewards health-care providers by paying them more if they succeed in meeting performance targets. A new contract for general practitioners in the United Kingdom represents the most radical shift towards pay-for-performance seen in any health-care system. The contract provides an important opportunity to address disparities in chronic disease management between ethnic and socioeconomic groups. We examined disparities in management of people with diabetes and intermediate clinical outcomes within a multiethnic population in primary care before and after the introduction of the new contract in April 2004. METHODS AND FINDINGS: We conducted a population-based longitudinal survey, using electronic general practice records, in an ethnically diverse part of southwest London. Outcome measures were prescribing levels and achievement of national treatment targets (HbA1c < or = 7.0%; blood pressure [BP] < 140/80 mm Hg; total cholesterol < or = 5 mmol/l or 193 mg/dl). The proportion of patients reaching treatment targets for HbA1c, BP, and total cholesterol increased significantly after the implementation of the new contract. The extents of these increases were broadly uniform across ethnic groups, with the exception of the black Caribbean patient group, which had a significantly lower improvement in HbA1c (adjusted odds ratio [AOR] 0.75, 95% confidence interval [CI] 0.57-0.97) and BP control (AOR 0.65, 95% CI 0.53-0.81) relative to the white British patient group. Variations in prescribing and achievement of treatment targets between ethnic groups present in 2003 were not attenuated in 2005. CONCLUSIONS: Pay-for-performance incentives have not addressed disparities in the management and control of diabetes between ethnic groups. Quality improvement initiatives must place greater emphasis on minority communities to avoid continued disparities in mortality from cardiovascular disease and the other major complications of diabetes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17564486&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 - Examining the candidacy of ghrelin as a gene responsible for variation in adult stature in a United Kingdom population with type 2 diabetes. A1 - Gueorguiev, M A1 - Wiltshire, S A1 - Garcia, EA A1 - Mein, C A1 - Lecoeur, C A1 - Kristen, B A1 - Allotey, R A1 - Hattersley, AT A1 - Walker, M A1 - O'rahilly, S A1 - Froguel, P A1 - Grossman, AB A1 - McCarthy, MI A1 - Hitman, GA A1 - Korbonits, M J1 - J Clin Endocrinol Metab Y1 - 2007/06// VL - 92 SN - 0021-972X SP - 2201 EP - 2204 N2 - CONTEXT: Recently, a quantitative trait locus for stature was reported on chromosome 3p26 in patients with type 2 diabetes. OBJECTIVE: Given that ghrelin is a peptide involved in GH release and located on 3p26, we hypothesized that variation within its gene (GHRL) may be responsible for the quantitative trait locus on 3p26. DESIGN: The evidence for linkage around GHRL was refined with the genotyping of an additional four microsatellites (D3S4545, D3S1537, D3S1597, and D3S3611), giving a total of 27 markers, followed by multipoint variance components linkage analysis. Probands from the linkage families were typed for five common single nucleotide polymorphisms (SNPs) within GHRL and tested for association with adult stature using haplotype trend regression. RESULTS: The maximum multipoint evidence for linkage between adult stature and the 27 microsatellites yielded an LOD score of 2.58 (P = 0.0003) between D3S1297 and D3S1304. Five common (frequency of > or =5%) SNPs were typed in the probands [two promoter SNPs (rs27647 and rs26802), two exonic (rs696217 and rs4684677), and one intronic (rs35683)] capturing 80% of the total common variation in GHRL. No association was found between any SNP (or haplotypes thereof) and adult stature. CONCLUSION: Common genetic variation within GHRL is not responsible for variation in adult stature in this population. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17389697&query_hl=1 ER - TY - JFULL T1 - Diabetes prevalence, process of care and outcomes in relation to practice size, caseload and deprivation: national cross-sectional study in primary care. A1 - Millett, C A1 - Car, J A1 - Eldred, D A1 - Khunti, K A1 - Mainous, AG A1 - Majeed, A J1 - J R Soc Med Y1 - 2007/06// VL - 100 SN - 0141-0768 SP - 275 EP - 283 N2 - OBJECTIVE: To examine the association between practice list size, deprivation and the quality of care of patients with diabetes. DESIGN: Population-based cross-sectional study using Quality and Outcomes Framework data. SETTING: England and Scotland. PARTICIPANTS: 55,522,778 patients and 8970 general practices with 1,852,762 people with diabetes. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Seventeen process and surrogate outcome measures of diabetes care. RESULTS: The prevalence of diabetes was 3.3%. Prevalence differed with practice list size and deprivation: smaller and more deprived practices had a higher mean prevalence than larger and more affluent practices (3.8% versus 2.8%). Practices with large patient list sizes had the highest quality of care scores, even after stratifying for deprivation. However, with the exception of retinal screening, peripheral pulses and neuropathy testing, differences in achievement between small and large practices were modest (<5%). Small practices performed nearly as well as the largest practices in achievement of intermediate outcome targets for HbA1c, blood pressure and cholesterol (smallest versus largest practices: 57.4% versus 58.7%; 70.7% versus 70.7%; and 69.5% versus 72.7%, respectively). Deprivation had a negative effect on the achieved scores and this was more pronounced for smaller practices. CONCLUSION: Our study provides some evidence of a volume-outcome association in the management of diabetes in primary care; this appears most pronounced in deprived areas. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17541098&query_hl=1 ER - TY - JFULL T1 - Hypogonadal bone loss: sex steroids or gonadotropins? A1 - Williams, GR J1 - Endocrinology Y1 - 2007/06// VL - 148 SN - 0013-7227 SP - 2610 EP - 2612 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17507579&query_hl=1 ER - TY - JFULL T1 - Relation of fasting plasma peptide YY to glucose metabolism and cardiovascular risk factors after restrictive bariatric surgery. A1 - Hanusch-Enserer, U A1 - Ghatei, MA A1 - Cauza, E A1 - Bloom, SR A1 - Prager, R A1 - Roden, M J1 - Wien Klin Wochenschr Y1 - 2007/06// VL - 119 SN - 0043-5325 SP - 291 EP - 296 N2 - INTRODUCTION: Surgically induced weight loss results in reduction of comorbidities in severely obese humans. Reversal of abnormal secretion of appetite-regulating gut hormones such as peptide YY (PYY) could be contributing to the improvement of cardiovascular risk factors. METHODS: Severely obese patients (n = 42, BMI = 45.7 +/- 5.3 kg/m(2)) underwent clinical examination and blood sampling for measurement of PYY, plasma lipids, oral glucose tolerance testing and assessment of insulin secretion (HOMA-%B) and action (HOMA-R, QUICKI) before and during 12 months following gastric banding. Comparisons were made at each time point of the study as well as across the total study period. RESULTS: Weight loss after bariatric surgery resulted in improvement of insulin resistance by 54% (p < 0.03) and plasma triglycerides by 26% (p < 0.01) without changes in fasting PYY (16.2 +/- 8.7 pmol/l at baseline, 15.1 +/- 6.3 pmol/l at 12 months). Fasting PYY correlated negatively with plasma total cholesterol at baseline (p = 0.02) but was not associated with body weight, body mass or abdominal diameter. Individual changes in PYY (DeltaPYY) related to changes in insulin (Deltafasting insulin) at 12 months (r = -0.582, p = 0.02) and HOMA-B at 6 months (r = -0.677, p = 0.006) and 12 months (r = -0.660, p = 0.007). Diabetic status had no impact on these correlations. DISCUSSION: PYY correlates with a major cardiovascular risk factor and surrogate parameters of insulin secretion but not to weight loss or body mass in severe obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17571233&query_hl=1 ER - TY - JFULL T1 - HRT and the primary prevention of cardiovascular disease. A1 - Stevenson, JC J1 - Maturitas Y1 - 2007/05/20/ VL - 57 SN - 0378-5122 SP - 31 EP - 34 N2 - Observational studies have consistently shown a benefit of hormone replacement therapy (HRT) on coronary heart disease (CHD), but some randomised studies have not shown any significant effect. Thus questions still remains as to whether HRT is beneficial for CHD, and in whom this benefit might be achieved. The biological effects of oestrogen on the cardiovascular system have been extensively studied, and beneficial effects on metabolic CHD risk factors, as well as on arterial function and on surrogate clinical markers of CHD, have been demonstrated. Thus it seems implausible that HRT should not benefit CHD in postmenopausal women. Most randomised trials using clinical outcomes have studied just one dose of one HRT regimen, a dose inappropriately high with the average starting age of the participants being in their mid-60s. The observational population studies largely comprise women starting on HRT at appropriate dose around the age of menopause, i.e. early 50s. In fact, it was the older women in the randomised trials that failed to show benefit, whereas there was a trend to benefit in the younger ones for whom the starting dose of HRT was appropriate. Furthermore, a pilot study of lower dose HRT in older women did not show any cardiovascular harm. Inappropriately high doses of oestrogen could cause cardiovascular harm due to transient disturbances in thrombogenesis and vascular remodelling. Whilst the greatest CHD benefit may be seen by starting HRT in the early postmenopause, this does not exclude benefit in older women given appropriate low dose therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17383835&query_hl=1 ER - TY - JFULL T1 - Use of administrative data or clinical databases as predictors of risk of death in hospital: comparison of models. A1 - Aylin, P A1 - Bottle, A A1 - Majeed, A J1 - BMJ Y1 - 2007/05/19/ VL - 334 SN - 1468-5833 SP - 1044 EP - 1044 N2 - OBJECTIVE: To compare risk prediction models for death in hospital based on an administrative database with published results based on data derived from three national clinical databases: the national cardiac surgical database, the national vascular database and the colorectal cancer study. DESIGN: Analysis of inpatient hospital episode statistics. Predictive model developed using multiple logistic regression. SETTING: NHS hospital trusts in England. PATIENTS: All patients admitted to an NHS hospital within England for isolated coronary artery bypass graft (CABG), repair of abdominal aortic aneurysm, and colorectal excision for cancer from 1996-7 to 2003-4. MAIN OUTCOME MEASURES: Deaths in hospital. Performance of models assessed with receiver operating characteristic (ROC) curve scores measuring discrimination (<0.7=poor, 0.7-0.8=reasonable, >0.8=good) and both Hosmer-Lemeshow statistics and standardised residuals measuring goodness of fit. RESULTS: During the study period 152 523 cases of isolated CABG with 3247 deaths in hospital (2.1%), 12 781 repairs of ruptured abdominal aortic aneurysm (5987 deaths, 46.8%), 31 705 repairs of unruptured abdominal aortic aneurysm (3246 deaths, 10.2%), and 144,370 colorectal resections for cancer (10,424 deaths, 7.2%) were recorded. The power of the complex predictive model was comparable with that of models based on clinical datasets with ROC curve scores of 0.77 (v 0.78 from clinical database) for isolated CABG, 0.66 (v 0.65) and 0.74 (v 0.70) for repairs of ruptured and unruptured abdominal aortic aneurysm, respectively, and 0.80 (v 0.78) for colorectal excision for cancer. Calibration plots generally showed good agreement between observed and predicted mortality. CONCLUSIONS: Routinely collected administrative data can be used to predict risk with similar discrimination to clinical databases. The creative use of such data to adjust for case mix would be useful for monitoring healthcare performance and could usefully complement clinical databases. Further work on other procedures and diagnoses could result in a suite of models for performance adjusted for case mix for a range of specialties and procedures. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17452389&query_hl=1 ER - TY - JFULL T1 - Creatine supplements in patients with idiopathic inflammatory myopathies who are clinically weak after conventional pharmacologic treatment: Six-month, double-blind, randomized, placebo-controlled trial. A1 - Chung, YL A1 - Alexanderson, H A1 - Pipitone, N A1 - Morrison, C A1 - Dastmalchi, M A1 - Ståhl-Hallengren, C A1 - Richards, S A1 - Thomas, EL A1 - Hamilton, G A1 - Bell, JD A1 - Lundberg, IE A1 - Scott, DL J1 - Arthritis Rheum Y1 - 2007/05/15/ VL - 57 SN - 0004-3591 SP - 694 EP - 702 N2 - OBJECTIVE: To test the hypothesis that oral creatine supplements with exercise are more effective than exercise alone in improving muscle function in patients with established dermatomyositis or polymyositis receiving chronic medical therapies who are clinically weak yet stable. METHODS: In a 6-month, 2-center, double-blind, randomized controlled trial, patients were randomized to receive oral creatine supplements (8 days, 20 gm/day then 3 gm/day) or placebo. All patients followed a home exercise program. The primary outcome was aggregate functional performance time (AFPT), reflecting the ability to undertake high-intensity exercise. Secondary outcomes included a functional index measuring endurance and muscle bioenergetics on (31)P magnetic resonance spectroscopy ((31)P MRS). Patients were receiving stable immunosuppressive treatment and/or corticosteroids. RESULTS: A total of 37 patients with polymyositis or dermatomyositis were randomized (19 to creatine, 18 to placebo); 29 completed 6 months. Intent-to-treat analyses demonstrated that AFPT improved significantly at 6 months with creatine (median decrease 13%, range -32-8%) compared with placebo (median decrease 3%, range -13-16%; P = 0.029 by Mann-Whitney U test). A completer analysis also showed significant benefits from creatine (P = 0.014). The functional index improved significantly with both creatine and placebo (P < 0.05 by paired Wilcoxon's rank sum test), with a significant benefit between groups in the completer analysis only. Phosphocreatine/beta-nucleoside triphosphate ratios using MRS increased significantly in the creatine group (P < 0.05) but not in the control group. No clinically relevant adverse events were associated with creatine. CONCLUSION: Oral creatine supplements combined with home exercises improve functional performance without significant adverse effects in patients with polymyositis or dermatomyositis. They appear safe, effective, and inexpensive. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17471547&query_hl=1 ER - TY - JFULL T1 - Preadipocyte response and impairment of differentiation in an inflammatory environment. A1 - Poulain-Godefroy, O A1 - Froguel, P J1 - Biochem Biophys Res Commun Y1 - 2007/05/11/ VL - 356 SN - 0006-291X SP - 662 EP - 667 N2 - Recent reports suggest the potential role of toll-like receptor 4 (TLR4) in initiation of inflammatory responses and fatty acid-induced insulin resistance. We describe here the synthesis of pro-inflammatory products in 3T3-L1 preadipocyte cell line after stimulation with lipopolysaccharide (LPS), a TLR4 agonist. Expression profiles of mRNA coding for IL6, CCL2, CCL5, CCL11, NOS2, and PTGS2 demonstrated a higher responsiveness to LPS of these transcripts in preadipocytes than in fully differentiated adipocytes, confirming inflammatory features of preadipocytes. IL6, CCL2, CCL5 and CCL11 were secreted in 3T3-L1 supernatants within 4 h after LPS stimulation. In addition, continuous exposure to LPS during adipocyte differentiation impaired this process as was demonstrated by analysis of mRNA profiles of lipogenesis enzymes (FABP4, GPD1, LPL), adipokines (adiponectin, resistin, visfatin, leptin), and of the transcription factor PPARgamma. This suggests that toll-like receptor mediated activation could regulate maintenance of preadipocyte status, and inflammatory environment encountered in inflamed white adipose tissue. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17383612&query_hl=1 ER - TY - JFULL T1 - In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol. A1 - Chander, SK A1 - Foster, PA A1 - Leese, MP A1 - Newman, SP A1 - Potter, BV A1 - Purohit, A A1 - Reed, MJ J1 - Br J Cancer Y1 - 2007/05/07/ VL - 96 SN - 0007-0920 SP - 1368 EP - 1376 N2 - Drugs that inhibit growth of tumours and their blood supply could have considerable therapeutic potential. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE) has been shown to inhibit the proliferation of MCF-7 (ER+) breast cancer cells and angiogenesis in vitro. 2-MeOE2bisMATE and its analogue, 17-Cym-2-MeOE2MATE, were investigated for their ability to inhibit in vivo angiogenesis and tumour growth. The mouse Matrigel plug assay for angiogenesis was used to investigate the effect of compounds on neovascularisation and was quantified using a FITC-dextran injection technique. Nude mice bearing tumours derived from MCF-7 cells were used to assess efficacy on tumour growth. Tumour sections were stained for VEGFR-2 and Ki67 to assess tumour angiogenesis and cell proliferation respectively. Matrigel plugs supplemented with basic fibroblast growth factor resulted in increased neovascularisation over 7 days. Oral administration of 2-MeOE2bisMATE for 7 days at 10 or 50 mg kg(-1) significantly reduced neovascularisation to or below control levels respectively. 17-Cym-2-MeOE2MATE at 20 mg kg(-1) was equally effective. 2-MeOE2bisMATE, dosed daily for 21 days, caused a 52% reduction in tumour growth at 5 mg kg(-1) and 38% regression at 20 mg kg(-1). 17-Cym-2-MeOE2MATE (20 mg kg(-1)) reduced tumour growth by 92%. Immunohistochemistry revealed a reduction in angiogenesis and proliferation. Matrigel plug and tumour imaging after FITC-dextran injection indicated that 2-MeOE2bisMATE caused a marked disruption of vasculature. These sulphamoylated oestrogen derivatives have been shown to be potent inhibitors of angiogenesis in vivo. This, together with their ability to inhibit tumour growth, indicates the potential of this new class of drugs for further development for cancer therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17426705&query_hl=1 ER - TY - JFULL T1 - Pioglitazone added to conventional lipid-lowering treatment in familial combined hyperlipidaemia improves parameters of metabolic control: Relation to liver, muscle and regional body fat content. A1 - Thomas, EL A1 - Potter, E A1 - Tosi, I A1 - Fitzpatrick, J A1 - Hamilton, G A1 - Amber, V A1 - Hughes, R A1 - North, C A1 - Holvoet, P A1 - Seed, M A1 - Betteridge, DJ A1 - Bell, JD A1 - Naoumova, RP J1 - Atherosclerosis Y1 - 2007/05/04/ SN - 0021-9150 N2 - Familial combined hyperlipidaemia (FCHL) is a complex genetic disorder conferring high risk of premature atherosclerosis, characterized by high cholesterol and/or triglyceride, low high density lipoprotein (HDL) cholesterol and insulin resistance. We examined whether pioglitazone, added to conventional lipid-lowering therapy, would favourably affect metabolic parameters and alter body fat content. We undertook a randomized, double blind, placebo-controlled study in 22 male patients with FCHL treated with pioglitazone or matching placebo 30mg daily for 4 weeks, increasing to 45mg for 12 weeks. Magnetic resonance imaging and proton magnetic resonance spectroscopy were performed to measure adipose tissue (AT) body content as well as intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL) at baseline and after treatment. Significantly improved in the pioglitazone group were: triglyceride/HDL (atherogenic index of plasma) -32.3% (p=0.002), plasma glucose -4.4% (p=0.03), alanine-aminotransferase (ALT) -7.7% (p=0.005) and adiponectin 130.1% (p=0.001). Pioglitazone treatment resulted in a significant increase in total (5.3%, p=0.02) and subcutaneous (7.1%, p=0.003) adipose tissue as well as in soleus-IMCL levels (47.4%, p=0.02) without alteration in intra-abdominal AT or IHCL. Changes in ALT and AST and IHCL were strongly correlated (r=0.72, p<0.01; r=.0.86, p<0.01, respectively). In patients with FCHL on conventional lipid-lowering therapy, the addition of pioglitazone acts favourably on several metabolic parameters. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17482623&query_hl=1 ER - TY - JFULL T1 - Tibolone and its delta-4, 7alpha-methyl norethisterone metabolite are reversible inhibitors of human aromatase. A1 - Raobaikady, B A1 - Parsons, MF A1 - Reed, MJ A1 - Purohit, A J1 - J Steroid Biochem Mol Biol Y1 - 2007/05// VL - 104 SN - 0960-0760 SP - 154 EP - 160 N2 - Tibolone is used for the treatment of climacteric symptoms and osteoporosis in menopausal women. After ingestion, it is rapidly converted to a number of metabolites including 3alpha- and 3beta-hydroxy derivatives and the delta-4, 7alpha-methylnorethisterone (7alpha-MeNET) metabolite, which is rapidly cleared from circulation. Tibolone and some of its metabolites act in a tissue-selective manner to inhibit steroid sulphatase (STS) and 17beta-hydroxysteroid dehydrogenase Type 1 (17beta-HSD1) activities but also stimulate steroid sulphotransferase and 17beta-HSD2 activities. In the present study we have examined whether the ability of tibolone and its 7alpha-MeNET metabolites to regulate the activities of enzymes involved in oestrogen formation or inactivation extends to another key enzyme involved in oestrogen synthesis, the aromatase, which converts androstenedione to oestrone. Using JEG-3 choriocarcinoma cells, which have a high level of aromatase activity, tibolone and 7alpha-MeNET, but not the 3alpha- or 3beta-hydroxy metabolites, were found to inhibit aromatase activity in intact cells and also lysates prepared from these cells (up to 61% inhibition at 10muM). An investigation into the nature of aromatase inhibition by these compounds revealed that they inhibit aromatase activity by a reversible mechanism. Tibolone and 7alpha-MeNET also inhibited aromatase activity in MCF-7 breast cancer cells, which have a much lower level of aromatase activity than JEG-3 cells. It is concluded that, in addition to inhibiting STS and 17beta-HSD1, tibolone and 7alpha-MeNET may exert some of their tissue-selective effects in regulating oestrogen synthesis by also inhibiting aromatase activity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17467267&query_hl=1 ER - TY - JFULL T1 - Metformin prolongs the postprandial fall in plasma ghrelin concentrations in type 2 diabetes. A1 - English, PJ A1 - Ashcroft, A A1 - Patterson, M A1 - Dovey, TM A1 - Halford, JC A1 - Harrison, J A1 - Eccleston, D A1 - Bloom, SR A1 - Ghatei, MA A1 - Wilding, JP J1 - Diabetes Metab Res Rev Y1 - 2007/05// VL - 23 SN - 1520-7552 SP - 299 EP - 303 N2 - BACKGROUND: Weight loss is difficult to achieve in type 2 diabetes and many therapies are associated with weight gain, an effect attenuated by metformin. We studied the effects of metformin on energy expenditure, appetite and the regulation of PYY and ghrelin in type 2 diabetes. METHODS: Plasma peptide YY (PYY), ghrelin, resting metabolic rate (RMR), postprandial thermogenesis (PPTG), and appetite ratings were measured at baseline and following a mixed meal in 11 type 2 diabetic subjects treated with diet alone (T2D) and 10 treated with metformin monotherapy (T2MF). The groups were similar in age, gender and adiposity. RESULTS: There were no differences in baseline anthropometric, or metabolic variables between the groups. Postprandially, plasma ghrelin fell equally in both groups (23% versus 24.5%, p < 0.05 versus baseline, p = NS between groups) but were reduced for longer in T2MF (below baseline 60-240 min T2MF versus 60-180 min T2D) coincidentally with a prolonged sensation of fullness and suppression of hunger in the metformin-treated group. There were no differences in PYY concentrations, RMR or PPTG. CONCLUSIONS: Metformin prolongs the postprandial fall in ghrelin concentrations. These effects may prolong the inter-meal interval, thereby decreasing snack intake and daily energy intake, promoting weight loss. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16952199&query_hl=1 ER - TY - JFULL T1 - Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3. A1 - Villegas-Mendez, A A1 - Montes, R A1 - Ambrose, LR A1 - Warrens, AN A1 - Laffan, M A1 - Lane, DA J1 - J Thromb Haemost Y1 - 2007/05// VL - 5 SN - 1538-7933 SP - 980 EP - 988 N2 - BACKGROUND: The endothelial cell protein C receptor (EPCR) presents protein C to the thrombin:thrombomodulin complex on the endothelium of large vessels, and enhances the generation of activated protein C (APC) and activation of protease-activated receptor-1. A previous report has demonstrated binding of soluble (s) EPCR to activated neutrophils via surface proteinase 3 (PR3). METHODS: We now report further characterization of this interaction. Activated neutrophils and purified PR3 both decrease endothelial cell (EC) surface EPCR, suggestive of its proteolysis. RESULTS: When added to purified recombinant sEPCR, PR3 produced multiple cleavages, with early products including 20 kDa N-terminal and C-terminal (after Lys(176)) fragments. The binding of active site blocked PR3 to sEPCR was studied by surface plasmon resonance. Estimates of the K(D) of 18.5-102 nM were obtained with heterogeneous binding, suggestive of more than a single interaction site. CONCLUSIONS: This work demonstrates PR3 binding to and proteolysis of EPCR and suggests a mechanism by which anticoagulant and cell protective pathways can be down-regulated during inflammation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17459006&query_hl=1 ER - TY - JFULL T1 - Low-dose oral tri-iodothyronine does not directly increase food intake in man. A1 - Martin, NM A1 - Small, CJ A1 - Lee, JL A1 - Ellis, S A1 - Dhillo, WS A1 - Smith, KL A1 - Kong, WM A1 - Frost, GS A1 - Bloom, SR J1 - Diabetes Obes Metab Y1 - 2007/05// VL - 9 SN - 1462-8902 SP - 435 EP - 437 N2 - Previously, we have shown that low-dose tri-iodothyronine (T3) increases food intake in rodents. This randomised, double-blind, placebo-controlled study aimed to investigate the effects of low-dose T3 on food intake in normal body weight individuals. However, despite an elevation in fT3 comparable to our earlier studies, administration of low-dose T3 in the fasted state did not stimulate food intake in man. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17391172&query_hl=1 ER - TY - JFULL T1 - Gut hormones and appetite control. A1 - Wren, AM A1 - Bloom, SR J1 - Gastroenterology Y1 - 2007/05// VL - 132 SN - 0016-5085 SP - 2116 EP - 2130 N2 - Many peptides are synthesized and released from the gastrointestinal tract. Although their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that they also physiologically influence eating behavior. Our understanding of how neurohormonal gut-brain signaling regulates energy homeostasis has advanced significantly in recent years. Ghrelin is an orexigenic peptide produced by the stomach, which appears to act as a meal initiator. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, and cholecystokinin. Recent research suggests that gut hormones can be manipulated to regulate energy balance in humans, and that obese subjects retain sensitivity to the actions of gut hormones. Gut hormone-based therapies may thus provide an effective and well-tolerated treatment for obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17498507&query_hl=1 ER - TY - JFULL T1 - Cytokines in human breast cyst fluid. A1 - Parish, DC A1 - Ghilchik, MW A1 - Day, JM A1 - Eaton, J A1 - Purohit, A A1 - Reed, MJ J1 - J Steroid Biochem Mol Biol Y1 - 2007/05// VL - 104 SN - 0960-0760 SP - 241 EP - 245 N2 - Gross cystic breast disease is a common benign disorder in which palpable cysts occur in the breast and are normally treated by aspiration of the contents. The cysts are classified as either Type 1, containing a high level of potassium ions and a low level of sodium ions, or as Type 2, with low potassium and high sodium ion concentrations. Steroid sulphatase activity in MDA-MB-231 and MCF-7 cell lines is regulated by exogenous breast cyst fluid (BCF), possibly because of cytokines in the BCF. A screening method was used to determine the range of cytokines in eight BCFs, four of each type. This was an array system, which uses antibodies immobilised on a membrane to qualitatively detect 79 different cytokines or growth factors. Nine cytokines were detected well above background levels: all were found in both types of BCF, but only epidermal growth factor (EGF) was higher in Type 1. All the other factors were higher in Type 2 BCF. Two of these cytokines, IL-6 and EGF, have previously been suggested to affect steroid sulphatase expression and several (MIP-1beta, IL-8, NAP-2) are known to affect MCF-7 cell chemotaxis. In addition two cytokines were measured by ELISA in 57 BCFs, and both IL-1beta and IL-13 were found in BCF, with significantly higher amounts of IL-1beta in Type 1 than Type 2 BCF (35.5+/-4.4 pg/ml versus 9.9+/-2.9 pg/ml). L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17467271&query_hl=1 ER - TY - JFULL T1 - Prolonged survival in culture of preantral follicles from polycystic ovaries. A1 - Webber, LJ A1 - Stubbs, SA A1 - Stark, J A1 - Margara, RA A1 - Trew, GH A1 - Lavery, SA A1 - Hardy, K A1 - Franks, S J1 - J Clin Endocrinol Metab Y1 - 2007/05// VL - 92 SN - 0021-972X SP - 1975 EP - 1978 N2 - CONTEXT: In polycystic ovary syndrome (PCOS), an increased proportion of follicles leave the primordial (resting) pool and initiate growth. However, there is little evidence for a reduced reproductive life span (early menopause) in women with PCOS, suggesting that the dynamics of follicle growth, and of follicle loss by atresia, is altered in PCOS. OBJECTIVE: The aim of this study was to investigate the possibility that loss of preantral follicles by atresia is reduced in PCOS, leading to prolonged follicle survival. DESIGN: We compared follicle growth in normal and polycystic ovaries using cultures of small ovarian biopsies. SETTING: Tissue samples were obtained at routine laparoscopy from 12 patients with anovulatory PCOS and 16 controls and processed in an ovarian physiology laboratory. MAIN OUTCOME MEASURES: We performed morphometric analysis of follicle population in tissue fixed at time of biopsy (d 0) or after 5, 10, or 15 d in culture. Analyses included assessment of follicle and oocyte diameter, number and proportion of primordial and growing follicles, and number and proportion of atretic follicles. RESULTS: In tissue fixed on d 0, the proportion of healthy growing follicles was, as expected, greater in ovaries from PCOS patients than in normal ovaries (64 vs. 28%; P = 0.0005), but there were no differences between PCOS and normal tissue during culture. The rate of atresia throughout the period of culture in follicles was, however, significantly lower in PCOS tissue (P < 0.0001). After culture, 80% of follicles in normal ovarian tissue were atretic compared with 53% in PCOS biopsies. CONCLUSION: Follicles from polycystic ovaries demonstrate a decreased rate of atresia in culture, suggesting a mechanism for maintaining a larger follicle pool throughout reproductive life. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17341570&query_hl=1 ER - TY - JFULL T1 - Direct quantitative trait locus mapping of mammalian metabolic phenotypes in diabetic and normoglycemic rat models. A1 - Dumas, ME A1 - Wilder, SP A1 - Bihoreau, MT A1 - Barton, RH A1 - Fearnside, JF A1 - Argoud, K A1 - D'Amato, L A1 - Wallis, RH A1 - Blancher, C A1 - Keun, HC A1 - Baunsgaard, D A1 - Scott, J A1 - Sidelmann, UG A1 - Nicholson, JK A1 - Gauguier, D J1 - Nat Genet Y1 - 2007/05// VL - 39 SN - 1061-4036 SP - 666 EP - 672 N2 - Characterizing the relationships between genomic and phenotypic variation is essential to understanding disease etiology. Information-dense data sets derived from pathophysiological, proteomic and transcriptomic profiling have been applied to map quantitative trait loci (QTLs). Metabolic traits, already used in QTL studies in plants, are essential phenotypes in mammalian genetics to define disease biomarkers. Using a complex mammalian system, here we show chromosomal mapping of untargeted plasma metabolic fingerprints derived from NMR spectroscopic analysis in a cross between diabetic and control rats. We propose candidate metabolites for the most significant QTLs. Metabolite profiling in congenic strains provided evidence of QTL replication. Linkage to a gut microbial metabolite (benzoate) can be explained by deletion of a uridine diphosphate glucuronosyltransferase. Mapping metabotypic QTLs provides a practical approach to understanding genome-phenotype relationships in mammals and may uncover deeper biological complexity, as extended genome (microbiome) perturbations that affect disease processes through transgenomic effects may influence QTL detection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17435758&query_hl=1 ER - TY - JFULL T1 - Impact of the population at risk of diabetes on projections of diabetes burden in the United States: an epidemic on the way. A1 - Mainous, AG A1 - Baker, R A1 - Koopman, RJ A1 - Saxena, S A1 - Diaz, VA A1 - Everett, CJ A1 - Majeed, A J1 - Diabetologia Y1 - 2007/05// VL - 50 SN - 0012-186X SP - 934 EP - 940 N2 - AIMS/HYPOTHESIS: The aim of this study was to make projections of the future diabetes burden for the adult US population based in part on the prevalence of individuals at high risk of developing diabetes. MATERIALS AND METHODS: Models were created from data in the nationally representative National Health and Nutrition Examination Survey (NHANES) II mortality survey (1976-1992), the NHANES III (1988-1994) and the NHANES 1999-2002. Population models for adults (>20 years of age) from NHANES III data were fitted to known diabetes prevalence in the NHANES 1999-2002 before making future projections. We used a multivariable diabetes risk score to estimate the likelihood of diabetes incidence in 10 years. Estimates of future diabetes (diagnosed and undiagnosed) prevalence in 2011, 2021, and 2031 were made under several assumptions. RESULTS: Based on the multivariable diabetes risk score, the number of adults at high risk of diabetes was 38.4 million in 1991 and 49.9 million in 2001. The total diabetes burden is anticipated to be 11.5% (25.4 million) in 2011, 13.5% (32.6 million) in 2021, and 14.5% (37.7 million) in 2031. Among individuals aged 30 to 39 years old who are not currently targeted for screening according to age, the prevalence of diabetes is expected to rise from 3.7% in 2001 to 5.2% in 2031. By 2031, 20.2% of adult Hispanic individuals are expected to have diabetes. CONCLUSIONS/INTERPRETATION: The prevalence of diabetes is projected to rise to substantially greater levels than previously estimated. Diabetes prevalence within the Hispanic community is projected to be potentially overwhelming. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17119914&query_hl=1 ER - TY - JFULL T1 - Physiological blockade of gut hormones increases food intake. A1 - Vincent, R A1 - le Roux, C A1 - Kokkinos, A A1 - Ghatei, M A1 - Bloom, S J1 - INT J OBESITY Y1 - 2007/05// VL - 31 SN - 0307-0565 SP - S21 EP - S21 ER - TY - JFULL T1 - Brain-gut axis and food intake A1 - Bloom, S J1 - INT J OBESITY Y1 - 2007/05// VL - 31 SN - 0307-0565 SP - S6 EP - S6 ER - TY - JFULL T1 - Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism. A1 - Bassett, JH A1 - O'Shea, PJ A1 - Sriskantharajah, S A1 - Rabier, B A1 - Boyde, A A1 - Howell, PG A1 - Weiss, RE A1 - Roux, JP A1 - Malaval, L A1 - Clement-Lacroix, P A1 - Samarut, J A1 - Chassande, O A1 - Williams, GR J1 - Mol Endocrinol Y1 - 2007/05// VL - 21 SN - 0888-8809 SP - 1095 EP - 1107 N2 - Thyrotoxicosis is an important but under recognized cause of osteoporosis. Recently, TSH deficiency, rather than thyroid hormone excess, has been suggested as the underlying cause. To investigate the molecular mechanism of osteoporosis in thyroid disease, we characterized the skeleton in mice lacking either thyroid hormone receptor alpha or beta (TRalpha(0/0), TRbeta-/-). Remarkably, in the presence of normal circulating thyroid hormone and TSH concentrations, adult TRalpha(0/0) mice had osteosclerosis accompanied by reduced osteoclastic bone resorption, whereas juveniles had delayed endochondral ossification with reduced bone mineral deposition. By contrast, adult TRbeta-/- mice with elevated TSH and thyroid hormone levels were osteoporotic with evidence of increased bone resorption, whereas juveniles had advanced ossification with increased bone mineral deposition. Analysis of T3 target gene expression revealed skeletal hypothyroidism in TRalpha(0/0) mice, but skeletal thyrotoxicosis in TRbeta-/- mice. These studies demonstrate that bone loss in thyrotoxicosis is independent of circulating TSH levels and mediated predominantly by TRalpha, thus identifying TRalpha as a novel drug target in the prevention and treatment of osteoporosis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17327419&query_hl=1 ER - TY - JFULL T1 - Further characterization of ADAMTS-13 inactivation by thrombin. A1 - Lam, JK A1 - Chion, CK A1 - Zanardelli, S A1 - Lane, DA A1 - Crawley, JT J1 - J Thromb Haemost Y1 - 2007/05// VL - 5 SN - 1538-7933 SP - 1010 EP - 1018 N2 - BACKGROUND: The multimeric size and platelet-tethering function of von Willebrand factor (VWF) are modulated by the plasma metalloprotease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13). In vitro ADAMTS-13 is susceptible to proteolytic inactivation by thrombin. OBJECTIVES: In this study, we aimed to characterize the inactivation of ADAMTS-13 by thrombin and to assess its physiological significance. METHODS AND RESULTS: By N-terminal sequencing of cleavage products, and by mutagenesis, we identified the principal thrombin cleavage sites in ADAMTS-13 as R257 and R1176. Using a library of 76 thrombin mutants, we highlighted the functional importance of exosite I on thrombin in the proteolysis of ADAMTS-13. Proteolysis of ADAMTS-13 by thrombin caused an 8-fold reduction in its affinity for VWF that contributed to its loss of VWF-cleaving function. Intriguingly, thrombin-cleaved ADAMTS-13 both bound and proteolyzed a short recombinant VWF A2 domain substrate (VWF115) normally. Following activation of coagulation in normal plasma, endogenous ADAMTS-13, but not added ADAMTS-13, appeared resistant to coagulation-induced fragmentation. An estimation of the K(m) for ADAMTS-13 proteolysis by thrombin was appreciably higher than the physiological concentration of ADAMTS-13. This was corroborated by the comparatively low affinity of ADAMTS-13 for thrombin (K(D) 95 nM). CONCLUSIONS: Together, our data suggest that ADAMTS-13 is protected from rapid proteolytic inactivation by thrombin in normal plasma. Whether this remains the case under pathological situations involving elevated/sustained generation of thrombin remains unclear. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17355572&query_hl=1 ER - TY - JFULL T1 - Effects of exercise on gut peptides, energy intake and appetite A1 - Martins, C A1 - Morgan, LM A1 - Bloom, SR A1 - Robertson, MD J1 - J ENDOCRINOL Y1 - 2007/05// VL - 193 SN - 0022-0795 SP - 251 EP - 258 N2 - This study investigated the acute effects of exercise on the postprandial levels of appetite-related hormones and metabolites, energy intake (EI) and subjective measures of appetite. Ghrelin, polypeptide YY (PYY), glucagon-like peptide-1 (GLP-1) and pancreatic polypeptide (PP) were measured in the fasting state and postprandially in 12 healthy, normal-weight volunteers (six males and six females) using a randomised crossover design. One hour after a standardised breakfast, subjects either cycled for 60 min at 65% of their maximal heart rate or rested. Subjective appetite was assessed throughout the study using visual analogue scales and subsequent El at a buffet meal was measured at the end (3-h post-breakfast and I-h post-exercise). Exercise significantly increased mean PYY, GLP-1 and PP levels, and this effect was maintained during the post-exercise period for GLP-1 and PP. No significant effect of exercise was observed on postprandial levels of ghrehn. During the exercise period, hunger scores were significantly decreased; however, this effect disappeared in the post-exercise period. Exercise significantly increased subsequent absolute El, but produced a significant decrease in relative El after accounting for the energy expended during exercise. Hunger scores and PYY, GLP-1 and PP levels showed an inverse temporal pattern during the 1-h exercise/control intervention. In conclusion, acute exercise, of moderate intensity, temporarily decreased hunger sensations and was able to produce a short-term negative energy balance. This impact on appetite and subsequent energy homeostasis was not explained by changes in postprandial levels of ghrelin; however, 'exercise-induced anorexia' may potentially be linked to increased PYY, GLP-1 and PP levels. ER - TY - JFULL T1 - Appetite regulation: an overview. A1 - Dhillo, WS J1 - Thyroid Y1 - 2007/05// VL - 17 SN - 1050-7256 SP - 433 EP - 445 N2 - Obesity is a major public health problem associated with morbidity and mortality and continues to increase worldwide. This review focuses on the regions of the brain that are important in appetite regulation and the circulating factors implicated in the control of food intake. The hypothalamus is critical in the regulation of food intake containing neural circuits, which produce a number of peptides that influence food intake. The arcuate nucleus of the hypothalamus produces both orexigenic peptides (agouti-related protein and neuropeptide Y) and anorectic peptides (alpha-melanocyte-stimulating hormone and cocaine- and amphetamine-related transcript). The lateral hypothalamus produces the orexigenic peptides (melanin-concentrating hormone and orexins). Other hypothalamic factors recently implicated in appetite regulation include the endocannabinoids, brain-derived neurotrophic factor, nesfatin-1, AMP-activated protein kinase, mammalian target of rapamycin protein, and protein tyrosine phosphatase. Circulating factors that affect food intake mediate their effects by signaling to the hypothalamus and/or brainstem. A number of circulating factors are produced by peripheral organs, for example, leptin by adipose tissue, insulin and pancreatic polypeptide by the pancreas, gut hormones (e.g., ghrelin, obestatin, glucagon-like peptide-1, oxyntomodulin, peptide YY), and triiodothyronine by the thyroid gland. Circulating carbohydrates, lipids, and amino acids also affect appetite regulation. Knowledge regarding appetite regulation has vastly expanded in recent years providing targets for antiobesity drug design. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17542673&query_hl=1 ER - TY - JFULL T1 - Let science speak for itself A1 - Butler, D A1 - Chambon, P A1 - Brezin, E A1 - Corrignan, M A1 - Trautmann, A A1 - Choulika, A A1 - Froguel, P A1 - Rutherford, W J1 - NATURE Y1 - 2007/04/19/ VL - 446 SN - 0028-0836 SP - 850 EP - U1 ER - TY - JFULL T1 - Gender differences in the relationship between leptin, insulin resistance and the autonomic nervous system. A1 - Flanagan, DE A1 - Vaile, JC A1 - Petley, GW A1 - Phillips, DI A1 - Godsland, IF A1 - Owens, P A1 - Moore, VM A1 - Cockington, RA A1 - Robinson, JS J1 - Regul Pept Y1 - 2007/04/05/ VL - 140 SN - 0167-0115 SP - 37 EP - 42 N2 - OBJECTIVES: Leptin, an important hormonal regulator of body weight, has been shown to stimulate the sympathetic nervous system (SNS) in vitro although the physiological relevance remains unclear. Increased SNS activity has been implicated in the pathogenesis of insulin resistance and an increased cardiovascular risk. We have therefore investigated the relationship between leptin, insulin resistance and cardiac autonomic activity in healthy young adults. 130 healthy men and women age 20.9 years were studied. Insulin sensitivity was assessed using the IVGTT and minimal model with simultaneous measures of leptin. Cardiac autonomic activity was assessed using spectral analysis of heart rate variability. RESULTS: Women showed significantly higher fasting leptin, heart rate and cardiac sympathetic activity, and lower insulin sensitivity. Men showed inverse correlations between insulin resistance and heart rate, and between insulin resistance and cardiac sympatho-vagal ratio. Women, in contrast, showed no SNS relationship with insulin resistance, but rather an inverse correlation between leptin and the sympatho-vagal ratio, suggesting that leptin in women is associated with SNS activity. The correlation remained significant after adjustment for BMI and waist-to-hip ratio (beta=-0.33 and p=0.008). CONCLUSION: Insulin resistance and SNS activity appear to be linked, although the relationship showed marked gender differences, and the direction of causality was unclear from this cross-sectional study. Leptin appears to exert a greater effect on the SNS in women, possibly because of their greater fat mass. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17187873&query_hl=1 ER - TY - JFULL T1 - A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population A1 - Horikoshi, M A1 - Hara, K A1 - Ito, C A1 - Nagai, R A1 - Froguel, P A1 - Kadowaki, T J1 - DIABETOLOGIA Y1 - 2007/04// VL - 50 SN - 0012-186X SP - 747 EP - 751 N2 - It has been suggested that transcription factor 7-like 2 protein (TCF7L2) plays an important role in glucose metabolism by regulating the production level of glucagon-like peptide-1, a hormone which modifies glucose-dependent insulin secretion. Recently, variants of TCF7L2 gene were reported to confer an increased risk of type 2 diabetes in three different samples from European and European-origin populations. We studied whether the single nucleotide polymorphisms (SNPs) in TCF7L2 were associated with type 2 diabetes in samples from a Japanese population.Five SNPs were genotyped in three different sample sets. Association with type 2 diabetes was investigated in each, as well as in combined sample sets.The SNP rs7903146 was nominally associated with type 2 diabetes in the initial (p = 0.08) and two replication sample sets (p = 0.05 and 0.06). For the combined sample set, in which we successfully genotyped 1,174 type 2 diabetes patients and 823 control subjects, rs7903146 showed a significant association with type 2 diabetes (odds ratio = 1.69 [95% CI 1.21-2.36], p = 0.002) with the same direction as the previous reports in samples from European and European-origin populations. SNPs rs7903146 and rs7901695 were in complete linkage disequilibrium. The rest of the five SNPs (rs7895340, rs11196205 and rs12255372) did not show any significant associations with type 2 diabetes.The consistent association between rs7903146 in TCF7L2 and type 2 diabetes in different ethnic groups, including the Japanese population, suggests that TCF7L2 is a common susceptibility gene for type 2 diabetes. ER - TY - JFULL T1 - Exaggerated postprandial GLP-2 response after Roux-en-Y gastric bypass might be causative for post surgical intestinal adaptation A1 - Wallis, K A1 - Le Roux, CW A1 - Aylwin, SJ A1 - Patel, AG A1 - Welbourn, R A1 - Bloom, SR A1 - Forbes, A A1 - Ghatei, MA A1 - Walters, JR J1 - GASTROENTEROLOGY Y1 - 2007/04// VL - 132 SN - 0016-5085 SP - A71 EP - A71 ER - TY - JFULL T1 - Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin. A1 - Germain, N A1 - Galusca, B A1 - Le Roux, CW A1 - Bossu, C A1 - Ghatei, MA A1 - Lang, F A1 - Bloom, SR A1 - Estour, B J1 - Am J Clin Nutr Y1 - 2007/04// VL - 85 SN - 0002-9165 SP - 967 EP - 971 N2 - BACKGROUND: Food intake is controlled by the arcuate nucleus through integration of peripheral hormonal signals such as leptin, ghrelin, peptide YY (PYY), and glucagon-like peptide 1 (GLP-1). The most common condition resulting in underweight young women in the developed world is restrictive anorexia nervosa (AN). However, constitutional thinness (CT) is also known to exist in the same low-weight range. Women with CT have normal menstrual periods and do not have the psychological or hormonal features of AN. Little is currently known about regulation of food intake in subjects with CT. OBJECTIVE: We tested the hypothesis that concentrations of leptin, ghrelin, PYY, and GLP-1 in persons with AN are significantly different from those in persons with CT. DESIGN: Concentrations of PYY, GLP-1, ghrelin, and leptin were measured in 3 groups of young women: normal weight (n = 7), CT (n = 10), and AN (n = 12). Samples were collected every 4 h for 24 h. RESULTS: PYY concentrations were significantly higher in CT subjects than in AN or control subjects. GLP-1 concentrations were significantly higher in AN than in CT subjects, whereas ghrelin was significantly higher in AN subjects than in control and CT subjects. CT subjects had the lowest ghrelin concentrations. Leptin concentrations were significantly lower in AN subjects. PYY and leptin circadian variations were not significantly different between CT and control subjects, whereas these profiles were blunted in AN subjects. CONCLUSIONS: Orexigenic and anorexigenic hormones in CT contrast with an adaptative profile characterizing AN. The hormones appear to be valuable biomarkers for distinguishing these 2 categories of severely underweight subjects. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17413094&query_hl=1 ER - TY - JFULL T1 - Interrupted time-series analysis of regulations to reduce paracetamol (acetaminophen) poisoning. A1 - Morgan, OW A1 - Griffiths, C A1 - Majeed, A J1 - PLoS Med Y1 - 2007/04// VL - 4 SN - 1549-1676 SP - e105 EP - e105 N2 - BACKGROUND: Paracetamol (acetaminophen) poisoning is the leading cause of acute liver failure in Great Britain and the United States. Successful interventions to reduced harm from paracetamol poisoning are needed. To achieve this, the government of the United Kingdom introduced legislation in 1998 limiting the pack size of paracetamol sold in shops. Several studies have reported recent decreases in fatal poisonings involving paracetamol. We use interrupted time-series analysis to evaluate whether the recent fall in the number of paracetamol deaths is different to trends in fatal poisoning involving aspirin, paracetamol compounds, antidepressants, or nondrug poisoning suicide. METHODS AND FINDINGS: We calculated directly age-standardised mortality rates for paracetamol poisoning in England and Wales from 1993 to 2004. We used an ordinary least-squares regression model divided into pre- and postintervention segments at 1999. The model included a term for autocorrelation within the time series. We tested for changes in the level and slope between the pre- and postintervention segments. To assess whether observed changes in the time series were unique to paracetamol, we compared against poisoning deaths involving compound paracetamol (not covered by the regulations), aspirin, antidepressants, and nonpoisoning suicide deaths. We did this comparison by calculating a ratio of each comparison series with paracetamol and applying a segmented regression model to the ratios. No change in the ratio level or slope indicated no difference compared to the control series. There were about 2,200 deaths involving paracetamol. The age-standardised mortality rate rose from 8.1 per million in 1993 to 8.8 per million in 1997, subsequently falling to about 5.3 per million in 2004. After the regulations were introduced, deaths dropped by 2.69 per million (p = 0.003). Trends in the age-standardised mortality rate for paracetamol compounds, aspirin, and antidepressants were broadly similar to paracetamol, increasing until 1997 and then declining. Nondrug poisoning suicide also declined during the study period, but was highest in 1993. The segmented regression models showed that the age-standardised mortality rate for compound paracetamol dropped less after the regulations (p = 0.012) but declined more rapidly afterward (p = 0.031). However, age-standardised rates for aspirin and antidepressants fell in a similar way to paracetamol after the regulations. Nondrug poisoning suicide declined at a similar rate to paracetamol after the regulations were introduced. CONCLUSIONS: Introduction of regulations to limit availability of paracetamol coincided with a decrease in paracetamol-poisoning mortality. However, fatal poisoning involving aspirin, antidepressants, and to a lesser degree, paracetamol compounds, also showed similar trends. This raises the question whether the decline in paracetamol deaths was due to the regulations or was part of a wider trend in decreasing drug-poisoning mortality. We found little evidence to support the hypothesis that the 1998 regulations limiting pack size resulted in a greater reduction in poisoning deaths involving paracetamol than occurred for other drugs or nondrug poisoning suicide. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17407385&query_hl=1 ER - TY - JFULL T1 - Leptin receptor genotype at Gln223Arg is associated with body composition, BMD, and vertebral fracture in postmenopausal Danish women. A1 - Fairbrother, UL A1 - Tankó, LB A1 - Walley, AJ A1 - Christiansen, C A1 - Froguel, P A1 - Blakemore, AI J1 - J Bone Miner Res Y1 - 2007/04// VL - 22 SN - 0884-0431 SP - 544 EP - 550 N2 - Leptin is emerging as a key regulator of bone remodeling. In a population-based study of 1306 postmenopausal Danish women, nonsynonymous LEPR SNPs were associated with risk of adiposity, BMD, and vertebral fracture. Smoking exacerbates this LEPR-associated fracture risk. INTRODUCTION: Nonsynonymous single nucleotide polymorphisms (SNPs) in the human LEPR gene have been associated with adiposity in a number of studies, but there have been no large-scale studies of their implications for BMD and osteoporotic fracture risk in postmenopausal women. MATERIALS AND METHODS: We carried out a population-based study of 1430 women. Three well-known nonsynonymous leptin receptor (LEPR) SNPs (Lys109Arg, Gln223Arg, and Lys656Asn) were genotyped for qualitative and quantitative association analysis. Phenotype characteristics of main interest were DXA measures of body fat and lean tissue mass, BMD, and radiographic vertebral fractures. RESULTS: Gln223Arg associated with risk of vertebral fracture (overall OR = 1.76; OR in smokers = 2.31; p = 0.0004), in addition to BMD of the femoral neck and total hip (p = 0.036 and 0.008, respectively). Heterozygote carriers showed lower BMD at both sites. Gln223Arg was also associated with adiposity (p = 0.001 for total fat mass). For adiposity, the at-risk allele was G (resulting in an arginine at position 223). CONCLUSIONS: Variation in LEPR seemed to contribute to the variation in BMD and fracture risk in Danish postmenopausal women; the heterozygous genotype was associated with increased risk of manifest osteoporosis. Further studies are needed to replicate these data and to clarify the mechanisms involved. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17243864&query_hl=1 ER - TY - JFULL T1 - Steroid sulfatase: a new target for the endocrine therapy of breast cancer. A1 - Stanway, SJ A1 - Delavault, P A1 - Purohit, A A1 - Woo, LW A1 - Thurieau, C A1 - Potter, BV A1 - Reed, MJ J1 - Oncologist Y1 - 2007/04// VL - 12 SN - 1083-7159 SP - 370 EP - 374 N2 - Inhibitors of steroid sulfatase are being developed as a novel therapy for hormone-dependent breast cancer in postmenopausal women. Data suggest that steroid sulfatase (STS) activity is much higher than aromatase activity in breast tumors and high levels of STS mRNA expression in tumors are associated with a poor prognosis. STS hydrolyzes steroid sulfates, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS), to estrone and DHEA, which can be converted to steroids with potent estrogenic properties, that is, estradiol and androstenediol, respectively. Several potent irreversible STS inhibitors have now been identified, including STX64 (BN83495), a tricyclic sulfamate ester. This drug recently completed the first-ever trial of this new type of therapy in postmenopausal women with estrogen receptor-positive metastatic breast cancer. STX64, tested at 5-mg and 20-mg doses, was able to almost completely block STS activity in peripheral blood lymphocytes and tumor tissues. Inhibition of STS activity was associated with significant reductions in serum concentrations of androstenediol and estrogens. Unexpectedly, serum androstenedione concentrations also decreased by up to 86%, showing that this steroid, which is the main substrate for the aromatase in postmenopausal women, is derived mainly from the peripheral conversion of DHEAS. Of eight patients who completed therapy, five showed evidence of stable disease for up to 7.0 months. This new endocrine therapy offers considerable potential for the treatment of hormone-dependent breast cancer in postmenopausal women. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17470679&query_hl=1 ER - TY - JFULL T1 - Haemochromatosis: Rising hospital admission rates but stable mortality 1989/90 to 2002/03 A1 - Cowan, ML A1 - Westlake, S A1 - Majeed, A A1 - Rahman, TM A1 - Maxwell, JD A1 - Kang, J J1 - GUT Y1 - 2007/04// VL - 56 SN - 0017-5749 SP - A123 EP - A124 ER - TY - JFULL T1 - The rat thyroid hormone receptor (TR) Deltabeta3 displays cell-, TR isoform-, and thyroid hormone response element-specific actions. A1 - Harvey, CB A1 - Bassett, JH A1 - Maruvada, P A1 - Yen, PM A1 - Williams, GR J1 - Endocrinology Y1 - 2007/04// VL - 148 SN - 0013-7227 SP - 1764 EP - 1773 N2 - The THRB gene encodes the well-described thyroid hormone (T3) receptor (TR) isoforms TRbeta1 and TRbeta2 and two additional variants, TRbeta3 and TRDeltabeta3, of unknown physiological significance. TRbeta1, TRbeta2, and TRbeta3 are bona fide T3 receptors that bind DNA and T3 and regulate expression of T3-responsive target genes. TRDeltabeta3 retains T3 binding activity but lacks a DNA binding domain and does not activate target gene transcription. TRDeltabeta3 can be translated from a specific TRDeltabeta3 mRNA or is coexpressed with TRbeta3 from a single transcript that contains an internal TRDeltabeta3 translation start site. In these studies, we provide evidence that the TRbeta3/Deltabeta3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TRbeta3 with other TR isoforms and investigated mechanisms of action of TRDeltabeta3 at specific thyroid hormone response elements (TREs) in two cell types. TRbeta3 was the most potent isoform, but TR potency was TRE dependent. TRDeltabeta3 acted as a cell-specific and TRE-dependent modulator of TRbeta3 when coexpressed at low concentrations. At higher concentrations, TRDeltabeta3 was a TRE-selective and cell-specific antagonist of TRalpha1, -beta1, and -beta3. Both TRbeta3 and TRDeltabeta3 were expressed in the nucleus in the absence and presence of hormone, and their actions were determined by cell type and TRE structure, whereas TRDeltabeta3 actions were also dependent on the TR isoform with which it interacted. Analysis of these complex responses implicates a range of nuclear corepressors and coactivators as cell-, TR isoform-, and TRE-specific modulators of T3 action. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17218414&query_hl=1 ER - TY - JFULL T1 - Early metabolic defects following gestational diabetes in three ethnic groups of anti-GAD antibodies negative women with normal fasting glucose. A1 - Kousta, E A1 - Lawrence, NJ A1 - Godsland, IF A1 - Penny, A A1 - Anyaoku, V A1 - Millauer, BA A1 - Robinson, S A1 - Johnston, DG A1 - McCarthy, MI J1 - Hormones (Athens) Y1 - 2007/04// VL - 6 SN - 1109-3099 SP - 138 EP - 147 N2 - OBJECTIVE: To characterise early metabolic abnormalities and the impact of ethnicity following gestational diabetes mellitus (GDM). DESIGN: Women with a history of GDM belonging to three different ethnic groups were evaluated. Using the insulin-modified, frequently-sampled intravenous glucose tolerance test (FSIVGTT) and HOMA we studied 34 European, 16 South Asian and 10 Afro-Caribbean women with normal fasting glucose following GDM and 44 European, 16 South Asian and 19 Afro-Caribbean controls to assess insulin action and secretion. RESULTS: European post-GDM women had lower insulin sensitivity by FSIVGTT [0.6 (0.1-5.1) vs 1.5 (0.8-2.8) x10(-4).min(-1).pmol(-1).l(-1), p=0.010, adjusted for BMI p=0.054] and by HOMA [72(22-235) vs 153(55-421)%, p=0.004, adjusted for BMI p=0.006], and reduced -cell function [lower disposition index 0.05(0.01-0.40) vs 0.11(0.05-0.25)min(-1), p=0.017] compared with controls. South Asian post-GDM women had decreased -cell function [lower HOMA (%B) (73 (37-147) vs 124 (59-262) %, p=0.048 and acute insulin response to glucose (463 (131-1639) vs 1039 (393-2748) pmol/l h, p=0.052] than controls. Afro-Caribbean post-GDM women had lower glucose disappearance rate [1.3(0.6-2.8) vs 2.6 (1.8-3.8) 10(-2)/min, p=0.003] than controls, suggesting subtle glucose intolerance. CONCLUSIONS: Women with a history of GDM of three different ethnic groups, even in the presence of normal fasting glucose, display a range of metabolic abnormalities, including -cell dysfunction with variable insulin resistance. These derangements may be influenced by ethnicity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17704045&query_hl=1 ER - TY - JFULL T1 - A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. A1 - Khor, CC A1 - Chapman, SJ A1 - Vannberg, FO A1 - Dunne, A A1 - Murphy, C A1 - Ling, EY A1 - Frodsham, AJ A1 - Walley, AJ A1 - Kyrieleis, O A1 - Khan, A A1 - Aucan, C A1 - Segal, S A1 - Moore, CE A1 - Knox, K A1 - Campbell, SJ A1 - Lienhardt, C A1 - Scott, A A1 - Aaby, P A1 - Sow, OY A1 - Grignani, RT A1 - Sillah, J A1 - Sirugo, G A1 - Peshu, N A1 - Williams, TN A1 - Maitland, K A1 - Davies, RJ A1 - Kwiatkowski, DP A1 - Day, NP A1 - Yala, D A1 - Crook, DW A1 - Marsh, K A1 - Berkley, JA A1 - O'Neill, LA A1 - Hill, AV J1 - Nat Genet Y1 - 2007/04// VL - 39 SN - 1061-4036 SP - 523 EP - 528 N2 - Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17322885&query_hl=1 ER - TY - JFULL T1 - Myocardial infarction (MI) in a 28 year old woman following treatment with DDAVP and tranexamic acid A1 - Patel, A A1 - Laffan, M J1 - BRIT J HAEMATOL Y1 - 2007/04// VL - 137 SN - 0007-1048 SP - 52 EP - 53 ER - TY - JFULL T1 - Is there an association between quality of primary care and admissions for diabetes? A1 - Bottle, A A1 - Xie, Y A1 - Majeed, A A1 - Millett, C J1 - DIABETIC MED Y1 - 2007/03// VL - 24 SN - 0742-3071 SP - 68 EP - 68 ER - TY - JFULL T1 - ADAMTS13 and von Willebrand factor and the risk of myocardial infarction in men. A1 - Chion, CK A1 - Doggen, CJ A1 - Crawley, JT A1 - Lane, DA A1 - Rosendaal, FR J1 - Blood Y1 - 2007/03/01/ VL - 109 SN - 0006-4971 SP - 1998 EP - 2000 N2 - Von Willebrand factor (VWF) mediates the tethering/adhesion of platelets at sites of vascular injury. This function depends on its multimeric size, which is controlled by ADAMTS13. We measured plasma ADAMTS13 and VWF antigen levels by enzyme-linked immunosorbent assay (ELISA) in a large population-based case-control study (Study of Myocardial Infarctions Leiden [SMILE]), consisting of 560 men with a first myocardial infarction (MI) and 646 control subjects. Although ABO blood groups influenced VWF levels, they had no influence on ADAMTS13. Furthermore, there was no relationship between plasma ADAMTS13 and VWF levels. Similar to VWF, the estimated risk of MI was increased for every quartile of ADAMTS13 when compared to the lowest quartile (odds ratio, 1.5-1.6). If confirmed, the association of ADAMTS13 with MI may suggest an unexpected mechanistic action of ADAMTS13. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17053057&query_hl=1 ER - TY - JFULL T1 - Activating transcription factor 6 (ATF6) sequence polymorphisms in type 2 diabetes and pre-diabetic traits A1 - Chu, WS A1 - Das, SK A1 - Wang, H A1 - Chan, JC A1 - Deloukas, P A1 - Froguel, P A1 - Baier, LJ A1 - Jia, WP A1 - McCarthy, MI A1 - Ng, MCY A1 - Damcott, C A1 - Shuldiner, AR A1 - Zeggini, E A1 - Elbein, SC J1 - DIABETES Y1 - 2007/03// VL - 56 SN - 0012-1797 SP - 856 EP - 862 N2 - Activating transcription factor 6 (ATF6) is located within the region of linkage to type 2 diabetes on chromosome 1q21-q23 and is a key activator of the endoplasmic reticulum stress response. We evaluated 78 single nucleotide polymorphisms (SNPs) spanning > 213 kb in 95 people, from which we selected 64 SNPs for evaluation in 191 Caucasian case subjects from Utah and between 165 and 188 control subjects. Six SNPs showed nominal associations with type 2 diabetes (P = 0.001-0.04), including the nonsynonymous SNP rs1058405 (M67V) in exon 3 and rs11579627 in the 3' flanking region. Only rs1159627 remained significant on permutation testing. The associations were not replicated in 353 African-American case subjects and 182 control subjects, nor were ATF6 SNPs associated with altered insulin secretion or insulin sensitivity in nondiabetic Caucasian individuals. No association with type 2 diabetes was found in a subset of 44 SNPs in Caucasian (a = 2,099), Pima Indian (n = 293), and Chinese (n = 287) samples. Allelic expression imbalance was found in transformed lymphocyte cDNA for 3' untranslated region variants, thus suggesting cis-acting regulatory variants. ATF6 does not appear to play a major role in type 2 diabetes, but further work is required to identify the cause of the allelic expression imbalance. ER - TY - JFULL T1 - Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes - Association analyses in 9,518 subjects A1 - Owen, KR A1 - Groves, CJ A1 - Hanson, RL A1 - Knowler, WC A1 - Shuldiner, AR A1 - Elbein, SC A1 - Mitchell, BD A1 - Froguel, P A1 - Ng, MCY A1 - Chan, JC A1 - Jia, WP A1 - Deloukas, P A1 - Hitman, GA A1 - Walker, M A1 - Frayling, TM A1 - Hattersley, AT A1 - Zeggini, E A1 - McCarthy, MI A1 - Int Type 2 Diabetes 1q Consortium J1 - DIABETES Y1 - 2007/03// VL - 56 SN - 0012-1797 SP - 879 EP - 883 N2 - Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing > 90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001). ER - TY - JFULL T1 - Insulin and cancer mortality during 19.2 years of follow-up in the heart disease and diabetes risk in a screened cohort (HDDRISC) study A1 - Godsland, IF A1 - Loh, WJ A1 - Johnston, DG J1 - DIABETIC MED Y1 - 2007/03// VL - 24 SN - 0742-3071 SP - 25 EP - 26 ER - TY - JFULL T1 - Trends in the prescription and cost of diabetic medications and monitoring equipment in England 1991-2004. A1 - Patel, H A1 - Srishanmuganathan, J A1 - Car, J A1 - Majeed, A J1 - J Public Health (Oxf) Y1 - 2007/03// VL - 29 SN - 1741-3842 SP - 48 EP - 52 N2 - BACKGROUND: To report the trend in prescriptions and cost of antidiabetic drugs and glucose monitoring equipment in England from 1991 to 2004. METHODS: We analysed data on all community antidiabetic drug prescriptions in England collated from the Prescription Cost Analysis system. RESULTS: The total number of diabetes prescriptions (medicines and monitoring) rose from 7,613,000 (1991) to 24,325,640 (2004) (>300% increase). Meanwhile, total costs increased by 650%. Insulins are the biggest contributor to cost followed by monitoring equipment and then oral medications. Three times as many items of oral tablets are prescribed than insulins. Metformin accounts for 40% of all diabetic drug dispensations but only 7% of the costs. More is spent on glitazones now than on either metformin or sulphonylureas. CONCLUSIONS: There has been a substantial increase in the cost of managing diabetes in the community. Costs are likely to continue to rise in the future, as the prevalence of diabetes increases and through more aggressive identification and management of patients with diabetes in the hope of reducing the even more costly complications. The cost implications of glucose monitoring merits further study. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17124257&query_hl=1 ER - TY - JFULL T1 - Hormonal regulation of appetite. A1 - Bloom, S J1 - Obes Rev Y1 - 2007/03// VL - 8 Suppl 1 SN - 1467-7881 SP - 63 EP - 65 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17316304&query_hl=1 ER - TY - JFULL T1 - Systematic review of quality of diabetes care in Europe from published papers and comparison with Quality and Outcomes Framework results from the UK A1 - Gadsby, R A1 - Davies, M A1 - Majeed, A A1 - Khunti, K J1 - DIABETIC MED Y1 - 2007/03// VL - 24 SN - 0742-3071 SP - 68 EP - 68 ER - TY - JFULL T1 - Surrogate indices of the insulin resistance syndrome as predictors of atherosclerotic vascular disease during 9.4 years follow-up A1 - Godsland, IF A1 - Lecamwasam, KL A1 - Johnston, DG J1 - DIABETIC MED Y1 - 2007/03// VL - 24 SN - 0742-3071 SP - 25 EP - 25 ER - TY - JFULL T1 - Relationship between intrahepatocellular lipid content and features of the metabolic syndrome in subjects with known nonalcoholic fatty liver disease and healthy volunteers A1 - Mehta, SR A1 - Godsland, IF A1 - Thomas, EL A1 - Bell, JD A1 - Patel, N A1 - Fitzpatrick, J A1 - Durighel, G A1 - Westerland, O A1 - Anyakou, U A1 - Pavitt, D A1 - Taylor-Robinson, SD A1 - Johnston, DG J1 - DIABETIC MED Y1 - 2007/03// VL - 24 SN - 0742-3071 SP - 45 EP - 46 ER - TY - JFULL T1 - Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions A1 - Yamauchi, T A1 - Nio, Y A1 - Maki, T A1 - Kobayashi, M A1 - Takazawa, T A1 - Iwabu, M A1 - Okada-Iwabu, M A1 - Kawamoto, S A1 - Kubota, N A1 - Kubota, T A1 - Ito, Y A1 - Kamon, J A1 - Tsuchida, A A1 - Kumagai, K A1 - Kozono, H A1 - Hada, Y A1 - Ogata, H A1 - Tokuyama, K A1 - Tsunoda, M A1 - Ide, T A1 - Murakami, K A1 - Awazawa, M A1 - Takamoto, I A1 - Froguel, P A1 - Hara, K A1 - Tobe, K A1 - Nagai, R A1 - Ueki, K A1 - Kadowaki, T J1 - NAT MED Y1 - 2007/03// VL - 13 SN - 1078-8956 SP - 332 EP - 339 N2 - Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo. ER - TY - JFULL T1 - Low-dose pancreatic polypeptide inhibits food intake in man. A1 - Jesudason, DR A1 - Monteiro, MP A1 - McGowan, BM A1 - Neary, NM A1 - Park, AJ A1 - Philippou, E A1 - Small, CJ A1 - Frost, GS A1 - Ghatei, MA A1 - Bloom, SR J1 - Br J Nutr Y1 - 2007/03// VL - 97 SN - 0007-1145 SP - 426 EP - 429 N2 - Pancreatic polypeptide (PP) is a gut hormone released from the pancreas in response to food ingestion and remains elevated for up to 6 h postprandially. Plasma levels are elevated in patients with pancreatic tumours. An intravenous infusion of PP has been reported to reduce food intake in man, suggesting that PP is a satiety hormone. We investigated whether a lower infusion rate of PP would induce significant alterations in energy intake. The study was randomised and double-blinded. Fourteen lean fasted volunteers (five men and nine women) received 90 min infusions of PP (5 pmol/kg per min) and saline on two separate days. The dose chosen was half that used in a previous human study which reported a decrease in appetite but at supra-physiological levels of PP. One hour after the end of the infusion, a buffet lunch was served and energy intake measured. PP infusion was associated with a significant 11 % reduction in energy intake compared with saline (2440 (se 200) v. 2730 (se 180) kJ; P<0 x 05). Preprandial hunger as assessed by a visual analogue score was decreased in the PP-treated group compared to saline. These effects were achieved with plasma levels of PP within the pathophysiological range of pancreatic tumours. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17313701&query_hl=1 ER - TY - JFULL T1 - The neuroendocrine physiology of kisspeptin in the human. A1 - Dhillo, WS A1 - Murphy, KG A1 - Bloom, SR J1 - Rev Endocr Metab Disord Y1 - 2007/03// VL - 8 SN - 1389-9155 SP - 41 EP - 46 N2 - Kisspeptin is a 54-amino acid peptide, encoded by the KiSS-1 gene, which activates the G protein-coupled receptor GPR54. Recent evidence suggests the kisspeptin/GPR54 system is a key regulator of reproduction. GPR54-deficient mice have abnormal sexual development. Central or peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis in animal models. This review discusses the evidence that kisspeptin also plays a key role in human reproduction. Inactivating GPR54 mutations cause normosmic hypogonadotrophic hypogonadism in humans. Mutations which increase GPR54 signaling are associated with gonadotrophin-dependent premature puberty. Acute intravenous administration of kisspeptin to healthy human male volunteers potently increased plasma LH levels and significantly increased plasma FSH and testosterone without side effects. Plasma kisspeptin is found at low concentrations in the circulation of men and non-pregnant women, but is markedly increased in pregnancy. The placenta is believed to be the source of these high levels of circulating kisspeptin. The kisspeptin-GPR54 system is also implicated in tumour biology. Consistent with this role, plasma kisspeptin concentrations are elevated in patients with abnormal proliferation of placental tissue (gestational trophoblastic neoplasia or GTN) at presentation and fall after treatment with chemotherapy. The kisspeptin/GPR54 system therefore appears to play an important role in the regulation of reproduction in humans. Kisspeptin represents a novel tool for the manipulation of the HPG axis in humans and plasma kisspeptin may be a novel tumour marker in patients with GTN. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17323132&query_hl=1 ER - TY - JFULL T1 - Hypothalamic mapping of orexigenic action and Fos-like immunoreactivity following relaxin-3 administration in male Wistar rats. A1 - McGowan, BM A1 - Stanley, SA A1 - White, NE A1 - Spangeus, A A1 - Patterson, M A1 - Thompson, EL A1 - Smith, KL A1 - Donovan, J A1 - Gardiner, JV A1 - Ghatei, MA A1 - Bloom, SR J1 - Am J Physiol Endocrinol Metab Y1 - 2007/03// VL - 292 SN - 0193-1849 SP - E913 EP - E919 N2 - The insulin superfamily, characterized by common disulphide bonds, includes not only insulin but also insulin-like peptides such as relaxin-1 and relaxin-3. The actions of relaxin-3 are largely unknown, but recent work suggests a role in regulation of food intake. Relaxin-3 mRNA is highly expressed in the nucleus incertus, which has extensive projections to the hypothalamus, and relaxin immunoreactivity is present in several hypothalamic nuclei. In the rat, relaxin-3 binds and activates both relaxin family peptide receptor 1, which also binds relaxin-1, and a previously orphaned G protein-coupled receptor, RXFP3. These receptors are extensively expressed in the hypothalamus. The aims of these studies were twofold: 1) map the hypothalamic site(s) of the orexigenic action of relaxin-3 and 2) examine the site(s) of neuronal activation following central relaxin-3 administration. After microinjection into hypothalamic sites, human relaxin-3 (H3; 180 pmol) significantly stimulated 0- to 1-h food intake in the supraoptic nucleus (SON), arcuate nucleus (ARC), and the anterior preoptic area (APOA) [SON 0.4+/-0.2 (vehicle) vs. 2.9+/-0.5 g (H3), P<0.001; ARC 0.7+/-0.3 (vehicle) vs. 2.7+/-0.2 g (H3), P<0.05; and APOA 0.8+/-0.1 (vehicle) vs. 2.2+/-0.2 g (H3), P<0.05]. Cumulative food intake was significantly increasedT. Subjects bearing the -3608 C allele present a plasma lipid profile protective against atherogenesis: decrease of plasma LDL-cholesterol level (p=0.001) and of the LDL/HDL ratio (p=0.0003). This result offers new evidences for a potential implication of the CART gene in lipid metabolism and in atherogenesis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17008116&query_hl=1 ER - TY - JFULL T1 - Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism A1 - Shojaee-Moradie, F A1 - Baynes, KCR A1 - Pentecost, C A1 - Bell, JD A1 - Thomas, EL A1 - Jackson, NC A1 - Stolinski, M A1 - Whyte, M A1 - Lovell, D A1 - Bowes, SB A1 - Gibney, J A1 - Jones, RH A1 - Umpleby, AM J1 - DIABETOLOGIA Y1 - 2007/02// VL - 50 SN - 0012-186X SP - 404 EP - 413 N2 - It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables.We randomised 17 sedentary overweight male subjects (age 50 +/- 2.6 years, BMI 27.6 +/- 0.5 kg/m(2)) to a 6-week exercise programme (n=10) or control group (n=7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic-euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg(-1) min(-1)]. In the exercise group subjects were studied > 72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning.After 6 weeks, fasting glycerol, palmitic acid Ra (p=0.003, p=0.042) and NEFA concentration (p=0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p=0.026; p=0.007 and p=0.04). There was no change in muscle triacylglycerol and liver fat in either group.Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise. ER - TY - JFULL T1 - Disordered follicle development in ovaries of prenatally androgenized ewes. A1 - Forsdike, RA A1 - Hardy, K A1 - Bull, L A1 - Stark, J A1 - Webber, LJ A1 - Stubbs, S A1 - Robinson, JE A1 - Franks, S J1 - J Endocrinol Y1 - 2007/02// VL - 192 SN - 0022-0795 SP - 421 EP - 428 N2 - Exposure to excess androgens in utero induces irreversible changes in gonadotrophin secretion and results in disrupted reproductive endocrine and ovarian function in adulthood, in a manner reminiscent of the common clinical endocrinopathy of polycystic ovary syndrome (PCOS). We have recently identified an abnormality in early follicle development in PCOS which we suggested might be an androgenic effect. We propose that altered ovarian function in androgenized ewes is due to prenatal androgens not only causing an abnormality of gonadotrophin secretion, but also exerting a direct effect on the early stages of folliculogenesis. Therefore, in this study, we explored the possible differences between small preantral follicles in the ovarian cortex of androgenized female lambs with those of normal lambs. At 8 months of age, small ovarian cortical biopsies (approximately 5 mm3) were obtained at laparotomy from nine female lambs that had been exposed to androgens in utero from embryonic days 30 to 90 of a 147-day pregnancy, and 11 control female lambs. Further, ovarian tissue was obtained at 20 months of age from ten androgenized and nine control animals. Tissue was either fixed immediately for histology or cultured for up to 15 days prior to fixing. The number of follicles in haematoxylin and eosin-stained sections was counted and recorded along with the stage of development. Before culture, the total follicle density (follicles/mm3 tissue) was not statistically significantly different between the two types of ovary at either 8 or 20 months of age. Furthermore, there were no statistically significant differences in the density of follicles at each stage of development. However, there was a lower percentage of primordial follicles, but a higher percentage of primary follicles, in biopsies taken at 8 months from androgenized lambs when compared with controls. At 20 months, the proportions of follicles at the primordial and primary stages were not significantly different between the two groups, but this was mainly attributable to an increase in the proportion of growing follicles in biopsies from control animals. Culture of ovarian cortex from 8-month-old lambs resulted in a progressive increase in the proportion of growing follicles when compared with tissue fixed on the day of surgery. However, there was no difference between androgenized and control tissue in the percentage of growing follicles. The increase in the proportion of growing follicles in the cortex of androgenized animals is reminiscent of similar observations in human polycystic ovaries and suggests that excess exposure to androgen in early life plays a part in the accelerated progression of follicle development from the primordial to the primary stage in polycystic ovaries. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17283242&query_hl=1 ER - TY - JFULL T1 - Recent progress in PYY research--an update report for 8th NPY meeting. A1 - Ashby, D A1 - Bloom, SR J1 - Peptides Y1 - 2007/02// VL - 28 SN - 0196-9781 SP - 198 EP - 202 N2 - PYY(3-36) is a gut regulatory peptide which has recently been found to reduce appetite. Variability of this effect across different experimental conditions has led to confusion and polarization of opinion on its potential as an anti-obesity treatment. This review summarizes recent progress in this area. The basic anorexigenic effect leading to weight loss in rodents has now been confirmed by several groups. Anorexia has also been confirmed in human studies although optimal route and dosing remain to be defined. Gastric bypass causes PYY levels to rise, which may in part mediate the weight loss occurring after this surgery, and levels have been found to be normal or low in obese people. The straightforward ARC model of mechanism, involving inhibition and activation, respectively, of NPY and POMC neurons, is giving way to a more complicated system involving vagal afferent signals. Conclusion: It works, but not how we thought it did. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17354277&query_hl=1 ER - TY - JFULL T1 - Nonpeptidic glucagon-like peptide 1 receptor agonists: a magic bullet for diabetes? A1 - Murphy, KG A1 - Bloom, SR J1 - Proc Natl Acad Sci U S A Y1 - 2007/01/16/ VL - 104 SN - 0027-8424 SP - 689 EP - 690 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17213306&query_hl=1 ER - TY - JFULL T1 - Diabetes care in developing countries. A1 - Car, J A1 - Patel, H A1 - Srishanmuganathan, J A1 - Majeed, A J1 - CMAJ Y1 - 2007/01/16/ VL - 176 SN - 1488-2329 SP - 209 EP - 212 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17224601&query_hl=1 ER - TY - JFULL T1 - Localized and non-contact mechanical stimulation of dorsal root ganglion sensory neurons using scanning ion conductance microscopy. A1 - Sánchez, D A1 - Anand, U A1 - Gorelik, J A1 - Benham, CD A1 - Bountra, C A1 - Lab, M A1 - Klenerman, D A1 - Birch, R A1 - Anand, P A1 - Korchev, Y J1 - J Neurosci Methods Y1 - 2007/01/15/ VL - 159 SN - 0165-0270 SP - 26 EP - 34 N2 - Mechanosensitive ion channels convert external mechanical force into electrical and chemical signals in cells, but their physiological function in different tissues is not clearly understood. One reason for this is that there is as yet no satisfactory physiological method to stimulate these channels in living cells. Using the nanopipette-probe of the Scanning Ion Conductance Microscope (SICM), we have developed a new technique to apply local mechanical stimulus to living cells to an area of about 0.385 microm2, determined by the pipette diameter. Our method prevents any physical contact and damage to the cell membrane by use of a pressure jet applied via the nanopipette. The study used whole-cell patch-clamp recordings and measurements of intracellular Ca2+ concentration to validate the application of the mechanical stimulation protocols in human and rat dorsal root ganglia (DRG) sensory neurons. We were able, for the first time, to produce a non-contact, controlled mechanical stimulation on living neurites of human DRG neurons. Our methods will enable the identification and characterisation of compounds being developed for the treatment of clinical mechanical hypersensitivity states. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16887195&query_hl=1 ER - TY - JFULL T1 - Comment on "A common genetic variant is associated with adult and childhood obesity". A1 - Dina, C A1 - Meyre, D A1 - Samson, C A1 - Tichet, J A1 - Marre, M A1 - Jouret, B A1 - Charles, MA A1 - Balkau, B A1 - Froguel, P J1 - Science Y1 - 2007/01/12/ VL - 315 SN - 1095-9203 SP - 187; author reply 187 EP - 187; author reply 187 N2 - Herbert et al. (Reports, 14 April 2006, p. 279) reported an association between the INSIG2 gene variant rs7566605 and obesity in four sample populations, under a recessive model. We attempted to replicate this result in 10,265 Caucasian individuals, combining family-based, case-control, and general population studies, but found no support for a major role of this variant in obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17218508&query_hl=1 ER - TY - JFULL T1 - The influence of pharmacogenetics on fatty liver disease in the wistar and kyoto rats: a combined transcriptomic and metabonomic study. A1 - Griffin, JL A1 - Scott, J A1 - Nicholson, JK J1 - J Proteome Res Y1 - 2007/01// VL - 6 SN - 1535-3893 SP - 54 EP - 61 N2 - Although fatty liver disease is caused by a number of toxicological insults and the metabolic syndrome, the exact mechanisms by which many of these pathophysiological stimulii induce fatty liver are unknown. The rapid and profound steatosis caused by orotic acid, resulting from an impairment in the production of ApoB, has been investigated in the Wistar strain rat using a combined transcriptomic and metabonomic/metabolomic approach. Analysis of liver tissue from rats exposed to orotic acid for 1, 3, and 14 days was performed by DNA microarrays and high resolution 1H NMR spectroscopy based metabonomics of both tissue extracts and intact tissue (n = 3). Data were analyzed using a combination of ANOVA and principal components analysis, used as a data reduction tool to visualize the most perturbed transcripts and metabolites. Orotic acid produced a profound 8-fold increase in total lipids, and in particular increases in resonances associated with polyunsaturated fats (CH=CH and CH2CH=CH groups). This was accompanied by increases in the concentrations of trimethylamine-oxide (TMAO), betaine, choline, and phosphocholine, as well as a relative decrease in glucose and glycogen. At the transcriptional level, perturbations were detected in both oxidative stress and osmoregulation/pH homeostasis. However, this contrasts with a previous transcriptomic/metabolic study of fatty liver disease in a combined data set of Wistar (out-bred) and Kyoto (in-bred) strains of rats, with only 4 transcripts being found to be in common between the two analyses. This emphasizes the need to understand how strain background interacts with a given toxic lesion or genetic modification. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17203948&query_hl=1 ER - TY - JFULL T1 - Improved scanning ion conductance microscopy (SICM) for live cell imaging A1 - Johnson, N A1 - Li, C A1 - Ostanin, V A1 - Bruckbauer, A A1 - Korchev, Y A1 - Klenerman, D J1 - BIOPHYS J Y1 - 2007/01// SN - 0006-3495 SP - 323A EP - 323A ER - TY - JFULL T1 - TCF7L2 rs7903146 variant does not associate with smallness for gestational age in the French population. A1 - Cauchi, S A1 - Meyre, D A1 - Choquet, H A1 - Deghmoun, S A1 - Durand, E A1 - Gaget, S A1 - Lecoeur, C A1 - Froguel, P A1 - Levy-Marchal, C J1 - BMC Med Genet Y1 - 2007/// VL - 8 SN - 1471-2350 SP - 37 EP - 37 N2 - BACKGROUND: In adults, the TCF7L2 rs7903146 T allele, commonly associated with type 2 diabetes (T2D), has been also associated with a lower body mass index (BMI) in T2D individuals and with a smaller waist circumference in subjects with impaired glucose tolerance. METHODS: The present association study aimed at analyzing the contribution of the rs7903146 SNP to smallness for gestational age (SGA) and metabolic profiles in subjects with SGA or appropriate for gestational age birth weight (AGA). Two groups of French Caucasian subjects were selected on birth data: SGA (birth weight < 10th percentile; n = 764), and AGA (25th < birth weight < 75th percentile; n = 627). Family-based association tests were also performed in 3,012 subjects from 628 SGA and AGA pedigrees. RESULTS: The rs7903146 genotypic distributions between AGA (30.7%) and SGA (29.0%) were not statistically different (allelic OR = 0.92 [0.78-1.09], p = 0.34). Family association-based studies did not show a distortion of T allele transmission in SGA subjects (p = 0.52). No significant effect of the T allele was detected on any of the metabolic parameters in the SGA group. However, in the AGA group, trends towards a lower insulin secretion (p = 0.03) and a higher fasting glycaemia (p = 0.002) were detected in carriers of the T allele. CONCLUSION: The TCF7L2 rs7903146 variant neither increases the risk for SGA nor modulates birth weight and young adulthood glucose homeostasis in French Caucasian subjects born with SGA. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17593304&query_hl=1 ER - TY - JFULL T1 - Use of recombinant activated factor VII in massive obstetric haemorrhage. A1 - Haynes, J A1 - Laffan, M A1 - Plaat, F J1 - Int J Obstet Anesth Y1 - 2007/01// VL - 16 SN - 0959-289X SP - 40 EP - 49 N2 - Massive obstetric haemorrhage is a life-threatening emergency that remains a major cause of maternal mortality. Conventional management is aimed at optimising uterine tone, replacing circulating volume and blood products, and surgery to achieve haemostasis. Recently there have been numerous reports of the (unlicensed) use of recombinant activated factor VII in the management of major obstetric haemorrhage. We report our experience of using it in the treatment of major post-partum haemorrhage in four previously healthy parturients. The published reports of recombinant activated factor VII use in post-partum haemorrhage (unrelated to pre-existing coagulopathies) are compared. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17126006&query_hl=1 ER - TY - JFULL T1 - The UK Diabetes Research Network - an opportunity and a challenge A1 - Matthews, DR A1 - Kennedy, ED A1 - Darbyshire, JH A1 - Johnston, DG J1 - DIABETIC MED Y1 - 2007/01// VL - 24 SN - 0742-3071 SP - 7 EP - 9 N2 - The Department of Health has funded a national diabetes network to support clinical research. The network will facilitate recruitment into clinical trials and has been widely welcomed by clinicians. However, if the network is to reach its full potential, all those involved will need to advocate a change in attitude towards clinical trials and research, encouraging participation and contribution of data. Clinicians need to be willing to take a proactive view about research studies, and to encourage patients to adopt a positive and altruistic attitude towards trial participation. The future of trials and other important clinical research in the UK may depend on it. ER - TY - JFULL T1 - Two Caucasian families with the hepatocyte nuclear factor-1 alpha mutation Tyr218Cys A1 - Hummel, M A1 - Vasseur, F A1 - Mathieu, C A1 - Bellanne-Chantelot, C A1 - Froguel, P A1 - Standl, E A1 - Fuchtenbusch, M J1 - EXP CLIN ENDOCR DIAB Y1 - 2007/01// VL - 115 SN - 0947-7349 SP - 62 EP - 64 N2 - We report on the first two Caucasian families with the MODY3 HNF-1alpha mutation Tyr-218Cys. Clinical and laboratory examinations are shown in detail. Patients with HNF-1 alpha related MODY may develop the full spectrum of diabetic complications. Therefore, early detection of family members with MODY3 is warranted. ER - TY - JFULL T1 - The protein C anticoagulant pathway: new insights A1 - Lane, DA J1 - THROMB RES Y1 - 2007/01// VL - 119 SN - 0049-3848 SP - S6 EP - S7 ER - TY - JFULL T1 - "Non-contact" mechanical characterization and stimulation of cells using scanning ion conductance microscopy. A1 - Korchev, Y A1 - Sanchez, D A1 - Anand, P A1 - Gorelik, J A1 - Zhang, YJ A1 - Shevchuk, A A1 - Vodyanoy, I A1 - Lab, M A1 - Klenerman, D J1 - BIOPHYS J Y1 - 2007/01// SN - 0006-3495 SP - 33A EP - 33A ER - TY - JFULL T1 - No major contribution of TCF7L2 sequence variants to maturity onset of diabetes of the young (MODY) or neonatal diabetes mellitus in French white subjects. A1 - Cauchi, S A1 - Vaxillaire, M A1 - Choquet, H A1 - Durand, E A1 - Duval, A A1 - Polak, M A1 - Froguel, P J1 - Diabetologia Y1 - 2007/01// VL - 50 SN - 0012-186X SP - 214 EP - 216 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17093940&query_hl=1 ER - TY - JFULL T1 - Association of protein S p.Pro667Pro dimorphism with plasma protein S levels in normal individuals and patients with inherited protein S deficiency A1 - Castaman, G A1 - Biguzzi, E A1 - Razzari, C A1 - Tosetto, A A1 - Fontana, G A1 - Asti, D A1 - Brancaccio, V A1 - Castori, D A1 - Lane, DA A1 - Faioni, EM A1 - ProSIT Grp J1 - THROMB RES Y1 - 2007/// VL - 120 SN - 0049-3848 SP - 421 EP - 426 N2 - A dimorphism in PROS1 gene (c.A2001G, p.Pro667Pro) has been associated with significantly reduced levels of both free and total protein S in carriers of the GG genotype. It is not known how the GG genotype could influence PS levels in normals, whether it could influence the levels of protein S in carriers of mutations in PROS1 gene and whether this genotype acts as an isolated or additive risk factor for venous thrombosis. With this as background, we evaluated the association of p.Pro667Pro dimorphism with free and total protein S centrally measured in a panel of 119 normal controls, 222 individuals with low protein S and 137 individuals with normal PS Levels belonging to 76 families with protein S deficiency enrolled in the ProSIT study. Transient expression of recombinant wild type protein S and p.Pro667Pro protein S was performed to evaluate the role of the A to G transition at position 2001 in vitro. The p.Pro667Pro polymorphism was also expressed together with a p.Glu67ALa variant to assess a possible influence on protein S Levels in protein S deficient subjects. Free and total protein S levels were significantly tower in normal women. In normal women only was the GG genotype associated with significantly lower free protein S levels in comparison to AA and AG genotypes (P = 0.032). No significant influence of GG genotype was observed in patients, either with known mutations or with low protein S levels. These data were confirmed by in vitro transient expression, showing no difference in secretion levels of the p.Pro667Pro variant (even in association with the p.Glu67Ala mutation), compared to the wild type protein S. The genotype in itself was neither a significant risk factor for venous thrombosis nor a risk modifier in patients with known mutations. (c) 2006 Elsevier Ltd. All rights reserved. ER - TY - JFULL T1 - Practice size, caseload, deprivation and quality of care of patients with coronary heart disease, hypertension and stroke in primary care: national cross-sectional study. A1 - Saxena, S A1 - Car, J A1 - Eldred, D A1 - Soljak, M A1 - Majeed, A J1 - BMC Health Serv Res Y1 - 2007/// VL - 7 SN - 1472-6963 SP - 96 EP - 96 N2 - BACKGROUND: Reports of higher quality care by higher-volume secondary care providers have fuelled a shift of services from smaller provider units to larger hospitals and units. In the United Kingdom, most patients are managed in primary care. Hence if larger practices provide better quality of care; this would have important implications for the future organization of primary care services. We examined the association between quality of primary care for cardiovascular disease achieved by general practices in England and Scotland by general practice caseload, practice size and area based deprivation measures, using data from the New General Practitioner (GP) Contract. METHODS: We analyzed data from 8,970 general practices with a total registered population of 55,522,778 patients in England and Scotland. We measured practice performance against 26 cardiovascular disease (coronary heart disease, left ventricular disease, and stroke) Quality and Outcomes Framework (QOF) indicators for patients on cardiovascular disease registers and linked this with data on practice characteristics and census data. RESULTS: Despite wide variations in practice list sizes and deprivation, the prevalence of was remarkably consistent, (coronary heart disease, left ventricular dysfunction, hypertension and cerebrovascular disease was 3.7%; 0.45%; 11.4% and 1.5% respectively). Achievement in quality of care for cardiovascular disease, as measured by QOF, was consistently high regardless of caseload or size with a few notable exceptions: practices with larger list sizes, higher cardiovascular disease caseloads and those in affluent areas had higher achievement of indicators requiring referral for further investigation. For example, small practices achieved lower scores 71.4% than large practices 88.6% (P < 0.0001) for referral for exercise testing and specialist assessment of patients with newly diagnosed angina. CONCLUSION: The volume-outcome relationship found in hospital settings is not seen between practices in the UK in management of cardiovascular disorders in primary care. Further work is warranted to explain apparently poorer quality achievement in some aspects of cardiovascular management relating to initial diagnosis and management among practices in deprived areas, smaller practices and those with a smaller caseload. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17597518&query_hl=1 ER - TY - JFULL T1 - 2-substituted estradiol bis-sulfamates, multitargeted antitumor agents: synthesis, in vitro SAR, protein crystallography, and in vivo activity. A1 - Leese, MP A1 - Leblond, B A1 - Smith, A A1 - Newman, SP A1 - Di Fiore, A A1 - De Simone, G A1 - Supuran, CT A1 - Purohit, A A1 - Reed, MJ A1 - Potter, BV J1 - J Med Chem Y1 - 2006/12/28/ VL - 49 SN - 0022-2623 SP - 7683 EP - 7696 N2 - The anticancer activities and SARs of estradiol-17-O-sulfamates and estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) as steroid sulfatase (STS) inhibitors and antiproliferative agents are discussed. Estradiol 3,17-O,O-bis-sulfamates 20 and 21, in contrast to the 17-O-monosulfamate 11, proved to be excellent STS inhibitors. 2-Substituted E2bisMATEs 21 and 23 additionally exhibited potent antiproliferative activity with mean graph midpoint values of 18-87 nM in the NCI 60-cell-line panel. 21 Exhibited antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model, and 23 dosed p.o. caused marked growth inhibition in a nude mouse xenograft tumor model. Modeling studies suggest that the E2bisMATEs and 2-MeOE2 share a common mode of binding to tubulin, though COMPARE analysis of activity profiles was negative. 21 was cocrystallized with carbonic anhydrase II, and X-ray crystallography revealed unexpected coordination of the 17-O-sulfamate of 21 to the active site zinc and a probable additional lower affinity binding site. 2-Substituted E2bisMATEs are attractive candidates for further development as multitargeted anticancer agents. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17181151&query_hl=1 ER - TY - JFULL T1 - A renewable nanosensor based on a glass nanopipette. A1 - Piper, JD A1 - Clarke, RW A1 - Korchev, YE A1 - Ying, L A1 - Klenerman, D J1 - J Am Chem Soc Y1 - 2006/12/27/ VL - 128 SN - 0002-7863 SP - 16462 EP - 16463 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17177370&query_hl=1 ER - TY - JFULL T1 - Gut hormones and the regulation of energy homeostasis. A1 - Murphy, KG A1 - Bloom, SR J1 - Nature Y1 - 2006/12/14/ VL - 444 SN - 1476-4687 SP - 854 EP - 859 N2 - Food intake, energy expenditure and body adiposity are homeostatically regulated. Central and peripheral signals communicate information about the current state of energy balance to key brain regions, including the hypothalamus and brainstem. Hunger and satiety represent coordinated responses to these signals, which include neural and hormonal messages from the gut. In recent years our understanding of how neural and hormonal brain-gut signalling regulates energy homeostasis has advanced considerably. Gut hormones have various physiological functions that include specifically targeting the brain to regulate appetite. New research suggests that gut hormones can be used to specifically regulate energy homeostasis in humans, and offer a target for anti-obesity drugs. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17167473&query_hl=1 ER - TY - JFULL T1 - Identifying and treating UTIs A1 - Chada P A1 - Car J J1 - Independent Nurse Y1 - 2006/12/04/ SP - 26 EP - 26 ER - TY - JFULL T1 - Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. A1 - Wynne, K A1 - Park, AJ A1 - Small, CJ A1 - Meeran, K A1 - Ghatei, MA A1 - Frost, GS A1 - Bloom, SR J1 - Int J Obes (Lond) Y1 - 2006/12// VL - 30 SN - 0307-0565 SP - 1729 EP - 1736 N2 - BACKGROUND: Oxyntomodulin has recently been found to decrease body-weight in obese humans and may be a potential anti-obesity therapy. OBJECTIVE: To determine whether oxyntomodulin alters energy expenditure, in addition to reducing energy intake, in 'free-living' overweight and obese volunteers. DESIGN: Randomized double-blind controlled cross-over trial. SETTING: Community and hospital-based. PARTICIPANTS: Fifteen healthy overweight and obese men and women (age: 23-49 years, BMI: 25.1-39.0 kg/m(2)). All volunteers completed the study protocol. INTERVENTIONs: Four-day subcutaneous self-administration of pre-prandial oxyntomodulin, three times daily. Participants were advised to maintain their normal dietary and exercise regimen. MEASUREMENTS: (1) Energy expenditure, measured by indirect calorimetry and combined heart rate and movement monitoring; (2) energy intake, measured during a study meal. RESULTS: Oxyntomodulin administration reduced energy intake at the study meal by 128+/-29 kcal (P=0.0006) or 17.3+/-5.5% (P=0.0071), with no change in meal palatability. Oxyntomodulin did not alter resting energy expenditure; but increased activity-related energy expenditure by 143+/-109 kcal/day or 26.2+/-9.9% (P=0.0221); total energy expenditure by 9.4+/-4.8% (P=0.0454) and physical activity level by 9.5+/-4.6% (P=0.0495). A reduction in body weight of 0.5+/-0.2% was observed during the oxyntomodulin administration period (P=0.0232). CONCLUSIOn: Oxyntomodulin increases energy expenditure while reducing energy intake resulting in negative energy balance. This data supports the role of oxyntomodulin as a potential anti-obesity therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16619056&query_hl=1 ER - TY - JFULL T1 - Manganese-enhanced magnetic resonance imaging (MEMRI) without compromise of the blood-brain barrier detects hypothalamic neuronal activity in vivo. A1 - Kuo, YT A1 - Herlihy, AH A1 - So, PW A1 - Bell, JD J1 - NMR Biomed Y1 - 2006/12// VL - 19 SN - 0952-3480 SP - 1028 EP - 1034 N2 - There is growing interest in the use of manganese-enhanced MRI (MEMRI) to detect neuronal activity and architecture in animal models. The MEMRI neuronal activity studies have been generally performed either by stereotactic brain injection or by systemic administration of Mn(2+) in conjunction with the disruption of the blood-brain barrier (BBB). These approaches, however, have limited the use of MEMRI because of the procedure-related morbidity/mortality or because brain activity measured by these methods can diverge from genuine physiological responses. In this study, the hypothesis that MEMRI, performed with systemic administration of Mn(2+) without compromising the BBB integrity, is able to detect hypothalamic function associated with feeding was tested. This procedure was tested on a simple physiological condition, fasting, and with this method temporal and regional differences in Mn(2+) enhancement could be detected. It is concluded that MEMRI can be used to study hypothalamic function in the murine brain without compromising the BBB. It was also shown that region-specific Mn(2+) enhancement in the mouse brain can be modulated by fasting. More importantly, this non-invasive in vivo imaging technique is able to demonstrate differences in brain activities, previously possible only by in vitro studies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16845705&query_hl=1 ER - TY - JFULL T1 - A novel Z-groove index characterizing myocardial surface structure. A1 - Gorelik, J A1 - Yang, LQ A1 - Zhang, Y A1 - Lab, M A1 - Korchev, Y A1 - Harding, SE J1 - Cardiovasc Res Y1 - 2006/12/01/ VL - 72 SN - 0008-6363 SP - 422 EP - 429 N2 - OBJECTIVE: The role of t-tubule structures in excitation-contraction coupling of ventricular myocytes has been investigated by disruption using prolonged culture, or osmotic shock with formamide. We have used a new method, the Scanning Ion Conductance Microscope (SICM), to investigate in more detail the changes in surface structure of live myocytes during these interventions and to relate them to contractile effects. METHODS: Freshly isolated ventricular myocytes from adult rat hearts were either incubated with formamide, then washed to produce osmotic shock, or put into culture for 2, 4 and 7 days. Contractile characteristics of single myocytes were then measured using the IonOptix system, and in parallel imaged using the SICM which produces a 3-dimensional topographical representation of the cell surface. Loss of t-tubules was quantitated with confocal microscopy after staining with the membrane dye di-8-ANNEPS, and sarcomere structure revealed by immunocytochemical detection of alpha-actinin. RESULTS: Detubulation was produced by either method, with formamide equivalent to 4 day culture in quantitative measures of ANNEPS t-tubule/membrane ratio. SICM images confirmed the loss of t-tubule indentations. Disruption of the Z-groove structure and flattening of the surface were also noted with formamide and, to a lesser extent, culture. A novel Z-groove index was introduced to describe this effect more quantitatively. Contraction and relaxation were impaired by the detubulation methods, but formamide had a markedly greater depressant effect on contraction amplitude than equivalent detubulation by culture. CONCLUSION: Changes in contraction amplitude after detubulation with formamide were more closely related to the alteration in Z-groove structure than loss of t-tubules alone. As well as disrupting t-tubule-induced excitation and calcium movements, formamide may alter the transmission of contraction in the myocyte by interference with sarcomere attachment at the Z-line. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17054929&query_hl=1 ER - TY - JFULL T1 - Gut peptides in the regulation of food intake and energy homeostasis. A1 - Murphy, KG A1 - Dhillo, WS A1 - Bloom, SR J1 - Endocr Rev Y1 - 2006/12// VL - 27 SN - 0163-769X SP - 719 EP - 727 N2 - Gut hormones signal to the central nervous system to influence energy homeostasis. Evidence supports the existence of a system in the gut that senses the presence of food in the gastrointestinal tract and signals to the brain via neural and endocrine mechanisms to regulate short-term appetite and satiety. Recent evidence has shown that specific gut hormones administered at physiological or pathophysiological concentrations can influence appetite in rodents and humans. Gut hormones therefore have an important physiological role in postprandial satiety, and gut hormone signaling systems represent important pharmaceutical targets for potential antiobesity therapies. Our laboratory investigates the role of gut hormones in energy homeostasis and has a particular interest in this field of translational research. In this review we describe our initial studies and the results of more recent investigations into the effects of the gastric hormone ghrelin and the intestinal hormones peptide YY, pancreatic polypeptide, glucagon-like peptide-1, and oxyntomodulin on energy homeostasis. We also speculate on the role of gut hormones in the future treatment of obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17077190&query_hl=1 ER - TY - JFULL T1 - Patient confidentiality and telephone consultations: time for a password. A1 - Sokol, DK A1 - Car, J J1 - J Med Ethics Y1 - 2006/12// VL - 32 SN - 0306-6800 SP - 688 EP - 689 N2 - Although telephone consultations are widely used in the delivery of healthcare, they are vulnerable to breaches of patient confidentiality. Current guidelines on telephone consultations do not address adequately the issue of confidentiality. In this paper, we propose a solution to the PROBLEM: a password system to control access to patient information. Authorised persons will be offered the option of selecting a password which they will use to validate their request for information over the telephone. This simple yet stringent method of access control should improve security while allowing the continuing evolution of telephone consultations. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17145905&query_hl=1 ER - TY - JFULL T1 - Genotype-by-nutrient interactions assessed in European obese women - A case-only study A1 - Santos, JL A1 - Boutin, P A1 - Verdich, C A1 - Holst, C A1 - Larsen, LH A1 - Toubro, S A1 - Dina, C A1 - Saris, WHM A1 - Blaak, EE A1 - Hoffstedt, J A1 - Taylor, MA A1 - Polak, J A1 - Clement, K A1 - Langin, D A1 - Astrup, A A1 - Froguel, P A1 - Pedersen, O A1 - Sorensen, TIA A1 - Martinez, JA A1 - NUGENOB consortium J1 - EUR J NUTR Y1 - 2006/12// VL - 45 SN - 1436-6207 SP - 454 EP - 462 N2 - The development of obesity is influenced by both genetic and environmental risk factors. Whereas changes in the environment appear to be responsible for the increasing prevalence of obesity, genetic factors interacting with environmental factors would contribute to explain obesity onset and severity.To explore epidemiologic genotype-by-nutrient interactions in obesity.A total of 42 polymorphisms of 26 candidate genes for obesity were genotyped in 549 adult obese women recruited from eight European centres in a case-only study. The nutritional variables assessed in this study were the dietary fibre intake (grams per day), the ratio of dietary polyunsaturated fat to saturated fat (P:S ratio) and the percentage of energy derived from fat in the diet as calculated from a weighed three-day food record (%E). Under the assumption of genotype-nutrient independence in the population, the odds ratio calculated in a sample of obese women would indicate the existence of genotype-by-nutrient interactions, measured as deviations from the multiplicative effects of the genetic and the nutrient factors separately.No new but confirmaty evidences for genotype-by-nutrient interactions in obesity were detected in this case-only study. The test of interaction between fibre intake and the -514 C > T polymorphism of the hepatic lipase gene (LIPC) yielded P-values of 0.01 across different statistical models. Likewise, the -11377G > C polymorphism of the adiponectin gene (ADIPOQ) and the -681 C > G polymorphism of the PPARG3 gene might interact with the percentage of energy derived from fat in the diet for the development of obesity (P-values in the range of 0.01-0.05 across different statistical models). The P-values were not adjusted for multiple testing, so these results should be considered with caution.Although the use of obese-only samples is theoretically a useful approach to detect interactions, few genotype-by-nutrient interactions have been suggested in obese European women after the analysis of candidate polymorphisms and the selected nutrient variables. The most remarkable multiplicative interaction found in this study refers to the combination of the hepatic lipase gene polymorphism -514 C > T and fibre intake. ER - TY - JFULL T1 - Differential hypothalamic neuronal activation following peripheral injection of GLP-1 and oxyntomodulin in mice detected by manganese-enhanced magnetic resonance imaging. A1 - Chaudhri, OB A1 - Parkinson, JR A1 - Kuo, YT A1 - Druce, MR A1 - Herlihy, AH A1 - Bell, JD A1 - Dhillo, WS A1 - Stanley, SA A1 - Ghatei, MA A1 - Bloom, SR J1 - Biochem Biophys Res Commun Y1 - 2006/11/17/ VL - 350 SN - 0006-291X SP - 298 EP - 306 N2 - The anorexigenic gut hormones oxyntomodulin (OXM) and glucagon-like peptide-1 (GLP-1) are thought to physiologically regulate appetite and food intake. Using manganese-enhanced magnetic resonance imaging, we have shown distinct patterns of neuronal activation in the hypothalamus in response to intraperitoneal injections into fasted mice of 900 and 5400 nmol/kg OXM or 900 nmol/kg GLP-1. Administration of OXM at either dose resulted in a reduced rate of signal enhancement, reflecting a reduction in neuronal activity, in the arcuate, paraventricular, and supraoptic nuclei of the hypothalamus. Conversely, GLP-1 caused a reduction in signal enhancement in the paraventricular nucleus only and an increase in the ventromedial hypothalamic nucleus. Our data show that these two apparently similar peptides generate distinct patterns of activation within the hypothalamus, suggesting that GLP-1 and OXM may act via different hypothalamic pathways. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17007819&query_hl=1 ER - TY - JFULL T1 - The effect of Von Willebrand factor glycans on the interaction with ADAMTS13. A1 - McKinnon, TAJ A1 - Chion, ACK A1 - Laffan, MA J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 484A EP - 484A ER - TY - JFULL T1 - The South East England thrombotic thrombocytopenic purpura registry. A1 - Scully, M A1 - Yarranton, H A1 - Liesner, R A1 - Cavenagh, J A1 - Hunt, B A1 - Benjamin, S A1 - Laffan, M A1 - Bevan, D A1 - Mackie, I A1 - Machin, SJ J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 317A EP - 317A ER - TY - JFULL T1 - The role of oxyntomodulin and peptide tyrosine-tyrosine (PYY) in appetite control. A1 - Wynne, K A1 - Bloom, SR J1 - Nat Clin Pract Endocrinol Metab Y1 - 2006/11// VL - 2 SN - 1745-8366 SP - 612 EP - 620 N2 - Oxyntomodulin and peptide tyrosine-tyrosine (PYY) are released from intestinal enteroendocrine cells in response to a meal. These circulating hormones are considered to be satiety signals, as they have been found to decrease food intake, body weight and adiposity in rodents. Their effect on energy homeostasis is mediated by the hypothalamus and brainstem, and several studies have demonstrated alterations in neuropeptide signaling within the arcuate nucleus. The weight loss that has been observed in animal models after repeated administration of oxyntomodulin and PYY has led to interest in developing these peptides as antiobesity therapies in humans. Indeed, preliminary studies have found that oxyntomodulin or PYY administration reduces food intake and body weight effectively in overweight human volunteers. This research suggests that modulation of these gut hormones could prove to be effective long-term therapies in the quest to combat the obesity epidemic. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17082808&query_hl=1 ER - TY - JFULL T1 - Coronary calcification, homocysteine, C-reactive protein and the metabolic syndrome in Type 2 diabetes: the Prospective Evaluation of Diabetic Ischaemic Heart Disease by Coronary Tomography (PREDICT) Study. A1 - Godsland, IF A1 - Elkeles, RS A1 - Feher, MD A1 - Nugara, F A1 - Rubens, MB A1 - Richmond, W A1 - Khan, M A1 - Donovan, J A1 - Anyaoku, V A1 - Flather, MD A1 - PREDICT Study Group J1 - Diabet Med Y1 - 2006/11// VL - 23 SN - 0742-3071 SP - 1192 EP - 1200 N2 - AIMS: The PREDICT Study aims to determine: (i) the association between cardiovascular risk factors and coronary artery calcification score (CACS) obtained by electron beam tomography and (ii) the predictive value of CACS for coronary heart disease (CHD) events in Type 2 diabetes. METHODS: Having previously reported relationships between CACS and conventional risk factors, we have now studied the novel risk factors, plasma high-sensitivity C-reactive protein (CRP) and homocysteine, insulin resistance, serum apoprotein A1 and B concentrations, the serum triglyceride/high-density lipoprotein cholesterol ratio and metabolic syndrome (International Diabetes Federation definition) in 573 subjects of the PREDICT Type 2 diabetes cohort. RESULTS: In univariate analyses, the only significant positive novel correlate of CACS was homocysteine (P = 0.0004). CRP was increased in those with detectable calcification, but decreased with increasing calcification score (P = 0.006). In a multivariate model that included all significant univariate correlates, CACS was independently associated with age (P < 0.0001), waist-hip ratio (P < 0.02), male gender (P < 0.05) and duration of diabetes (P < 0.05), but the association with homocysteine was no longer significant. The negative association between CACS and CRP remained in multivariate analysis, and was independent of statin use. CONCLUSIONS: Age was the major factor influencing CACS in Type 2 diabetes, with weaker contributions from waist hip-ratio and duration of diabetes. Other novel cardiovascular risk factors appear to have little positive effect. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17054594&query_hl=1 ER - TY - JFULL T1 - Peptide hormones: Therapeutic targets in appetite regulation A1 - Wren, AM A1 - Bloom, SR J1 - LETT DRUG DES DISCOV Y1 - 2006/11// VL - 3 SP - 593 EP - 597 N2 - Recent studies have identified a novel role for gut-derived peptides in the physiological regulation of appetite and body weight. This data is reviewed and the potential of peptide hormones, particularly ghrelin, PYY, GLP-1 and oxyntomodulin, as therapies for anorexia and obesity is explored. ER - TY - JFULL T1 - TCF7L2 variation predicts hyperglycemia incidence in a French general population: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study. A1 - Cauchi, S A1 - Meyre, D A1 - Choquet, H A1 - Dina, C A1 - Born, C A1 - Marre, M A1 - Balkau, B A1 - Froguel, P A1 - DESIR Study Group J1 - Diabetes Y1 - 2006/11// VL - 55 SN - 0012-1797 SP - 3189 EP - 3192 N2 - Recently, case-control studies demonstrated that a TCF7L2 (transcription factor 7-like 2 gene) noncoding variant (rs7903146 T at-risk allele) was strongly associated with an increased risk of type 2 diabetes. However, the predictive value of this marker in a nonselected general population remains unknown. In this study, our aim was to assess the contribution of this variant to the prevalence and incidence of hyperglycemia (type 2 diabetes and impaired fasting glucose) and insulin regulation in a 9-year prospective study of 4,976 middle-aged participants in the French DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) cohort. Our data support previous studies associating the T at-risk allele with a higher prevalence of hyperglycemia at baseline (P = 0.049) and a higher incidence of hyperglycemia after 9 years of follow-up (P = 0.014). The population-attributable risk to develop hyperglycemia due to the T at-risk allele was estimated to be 10.4% at the end of the prospective study. The most likely inheritance model was found to be additive (P = 0.002) rather than deviating from linearity (hazard ratio 1.21 [95% CI 1.05-1.39], P = 0.008) [corrected] An increase in the incidence of hyperglycemia was confirmed by survival analyses among C/C, C/T, and T/T carriers during the 9 years of follow-up (P = 0.028 by log-rank test). Interestingly, in control individuals, there was weak evidence of association of the T at-risk allele with reduced fasting insulin levels and insulin secretion index (homeostasis model assessment of beta-cell function) in control individuals. We conclude that the TCF7L2 T at-risk allele variation (rs7903146) predicts hyperglycemia incidence in a general French population, possibly through a deleterious effect on insulin secretion. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17065361&query_hl=1 ER - TY - JFULL T1 - 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 - The role of STS and OATP-B mRNA expression in predicting the clinical outcome in human breast cancer A1 - Al Sarakbi, W A1 - Mokbel, R A1 - Salhab, M A1 - Jiang, WG A1 - Reed, MJ A1 - Mokbel, K J1 - ANTICANCER RES Y1 - 2006/11// VL - 26 SN - 0250-7005 SP - 4985 EP - 4990 N2 - Background: Steroid sulfatase (STS) is the enzyme responsible for hydrolysing biologically inactive estrogen sulfates to active estrogens. Therefore it plays a significant role in supporting the growth of hormone-dependent tumours of the breast, endometrium and prostate. OATP-B is a member of a family of membrane transporter proteins that regulates the uptake of steroid sulfates through cell membranes. Our objective was to determine, using quantitative PCR, whether the mRNA expression levels from these genes were positively correlated with clinical outcome in human breast cancer. This is the first study in the literature to examine the relationship between STS and OATP-B in human breast cancer and to investigate the potential prognostic value of OATP-B. Materials and Methods: A total of 153 samples (120 tumour tissues and 33 normal breast tissues) were ana sed. The levels of transcription of STS and OATP-B were determined using real-time quantitative PCR and normalized against cytokeratin 19. The levels of expression were analysed against tumour's stage, grade, nodal status, local relapse, distant metastasis, ER alpha, ER beta, and HER14 receptor status and survival over a 10 year follow up period. Results: The levels of STS mRNA were significantly higher in malignant samples (p=0.031) and in node positive disease (p=0.0222). STS mRNA expression increased with increasing tumour grade but this did not reach statistical significance. A significant increase was also noted in levels correlating with tumour stage when stages TNM1 and TNM2, TNM2 and TNM3, and TNM3 and TNM4 (p=0.00001, 0.0017 and 0.02, respectively) were compared. Furthermore, STS expression levels positively correlated with progression of disease, as levels were significantly higher in samples from patients who developed metastasis, local recurrence, or died of breast cancer when compared to those who were disease free for > 10 years (p=0. 0036). No significant correlation was found between the levels of STS expression and ER alpha/ER beta status. The levels positives correlated with HER1 and HER3 receptors. The levels of mRNA expression of OATP-B were higher in malignant tissue compared to normal tissue; this, however, did not reach statistical significance (p=0.4045). Levels were also higher in node positive disease (p=0.0672). Expression levels increased with increasing tumour grade and this became statistically significant when comparing grade I to 2, and grade 2 to 3 (p=0.0271 and 0.0289, respectively). An increase in levels correlating with TNM tumour staging was also observed; this, however, did not reach statistical significance. There was no significant correlation between OATP-B expression levels and clinical progression of breast cancer. No correlation was found between STS and OATP-B expression levels. Conclusion: This study demonstrates a compelling trend for STS transcription levels to be higher in cancer tissues and in patients who developed progressive disease. OATP-B expression levels correlated with the grade and stage of the disease, but not with the clinical outcome. These results suggest that STS mRNA has a significant potential as an important predictor of clinical outcome in patients with breast cancer. ER - TY - JFULL T1 - Development and evaluation of dual aromatase and sulfatase inhibitors with therapeutic potential A1 - Chander, SK A1 - Foster, PA A1 - Parsons, MFC A1 - Tutill, H A1 - Woo, LWL A1 - Potter, BVL A1 - Reed, MJ A1 - Purohit, A J1 - EJC SUPPL Y1 - 2006/11// VL - 4 SN - 1359-6349 SP - 154 EP - 155 ER - TY - JFULL T1 - Association of age, sex and deprivation with quality indicators for diabetes: population-based cross sectional survey in primary care. A1 - Gray, J A1 - Millett, C A1 - O'Sullivan, C A1 - Omar, RZ A1 - Majeed, A J1 - J R Soc Med Y1 - 2006/11// VL - 99 SN - 0141-0768 SP - 576 EP - 581 N2 - OBJECTIVES: To determine the quality of diabetes management in primary care after the publication of the National Service Framework and examine the impact of age, gender and deprivation on the achievement of established quality indicators. DESIGN: Population-based cross sectional survey using electronic general practice records carried out between June-October 2003. SETTING: Thirty-four practices in Wandsworth, South-West London, UK. PARTICIPANTS: 6035 adult patients (> or =18 years) with diabetes from a total registered population of 201,572 patients. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Success rates for the diabetes quality indicators within the General Medical Services contract for general practitioners. RESULTS: We identified large variations in diabetes management between general practitioner practices with poorer recording of quality care in younger patients (18-44 years). In addition, younger patients had a worse cholesterol and glycaemia profile, although hypertension was more common in older patients. Gender and deprivation did not appear to be important determinants of the quality of care received. CONCLUSIONS: There are large variations in diabetes management between general practitioner practices, with care seemingly worse for younger adults. Longitudinal studies are required to determine whether current UK quality improvement initiatives have been successful in attenuating existing variations in care and treatment outcomes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17082303&query_hl=1 ER - TY - JFULL T1 - Peptide YY (PYY) is increased in elderly patients with femoral neck fractures: a prospective cohort study. A1 - Nematy, M A1 - Powell, CA A1 - Brynes, AE A1 - Pearse, M A1 - Patterson, M A1 - Ghatei, MA A1 - Bloom, SR A1 - Frost, GS J1 - JPEN J Parenter Enteral Nutr Y1 - 2006/11// VL - 30 SN - 0148-6071 SP - 530 EP - 531 N2 - BACKGROUND: Peptide YY (PYY), a gut peptide, has recently been shown to inhibit appetite. The role of this peptide in elderly nutritionally-compromised patients with femoral neck fracture (FNF) has not been investigated. In this study, we investigated the longitudinal pattern of PYY levels during hospital stay and investigated the postprandial PYY response to a standard meal in patients with FNF and matched controls. METHODS: Fasting plasma concentrations of the PYY were measured on days 1, 4, 7, 14, 21 and 28 or on discharge from the hospital in 17 white patients with FNF. On the second week of stay, 13 patients with FNF consumed a standard breakfast following an overnight fasting. One fasting sample and one 45-minute postmeal sample were collected. A control group was made up of 17 matched healthy elderly patients. RESULTS: PYY concentrations were increased significantly over the length of hospital stay. Results of the test breakfast suggested a significant and exaggerated post-prandial PYY response, despite a smaller energy intake being consumed. CONCLUSIONS: This study shows PYY concentrations are increased during hospitalization and their post-prandial release exaggerated in this group of vulnerable patients, and suggests a role in the etiology of reduced appetite in this patient group. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17047180&query_hl=1 ER - TY - JFULL T1 - Regulation of food intake by gastrointestinal hormones. A1 - Baynes, KC A1 - Dhillo, WS A1 - Bloom, SR J1 - Curr Opin Gastroenterol Y1 - 2006/11// VL - 22 SN - 0267-1379 SP - 626 EP - 631 N2 - PURPOSE OF REVIEW: Complex physiological mechanisms have evolved to control food intake in mammals, which in health ensure the relative stability of body weight in adults. Central brain centres, gut-derived peptides and adipose-derived signals result in an integrative response to defend against starvation. Enteroendocrine cells throughout the gut and pancreas secrete a number of peptides with activity on gut motility, gut secretions and appetite. Understanding the interactions between different gut peptides has produced a rewardingly active research field with many unanswered questions. RECENT FINDINGS: Many gut peptides are now in translational research programmes to investigate their potential in human physiology and disease. Ghrelin has been shown in short-term human studies to both increase appetite and body weight. Oxyntomodulin has been shown to reduce weight and food intake in a 4 week study in humans. Anorectic activity of peptide YY(3-36) has been confirmed in a number of animal models. Obestatin has been identified as a novel gut peptide. Increasing evidence points to the effect of gastric-bypass surgery on body weight, including alteration of gut peptide activity. SUMMARY: Gut peptides, or gut-peptide mimetics, show great promise for use as therapeutic agents for the treatment of obesity and cachexia. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17053440&query_hl=1 ER - TY - JFULL T1 - Epistasis between type 2 diabetes susceptibility loci on chromosomes 1q21-25 and 10q23-26 in northern Europeans A1 - Wiltshire, S A1 - Bell, JT A1 - Groves, CJ A1 - Dina, C A1 - Hattersley, AT A1 - Frayling, TM A1 - Walker, M A1 - Hitman, GA A1 - Vaxillaire, M A1 - Farrall, M A1 - Froguel, P A1 - McCarthy, MI J1 - ANN HUM GENET Y1 - 2006/11// VL - 70 SN - 0003-4800 SP - 726 EP - 737 N2 - Characterisation of the interactions between susceptibility loci (epistasis) is central to a full understanding of the genetic aetiology and the molecular pathology of complex diseases. We have examined, in British and French pedigrees, evidence for epistasis between the type 2 diabetes susceptibility loci on chromosomes 1q21-25 and 10q23-26 using two complementary linkage-based approaches. Joint two-locus linkage analysis of 1q and 10q in British pedigrees provided significant evidence for interaction (P <= 0.003) when comparing a general epistasis model with multiplicative or additive-effects-only models. Conditional linkage analysis (which models epistasis as a deviation from multiplicativity only) confirmed these findings, with significant LOD score increases at the 1q (P = 0.0002) and 10q (P = 0.0023) loci. These analyses provided sizeable reductions in the 1-LOD support intervals for both loci. Analyses of the British and French pedigrees together yielded comparable, but not enhanced, findings, with significant (P <= 0.003) evidence for epistasis in joint two-locus linkage analysis, and during conditional linkage analysis significant increases in linkage evidence at the 1q (P = 0.0002) and 10q (P = 0.0036) loci. Our findings of epistasis nevertheless substantiate the evidence for genuine genetic effects at both loci, facilitate endeavours to fine-map these loci in population samples, and support further examination of this interaction at the nucleotide level by providing a robust prior hypothesis. ER - TY - JFULL T1 - The obesity pipeline: current strategies in the development of anti-obesity drugs. A1 - Cooke, D A1 - Bloom, S J1 - Nat Rev Drug Discov Y1 - 2006/11// VL - 5 SN - 1474-1776 SP - 919 EP - 931 N2 - This review provides a summary of currently available pharmaceutical therapies for the treatment of obesity, along with an overview of the pipeline of products currently in development, and the key mechanisms on which the major development candidates are based. In particular, the recent increase in understanding of the role of gut peptides in energy homeostasis is highlighted as a promising source of potential future obesity therapies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17080028&query_hl=1 ER - TY - JFULL T1 - Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment. A1 - Dhillo, WS A1 - Savage, P A1 - Murphy, KG A1 - Chaudhri, OB A1 - Patterson, M A1 - Nijher, GM A1 - Foggo, VM A1 - Dancey, GS A1 - Mitchell, H A1 - Seckl, MJ A1 - Ghatei, MA A1 - Bloom, SR J1 - Am J Physiol Endocrinol Metab Y1 - 2006/11// VL - 291 SN - 0193-1849 SP - E878 EP - E884 N2 - Kisspeptin is a 54-amino acid peptide, encoded by the anti-metastasis gene KiSS-1, that activates G protein-coupled receptor 54 (GPR54). The kisspeptin-GPR54 system is critical to normal reproductive development. KiSS-1 gene expression is increased in the human placenta in normal and molar pregnancies. Circulating kisspeptin is dramatically increased in normal pregnancy, but levels in GTN have not previously been reported. The present study was designed to determine whether plasma kisspeptin levels are altered in patients with malignant GTN. Thirty-nine blood samples were taken from 11 patients with malignant GTN at presentation during and after chemotherapy. Blood was also sampled from nonpregnant and pregnant volunteers. Plasma kisspeptin IR and hCG concentrations were measured. Plasma kisspeptin IR concentration in nonpregnant (n = 16) females was <2 pmol/l. Plasma kisspeptin IR in females was 803 +/- 125 pmol/l in the first trimester of pregnancy (n = 13), 2,483 +/- 302 pmol/l in the third trimester of pregnancy (n = 7), and <2 pmol/l on day 15 postpartum (n = 7). Plasma kisspeptin IR and hCG concentrations in patients with malignant GTN were elevated at presentation and fell during and after treatment with chemotherapy in each patient (mean plasma kisspeptin IR: prechemotherapy 1,363 +/- 1,076 pmol/l vs. post-chemotherapy <2 pmol/l, P < 0.0001; mean plasma hCG: prechemotherapy 227,191 +/- 152,354 U/l vs. postchemotherapy 2 U/l, P < 0.0001). Plasma kisspeptin IR strongly positively correlated with plasma hCG levels (r(2) = 0.99, P < 0.0001). Our results suggest that measurement of plasma kisspeptin IR may be a novel tumor marker in patients with malignant GTN. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16757546&query_hl=1 ER - TY - JFULL T1 - Genetics of obesity and the prediction of risk for health. A1 - Walley, AJ A1 - Blakemore, AI A1 - Froguel, P J1 - Hum Mol Genet Y1 - 2006/10/15/ VL - 15 Spec No 2 SN - 0964-6906 SP - R124 EP - R130 N2 - Obesity has always existed in human populations, but until very recently was comparatively rare. The availability of abundant, energy-rich processed foods in the last few decades has, however, resulted in a sharp rise in the prevalence of obesity in westernized countries. Although it is the obesogenic environment that has resulted in this major healthcare problem, it is acting by revealing a sub-population with a pre-existing genetic predisposition to excess adiposity. There is substantial evidence for the heritability of obesity, and research in both rare and common forms of obesity has identified genes with significant roles in its aetiology. Application of this understanding to patient care has been slower. Until very recently, the health risks of obesity were thought to be well understood, with a straightforward correlation between increasing obesity and increasing risk of health problems such as type 2 diabetes, coronary heart disease, hypertension, arthritis and cancer. It is becoming clear, however, that the location of fat deposition, variation in the secretion of adipokines and other factors govern whether a particular obese person develops such complications. Prediction of the health risks of obesity for individual patients is not straightforward, but continuing advances in understanding of genetic factors influencing obesity risk and improved diagnostic technologies mean that the future for such prediction is looking increasingly bright. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16987875&query_hl=1 ER - TY - JFULL T1 - Distinct impaired regulation of SOCS3 and long and short isoforms of the leptin receptor in visceral and subcutaneous fat of lean and obese women. A1 - Séron, K A1 - Corset, L A1 - Vasseur, F A1 - Boutin, P A1 - Gómez-Ambrosi, J A1 - Salvador, J A1 - Frühbeck, G A1 - Froguel, P J1 - Biochem Biophys Res Commun Y1 - 2006/10/06/ VL - 348 SN - 0006-291X SP - 1232 EP - 1238 N2 - Animal studies have illustrated the importance of the expression in adipose tissue of the leptin receptor (OB-R), and of SOCS3 an inhibitor of the leptin signaling pathway, in body weight regulation. The aim of the present study was to investigate in human adipose tissues of the same patients the OB-R isoforms and SOCS3 expression. Subcutaneous and omental adipose tissues were obtained from 6 lean and 18 morbidly obese women. The long isoform OB-Rb mRNA mediating leptin signaling, and SOCS3 mRNA are abundantly present in the subcutaneous fat of lean women, but are 90% and 70% decreased (P<0.0001) in obese women. In visceral fat from lean and obese women, both OB-Rb and SOCS3 mRNA are detected at very low levels. Subcutaneous/visceral ratios for OB-Ra the short OB-R isoform, OB-Rb, and SOCS3 mRNA abundance strongly correlate with the insulin sensitivity index, HOMA-% S, (r=0.49, P<0.0001, r=0.42, P=0.0002 and r=0.38, P=0.0002, respectively) in both lean and obese patients without type 2 diabetes. The near absence of OB-Rb mRNA and the similarly decreased SOCS3 expression in obese adipose tissue may reflect a defective leptin signaling pathway that could play a role in the impairment of insulin sensitivity associated with excess adiposity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16920065&query_hl=1 ER - TY - JFULL T1 - Paracrine role of ATP in aldosterone action on epithelial cells and cardiomyocytes A1 - Korchev, Y A1 - Zhang, Y A1 - Gorelik, J A1 - Edwards, CRW J1 - HYPERTENSION Y1 - 2006/10// VL - 48 SN - 0194-911X SP - 764 EP - 764 ER - TY - JFULL T1 - Microinjection of galanin-like peptide into the medial preoptic area stimulates food intake in adult male rats. A1 - Patterson, M A1 - Murphy, KG A1 - Thompson, EL A1 - Smith, KL A1 - Meeran, K A1 - Ghatei, MA A1 - Bloom, SR J1 - J Neuroendocrinol Y1 - 2006/10// VL - 18 SN - 0953-8194 SP - 742 EP - 747 N2 - Galanin-like peptide (GALP) is a neuropeptide implicated in the regulation of feeding behaviour, metabolism and reproduction. GALP is an endogenous ligand of the galanin receptors, which are widely expressed in the hypothalamus. GALP is predominantly expressed in arcuate nucleus (ARC) neurones, which project to the paraventricular nucleus (PVN) and medial preoptic area (mPOA). Intracerebroventricular or intraparaventricular (iPVN) injection of GALP acutely increases food intake in rats. The effect of GALP injection into the mPOA on feeding behaviour has not previously been studied. In the present study, intra-mPOA (imPOA) injection of GALP potently increased 0-1-h food intake in rats. The dose-response effect of imPOA GALP administration on food intake was similar to that previously observed following iPVN administration. The effects of GALP (1 nmol) or galanin (1 nmol) on food intake were then compared following injection into the PVN, mPOA, ARC, dorsal medial nucleus (DMN), lateral hypothalamus and rostral preoptic area (rPOA). GALP (1 nmol) increased food intake to a similar degree when injected into the imPOA or iPVN, but produced no significant effect when injected into the ARC, DMN, lateral hypothalamus or rPOA. Similarly, galanin (1 nmol) significantly increased food intake following injection imPOA and iPVN. However, the effect was significantly smaller than that following administration of GALP (1 nmol). Galanin also had no significant effect on food intake when administered into the ARC, DMN, lateral hypothalamus and rPOA. These data suggest that the mPOA and the PVN may have specific roles in mediating the orexigenic effect of GALP and galanin. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16965292&query_hl=1 ER - TY - JFULL T1 - Bardet-Biedl syndrome gene variants are associated with both childhood and adult common obesity in French Caucasians. A1 - Benzinou, M A1 - Walley, A A1 - Lobbens, S A1 - Charles, MA A1 - Jouret, B A1 - Fumeron, F A1 - Balkau, B A1 - Meyre, D A1 - Froguel, P J1 - Diabetes Y1 - 2006/10// VL - 55 SN - 0012-1797 SP - 2876 EP - 2882 N2 - Bardet-Biedl syndrome (BBS) is a rare developmental disorder with the cardinal features of abdominal obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, hypertension, and diabetes. BBS is genetically heterogeneous, with nine genes identified to date and evidence for additional loci. In this study, we performed mutation analysis of the coding and conserved regions of BBS1, BBS2, BBS4, and BBS6 in 48 French Caucasian individuals. Among the 36 variants identified, 12 were selected and genotyped in 1,943 French-Caucasian case subjects and 1,299 French-Caucasian nonobese nondiabetic control subjects. Variants in BBS2, BBS4, and BBS6 showed evidence of association with common obesity in an age-dependent manner, the BBS2 single nucleotide polymorphism (SNP) being associated with common adult obesity (P = 0.0005) and the BBS4 and BBS6 SNPs being associated with common early-onset childhood obesity (P = 0.0003) and common adult morbid obesity (0.0003 < P < 0.007). The association of the BBS4 rs7178130 variant was found to be supported by transmission disequilibrium testing (P = 0.006). The BBS6 variants also showed nominal evidence of association with quantitative components of the metabolic syndrome (e.g., dyslipidemia, hyperglycemia), a complication previously described in BBS patients. In summary, our preliminary data suggest that variations at BBS genes are associated with risk of common obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17003356&query_hl=1 ER - TY - JFULL T1 - Thyroid hormone-stimulated differentiation of primary rib chondrocytes in vitro requires thyroid hormone receptor beta A1 - Rabier, B A1 - Williams, AJ A1 - Mallein-Gerin, F A1 - Williams, GR A1 - Chassande, O J1 - J ENDOCRINOL Y1 - 2006/10// VL - 191 SN - 0022-0795 SP - 221 EP - 228 N2 - The active thyroid hormone, triiodothyronine (T-3), binds to thyroid hormone receptors (TR) and plays an essential role in the control of chondrocyte proliferation and differentiation. Hypo- and hyperthyroidism alter the structure of growth plate cartilage and modify chondrocyte gene expression in vivo, whilst TR mutations or deletions in mice result in altered growth plate architecture. Nevertheless, the particular roles of individual TR isoforms in mediating T-3 action in chondrocytes have not been studied and are difficult to determine in vivo because of complex cellular and molecular interactions that regulate growth plate maturation. Therefore, we studied the effects of TR alpha and TR beta on chondrocyte growth and differentiation in primary cultures of neonatal rib chondrocytes isolated from TR alpha- and TR beta-deficient mice. T-3 decreased proliferation but accelerated differentiation of rib chondrocytes from wild-type mice. T-3 treatment resulted in similar effects in TR alpha-deficient chondrocytes, but in TR beta-deficient chondrocytes, all T-3 responses were abrogated. Furthermore, T-3 increased TR beta 1 expression in wild-type and TR alpha-deficient chondrocytes. These data indicate that T-3-stimulated differentiation of primary rib chondrocytes in vitro requires TR beta and suggest that the TR beta 1 isoform mediates important T-3 actions in mouse rib chondrocytes. ER - TY - JFULL T1 - Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes. A1 - Cauchi, S A1 - Meyre, D A1 - Dina, C A1 - Choquet, H A1 - Samson, C A1 - Gallina, S A1 - Balkau, B A1 - Charpentier, G A1 - Pattou, F A1 - Stetsyuk, V A1 - Scharfmann, R A1 - Staels, B A1 - Frühbeck, G A1 - Froguel, P J1 - Diabetes Y1 - 2006/10// VL - 55 SN - 0012-1797 SP - 2903 EP - 2908 N2 - Recently, the transcription factor 7-like 2 (TCF7L2) gene has been associated with type 2 diabetes in subjects of European origin in the DeCode study. We genotyped the two most associated variants (rs7903146 and rs12255372) in 2,367 French type 2 diabetic subjects and in 2,499 control subjects. Both the T-allele of rs7903146 and the T-allele of rs12255372 significantly increase type 2 diabetes risk with an allelic odds ratio (OR) of 1.69 (95% CI 1.55-1.83) (P = 6.0 x 10(-35)) and 1.60 (1.47-1.74) (P = 7.6 x 10(-28)), respectively. In nonobese type 2 diabetic subjects (BMI <30 kg/m2, n = 1,346), the ORs increased to 1.89 (1.72-2.09) (P = 2.1 x 10(-38)) and 1.79 (1.62-1.97) (P = 5.7 x 10(-31)), respectively. The rs7903146 T at-risk allele associates with decreased BMI and earlier age at diagnosis in the type 2 diabetic subjects (P = 8.0 x 10(-3) and P = 3.8 x 10(-4), respectively), which is supported by quantitative family-based association tests. TCF7L2 is expressed in most human tissues, including mature pancreatic beta-cells, with the exception of the skeletal muscle. In the subcutaneous and omental fat from obese type 2 diabetic subjects, TCF7L2 expression significantly decreased compared with obese normoglycemic individuals. During rat fetal beta-cell differentiation, TCF7L2 expression pattern mimics the key marker NGN3 (neurogenin 3), suggesting a role in islet development. These data provide evidence that TCF7L2 is a major determinant of type 2 diabetes risk in European populations and suggests that this transcription factor plays a key role in glucose homeostasis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17003360&query_hl=1 ER - TY - JFULL T1 - Multifunctional specificity of the protein C/activated protein C Gla domain. A1 - Preston, RJ A1 - Ajzner, E A1 - Razzari, C A1 - Karageorgi, S A1 - Dua, S A1 - Dahlbäck, B A1 - Lane, DA J1 - J Biol Chem Y1 - 2006/09/29/ VL - 281 SN - 0021-9258 SP - 28850 EP - 28857 N2 - Activated protein C (APC) has potent anticoagulant and anti-inflammatory properties that are mediated in part by its interactions with its cofactor protein S and the endothelial cell protein C receptor (EPCR). The protein C/APC Gla domain is implicated in both interactions. We sought to identify how the protein C Gla domain enables specific protein-protein interactions in addition to its conserved role in phospholipid binding. The human prothrombin Gla domain, which cannot bind EPCR or support protein S cofactor activity, has 22/45 residues that are not shared with the human protein C Gla domain. We hypothesized that the unique protein C/APC Gla domain residues were responsible for mediating the specific interactions. To assess this, we generated 13 recombinant protein C/APC variants incorporating the prothrombin residue substitutions. Despite anticoagulant activity similar to wild-type APC in the absence of protein S, APC variants APC(PT33-39) (N33S/V34S/D35T/D36A/L38D/A39V) and APC(PT36/38/39) (D36A/L38D/A39V) were not stimulated by protein S, whereas APC(PT35/36) (D35T/D36A) exhibited reduced protein S sensitivity. Moreover, PC(PT8/10) (L8V/H10K) displayed negligible EPCR affinity, despite normal binding to anionic phospholipid vesicles and factor Va proteolysis in the presence and absence of protein S. A single residue variant, PC(PT8), also failed to bind EPCR. Factor VIIa, which also possesses Leu-8, bound soluble EPCR with similar affinity to wild-type protein C, collectively confirming Leu-8 as the critical residue for EPCR recognition. These results reveal the specific Gla domain residues responsible for mediating protein C/APC molecular recognition with both its cofactor and receptor and further illustrate the multifunctional potential of Gla domains. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16867987&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 - In vivo efficacy of STX213, a second-generation steroid sulfatase inhibitor, for hormone-dependent breast cancer therapy. A1 - Foster, PA A1 - Newman, SP A1 - Chander, SK A1 - Stengel, C A1 - Jhalli, R A1 - Woo, LL A1 - Potter, BV A1 - Reed, MJ A1 - Purohit, A J1 - Clin Cancer Res Y1 - 2006/09/15/ VL - 12 SN - 1078-0432 SP - 5543 EP - 5549 N2 - PURPOSE: Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model. EXPERIMENTAL DESIGN: MCF-7 cells stably expressing STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7STS and wild-type MCF-7 (MCF-7WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly. RESULTS: STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7WT and 3.8-fold for MCF-7STS after 49 days compared with day 0. MCF-7WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7STS tumors, and recovery of these tumors was significantly retarded (P<0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7STS tumors directly correlated with the corresponding STS enzyme activity. CONCLUSIONS: This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17000691&query_hl=1 ER - TY - JFULL T1 - Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats. A1 - McGowan, BM A1 - Stanley, SA A1 - Smith, KL A1 - Minnion, JS A1 - Donovan, J A1 - Thompson, EL A1 - Patterson, M A1 - Connolly, MM A1 - Abbott, CR A1 - Small, CJ A1 - Gardiner, JV A1 - Ghatei, MA A1 - Bloom, SR J1 - Regul Pept Y1 - 2006/09/11/ VL - 136 SN - 0167-0115 SP - 72 EP - 77 N2 - The effects of acute and repeated intraparaventricular (iPVN) administration of human relaxin-3 (H3) were examined on food intake, energy expenditure, and the hypothalamo-pituitary thyroid axis in male Wistar rats. An acute high dose iPVN injection of H3 significantly increased food intake 1 h post-administration [0.4+/-0.1 g (vehicle) vs 1.6+/-0.5 g (180 pmol H3), 2.4+/-0.5 g (540 pmol H3) and 2.2+/-0.5 g (1,620 pmol H3), p<0.05 for all doses vs vehicle]. Repeated iPVN H3 injection (180 pmol/twice a day for 7 days) significantly increased cumulative food intake in ad libitum fed animals compared with vehicle [211.8+/-7.1 g (vehicle) vs 261.6+/-6.7 g (ad libitum fed H3), p<0.05]. Plasma leptin was increased in the H3 ad libitum fed group. Plasma thyroid stimulating hormone was significantly decreased after acute and repeated administration of H3. These data suggest H3 may play a role in long-term control of food intake. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16764952&query_hl=1 ER - TY - JFULL T1 - Binding of calcium to anticoagulant protein S: role of the fourth EGF module. A1 - Persson, KE A1 - Stenflo, J A1 - Linse, S A1 - Stenberg, Y A1 - Preston, RJ A1 - Lane, DA A1 - Rezende, SM J1 - Biochemistry Y1 - 2006/09/05/ VL - 45 SN - 0006-2960 SP - 10682 EP - 10689 N2 - Protein S is an anticoagulant protein containing a Gla (enclosing gamma-carboxyglutamic acids) module, a TSR (thrombin sensitive region) module, four EGF (epidermal growth factor)-like modules, and a SHBG (sex hormone binding globulin)-like region. Protein S is a cofactor to activated protein C (APC) in the degradation of coagulation factors Va and VIIIa but also has APC-independent activities. The function of the fourth EGF module (EGF4) in protein S has so far not been clear. We have now investigated this module through studies of recombinant wild-type protein S and a naturally occurring mutant (Asn217Ser). The mutant has essentially normal APC anticoagulant activity and a previously reported secretion defect. In the wild-type protein, Asn217 is normally beta-hydroxylated. The binding of calcium to wild-type protein S is characterized by four high-affinity binding sites with K(D) values ranging from 10(-)(7) to 10(-)(9) M. Three of these binding sites are located in EGF modules. Using surface plasmon resonance, competition with a calcium chelator, and antibody-based methods, we found that one high-affinity binding site for calcium was lost in protein S Asn217Ser but that the mutation also affected the calcium-dependent conformation of EGF1. We conclude that binding of calcium to EGF4 of protein S, involving Asn217, is important for the maintenance of the structure of protein S. Also, the abolition of binding of calcium to EGF4, related to Asn217, impairs both the structure and function of EGF1. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16939220&query_hl=1 ER - TY - JFULL T1 - Determinants of adiposity during preweaning postnatal growth in appropriately grown and growth-restricted term infants. A1 - Modi, N A1 - Thomas, EL A1 - Harrington, TA A1 - Uthaya, S A1 - Doré, CJ A1 - Bell, JD J1 - Pediatr Res Y1 - 2006/09// VL - 60 SN - 0031-3998 SP - 345 EP - 348 N2 - The distribution and quantity of adipose tissue are markers of morbidity risk in children and adults. Poor intrauterine growth and accelerated postnatal growth are believed to add to these risks. The aim of this study was to assess adipose tissue content and distribution at birth and 6 wk in relation to intrauterine growth restriction, postnatal growth, and infant diet. We measured weight, length, and head circumference and adipose content and distribution using magnetic resonance imaging at 6 wk of age in appropriately grown for gestational age (AGA) and growth-restricted (GR) infants and compared this with birth data. By 6 wk, GR infants showed complete catch-up in comparison to AGA infants in relation to head growth and adiposity. Catch-up in length and weight was not complete. Accelerated linear growth, but not accelerated weight gain, was associated with a highly significant increase in adiposity (r = 0.57, p = 0.001) regardless of AGA/GR status. The highest adiposity at 6 wk, allowing for baseline variables and linear growth, was seen in exclusively breast-fed GR infants (mean, 95% confidence interval: 33.5%, 29.51-37.5). Adipose tissue distribution remained constant and was unrelated to growth and diet. Reduced birth adiposity (B = -0.185, p = 0.003), but not low birth head size (B = 0.32, p = 0.093), was a significant predictor of accelerated postnatal head growth (R(2) = 0.29, adjusted R(2) = 0.23, p = 0.012). Increasing adiposity appears to be an inevitable accompaniment of accelerated linear growth. Low total adipose tissue quantity at birth appears to direct nutrition toward head growth. Adipose tissue may be involved in the signaling of catch-up growth. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16857778&query_hl=1 ER - TY - JFULL T1 - Polymorphisms in the glucokinase-associated, dual-specificity phosphatase 12 (DUSP12) gene under chromosome 1q21 linkage peak are associated with type 2 diabetes A1 - Das, SK A1 - Chu, WS A1 - Hale, TC A1 - Wang, XQ A1 - Craig, RI A1 - Wang, H A1 - Shuldiner, AR A1 - Froguel, P A1 - Deloukas, P A1 - McCarthy, MI A1 - Zeggini, E A1 - Hasstedt, SJ A1 - Elbein, SC J1 - DIABETES Y1 - 2006/09// VL - 55 SN - 0012-1797 SP - 2631 EP - 2639 N2 - Linkage of type 2 diabetes to chromosome 1q21-q23 is well replicated across populations. In an initial 50-kb marker map (580 markers) across the linked region, one of the two strongest associations observed in Utah Caucasians was at marker rs1503814 (P < 0.00001 in pools, P < 0.004 in individuals). Based on this association, we typed additional markers and screened for sequence variation in the nearby DUSP12 gene. The strongest associations mapped to a highly conserved nongenic sequence just telomeric to rs1503814 and extended 10 kb telomeric through the DUSP12 gene and into the 5' end of the adjacent ATF6 gene. No coding variant could explain the association in the DUSP12 gene. An extended haplotype encompassing markers from -8,379 to +10,309 bp relative to the ATG start was more common in Caucasian case (0.381) than control subjects (0.285, P = 0.005) and was uniquely tagged by a 194-bp allele at either of two simple tandem repeat variants or by the T allele at marker +7,580. Markers -8,379 and +7,580 were nominally associated with type 2 diabetes in African-American subjects (P < 0.05), but with different alleles. Marker rs1503814 was strongly associated with postchallenge insulin levels among family members (P = 0.000002), but sequence variation in this region was not associated with type 2 diabetes in three other populations of European ancestry. Our data suggest that sequences in or upstream of DUSP12 may contribute to type 2 diabetes susceptibility, but the lack of replication suggests a small effect size. ER - TY - JFULL T1 - Fasting plasma peptide-YY concentrations are elevated but do not rise postprandially in type 2 diabetes. A1 - English, PJ A1 - Ashcroft, A A1 - Patterson, M A1 - Dovey, TM A1 - Halford, JC A1 - Harrison, J A1 - Eccleston, D A1 - Bloom, SR A1 - Ghatei, MA A1 - Wilding, JP J1 - Diabetologia Y1 - 2006/09// VL - 49 SN - 0012-186X SP - 2219 EP - 2221 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16832662&query_hl=1 ER - TY - JFULL T1 - Sustained endogenous glucose production, diminished lipolysis and non-esterified fatty acid appearance and oxidation in non-obese women at high risk of type 2 diabetes. A1 - Forbes, S A1 - Robinson, S A1 - Dungu, J A1 - Anyaoku, V A1 - Bannister, P A1 - Forster, D A1 - Dissanayake, S A1 - McCarthy, MI A1 - MacDonald, IA A1 - Venkatesan, S A1 - Johnston, DG J1 - Eur J Endocrinol Y1 - 2006/09// VL - 155 SN - 0804-4643 SP - 469 EP - 476 N2 - OBJECTIVE: To evaluate early defects in glucose production, lipolysis and fatty acid oxidation in non-obese, normally glucose tolerant women, who are nevertheless at risk of type 2 diabetes. METHODS: Ten women with previous gestational diabetes (pGDM) and ten controls were studied in two 4 h infusions of stable isotopes 6,6-(2)H(2)-glucose, 1-(13)C-palmitate, and 1,1,2,3,3-(2)H(5)-glycerol with and without infusion of adrenaline. Fatty acid oxidation was quantified using indirect calorimetry and (13)CO(2) measurements. Insulin sensitivity was evaluated using the short insulin tolerance test. RESULTS: The pGDM and control women were non-obese and carefully matched for body mass index and fat mass. Whole body insulin sensitivity and basal insulin concentrations did not differ significantly but basal glucose concentrations were increased in women with pGDM. During a 0.9% saline infusion, glucose appearance was not significantly different at the first (90-120 min) and second (210-240 min) steady states. However, glucose appearance decreased in controls but was maintained in the pGDM women (-0.33 +/- 0.02 vs -0.03 +/- 0.08 mg/kg per min; P = 0.004). Basal glycerol appearance (0.27 +/- 0.02 vs 0.38 +/- 0.03 mg/kg per min; P = 0.02), palmitate appearance (0.74 +/- 0.09 vs 1.05 +/- 0.09 mg/kg per min; P = 0.03) and palmitate oxidation (0.07 +/- 0.01 vs 0.10 +/- 0.01 mg/kg per min; P = 0.03) were lower in the pGDM women. During the adrenaline infusion, changes in glucose, glycerol and palmitate concentrations and kinetics were similar in both groups. CONCLUSIONS: Sustained glucose production during fasting is an early abnormality in non-obese subjects at risk of type 2 diabetes. Lipolysis and non-esterified fatty acid appearance and oxidation are diminished, suggesting an increased tendency to store fat. The observations are not readily attributable to differences in insulin or catecholamine sensitivity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16914602&query_hl=1 ER - TY - JFULL T1 - ENPP1 K121Q associates with severe obesity and T2D, and predicts overweight/class III obesity and familial glucose intolerance/T2D incidence in the prospective DESIR Study A1 - Meyre, D A1 - Samson, C A1 - Vatin, V A1 - Tichet, J A1 - Marre, M A1 - Balkau, B A1 - Froguel, P J1 - DIABETOLOGIA Y1 - 2006/09// VL - 49 SN - 0012-186X SP - 217 EP - 218 ER - TY - JFULL T1 - The TT genotype of the subtype 2 bradykinin receptor (BDKRB2) is associated with a high risk for type 2 diabetes (T2D) in the general population: the DESIR study A1 - Roussel, R A1 - Bellili, N A1 - Fumeron, F A1 - Meyre, D A1 - Fysekidis, M A1 - Velho, G A1 - Hadjadj, S A1 - Tichet, J A1 - Vaxillaire, M A1 - Alhenc-Gelas, F A1 - Balkau, B A1 - Froguel, P A1 - Marrel, M J1 - DIABETOLOGIA Y1 - 2006/09// VL - 49 SN - 0012-186X SP - 36 EP - 37 ER - TY - JFULL T1 - A KLF9 promoter variant that is predicted to affect TCF7L2 binding is associated with type 2 diabetes A1 - Neve, B A1 - Gutierrez-Aguilar, R A1 - Benmezroua, Y A1 - Vaillant, E A1 - Dina, C A1 - Balkau, B A1 - Marre, M A1 - Charpentier, G A1 - Froguel, P J1 - DIABETOLOGIA Y1 - 2006/09// VL - 49 SN - 0012-186X SP - 17 EP - 17 ER - TY - JFULL T1 - Cannabinoid receptor 1 gene variation increases risk for obesity and type 2 diabetes and modulates phenotypes related to endocannabinoid-mediated physiological pathways A1 - Ward, KJ A1 - Boutin, P A1 - Chevre, JC A1 - Lobbens, S A1 - Lecoeur, C A1 - Wachter, C A1 - Dina, C A1 - Larsen, PJ A1 - Tanko, LB A1 - Horber, FF A1 - Charpentier, G A1 - Balkau, B A1 - Meyre, D A1 - Froguel, P J1 - DIABETOLOGIA Y1 - 2006/09// VL - 49 SN - 0012-186X SP - 215 EP - 216 ER - TY - JFULL T1 - TCF7L2 gene strongly associates with type 2 diabetes, with lower age of onset and BMI in the French population, and its adipose expression is impaired in diabetes A1 - Cauchi, S A1 - Meyrel, D A1 - Choquet, H A1 - Samson, C A1 - Polychronakos, C A1 - Balkau, B A1 - Scharfmann, R A1 - Fruhbeck, G A1 - Charpentier, G A1 - Sladek, R A1 - Froguel, P J1 - DIABETOLOGIA Y1 - 2006/09// VL - 49 SN - 0012-186X SP - 14 EP - 15 ER - TY - JFULL T1 - Critical role for peptide YY in protein-mediated satiation and body-weight regulation. A1 - Batterham, RL A1 - Heffron, H A1 - Kapoor, S A1 - Chivers, JE A1 - Chandarana, K A1 - Herzog, H A1 - Le Roux, CW A1 - Thomas, EL A1 - Bell, JD A1 - Withers, DJ J1 - Cell Metab Y1 - 2006/09// VL - 4 SN - 1550-4131 SP - 223 EP - 233 N2 - Dietary protein enhances satiety and promotes weight loss, but the mechanisms by which appetite is affected remain unclear. We investigated the role of gut hormones, key regulators of ingestive behavior, in mediating the satiating effects of different macronutrients. In normal-weight and obese human subjects, high-protein intake induced the greatest release of the anorectic hormone peptide YY (PYY) and the most pronounced satiety. Long-term augmentation of dietary protein in mice increased plasma PYY levels, decreased food intake, and reduced adiposity. To directly determine the role of PYY in mediating the satiating effects of protein, we generated Pyy null mice, which were selectively resistant to the satiating and weight-reducing effects of protein and developed marked obesity that was reversed by exogenous PYY treatment. Our findings suggest that modulating the release of endogenous satiety factors, such as PYY, through alteration of specific diet constituents could provide a rational therapy for obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16950139&query_hl=1 ER - TY - JFULL T1 - Association of KLF11 with insulin resistance is mediated via STAT3 binding to KLF11 variant -1659 G > C A1 - Gutierrez-Aguilar, R A1 - Hamid, YH A1 - Vaillant, E A1 - Benmezroua, Y A1 - Jorgensen, T A1 - Borch-Johnsen, K A1 - Hansen, T A1 - Froguel, P A1 - Pedersen, O A1 - Neve, B J1 - DIABETOLOGIA Y1 - 2006/09// VL - 49 SN - 0012-186X SP - 162 EP - 163 ER - TY - JFULL T1 - Association of the calpain-10 gene with type 2 diabetes in Europeans: Results of pooled and meta-analyses A1 - Tsuchiya, T A1 - Schwarz, PEH A1 - del Bosque-Plata, L A1 - Hayes, MG A1 - Dina, C A1 - Froguel, P A1 - Towers, GW A1 - Fischer, S A1 - Temelkova-Kurktschiev, T A1 - Rietzsch, H A1 - Graessler, J A1 - Vcelak, J A1 - Palyzova, D A1 - Selisko, T A1 - Bendlova, B A1 - Schulze, J A1 - Julius, U A1 - Hanefeld, M A1 - Weedon, MN A1 - Evans, JC A1 - Frayling, TM A1 - Hattersley, AT A1 - Orho-Melander, M A1 - Groop, L A1 - Malecki, MT A1 - Hansen, T A1 - Pedersen, O A1 - Fingerlin, TE A1 - Boehnke, M A1 - Hanis, CL A1 - Cox, NJ A1 - Bell, GI J1 - MOL GENET METAB Y1 - 2006/09// VL - 89 SN - 1096-7192 SP - 174 EP - 184 N2 - We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR) = 1.11 (95% confidence interval (0), 1.02-1.20), P = 0.01). Two haplotype combinations were associated with increased risk of T2D) (1-2-1/1-2-1, OR = 1.20 (1.03-1.41), P = 0.02; and 1-1-2/1-2-1, OR = 1.26 (1.01-1.59), P = 0.04) and one with decreased risk (1-1-1/2-2-1, OR = 0.86 (0.75-0.99), P = 0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR = 1.25 (1.05-1.50), P = 0.01). However, there was evidence for heterogeneity with respect to this effect (P = 0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P = 0.89) and strengthened the evidence for association with T2D) in both the pooled (SNP-43*G, OR = 1.19 (1.07-1.32), P = 0.001; 1-2-1/1-2-1 haplogenotype, OR = 1.46 (1.19-1.78), P = 0.0003; 1-1-2/1-2-1 haplogenotype, OR = 1.52 (1.12-2.06), P = 0.007; and 1-1-1/2-2-1 haplogenotype, OR = 0.83 (0.70-0.99), P = 0.03) and the meta-analysis (SNP-43*G, OR = 1.18 (1.05-1.32), P = 0.005; 1-2-1/1-2-1 haplogenotype, OR = 1.68 (1.33-2.11), P = 0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans. (c) 2006 Elsevier Inc. All rights reserved. ER - TY - JFULL T1 - Single-nucleotide polymorphism of the cannabinoid receptor 1 gene: A genetic link between osteoporosis and cardiovascular disease? A1 - Tanko, LB A1 - Boutin, P A1 - Larsen, P A1 - Froguel, P A1 - Christiansen, C J1 - J BONE MINER RES Y1 - 2006/09// VL - 21 SN - 0884-0431 SP - S148 EP - S148 ER - TY - JFULL T1 - The role of aromatase and 17-beta-hydroxysteroid dehydrogenase type 1 mRNA expression in predicting the clinical outcome of human breast cancer A1 - Salhab, M A1 - Reed, MJ A1 - Al Sarakbi, W A1 - Jiang, WG A1 - Mokbel, K J1 - BREAST CANCER RES TR Y1 - 2006/09// VL - 99 SN - 0167-6806 SP - 155 EP - 162 N2 - Introduction. There is substantial evidence that breast cancer tissue contains all the enzymes responsible for the local biosynthesis of estrogens from circulating precursors. The cytochrome P-450 aromatase enzyme complex is responsible for the conversion of C19 androgens to estrogens and 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) type 1 catalyses the inter-conversion of estrone to the biologically more potent estradiol. The gene encoding for the cytochrome P-450 aromatase is known as CYP19 (15q21.2). It is well established that increased exposure to local estrogens is an important risk factor in the genesis and growth of breast cancer. The aim of this study is to investigate the relationship between CYP19 and 17-beta-HSD type 1 RNA expression and clinico-pathological parameters of human breast cancer.Methods. One hundred and twenty seven tumor tissues and 33 normal tissues were analyzed. The levels of transcription of CYP19 and 17-beta-HSD type 1 were determined using real-time quantitative PCR. The mRNA expression was normalized against CK19. Levels of expression were analyzed against tumor's stage, grade, nodal status, local relapse, distant metastasis and survival over a 120 months follow up period. In addition, the levels were analyzed against estrogen receptor (ER) and HER1-4 status.Results. Overall, high tumor levels of mRNA expression of CYP19 and 17-beta-HSD type 1 correlated with poor survival (p=0.0105 and p=0.0182, respectively). Increased levels of CYP19 mRNA expression positively correlated with disease progression as levels were significantly higher in samples of patients who had distant metastasis and local recurrence and/or died of breast related causes when compared to those who were disease free for > 10 years (p=0.0015). We also observed higher levels of CYP19 mRNA in tumor samples compared to normal breast tissue. However, this reached statistical significance only when comparing grade 1 tumors with normal tissue (p=0.01). There was no correlation between CYP19 mRNA expression and tumor stage, lymph node status and tumor grade. There was however a trend for a positive correlation between CYP19 and ER mRNA expressions (p=0.06). No significant difference in 17-beta-HSD type 1 expression between normal and cancerous tissues was observed. In tumor samples, we observed an increase in levels correlating with tumor's grade. This correlation was statistically significant when we compared grade 1 with grade 2 and grade 1 with grade3 (p=0.0031 and 0.0251, respectively).Conclusions. Our study shows that higher levels of the enzymes responsible for the local biosynthesis of estrogens especially aromatase are associated with a poor clinical outcome in patients with breast cancer. ER - TY - JFULL T1 - Randomized trial of effects of continuous combined HRT on markers of lipids and coagulation in women with acute coronary syndromes: WHISP Pilot Study. A1 - Collins, P A1 - Flather, M A1 - Lees, B A1 - Mister, R A1 - Proudler, AJ A1 - Stevenson, JC A1 - WHISP (Women's Hormone Intervention Secondary Prevention Study) Pilot Study Investigators J1 - Eur Heart J Y1 - 2006/09// VL - 27 SN - 0195-668X SP - 2046 EP - 2053 N2 - AIMS: Randomized trials have not demonstrated coronary heart disease benefit from hormone replacement therapy (HRT). We hypothesized that low-dose HRT may avoid harm. METHODS AND RESULTS: We studied the effects of HRT on lipids and coagulation in women with acute coronary syndromes. A total of 100 post-menopausal women >55 years were enrolled between 2 and 28 days after an acute coronary syndrome and randomized to oral oestradiol-17beta 1 mg plus norethisterone acetate 0.5 mg daily, or matching placebo, and followed for up to 12 months. Levels of lipids, lipoproteins, and haemostasis markers were measured at baseline, 3, and 6 months. There were no significant differences in lipid levels between the two groups, probably due to concomitant statin use. Antithrombin and factor VII levels were significantly lower in the HRT group, whereas fibrinogen was significantly decreased in the placebo group. No evidence of increased coagulation activation was observed, nor of adverse cardiovascular outcomes [odds ratio (OR) 0.63 (95% confidence intervals 0.31-1.31)]. CONCLUSION: Low-dose HRT may give cardiovascular benefit. These findings require confirmation in a full clinical trial with evaluation of cardiovascular outcomes as the primary objective. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16899475&query_hl=1 ER - TY - JFULL T1 - Variation within the gene encoding the upstream stimulatory factor 1 does not influence susceptibility to type 2 diabetes in samples from populations with replicated evidence of linkage to chromosome 1q A1 - Zeggini, E A1 - Damcott, CM A1 - Hanson, RL A1 - Karim, MA A1 - Rayner, NW A1 - Groves, CJ A1 - Baier, LJ A1 - Hale, TC A1 - Hattersley, AT A1 - Hitman, GA A1 - Hunt, SE A1 - Knowler, WC A1 - Mitchell, BD A1 - Ng, MCY A1 - O'Connell, JR A1 - Pollin, TI A1 - Vaxillaire, M A1 - Walker, M A1 - Wang, XQ A1 - Whittaker, P A1 - Kunsun, X A1 - Jia, WP A1 - Chan, JCN A1 - Froguel, P A1 - Deloukas, P A1 - Shuldiner, AR A1 - Elbein, SC A1 - McCarthy, MI A1 - Int Type 2 Diabet 1q Consortium J1 - DIABETES Y1 - 2006/09// VL - 55 SN - 0012-1797 SP - 2541 EP - 2548 N2 - The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97-1.24, P = 0.13). In 124 Utah subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a major contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits. ER - TY - JFULL T1 - Determination of androgen bioactivity in human serum samples using a recombinant cell based in vitro bioassay. A1 - Roy, P A1 - Franks, S A1 - Read, M A1 - Huhtaniemi, IT J1 - J Steroid Biochem Mol Biol Y1 - 2006/09// VL - 101 SN - 0960-0760 SP - 68 EP - 77 N2 - The present study describes the development and optimization of a cell-based reporter assay for the determination of androgen bioactivity levels in human serum samples. Towards this end, human embryonic kidney (HEK) 293 cells were cotransfected with two plasmids, one encoding the mouse mammary tumor virus (MMTV)-driven luciferase reporter gene and the other the SV40 promoter-driven human androgen receptor (AR), and a stable cell line, expressing human AR and androgen-responsive luciferase was established by antibiotic selection. RT-PCR confirmed proper transcription and stable integration of AR in the cell line. On stimulation of the cells with testosterone (T) for 24h, luciferase activity was increased in dose-dependent fashion up to 15-fold, with the minimum effective concentration of T being 0.03 nmol/l. T-induced reporter gene expression of the cells was inhibited by the anti-androgens cyproterone acetate and hydroxyflutamide. Upon stimulation with non-androgenic steroids like estradiol, progesterone, dexamethasone and cortisol, the cells showed only marginal activity except for a weak glucocorticoid effect at high concentration. The cells also responded well to various chemicals (mostly pesticides, their metabolites and common industrial chemicals) with known androgenic activity. The cell line was further optimized by measuring the levels of androgens from male and female serum samples. Our data indicated that the cells can be used to estimate androgen bioactivity in serum of females suffering from polycystic ovary syndrome (PCOS) and males of different age groups. In conclusion, we demonstrate that the bioassay based on this cell line provides a reliable method to determine serum levels of androgen bioactivity from biological samples even at the low concentrations present in female circulation. The 96-well plate format makes the assay suitable for high throughput measurements. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16893644&query_hl=1 ER - TY - JFULL T1 - Diabetes management in the USA and England: comparative analysis of national surveys. A1 - Mainous, AG A1 - Diaz, VA A1 - Saxena, S A1 - Baker, R A1 - Everett, CJ A1 - Koopman, RJ A1 - Majeed, A J1 - J R Soc Med Y1 - 2006/09// VL - 99 SN - 0141-0768 SP - 463 EP - 469 N2 - OBJECTIVES: To compare diabetes management in adults between England and the United States, particularly focusing on the impact of a universal access health insurance system. DESIGN: Analysis of the nationally-representative surveys Health Survey of England, 2003 (unweighted n =14 057) and the National Health and Nutrition Examination Survey, 2001-2002 (unweighted n =5411). SETTING AND PARTICIPANTS: Adults 20-64 years of age; individuals >65. MAIN OUTCOME MEASURES: Glycaemic, lipid and blood pressure control and medication use among individuals with previously diagnosed diabetes. RESULTS: Among those aged 20-64 the prevalence of diagnosed diabetes was lower in England (2.7%) than in the USA (5.0%). The proportion with diabetes receiving treatment was similar for the two countries. However, the mean HbA1c in England was 7.6%: in the USA it was 7.5% for those with insurance and 8.6% for those without insurance. The proportion of individuals on ACE inhibitors in England was 39%: in USA it was 39% for those with insurance, and 14% for those without. CONCLUSIONS: Individuals in a healthcare system providing universal access have better managed diabetes than those in a market based system once one accounts for insurance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16946390&query_hl=1 ER - TY - JFULL T1 - Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. A1 - Dumas, ME A1 - Barton, RH A1 - Toye, A A1 - Cloarec, O A1 - Blancher, C A1 - Rothwell, A A1 - Fearnside, J A1 - Tatoud, R A1 - Blanc, V A1 - Lindon, JC A1 - Mitchell, SC A1 - Holmes, E A1 - McCarthy, MI A1 - Scott, J A1 - Gauguier, D A1 - Nicholson, JK J1 - Proc Natl Acad Sci U S A Y1 - 2006/08/15/ VL - 103 SN - 0027-8424 SP - 12511 EP - 12516 N2 - Here, we study the intricate relationship between gut microbiota and host cometabolic phenotypes associated with dietary-induced impaired glucose homeostasis and nonalcoholic fatty liver disease (NAFLD) in a mouse strain (129S6) known to be susceptible to these disease traits, using plasma and urine metabotyping, achieved by (1)H NMR spectroscopy. Multivariate statistical modeling of the spectra shows that the genetic predisposition of the 129S6 mouse to impaired glucose homeostasis and NAFLD is associated with disruptions of choline metabolism, i.e., low circulating levels of plasma phosphatidylcholine and high urinary excretion of methylamines (dimethylamine, trimethylamine, and trimethylamine-N-oxide), coprocessed by symbiotic gut microbiota and mammalian enzyme systems. Conversion of choline into methylamines by microbiota in strain 129S6 on a high-fat diet reduces the bioavailability of choline and mimics the effect of choline-deficient diets, causing NAFLD. These data also indicate that gut microbiota may play an active role in the development of insulin resistance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16895997&query_hl=1 ER - TY - JFULL T1 - Role of a 5'-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene. A1 - Mollica, LR A1 - Crawley, JT A1 - Liu, K A1 - Rance, JB A1 - Cockerill, PN A1 - Follows, GA A1 - Landry, JR A1 - Wells, DJ A1 - Lane, DA J1 - Blood Y1 - 2006/08/15/ VL - 108 SN - 0006-4971 SP - 1251 EP - 1259 N2 - The endothelial cell protein C receptor (EPCR) is expressed by endothelial cells of large blood vessels and by hematopoietic stem cells. DNaseI hypersensitive (DH) site mapping across 38 kb of the human EPCR gene (hEPCR) locus identified 3 potential regulatory elements. By itself, the DH region spanning the proximal promoter (PP) was unable to direct cell-specific transcription in transgenic mice. A second DH element, located upstream of PP and termed -5.5HS was hypersensitive only in endothelial cells (ECs) and immature hematopoietic cell lines. Transgenes expressing LacZ under the control of -5.5HS coupled to either PP or the SV40 promoter were able to direct beta-galactosidase activity to the endothelium of large vessels during embryogenesis and adulthood. The -5.5HS exhibited enhancer activity that was conferred by the interplay of transcription factors interacting with conserved Ets and composite GATA/Tal1 motifs. The third DH element, located in intron 2, was primarily hypersensitive in EPCR-negative cells, and capable of initiating antisense transcription, suggesting a role in hEPCR silencing. This study identifies critical elements required for the tissue specificity of hEPCR and suggests a mechanism for endothelial and hematopoietic stem cell-specific transcriptional regulation that reflects the common origin of these cell types. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16627757&query_hl=1 ER - TY - JFULL T1 - Activating mutations in the ABCC8 gene in neonatal diabetes mellitus A1 - Babenko, AP A1 - Polak, M A1 - Cave, H A1 - Busiah, K A1 - Czernichow, P A1 - Scharfmann, R A1 - Bryan, J A1 - Aguilar-Bryan, L A1 - Vaxillaire, M A1 - Froguel, P J1 - NEW ENGL J MED Y1 - 2006/08/03/ VL - 355 SN - 0028-4793 SP - 456 EP - 466 N2 - BACKGROUND:The ATP-sensitive potassium (K(sub ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(sub O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes.METHODS:We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(sub ATP) channels.RESULTS:We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(sub O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia.CONCLUSIONS:Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved. ER - TY - JFULL T1 - Impaired insulin secretion after prenatal exposure to the Dutch famine. A1 - de Rooij, SR A1 - Painter, RC A1 - Phillips, DI A1 - Osmond, C A1 - Michels, RP A1 - Godsland, IF A1 - Bossuyt, PM A1 - Bleker, OP A1 - Roseboom, TJ J1 - Diabetes Care Y1 - 2006/08// VL - 29 SN - 0149-5992 SP - 1897 EP - 1901 N2 - OBJECTIVE: We previously reported that people prenatally exposed to famine during the Dutch Hunger Winter of 1944-1945 have higher 2-h glucose concentrations after an oral glucose tolerance test in later life. We aimed to determine whether this association is mediated through alterations in insulin secretion, insulin sensitivity, or a combination of both. RESEARCH DESIGN AND METHODS: We performed a 15-sample intravenous glucose tolerance test in a subsample of 94 normoglycemic men and women from the Dutch Famine Birth Cohort. We used the disposition index, derived as the product of insulin sensitivity and the first-phase insulin response to glucose as a measure of the activity of the beta-cells adjusted for insulin resistance. In all analyses, we adjusted for sex and BMI. RESULTS: Glucose tolerance was impaired in people who had been prenatally exposed to famine compared with people unexposed to famine (difference in intravenous glucose tolerance test K(g) value -21% [95% CI -41 to -4]). People exposed to famine during midgestation had a significantly lower disposition index (-53% [-126 to -3]) compared with people unexposed to famine. Prenatal exposure to famine during early gestation was also associated with a lower disposition index, but this difference did not reach statistical significance. CONCLUSIONS: Impaired glucose tolerance after exposure to famine during mid-gestation and early gestation seems to be mediated through an insulin secretion defect. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16873799&query_hl=1 ER - TY - JFULL T1 - Identifying patients at high risk of emergency hospital admissions: a logistic regression analysis. A1 - Bottle, A A1 - Aylin, P A1 - Majeed, A J1 - J R Soc Med Y1 - 2006/08// VL - 99 SN - 0141-0768 SP - 406 EP - 414 N2 - OBJECTIVE: To use routine data to identify patients at high risk of future emergency hospital admissions. DESIGN: Descriptive analysis of inpatient hospital episode statistics. Predictive model developed using multiple logistic regression. SETTING: National Health Service hospital trusts in England. PARTICIPANTS: All patients with an emergency admission to an NHS hospital between 1 April 2000 and 31 March 2001. MAIN OUTCOME MEASURES: 'High-impact users' were defined as patients who had at least one emergency inpatient admission and who then went on to have at least two further emergency hospital admissions in the 12 months following the start date of that index admission. RESULTS: 2,895,234 patients were admitted as emergencies in 2000/2001, of whom 147,725 (5.1%) did not survive their first spell. Of the 2,747,509 surviving patients, 269,686 (9.8%) subsequently had at least two or more emergency admissions within 365 days of the index date of admission. A further 236,779 (8.6%) died during this period. Risk factors for becoming a high-impact user included the number of emergencies in the 36 months before index spell, comorbidity, age, an admission for an ambulatory care sensitive condition, ethnicity, area-level socioeconomic data, local admission rates, the number of episodes in the index spell, sex and the source of admission. The predictive model based on all emergency admissions produced a receiver operating characteristic curve score of 0.72. CONCLUSIONS: Routine hospital episode statistics can be used to identify patients who are at high risk of suffering future multiple emergency hospital admissions. The potential cost savings in preventing a proportion of these subsequent admissions need to be compared with the costs of case management of these patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16893941&query_hl=1 ER - TY - JFULL T1 - The effect of different macronutrient infusions on appetite, ghrelin and peptide YY in parenterally fed patients. A1 - Murray, CD A1 - le Roux, CW A1 - Gouveia, C A1 - Bassett, P A1 - Ghatei, MA A1 - Bloom, SR A1 - Emmanuel, AV A1 - Gabe, SM J1 - Clin Nutr Y1 - 2006/08// VL - 25 SN - 0261-5614 SP - 626 EP - 633 N2 - BACKGROUND & AIMS: Patients receiving parenteral nutrition (PN) still feel hungry despite adequate provision of calories intravenously. It is not known whether PN or its constituent macronutrients acutely affect appetite and to what degree this may be mediated by ghrelin and peptide YY (PYY). METHODS: Six medically stable patients (four men) with intestinal failure receiving PN received an isocaloric 200 kcal infusion on three separate occasions following a 12 h fast. The infusions consisted of either carbohydrate (10% dextrose), fat (10% intralipid) or mixed protein/carbohydrate (PN). Changes in ghrelin and peptide YY levels and changes in subjective symptoms of hunger, satiety and nausea during each macronutrient infusion were assessed. RESULTS: None of the three infusions acutely affected subjective symptoms of hunger, satiety and nausea (P>0.05 ANOVA). Ghrelin levels decreased significantly during dextrose [-19.1 (-35.9, -12.4), regression coefficient (95% CI), P<0.001] and parenteral nutrition infusions [-18.2 (-26.8, -9.6), P<0.001]. Lipid infusion had no effect on ghrelin levels but led to a significant decrease in PYY [-0.076 (-0.0123, -0.028), P=0.004]. Dextrose and PN infusion had no significant effect on PYY levels. CONCLUSIONS: Dextrose and PN infusions decrease ghrelin levels. Lipid infusion does not affect ghrelin levels but in contrast to oral nutrients leads to a significant decrease in PYY. Despite these changes, in patients receiving PN, macronutrient infusions do no acutely affect appetite. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16698143&query_hl=1 ER - TY - JFULL T1 - Peptide YY responses after food intake correlates with weight reduction following Roux-en-Y Gastric Bypass surgery. A1 - Werling, M A1 - le Roux, C A1 - Laurenius, A A1 - Bjorklund, P A1 - Lonroth, H A1 - Fandriks, L A1 - Ghatei, M A1 - Bloom, S A1 - Olbers, T J1 - OBES SURG Y1 - 2006/08// VL - 16 SN - 0960-8923 SP - 984 EP - 985 ER - TY - JFULL T1 - Gastrointestinal hormones regulating appetite. A1 - Chaudhri, O A1 - Small, C A1 - Bloom, S J1 - Philos Trans R Soc Lond B Biol Sci Y1 - 2006/07/29/ VL - 361 SN - 0962-8436 SP - 1187 EP - 1209 N2 - The role of gastrointestinal hormones in the regulation of appetite is reviewed. The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones function to optimize the process of digestion and absorption of nutrients by the gut. In this capacity, their local effects on gastrointestinal motility and secretion have been well characterized. By altering the rate at which nutrients are delivered to compartments of the alimentary canal, the control of food intake arguably constitutes another point at which intervention may promote efficient digestion and nutrient uptake. In recent decades, gut hormones have come to occupy a central place in the complex neuroendocrine interactions that underlie the regulation of energy balance. Many gut peptides have been shown to influence energy intake. The most well studied in this regard are cholecystokinin (CCK), pancreatic polypeptide, peptide YY, glucagon-like peptide-1 (GLP-1), oxyntomodulin and ghrelin. With the exception of ghrelin, these hormones act to increase satiety and decrease food intake. The mechanisms by which gut hormones modify feeding are the subject of ongoing investigation. Local effects such as the inhibition of gastric emptying might contribute to the decrease in energy intake. Activation of mechanoreceptors as a result of gastric distension may inhibit further food intake via neural reflex arcs. Circulating gut hormones have also been shown to act directly on neurons in hypothalamic and brainstem centres of appetite control. The median eminence and area postrema are characterized by a deficiency of the blood-brain barrier. Some investigators argue that this renders neighbouring structures, such as the arcuate nucleus of the hypothalamus and the nucleus of the tractus solitarius in the brainstem, susceptible to influence by circulating factors. Extensive reciprocal connections exist between these areas and the hypothalamic paraventricular nucleus and other energy-regulating centres of the central nervous system. In this way, hormonal signals from the gut may be translated into the subjective sensation of satiety. Moreover, the importance of the brain-gut axis in the control of food intake is reflected in the dual role exhibited by many gut peptides as both hormones and neurotransmitters. Peptides such as CCK and GLP-1 are expressed in neurons projecting both into and out of areas of the central nervous system critical to energy balance. The global increase in the incidence of obesity and the associated burden of morbidity has imparted greater urgency to understanding the processes of appetite control. Appetite regulation offers an integrated model of a brain-gut axis comprising both endocrine and neurological systems. As physiological mediators of satiety, gut hormones offer an attractive therapeutic target in the treatment of obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16815798&query_hl=1 ER - TY - JFULL T1 - Management of cardiovascular risk factors in people with diabetes in primary care: cross-sectional study. A1 - Petri, A A1 - de Lusignan, S A1 - Williams, J A1 - Chan, T A1 - Majeed, A J1 - Public Health Y1 - 2006/07// VL - 120 SN - 0033-3506 SP - 654 EP - 663 N2 - OBJECTIVES: Cardiovascular disease is the major cause of morbidity and mortality in people with diabetes. The management of cardiovascular risk factors in people with diabetes in primary care was compared with National Institute of Clinical Excellence guidelines. DESIGN: A cross-sectional study in 26 general practices, with a combined list size of 256,188 patients, participating in the Kent, Surrey and Sussex Primary Care Research Network. Primary outcomes were process of care measures. METHODS: Analysis of general practice computer data on the management of 5980 patients with diabetes, of whom 86% were aged 45 years and over. RESULTS: The prevalence of diabetes was 2.0% in women and 2.6% in men, much lower than the estimated expected prevalence of 4.8% for women and 3.3% in men. Blood pressure was well recorded (96% in both sexes), cholesterol levels less well (79% of women, 84% of men). Hypertension (78% of women, 72% of men) was common. Twenty-one percent of women and 16% of men had a blood pressure above 160/100 mmHg, suggesting under use of antihypertensive therapy. Cholesterol levels were >or=5 mmol/l in 46% of women and 38% of men. Lipid-lowering drugs were prescribed in 38% of women and men. Aspirin was prescribed in 38% of women and 40% of men. CONCLUSIONS: There is an under-diagnosis of diabetes and an under-treatment of blood pressure and blood cholesterol, more marked in women than in men. There is scope for improved management within general practice, including addressing sex inequalities. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16725165&query_hl=1 ER - TY - JFULL T1 - HRT, osteoporosis and regulatory authorities Quis custodiet ipsos custodes? A1 - Stevenson, JC A1 - International Consensus Group on HRT and Regulatory Issues J1 - Hum Reprod Y1 - 2006/07// VL - 21 SN - 0268-1161 SP - 1668 EP - 1671 N2 - HRT has been widely used for the relief of menopausal symptoms and the prevention and treatment of post-menopausal osteoporosis. However, following the publication of the Women's Health Initiative (WHI) and the Million Women Study (MWS), regulatory authorities issued an urgent safety restriction on HRT use in preventing post-menopausal osteoporosis, recommending that it now be considered a second-line treatment. Are such recommendations justified? Treatments for osteoporosis, in women with increased future risk for fractures but who have not yet developed the disease, should prevent all types of osteoporotic fractures. Of the available therapies, none other than HRT has been clearly demonstrated to prevent hip fractures in such women. Thus, HRT should be recommended as first-line treatment for osteoporosis prevention. Potential risks of HRT, such as increased development of breast cancer and increased thromboembolism, have long been known. The WHI showed risks in less than 0.3% of women studied, and the MWS appears to have overestimated the risk of breast cancer. Thus, no new safety issues have been identified, and the regulatory authorities may have misinterpreted the data from these recent studies. When given for the correct indications, HRT is of major benefit to many women. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16556675&query_hl=1 ER - TY - JFULL T1 - Ambulatory antibiotic prescribing for acute bronchitis and cough and hospital admissions for respiratory infections: time trends analysis. A1 - Mainous, AG A1 - Saxena, S A1 - Hueston, WJ A1 - Everett, CJ A1 - Majeed, A J1 - J R Soc Med Y1 - 2006/07// VL - 99 SN - 0141-0768 SP - 358 EP - 362 N2 - OBJECTIVES: To examine the relationship between ambulatory antibiotic prescribing for acute bronchitis and cough with hospital admissions for respiratory infections in the USA between 1996 and 2003. DESIGN: Analysis of data on antibiotic prescribing for episodes of acute bronchitis/cough illness in ambulatory care and hospitalization for respiratory infections for adults between 1996 and 2003 in the USA. SETTING: USA: ambulatory prescribing behaviour was derived from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey while hospitalizations in acute care hospitals were assessed in the National Hospital Discharge Survey. PARTICIPANTS: Adults 18-64 years old. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Proportion of visits for acute bronchitis/cough receiving a prescription for antibiotics and hospitalization for respiratory infections. RESULTS: Ambulatory antibiotic prescribing practices for acute bronchitis/cough and hospitalizations for respiratory infections exhibited non-linear patterns over the 8 year period. However, antibiotic prescribing practices for acute bronchitis/cough and hospitalizations for respiratory infections had a weak/moderate negative association. For three of the seven yearly changes in prescribing and hospitalizations as one increased the other decreased (P<0.01). CONCLUSIONS: Ambulatory antibiotic prescribing for respiratory tract infections was inversely associated with hospital admissions for respiratory tract infections. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16816266&query_hl=1 ER - TY - JFULL T1 - Evaluation of nonlinear regression approaches to estimation of insulin sensitivity by the minimal model with reference to Bayesian hierarchical analysis. A1 - Godsland, IF A1 - Agbaje, OF A1 - Hovorka, R J1 - Am J Physiol Endocrinol Metab Y1 - 2006/07// VL - 291 SN - 0193-1849 SP - E167 EP - E174 N2 - Minimal model analysis of intravenous glucose tolerance test (IVGTT) glucose and insulin concentrations offers a validated approach to measuring insulin sensitivity, but model identification is not always successful. Improvements may be achieved by using alternative settings in the modeling process, although results may differ according to setting, and care must be exercised in combining results. IVGTT data (12 samples, regular test) from 533 men without diabetes was modeled by the traditional nonlinear regression (NLR) approach, using five different permutations of settings. Results were evaluated with reference to the more robust Bayesian hierarchical (BH) approach to model identification and to the proportion of variance they explained in known correlates of insulin sensitivity (age, BMI, blood pressure, fasting glucose and insulin, serum triglyceride, HDL cholesterol, and uric acid concentration). BH analysis was successful in all cases. With NLR analysis, between 17 and 35 IVGTTs were associated with parameter coefficients of variation (PCVs) for minimal model parameters S(I) (insulin sensitivity) and S(G) (glucose effectiveness) of >100%. Systematic use of each different approach in combination reduced this number to five. Mean (interquartile range) S(I)(NLR) was then 3.14 (2.29-4.63) min(-1).mU(-1).l x 10(-4) and 2.56 (1.74-3.83) min(-1).mU(-1).l x 10(-4) for S(I)(BH) (correlation 0.86, P < 0.0001). S(I)(NLR) explained, on average, 10.6% of the variance in known correlates of insulin sensitivity, whereas S(I)(BH) explained 8.5%. In a large body of data, which BH analysis demonstrated could be fully identified, use of alternative modeling settings in NLR analysis could substantially reduce the number of analyses with PCVs >100%. S(I)(NLR) compared favorably with S(I)(BH) in the proportion of variance explained in known correlates of insulin sensitivity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16478778&query_hl=1 ER - TY - JFULL T1 - Efficacy of recombinant activated factor VII in unselected patients with uncontrolled haemorrhage: a single centre experience. A1 - Payne, EM A1 - Brett, SJ A1 - Laffan, MA J1 - Blood Coagul Fibrinolysis Y1 - 2006/07// VL - 17 SN - 0957-5235 SP - 397 EP - 402 N2 - Recombinant activated factor VII (rFVIIa /Novoseven) has been used in a wide variety of circumstances as a treatment for uncontrolled bleeding. We present a retrospective report of the use of rFVIIa in 40 consecutive patients without inherited bleeding disorders in a single centre. Twenty-one (68%) of the 31 patients whose response to rFVIIa was documented showed a reduction or cessation in bleeding; in nine patients (29%) bleeding was unchanged and in one patient (3%) bleeding increased despite rFVIIa. One person suffered a thrombotic stroke after rFVIIa treatment. There were no other adverse events directly attributable to rFVIIa. Twenty-four patients (60%) died during the hospital admission in which the rFVIIa was administered. Twelve patients (30%) who received rFVIIa had bleeding secondary to haematological malignancy and 21 patients (53%) had bleeding complicating a surgical procedure. There were 11 deaths (92%) in the haematological malignancy group and 10 deaths (48%) in the surgical group. Patients with haematological malignancy received a significantly greater median number of doses of rFVIIa than patients with surgical bleeding complications (three versus one dose, P = 0.04). We conclude that rFVIIa can be used safely in uncontrolled haemorrhage and the majority of patients show a response. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16788316&query_hl=1 ER - TY - JFULL T1 - Comparison of the dexamethasone-suppressed corticotropin-releasing hormone test and low-dose dexamethasone suppression test in the diagnosis of Cushing's syndrome. A1 - Martin, NM A1 - Dhillo, WS A1 - Banerjee, A A1 - Abdulali, A A1 - Jayasena, CN A1 - Donaldson, M A1 - Todd, JF A1 - Meeran, K J1 - J Clin Endocrinol Metab Y1 - 2006/07// VL - 91 SN - 0021-972X SP - 2582 EP - 2586 N2 - CONTEXT: The low-dose dexamethasone suppression test (LDDST) is widely used in confirming a diagnosis of Cushing's syndrome. CRH administration at the end of an LDDST has been reported to improve the diagnostic accuracy of this test. OBJECTIVE: Our objective was to assess whether CRH administration after a standard LDDST (LDDST-CRH test) improves diagnostic accuracy in Cushing's syndrome. DESIGN, SETTING, AND PARTICIPANTS: Thirty-six individuals with a clinical suspicion of Cushing's syndrome each completed a standard LDDST and an LDDST-CRH test at Hammersmith Hospitals NHS Trust, London. The LDDST involved administration of 0.5 mg oral dexamethasone given 6-hourly for 48 h. Serum cortisol was measured 6 h after the last dose of dexamethasone, with a value of 50 nmol/liter or below excluding Cushing's syndrome. Immediately after this, the LDDST-CRH test commenced with administration of a ninth dose of 0.5 mg dexamethasone. Exactly 2 h later, 100 mug human-sequence CRH was administered. Serum cortisol was measured 15 min after the CRH injection, with a value of less than 38 nmol/liter also excluding Cushing's syndrome. MAIN OUTCOME MEASURE: Diagnosis or exclusion of Cushing's syndrome was the main outcome measure. RESULTS: Twelve subjects were diagnosed with Cushing's syndrome (eight Cushing's disease and four primary adrenal). The sensitivity of the LDDST in diagnosing Cushing's syndrome was 100%, with a specificity of 88%. In contrast, although the sensitivity of the LDDST-CRH test was also 100%, specificity was reduced at 67%. These results give a positive predictive value of 80% for the LDDST and 60% for the LDDST-CRH test. CONCLUSION: This small study suggests that the addition of CRH to the LDDST does not improve the diagnostic accuracy of the standard LDDST in Cushing's syndrome. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16670165&query_hl=1 ER - TY - JFULL T1 - Endocrinology: the next 60 years. A1 - Dhillo, WS A1 - Murphy, KG A1 - Bloom, S J1 - J Endocrinol Y1 - 2006/07// VL - 190 SN - 0022-0795 SP - 7 EP - 10 N2 - The next 60 years promise to arouse the interest of scientists and clinicians while challenging the central dogmas of endocrine physiology. In this review we consider the fundamental changes in the understanding of endocrine physiology that have taken place in recent years and the new hormones discovered. We discuss how the brain is emerging as an important regulator of endocrine and neuroendocrine circuits. Advances in molecular biology techniques and the use of genomics and other -omics in furthering our understanding of endocrine physiology are also discussed. Finally, we propose that in 2066 we may prescribe designer hormones to healthy subjects. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16837604&query_hl=1 ER - TY - JFULL T1 - Recent trends in hospital admissions and mortality rates for peptic ulcer in Scotland 1982-2002. A1 - Kang, JY A1 - Elders, A A1 - Majeed, A A1 - Maxwell, JD A1 - Bardhan, KD J1 - Aliment Pharmacol Ther Y1 - 2006/07/01/ VL - 24 SN - 0269-2813 SP - 65 EP - 79 N2 - BACKGROUND: While overall hospital admission rates for peptic ulcer declined in England in the 1990 s, they increased among the elderly, especially for complicated ulcer. However, peptic ulcer admissions fell for all age groups in the United States. AIM: To examine time trends in the incidence of hospital admissions, mortality and operations because of peptic ulcer in Scotland from 1982 to 2002, and the use of various drugs relevant to the aetiology and treatment of peptic ulcer from 1992 to 2002. RESULTS: There was a general decrease in admission rates, especially for younger individuals. For individuals aged above 74 years, admission rates actually increased for gastric ulcer with haemorrhage among men, and for duodenal ulcer haemorrhage between both sexes. The number of operations fell dramatically, especially for younger patients. Mortality rates generally declined. Case fatality rates were greater for women than men, and declined over the study period for gastric ulcer, but increased for duodenal ulcer. The use of low-dose aspirin, oral anticoagulants, selective serotonin reuptake inhibitors and proton-pump inhibitors increased while those of non-steroidal anti-inflammatory drugs and histamine-2 antagonists declined. CONCLUSIONS: Admission rates for peptic ulcer generally fell for younger individuals, but increased for older people with haemorrhage. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16803604&query_hl=1 ER - TY - JFULL T1 - Neuropeptide S stimulates the hypothalamo-pituitary-adrenal axis and inhibits food intake. A1 - Smith, KL A1 - Patterson, M A1 - Dhillo, WS A1 - Patel, SR A1 - Semjonous, NM A1 - Gardiner, JV A1 - Ghatei, MA A1 - Bloom, SR J1 - Endocrinology Y1 - 2006/07// VL - 147 SN - 0013-7227 SP - 3510 EP - 3518 N2 - Neuropeptide S (NPS) is a recently discovered peptide shown to be involved in the modulation of arousal and fear responses. It has also been shown that lateral ventricle administration of NPS causes a significant decrease in food intake. Neuropeptides involved in the modulation of arousal have been shown to be involved in the regulation of the hypothalamo-pituitary adrenal (HPA) axis and food intake. In this study, we have examined the effect of intracerebroventricular (ICV) administration of NPS on behavior, regulation of the HPA axis, and food intake. ICV NPS significantly increased plasma ACTH and corticosterone 10 and 40 min after injection, respectively. A single ICV injection of NPS caused a significant increase in rearing activity as well as ambulatory movement for up to 45 min after injection. We then studied the effect of paraventricular nucleus (PVN) administration of NPS on the regulation of the HPA axis, behavior, and food intake. There was a significant increase in plasma ACTH and corticosterone after a single NPS PVN injection. Incubation of hypothalamic explants with increasing concentrations of NPS caused a significant increase in CRH and arginine vasopressin release. In addition, PVN administration of NPS dose-dependently inhibited food intake in the first hour after injection, although no effect on food intake was seen after this time. PVN administration of NPS caused a significant increase in rearing activity. These data demonstrate a novel role for NPS in the stimulation of the HPA axis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16574794&query_hl=1 ER - TY - JFULL T1 - Lack of aromatisation of the 3-keto-4-ene metabolite of tibolone to an estrogenic derivative. A1 - Raobaikady, B A1 - Parsons, MF A1 - Reed, MJ A1 - Purohit, A J1 - Steroids Y1 - 2006/07// VL - 71 SN - 0039-128X SP - 639 EP - 646 N2 - Tibolone is used for the treatment of climacteric symptoms in postmenopausal women. It is metabolised in a tissue-specific manner so that while some metabolites exert estrogenic effects on bone and the CNS, others are thought to protect the breast and endometrium from estrogenic stimulation. Tibolone is a 7alpha-methyl derivative of 19-norethynodrel. Since the introduction of synthetic progestagens for therapeutic use there has been considerable controversy as to whether they can undergo aromatisation to give rise to the potent estrogen, ethinylestradiol. In this study, we examined whether the delta-4-ene (7alpha-methyl norethisterone) metabolite of tibolone, which has a similar delta-4-ene A-ring structure to that of the estrone precursor, androstenedione, could undergo aromatisation to the potent estrogen, 7alpha-methyl ethinylestradiol. For these studies, JEG-3 choriocarcinoma cells were employed as they have a very high level of aromatase activity. TLC and HPLC procedures were developed to separate phenolic from non-phenolic compounds and were initially used to confirm that JEG-3 cells readily aromatised androstenedione to estrogens (up to 74%). The aromatisation of androstenedione to estrogens by these cells could be completely blocked with the potent aromatase inhibitor letrozole. When [(3)H] 7alpha-methyl norethisterone was incubated with JEG-3 cells no evidence for its conversion to [(3)H] 7alpha-ethinylestradiol was obtained. Radioactivity detected on the TLC plate or HPLC fractions where standard 7alpha-methyl ethinylestradiol was located, revealed that similar levels were present when 7alpha-methyl norethisterone was incubated with culture medium alone or with JEG-3 cells in the absence or presence of letrozole. From these investigations, it is concluded that 7alpha-methyl norethisterone does not undergo aromatisation to an estrogenic derivative. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16712888&query_hl=1 ER - TY - JFULL T1 - Effect of fatty acid chain length on suppression of ghrelin and stimulation of PYY, GLP-2 and PP secretion in healthy men. A1 - Feltrin, KL A1 - Patterson, M A1 - Ghatei, MA A1 - Bloom, SR A1 - Meyer, JH A1 - Horowitz, M A1 - Feinle-Bisset, C J1 - Peptides Y1 - 2006/07// VL - 27 SN - 0196-9781 SP - 1638 EP - 1643 N2 - We have evaluated the effects of fatty acid chain length on ghrelin, peptide YY (PYY), glucagon-like peptide-2 (GLP-2) and pancreatic polypeptide (PP) secretion and hypothesized that intraduodenal administration of dodecanoic ("C12"), but not decanoic ("C10"), acid would decrease plasma ghrelin and increase PYY, GLP-2 and PP concentrations. Plasma hormone concentrations were measured in seven healthy men during 90-min intraduodenal infusions of: (i) C12, (ii) C10 or (iii) control (rate: 2 ml/min, 0.375 kcal/min for C12/C10) and after a buffet-meal consumed following the infusion. C12 markedly suppressed plasma ghrelin and increased both PYY and GLP-2 (all P < 0.05) compared with control and C10, while C10 had no effect. Both C10 and C12 increased PP concentrations slightly (P < 0.05). We conclude that the effects of intraduodenal fatty acids on ghrelin, PYY and GLP-2 secretion are dependent on their chain length. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16563563&query_hl=1 ER - TY - JFULL T1 - Gender differences in the insulin-like growth factor axis response to a glucose load. A1 - Flanagan, DE A1 - Holt, RI A1 - Owens, PC A1 - Cockington, RJ A1 - Moore, VM A1 - Robinson, JS A1 - Godsland, IF A1 - Phillips, DI J1 - Acta Physiol (Oxf) Y1 - 2006/07// VL - 187 SN - 1748-1708 SP - 371 EP - 378 N2 - AIMS: The insulin-like growth factors (IGFs) are thought to contribute to glucose homeostasis. The aim of our study was to examine the response of the IGFs and their binding proteins to an intravenous load of glucose in a cohort of young men and women with normal glucose tolerance. METHODS: The intravenous glucose tolerance test (IVGTT) was used to quantify insulin sensitivity and insulin secretion in 160 adults aged 20-21 years in Adelaide, Australia. Serum IGF-I, IGF-II, IGF-binding protein (IGFBP)-1 and IGFBP-3 were measured during the IVGTT. RESULTS: Women were less insulin sensitive than men with higher fasting insulin (women 55.6 +/- 4.4, men 44.1 +/- 3.6 pmol L(-1), P = 0.001) and first phase insulin secretion (women 3490 +/- 286, men 3038 +/- 271 pmol L(-1) min, P = 0.042). Women showed lower fasting free IGF-I (women 0.29 +/- 0.02, men 0.36 +/- 0.02 mug L(-1), P = 0.004) but higher IGFBP-3 (women 46.3 +/- 0.53, men 43.3 +/- 0.58 mg dL(-1), P = 0.001) and higher IGFBP-1 concentrations (women 37.0 +/- 2.9, men 24.8 +/- 2.3 mug L(-1), P = 0.012). IGFBP-1 fell by 5 min and remained suppressed. IGFBP-3 and total IGF-I fell until 60 min rising again by 2 h. IGF and IGFBP values were all higher in women. IGFBP-1 showed a negative association with fasting and stimulated insulin concentrations in both genders. First phase insulin secretion however showed positive correlations with IGFBP-3 (r = 0.321, P = 0.004) and IGF-I (r = 0.339 P = 0.002) in men but not women. CONCLUSION: Our data show that IGFBP-1, IGFBP-3 and IGF-I show acute changes following a glucose load and there are marked gender differences in these responses. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16776662&query_hl=1 ER - TY - JFULL T1 - Statistical search space reduction and two-dimensional data display approaches for UPLC-MS in biomarker discovery and pathway analysis. A1 - Crockford, DJ A1 - Lindon, JC A1 - Cloarec, O A1 - Plumb, RS A1 - Bruce, SJ A1 - Zirah, S A1 - Rainville, P A1 - Stumpf, CL A1 - Johnson, K A1 - Holmes, E A1 - Nicholson, JK J1 - Anal Chem Y1 - 2006/07/01/ VL - 78 SN - 0003-2700 SP - 4398 EP - 4408 N2 - A new analytical strategy for biomarker recovery from directly coupled ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC Tof MS) data on biofluids is presented and exemplified using a study on hydrazine-induced liver toxicity. A key step in the strategy involves a novel procedure for reducing the spectroscopic search space by differential analysis of cohorts of normal and pathological samples using an orthogonal projection to latent structures discriminant analysis (O-PLS-DA). This efficiently sorts principal discriminators of toxicity from the background of thousands of metabolic features commonly observed in data sets generated by UPLC-MS analysis of biological fluids and is thus a powerful tool for biomarker discovery. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16808447&query_hl=1 ER - TY - JFULL T1 - Genetic polymorphisms and weight loss in obesity: A randomised trial of hypo-energetic high-versus low-fat diets A1 - Sorensen, TIA A1 - Boutin, P A1 - Taylor, MA A1 - Larsen, LH A1 - Verdich, C A1 - Petersen, L A1 - Holst, C A1 - Echwald, SM A1 - Dina, C A1 - Toubro, S A1 - Petersen, M A1 - Polak, J A1 - Clement, K A1 - Martinez, JA A1 - Langin, D A1 - Oppert, JM A1 - Stich, V A1 - Macdonald, I A1 - Arner, P A1 - Saris, WHM A1 - Pedersen, O A1 - Astrup, A A1 - Froguel, P A1 - NUGENOB Consortium J1 - PLOS CLIN TRIALS Y1 - 2006/06/30/ VL - 1 N2 - Objectives: To study if genes with common single nucleotide polymorphisms ( SNPs) associated with obesity-related phenotypes influence weight loss (WL) in obese individuals treated by a hypo-energetic low-fat or high-fat diet.Design: Randomised, parallel, two-arm, open-label multi-centre trial.Setting: Eight clinical centres in seven European countries.Participants: 771 obese adult individuals.Interventions: 10-wk dietary intervention to hypo-energetic ( - 600 kcal/d) diets with a targeted fat energy of 20%-25% or 40%- 45%, completed in 648 participants.Outcome Measures: WL during the 10 wk in relation to genotypes of 42 SNPs in 26 candidate genes, probably associated with hypothalamic regulation of appetite, efficiency of energy expenditure, regulation of adipocyte differentiation and function, lipid and glucose metabolism, or production of adipocytokines, determined in 642 participants.Results: Compared with the noncarriers of each of the SNPs, and after adjusting for gender, age, baseline weight and centre, heterozygotes showed WL differences that ranged from - 0.6 to 0.8 kg, and homozygotes, from - 0.7 to 3.1 kg. Genotype-dependent additional WL on low-fat diet ranged from 1.9 to - 1.6 kg in heterozygotes, and from 3.8 kg to - 2.1 kg in homozygotes relative to the noncarriers. Considering the multiple testing conducted, none of the associations was statistically significant.Conclusions: Polymorphisms in a panel of obesity-related candidate genes play a minor role, if any, in modulating weight changes induced by a moderate hypo-energetic low-fat or high-fat diet. ER - TY - JFULL T1 - Endocrine and clinical responses to steroid sulfatase inhibition: Results from the first phase I trial in women with breast cancer. A1 - Stanway, S A1 - Purohit, A A1 - Woo, LW A1 - Wilson, RH A1 - Stanczyk, FZ A1 - Dobbs, N A1 - Delavault, P A1 - Potter, BV A1 - Reed, MJ A1 - Coombes, RC J1 - J CLIN ONCOL Y1 - 2006/06/20/ VL - 24 SN - 0732-183X SP - 22S EP - 22S ER - TY - JFULL T1 - Neuromedin U partially mediates leptin-induced hypothalamo-pituitary adrenal (HPA) stimulation and has a physiological role in the regulation of the HPA axis in the rat. A1 - Jethwa, PH A1 - Smith, KL A1 - Small, CJ A1 - Abbott, CR A1 - Darch, SJ A1 - Murphy, KG A1 - Seth, A A1 - Semjonous, NM A1 - Patel, SR A1 - Todd, JF A1 - Ghatei, MA A1 - Bloom, SR J1 - Endocrinology Y1 - 2006/06// VL - 147 SN - 0013-7227 SP - 2886 EP - 2892 N2 - Intracerebroventricular (ICV) administration of the hypothalamic neuropeptide neuromedin U (NMU) or the adipostat hormone leptin increases plasma ACTH and corticosterone. The relationship between leptin and NMU in the regulation of the hypothalamo-pituitary adrenal (HPA) axis is currently unknown. In this study, leptin (1 nm) significantly increased the release of CRH from ex vivo hypothalamic explants by 207 +/- 8.4% (P < 0.05 vs. basal), an effect blocked by the administration of anti-NMU IgG. The ICV administration of leptin (10 mug, 0.625 nmol) increased plasma ACTH and corticosterone 20 min after injection [plasma ACTH (picograms per milliliter): vehicle, 63 +/- 20, leptin, 135 +/- 36, P < 0.05; plasma corticosterone (nanograms per milliliter): vehicle, 285 +/- 39, leptin, 452 +/- 44, P < 0.01]. These effects were partially attenuated by the prior administration of anti-NMU IgG. Peripheral leptin also stimulated ACTH release, an effect attenuated by prior ICV administration of anti-NMU IgG. We examined the diurnal pattern of hypothalamic NMU mRNA expression and peptide content, plasma leptin, and plasma corticosterone. The diurnal changes in hypothalamic NMU mRNA expression were positively correlated with hypothalamic NMU peptide content, plasma corticosterone, and plasma leptin. The ICV administration of anti-NMU IgG significantly attenuated the dark phase rise in corticosterone [corticosterone (nanograms per milliliter): vehicle, 493 +/- 38; NMU IgG, 342 +/- 47 (P < 0.05)]. These studies suggest that NMU may play a role in the regulation of the HPA axis and partially mediate leptin-induced HPA stimulation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16556758&query_hl=1 ER - TY - JFULL T1 - Increase in beta(1)AR-Gi coupling after detubulation in rat ventricular myocytes A1 - Yang, LQ A1 - Gorelik, J A1 - Korchev, Y A1 - Harding, SE J1 - J MOL CELL CARDIOL Y1 - 2006/06// VL - 40 SN - 0022-2828 SP - 923 EP - 924 ER - TY - JFULL T1 - Understanding reasons for asthma outpatient (non)-attendance and exploring the role of telephone and e-consulting in facilitating access to care: exploratory qualitative study. A1 - van Baar, JD A1 - Joosten, H A1 - Car, J A1 - Freeman, GK A1 - Partridge, MR A1 - van Weel, C A1 - Sheikh, A J1 - Qual Saf Health Care Y1 - 2006/06// VL - 15 SN - 1475-3901 SP - 191 EP - 195 N2 - OBJECTIVE: To understand factors influencing patients' decisions to attend for outpatient follow up consultations for asthma and to explore patients' attitudes to telephone and email consultations in facilitating access to asthma care. DESIGN: Exploratory qualitative study using in depth interviews. SETTING: Hospital outpatient clinic in West London. PARTICIPANTS: Nineteen patients with moderate to severe asthma (12 "attenders" and 7 "non-attenders"). RESULTS: Patients' main reasons for attending were the wish to improve control over asthma symptoms and a concern not to jeopardise the valued relationship with their doctor. Memory lapses, poor health, and disillusionment with the structure of outpatient care were important factors implicated in non-attendance. The patients were generally sceptical about the suggestion that greater opportunity for telephone consulting might improve access to care. They expressed concerns about the difficulties in effectively communicating through non-face to face media and were worried that clinicians would not be in a position to perform an adequate physical examination over the telephone. Email and text messaging were viewed as potentially useful for sending appointment reminders and sharing clinical information but were not considered to be acceptable alternatives to the face to face clinic encounter. CONCLUSIONS: Memory lapses, impaired mobility due to poor health, and frustration with outpatient clinic organisation resulting in long waiting times and discontinuity of care are factors that deter patients from attending for hospital asthma assessments. The idea of telephone review assessments was viewed with scepticism by most study subjects. Particular attention should be given to explaining to patients the benefits of telephone consultations, and to seeking their views as to whether they would like to try them out before replacing face to face consultations with them. Email and text messaging may have a role in issuing reminders about imminent appointments. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16751469&query_hl=1 ER - TY - JFULL T1 - Genetic basis of maturity-onset diabetes of the young. A1 - Vaxillaire, M A1 - Froguel, P J1 - Endocrinol Metab Clin North Am Y1 - 2006/06// VL - 35 SN - 0889-8529 SP - 371 EP - 384 N2 - Most valuable breakthroughs in the genetics of type 2 diabetes mellitus have arisen from familial linkage analysis of maturity-onset diabetes of the young, an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin-secretion defects. Despite its low prevalence, MODY is not a single entity but presents genetic, metabolic, and clinical heterogeneity. MODY can result from mutations in at least six different genes;one encodes the glycolytic enzyme glucokinase, which is an important glucose sensor, whereas all the others encode transcription factors that participate in a regulatory network essential for adult beta cell function. Additional genes, yet unidentified, may explain the other MODY cases unlinked to a mutation in the known genes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16632099&query_hl=1 ER - TY - JFULL T1 - The INS VNTR locus does not associate with smallness for gestational age (SGA) but interacts with SGA to increase insulin resistance in young adults. A1 - Vu-Hong, TA A1 - Durand, E A1 - Deghmoun, S A1 - Boutin, P A1 - Meyre, D A1 - Chevenne, D A1 - Czernichow, P A1 - Froguel, P A1 - Levy-Marchal, C J1 - J Clin Endocrinol Metab Y1 - 2006/06// VL - 91 SN - 0021-972X SP - 2437 EP - 2440 N2 - CONTEXT: Both adverse intrauterine events and genetic background have been suggested to promote insulin resistance in subjects born small for gestational age (SGA). Among candidate genes that potentially influence both fetal growth and glucose metabolism is insulin. The potential effect of the insulin gene VNTR (INS) on birth weight has been controversial so far. OBJECTIVE: The present association study aimed at testing for the contribution of the INS VNTR locus on birth weight and on the metabolic profile of young adults born SGA (mean age, 22 yr). Two groups of subjects were selected on birth data: SGA (birth weight < 10th percentile; n = 735), and appropriate for gestational age (AGA; birth weight between 25th and 75th percentiles; n = 886). All subjects were genotyped for rs689 A/T single nucleotide polymorphism, in complete linkage disequilibrium with the INS VNTR classes I and III, respectively. RESULTS: Class I INS frequencies were similar in the two groups (70% in AGA; 72% in SGA; P = 0.42). There was significant effect on mean birth weight in neither SGA (P = 0.99) nor AGA (P = 0.18). Although the INS VNTR locus did not associate with anomalies of insulin resistance indices in the AGA group, in the SGA group, INS VNTR class III allele was associated with higher insulin resistance (quantitative insulin sensitivity check index = 0.38 vs. 0.39; P = 0.05). Furthermore, there was evidence of an interaction between the SGA/AGA status and INS VNTR locus on insulin resistance indices (P = 0.01) in a multivariate analysis. CONCLUSION: The INS VNTR locus does not associate in a major way with SGA in the French population. However, our data support an interaction between severe fetal growth restriction and INS VNTR locus, which were associated with insulin resistance in young adults born SGA. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16595598&query_hl=1 ER - TY - JFULL T1 - Potential biomedical applications of the scanned nanopipette. A1 - Klenerman, D A1 - Korchev, Y J1 - Nanomed Y1 - 2006/06// VL - 1 SN - 1748-6963 SP - 107 EP - 114 N2 - One grand challenge in current biology is to understand how individual cellular molecules interact together to form a functioning living cell. This requires new methods to image a live cell on the nanoscale. The scanned nanopipette can be used to obtain high resolution noncontact images of the surface of live cells under physiological conditions and has been used to develop a family of related methods that allow mapping of cell function on the nanoscale, and hence allow the relationship between cell structure and function to be probed. This is a powerful method to bridge the current gap between high resolution structures of individual molecular complexes and low resolution imaging of live cell structure and function. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17716213&query_hl=1 ER - TY - JFULL T1 - New insight into the genetics of childhood obesity A1 - Froguel, P J1 - INT J OBESITY Y1 - 2006/06// VL - 30 SN - 0307-0565 SP - S19 EP - S19 ER - TY - JFULL T1 - The effect of medroxyprogesterone acetate on estrogen-dependent risks and benefits - an attempt to interpret the Women's Health Initiative results A1 - Kuhl, H A1 - Stevenson, J J1 - GYNECOL ENDOCRINOL Y1 - 2006/06// VL - 22 SN - 0951-3590 SP - 303 EP - 317 N2 - The results of the two arms of the Women's Health Initiative (WHI) study allow a comparative assessment of the contribution of the progestogen component to the changes in risk of cardiovascular disease and cancer during treatment of postmenopausal women with conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA). However, the high proportion of older and overweight or obese women compromises any conclusions, since we estimate that 50% of the women would have the metabolic syndrome. In overweight postmenopausal women with hyperinsulinemia, the risk of breast cancer is elevated and cannot be increased further by hormone replacement therapy (HRT). Therefore, the non-significant, but consistent reduction in breast cancer risk during treatment with CEE alone might be based on an improvement of hyperinsulinemia. The 24% increase in breast cancer risk in the CEE/MPA group can be regarded as an artifact due to very low numbers of breast cancer diagnoses in the placebo group of women who had received HRT prior to the WHI study. The elevated risk of venous thromboembolism and the transient increase in the risk of coronary heart disease (CHD) during treatment with CEE/MPA but not CEE alone suggests a direct effect of MPA on the vessel wall. MPA has been demonstrated to upregulate the thrombin receptor, the thrombin-induced production of tissue factor and procoagulatory activity in the vessel wall owing to its glucocorticoid activity. In contrast, CEE alone reduced non-significantly the risk of CHD in women aged 50-59 years, suggesting that primary prevention is possible if estrogen replacement therapy is initiated early. As clinical studies on the effect of different progestogens combined with estrogens are scarce, a possible superiority of progestogens other than MPA remains to be proven. ER - TY - JFULL T1 - The genetics of human obesity A1 - Froguel, P J1 - ATHEROSCLEROSIS SUPP Y1 - 2006/06// VL - 7 SN - 1567-5688 SP - 310 EP - 311 ER - TY - JFULL T1 - Metabolic syndrome and its surrogates explored by factor analysis in 472 men with insulin sensitivity measured by minimal model analysis A1 - Godsland, IF A1 - Johnston, DG J1 - DIABETES Y1 - 2006/06// VL - 55 SN - 0012-1797 SP - A211 EP - A211 ER - TY - JFULL T1 - Inhaled insulin: concerns remain. A1 - Martin, NM A1 - Meeran, K J1 - BMJ Y1 - 2006/05/27/ VL - 332 SN - 1468-5833 SP - 1273 EP - 1274 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16735346&query_hl=1 ER - TY - JFULL T1 - Protecting patient confidentiality in telephone consultations in general practice. A1 - Sokol, D A1 - Car, J J1 - Br J Gen Pract Y1 - 2006/05// VL - 56 SN - 0960-1643 SP - 384 EP - 385 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16638265&query_hl=1 ER - TY - JFULL T1 - Continuous subcutaneous administration of kisspeptin-54 causes testicular degeneration in rats A1 - Murphy, KG A1 - Thompson, EL A1 - Patterson, M A1 - Bewick, GA A1 - Jethwa, PH A1 - Stamp, GWH A1 - Todd, JF A1 - Ghatei, MA A1 - Bloom, SR J1 - FRONT NEUROENDOCRIN Y1 - 2006/05// VL - 27 SN - 0091-3022 SP - 77 EP - 77 ER - TY - JFULL T1 - Genes encoding bile acid, phospholipid and anion transporters are expressed in a human fetal cardiomyocyte culture. A1 - Gorelik, J A1 - Patel, P A1 - Ng'andwe, C A1 - Vodyanoy, I A1 - Diakonov, I A1 - Lab, M A1 - Korchev, Y A1 - Williamson, C J1 - BJOG Y1 - 2006/05// VL - 113 SN - 1470-0328 SP - 552 EP - 558 N2 - OBJECTIVES: To establish a human fetal cardiomyocyte culture and to investigate whether the genes that encode transporters that may influence influx or efflux of bile acids are expressed in human fetal cardiomyocytes. DESIGN: Laboratory study. SETTING: Imperial College London. SAMPLE: Six fetal hearts were obtained at the time of termination of pregnancy at 12-13 weeks of gestation and used to generate primary human cardiomyocyte cultures. METHODS: To confirm the presence of cardiomyocytes, the cells were incubated with monoclonal antibodies to sarcomeric alpha-actinin and anticardiac myosin heavy chain. Real-time reverse transcription polymerase chain reaction was used to establish whether transcripts of genes that may influence bile acid transport are present in the culture (NTCP, BSEP, MDR3, FIC1, MRP2, MRP3, OATP-A, OATP-C, OATP-D, OATP-E) and whether taurocholate administration alters messenger RNA (mRNA) expression. MAIN OUTCOME MEASURES: Relative mRNA expression of genes of interest. RESULTS: Real-time polymerase chain reaction demonstrated the presence of mRNA for BSEP, MDR3, FIC1, OATP-C, OATP-D and OATP-E in fetal heart. Four transcripts remained in the cardiomyocyte culture (BSEP, MDR3, FIC1 and OATP-D), and we demonstrated the influence of taurocholate on gene expression. CONCLUSIONS: We have developed an in vitro model of the fetal heart that may be used for studies of the cardiac effect of endobiotics, e.g. bile acids, or of specific agents that may be used to treat the mother or fetus in pregnancy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16637898&query_hl=1 ER - TY - JFULL T1 - English language skills and diabetes and hypertension among foreign-born South Asian adults in England. A1 - Mainous, AG A1 - Baker, R A1 - Majeed, A A1 - Koopman, RJ A1 - Everett, CJ A1 - Saxena, S A1 - Tilley, BC J1 - Public Health Rep Y1 - 2006/05// VL - 121 SN - 0033-3549 SP - 331 EP - 336 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16640158&query_hl=1 ER - TY - JFULL T1 - Administration of kisspeptin-54 into discrete regions of the hypothalamus potently increases plasma luteinising hormone and testosterone in male adult rats. A1 - Patterson, M A1 - Murphy, KG A1 - Thompson, EL A1 - Patel, S A1 - Ghatei, MA A1 - Bloom, SR J1 - J Neuroendocrinol Y1 - 2006/05// VL - 18 SN - 0953-8194 SP - 349 EP - 354 N2 - Kisspeptin-54 is the peptide product of the KiSS-1 gene and an endogenous agonist of the GPR54 receptor. KiSS-1 was initially discovered as a metastasis suppressor gene, but recent studies demonstrate that the kisspeptin/GPR54 system is a key regulator of the reproductive system. Disrupted GPR54 signalling causes hypogonadotrophic hypogonadism in rodents and man. Intracerebroventricular or peripheral administration of kisspeptin potently stimulates the hypothalamic-pituitary-gonadal (HPG) axis via the hypothalamic gonadotrophin-releasing hormone system. We have investigated the effect of injection of kisspeptin-54 into discrete hypothalamic regions on the HPG axis. To construct a dose-response curve for the effects of intrahypothalamic kisspeptin administration, adult male Wistar rats were cannulated into the medial preoptic area (MPOA) at the level of the organum vasculosum laminae terminalis (OVLT). Kisspeptin-54 was injected into the MPOA at doses of 0.01, 0.1, 1, 10 and 100 pmol. At 60 min following injection of 1, 10 or 100 pmol kisspeptin-54, plasma luteinising hormone (LH) and total testosterone levels were significantly increased. Adult male Wistar rats were then cannulated into the rostral preoptic area at the level of the OVLT (RPOA), the MPOA, the paraventricular (PVN), dorsomedial (DMN) and arcuate hypothalamic nuclei, and the lateral hypothalamic area. A dose of 1 pmol kisspeptin-54 was administered into all areas. The circulating levels of LH and total testosterone were significantly increased 60 min postinjection of kisspeptin-54 into the RPOA, MPOA, PVN and arcuate nucleus. Our results suggest that kisspeptin may mediate its effects on the HPG axis via these regions of the hypothalamus. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16629833&query_hl=1 ER - TY - JFULL T1 - Hepatocyte nuclear factor-4 alpha P2 promoter haplotypes are associated with type 2 diabetes in the Japanese population A1 - Hara, K A1 - Horikoshi, M A1 - Kitazato, H A1 - Lto, C A1 - Noda, M A1 - Ohashi, J A1 - Froguel, P A1 - Tokunaga, K A1 - Tobe, K A1 - Nagai, R A1 - Kadowaki, T J1 - DIABETES Y1 - 2006/05// VL - 55 SN - 0012-1797 SP - 1260 EP - 1264 N2 - Hepatocyte nuclear factor (HNF)-4 alpha is a transcription factor known as a key molecule in the development and functions of the R-cells. In a previously performed genome-wide scan of Japanese type 2 diabetic sibpairs, we observed linkage of type 2 diabetes to chromosome 20q12-q13, a region in which the HNF4A gene is located. Recent studies have reported associations between type 2 diabetes and polymorphisms in the P2 promoter region specific to P-cells. In this study, we attempted to assess whether the HNF4A gene plays a role in the genetic susceptibility to type 2 diabetes in the Japanese population by analyzing polymorphisms and haplotypes of the HNF4A gene. Linkage disequilibrium. across the P2 promoter region was preserved in the Japanese population, consistent with previous reports. Although none of the individual polymorphisms examined showed any significant association with type 2 diabetes, we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene (P = 3.82 x 10(-4)). In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The association was replicated using two additional cohorts (P = 1.51 X 10(-4) and 0.019, respectively). The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene that directly influences susceptibility to type 2 diabetes. ER - TY - JFULL T1 - Effects of fasting and refeeding on luteinising hormone pulses and on multiple indices of metabolic state in female rats A1 - Coen, CW A1 - Grimshaw, SE A1 - Goubillon, ML A1 - Strutton, PH A1 - Ghatei, MA A1 - Bloom, SR A1 - Wilson, CA J1 - FRONT NEUROENDOCRIN Y1 - 2006/05// VL - 27 SN - 0091-3022 SP - 70 EP - 70 ER - TY - JFULL T1 - Small intestinal cancer in England & Wales and Scotland: time trends in incidence, mortality and survival. A1 - Shack, LG A1 - Wood, HE A1 - Kang, JY A1 - Brewster, DH A1 - Quinn, MJ A1 - Maxwell, JD A1 - Majeed, A J1 - Aliment Pharmacol Ther Y1 - 2006/05/01/ VL - 23 SN - 0269-2813 SP - 1297 EP - 1306 N2 - BACKGROUND: Time trends in mortality from small intestinal cancer have not been studied for the 1990s. OBJECTIVE: To examine secular trends in incidence of, mortality from, and survival from, small intestinal cancer in England & Wales and Scotland from 1975 to 2002, considering also histological type (incidence), subsite (incidence) and indices of social deprivation (incidence and survival). METHODS: Data were extracted from the Scottish Cancer Registry database and the General Register Office for Scotland, and from the National Cancer Intelligence Centre at the Office for National Statistics for England & Wales. RESULTS: Incidence rates for small intestinal cancer increased for both England & Wales and Scotland over the study period. They were highest among older individuals and generally greater for males than for females. Despite the increase in incidence rates, mortality rates from small intestinal tumours tended to remain stable over the study period, and the general trend was towards increasing survival. Indices of social deprivation were not obviously related to the incidence of small intestinal cancer and did not influence survival. CONCLUSIONS: Incidence rates for small intestinal cancer for both England & Wales and Scotland increased in the last quarter of the 20th century, but survival rates improved and mortality rates declined. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16629934&query_hl=1 ER - TY - JFULL T1 - Pancreatic cancer in England and Wales 1975-2000: patterns and trends in incidence, survival and mortality. A1 - Wood, HE A1 - Gupta, S A1 - Kang, JY A1 - Quinn, MJ A1 - Maxwell, JD A1 - Mudan, S A1 - Majeed, A J1 - Aliment Pharmacol Ther Y1 - 2006/04/15/ VL - 23 SN - 0269-2813 SP - 1205 EP - 1214 N2 - BACKGROUND: Rates and time trends in mortality from pancreatic cancer vary considerably between countries. AIM: To examine trends and patterns in the incidence of, and the survival and mortality from, pancreatic cancer in England and Wales from 1975 to 2000; in particular, whether incidence and survival rates are related to socio-economic deprivation. METHODS: We calculated annual age-specific and overall age-standardized incidence and mortality rates by sex for pancreatic cancer in total, and by subsite. We also estimated survival by sex and age group and by subsite. RESULTS: In males, the age-standardized rate fluctuated in the late 1970s, to peak at 13.0 per 100,000 in 1979, declined steadily by an average of 1.3% per year to around 10.3 per 100,000 in the mid-1990s and then levelled off. For females, the rate peaked at 8.4 per 100,000 in the late 1980s before declining and fluctuating around 7.7 per 100,000 in the late 1990s. Patterns and trends in mortality rates were closely similar to those in incidence, due to the very low survival rates: only 2-3% at 5 years from diagnosis. Survival rates improved only minimally over the period 1971-99. Incidence and mortality rates were slightly higher in both males and females living in the most deprived areas, but survival was not consistently related to socio-economic deprivation. CONCLUSIONS: The incidence of, and mortality from, pancreatic cancer in England and Wales have fallen from peak levels observed in the 1970s and 1980s, and levelled off in the 1990s for both sexes; survival rates remain very low. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16611282&query_hl=1 ER - TY - JFULL T1 - Gut hormone profiles may explain reduced appetite and food intake following bariatric surgery A1 - le Roux, CW A1 - Aylwin, SJB A1 - Batterham, RL A1 - Borg, CM A1 - Coyle, F A1 - Prasad, V A1 - Shurey, S A1 - Ghateil, MA A1 - Patel, AG A1 - Bloom, SR J1 - OBES SURG Y1 - 2006/04// VL - 16 SN - 0960-8923 SP - 402 EP - 402 ER - TY - JFULL T1 - A novel inherited form of familial thrombocytopenia due to an autosomal dominant mutation in the cytoplasmic domain of the platelet beta3 integrin that is associated with the expression of activation dependent alphaIIb/beta3 epitopes A1 - Watkins, NA A1 - Rankin, A A1 - Smith, GA A1 - Schaffner-Reckinger, E A1 - Kieffer, N A1 - Laffan, M A1 - Ouwehand, WH J1 - BRIT J HAEMATOL Y1 - 2006/04// VL - 133 SN - 0007-1048 SP - 19 EP - 19 ER - TY - JFULL T1 - (39)K nuclear magnetic resonance and a mathematical model of K(+) transport in human erythrocytes. A1 - Maher, AD A1 - Chapman, BE A1 - Kuchel, PW J1 - Eur Biophys J Y1 - 2006/04// VL - 35 SN - 0175-7571 SP - 293 EP - 301 N2 - (39)K nuclear magnetic resonance was used to measure the efflux of K(+) from suspensions of human erythrocytes [red blood cells (RBCs)], that occurred in response to the calcium ionophore, A23187 and calcium ions; the latter activate the Gárdos channel. Signals from the intra- and extracellular populations of (39)K(+) were selected on the basis of their longitudinal relaxation times, T (1), by using an inversion- recovery pulse sequence with the mixing time, tau(1), chosen to null one or other of the signals. Changes in RBC volume consequent upon efflux of the ions also changed the T (1) values so a new theory was implemented to obviate a potential artefact in the data analysis. The velocity of the K(+) efflux mediated by the Gárdos channel was 1.19+/-0.40 mmol (L RBC)(-1) min(-1) at 37 degrees C. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16341859&query_hl=1 ER - TY - JFULL T1 - Glucose production in the human placenta. A1 - Leonce, J A1 - Brockton, N A1 - Robinson, S A1 - Venkatesan, S A1 - Bannister, P A1 - Raman, V A1 - Murphy, K A1 - Parker, K A1 - Pavitt, D A1 - Teoh, TG A1 - Regan, L A1 - Burchell, A A1 - Steer, P A1 - Johnston, DG J1 - Placenta Y1 - 2006/04// VL - 27 Suppl A SN - 0143-4004 SP - S103 EP - S108 N2 - Glucose transfer from mother to fetus by placental facilitated diffusion is the dominant mechanism by which the fetus acquires glucose. In small for gestational age pregnancies, fetal glucose concentrations tend to be lower than normal and this persists following delivery. GLUT1 is the major glucose transporter in human placenta but there is no evidence of GLUT1 deficiency as a cause of the lower fetal glucose concentration in small for gestational age pregnancy. The physiological and pathological roles of the other glucose transporters (and there are 14 currently described) are unknown. In recent years, the possibility has been raised that the placenta is itself capable of supplying glucose for fetal needs. This hypothesis derived from glucose isotope studies in normal pregnancy, where dilution of glucose isotope was demonstrated in blood samples taken from the fetal circulation during intravenous infusion of glucose isotope in the mother. Although other gluconeogenic enzymes were known to be present, the placenta was previously considered incapable of glucose secretion because it lacked functional glucose-6-phosphatase. Recent studies, however, have suggested that specific glucose-6-phosphatase may be present in placenta but it may be the product of a different gene from conventional hepatic glucose-6-phosphatase. The presence of the specific transporters necessary for glucose-6-phosphatase activity is currently being investigated. The role of placental glucose secretion in normal and growth-restricted pregnancies is an area of current study. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16618444&query_hl=1 ER - TY - JFULL T1 - The PPARG pro12Ala polymorphism is associated with a decreased risk of developing hyperglycemia over 6 years and combines with the effect of the APM1 G-11391A single nucleotide polymorphism - The Data From an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study A1 - Jaziri, R A1 - Lobbens, S A1 - Aubert, R A1 - Pean, F A1 - Lahmidi, S A1 - Vaxillaire, M A1 - Porchay, I A1 - Bellili, N A1 - Tichet, J A1 - Balkau, B A1 - Froguel, P A1 - Marre, M A1 - Fumeron, F A1 - DESIR Study Grp J1 - DIABETES Y1 - 2006/04// VL - 55 SN - 0012-1797 SP - 1157 EP - 1162 N2 - Although cross-sectional studies have associated the Pro12Ala polymorphism of PPARG with type 2 diabetes, prospective studies offer more opportunities to investigate genetic variants. Associations between PPARG polymorphisms with insulin resistance parameters and with the 6-year incidence of impaired fasting glucose or type 2 diabetes were tested in 3,914 French Caucasians from the DESIR (Data Froman Epidemiological Study on the Insulin Resistance Syndrome) cohort. In subjects normoglycemic at baseline (n = 3,498), the 6-year risk of hyperglycemia was lower in PPARG Ala carriers (odds ratio [OR] vs. ProPro = 0.66 [95% CI 0.44-0.991, P = 0.046 adjusted for sex, age, and BMI). Similar results were found with the PPARG C1431T single nucleotide polymorphism (SNP; adjusted OR = 0.65 [0.44-0.96], P = 0.036). Both alleles are in strong linkage disequilibrium (D' = 0.669, P < 0.001). The baseline mean fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in Ala carriers compared with ProPro homozygotes (P = 0.001 for both), with smaller increases in mean insulin and HOMA-IR during follow-up (P = 0.007 and 0.018, respectively). No association with insulin levels or HOM-IR was found with C1431T. In this cohort, the APM1 G-11391A SNP is associated with the development of hyperglycemia. The combined effects of PPARG Pro12Ala and APM1 G-11391A SNPs showed no interaction on the risk of 6-year hyperglycemia. The PPARG Ala allele showed a relatively high protective effect in developing hyperglycemia and hyperinsulinemia during a 6-year period. Cumulative rather than synergistic effects of PPARG Pro12Ala and APM1 SNPs on diabetes risk are suggested. ER - TY - JFULL T1 - Use of prothrombin concentrate (PCC) for warfarin reversal: audit of North Thames practice A1 - Allard, S A1 - Mold, D A1 - Harvey, D A1 - Laffan, M J1 - BRIT J HAEMATOL Y1 - 2006/04// VL - 133 SN - 0007-1048 SP - 40 EP - 40 ER - TY - JFULL T1 - EIF4A2 is a positional candidate gene at the 3q27 locus linked to type 2 diabetes in French families. A1 - Cheyssac, C A1 - Dina, C A1 - Leprêtre, F A1 - Vasseur-Delannoy, V A1 - Dechaume, A A1 - Lobbens, S A1 - Balkau, B A1 - Ruiz, J A1 - Charpentier, G A1 - Pattou, F A1 - Joly, E A1 - Prentki, M A1 - Hansen, T A1 - Pedersen, O A1 - Vaxillaire, M A1 - Froguel, P J1 - Diabetes Y1 - 2006/04// VL - 55 SN - 0012-1797 SP - 1171 EP - 1176 N2 - One of the most replicated loci influencing type 2 diabetes-related quantitative traits (quantitative trait loci [QTL]) is on chromosome 3q27 and modulates both type 2 diabetes-and metabolic syndrome-associated phenotypes. A QTL for type 2 diabetes age of onset (logarithm of odds [LOD] score = 3.01 at D3S3686, P = 0.0001) was identified in a set of French families. To assess genetic variation underlying both age-of-onset QTL and our previous type 2 diabetes linkage in a 3.87-Mb interval, we explored 36 single nucleotide polymorphisms (SNPs) in two biologically relevant candidate genes for glucose homeostasis, kininogen (KNG1), and eukaryotic translation initiation factor 4alpha2 (EIF4A2). Analysis of 148 families showed significant association of a frequent SNP, rs266714, located 2.47 kb upstream of EIF4A2, with familial type 2 diabetes (family-based association test, P = 0.0008) and early age of onset (P = 0.0008). This SNP also contributes to both age-of-onset QTL (1.13 LOD score decrease P = 0.02) and type 2 diabetes linkage (genotype identical-by-descent sharing test, P = 0.02). However, no association was observed in three independent European diabetic cohorts. EIF4A2 controls specific mRNA translation and protein synthesis rate in pancreatic beta-cells, and our data indicates that EIF4A2 is downregulated by high glucose in rat beta-INS832/13 cells. The potential role of EIF4A2 in glucose homeostasis and its putative contribution to type 2 diabetes in the presence of metabolic stress will require further investigation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16567544&query_hl=1 ER - TY - JFULL T1 - Antithrombin Nagasaki (Ser 116 to Pro): a rare antithrombin variant with abnormal heparin binding presenting during pregnancy. A1 - O'Ddonnell, JS A1 - Hinkson, L A1 - McCarthy, A A1 - Manning, R A1 - Khan, A A1 - Laffan, MA J1 - Blood Coagul Fibrinolysis Y1 - 2006/04// VL - 17 SN - 0957-5235 SP - 217 EP - 220 N2 - Quantitative antithrombin deficiency constitutes an important risk factor for venous thromboembolism, stillbirth, and other complications of pregnancy. Studies suggest, however, that individuals heterozygous for missense mutations involving the heparin-binding site of antithrombin do not have a significantly increased thrombotic risk. Owing to the rarity of such mutations, it remains unclear whether any specific heparin-binding site defects might be associated with thrombotic potential. We report here the case of a pregnant woman with an exceptionally rare Type II heparin-binding site antithrombin variant. This case highlights the difficult issues that are associated with the management of Type II antithrombin deficiency during pregnancy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16575261&query_hl=1 ER - TY - JFULL T1 - Functional characterization of embryonic stem cell-derived cardiomyocytes using scanning ion conductance microscopy. A1 - Gorelik, J A1 - Ali, NN A1 - Shevchuk, AI A1 - Lab, M A1 - Williamson, C A1 - Harding, SE A1 - Korchev, YE J1 - Tissue Eng Y1 - 2006/04// VL - 12 SN - 1076-3279 SP - 657 EP - 664 N2 - We report here the novel use of scanning ion conductance microscopy (SICM) to produce surface images of embryonic stem cell-derived cardiomyocytes (ESCM) to identify individual contracting cardiomyocytes among different cell types. By measuring amplitude and rhythm we can quantitate contraction of ESCM. This method gives, within the same experiment, an assessment of the number and position of ESCM within the layer of mixed cell types, as well as an accurate measure of the response of individual ESCM. Using different modulators of contraction as examples we showed how SICM could be used for recording their responses. We subsequently demonstrated that this model can be used to investigate the protective effect of antiarrhythmogenic drugs. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16674281&query_hl=1 ER - TY - JFULL T1 - Focused libraries of 16-substituted estrone derivatives and modified e-ring steroids: inhibitors of 17beta-hydroxysteroid dehydrogenase type 1. A1 - Vicker, N A1 - Lawrence, HR A1 - Allan, GM A1 - Bubert, C A1 - Smith, A A1 - Tutill, HJ A1 - Purohit, A A1 - Day, JM A1 - Mahon, MF A1 - Reed, MJ A1 - Potter, BV J1 - ChemMedChem Y1 - 2006/04// VL - 1 SN - 1860-7179 SP - 464 EP - 481 N2 - 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), an oxidoreductase which has a preferential reductive activity using NADPH as cofactor, converts estrone to estradiol and is expressed in many steroidogenic tissues including breast and in malignant breast cells. As estradiol stimulates the growth and development of hormone-dependent breast cancer, inhibition of the final step of its synthesis is an attractive target for the treatment of this disease. The parallel synthesis of novel focused libraries of 16-substituted estrone derivatives and modified E-ring pyrazole steroids as new potent 17beta-HSD1 inhibitors is described. Substituted 3-O-sulfamoylated estrone derivatives were used as templates and were immobilised on 2-chlorotrityl chloride resin to give resin-bound scaffolds with a multi-detachable linker. Novel focused libraries of 16-substituted estrone derivatives and new modified E-ring steroids were assembled from these immobilised templates using solid-phase organic synthesis and solution-phase methodologies. Among the derivatives synthesised, the most potent 17beta-HSD1 inhibitors were 25 and 26 with IC50 values in T-47D human breast cancer cells of 27 and 165 nm, respectively. Parallel synthesis resulting in a library of C5'-linked amides from the pyrazole E-ring led to the identification of 62 with an IC50 value of 700 nM. These potent inhibitors of 17beta-HSD1 have a 2-ethyl substituent which will decrease their estrogenic potential. Several novel 17beta-HSD1 inhibitors emerged from these libraries and these provide direction for further template exploration in this area. A new efficient diastereoselective synthesis of 25 has also been developed to facilitate supply for in vivo evaluation, and an X-ray crystal structure of this inhibitor is presented. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16892382&query_hl=1 ER - TY - JFULL T1 - Lupus anticoagulant and anticardiolipin antibody testing identify populations with limited overlap A1 - Eccersley, LRJ A1 - Laffan, MA J1 - BRIT J HAEMATOL Y1 - 2006/04// VL - 133 SN - 0007-1048 SP - 96 EP - 96 ER - TY - JFULL T1 - Novel, potent inhibitors of 17 beta-hydroxy steroid dehydrogenase type 1 A1 - Allan, GM A1 - Bubert, C A1 - Vicker, N A1 - Smith, A A1 - Tutill, HJ A1 - Purohit, A A1 - Reed, MJ A1 - Potter, BVL J1 - MOL CELL ENDOCRINOL Y1 - 2006/03/27/ VL - 248 SN - 0303-7207 SP - 204 EP - 207 N2 - Many breast turnouts are hortrione-responsive and rely on estrogens for their sustained growth and development. The enzyme 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) is primarily responsible for the conversion of estrone (EI) into the most potent of the human estrogens 17 beta-estradiol (E2). Here we report the syntheses, inhibitory activities and docking studies for a novel series of pyrazole amides which have been discovered with the aim of probing the structure activity relationships (SAR) for such a template and of using this template to mimic the potent inhibitor 1 (Fig. 1). Amides containing an aromatic pyridyl moiety have been found to give the best inhibition, indicating that the pyridyl group interacts beneficially in the active site. This work has shown that extension from this position on the pyrazole template is well tolerated and the optimization of such systems is under investigation. (c) 2005 Elsevier Ireland Ltd. All rights reserved. ER - TY - JFULL T1 - Imaging proteins in membranes of living cells by high-resolution scanning ion conductance microscopy. A1 - Shevchuk, AI A1 - Frolenkov, GI A1 - Sánchez, D A1 - James, PS A1 - Freedman, N A1 - Lab, MJ A1 - Jones, R A1 - Klenerman, D A1 - Korchev, YE J1 - Angew Chem Int Ed Engl Y1 - 2006/03/27/ VL - 45 SN - 1433-7851 SP - 2212 EP - 2216 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16506257&query_hl=1 ER - TY - JFULL T1 - Benzothiazole derivatives as novel inhibitors of human 11 beta-hydroxysteroid dehydrogenase type 1 A1 - Su, XD A1 - Vicker, N A1 - Ganeshapillai, D A1 - Smith, A A1 - Purohit, A A1 - Reed, MJ A1 - Potter, BVL J1 - MOL CELL ENDOCRINOL Y1 - 2006/03/27/ VL - 248 SN - 0303-7207 SP - 214 EP - 217 N2 - Selective inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSDl) have considerable potential as treatments for metabolic diseases, such as diabetes mellitus type 2 or obesity. Here, we report the discovery and synthesis of a series of novel benzothiazole derivatives and their inhibitory activities against 11 beta-HSDl from human hepatic microsomes measured using a radioimmunoassay (R[A) method. The benzothiazole derivatives 1 and 2 showed greater than 80% inhibition for 11 beta-HSDl at 10 mu M and exhibited IC50 values in the low micromolar range. The preliminary SAR study suggested the introduction of a chlorine substituent at the 4 position of the benzothiazole ring greatly enhanced the inhibitory activities. Docking studies with the benzothiazole derivative 1 into the crystal structure of human 11 beta-HSDl revealed how the molecule may interact with the enzyme and cofactor. (c) 2005 Elsevier Ireland Ltd. All rights reserved. ER - TY - JFULL T1 - The regulation and inhibition of 17beta-hydroxysteroid dehydrogenase in breast cancer. A1 - Purohit, A A1 - Tutill, HJ A1 - Day, JM A1 - Chander, SK A1 - Lawrence, HR A1 - Allan, GM A1 - Fischer, DS A1 - Vicker, N A1 - Newman, SP A1 - Potter, BV A1 - Reed, MJ J1 - Mol Cell Endocrinol Y1 - 2006/03/27/ VL - 248 SN - 0303-7207 SP - 199 EP - 203 N2 - 17Beta-hydroxysteroid dehydrogenase Type 1 (17beta-HSD1) has a pivotal role in regulating the synthesis of oestradiol (E2) within breast tumours. In whole body studies in postmenopausal women with breast cancer the conversion of oestrone (E1) to E2 (4.4+/-1.1%) was much lower than the inactivation of E2 to E1 (17.3+/-5.0%). In contrast, an examination of in vivo oestrogen metabolism within breast tumours revealed that whereas little metabolism of E2 occurred, E1 was converted to E2 to a much greater extent in malignant (48+/-14%) than in normal (19+/-6%) breast tissue. Findings from these studies originally suggested that oestrogen metabolism within breast tumours may differ from the mainly oxidative direction found in most other body tissues and that the activity of 17beta-HSD1 might be regulated by tumour-derived factors. Several growth factors (e.g. IGF-I, IGF-II) and cytokines (e.g. IL-6, TNFalpha) have now been identified which can markedly stimulate the activity of 17beta-HSD1 and such a mechanism may account for the high concentrations of E2 found in most breast tumours. Cells of the immune system, which can infiltrate breast tumours, are thought to be a major source of the growth factors and cytokines which can modulate 17beta-HSD1 activity. Given the central role that 17beta-HSD1 has in regulating breast tumour E2 concentrations the development of potent inhibitors of this enzyme has recently attracted considerable attention. Our initial studies in this area explored the use of derivatives of E1 as inhibitors, with 2-ethyl- and 2-methoxy E1 being found to inhibit 17beta-HSD1 activity in T-47D breast cancer cells by 96+/-2 and 91+/-1% respectively at 10 microM, but with a lack of specificity. Using the E1 scaffold a number of potent, selective 17beta-HSD1 inhibitors have now been identified including E1- and 2-ethyl-E1 containing a side chain with a m-pyridylmethylamidomethyl functionality extending from the 16beta position of the steroid nucleus. At 10 microM these compounds both inhibited 17beta-HSD1 activity by >90%, however some inhibition of 17beta-HSD2 activity was exhibited by the E1 derivative (25%) but not the 2-ethyl analogue. It is now apparent that 17beta-HSD1 activity contributes to the high E2 concentrations found in most breast tumours. The identification of potent, selective novel 17beta-HSD1 inhibitors will allow their efficacy to be tested in in vitro and in vivo studies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16414180&query_hl=1 ER - TY - JFULL T1 - 17Beta-hydroxysteroid dehydrogenase Type 1 and Type 2: association between mRNA expression and activity in cell lines. A1 - Day, JM A1 - Tutill, HJ A1 - Newman, SP A1 - Purohit, A A1 - Lawrence, HR A1 - Vicker, N A1 - Potter, BV A1 - Reed, MJ J1 - Mol Cell Endocrinol Y1 - 2006/03/27/ VL - 248 SN - 0303-7207 SP - 246 EP - 249 N2 - 17Beta-hydroxysteroid dehydrogenases (17beta-HSDs) are a family of enzymes that regulate steroid availability within a tissue by catalysing the interconversion of active and inactive forms. Type 1 is up-regulated in many breast tumours, and is responsible for the reduction of oestrone to active oestradiol which stimulates cell proliferation within the tumour. Type 2 oxidises many active steroids to their inactive forms, including oestradiol to oestrone. In this study, we have compared the mRNA expression and enzyme activities of Type 1 and Type 2 in MCF-7, MDA-MB-231, T47D, JEG3 and 293-EBNA cell lines. Also studied were two cell lines stably expressing transfected Type 1 cDNA. RT-PCR indicated that little Type 1 mRNA is expressed in two of the breast cancer cell lines, MCF-7 and MDA-MB-231, and in 293-EBNA cells, but that expression is much higher in the T47D breast cancer cell line, and in the choriocarcinoma cell line, JEG3. However, a higher level of expression of Type 1 is seen in the transfected cell lines MCF-7.8H and 293-EBNA[His617beta-HSD1]. Activity assays show that there is high association between mRNA expression and enzyme activity. Assays indicate that, with the exception of MDA-MB-231 cells, Type 2 activity is low in these lines. The study of the basal activities of these enzymes will be used in future studies investigating the regulation of the enzymes by endogenous and exogenous factors. An understanding of their regulation in both healthy and malignant tissues may lead to future therapeutic intervention at the regulatory level. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16490301&query_hl=1 ER - TY - JFULL T1 - Ghrelin stimulates insulin-induced glucose uptake in adipocytes. A1 - Patel, AD A1 - Stanley, SA A1 - Murphy, KG A1 - Frost, GS A1 - Gardiner, JV A1 - Kent, AS A1 - White, NE A1 - Ghatei, MA A1 - Bloom, SR J1 - Regul Pept Y1 - 2006/03/15/ VL - 134 SN - 0167-0115 SP - 17 EP - 22 N2 - The gastric and hypothalamic hormone ghrelin is the endogenous agonist of the growth hormone secretagogue receptor GHS-R1(a). Ghrelin stimulates growth hormone release and appetite via the hypothalamus. However, putative direct peripheral effects of ghrelin remain poorly understood. Rat adipose tissue expresses GHS-R1(a) mRNA, suggesting ghrelin may directly influence adipocyte function. We have investigated the effects of ghrelin on insulin-stimulated glucose uptake in isolated white adipocytes in vitro. RT-PCR confirmed the expression of GHS-R1(a) mRNA in epididymal adipose tissue. However, GHS-R1(a) expression was not detected in the peri-renal fat pads. Ghrelin increased insulin-stimulated deoxyglucose uptake in isolated white adipocytes extracted from the epididymal fat pads of male Wistar rats. Ghrelin 1000 nM significantly increased deoxyglucose uptake by 55% in the presence of 0.1 nM insulin. However, ghrelin administration in the absence of insulin had no effect on adipocyte deoxyglucose uptake, suggesting that ghrelin acts synergistically with insulin. Des-acyl ghrelin, a major circulating non-octanylated form of ghrelin, had no effect on insulin-stimulated glucose uptake. Furthermore, acylated ghrelin had no effect on deoxyglucose uptake in adipocytes from peri-renal fat pads suggesting that ghrelin may influence glucose uptake via the GHS-R1(a). Ghrelin therefore appears to directly potentiate adipocyte insulin-stimulated glucose uptake in selective adipocyte populations. Ghrelin may play a role in adipocyte regulation of glucose homeostasis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16338009&query_hl=1 ER - TY - JFULL T1 - Abnormalities of the somatotrophic axis in the obese agouti mouse. A1 - Martin, NM A1 - Houston, PA A1 - Patterson, M A1 - Sajedi, A A1 - Carmignac, DF A1 - Ghatei, MA A1 - Bloom, SR A1 - Small, CJ J1 - Int J Obes (Lond) Y1 - 2006/03// VL - 30 SN - 0307-0565 SP - 430 EP - 438 N2 - OBJECTIVE: Abnormalities of the melanocortin system produce obesity and increased linear growth. While the obesity phenotype is well characterised, the mechanism responsible for increased linear growth is unclear. The somatotrophic axis was studied in the obese agouti (A(y)/a) mouse as a model of a perturbed melanocortin system. DESIGN: Adult obese A(y)/a mice were compared to age- and sex-matched wild-type (WT) controls. Weight and body length (nose-anus) were recorded. Plasma growth hormone (GH), insulin-like growth factor-I (IGFI), insulin and leptin were measured using radioimmunoassay. Since ghrelin is a potent GH secretagogue, plasma ghrelin, stomach ghrelin peptide and stomach ghrelin mRNA expression were studied. Hypothalamic periventricular (PeVN) somatostatin neurones and arcuate (Arc) neuropeptide Y (NPY) neurones inhibit the growth axis, whereas Arc growth hormone-releasing hormone (GHRH) neurones are stimulatory. Therefore, specific hypothalamic expression of somatostatin, NPY and GHRH was measured using quantitative in situ hybridisation. RESULTS: Obese A(y)/a mice were significantly heavier and longer than WT controls. Plasma IGFI concentrations were 30% greater in obese A(y)/a mice. Obese A(y) /a mice were hyperinsulinaemic and hyperleptinaemic, yet plasma ghrelin, and stomach ghrelin peptide and mRNA were significantly reduced. In obese A(y)/a mice, PeVN somatostatin and Arc NPY mRNA expression were reduced by 50% compared to WT controls, whereas Arc GHRH mRNA expression was unchanged. CONCLUSION: Increased body length in adult obese A(y)/a mice may result from reduced Arc NPY and PeVN somatostatin mRNA expression, which in turn, may increase plasma IGFI concentrations and upregulate the somatotrophic axis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16172617&query_hl=1 ER - TY - JFULL T1 - Phase I study of STX 64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor. A1 - Stanway, SJ A1 - Purohit, A A1 - Woo, LW A1 - Sufi, S A1 - Vigushin, D A1 - Ward, R A1 - Wilson, RH A1 - Stanczyk, FZ A1 - Dobbs, N A1 - Kulinskaya, E A1 - Elliott, M A1 - Potter, BV A1 - Reed, MJ A1 - Coombes, RC J1 - Clin Cancer Res Y1 - 2006/03/01/ VL - 12 SN - 1078-0432 SP - 1585 EP - 1592 N2 - PURPOSE: Inhibition of steroid sulfatase (STS), the enzyme responsible for the hydrolysis of steroid sulfates, represents a potential novel treatment for postmenopausal women with hormone-dependent breast cancer. Estrone and DHEA are formed by this sulfatase pathway and can be converted to steroids (estradiol and androstenediol, respectively), which have potent estrogenic properties. EXPERIMENTAL DESIGN: STX64 (667 Coumate), a tricylic coumarin-based sulfamate that irreversibly inhibits STS activity, was selected for entry into the first phase I trial of a STS inhibitor in postmenopausal women with breast cancer. STX64 was administered orally (nine patients at 5 mg and five patients at 20 mg) as an initial dose followed 1 week later by 3 x 2 weekly cycles, with each cycle comprising daily dosing for 5 days followed by 9 days off treatment. Blood and tumor tissue samples were collected for the assessment of STS activity and serum was obtained for steroid hormone measurements before and after treatment. RESULTS: The median inhibition of STS activity by STX64 was 98% in peripheral blood lymphocytes (PBL) and 99% in breast tumor tissue at the end of the 5-day dosing period. As expected, serum concentrations of estrone, estradiol, androstenediol, and DHEA all decreased significantly from pretreatment levels. Unexpectedly, androstenedione and testosterone concentrations also decreased. Four patients, all of whom had previously progressed on aromatase inhibitors, showed evidence of stable disease for 2.75 to 7 months. The drug was well tolerated with only minor drug-related adverse events recorded. CONCLUSION: STX64 is a potent, well-tolerated STS inhibitor. It inhibits STS activity in PBLs and tumor tissues and causes significant decreases in serum concentrations of steroids with estrogenic properties. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16533785&query_hl=1 ER - TY - JFULL T1 - A new hormone replacement therapy containing a progestogen with anti-mineralocorticoid activity. A1 - Stevenson, JC J1 - J Br Menopause Soc Y1 - 2006/03// VL - 12 Suppl 1 SN - 1362-1807 SP - 8 EP - 10 N2 - Drospirenone is a new progestogen in hormone replacement therapy, with anti-mineralocorticoid activity. This anti-mineralocorticoid activity counteracts water and sodium retention, helping to reduce the likelihood of fluid retention that some women experience with hormone replacement therapy. In a post hoc analysis of women with mild hypertension, estradiol (1 mg) plus drospirenone (2 mg) was found to lower blood pressure in mildly hypertensive women. The introduction of estradiol plus drospirenone may offer the opportunity to re-evaluate the contribution of the progestogen component of hormone replacement therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16513013&query_hl=1 ER - TY - JFULL T1 - [ENPP1, the first example of common genetic link between childhood and adult obesity and type 2 diabetes] A1 - Meyre, D A1 - Froguel, P J1 - Med Sci (Paris) Y1 - 2006/03// VL - 22 SN - 0767-0974 SP - 308 EP - 312 N2 - Clinical studies have established the strong link between obesity and type 2 diabetes, especially in children, where the rising prevalence of childhood severe obesity has preceded the recent emergence of early-onset forms of "diabesity". These data suggested a common genetic background shared by both conditions, which was also supported by the identification by genome scans of several diabesity chromosomal regions of linkage. The genetic investigation of early-onset form of familial obesity linkage to chromosome 6q led to the identification of ENPP1, an inhibitor of the insulin receptor, as a possible molecular mechanism behind both obesity and type 2 diabetes. Analysis of the DNA variations of ENPP1 in 6,147 subjects showed association between a combination of variants and both childhood obesity, morbid or moderate obesity in adults and also with type 2 diabetes. This study provides a first molecular basis for the physiopathologic association between severe insulin resistance and obesity, and further type 2 diabetes, and offers a new perspective for prevention and treatment of these conditions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16527214&query_hl=1 ER - TY - JFULL T1 - Variant AS-1659 G > C of KLF11, associated to the diabetes of type 2, modifies transcription of KLF11. A1 - Gutierrez-Aguilar, R A1 - Vaillant, E A1 - Benmezroua, Y A1 - Froguel, P A1 - Neve, B J1 - DIABETES METAB Y1 - 2006/03// VL - 32 SN - 1262-3636 SP - S44 EP - S44 ER - TY - JFULL T1 - Plasma gastrin measurement cannot be used to diagnose a gastrinoma in patients on either proton pump inhibitors or histamine type-2 receptor antagonists. A1 - Dhillo, WS A1 - Jayasena, CN A1 - Lewis, CJ A1 - Martin, NM A1 - Tang, KC A1 - Meeran, K A1 - Todd, JF J1 - Ann Clin Biochem Y1 - 2006/03// VL - 43 SN - 0004-5632 SP - 153 EP - 155 N2 - BACKGROUND: Patients with a gastrinoma are treated with proton pump inhibitors (PPI) and histamine type-2 receptor antagonists (H2). In order to diagnose a gastrinoma these drugs must be discontinued, but this increases the risk of gastrointestinal perforation. We aimed to determine if a gastrinoma could be diagnosed without cessation of PPI/H2 therapy. METHODS: In all, 90 patients (controls and patients diagnosed with a gastrinoma both on and off PPI/H2 therapy) were recruited, and plasma gastrin measured. RESULTS: Patients with a gastrinoma on PPI/H2 medication had a significantly higher fasting plasma gastrin concentration than control patients on PPI/H2 medication (298+/-33 versus 204+/-30 pmol/L, P = 0.01). However, there was substantial overlap between gastrin levels in these two groups. CONCLUSION: This study confirms that a gastrinoma cannot be diagnosed on the basis of a fasting plasma gastrin assay while patients remain on PPI/H2 therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16536918&query_hl=1 ER - TY - JFULL T1 - Effect of variable C gene PTPN1, coding tyrosine phosphatase 1B protein (PTP1B), on the risk of diabetes of the type 2 (DT2) and obesity in French population A1 - Cheyssac, C A1 - Lecoeur, C A1 - Dechaume, A A1 - Charpentier, G A1 - Balkau, B A1 - Marre, M A1 - Froguel, P A1 - Vaxillaire, M J1 - DIABETES METAB Y1 - 2006/03// VL - 32 SN - 1262-3636 SP - S45 EP - S45 ER - TY - JFULL T1 - Analytical analysis of the variants of the LEPROTL1 gene, the new gene candidate of the infantile obesity A1 - Bacart, J A1 - Seron, K A1 - Choquet, H A1 - Charles, MA A1 - Balkau, B A1 - Fumeron, F A1 - Meyre, D A1 - Boutin, P A1 - Froguel, P J1 - DIABETES METAB Y1 - 2006/03// VL - 32 SN - 1262-3636 SP - S44 EP - S44 ER - TY - JFULL T1 - Analysis of skeletal phenotypes in thyroid hormone receptor mutant mice A1 - Bassett, JHD A1 - O'Shea, PJ A1 - Chassande, O A1 - Samarut, J A1 - Cheng, SY A1 - Vennstrom, B A1 - Howell, PGT A1 - Boyde, A A1 - Williams, GR J1 - SCANNING Y1 - 2006/03// VL - 28 SN - 0161-0457 SP - 91 EP - 93 ER - TY - JFULL T1 - Genetic analysis of ADIPOR1 and ADIPOR2 candidate polymorphisms for type 2 diabetes in the Caucasian population. A1 - Vaxillaire, M A1 - Dechaume, A A1 - Vasseur-Delannoy, V A1 - Lahmidi, S A1 - Vatin, V A1 - Leprêtre, F A1 - Boutin, P A1 - Hercberg, S A1 - Charpentier, G A1 - Dina, C A1 - Froguel, P J1 - Diabetes Y1 - 2006/03// VL - 55 SN - 0012-1797 SP - 856 EP - 861 N2 - Adiponectin is a metabolic link between adipose tissue and insulin action, mediating part of obesity-associated insulin resistance and type 2 diabetes. Two adiponectin receptors have been identified, and we investigated whether sequence variations in adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) genes could contribute to the genetic risk for type 2 diabetes in a case-control study of 1,498 Caucasian subjects. We sequenced the putative functional regions of the two genes in 48 subjects and selected single nucleotide polymorphisms (SNPs) from the public database. Five SNPs in ADIPOR1 and 12 in ADIPOR2 were tested for association with type 2 diabetes. No SNP of ADIPOR1 showed association in any of the samples from the French population. In contrast, three SNPs of ADIPOR2 showed nominal evidence for association with type 2 diabetes before correction for multiple testing (odds ratio [OR] 1.29-1.37, P = 0.034-0.014); only rs767870, located in intron 6, was replicated in an additional diabetes dataset (n = 636, OR 1.29, P = 0.020) with significant allelic association from the overall meta-analysis of 2,876 subjects (adjusted OR 1.25 [95% CI 1.07-1.45], P = 0.0051). In conclusion, our data suggest a modest contribution of ADIPOR2 variants in diabetes risk in the French population. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16505255&query_hl=1 ER - TY - JFULL T1 - Role of proteins from the OB-RGRP family in the expression of the receptor in leptin on the surface of cells A1 - Seron, K A1 - Belousard, S A1 - Corset, L A1 - Rouille, Y A1 - Froguel, P J1 - DIABETES METAB Y1 - 2006/03// VL - 32 SN - 1262-3636 SP - S104 EP - S105 ER - TY - JFULL T1 - Activator mutations of the sulfamids receptor SUR1/ABCC8 in neonatal permanent diabetes and transitional with the frequent inherited congregation of diabetes A1 - Vaxillaire, M A1 - Dechaume, A A1 - Busiah, K A1 - Cave, H A1 - Aguilar-Bryan, L A1 - Polak, M A1 - Froguel, P J1 - DIABETES METAB Y1 - 2006/03// VL - 32 SN - 1262-3636 SP - S29 EP - S30 ER - TY - JFULL T1 - Contribution of the variants of the gene SIM1 in severe forms of obesity in French population A1 - Ghoussaini, M A1 - Meyre, D A1 - Couturier, C A1 - Vatin, V A1 - Lecoeur, C A1 - Samson, C A1 - Froguel, P J1 - DIABETES METAB Y1 - 2006/03// VL - 32 SN - 1262-3636 SP - S11 EP - S11 ER - TY - JFULL T1 - Editorial: from gut to mind--hormonal satiety signals and anorexia nervosa. A1 - Chaudhri, OB A1 - Field, BC A1 - Bloom, SR J1 - J Clin Endocrinol Metab Y1 - 2006/03// VL - 91 SN - 0021-972X SP - 797 EP - 798 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16522706&query_hl=1 ER - TY - JFULL T1 - Genetic variants of the adiponectin gene (ACDC) are associated with the infantile obesity and morbid obesity in adults A1 - Bouatia-Naji, N A1 - Meyre, D A1 - Lobbens, S A1 - Seron, K A1 - Fumeron, F A1 - Balkau, B A1 - Heude, B A1 - Jouret, B A1 - Scherer, PE A1 - Dina, C A1 - Weill, J A1 - Froguel, P J1 - DIABETES METAB Y1 - 2006/03// VL - 32 SN - 1262-3636 SP - S9 EP - S9 ER - TY - JFULL T1 - Congenital anomaly surveillance in England and Wales. A1 - Misra, T A1 - Dattani, N A1 - Majeed, A J1 - Public Health Y1 - 2006/03// VL - 120 SN - 0033-3506 SP - 256 EP - 264 N2 - The National Congenital Anomaly System (NCAS) was set up in 1964, following the thalidomide epidemic, as a monitoring system designed to detect changes in the frequency of reporting of malformations. Its original aim was to detect anomalies reported within 7 days of birth. The NCAS is voluntary at all stages and covers all live- and stillbirths. It has two tiers; a 'passive system' receiving congenital anomaly notifications through a standard paper notification form, known as the SD56, and the congenital anomaly registers that send notifications electronically. Congenital anomalies are classified using the International Classification of Diseases codes and 10 monitoring groups. The Office for National Statistics performs a statistical analysis on a monthly, quarterly and annual basis, using the cumulative sum technique, which is the basis upon which surveillance alerts are raised within the system. The NCAS is now an open database where congenital anomalies can be notified whenever they are detected. The aim of this paper is to describe the current operation and uses of the NCAS based on guidelines for the evaluation of public health surveillance systems published by the Centers for Disease Control and Prevention. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16337977&query_hl=1 ER - TY - JFULL T1 - Evidence for a stimulatory action of melanin-concentrating hormone on luteinising hormone release involving MCH1 and melanocortin-5 receptors A1 - Murray, JF A1 - Hahn, JD A1 - Kennedy, AR A1 - Small, CJ A1 - Bloom, SR A1 - Haskell-Luevano, C A1 - Coen, CW A1 - Wilson, CA J1 - J NEUROENDOCRINOL Y1 - 2006/03// VL - 18 SN - 0953-8194 SP - 157 EP - 167 N2 - The present series of studies aimed to further our understanding of the role of melanin-concentrating hormone (MCH) neurones in the central regulation of luteinising hormone (LH) release in the female rat. LH release was stimulated when MCH was injected bilaterally into the rostral preoptic area (rPOA) or medial preoptic area (mPOA), but not when injected into the zona incerta (ZI), of oestrogen-primed ovariectomised rats. In rats that were steroid-primed to generate a surge-like release of LH, MCH administration into the ZI blocked this rise in LH release: no such effect occurred when MCH was injected into the rPOA or mPOA. In vitro, MCH stimulated gonadotrophin-releasing hormone (GnRH) release from hypothalamic explants. Double-label immunohistochemistry showed GnRH-immunoreactive neurones in the vicinity of and intermingled with immunoreactive MCH processes. MCH is the endogenous ligand of the MCH type 1 receptor (MCH1-R). Previously, we have shown a role for melanocortin-5 receptors (MC5-R) in the stimulatory action of MCH, so we next investigated the involvement of both MCH1-R and/or MC5-R in mediating the actions of MCH on GnRH and hence LH release. The stimulatory action of MCH in the rPOA was inhibited by administration of antagonists for either MCH1-R or MC5-R. However, in the mPOA, the action of MCH was blocked only by the MC5-R antagonist. LH release was stimulated by an agonist for MC5-R injected into the rPOA or mPOA; this was blocked by the MC5-R antagonist but not the MCH1-R antagonist. These results indicate that both MCH1-R and MC5-R are involved in the central control of LH release by MCH. ER - TY - JFULL T1 - VNTR of the insulin: molecular determiner of thrifty genotype? A1 - Meyre, D A1 - Degraeve, F A1 - Heude, B A1 - Vatin, V A1 - Ghoussaini, M A1 - Durand, E A1 - Boutin, P A1 - Dina, C A1 - Charles, MA A1 - Froguel, P J1 - DIABETES METAB Y1 - 2006/03// VL - 32 SN - 1262-3636 SP - S45 EP - S46 ER - TY - JFULL T1 - Modification of estrone at the 6, 16, and 17 positions: novel potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 1. A1 - Allan, GM A1 - Lawrence, HR A1 - Cornet, J A1 - Bubert, C A1 - Fischer, DS A1 - Vicker, N A1 - Smith, A A1 - Tutill, HJ A1 - Purohit, A A1 - Day, JM A1 - Mahon, MF A1 - Reed, MJ A1 - Potter, BV J1 - J Med Chem Y1 - 2006/02/23/ VL - 49 SN - 0022-2623 SP - 1325 EP - 1345 N2 - The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyze the interconversion between the oxidized and reduced forms of androgens and estrogens at the 17 position. The 17beta-HSD type 1 enzyme (17beta-HSD1) catalyzes the reduction of estrone to estradiol and is expressed in malignant breast cells. Inhibitors of this enzyme thus have potential as treatments for hormone dependent breast cancer. Here we report the syntheses and biological evaluation of novel inhibitors based on the estrone or estradiol template. These have been investigated by modification at the 6, 16 or 17 positions or combinations of these in order to gain information about structure-activity relationships by probing different areas in the enzyme active site. Activity data have been incorporated into a QSAR with predictive power, and the X-ray crystal structures of compounds 15 and 16c have been determined. Compound 15 has an IC50 of 320 nM for 17beta-HSD1 and is selective for 17beta-HSD1 over 17beta-HSD2. Three libraries of amides are also reported that led to the identification of inhibitors 19e and 20a, which have IC50 values of 510 and 380 nM respectively, and 20 h which, having an IC50 value of 37 nM, is the most potent inhibitor of 17beta-HSD1 reported to date. These amides are also selective for 17beta-HSD1 over 17beta-HSD2. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16480268&query_hl=1 ER - TY - JFULL T1 - Trends in sexually transmitted infections in general practice 1990-2000: population based study using data from the UK general practice research database. A1 - Cassell, JA A1 - Mercer, CH A1 - Sutcliffe, L A1 - Petersen, I A1 - Islam, A A1 - Brook, MG A1 - Ross, JD A1 - Kinghorn, GR A1 - Simms, I A1 - Hughes, G A1 - Majeed, A A1 - Stephenson, JM A1 - Johnson, AM A1 - Hayward, AC J1 - BMJ Y1 - 2006/02/11/ VL - 332 SN - 1468-5833 SP - 332 EP - 334 N2 - OBJECTIVE: To describe the contribution of primary care to the diagnosis and management of sexually transmitted infections in the United Kingdom, 1990-2000, in the context of increasing incidence of infections in genitourinary medicine clinics. DESIGN: Population based study. SETTING: UK primary care. PARTICIPANTS: Patients registered in the UK general practice research database. MAIN OUTCOME MEASURES: Incidence of diagnosed sexually transmitted infections in primary care and estimation of the proportion of major such infections diagnosed in primary care. RESULTS: An estimated 23.0% of chlamydia cases in women but only 5.3% in men were diagnosed and treated in primary care during 1998-2000, along with 49.2% cases of non-specific urethritis and urethral discharge in men and 5.7% cases of gonorrhoea in women and 2.9% in men. Rates of diagnosis in primary care rose substantially in the late 1990s. CONCLUSIONS: A substantial and increasing number of sexually transmitted infections are diagnosed and treated in primary care in the United Kingdom, with sex ratios differing from those in genitourinary medicine clinics. Large numbers of men are treated in primary care for presumptive sexually transmitted infections. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16439371&query_hl=1 ER - TY - JFULL T1 - Unexpected shortness of breath in a patient with Cushing's syndrome. A1 - Keenan, N A1 - Dhillo, WS A1 - Williams, GR A1 - Todd, JF J1 - Lancet Y1 - 2006/02/04/ VL - 367 SN - 1474-547X SP - 446 EP - 446 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16458772&query_hl=1 ER - TY - JFULL T1 - The regulation of appetite. A1 - Druce, M A1 - Bloom, SR J1 - Arch Dis Child Y1 - 2006/02// VL - 91 SN - 1468-2044 SP - 183 EP - 187 N2 - The worsening global obesity epidemic, particularly the increase in childhood obesity, has prompted research into the mechanisms of appetite regulation. Complex pathways modulate energy balance, involving appetite centres in the hypothalamus and brain stem, and hormonal signals of energy status released by the gut and by the periphery. Better understanding of appetite regulation improves understanding of the aetiology of obesity. Manipulation of this homoeostatic system offers potentially useful treatments for obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16428368&query_hl=1 ER - TY - JFULL T1 - Autoantibodies to thrombin directed against both of its cryptic exosites. A1 - Mollica, L A1 - Preston, RJ A1 - Chion, AC A1 - Lees, SJ A1 - Collins, P A1 - Lewis, S A1 - Lane, DA J1 - Br J Haematol Y1 - 2006/02// VL - 132 SN - 0007-1048 SP - 487 EP - 493 N2 - Immunoglobulin G (IgG) anti-thrombin autoantibodies (ATA) were purified from the plasma of a patient referred for haematological investigation because of bleeding for 24 h following a dental extraction. The ATA did not inhibit the catalytic activity of thrombin against a chromogenic substrate, suggesting that they did not interact with the active site of thrombin. The ATA did, however, prolong the time required to generate thrombin in plasma, suggesting that they inhibited factor V and factor VIII activation. Surface plasmon resonance (SPR) was used to demonstrate that ATA bound to thrombin with high affinity. Competition of thrombin-ATA binding, using known thrombin exosite I and II ligands (hirudin, thrombomodulin and heparin), demonstrated that ATA bound to both thrombin exosites. Thrombin residues that are important for ATA binding were identified using a library of 53 recombinant thrombin variants encompassing alanine substitutions of 78 surface-exposed residues. They were H66, R68, R70 and Y71 in exosite I, and R89, R93, E94, R98, R245 and K248 in exosite II. ATA bound predominantly to exosite II. They did not bind to prothrombin, illustrating the cryptic nature of both exosites exposed and presented as potential antigens following prothrombin conversion to thrombin. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16412021&query_hl=1 ER - TY - JFULL T1 - Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers. A1 - Druce, MR A1 - Neary, NM A1 - Small, CJ A1 - Milton, J A1 - Monteiro, M A1 - Patterson, M A1 - Ghatei, MA A1 - Bloom, SR J1 - Int J Obes (Lond) Y1 - 2006/02// VL - 30 SN - 0307-0565 SP - 293 EP - 296 N2 - BACKGROUND: The gastric hormone ghrelin appears a useful agent to stimulate food intake in people with anorexia of illness. The loss of ghrelin's acyl group renders it inactive, thus it has been thought that subcutaneous administration may be problematic. OBJECTIVE: To investigate whether human subjects are sensitive to the effects of ghrelin administered by single subcutaneous injection. STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. SUBJECTS: Sixteen healthy lean volunteers (eight men and eight women). PROTOCOL: Fasted subjects received subcutaneous injections of ghrelin (3.6 nmol/kg) or saline. After 30 min, a buffet breakfast was served. RESULTS: Ghrelin injection increased energy intake by 27% (ghrelin 5076 +/- 691 kJ versus saline 4230+/-607 kJ, P = 0.04). Ghrelin appeared to enhance the perceived palatability of the food offered (palatability score: ghrelin 81.1 +/- 3.6 versus saline 70.0 +/- 4.4; P = 0.03). CONCLUSIONS: These results suggest that subcutaneous ghrelin is effective at stimulating energy intake and improving palatability and may be of direct use in the treatment of appetite loss. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16247504&query_hl=1 ER - TY - JFULL T1 - Association of population and practice factors with potentially avoidable admission rates for chronic diseases in London: cross sectional analysis. A1 - Saxena, S A1 - George, J A1 - Barber, J A1 - Fitzpatrick, J A1 - Majeed, A J1 - J R Soc Med Y1 - 2006/02// VL - 99 SN - 0141-0768 SP - 81 EP - 89 N2 - OBJECTIVES: To examine the association between underlying ill health, material deprivation and primary care supply factors and hospital admission rates for potentially avoidable admissions in primary care trusts in London. DESIGN: Cross sectional analysis at primary care trusts level using routine data from multiple sources. SETTING: All 31 primary care trusts in London with a total resident population of 7 million patients. MAIN OUTCOME MEASURES: Age-standardized hospital admission rates for asthma, diabetes, heart failure, hypertension and chronic obstructive pulmonary disease. RESULTS: Admission rates varied widely for the conditions examined across the 31 primary care trusts. In 2001, age adjusted admission rates for asthma varied from 76 to 189 per 100,000 and for diabetes from 38 to 183 per 100,000. There was a significant association between higher admission rates and measures of underlying ill health and material deprivation but not quantitative measures of primary care service provision. Provision of specialist chronic disease services in primary care for diabetes but not for asthma were significantly associated with reduced admission rates. There was no association of prescribing levels in primary care trusts with admission rates for any of the conditions examined. CONCLUSIONS: Although hospital admission for some chronic diseases is potentially avoidable and rates of hospital admission for these conditions are possible indicators of the quality of care, they should be interpreted in conjunction with measures of population composition and deprivation. Failure to do this may result in primary care trusts and general practitioners being criticized for aspects of health care utilization that are not under their direct control. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16449782&query_hl=1 ER - TY - JFULL T1 - Nanoscale pipetting for controlled chemistry in small arrayed water droplets using a double-barrel pipet. A1 - Rodolfa, KT A1 - Bruckbauer, A A1 - Zhou, D A1 - Schevchuk, AI A1 - Korchev, YE A1 - Klenerman, D J1 - Nano Lett Y1 - 2006/02// VL - 6 SN - 1530-6984 SP - 252 EP - 257 N2 - We present a new methodology which provides for the miniaturization of one of the most common tools in use in chemistry and biology laboratories today-the micropipet. We have used glass-fabricated double-barrel nanopipets to controllably produce arrayed water droplets with volumes as small as a few attoliters under an organic layer. We have addressed individual droplets and added controlled amounts of either additional volume or reagents from one of the barrels of the pipet. We demonstrate that this method can be used for miniaturized cell-free protein expression. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16464045&query_hl=1 ER - TY - JFULL T1 - The importance of acclimatisation and habituation to experimental conditions when investigating the anorectic effects of gastrointestinal hormones in the rat. A1 - Abbott, CR A1 - Small, CJ A1 - Sajedi, A A1 - Smith, KL A1 - Parkinson, JR A1 - Broadhead, LL A1 - Ghatei, MA A1 - Bloom, SR J1 - Int J Obes (Lond) Y1 - 2006/02// VL - 30 SN - 0307-0565 SP - 288 EP - 292 N2 - OBJECTIVE: Peptide YY3-36 (PYY(3-36)), glucagon-like peptide-1 (GLP-1), oxyntomodulin and cholecystokinin (CCK) are gastrointestinal-derived hormones that are released postprandially in proportion to the amount of calories ingested. All significantly reduce food intake following peripheral administration to rodents. We have investigated the effect of handling, exposure to a novel environment or to environmental enrichment on the anorectic effect of these gut hormones. RESULTS: Results suggest that the transfer of a rat into a novel environment (cage change) inhibits the anorectic response to peripherally administered PYY(3-36) and oxyntomodulin (1 h food intake reduction (% saline control): PYY/home cage 82.3 +/- 5.9%, P < 0.05; PYY/clean cage 103.4 +/- 9.7%; oxyntomodulin/home cage 71.6 +/- 12.1%, P < 0.05; oxyntomodulin/clean cage 103.0 +/- 8.5%) and attenuates the anorectic response to GLP-1 and CCK (1 h food intake reduction (% saline control): GLP-1/home cage 68.8 +/- 6.4%, P < 0.01; GLP-1/clean cage 80.0 +/- 9.3%; CCK/home cage 49.8 +/- 6.2%, P < 0.001; CCK/clean cage 69.4 +/- 10.6%, P < 0.05). We have also observed that exposure to a novel environment does not alter anorectic effect of peripherally administered melanocortin 3/4 receptor agonist, melanotan II (MTII) (1 h food intake reduction (% saline control): MTII/home cage 32.0 +/- 6.3%, P < 0.001; MTII/clean cage 24.8 +/- 4.2%, P < 0.001). The attenuation in food intake observed following exposure to a novel environment can be attributed, in part, to a significant reduction in the food intake of the saline treated animals. In a further study, the anorectic effect of peripherally administered PYY(3-36) is attenuated in unhandled rats (88 +/- 4.2% saline control, P = ns) or rats exposed to environmental enrichment (103.3 +/- 9.7% saline control, P = ns), but not in animals that were handled extensively prior to the study (80.1 +/- 7.3% saline control, P < 0.05). CONCLUSION: These studies highlight the importance of handling, acclimatisation and habituation of rodents to experimental conditions prior to investigating the ability of gut hormones to alter food intake. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16231018&query_hl=1 ER - TY - JFULL T1 - Progressive rise in gut hormone levels after Roux-en-Y gastric bypass suggests gut adaptation and explains altered satiety. A1 - Borg, CM A1 - le Roux, CW A1 - Ghatei, MA A1 - Bloom, SR A1 - Patel, AG A1 - Aylwin, SJ J1 - Br J Surg Y1 - 2006/02// VL - 93 SN - 0007-1323 SP - 210 EP - 215 N2 - BACKGROUND: Bariatric surgery is the most effective treatment for achieving long-term weight loss in morbidly obese patients. This study investigated prospective changes in gut hormones and metabolic indices after Roux-en-Y gastric bypass (RYGB). METHODS: Six patients were seen before, and at 1, 3 and 6 months after operation. Blood was collected after a 12-h fast and at regular intervals after a mixed 420-kcal meal. Hormonal responses were determined, and comparisons between basal levels and areas under the curve were made. Visual analogue scores were used to assess satiety, hunger and nausea. RESULTS: Mean body mass index decreased from 48.3 kg/m(2) before surgery to 36.4 kg/m(2) 6 months after RYGB. This was accompanied by a decrease in fasting leptin (P < 0.001) and insulin (P = 0.021) levels. At 1, 3 and 6 months after operation, progressively increasing peptide YY (P < 0.001), enteroglucagon (P = 0.045) and glucagon-like peptide 1 (P = 0.042) responses were observed. There was no change in fasting ghrelin levels (P = 0.144). Postprandial satiety was significantly increased by 1 month after surgery and this was maintained until the end of the study (P < 0.001). CONCLUSION: RYGB resulted in substantial weight loss with enhanced postprandial satiety, a sustained weight plateau, and proportionate reduction in fasting insulin and leptin levels. Lack of the expected increase in appetite and food intake as components of a counter-regulatory response may be explained by gut adaptation and the consequent graded rise in the levels of gut hormones that promote satiety. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16392104&query_hl=1 ER - TY - JFULL T1 - A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance A1 - Lee, YS A1 - Challis, BG A1 - Thompson, DA A1 - Yeo, GSH A1 - Keogh, JM A1 - Madonna, ME A1 - Wraight, V A1 - Sims, M A1 - Vatin, V A1 - Meyre, D A1 - Shield, J A1 - Burren, C A1 - Ibrahim, Z A1 - Cheetham, T A1 - Swift, P A1 - Blackwood, A A1 - Hung, CCC A1 - Wareham, NJ A1 - Froguel, P A1 - Millhauser, GL A1 - O'Rahilly, S A1 - Farooqi, IS J1 - CELL METAB Y1 - 2006/02// VL - 3 SN - 1550-4131 SP - 135 EP - 140 N2 - The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, alpha- and beta-MSH, the majority of attention has focused on alpha-MSH, partly reflecting the absence of beta-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding beta-MSH, Tyr221 Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type beta-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for beta-MSH in the control of human energy homeostasis. ER - TY - JFULL T1 - Changes in appetite related gut hormones in intensive care unit patients: a pilot cohort study. A1 - Nematy, M A1 - O'Flynn, JE A1 - Wandrag, L A1 - Brynes, AE A1 - Brett, SJ A1 - Patterson, M A1 - Ghatei, MA A1 - Bloom, SR A1 - Frost, GS J1 - Crit Care Y1 - 2006/02// VL - 10 SN - 1466-609X SP - R10 EP - R10 N2 - INTRODUCTION: The nutritional status of patients in the intensive care unit (ICU) appears to decline not only during their stay in the ICU but also after discharge from the ICU. Recent evidence suggests that gut released peptides, such as ghrelin and peptide YY (PYY) regulate the initiation and termination of meals and could play a role in the altered eating behaviour of sick patients. The aim of this study was to assess the patterns of ghrelin and PYY levels during the stay of ICU patients in hospital. METHODS: Sixteen ICU patients (60 +/- 4.7 years, body mass index (BMI) 28.1 +/- 1.7 kg/m2 (mean +/- standard error of the mean)) underwent fasting blood sample collections on days 1, 3, 5, 14, 21 and 28 of their stay at Hammersmith and Charing Cross Hospitals. Changes in appetite and biochemical and anthropometric markers of nutritional status were recorded. A comparison was made to a group of 36 healthy volunteers matched for age and BMI (54.3 +/- 2.9 years, p = 0.3; BMI 25.8 +/- 0.8 kg/m2 p = 0.2). RESULTS: Compared to healthy subjects, ICU patients exhibited a significantly lower level of ghrelin (day one 297.8 +/- 76.3 versus 827.2 +/- 78.7 pmol/l, p < 0.001) during their stay in the ICU. This tended to rise to the normal level during the last three weeks of hospital stay. Conversely, ICU patients showed a significantly higher level of PYY (day one 31.5 +/- 9.6 versus 11.3 +/- 1.0 pmol/l, p < 0.05) throughout their stay in the ICU and on the ward, with a downward trend to the normal level during the last three weeks of stay. CONCLUSIONS: Results from our study show high levels of PYY and low levels of ghrelin in ICU patients compared to healthy controls. There appears to be a relationship between the level of these gut hormones and nutritional intake. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16420657&query_hl=1 ER - TY - JFULL T1 - Interactions between the melanocortin system and the hypothalamo-pituitary-thyroid axis. A1 - Martin, NM A1 - Smith, KL A1 - Bloom, SR A1 - Small, CJ J1 - Peptides Y1 - 2006/02// VL - 27 SN - 0196-9781 SP - 333 EP - 339 N2 - Recent studies of transgenic mice and humans have provided compelling evidence for the importance of the hypothalamic melanocortin system in the regulation of energy balance. Energy homeostasis is a balance between food intake (energy input) and energy expenditure. The melanocortin system regulates feeding via effects of the endogenous agonist, alpha-melanocyte stimulating hormone (alpha-MSH) and the endogenous antagonist agouti-related protein (AGRP) on melanocortin 3 and 4 receptors (MC3-Rs and MC4-Rs). It has been demonstrated that the melanocortin system interacts with the hypothalamo-pituitary-thyroid (HPT) axis. Thyroid hormones influence metabolism and hence energy expenditure. Therefore, an interaction between the HPT axis and the melanocortin system would allow control of both sides of the energy balance equation, by the regulation of both energy input and energy expenditure. Here we will discuss the evidence demonstrating interactions between the melanocortin system and the HPT axis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16388877&query_hl=1 ER - TY - JFULL T1 - Neural representations of hunger and satiety in Prader-Willi syndrome. A1 - Hinton, EC A1 - Holland, AJ A1 - Gellatly, MS A1 - Soni, S A1 - Patterson, M A1 - Ghatei, MA A1 - Owen, AM J1 - Int J Obes (Lond) Y1 - 2006/02// VL - 30 SN - 0307-0565 SP - 313 EP - 321 N2 - OBJECTIVE: To investigate the neural basis of the abnormal eating behaviour in Prader-Willi syndrome (PWS), using brain imaging. We predicted that the satiety response in those with PWS would be delayed and insensitive to food intake. DESIGN AND PARTICIPANTS: The design of this study was based on a previous investigation of the neural activation associated with conditions of fasting and food intake in a nonobese, non-PWS group. The findings were used to generate specific hypotheses regarding brain regions of interest for the current study, in which 13 adults with PWS took part (mean +/- s.d. age = 29 +/- 6; BMI = 31.5 +/- 5.1; IQ = 71 +/- 8, six were female). MEASUREMENTS: Regional cerebral blood flow was measured using positron emission tomography in three sessions: one following an overnight fast and two following disguised energy controlled meals of similar volume and appearance--one of 1674 kJ (400 kcal) and another of 5021 kJ (1200 kcal). Subjective ratings of hunger, fullness and desire to eat, and blood plasma levels of glucose, insulin, leptin, ghrelin and PYY were measured before and after each imaging session. RESULTS: The neural representation of hunger, after an overnight fast, was similar to that found in nonobese individuals in the control study. In contrast, after food intake, the patterns of neural activation previously associated with satiety were not found, even after the higher-energy load. Lateral and medial orbitofrontal cortical activation was associated with consumption of the 400- and 1200-kcal meals, respectively. The medial orbitofrontal activation, however, was only found in those who had shown a large percentage change in fullness ratings following the higher-energy meal. CONCLUSION: We conclude that there is a dysfunction in the satiety system in those with PWS. These findings suggest that brain regions associated with satiety are insensitive even to high-energy food intake in those with the syndrome. This may be the neural basis of the hyperphagia seen in PWS. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16276365&query_hl=1 ER - TY - JFULL T1 - ACDC/adiponectin polymorphisms are associated with severe childhood and adult obesity. A1 - Bouatia-Naji, N A1 - Meyre, D A1 - Lobbens, S A1 - Séron, K A1 - Fumeron, F A1 - Balkau, B A1 - Heude, B A1 - Jouret, B A1 - Scherer, PE A1 - Dina, C A1 - Weill, J A1 - Froguel, P J1 - Diabetes Y1 - 2006/02// VL - 55 SN - 0012-1797 SP - 545 EP - 550 N2 - Common single nucleotide polymorphisms (SNPs) in the ACDC adiponectin encoding gene have been associated with insulin resistance and type 2 diabetes in several populations. Here, we investigate the role of SNPs -11,377C > G, -11,391G > A, +45T > G, and +276G > T in 2,579 French Caucasians (1,229 morbidly obese and 1,350 control subjects). We found an association between severe forms of obesity and -11,377C (odds ratio 1.23, P = 0.001) and +276T (1.19, P = 0.006). Surprisingly, alternative alleles -11,377G and +276G have been previously reported as risk factors for type 2 diabetes. Transmission disequilibrium tests showed a trend in overtransmission (56.7%) of a risk haplotype 1((C))-1((G))-1((T))-2((T)) including -11,377C and +276T in 634 obesity trios (P = 0.097). Family-based analysis in 400 trios from the general population indicated association between obesity haplotype and higher adiponectin levels, suggesting a role of hyperadiponectinemia in weight gain. However, experiments studying the putative roles of SNPs -11,377C > G and +276G > T on ACDC functionality were not conclusive. In contrast, promoter SNP -11,391G > A was associated with higher adiponectin levels in obese children (P = 0.005) and in children from the general population (0.00007). In vitro transcriptional assays showed that -11,391A may increase ACDC activity. In summary, our study suggests that variations at the ACDC/adiponectin gene are associated with risk of severe forms of obesity. However, the mechanisms underlying these possible associations are not fully understood. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16443793&query_hl=1 ER - TY - JFULL T1 - Development of polycystic ovary syndrome: involvement of genetic and environmental factors. A1 - Franks, S A1 - McCarthy, MI A1 - Hardy, K J1 - Int J Androl Y1 - 2006/02// VL - 29 SN - 0105-6263 N2 - We have recently proposed that polycystic ovary syndrome (PCOS) has its origin in fetal life. This hypothesis is based on data from animal models (rhesus monkey or sheep that have been exposed prenatally to high doses of androgen) and is supported by clinical studies. It is suggested that, in human females, exposure to excess androgen, at any stage from fetal development of the ovary to the onset of puberty, leads to many of the characteristic features of PCOS, including abnormalities of luteinizing hormone secretion and insulin resistance. It is likely that, in humans with PCOS, the development of the PCOS phenotype results primarily from a genetic predisposition for the fetal ovary to hypersecrete androgen. At present, it is unclear whether the maternal environment directly influences the development of PCOS in the offspring. Maternal androgen excess is unlikely to affect the fetus, because the placenta presents an effective barrier, but metabolic disturbances during pregnancy could affect development of the syndrome in the fetus. In postnatal life, the natural history of PCOS can be further modified by factors affecting insulin secretion and/or action, most importantly, nutrition. We now have evidence for a disorder of early follicular development in the polycystic ovary that is consistent with an increased population of primordial follicles in the fetal ovary. It remains to be determined whether this phenomenon is the cause or the effect of increased exposure to androgen within the ovary. PCOS is the commonest endocrine disorder in women. It is not only a very prevalent cause of anovulatory infertility, menstrual disturbances and hirsutism, but it is also a major risk factor for the development of type 2 diabetes mellitus in later life. The aetiology of the syndrome remains uncertain but there is increasing evidence for a genetic basis. PCOS very often becomes clinically manifest during adolescence with maturation of the hypothalamic-pituitary-ovarian axis but the genesis of the syndrome may be during very early development - perhaps even in utero. In this review, this hypothesis is explored in the light of clinical, biochemical and genetic research. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16390494&query_hl=1 ER - TY - JFULL T1 - The relationship between neuropeptide Y expression and headache in pituitary tumours. A1 - Levy, MJ A1 - Classey, JD A1 - Maneesri, S A1 - Meeran, K A1 - Powell, M A1 - Goadsby, PJ J1 - Eur J Neurol Y1 - 2006/02// VL - 13 SN - 1351-5101 SP - 125 EP - 129 N2 - Patients with pituitary tumours often present with disabling headache but there is no clear relationship between tumour size and headache. Neuropeptide Y (NPY) has been identified in pituitary tumours and may serve as a biochemical marker of the propensity for headache. Using immunohistochemical techniques we examined 27 consecutive pituitary adenoma specimens for NPY (including one normal postmortem control anterior pituitary specimen). A separate observer divided the patients into two groups: headache and non-headache. The association between the presence of NPY and headache was tested. NPY positive immunoreactivity was seen in 13 tumour specimens (50%, 13 of 26 pituitary tumour specimens), characterized by cytoplasmic and nuclear staining patterns. There was no significant association between the presence of NPY and headache (chi(2) = 0.9, P = 0.34). We did not observe NPY in the normal anterior pituitary control specimen. NPY was present in four of five (80%) growth hormone-secreting tumours and two of two (100%) prolactinomas, compared with four of 11 (36%) non-functioning adenomas. The mechanism of many pituitary tumour-associated headaches remains undetermined. The significance of NPY positivity in pituitary tumours is unknown, although the results of this study may implicate this peptide in the control of somatotroph and lactotroph activity. Our data do not support a clear role for NPY pituitary tumour-associated headache. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16490041&query_hl=1 ER - TY - JFULL T1 - ADAMTS13 substrate recognition of von Willebrand factor A2 domain. A1 - Zanardelli, S A1 - Crawley, JT A1 - Chion, CK A1 - Lam, JK A1 - Preston, RJ A1 - Lane, DA J1 - J Biol Chem Y1 - 2006/01/20/ VL - 281 SN - 0021-9258 SP - 1555 EP - 1563 N2 - ADAMTS13 controls the multimeric size of circulating von Willebrand factor (VWF) by cleaving the Tyr1605-Met1606 bond in theA2 domain. To examine substrate recognition, we expressed in bacteria and purified three A2 (VWF76-(1593-1668), VWF115-(1554-1668), VWFA2-(1473-1668)) and one A2-A3 (VWF115-A3-(1554-1874)) domain fragments. Using high pressure liquid chromatography analysis, the initial rates of VWF115 cleavage by ADAMTS13 at different substrate concentrations were determined, and from this the kinetic constants were derived (Km 1.61 microM; kcat 0.14 s(-1)), from which the specificity constant kcat/Km was calculated, 8.70 x 10(4) m(-1) s(-1). Similar values of the specificity constant were obtained for VWF76 and VWF115-A3. To identify residues important for recognition and proteolysis of VWF115, we introduced certain type 2A von Willebrand disease mutations by site-directed mutagenesis. Although most were cleaved normally, one (D1614G) was cleaved approximately 8-fold slower. Mutagenesis of additional charged residues predicted to be in close proximity to Asp1614 on the surface of the A2 domain (R1583A, D1587A, D1614A, E1615A, K1617A, E1638A, E1640A) revealed up to 13-fold reduction in kcat/Km for D1587A, D1614A, E1615A, and K1617A mutants. When introduced into the intact VWFA2 domain, proteolysis of the D1587A, D1614A, and E1615A mutants was also slowed, particularly in the presence of urea. Surface plasmon resonance demonstrated appreciable reduction in binding affinity between ADAMTS13 and VWF115 mutants (KD up to approximately 1.3 microM), compared with VWF115 (KD 20 nM). These results demonstrate an important role for Asp1614 and surrounding charged residues in the binding and cleavage of the VWFA2 domain by ADAMTS13. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16221672&query_hl=1 ER - TY - JFULL T1 - Statistical heterospectroscopy, an approach to the integrated analysis of NMR and UPLC-MS data sets: application in metabonomic toxicology studies. A1 - Crockford, DJ A1 - Holmes, E A1 - Lindon, JC A1 - Plumb, RS A1 - Zirah, S A1 - Bruce, SJ A1 - Rainville, P A1 - Stumpf, CL A1 - Nicholson, JK J1 - Anal Chem Y1 - 2006/01/15/ VL - 78 SN - 0003-2700 SP - 363 EP - 371 N2 - Statistical heterospectroscopy (SHY) is a new statistical paradigm for the coanalysis of multispectroscopic data sets acquired on multiple samples. This method operates through the analysis of the intrinsic covariance between signal intensities in the same and related molecules measured by different techniques across cohorts of samples. The potential of SHY is illustrated using both 600-MHz 1H NMR and UPLC-TOFMS data obtained from control rat urine samples (n = 54) and from a corresponding hydrazine-treated group (n = 58). We show that direct cross-correlation of spectral parameters, viz. chemical shifts from NMR and m/z data from MS, is readily achievable for a variety of metabolites, which leads to improved efficiency of molecular biomarker identification. In addition to structure, higher level biological information can be obtained on metabolic pathway activity and connectivities by examination of different levels of the NMR to MS correlation and anticorrelation matrixes. The SHY approach is of general applicability to complex mixture analysis, if two or more independent spectroscopic data sets are available for any sample cohort. Biological applications of SHY as demonstrated here show promise as a new systems biology tool for biomarker recovery. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16408915&query_hl=1 ER - TY - JFULL T1 - Urinary tract infections in women: diagnosis and management in primary care. A1 - Car, J J1 - BMJ Y1 - 2006/01/14/ VL - 332 SN - 1468-5833 SP - 94 EP - 97 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16410583&query_hl=1 ER - TY - JFULL T1 - The impact of ethnicity on glucose regulation and the metabolic syndrome following gestational diabetes. A1 - Kousta, E A1 - Efstathiadou, Z A1 - Lawrence, NJ A1 - Jeffs, JA A1 - Godsland, IF A1 - Barrett, SC A1 - Doré, CJ A1 - Penny, A A1 - Anyaoku, V A1 - Millauer, BA A1 - Cela, E A1 - Robinson, S A1 - McCarthy, MI A1 - Johnston, DG J1 - Diabetologia Y1 - 2006/01// VL - 49 SN - 0012-186X SP - 36 EP - 40 N2 - AIMS/HYPOTHESIS: We assessed the impact of ethnic origin on metabolism in women following gestational diabetes mellitus (GDM). MATERIALS AND METHODS: Glucose regulation and other features of the metabolic syndrome were studied at 20.0 (18.2-22.1) months (geometric mean [95% CI]) post-partum in women with previous GDM (185 European, 103 Asian-Indian, 80 African-Caribbean). They were compared with the same features in 482 normal control subjects who had normal glucose regulation during and following pregnancy. RESULTS: Impaired glucose regulation or diabetes by WHO criteria were present in 37% of women with previous GDM (diabetes in 17%), especially in those of African-Caribbean and Asian-Indian origin (50 and 44%, respectively vs 28% in European, p=0.009). BMI, waist circumference, diastolic blood pressure, fasting triglyceride and insulin levels, and insulin resistance by homeostatic model assessment (HOMA), were increased following GDM (p<0.001 for all, vs control subjects). Where glucose regulation was normal following GDM, basal insulin secretion (by HOMA) was high (p<0.001 vs control subjects). Irrespective of glucose regulation in pregnancy, Asian-Indian origin was associated with high triglyceride and low HDL cholesterol levels, and African-Caribbean with increased waist circumference, blood pressure, and insulin levels, together with insulin resistance and low triglyceride concentrations. Nonetheless, the GDM-associated features were consistent within each ethnic group. The metabolic syndrome by International Diabetes Federation criteria was present in 37% of women with previous GDM, especially in non-Europeans (Asian-Indian 49%, African-Caribbean 43%, European 28%, p=0.001), and in 10% of controls. CONCLUSIONS/INTERPRETATION: Following GDM, abnormal glucose regulation and the metabolic syndrome are common, especially in non-European women, indicating a need for diabetes and cardiovascular disease prevention strategies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16341688&query_hl=1 ER - TY - JFULL T1 - Are all fats created equal? A1 - Murphy, KG A1 - Bloom, SR J1 - Nat Med Y1 - 2006/01// VL - 12 SN - 1078-8956 SP - 32 EP - 33 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16397555&query_hl=1 ER - TY - JFULL T1 - Attenuated peptide YY release in obese subjects is associated with reduced satiety. A1 - le Roux, CW A1 - Batterham, RL A1 - Aylwin, SJ A1 - Patterson, M A1 - Borg, CM A1 - Wynne, KJ A1 - Kent, A A1 - Vincent, RP A1 - Gardiner, J A1 - Ghatei, MA A1 - Bloom, SR J1 - Endocrinology Y1 - 2006/01// VL - 147 SN - 0013-7227 SP - 3 EP - 8 N2 - The responses of the gut hormone peptide YY (PYY) to food were investigated in 20 normal-weight and 20 obese humans in response to six test meals of varying calorie content. Human volunteers had a graded rise in plasma PYY (R2 = 0.96; P < 0.001) during increasing calorific meals, but the obese subjects had a lower endogenous PYY response at each meal size (P < 0.05 at all levels). The ratio of plasma PYY(1-36) to PYY(3-36) was similar in normal-weight and obese subjects. The effect on food intake and satiety of graded doses of exogenous PYY(3-36) was also evaluated in 12 human volunteers. Stepwise increasing doses of exogenous PYY(3-36) in humans caused a graded reduction in food intake (R2 = 0.38; P < 0.001). In high-fat-fed (HF) mice that became obese and low-fat-fed mice that remained normal weight, we measured plasma PYY, tissue PYY, and PYY mRNA levels and assessed the effect of exogenous administered PYY(3-36) on food intake in HF mice. HF mice remained sensitive to the anorectic effects of exogenous ip PYY(3-36). Compared with low-fat-fed fed mice, the HF mice had lower endogenous plasma PYY and higher tissue PYY but similar PYY mRNA levels, suggesting a possible reduction of PYY release. Thus, fasting and postprandial endogenous plasma PYY levels were attenuated in obese humans and rodents. The PYY(3-36) infusion study showed that the degree of plasma PYY reduction in obese subjects were likely associated with decreased satiety and relatively increased food intake. We conclude that obese subjects have a PYY deficiency that would reduce satiety and could thus reinforce their obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16166213&query_hl=1 ER - TY - JFULL T1 - Thyroid hormone regulates heparan sulfate proteoglycan expression in the growth plate. A1 - Bassett, JH A1 - Swinhoe, R A1 - Chassande, O A1 - Samarut, J A1 - Williams, GR J1 - Endocrinology Y1 - 2006/01// VL - 147 SN - 0013-7227 SP - 295 EP - 305 N2 - Thyroid hormone is essential for normal skeletal development. Hypothyroidism is associated with growth arrest, failure of chondrocyte differentiation, and abnormal matrix synthesis. Thyroid hormone modulates the Indian hedgehog/PTHrP feedback loop and regulates fibroblast growth factor (FGF)/FGF receptor signaling. Because heparan sulfate (HS) proteoglycans (Prgs) (HSPGs) are absolutely required by these signaling pathways, we have investigated whether thyroid status affects HSPG expression within the growth plate. Tibial growth plate sections were obtained from 12-wk-old rats rendered euthyroid, thyrotoxic, or hypothyroid at 6 wk of age, 14-d-old congenitally hypothyroid Pax8-null mice, and TRalpha/TRbeta double-null mice lacking all thyroid hormone receptors. HS and chondroitin sulfate Prg expression was determined by immunohistochemistry using three monoclonal antibodies. There was increased HS staining in growth plates from hypothyroid animals predominantly within the extracellular matrix of reserve and proliferative zones. Cellular HS staining was also increased particularly in prehypertrophic chondrocytes. T3 regulation of HSPG core protein and HS synthetic and modification enzyme expression was studied in ATDC5 cells using semiquantitative RT-PCR. Thyroid hormone negatively regulated expression of the core protein Gpc6, the polymerase Ext1, and the modification enzyme Hs6st2. These studies demonstrate that the expression and distribution of growth plate Prgs are regulated by thyroid hormone, and the regulation of HSPG expression provides an important additional link between FGF and Indian hedgehog signaling and T3. These novel observations suggest that the cartilage matrix and especially HSPGs are critical mediators of the skeletal response to thyroid hormone. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16223867&query_hl=1 ER - TY - JFULL T1 - Characterization of skeletal phenotypes of TRalpha1 and TRbeta mutant mice: implications for tissue thyroid status and T3 target gene expression. A1 - O'Shea, PJ A1 - Bassett, JH A1 - Cheng, SY A1 - Williams, GR J1 - Nucl Recept Signal Y1 - 2006/// VL - 4 SN - 1550-7629 SP - e011 EP - e011 N2 - Bone development is extremely sensitive to alterations in thyroid status. Recently, we analyzed the skeletal phenotypes of mice with the dominant negative resistance to thyroid hormone (RTH) mutation PV targeted to either the thyroid hormone receptor (TR) alpha1 or beta gene. This perspective summarizes our findings to date and explores the wider implications for thyroid status and T3 target gene expression in individual tissues. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16862217&query_hl=1 ER - TY - JFULL T1 - Oxyntomodulin : a novel potential treatment for obesity. A1 - Druce, MR A1 - Bloom, SR J1 - Treat Endocrinol Y1 - 2006/// VL - 5 SN - 1175-6349 SP - 265 EP - 272 N2 - The prevalence of obesity is increasing rapidly and the associated morbidity and mortality has led to an urgent need for potential therapeutic targets to reduce appetite and food intake. Gut hormones released after eating that coordinate digestive activity and promote satiety are novel potential treatments for obesity. Oxyntomodulin is a gut hormone that is produced by the L cells in the small intestine and reduces food intake. It is timely to review some of the original literature on oxyntomodulin, to evaluate what is already known about the peptide, and also to set the recent findings on its effects on food intake and bodyweight into context.Recent studies have shown that long-term peripheral administration of oxyntomodulin to rats leads to reduced food intake and reduced weight gain. Studies in humans have demonstrated that acute administration reduces food intake by 19%. When given preprandially by subcutaneous injection three times daily, oxyntomodulin resulted in a reduction in food intake and mean weight loss of 2.8kg over 4 weeks. Oxyntomodulin thus represents a potential therapy for obesity.The mechanism of action of oxyntomodulin is not known. Current evidence suggests that it acts via the glucagon-like peptide 1 (GLP-1) receptor. There may be an additional receptor in the gastric mucosa mediating its effects on gastric acid secretion. Although oxyntomodulin probably acts via the GLP-1 receptor, the two peptides differentially regulate food intake and energy expenditure in the mouse.Oxyntomodulin represents a potential therapy for obesity. Further work will help to clarify its mechanisms of action. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17002486&query_hl=1 ER - TY - JFULL T1 - The effects of an aromatase inhibitor (anastrozole) or sulfatase inhibitor (STX64) on androgen concentrations in postmenopausal women with breast cancer. A1 - Stanway, SJ A1 - Purohit, A A1 - Woo, LLW A1 - Stanczyk, FZ A1 - Potter, BVL A1 - Folkherd, EJ A1 - Dowsett, M A1 - Coombes, RC A1 - Reed, MJ J1 - BREAST CANCER RES TR Y1 - 2006/01// VL - 100 SN - 0167-6806 SP - S189 EP - S189 ER - TY - JFULL T1 - The potential role of steroid sulfatase and organic anion transporter protein B mRNA expression as a prognostic markers in breast cancer. A1 - Al Sarakbi, W A1 - Salhab, M A1 - Reed, MJ A1 - Jiang, WG A1 - Mokbel, K J1 - BREAST CANCER RES TR Y1 - 2006/01// VL - 100 SN - 0167-6806 SP - S270 EP - S270 ER - TY - JFULL T1 - Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. A1 - le Roux, CW A1 - Aylwin, SJ A1 - Batterham, RL A1 - Borg, CM A1 - Coyle, F A1 - Prasad, V A1 - Shurey, S A1 - Ghatei, MA A1 - Patel, AG A1 - Bloom, SR J1 - Ann Surg Y1 - 2006/01// VL - 243 SN - 0003-4932 SP - 108 EP - 114 N2 - OBJECTIVE: To study the effect of bariatric surgery on the entero-hypothalamic endocrine axis of humans and rodents. BACKGROUND: Bariatric surgery is the most effective obesity treatment as it achieves substantial and sustained weight loss. Glycemic control and enhanced satiation improve before substantial weight loss occurs. Gut peptides, acting both peripherally and centrally, contribute to glycemic control and regulate food intake. METHODS: We examined meal-stimulated responses of insulin, ghrelin, peptide YY (PYY), glucagon-like-peptide-1 (GLP-1), and pancreatic polypeptide (PP) in humans and rodents following different bariatric surgical techniques. RESULTS: Compared with lean and obese controls, patients following Roux-en-Y gastric bypass (RYGB) had increased postprandial plasma PYY and GLP-1 favoring enhanced satiety. Furthermore, RYGB patients had early and exaggerated insulin responses, potentially mediating improved glycemic control. None of these effects were observed in patients losing equivalent weight through gastric banding. Leptin, ghrelin, and PP were similar in both the surgical groups. Using a rodent model of jejuno-intestinal bypass (JIB), we showed elevated PYY and GLP-1 in JIB rats compared with sham-operated rats. Moreover, exogenous PYY reduced food intake and blockade of endogenous PYY increased food intake. Thus, higher plasma PYY following JIB may contribute to reduced food intake and contribute to weight loss. CONCLUSIONS: Following RYGB and JIB, a pleiotropic endocrine response may contribute to the improved glycemic control, appetite reduction, and long-term changes in body weight. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16371744&query_hl=1 ER - TY - JFULL T1 - Acculturation and diabetes among Hispanics: evidence from the 1999-2002 National Health and Nutrition Examination Survey. A1 - Mainous, AG A1 - Majeed, A A1 - Koopman, RJ A1 - Baker, R A1 - Everett, CJ A1 - Tilley, BC A1 - Diaz, VA J1 - Public Health Rep Y1 - 2006/01// VL - 121 SN - 0033-3549 SP - 60 EP - 66 N2 - OBJECTIVE: Hispanic individuals in the United States have a greater prevalence of diabetes mellitus than non-Hispanic white individuals; however, it is unclear whether Hispanics' risk of diabetes differs based on their level of acculturation. The purpose of our research was to examine acculturation among Hispanic Americans with respect to prevalence and control of diabetes. METHODS: We conducted an analysis of the National Health and Nutrition Examination Survey (NHANES), 1999-2002, a nationally representative sample of the noninstitutionalized U.S. population. We evaluated data on Hispanic adults (> or = 18 years of age, unweighted n=2,696), analyzing diagnosed diabetes, glycemic blood pressure and lipid control, and diabetes complications according to acculturation as measured by language and birth outside the United States. RESULTS: Hispanics with low acculturation were more likely to be without a routine place for health care, have no health insurance, and have low levels of education. In adjusted analyses, individuals with low acculturation, measured by language, were more likely to have diabetes (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.02, 3.54). Among individuals with diagnosed diabetes, no significant association was yielded between acculturation and diabetes control. However, individuals with low language acculturation were more likely to have the diabetes complication of peripheral neuropathy (OR 4.01, 95% CI 1.40, 11.48). CONCLUSIONS: Acculturation as measured through language is associated with diabetes and complications among Hispanics even after controlling for a variety of demographic characteristics including health insurance and education. The findings suggest that even within a "single" minority ethnic group, there are differences in disease prevalence and complications and access to health care. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16416699&query_hl=1 ER - TY - JFULL T1 - Interventions for improving patients' trust in doctors and groups of doctors. A1 - McKinstry, B A1 - Ashcroft, RE A1 - Car, J A1 - Freeman, GK A1 - Sheikh, A J1 - Cochrane Database Syst Rev Y1 - 2006/// VL - 3 SN - 1469-493X SP - CD004134 EP - CD004134 N2 - BACKGROUND: Trust is a fundamental component of the patient-doctor relationship and is associated with increased satisfaction, adherence to treatment, and continuity of care. It is not clear if there are interventions known to be effective in enhancing patient trust in doctors. OBJECTIVES: To assess the effects of interventions intended to improve a patient's trust in the doctor or a group of doctors. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1 2003), MEDLINE(1966 to week 4 2003), EMBASE (1985 to July 2003), Health Star (1975 to July 2004), PsycINFO (1967 to July 2004), CINAHL (1982 to June 2003), LILACS (1982 to April 2003), African Trials Register (1948 to April 2003), African Health Anthology (1924 to April 2003), Dissertation Abstracts International (1861 to April 2003) and the bibliographies of studies assessed for inclusion. We also searched the bibliographies of studies assessed for inclusion, and contacted researchers active in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs), controlled clinical trials, controlled before and after studies, and interrupted time series studies of interventions (informative, educational, behavioural, organisational) directed at doctors or patients (or carers) where trust was assessed as a primary or secondary outcome. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Three RCTs, all published in English and set in North American primary care, and involving 1916 participants, were included. There was considerable heterogeneity in terms of aims, format and content of the interventions. One trial of a training intervention for family doctors to improve communication behaviours (20 doctors assessed by 414 patients) showed no effect on trust. The other two interventions were patient focussed. One explored the impact on trust of disclosing physician incentives to patients (n= 918) in a Health Maintenance Organisation (HMO) and showed no diminution in trust. Another investigated the effect of induction visits on new HMO members' (n=564) trust in their HMO doctors. Trust in doctors rose compared with control following the visit for one type of induction visit, the group visit (Trust out of 10 (standard deviation (SD)) was 8.8 (1.5) and 7.1 (2.2), difference 1.7, (95% confidence interval 1.22 to 2.18)). However there were many drop-outs and analysis was not on intention to treat. AUTHORS' CONCLUSIONS: Overall there remains insufficient evidence to conclude that any intervention may increase or decrease trust in doctors. Further trials are required to explore the impact of policy changes, guidelines and specific doctors' training on patients' trust. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16856033&query_hl=1 ER - TY - JFULL T1 - Adiponectin, type 2 diabetes and the metabolic syndrome: lessons from human genetic studies. A1 - Vasseur, F A1 - Meyre, D A1 - Froguel, P J1 - Expert Rev Mol Med Y1 - 2006/// VL - 8 SN - 1462-3994 SP - 1 EP - 12 N2 - Adiponectin, a protein exclusively secreted by adipose tissue but present at low levels in obesity, is now widely recognised as a key determinant of insulin sensitivity and of protection against obesity-associated metabolic syndrome. In this review we explain how genetic findings have contributed to a better understanding of the physiological role of adiponectin in humans. The adiponectin-encoding gene, ADIPOQ (ACDC), is very polymorphic: many frequent exonic synonymous, intronic and promoter single-nucleotide polymorphisms (SNPs) have been identified, as well as a few rare exonic amino acid substitutions. Several of these variations additively contribute to the modulation of adiponectin level and function, and associate with insulin sensitivity, type 2 diabetes and vascular complications of obesity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17112391&query_hl=1 ER - TY - JFULL T1 - Acylated ghrelin stimulates food intake in the fed and fasted states but desacylated ghrelin has no effect. A1 - Neary, NM A1 - Druce, MR A1 - Small, CJ A1 - Bloom, SR J1 - Gut Y1 - 2006/01// VL - 55 SN - 0017-5749 SP - 135 EP - 135 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16344585&query_hl=1 ER - TY - JFULL T1 - Functional characterization of calcium sensing receptor polymorphisms and absence of association with indices of calcium homeostasis and bone mineral density A1 - Harding, B A1 - Curley, A J A1 - Hannan, F M A1 - Christie, P T A1 - Bowl, M R A1 - Turner, J J O A1 - Barber, M A1 - Gillham-Nasenya, I A1 - Hampson, G A1 - Spector, T D A1 - Thakker, R V J1 - Clinical Endocrinology Y1 - 2006/// IS - 5 VL - 65 PB - Blackwell Publishing Limited SN - 0300-0664 SP - 598 EP - 605 ER - TY - JFULL T1 - The role of 17beta-hydroxysteroid dehydrogenases in modulating the activity of 2-methoxyestradiol in breast cancer cells. A1 - Newman, SP A1 - Ireson, CR A1 - Tutill, HJ A1 - Day, JM A1 - Parsons, MF A1 - Leese, MP A1 - Potter, BV A1 - Reed, MJ A1 - Purohit, A J1 - Cancer Res Y1 - 2006/01/01/ VL - 66 SN - 0008-5472 SP - 324 EP - 330 N2 - The bis-sulfamoylated derivative of 2-methoxyestradiol (2-MeOE2), 2-methoxyestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE), has shown potent antiproliferative and antiangiogenic activity in vitro and inhibits tumor growth in vivo. 2-MeOE2bisMATE is bioavailable, in contrast to 2-MeOE2 that has poor bioavailability. In this study, we have examined the role of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 2 in the metabolism of 2-MeOE2. In MDA-MB-231 cells, which express high levels of 17beta-HSD type 2, and in MCF-7 cells transfected with 17beta-HSD type 2, high-performance liquid chromatography analysis showed that a significant proportion of 2-MeOE2 was metabolized to inactive 2-methoxyestrone. Furthermore, MCF-7 cells transfected with 17beta-HSD type 2 were protected from the cytotoxic effects of 2-MeOE2. In contrast, no significant metabolism of 2-MeOE2bisMATE was detected in transfected cells and 17beta-HSD type 2 transfection did not offer protection against 2-MeOE2bisMATE cytotoxicity. This study may go some way to explaining the poor bioavailability of 2-MeOE2, as the gastrointestinal mucosa expresses high levels of 17beta-HSD type 2. In addition, this study shows the value of synthesizing sulfamoylated derivatives of 2-MeOE2 with C17-position modifications as these compounds have improved bioavailability and potency both in vitro and in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16397246&query_hl=1 ER - TY - JFULL T1 - Less than 50% of variation in HDL cholesterol between and within individuals, is explained by established predictors. A1 - Jeffs, JA A1 - Godsland, IF A1 - Johnston, DG J1 - Atherosclerosis Y1 - 2006/01// VL - 184 SN - 0021-9150 SP - 178 EP - 187 N2 - Variation in serum high density lipoprotein cholesterol (HDL-C) concentrations is believed to be largely explained by triglycerides, but this has been mainly explored in cross-sectional analyses. Eight hundred and eighty one white male participants in a health screening program attended on a total of 2158 occasions for measurements that included fasting HDL-C, low density lipoprotein cholesterol (LDL-C) and homeostasis model assessment insulin resistance (HOMA-R). Baseline, change between-visit and repeated-measures regression models were used to analyse predictors of between- and within-individual variation in HDL-C. Independent predictors of between-individual variation included serum triglycerides (20.3 or 19.6% of the variance explained, depending on the model used), body mass index (BMI: 4.7 and 4.3%), cigarette smoking (3.3 and 1.5%) and alcohol consumption (0.4 and 1.1%). Within-individual variation in HDL-C was explained by changes in serum triglycerides (4.7 and 7.5%) and BMI (5.3 and 2.9%). In multivariate models, 24.3 and 24.9% of between-individual variation in HDL-C, and 7.9 and 8.8% of within-individual variation could be explained, depending on the model used. Sixty percent of the variation in HDL-C was due to unobserved factors. The majority of variation in HDL-C remains to be explained by influences other than the conventional variables: triglyceride and LDL cholesterol concentrations, insulin resistance, smoking and alcohol. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15907857&query_hl=1 ER - TY - JFULL T1 - Obesity susceptibility CART gene polymorphism contributes to bone remodeling in postmenopausal women. A1 - Guérardel, A A1 - Tankó, LB A1 - Boutin, P A1 - Christiansen, C A1 - Froguel, P J1 - Osteoporos Int Y1 - 2006/01// VL - 17 SN - 0937-941X SP - 156 EP - 157 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16228103&query_hl=1 ER - TY - JFULL T1 - Analysis of common PTPN1 gene variants in type 2 diabetes, obesity and associated phenotypes in the French population. A1 - Cheyssac, C A1 - Lecoeur, C A1 - Dechaume, A A1 - Bibi, A A1 - Charpentier, G A1 - Balkau, B A1 - Marre, M A1 - Froguel, P A1 - Gibson, F A1 - Vaxillaire, M J1 - BMC Med Genet Y1 - 2006/// VL - 7 SN - 1471-2350 SP - 44 EP - 44 N2 - BACKGROUND: The protein tyrosine phosphatase-1B, a negative regulator for insulin and leptin signalling, potentially modulates glucose and energy homeostasis. PTP1B is encoded by the PTPN1 gene located on chromosome 20q13 showing linkage with type 2 diabetes (T2D) in several populations. PTPN1 gene variants have been inconsistently associated with T2D, and the aim of our study was to investigate the effect of PTPN1 genetic variations on the risk of T2D, obesity and on the variability of metabolic phenotypes in the French population. METHODS: Fourteen single nucleotide polymorphisms (SNPs) spanning the PTPN1 locus were selected from previous association reports and from HapMap linkage disequilibrium data. SNPs were evaluated for association with T2D in two case-control groups with 1227 cases and 1047 controls. Association with moderate and severe obesity was also tested in a case-control study design. Association with metabolic traits was evaluated in 736 normoglycaemic, non-obese subjects from a general population. Five SNPs showing a trend towards association with T2D, obesity or metabolic parameters were investigated for familial association. RESULTS: From 14 SNPs investigated, only SNP rs914458, located 10 kb downstream of the PTPN1 gene significantly associated with T2D (p = 0.02 under a dominant model; OR = 1.43 [1.06-1.94]) in the combined sample set. SNP rs914458 also showed association with moderate obesity (allelic p = 0.04; OR = 1.2 [1.01-1.43]). When testing for association with metabolic traits, two strongly correlated SNPs, rs941798 and rs2426159, present multiple consistent associations. SNP rs2426159 exhibited evidence of association under a dominant model with glucose homeostasis related traits (p = 0.04 for fasting insulin and HOMA-B) and with lipid markers (0.02 = p = 0.04). Moreover, risk allele homozygotes for this SNP had an increased systolic blood pressure (p = 0.03). No preferential transmission of alleles was observed for the SNPs tested in the family sample. CONCLUSION: In our study, PTPN1 variants showed moderate association with T2D and obesity. However, consistent associations with metabolic variables reflecting insulin resistance and dyslipidemia are found for two intronic SNPs as previously reported. Thus, our data indicate that PTPN1 variants may modulate the lipid profile, thereby influencing susceptibility to metabolic disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16677372&query_hl=1 ER - TY - JFULL T1 - Use of a sulfatase and aromatase inhibitor in combination for the treatment of human breast cancer. A1 - Foster, PA A1 - Chander, SK A1 - Newman, SP A1 - Jhalli, R A1 - Woo, LLW A1 - Potter, BVL A1 - Reed, MJ A1 - Purohit, A J1 - BREAST CANCER RES TR Y1 - 2006/01// VL - 100 SN - 0167-6806 SP - S188 EP - S188 ER - TY - JFULL T1 - Measurement of gut hormones in plasma. A1 - Taheri, S A1 - Ghatei, M A1 - Bloom, S J1 - Methods Mol Biol Y1 - 2006/// VL - 324 SN - 1064-3745 SP - 213 EP - 233 N2 - The gastrointestinal tract is the largest endocrine organ and holds a special place in endocrinology since the concept of blood-borne communication between cells was first established through experiments on the gut. Gut peptide hormones and neurotransmitters regulate the complex processes of digestion, motility, epithelial growth, and integrity. Investigation of this complex endocrine organ has depended on the development of sensitive and specific radioimmunoassay. Radioimmunoassays have also increased our understanding of pathophysiological processes affecting the gut, including rare gastroenteropancreatic neuroendocrine tumours. The object of this chapter is to describe the techniques used in the radioimmunoassay of common gastrointestinal hormones. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16761381&query_hl=1 ER - TY - JFULL T1 - Trends in deaths related to drug misuse in England and Wales, 1993-2004. A1 - Morgan, O A1 - Griffiths, C A1 - Toson, B A1 - Rooney, C A1 - Majeed, A A1 - Hickman, M J1 - Health Stat Q Y1 - 2006/// SN - 1465-1645 SP - 23 EP - 27 N2 - In this article we report trends in deaths related to drug misuse in England and Wales from 1993 to 2004, looking particularly at the period between 1999 and 2004, for which there was a Government target to reduce these deaths by 20 per cent. Although there was an overall decline in deaths related to drug misuse between 1999 and 2004, the percentage reduction, at 9 per cent, was less than the Government target. There was an increase in deaths between 2003 and 2004, largely accounted for by deaths involving heroin/methadone and morphine. Mortality rates were highest in young adults and an increase in mortality rates within this group appears to have been the driver behind rising mortality trends during the 1990s. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16972692&query_hl=1 ER - TY - JFULL T1 - How Islam changed medicine. A1 - Majeed, A J1 - BMJ Y1 - 2005/12/24/ VL - 331 SN - 1468-5833 SP - 1486 EP - 1487 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16373721&query_hl=1 ER - TY - JFULL T1 - 2-Substituted estradiol bis-sulfamates: SAR, interaction with CAII and anti-tumor activity. A1 - Leese, MP A1 - Jourdan, F A1 - Kasprzyk, PG A1 - de Simone, G A1 - Newman, SP A1 - Purohit, A A1 - Supuran, CT A1 - Reed, MJ A1 - Potter, BV J1 - CLIN CANCER RES Y1 - 2005/12/15/ VL - 11 SN - 1078-0432 SP - 9091S EP - 9091S ER - TY - JFULL T1 - Implantation of fibre encapsulated RIN 1056a cells transfected with NPY cDNA into the lateral ventricle of rats alters body weight. A1 - Mahmoodi, M A1 - Gardiner, JV A1 - Asadi Karam, GR A1 - Khaksari, M A1 - Murphy, KG A1 - Ghatei, MA A1 - Bloom, SR J1 - Regul Pept Y1 - 2005/12/15/ VL - 132 SN - 0167-0115 SP - 80 EP - 84 N2 - Neuropeptide Y (NPY) is a hypothalamic neuropeptide thought to play an important role in the regulation of food intake and energy expenditure. Our aim was to over-express bioactive NPY in the lateral ventricle by implanting cells transfected with NPY cDNA. Cells from the RIN 1056a clonal rat islet cell line were transfected with NPY cDNA. Radioimmunoassay, chromatography and receptor binding assays were used to ensure the secreted NPY was bioactive, before and after implantation. NPY cDNA transfected and untransfected control cells were encapsulated in PVDF hollow fibres to prevent tumour formation and implanted into the lateral ventricle of male Wistar rats. The effects on body weight and food intake were measured for 15 days. Animals implanted with NPY cDNA transfected RIN 1056a cells showed a greater rise in body weight than controls. This difference was statistically significant five days after implantation, and remained so until the end of the experiment. Cumulative food intake was also increased in rats implanted with NPY cDNA transfected RIN 1056a cells, but this difference failed to reach statistical significance. We have demonstrated that implantation of NPY over-expressing cells into the lateral hypothalamus of rats increases body weight gain. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16202459&query_hl=1 ER - TY - JFULL T1 - Soil erodibility and erosion hazard: Extending these cornerstone soil conservation concepts to headwater streams in the forestry estate in Tasmania A1 - McIntosh, P A1 - Laffan, M J1 - FOREST ECOL MANAG Y1 - 2005/12/10/ VL - 220 SN - 0378-1127 SP - 128 EP - 139 N2 - Soil erodibility is defined as 'the inherent susceptibility of soil particles or aggregates to become detached or transported by erosive agents such as rainfall, runoff, throughflow, wind or frost'. In Tasmania soil erodibility is routinely assessed using a combination of standard laboratory methods and observations of profile characteristics. Five soil erodibility classes are defined: low, moderate, moderate-high, high and very high.A plot of soil erodibility against slope produces an erosion hazard matrix. Erosion hazard increases with increasing soil erodibility or slope. Informal matrices have been used in the Tasmanian Forest Practices Code to define the harvest machinery and cultivations techniques appropriate for different soil erodibility/slope combinations. We are formalising these matrices to define five erosion hazard classes, ranging from Class A (low erosion hazard) to Class E (very high erosion hazard), and extending the erosion hazard concept to riparian zones.At present forest streams in Tasmania receive riparian protection related to the size of the upstream catchment. Streams are classified into Class 1 (largest), Class 2, Class 3 and Class 4 (headwaters). Class 4 streams, which have a catchment area of 50 ha or less, are least protected. In the Tasmanian Forest Practices Code the standard prescription for Class 4 streams is to allow harvest of timber trees but to apply a 10 m machinery exclusion zone. Protection can be upgraded for biological conservation reasons or by the recommendation of a Forest Practices Officer or a specialist advisor.Observations in >400 headwater 4 streams in forestry coupes (harvest areas) indicates that, within a stream or its 0-10 m riparian zone, the incidence of seven 'erosion features' (channel >4 m wide; recent boulder movement; near-vertical stream banks > 1 m high; significant sediment accumulation; tunnel gully, gully and rill erosion; sheet erosion; landslides or slumps) is correlated with riparian erosion hazard class. For 66% of streams in coupes in which advice was sought for environmental protection reasons, measures to provide greater protection than the standard 0-10 m machinery exclusion zone were recommended. These measures ranged from wider machinery-exclusion zones where riparian zones are steep, to 20 m no-harvest streamside reserves where erosion risks are considered to be high. This paper formalises the decision-making process for applying such protection measures to 'at-risk' headwater streams.Prescribing headwater stream riparian buffer types and widths using the erosion hazard and erosion features concepts is considered to be superior to using riparian slope alone (as commonly done in overseas codes of practice) because the defined erosion hazard classes and erosion features identify the most vulnerable streams and riparian zones in the proposed forest harvest area, allow environmental risks to be objectively assessed, and tailor protection measures to the specific risks identified. The proposed system is generic and likely to be applicable to headwater streams in other temperate regions. (c) 2005 Elsevier B.V. All rights reserved. ER - TY - JFULL T1 - The ageing population of the United Kingdom and cardiovascular disease. A1 - Majeed, A A1 - Aylin, P J1 - BMJ Y1 - 2005/12/10/ VL - 331 SN - 1468-5833 SP - 1362 EP - 1362 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16339247&query_hl=1 ER - TY - JFULL T1 - Immunohistochemical expression of somatostatin (SST) 2, 3 and 5 receptor subtypes in the cat trigeminocervical complex (TCC) and hypothalamus A1 - Classey, JD A1 - Levy, MJ A1 - Meeran, K A1 - Goadsby, PJ J1 - CEPHALALGIA Y1 - 2005/12// VL - 25 SN - 0333-1024 SP - 1204 EP - 1204 ER - TY - JFULL T1 - Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1 A1 - Grasberger, H A1 - Vaxillaire, M A1 - Pannain, S A1 - Beck, JC A1 - Mimouni-Bloch, A A1 - Vatin, V A1 - Vassart, G A1 - Froguel, P A1 - Refetoff, S J1 - HUM GENET Y1 - 2005/12// VL - 118 SN - 0340-6717 SP - 348 EP - 355 N2 - Permanent congenital hypothyroidism is the most prevalent inborn endocrine disorder, and principally due to developmental defects leading to absent, ectopic or hypoplastic thyroid gland. Although commonly regarded as sporadic disease, nonsyndromic thyroid hypoplasia has, in rare cases, been attributed to inherited defects in PAX8 and the TSHR gene. The shared clinical picture caused by these defects is a variable degree of thyrotropin resistance (RTSH [MIM 275200]), accompanied in its severe form by thyroid gland hypoplasia. We recently identified six extended kindreds with autosomal dominant RTSH, only one of which was linked to a mutation in the PAX8 candidate gene. Genome wide scans conducted in two of the remaining five families revealed independently significant linkage to chromosome 15q25.3-26.1, with maximum multipoint LOD scores of 8.51 and 4.31. Linkage to this novel locus was replicated (P < 0.01) in each of the three remaining kindreds. Fine mapping of key recombinants in the largest family localized the causative gene within a 3 cM/2.9 Mb interval. Thus, we report the first locus for congenital nongoitrous hypothyroidism identified by a genome wide screening approach. ER - TY - JFULL T1 - Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta. A1 - O'Shea, PJ A1 - Bassett, JH A1 - Sriskantharajah, S A1 - Ying, H A1 - Cheng, SY A1 - Williams, GR J1 - Mol Endocrinol Y1 - 2005/12// VL - 19 SN - 0888-8809 SP - 3045 EP - 3059 N2 - Thyroid hormone (T(3)) regulates bone turnover and mineralization in adults and is essential for skeletal development. Surprisingly, we identified a phenotype of skeletal thyrotoxicosis in T(3) receptor beta(PV) (TRbeta(PV)) mice in which a targeted frameshift mutation in TRbeta results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TRalpha1(PV) mice in which the same PV mutation was targeted to TRalpha1. In contrast to TRbeta(PV) mice, TRalpha1(PV) mutants exhibited skeletal hypothyroidism with delayed endochondral and intramembranous ossification, severe postnatal growth retardation, diminished trabecular bone mineralization, reduced cortical bone deposition, and delayed closure of the skull sutures. Skeletal hypothyroidism in TRalpha1(PV) mutants was accompanied by impaired GH receptor and IGF-I receptor expression and signaling in the growth plate, whereas GH receptor and IGF-I receptor expression and signaling were increased in TRbeta(PV) mice. These data indicate that GH receptor and IGF-I receptor are physiological targets for T(3) action in bone in vivo. The divergent phenotypes observed in TRalpha1(PV) and TRbeta(PV) mice arise because the pituitary gland is a TRbeta-responsive tissue, whereas bone is TRalpha responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16051666&query_hl=1 ER - TY - JFULL T1 - Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. A1 - Murray, CD A1 - Martin, NM A1 - Patterson, M A1 - Taylor, SA A1 - Ghatei, MA A1 - Kamm, MA A1 - Johnston, C A1 - Bloom, SR A1 - Emmanuel, AV J1 - Gut Y1 - 2005/12// VL - 54 SN - 0017-5749 SP - 1693 EP - 1698 N2 - BACKGROUND: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis. METHODS: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)-3). RESULTS: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p < 0.05) but did not correlate with GER. CONCLUSIONS: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16085693&query_hl=1 ER - TY - JFULL T1 - Fat digestion is required for suppression of ghrelin and stimulation of peptide YY and pancreatic polypeptide secretion by intraduodenal lipid. A1 - Feinle-Bisset, C A1 - Patterson, M A1 - Ghatei, MA A1 - Bloom, SR A1 - Horowitz, M J1 - Am J Physiol Endocrinol Metab Y1 - 2005/12// VL - 289 SN - 0193-1849 SP - E948 EP - E953 N2 - Stimulation of cholecystokinin and glucagon-like peptide-1 secretion by fat is mediated by the products of fat digestion. Ghrelin, peptide YY (PYY), and pancreatic polypeptide (PP) appear to play an important role in appetite regulation, and their release is modulated by food ingestion, including fat. It is unknown whether fat digestion is a prerequisite for their suppression (ghrelin) or release (PYY, PP). Moreover, it is not known whether small intestinal exposure to fat is sufficient to suppress ghrelin secretion. Our study aimed to resolve these issues. Sixteen healthy young males received, on two separate occasions, 120-min intraduodenal infusions of a long-chain triglyceride emulsion (2.8 kcal/min) 1) without (condition FAT) or 2) with (FAT-THL) 120 mg of tetrahydrolipstatin (THL, lipase inhibitor), followed by a standard buffet-style meal. Blood samples for ghrelin, PYY, and PP were taken throughout. FAT infusion was associated with a marked, and progressive, suppression of plasma ghrelin from t = 60 min (P < 0.001) and stimulation of PYY from t = 30 min (P < 0.01). FAT infusion also stimulated plasma PP (P < or = 0.01), and the release was immediate. FAT-THL completely abolished the FAT-induced changes in ghrelin, PYY, and PP. In response to the meal, plasma ghrelin was further suppressed, and PYY and PP stimulated, during both FAT and FAT-THL infusions. In conclusion, in healthy humans, 1) the presence of fat in the small intestine suppresses ghrelin secretion, and 2) fat-induced suppression of ghrelin and stimulation of PYY and PP is dependent on fat digestion. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15998659&query_hl=1 ER - TY - JFULL T1 - Agouti related protein (AgRP) is upregulated in Cushing's syndrome. A1 - Dhillo, WS A1 - Gardiner, JV A1 - Castle, L A1 - Bewick, GA A1 - Smith, KL A1 - Meeran, K A1 - Todd, JF A1 - Ghatei, MA A1 - Bloom, SR J1 - Exp Clin Endocrinol Diabetes Y1 - 2005/12// VL - 113 SN - 0947-7349 SP - 602 EP - 606 N2 - Alpha melanocyte-stimulating hormone (alpha-MSH) is an agonist at the melanocortin 3 (MC3-R) and melanocortin 4 (MC4-R) receptors. Alpha-MSH stimulates corticosterone release from rat and human adrenal cells. Patients with Cushing's syndrome have elevated levels of serum alpha-MSH. Agouti related protein (AgRP) is an endogenous antagonist at the MC3-R and MC4-R and is expressed in the rat adrenal cortex. AgRP antagonises alpha-MSH-induced corticosterone release from rat and bovine adrenal cells. This suggests that AgRP may have an inhibitory paracrine role in the adrenal gland. We measured adrenal AgRP mRNA expression and circulating AgRP in 2 patients with Cushing's syndrome and controls. Adrenal AgRP mRNA expression and plasma AgRP were higher in the patients with Cushing's syndrome compared to controls. Plasma AgRP in the patients with Cushing's syndrome following bilateral adrenalectomy and hydrocortisone replacement were similar to the levels seen in controls. Our results suggest that AgRP may have a novel inhibitory paracrine role in the human adrenal gland. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16320160&query_hl=1 ER - TY - JFULL T1 - [Adipocytokins, obesity and development of type 2 diabetes] A1 - Lacquemant, C A1 - Vasseur, F A1 - Leprêtre, F A1 - Froguel, P J1 - Med Sci (Paris) Y1 - 2005/12// VL - 21 Spec No SN - 0767-0974 SP - 10 EP - 18 N2 - Normal metabolic balance is maintained by a complex homeostatic system involving multiple tissues and organs. Acquired or inherited defects associated to environmental factors in any part of this system can lead to metabolic disorders such as the syndrome X which is presently a frequent syndrome in industrialized countries. It is characterized by a cluster of risk factors of atherosclerosis including insulin resistance, hyperinsulinemia, impaired glucose tolerance or type 2 diabetes, hypertension, dyslipidemia, and coagulation abnormalities. Its pathophysiology is likely to involve insulin resistance at the level of both skeletal muscle and visceral adipose tissue and altered fluxes of metabolic substrates between these tissues that in turn impair liver metabolism. Therapeutic intervention favours at present diet and exercise prescriptions. In addition, if necessary, specific treatment of the metabolic disorders is required. In the treatment of insulin resistance, new promising drugs are likely to be used in the next future. In this regard, adipose tissue, once thought to function primarily as a passive depot for the storage of excess lipid, is now understood to play a much more active role in metabolic regulation, secreting a variety of metabolic hormones and actively functioning to prevent deleterious lipid accumulation in other tissues and to modulate the insulin resistance. Here, we review new advances in our understanding of mechanisms leading to insulin resistance and type 2 diabetes from the perspective of the role and interactions of recently identified adipocyte-specific chemical messengers, the adipocytokines, such as adiponectin, tumor necrosis factor-alpha, interleukin 6, and resistin. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16598899&query_hl=1 ER - TY - JFULL T1 - Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively. A1 - Neary, NM A1 - Small, CJ A1 - Druce, MR A1 - Park, AJ A1 - Ellis, SM A1 - Semjonous, NM A1 - Dakin, CL A1 - Filipsson, K A1 - Wang, F A1 - Kent, AS A1 - Frost, GS A1 - Ghatei, MA A1 - Bloom, SR J1 - Endocrinology Y1 - 2005/12// VL - 146 SN - 0013-7227 SP - 5120 EP - 5127 N2 - Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY(3-36) and GLP-1(7-36) inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY(3-36) with GLP-1(7-36) in rodents and man. Whereas high-dose PYY(3-36) (100 nmol/kg) and high-dose GLP-1(7-36) (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY(3-36) (1 nmol/kg) and GLP-1(7-36) (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY(3-36) or GLP-1(7-36) individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY(3-36) and GLP-1(7-36) in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-1(7-36) (0.4 pmol/kg.min), PYY(3-36) (0.4 pmol/kg.min), and PYY(3-36) (0.4 pmol/kg.min) + GLP-1(7-36) (0.4 pmol/kg.min) on four separate days. Energy intake from a buffet meal after combined PYY(3-36) + GLP-1(7-36) treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY(3-36) and GLP-1(7-36), cosecreted after a meal, may inhibit food intake additively. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16150917&query_hl=1 ER - TY - JFULL T1 - Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis. A1 - Barnard, JC A1 - Williams, AJ A1 - Rabier, B A1 - Chassande, O A1 - Samarut, J A1 - Cheng, SY A1 - Bassett, JH A1 - Williams, GR J1 - Endocrinology Y1 - 2005/12// VL - 146 SN - 0013-7227 SP - 5568 EP - 5580 N2 - Childhood hypothyroidism causes growth arrest with delayed ossification and growth-plate dysgenesis, whereas thyrotoxicosis accelerates ossification and growth. Thyroid hormone (T(3)) regulates chondrocyte proliferation and is essential for hypertrophic differentiation. Fibroblast growth factors (FGFs) are also important regulators of chondrocyte proliferation and differentiation, and activating mutations of FGF receptor-3 (FGFR3) cause achondroplasia. We investigated the hypothesis that T(3) regulates chondrogenesis via FGFR3 in ATDC5 cells, which undergo a defined program of chondrogenesis. ATDC5 cells expressed two FGFR1, four FGFR2, and one FGFR3 mRNA splice variants throughout chondrogenesis, and expression of each isoform was stimulated by T(3) during the first 6-12 d of culture, when T(3) inhibited proliferation by 50%. FGFR3 expression was also increased in cells treated with T(3) for 21 d, when T(3) induced an earlier onset of hypertrophic differentiation and collagen X expression. FGFR3 expression was reduced in growth plates from T(3) receptor alpha-null mice, which exhibit skeletal hypothyroidism, but was increased in T(3) receptor beta(PV/PV) mice, which display skeletal thyrotoxicosis. These findings indicate that FGFR3 is a T(3)-target gene in chondrocytes. In further experiments, T(3) enhanced FGF2 and FGF18 activation of the MAPK-signaling pathway but inhibited their activation of signal transducer and activator of transcription-1. FGF9 did not activate MAPK or signal transducer and activator of transcription-1 pathways in the absence or presence of T(3). Thus, T(3) exerted differing effects on FGFR activation during chondrogenesis depending on which FGF ligand stimulated the FGFR and which downstream signaling pathway was activated. These studies identify novel interactions between T(3) and FGFs that regulate chondrocyte proliferation and differentiation during chondrogenesis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16150908&query_hl=1 ER - TY - JFULL T1 - 1 and 2 mg 17beta-estradiol combined with sequential dydrogesterone have similar effects on the serum lipid profile of postmenopausal women. A1 - Stevenson, JC A1 - Rioux, JE A1 - Komer, L A1 - Gelfand, M J1 - Climacteric Y1 - 2005/12// VL - 8 SN - 1369-7137 SP - 352 EP - 359 N2 - OBJECTIVES: The aim of this study was to assess the effects of 1 and 2 mg 17beta-estradiol on serum lipid profile. Beneficial effects have been clearly established in previous studies with a 2 mg dose; further evidence was required to confirm the beneficial effects of a 1 mg dose. METHODS: This double-blind, placebo-controlled study involved 579 postmenopausal women randomized to oral treatment with placebo, 1 mg/day 17beta-estradiol sequentially combined with 5 or 10 mg/day dydrogesterone for the last 14 days of each 28-day cycle, or 2 mg/day 17beta-estradiol sequentially combined with 10 or 20 mg/day dydrogesterone for the last 14 days of each 28-day cycle. Treatment was continued for 26 cycles. RESULTS: High density lipoprotein (HDL) cholesterol levels were significantly (p<0.05) increased after 26 cycles in all active treatment groups compared with placebo. In addition, low density lipoprotein (LDL) cholesterol and lipoprotein(a) levels were significantly reduced, and apolipoprotein A1 and triglyceride levels were significantly increased, in all active treatment groups after 13 and 26 cycles. CONCLUSIONS: The results of this study clearly indicate that sequential combinations of either 1 or 2 mg 17beta-estradiol with dydrogesterone are associated with long-term, favorable changes in the serum lipid profile. There was no evidence that dydrogesterone compromised the 17beta-estradiol-induced improvements in lipid profile. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16390770&query_hl=1 ER - TY - JFULL T1 - Effects of thyroid status on bone metabolism: a primary role for thyroid stimulating hormone or thyroid hormone? A1 - Galliford, TM A1 - Murphy, E A1 - Williams, AJ A1 - Bassett, JH A1 - Williams, GR J1 - Minerva Endocrinol Y1 - 2005/12// VL - 30 SN - 0391-1977 SP - 237 EP - 246 N2 - Thyroid hormones are essential for normal skeletal growth and the maintenance of bone mass in adulthood, although their mechanism of action in bone is poorly understood. Hypothyroidism causes impaired bone formation and growth retardation whereas thyrotoxicosis results in accelerated growth, advanced bone age and decreased bone mass. Adults with thyrotoxicosis or a suppressed thyroid stimulating hormone (TSH) from any cause have an increased risk of osteoporotic fracture. Conventionally, bone loss in thyrotoxicosis has been regarded as a direct consequence of thyroid hormone excess acting locally on bone. Recently, however, it has been proposed that TSH may be a direct negative regulator of bone turnover acting via the TSH receptor on both osteoblasts and osteoclasts. Thus, TSH deficiency could be partly responsible for the skeletal loss seen in thyrotoxicosis. Here we provide an overview of the molecular actions of thyroid hormone in bone and discuss in detail the current evidence relating to a possible role for TSH in bone metabolism. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16319811&query_hl=1 ER - TY - JFULL T1 - Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. A1 - Dhillo, WS A1 - Chaudhri, OB A1 - Patterson, M A1 - Thompson, EL A1 - Murphy, KG A1 - Badman, MK A1 - McGowan, BM A1 - Amber, V A1 - Patel, S A1 - Ghatei, MA A1 - Bloom, SR J1 - J Clin Endocrinol Metab Y1 - 2005/12// VL - 90 SN - 0021-972X SP - 6609 EP - 6615 N2 - CONTEXT: Mutation of the G protein-coupled receptor 54 is associated with a failure of reproductive function. The endogenous neuropeptide agonist for G protein-coupled receptor 54, kisspeptin, potently stimulates the hypothalamic-pituitary-gonadal axis in rodents and primates. OBJECTIVE: The present study was designed to determine the effects of elevating circulating kisspeptin levels on LH, FSH, and testosterone in male volunteers. DESIGN: This was a double-blind, placebo-controlled, crossover study. Setting: This was a hospital-based study. PARTICIPANTS: Male volunteers (n = 6) were recruited. INTERVENTIONS: Each volunteer received a 90-min i.v. infusion of kisspeptin-54 (4 pmol/kg x min) and a control infusion of saline (0.9%) in random order. MAIN OUTCOME MEASURE: Plasma LH, FSH, and testosterone concentrations were measured. RESULTS: Kisspeptin-54 infusion significantly increased plasma LH, FSH, and testosterone concentrations compared with saline infusion (mean 90-min LH: kisspeptin, 10.8 +/- 1.5 vs. saline, 4.2 +/- 0.5 U/liter, P < 0.001; mean 90-min FSH: kisspeptin, 3.9 +/- 0.7 vs. saline, 3.2 +/- 0.6 U/liter, P < 0.001; mean 180-min testosterone: kisspeptin, 24.9 +/- 1.7 vs. saline, 21.7 +/- 2.2 nmol/liter, P < 0.001). The plasma half-life of kisspeptin-54 was calculated to be 27.6 +/- 1.1 min. The mean metabolic clearance rate was 3.2 +/- 0.2 ml/kg x min, and the volume of distribution was 128.9 +/- 12.5 ml/kg. CONCLUSION: Elevation of plasma concentrations of kisspeptin in human males significantly increases circulating LH, FSH, and testosterone levels. Kisspeptin infusion provides a novel mechanism for hypothalamic-pituitary-gonadal axis manipulation in disorders of the reproductive system. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16174713&query_hl=1 ER - TY - JFULL T1 - Endocrine (2) A1 - Meeran, K J1 - Medicine International Y1 - 2005/12// IS - 12 VL - 33 PB - The Medicine Publishing Company SN - 1357-3039 UR - http://www.extenza-eps.com/MPC/toc/medc/33/12 ER - TY - JFULL T1 - ACDC/adiponectin and PPAR-gamma gene polymorphisms: Implications for features of obesity A1 - Tanko, LB A1 - Siddiq, A A1 - Lecoeur, C A1 - Larsen, PJ A1 - Christiansen, C A1 - Walley, A A1 - Froguel, P J1 - OBES RES Y1 - 2005/12// VL - 13 SN - 1071-7323 SP - 2113 EP - 2121 N2 - Objective: The main Purpose of this Study was to investigate associations of single-nucleotide poly morphisms (SNPs) in the adipocyte Clq and collagen domain-containing (ACDC) gene and its regulator, the nuclear peroxisome proliferator-activated receptor (PPAR)-gamma gene, with body fat mass and its topographical distribution in postmenopausal women.Research Methods and Procedures: Participants were 1501 healthy women, 60 to 85 years old, who were genotyped for four SNPs in the ACDC gene (-11391G/A, -11377C/G +45T/G, +276G/T) and the Pro12Ala SNP in the PPAR-gamma gene. Total body fat mass and the central to peripheral fat mass ratio (CFM/PFM ratio) were measured using DXA. Adiponectin and homeostasis model assessment of insulin resistance were measured in 287 subjects.Results: The -11377C/G SNP was associated with adiponectin (p<0.001) and the CFM/PFM ratio (p=0.005); the G allele being associated with low adiponectin and high CFM/PFM ratio. Similar associations of adiponectin (p=0.0001) and the CFM/PFM ratio (p=0.002) characterized the 1_2 (G_G) promoter haplotype (11391G/A_11377C/G). Genotype variation of SNP Pro12AIa was associated with total body fat mass (p=0.04); women with GG being the most obese (p=0.01). The Ala/Ala (GG) genotype of Pro12Ala SNP interacted with the CC genotype of SNP-11377C/G in the determination of BMI (p=0.001), when analyzed using a codominant model.Discussion: Polymorphisms in the ACDC gene are associated with body fat distribution, whereas the Pro12Ala polymorphism in PPAR-gamma is associated with overall adiposity, apparently in interaction with an ACDC promoter SNP. ER - TY - JFULL T1 - Oestrogens and insulin secretion. A1 - Godsland, IF J1 - Diabetologia Y1 - 2005/11// VL - 48 SN - 0012-186X SP - 2213 EP - 2220 N2 - There is a persistent perception that oestrogens have an adverse effect on carbohydrate metabolism. It might therefore be expected that their use would result in a corresponding increase in the incidence of diabetes. Recent evidence from clinical trials suggesting that women on postmenopausal oestrogen hormone replacement therapy (HRT) have a reduced incidence of type 2 diabetes therefore appears paradoxical. Short-term supraphysiological oestrogen administration has an adverse effect on glucose tolerance, resulting from suppression of first-phase insulin secretion and increased insulin resistance. Oestrogen-induced increases in glucocorticoid activity could account for these effects. Oestrogen-induced deterioration in glucose tolerance is, however, accompanied by a reduction in fasting glucose, an effect that could be accounted for by glucagon antagonism. These short-term effects contrast with long-term preservation of insulin secretion and glucose homeostasis by oestrogens. In animal studies, ovariectomy is associated with decreased insulin secretion and increased risk of diabetes, whereas oestrogen administration protects against diabetes and increases the insulin response to glucose. The mechanism is uncertain, but direct effects on the pancreas via steroid receptors or indirect effects via oestrogen-induced glucagon antagonism and subclinical increases in glucocorticoids and growth hormone could all contribute. Recent evidence that HRT increases the risk of cardiovascular disease suggests that it should not be used for the prevention of diabetes, but the mechanism responsible for this benefit merits further investigation and might lead to new therapies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16193292&query_hl=1 ER - TY - JFULL T1 - Impaired insulin secretion after prenatal exposure to the Dutch famine A1 - de Rooij, SR A1 - Painter, RC A1 - Roseboom, TJ A1 - Phillips, DIW A1 - Osmond, C A1 - Barker, DJP A1 - Tanck, MW A1 - Michels, RPJ A1 - Godsland, IF A1 - Bossuyt, PMM A1 - Bleker, OP J1 - PEDIATR RES Y1 - 2005/11// VL - 58 SN - 0031-3998 SP - 1016 EP - 1017 ER - TY - JFULL T1 - Endocrine (1) A1 - Meeran, K J1 - Medicine International Y1 - 2005/11// IS - 11 VL - 33 PB - The Medicine Publishing Company SN - 1357-3039 UR - http://www.extenza-eps.com/MPC/toc/medc/33/11 ER - TY - JFULL T1 - Two-component graded deposition of biomolecules with a double-barreled nanopipette. A1 - Rodolfa, KT A1 - Bruckbauer, A A1 - Zhou, D A1 - Korchev, YE A1 - Klenerman, D J1 - Angew Chem Int Ed Engl Y1 - 2005/10/28/ VL - 44 SN - 1433-7851 SP - 6854 EP - 6859 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16249993&query_hl=1 ER - TY - JFULL T1 - Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiol mono- and bis-3-O-sulphamates. A1 - Raobaikady, B A1 - Reed, MJ A1 - Leese, MP A1 - Potter, BV A1 - Purohit, A J1 - Int J Cancer Y1 - 2005/10/20/ VL - 117 SN - 0020-7136 SP - 150 EP - 159 N2 - A natural metabolite of oestradiol (E2), 2-methoxyoestradiol (2-MeOE2), exerts both antitumour and antiangiogenic effects. 2-MeOE2 is currently in clinical trials for the treatment of a variety of cancers. We have previously shown that a number of sulphamoylated analogues of 2-MeOE2 possess enhanced potency and bioavailability with respect to 2-MeOE2. In our study, the effects of C-2-substituted E2 derivatives, with sulphamoylation at the C-3 and/or C-17 position, on ERalpha -ve MDA-MB-231 breast cancer cells were evaluated. Sulphamoylated derivatives were potent inhibitors of cell proliferation, and these effects were irreversible when compared to growth inhibitory effects induced by 2-MeOE2. Cell cycle analysis suggested that these derivatives caused cells to arrest at the G2-M phase of the cell cycle. Sulphamoylated analogues suppressed the clonogenic potential of MDA-MB-231 cells and also their growth on Matrigel culture substratum. Immunofluorescence studies showed fragmented nuclear bodies and an abnormal microtubule cytoskeleton in cells exposed to one of the potent compounds, 2-MeOE2-bis-sulphamate. In addition, these analogues induced phosphorylation of BCL-2, a protein considered to be the guardian of microtubule integrity. In each of the assays, the sulphamoylated derivatives were at least 10-fold more potent than the parent compound 2-MeOE2. In view of the enhanced potencies associated with sulphamoylated E2 derivatives in ERalpha -ve cells, these analogues should hold considerable therapeutic potential for the treatment of hormone-independent breast cancers. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15880363&query_hl=1 ER - TY - JFULL T1 - Aldosterone acts via an ATP autocrine/paracrine system: the Edelman ATP hypothesis revisited. A1 - Gorelik, J A1 - Zhang, Y A1 - Sánchez, D A1 - Shevchuk, A A1 - Frolenkov, G A1 - Lab, M A1 - Klenerman, D A1 - Edwards, C A1 - Korchev, Y J1 - Proc Natl Acad Sci U S A Y1 - 2005/10/18/ VL - 102 SN - 0027-8424 SP - 15000 EP - 15005 N2 - Aldosterone, the most important sodium-retaining hormone, was first characterized >50 years ago. However, despite numerous studies including the classical work of Isidore S. "Izzy" Edelman showing that aldosterone action depended on ATP production, the mechanism by which it activates sodium reabsorption via the epithelial sodium channel remains unclear. Here, we report experiments that suggest that one of the key steps in aldosterone action is via an autocrine/paracrine system. The hormone stimulates ATP release from the basolateral side of the target kidney cell. Prevention of ATP accumulation or its removal blocks aldosterone action. ATP then acts via a purinergic mechanism to produce contraction of small groups of adjacent epithelial cells. Patch clamping demonstrates that it is these contracted cells that have channel activity. With progressive recruitment of contracting cells, there is then a parallel increase in transepithelial electrical conductance. In common with other stimuli of sodium transport, this pathway involves phosphatidylinositol 3-kinase. Inhibition of phosphatidylinositol 3-kinase blocks both cell contraction and conductance. We put forward the hypothesis that redistribution of the cell volume caused by the lateral contraction results in apical swelling and that this change, in turn, disrupts the epithelial sodium channel interaction with the F-actin cytoskeleton, opening the channel and hence increasing sodium transport. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16230642&query_hl=1 ER - TY - JFULL T1 - Directing thrombin. A1 - Lane, DA A1 - Philippou, H A1 - Huntington, JA J1 - Blood Y1 - 2005/10/15/ VL - 106 SN - 0006-4971 SP - 2605 EP - 2612 N2 - Following initiation of coagulation as part of the hemostatic response to injury, thrombin is generated from its inactive precursor prothrombin by factor Xa as part of the prothrombinase complex. Thrombin then has multiple roles. The way in which thrombin interacts with its many substrates has been carefully scrutinized in the past decades, but until recently there has been little consideration of how its many functions are coordinated or directed. Any understanding of how it is directed requires knowledge of its structure, how it interacts with its substrates, and the role of any cofactors for its interaction with substrates. Recently, many of the interactions of thrombin have been clarified by crystal structure and site-directed mutagenesis analyses. These analyses have revealed common residues used for recognition of some substrates and overlapping surface exosites used for recognition by cofactors. As many of its downstream reactions are cofactor driven, competition between cofactors for exosites must be a dominant mechanism that determines the fate of thrombin. This review draws together much recent work that has helped clarify structure function relationships of thrombin. It then attempts to provide a cogent proposal to explain how thrombin activity is directed during the hemostatic response. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15994286&query_hl=1 ER - TY - JFULL T1 - Low-density lipoprotein receptor-related protein polymorphisms in patients with elevated factor VIII coagulant activity and venous thrombosis. A1 - Cunningham, N A1 - Laffan, MA A1 - Manning, RA A1 - O'Donnell, JS J1 - Blood Coagul Fibrinolysis Y1 - 2005/10// VL - 16 SN - 0957-5235 SP - 465 EP - 468 N2 - Elevated factor VIII coagulant activity (FVIII:C) levels (>150 IU/dl) represent a prevalent independent risk factor for venous thromboembolism (VTE). Low-density lipoprotein receptor-related protein (LRP) is involved in factor VIII clearance in vivo, and elevated FVIII:C was a feature of the LRP knockout mouse model. Three coding polymorphisms of LRP1 (exon 3, C766T; exon 14, A217V; and exon 39, D2080N), together with an insertion/deletion polymorphism within the first intron of lipoprotein receptor-associated protein (LRPAP1), have been identified. In addition, LRP1 2080D was recently reported to be associated with increased plasma FVIII:C levels in normal individuals. In this study, we investigated the role of these four polymorphisms in patients with objectively confirmed VTE and