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81.
Baeza-Raja B Li P Le Moan N Sachs BD Schachtrup C Davalos D Vagena E Bridges D Kim C Saltiel AR Olefsky JM Akassoglou K 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(15):5838-5843
Insulin resistance is a key factor in the etiology of type 2 diabetes. Insulin-stimulated glucose uptake is mediated by the glucose transporter 4 (GLUT4), which is expressed mainly in skeletal muscle and adipose tissue. Insulin-stimulated translocation of GLUT4 from its intracellular compartment to the plasma membrane is regulated by small guanosine triphosphate hydrolases (GTPases) and is essential for the maintenance of normal glucose homeostasis. Here we show that the p75 neurotrophin receptor (p75(NTR)) is a regulator of glucose uptake and insulin resistance. p75(NTR) knockout mice show increased insulin sensitivity on normal chow diet, independent of changes in body weight. Euglycemic-hyperinsulinemic clamp studies demonstrate that deletion of the p75(NTR) gene increases the insulin-stimulated glucose disposal rate and suppression of hepatic glucose production. Genetic depletion or shRNA knockdown of p75(NTR) in adipocytes or myoblasts increases insulin-stimulated glucose uptake and GLUT4 translocation. Conversely, overexpression of p75(NTR) in adipocytes decreases insulin-stimulated glucose transport. In adipocytes, p75(NTR) forms a complex with the Rab5 family GTPases Rab5 and Rab31 that regulate GLUT4 trafficking. Rab5 and Rab31 directly interact with p75(NTR) primarily via helix 4 of the p75(NTR) death domain. Adipocytes from p75(NTR) knockout mice show increased Rab5 and decreased Rab31 activities, and dominant negative Rab5 rescues the increase in glucose uptake seen in p75(NTR) knockout adipocytes. Our results identify p75(NTR) as a unique player in glucose metabolism and suggest that signaling from p75(NTR) to Rab5 family GTPases may represent a unique therapeutic target for insulin resistance and diabetes. 相似文献
82.
83.
Fourteen face transplants have been performed worldwide since the procedure was successfully introduced in 2005. Vascularized composite tissue allotransplantation may now be considered a viable option for the repair of complex craniofacial defects, for which the results of autologus reconstruction remain suboptimal. However, the benefits must be balanced against the risks inherent in major surgery and the adverse effects of lifelong immunosuppression. In this article, we review the current practice and areas of controversy in facial vascularized composite tissue allotransplantation with particular respect to the unique immunobiology of this procedure. We also describe promising recent advances in immunotherapy and tolerance induction strategies that may soon reach clinical application. 相似文献
84.
85.
B D Sachs J P R Jacobsen T L Thomas W B Siesser W L Roberts M G Caron 《Translational psychiatry》2013,3(8):e291
The importance of reversing brain serotonin (5-HT) deficiency and promoting hippocampal neurogenesis in the mechanisms of action for antidepressants remain highly controversial. Here we examined the behavioral, neurochemical and neurogenic effects of chronic fluoxetine (FLX) in a mouse model of congenital 5-HT deficiency, the tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mouse. Our results demonstrate that congenital 5-HT deficiency prevents a subset of the signature molecular, cellular and behavioral effects of FLX, despite the fact that FLX restores the 5-HT levels of Tph2KI mice to essentially the levels observed in wild-type mice at baseline. These results suggest that inducing supra-physiological levels of 5-HT, not merely reversing 5-HT deficiency, is required for many of the antidepressant-like effects of FLX. We also demonstrate that co-administration of the 5-HT precursor, 5-hydroxytryptophan (5-HTP), along with FLX rescues the novelty suppressed feeding (NSF) anxiolytic-like effect of FLX in Tph2KI mice, despite still failing to induce neurogenesis. Thus, our results indicate that brain 5-HT deficiency reduces the efficacy of FLX and that supplementation with 5-HTP can restore some antidepressant-like responses in the context of 5-HT deficiency. Our findings also suggest that feeding latency reductions in the NSF induced by chronic 5-HT elevation are not mediated by drug-induced increments in neurogenesis in 5-HT-deficient animals. Overall, these findings shed new light on the impact of 5-HT deficiency on responses to FLX and may have important implications for treatment selection in depression and anxiety disorders. 相似文献
86.
U. J. Sachs 《ISBT科学丛刊》2013,8(1):142-148
This paper will summarize the experimental and clinical literature on the pathogenesis of transfusion-related acute lung injury (TRALI). Several mechanisms by which leukocyte antibodies including, HLA class I, HLA class II, and HNA-3a antibodies, induce TRALI have been unraveled, although some aspects remain a matter of debate. Significant advances have also been made in the field of recipient-related factors that contribute to the development of TRALI. In contrast, the pathomechanism behind antibody-negative TRALI (associated with the transfusion of blood components which do not contain antibodies) is less well understood, and further research is urgently required. 相似文献
87.
88.
Najaoui A Bakchoul T Stoy J Bein G Rummel MJ Santoso S Sachs UJ 《European journal of haematology》2012,88(2):167-174
Background: It is commonly accepted that antibody‐mediated removal of platelets represents a major mechanism of platelet destruction in immune thrombocytopenic purpura (ITP). Although complement activation may participate in platelet clearance, frequency and specificity of complement activation have not yet been studied systematically in ITP. Patients and methods: We examined blood samples from 240 patients with ITP. Samples were assessed for the presence of free and bound platelet autoantibodies by a standard glycoprotein‐specific assay (monoclonal antibody‐specific immobilization of platelet antigens). The ability of all sera to fix complement to a panel of human platelets was investigated in a complement fixation (CF) assay. Fixation of C1q to isolated GP IIb/IIIa was assessed by flow cytometry. Results: Glycoprotein‐specific autoantibodies were detected as platelet‐bound antibodies in 129 (54%) and as additional free antibodies in 26 (11%) and were undetectable in 111 (46%) patients. Assessing these subgroups for CF, 103 (65%), 21 (81%), and 33 (30%) sera gave positive results. If GP IIb/IIIa was absent from the test platelets, 81 (67%) lost their ability to fix complement; if GP Ib/IX was absent, 37 (30%) lost their ability to fix complement. C1q fixation to immunobeads coated with GP IIb/IIIa was observed in 50% of sera containing anti‐GP IIb/IIIa antibodies. Conclusions: In a significant number of patients with chronic ITP, platelet autoantibodies are capable of activating the classical complement pathway. CF is even present in ITP sera without detectable autoantibodies, indicating that current techniques for autoantibody detection may be insufficient. The major targets for complement‐fixing autoantibodies in ITP are GP IIb/IIIa and GP Ib/IX. 相似文献
89.
Maryam Afkarian Michael C. Sachs Bryan Kestenbaum Irl B. Hirsch Katherine R. Tuttle Jonathan Himmelfarb Ian H. de Boer 《Journal of the American Society of Nephrology : JASN》2013,24(2):302-308
Type 2 diabetes associates with increased risk of mortality, but how kidney disease contributes to this mortality risk among individuals with type 2 diabetes is not completely understood. Here, we examined 10-year cumulative mortality by diabetes and kidney disease status for 15,046 participants in the Third National Health and Nutrition Examination Survey (NHANES III) by linking baseline data from NHANES III with the National Death Index. Kidney disease, defined as urinary albumin/creatinine ratio ≥30 mg/g and/or estimated GFR ≤60 ml/min per 1.73 m2, was present in 9.4% and 42.3% of individuals without and with type 2 diabetes, respectively. Among people without diabetes or kidney disease (reference group), 10-year cumulative all-cause mortality was 7.7% (95% confidence interval [95% CI], 7.0%–8.3%), standardized to population age, sex, and race. Among individuals with diabetes but without kidney disease, standardized mortality was 11.5% (95% CI, 7.9%–15.2%), representing an absolute risk difference with the reference group of 3.9% (95% CI, 0.1%–7.7%), adjusted for demographics, and 3.4% (95% CI, −0.3% to 7.0%) when further adjusted for smoking, BP, and cholesterol. Among individuals with both diabetes and kidney disease, standardized mortality was 31.1% (95% CI, 24.7%–37.5%), representing an absolute risk difference with the reference group of 23.4% (95% CI, 17.0%–29.9%), adjusted for demographics, and 23.4% (95% CI, 17.2%–29.6%) when further adjusted. We observed similar patterns for cardiovascular and noncardiovascular mortality. In conclusion, those with kidney disease predominantly account for the increased mortality observed in type 2 diabetes.In 2012, there were an estimated 346 million individuals with diabetes worldwide.1 This number is expected to rise to >430 million by 2030.2 Diabetes is associated with substantially increased risk of mortality, particularly due to cardiovascular disease.3Kidney disease, defined by increased urine albumin excretion and/or impaired GFR, is also strongly associated with increased risk of all-cause and cardiovascular mortality, both among persons with diabetes4,5 and in the general population.6–10 The critical effect of kidney disease on mortality in type 1 diabetes was emphasized in two recent reports.11,12 Each study demonstrated that excess mortality was confined to the subgroup with kidney disease.The degree to which kidney disease captures risk of adverse health outcomes in type 2 diabetes has not been determined. The findings from type 1 diabetes may not extrapolate to type 2 diabetes because the latter is frequently associated with other comorbidities that affect mortality. This question has crucial public health implications because type 2 diabetes predominates among the 26 million US adults with diabetes13,14 and identifying predictors of excess mortality in type 2 diabetes is essential in order to optimally target risk-reduction strategies. The primary objective of this study was to quantify and compare the excess risk of all-cause and cause-specific mortality among individuals with type 2 diabetes in presence or absence of kidney disease. 相似文献
90.
Nutritional rehabilitation and weight restoration are key underpinnings of the treatment protocol for patients with anorexia nervosa. While their inherent state of malnutrition and weight loss is certainly not a healthy one, ironically, the very essence of the refeeding process, if done injudiciously, can also be unsafe for patients with anorexia nervosa. In this article we will provide a review of the major complications that may arise during refeeding, how best to avoid them, and how to treat them. 相似文献