By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 \u00d7 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits. \u00a9 2010 Nature America, Inc. All rights reserved.
\n \n\n \n \nAs islet transplantation increasingly enters the clinical arena, its coexistence with vascularized pancreas transplantation makes it necessary to reassess the questions of donor selection and allocation. In answering these questions, one must put in the balance the short-term morbidity of pancreas transplantation with the long-term attrition of islet grafts. The preferential allocation of pancreases from obese and older donors for islet isolation has been based on their association with worse pancreas transplant outcomes and better islet isolation results in islet yields. In this overview, we show that transplanted islet mass does not necessarily correlate with graft function and make the case that donor selection criteria for islet transplantation, and hence allocation rules, may need to be redefined.
\n \n\n \n \nIn vivo alemtuzumab reduces the risk of graft-versus-host disease (GVHD) and nonrelapse mortality after reduced intensity allogeneic transplantation. However, it also delays immune reconstitution, leading to frequent infections and potential loss of graft-versus-tumor responses. Here, we tested the feasibility of alemtuzumab dose deescalation in the context of fludarabine-melphalan conditioning and human leukocyte antigen (HLA)-identical sibling transplantation. Alemtuzumab was given 1-2 days before graft infusion, and dose reduced from 60 mg to 20 mg in 4 sequential cohorts (total n = 106). Pharmacokinetic studies were fitted to a linear, 2-compartment model in which dose reduction led to incomplete saturation of CD52 binding sites and greater antibody clearance. Increased elimination was particularly evident in the 20-mg group in patients who had CD52-expressing tumors at time of transplantation. The 20-mg dose was also associated with greater risk of severe GVHD (acute grade III-IV or chronic extensive) compared with > 20 mg (hazard ratio, 6.7; 95% CI, 2.5-18.3). In contrast, dose reduction to 30 mg on day -1 was associated with equivalent clinical outcomes to higher doses but better lymphocyte recovery at 12 months. In conclusion, alemtuzumab dose reduction to 30 mg is safe in the context of reduced intensity conditioning and HLA-identical sibling transplantation. This trial was registered at http://www.ncrn.org.uk as UKCRN study 1415.
\n \n\n \n \nWe quantified livestock (cattle, shoats, horses and donkeys) losses to lions (Panthera leo) and attitudes to lions, livestock losses and tourism among livestock owners, village residents and tourism workers around Makgadikgadi Pans National Park in Botswana. Losses were not correlated with the size or structure of livestock enclosures, numbers of dogs or herders. Rather losses increased with the amount of livestock owned. Most were stray animals preyed upon at night. Attitudes to wildlife, conservation and lions were also not consistently distributed within the society we studied. Negative attitudes to lions were almost ubiquitous among cattleposts but less widespread among people living in the more urbanized society of villages or among people working in tourism. Although four tourist camps were operating in the area, benefits from these operations were largely limited to employees. Despite considerable sums of money being paid to Botswana by local tourist facilities few respondents viewed tourism as valuable and most felt that the government and not they or their community was the main beneficiary of tourism. Tourism employees made up a small sub-section of the adult population drawn predominately from larger villages while the costs of livestock losses were spread among cattleposts near the park boundary. These same cattlepost respondents were not prepared to improve stock care to protect livestock, but indicated a willingness to kill lions instead. If tourism is to play a role in reducing human-wildlife conflict, communities must not be regarded as homogenous entities into which to distribute benefits evenly. Benefits might usefully be distributed in relation to the costs of coexisting with wildlife or used as incentives to better protect livestock or other human resources. \u00a9 2009 Elsevier Ltd. All rights reserved.
\n \n\n \n \nX-ray crystallographic analysis of the title hydro-bromide salt, C(10)H(20)N(+)\u00b7Br(-), of (1R,2S,3R,5R,8aR)-3-hydroxy-meth-yl-5-methyl-octa-hydro-indolizine-1,2-diol defines the absolute and relative stereochemistry at the five chiral centres in steviamine, a new class of polyhydroxy-lated indolizidine alkaloid isolated from Stevia rebaudiana (Asteraceae) leaves. In the crystal structure, mol-ecules are linked by inter-molecular O-H\u22efBr and N-H\u22efBr hydrogen bonds, forming double chains around the twofold screw axes along the b-axis direction. Intra-molecular O-H\u22efO inter-actions occur.
\n \n\n \n \nOBJECTIVE: Zinc ions are essential for the formation of hexameric insulin and hormone crystallization. A nonsynonymous single nucleotide polymorphism rs13266634 in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8, is associated with type 2 diabetes. We describe the effects of deleting the ZnT8 gene in mice and explore the action of the at-risk allele. RESEARCH DESIGN AND METHODS: Slc30a8 null mice were generated and backcrossed at least twice onto a C57BL/6J background. Glucose and insulin tolerance were measured by intraperitoneal injection or euglycemic clamp, respectively. Insulin secretion, electrophysiology, imaging, and the generation of adenoviruses encoding the low- (W325) or elevated- (R325) risk ZnT8 alleles were undertaken using standard protocols. RESULTS: ZnT8(-/-) mice displayed age-, sex-, and diet-dependent abnormalities in glucose tolerance, insulin secretion, and body weight. Islets isolated from null mice had reduced granule zinc content and showed age-dependent changes in granule morphology, with markedly fewer dense cores but more rod-like crystals. Glucose-stimulated insulin secretion, granule fusion, and insulin crystal dissolution, assessed by total internal reflection fluorescence microscopy, were unchanged or enhanced in ZnT8(-/-) islets. Insulin processing was normal. Molecular modeling revealed that residue-325 was located at the interface between ZnT8 monomers. Correspondingly, the R325 variant displayed lower apparent Zn(2+) transport activity than W325 ZnT8 by fluorescence-based assay. CONCLUSIONS: ZnT8 is required for normal insulin crystallization and insulin release in vivo but not, remarkably, in vitro. Defects in the former processes in carriers of the R allele may increase type 2 diabetes risks.
\n \n\n \n \nBACKGROUND/PURPOSE: beta-Cell replacement offers a potential cure for type 1 diabetes mellitus in children. We have previously shown that stomach mesenchyme (SM) is competent to derive islet tissue by mesenchymal-to-epithelial transition (iMET). The aim of this study was to further characterize the developmental fate of this SM in the presence of pancreatic epithelia (PE) in SM/PE recombinants. The homeobox ISL-1 was examined in these recombinants because this gene is restricted to the dorsal pancreatic mesenchyme and endocrine cells in early pancreatic development. METHODS: Chick-quail recombinants of SM + PE (n = 15) and whole stomach controls (n = 8) were cultured for 7 days. In addition, organ blocks were examined after normal development at days 4 to 10 (n = 4 for each stage). Tissues were analyzed using immunochemistry against quail-specific antigen and ISL-1. RESULTS: Thirteen of 15 SM + PE recombinants expressed the ISL-1 protein in cells from SM origin. Nine of 15 of these recombinants showed iMET and coexpression of insulin, and ISL-1 was recorded. CONCLUSIONS: Pancreatic epithelium is able to reprogram SM to a more caudal pancreatic fate when cocultured. Islet tissue by mesenchymal-to-epithelial transition observed in recombinants showed coexpression of insulin and ISL-1. These experiments are important to identify the molecular mechanisms behind iMET for potential therapeutic use for treating children with diabetes.
\n \n\n \n \nEffects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Fiveone with breast cancer, one with basal-cell carcinoma and three with type 2 diabeteshave parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site. \u00a9 2009 Macmillan Publishers Limited. All rights reserved.
\n \n\n \n \nAIMS: Nocturnal breathing disorders in the form of periodic breathing (PB) are very common in heart failure (HF) patients. There is an increasing interest in simple and affordable tools to screen patients and monitor these disorders at home on a long-term basis. We aimed to assess the pathophysiological and clinical relevance of a simplified method for monitoring of PB suitable to be self-managed by the patient at home. METHODS AND RESULTS: A night-time respiratory recording was performed in 397 optimally treated HF patients (age 60 +/- 11 years, NYHA class 2.4 +/- 0.6, left ventricular ejection fraction 29 +/- 7%) and the duration of PB (PB(Dur)) automatically computed. Patients were followed-up for 1 year and the prognostic value of PB(Dur) evaluated. In 45 patients, we assessed the association between PB(Dur) and severity of oxygen desaturations (number of desaturations >3%). Twenty six of the 397 patients died of cardiac causes. A PB(Dur) > or =2 h was significantly associated with an increased risk of cardiac death after adjustment for major clinical predictors [hazard ratio (95% CI): 3.5 (1.6-7.9), P = 0.002]. The correlation between PB(Dur) and severity of desaturations was 0.94 (P < 0.0001). CONCLUSION: Relevant pathophysiological and clinical information can be obtained from simplified monitoring of breathing disorders managed by the patient. These results provide new perspectives in the investigation of the clinical impact of abnormal breathing in HF patients.
\n \n\n \n \nCircumcision is one the most frequently performed operations in males worldwide and is an integral part of several religions, including Judaism and lslam. Circumcision rates in the UK have reduced over the last few decades from 24% of males in the 1950s to an estimated 6% today. This reduction is largely as a result of better understanding of the physiology of the normal foreskin as well as rationalization of health care provision. The normal foreskin is non-retractable at birth and gradually separates spontaneously such that 90% of foreskins are retractable by three years of age. Medical indications for circumcision are few. Circumcision is contraindicated in a number of congenital penile disorders, including hypospadias, epispadias, chordee, buried penis, and micropenis. Various techniques are available for performing circumcision, including non-surgical techniques for use in neonates using devices such as the PlastibellTM, as well as surgical circumcision. Complications of circumcision include haemorrhage, infection, meatal stenosis, removal of incorrect amount of foreskin, penile injury, urethral injury, and painful scarring. However, many of these complications can be prevented using precise surgical techniques, including avoidance of monopolar diathermy and meticulous haemostasis. \u00a9 2008.
\n \n\n \n \nBACKGROUND/PURPOSE: Islet transplantation offers the potential to reverse diabetes soon after diagnosis and has achieved considerable success in adults. Its use in children has been limited by long-term immunosuppression requirements and donor pancreas shortages. An ideal alternative source of islets would be from autologous precursor cells. The aim of this study was to determine whether the spleen can produce insulin-producing cells (IPCs) in our established model of pancreatic development. METHODS: Embryonic quail spleens (day 4.5) and chick pancreatic epithelium (day 4) were microdissected and recombined in a ratio of 1:1 (n = 12), 2:1 (n = 9) and 2:2 (n = 5). They were cultured for 7 days, sectioned, and analysed by fluorescent immunochemistry. Controls were performed to ensure clean separation. RESULTS: Overall, 12 (46%) of 26 recombinants contained IPCs of splenic origin, occurring in 5 (42%) of 12 of the of 1 spleen-1 epithelium recombinants, 3 (33%) of 9 of the 2 spleen-1 epithelium recombinants, and 4 (80%) of 5 of the 2 spleen-2 epithelia recombinants. Controls were negative. CONCLUSIONS: Preliminary results suggest developing avian spleens can differentiate into IPCs. Increased tissue mass enhanced the likelihood of this occurring. Mesenchyme-to-epithelia ratio did not influence this. The spleen could be an ideal autologous islet source for transplantation in children.
\n \n\n \n \nHabitat loss and reduction in quality, together with increasing homogeneity of the farmed landscape and more intensive field management, are believed to be major drivers of biodiversity loss on farmland. Organic farms demonstrate features that are now rare elsewhere in UK farming systems, such as crop rotations incorporating grass leys, exclusion of synthetic pesticides and fertilizers, and reliance on animal and green manures. They may also contain greater densities of uncropped habitats such as hedgerows. In this study, we examined whether organic farming affected populations of one group of insects of conservation interest, butterflies, on farmland. The abundance of butterflies on pairs of organically and conventionally managed farms was recorded over 3 years and a number of habitat and crop variables, likely to be related to butterfly abundance, were also measured. Organic farms attracted significantly more butterflies overall than conventional farms. Significantly more butterflies in both farming systems were recorded over the uncropped field margin than the crop edge. The difference in butterfly abundance between crop edge and field margin was relatively greater in conventional than organic systems. Species richness of butterflies tended to be greater on organic farms. Five species of butterfly were significantly more abundant on organic farms in at least 1 year, while no species was significantly more abundant on conventional farms. Organic and conventional cropping patterns differed, the former having proportionally more grass leys, and hedgerows were larger on organic farms. Although no significant effects of farming system on the numbers of grass or forb species present in the field margin or crop edge were detected, some individual plant species showed differences in frequency between organic and conventional field boundaries. Increasing the extent of organic farming, or practices associated with it, could help to restore biodiversity in agricultural landscapes. \u00a9 2007 The Authors.
\n \n\n \n \nGlucagon, secreted from pancreatic islet alpha cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring beta cells, or to an intrinsic glucose sensing by the alpha cells themselves. We examined hormone secretion and Ca(2+) responses of alpha and beta cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn(2+) signalling was blocked, but was reversed by low concentrations (1-20 muM) of the ATP-sensitive K(+) (KATP) channel opener diazoxide, which had no effect on insulin release or beta cell responses. This effect was prevented by the KATP channel blocker tolbutamide (100 muM). Higher diazoxide concentrations ( > /=30 muM) decreased glucagon and insulin secretion, and alpha- and beta-cell Ca(2+) responses, in parallel. In the absence of glucose, tolbutamide at low concentrations ( < 1 muM) stimulated glucagon secretion, whereas high concentrations ( > 10 muM) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the KATP channel, inhibition of voltage-gated Na(+) (TTX) and N-type Ca(2+) channels (omega-conotoxin), but not L-type Ca(2+) channels (nifedipine), prevented glucagon secretion. Both the N-type Ca(2+) channels and alpha-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an alpha-cell KATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion.
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