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991.
Rachael F. Grace Kristin A. Shimano Rukhmi Bhat Cindy Neunert James B. Bussel Robert J. Klaassen Michele P. Lambert Jennifer A. Rothman Vicky R. Breakey Kerry Hege Carolyn M. Bennett Melissa J. Rose Kristina M. Haley George R. Buchanan Amy Geddis Adonis Lorenzana Michael Jeng Yves D. Pastore Shelley E. Crary Michelle Neier Ellis J. Neufeld Nolan Neu Peter W. Forbes Jenny M. Despotovic 《American journal of hematology》2019,94(7):741-750
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding, or to improve health related quality of life (HRQoL). There are a number of available second-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi-center, observational study of 120 children starting second-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (P = .04). Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84% to 48%, P = .01 and 81% to 43%, P = .004) and non-skin-related bleeding symptoms (58% to 14%, P = .0001 and 54% to 17%, P = .0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP. 相似文献
992.
Pluim BM de Hon O Staal JB Limpens J Kuipers H Overbeek SE Zwinderman AH Scholten RJ 《Sports medicine (Auckland, N.Z.)》2011,41(1):39-57
Inhaled β?-agonists are commonly used as bronchodilators in the treatment of asthma. Their use in athletes, however, is restricted by anti-doping regulations. Controversies remain as to whether healthy elite athletes who use bronchodilators may gain a competitive advantage. The aim of this systematic review and meta-analysis is to assess the effects of inhaled and systemic β?-agonists on physical performance in healthy, non-asthmatic subjects. To this end, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched up to August 2009. Reference lists were searched for additional relevant studies. The search criteria were for randomized controlled trials examining the effect of inhaled or systemic β?-agonists on physical performance in healthy, non-asthmatic subjects. Two authors independently performed the selection of studies, data extraction and risk of bias assessment. Parallel-group and crossover trials were analysed separately. Mean difference (MD) and 95% confidence intervals were calculated for continuous data and, where possible, data were pooled using a fixed effects model. Twenty-six studies involving 403 participants (age range 7-30 years) compared inhaled β?-agonists with placebo. No significant effect could be detected for inhaled β?-agonists on maximal oxygen consumption (VO?(max)) [MD -0.14?mL?·?kg?1?·?min?1; 95% CI -1.07, 0.78; 16 studies], endurance time to exhaustion at 105-110% VO?(max) (MD -1.5 s; 95% CI -15.6, 12.6; four studies), 20-km time trial duration (MD -4.4 s; 95% CI -23.5, 14.7; two studies), peak power (MD -0.14 W?·?kg?1; 95% CI -0.54, 0.27; four studies) and total work during a 30-second Wingate test (MD 0.80 J?·?kg?1; 95% CI -2.44, 4.05; five studies). Thirteen studies involving 172 participants (age range 7-22 years) compared systemic β?-agonists with placebo, with 12 studies involving oral and one study involving intravenous salbutamol. A significant effect was detected for systemic β?-agonists on endurance time to exhaustion at 80-85% VO?(max) (MD 402 s; 95% CI 34, 770; two studies), but not for VO?(max) (placebo 42.5?±?1.7?mL?·?kg?1?·?min?1, salbutamol 42.1?±?2.9?mL?·?kg?1?·?min?1, one study), endurance time to exhaustion at 70% VO?(max) (MD 400 s; 95% CI -408, 1208; one study) or power output at 90% VO?(max) (placebo 234.9?±?16 W, salbutamol 235.5?±?18.1 W, one study). A significant effect was shown for systemic β?-agonists on peak power (MD 0.91 W?·?kg?1; 95% CI 0.25, 1.57; four studies), but not on total work (MD 7.8 J?·?kg?1; 95% CI -3.3, 18.9; four studies) during a 30-second Wingate test. There were no randomized controlled trials assessing the effects of systemic formoterol, salmeterol or terbutaline on physical performance. In conclusion, no significant effects were detected for inhaled β?-agonists on endurance, strength or sprint performance in healthy athletes. There is some evidence indicating that systemic β?-agonists may have a positive effect on physical performance in healthy subjects, but the evidence base is weak. 相似文献
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996.
Mellado-Gil J Rosa TC Demirci C Gonzalez-Pertusa JA Velazquez-Garcia S Ernst S Valle S Vasavada RC Stewart AF Alonso LC Garcia-Ocaña A 《Diabetes》2011,60(2):525-536
OBJECTIVE
To determine the role of hepatocyte growth factor (HGF)/c-Met on β-cell survival in diabetogenic conditions in vivo and in response to cytokines in vitro.RESEARCH DESIGN AND METHODS
We generated pancreas-specific c-Met-null (PancMet KO) mice and characterized their response to diabetes induced by multiple low-dose streptozotocin (MLDS) administration. We also analyzed the effect of HGF/c-Met signaling in vitro on cytokine-induced β-cell death in mouse and human islets, specifically examining the role of nuclear factor (NF)-κB.RESULTS
Islets exposed in vitro to cytokines or from MLDS-treated mice displayed significantly increased HGF and c-Met levels, suggesting a potential role for HGF/c-Met in β-cell survival against diabetogenic agents. Adult PancMet KO mice displayed normal glucose and β-cell homeostasis, indicating that pancreatic c-Met loss is not detrimental for β-cell growth and function under basal conditions. However, PancMet KO mice were more susceptible to MLDS-induced diabetes. They displayed higher blood glucose levels, marked hypoinsulinemia, and reduced β-cell mass compared with wild-type littermates. PancMet KO mice showed enhanced intraislet infiltration, islet nitric oxide (NO) and chemokine production, and β-cell apoptosis. c-Met-null β-cells were more sensitive to cytokine-induced cell death in vitro, an effect mediated by NF-κB activation and NO production. Conversely, HGF treatment decreased p65/NF-κB activation and fully protected mouse and, more important, human β-cells against cytokines.CONCLUSIONS
These results show that HGF/c-Met is critical for β-cell survival by attenuating NF-κB signaling and suggest that activation of the HGF/c-Met signaling pathway represents a novel strategy for enhancing β-cell protection.Type I diabetes is an autoimmune disease that results from cellular cytotoxicity leading to selective and progressive destruction of insulin-secreting cells (1–3). Many growth factors known to control cell growth and survival in physiologic and pathologic conditions are expressed in the pancreas and could potentially participate in an autocrine/paracrine fashion in the final fate of β-cells in an autoimmune environment. Overexpression of IGF-1, transforming growth factor-β, or granulocyte macrophage-colony stimulating factor ameliorates islet infiltration and β-cell death in mouse models of increased islet inflammation and diabetes (4–6). However, the role of endogenous pancreatic growth factors in type I diabetes has not been examined. Because growth factors can locally affect β-cell survival, neogenesis, and regeneration, and modulate chemokine production and immune responses, alterations in the level/activation of growth factor signaling pathways might contribute to the delay/acceleration of the onset of diabetes.Hepatocyte growth factor (HGF)/c-Met signaling pathway participates in the control of multiple biological functions, including development, proliferation, survival, regeneration, and branching morphogenesis (7). HGF binds with high affinity to, and induces the dimerization of, c-Met, its transmembrane tyrosine kinase receptor (8). Deletion of exon 16 of the c-Met gene, which encodes Lys1108 (ATP binding site), essential for the kinase activity of this receptor, in knockout mice results in embryonic lethality (9). These mice display a phenotype identical to HGF knockout mice (10). Both HGF and c-Met are expressed in the pancreas; HGF localizes to endothelial, islet, and mesenchymal cells, and c-Met is expressed in islet, ductal, and pancreatic progenitor cells (11–14). Conditional ablation of the c-Met gene in mouse β-cells using RIP-Cre and lox-c-Met mice leads to deficient insulin secretion without alteration of β-cell mass (12,13). On the other hand, HGF overexpression in the β-cell of transgenic mice increases β-cell replication, mass, and function (15,16). Furthermore, HGF improves islet graft survival in animal models of diabetes (17–19). HGF positively influences autoimmune responses, reducing the severity of autoimmune myocarditis and arthritis (20,21). HGF also downregulates airway and kidney inflammation, and inflammatory bowel disease (22–24). Whether HGF plays a role in autoimmune diabetes is unknown.To address the function of c-Met in the development, growth, and maintenance of β-cells under physiologic conditions, as well as its role in β-cell survival and response to injury in vivo, we generated pancreas-specific c-Met-null (PancMet KO) mice. We report that although c-Met is dispensable for normal β-cell growth and function under basal conditions, it is critically important for β-cell survival in diabetogenic conditions. β-Cell survival is dramatically worsened in the absence of HGF/c-Met signaling, resulting in accelerated diabetes onset. These observations also apply to human β-cells, underscoring a therapeutic opportunity for the HGF/c-Met signaling pathway in human diabetes. 相似文献997.
998.
Bailey-Wilson JE Brennan JS Bull SB Culverhouse R Kim Y Jiang Y Jung J Li Q Lamina C Liu Y Mägi R Niu YS Simpson CL Wang L Yilmaz YE Zhang H Zhang Z 《Genetic epidemiology》2011,35(Z1):S92-100
Group 14 of Genetic Analysis Workshop 17 examined several issues related to analysis of complex traits using DNA sequence data. These issues included novel methods for analyzing rare genetic variants in an aggregated manner (often termed collapsing rare variants), evaluation of various study designs to increase power to detect effects of rare variants, and the use of machine learning approaches to model highly complex heterogeneous traits. Various published and novel methods for analyzing traits with extreme locus and allelic heterogeneity were applied to the simulated quantitative and disease phenotypes. Overall, we conclude that power is (as expected) dependent on locus-specific heritability or contribution to disease risk, large samples will be required to detect rare causal variants with small effect sizes, extreme phenotype sampling designs may increase power for smaller laboratory costs, methods that allow joint analysis of multiple variants per gene or pathway are more powerful in general than analyses of individual rare variants, population-specific analyses can be optimal when different subpopulations harbor private causal mutations, and machine learning methods may be useful for selecting subsets of predictors for follow-up in the presence of extreme locus heterogeneity and large numbers of potential predictors. 相似文献
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Lees CH Avery C Asherin R Rainbow J Danila R Smelser C Schmitz A Ladd-Wilson S Nolte KB Nagle K Lynfield R 《Emerging infectious diseases》2011,17(8):1479-1483
During the pandemic (H1N1) 2009 outbreak, Minnesota, New Mexico, and Oregon used several surveillance methods to detect associated deaths. Surveillance using unexplained death and medical examiner data allowed for detection of 34 (18%) pandemic (H1N1) 2009-associated deaths that were not detected by hospital-based surveillance. 相似文献