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排序方式: 共有142条查询结果,搜索用时 343 毫秒
51.
Erik JM Toonen Pilar Barrera Jaap Fransen Arjan PM de Brouwer Agnes M Eijsbouts Pierre Miossec Hubert Marotte Hans Scheffer Piet LCM van Riel Barbara Franke Marieke JH Coenen 《Arthritis research & therapy》2012,14(6):R264
Introduction
The goal of this study is to investigate whether the -308G > A promoter polymorphism in the tumor necrosis factor alpha (TNFA) gene is associated with disease severity and radiologic joint damage in a large cohort of patients with rheumatoid arthritis (RA).Methods
A long-term observational early RA inception cohort (n = 208) with detailed information about disease activity and radiologic damage after 3, 6 and 9 years of disease was genotyped for the TNFA -308G > A promoter polymorphism (rs1800629). A longitudinal regression analysis was performed to assess the effect of genotype on RA disease severity and joint damage. Subsequently, a meta-analysis, including all publically available data, was performed to further test the association between joint erosions and the TNFA polymorphism. To learn more about the mechanism behind the effect of the polymorphism, RNA isolated from peripheral blood from RA patients (n = 66) was used for TNFA gene expression analysis by quantitative PCR.Results
Longitudinal regression analysis with correction for gender and disease activity showed a significant difference in total joint damage between GG and GA+AA genotype groups (P = 0.002), which was stable over time. The meta-analysis, which included 2,053 patients, confirmed an association of the genetic variant with the development of erosions (odds ratio 0.78, 95% CI 0.62, 0.98). No significant differences in TNFA gene expression were observed for the different genotypes, confirming earlier findings in healthy individuals.Conclusions
Our data confirm that the TNFA -308G > A promoter polymorphism is associated with joint damage in patients with RA. This is not mediated by differences in TNFA gene expression between genotypes. 相似文献52.
Steve Horvath Yafeng Zhang Peter Langfelder René S Kahn Marco PM Boks Kristel van Eijk Leonard H van den Berg Roel A Ophoff 《Genome biology》2012,13(10):1-18
Background
Several recent studies reported aging effects on DNA methylation levels of individual CpG dinucleotides. But it is not yet known whether aging-related consensus modules, in the form of clusters of correlated CpG markers, can be found that are present in multiple human tissues. Such a module could facilitate the understanding of aging effects on multiple tissues.Results
We therefore employed weighted correlation network analysis of 2,442 Illumina DNA methylation arrays from brain and blood tissues, which enabled the identification of an age-related co-methylation module. Module preservation analysis confirmed that this module can also be found in diverse independent data sets. Biological evaluation showed that module membership is associated with Polycomb group target occupancy counts, CpG island status and autosomal chromosome location. Functional enrichment analysis revealed that the aging-related consensus module comprises genes that are involved in nervous system development, neuron differentiation and neurogenesis, and that it contains promoter CpGs of genes known to be down-regulated in early Alzheimer's disease. A comparison with a standard, non-module based meta-analysis revealed that selecting CpGs based on module membership leads to significantly increased gene ontology enrichment, thus demonstrating that studying aging effects via consensus network analysis enhances the biological insights gained.Conclusions
Overall, our analysis revealed a robustly defined age-related co-methylation module that is present in multiple human tissues, including blood and brain. We conclude that blood is a promising surrogate for brain tissue when studying the effects of age on DNA methylation profiles. 相似文献53.
Sheung-Tak Cheng Rosanna WL Lau Emily PM Mak Natalie SS Ng Linda CW Lam Helene H Fung Julian CL Lai Timothy Kwok Diana TF Lee 《Trials》2012,13(1):1-10
Background
Patients with ST-elevation myocardial infarction (STEMI) not treated with primary or rescue percutaneous coronary intervention (PCI) are at risk for recurrent ischemia, especially when viability in the infarct-area is present. Therefore, an invasive strategy with PCI of the infarct-related coronary artery in patients with viability would reduce the occurrence of a composite end point of death, reinfarction, or unstable angina (UA).Methods
Patients admitted with an (sub)acute myocardial infarction, who were not treated by primary or rescue PCI, and who were stable during the first 48 hours after the acute event, were screened for the study. Eventually, we randomly assigned 216 patients with viability (demonstrated with low-dose dobutamine echocardiography) to an invasive or a conservative strategy. In the invasive strategy stenting of the infarct-related coronary artery was intended with abciximab as adjunct treatment. Seventy-five (75) patients without viability served as registry group. The primary endpoint was the composite of death from any cause, recurrent myocardial infarction (MI) and unstable angina at one year. As secondary endpoint the need for (repeat) revascularization procedures and anginal status were recorded.Results
The primary combined endpoint of death, recurrent MI and unstable angina was 7.5% (8/106) in the invasive group and 17.3% (19/110) in the conservative group (Hazard ratio 0.42; 95% confidence interval [CI] 0.18-0.96; p = 0.032). During follow up revascularization-procedures were performed in 6.6% (7/106) in the invasive group and 31.8% (35/110) in the conservative group (Hazard ratio 0.18; 95% CI 0.13-0.43; p < 0.0001). A low rate of recurrent ischemia was found in the non-viable group (5.4%) in comparison to the viable-conservative group (14.5%). (Hazard-ratio 0.35; 95% CI 0.17-1.00; p = 0.051).Conclusion
We demonstrated that after acute MI (treated with thrombolysis or without reperfusion therapy) patients with viability in the infarct-area benefit from a strategy of early in-hospital stenting of the infarct-related coronary artery. This treatment results in a long-term uneventful clinical course. The study confirmed the low risk of recurrent ischemia in patients without viability.Trial registration
ClinicalTrials.gov: NCT00149591. 相似文献54.
Binding of [3H]ouabain to split frog skin: the role of the Na,K-ATPase in the generation of short circuit current 总被引:4,自引:2,他引:2 下载免费PDF全文
The binding of [3H]ouabain to the serosal side was studied in a chambered preparation of frog skin, free of connective tissue, while the short circuit (Isc) was concurrently monitored. Both ouabain binding and Isc inhibition proceeded as hyperbolic functions of time. A plot of the number of ouabain molecules bound vs. the corresponding values of Isc inhibition (percent) yielded a straight line, yet showed that one-third of the binding occurred before any inhibition of Isc. Upon separation of the skins into two groups based upon initial Isc(Isci)--high, greater than 20 microamperemeter/cm2 and low, less than 10 microamperemeter/cm2, we observed two distinct populations. The high Isci skins bound very little ouabain before inhibition of Isc whereas low Isci skins bound one-half of the total number of sites before exhibiting any inhibition of Isc. These observations strongly suggest that (a) the Na,K-ATPase is directly involved in the generation of Isc, and (b) at low Isc, inhibition of some pumps by ouabain causes a "recruitment" of other pumps to increase their turnover rate and maintain Isc relatively unaffected. In addition, the binding of ouabain also displayed various characteristics that were consistent with known properties of the Na,K-ATPase: (a) increased intracellular K/Na concentrations, whether achieved through the addition of amiloride or removal of Na from the outside medium, led to a significant decrease in ouabain binding rate relative to paired controls; and (b) ouabain binding, either with normal or decreased intracellular Na, was significantly reduced in the presence of elevated K in the serosal bathing medium. Finally, the number of ouabain molecules bound to the frog skins was not correlated with their initial Isc values, indicating that the spontaneous skin-to-skin variation in Isc was not related to the number of functional pump sites but, rather, to their turnover rate. 相似文献
55.
Models of rheumatoid arthritis (RA) in laboratory animals are important tools for research into pathogenic mechanisms and
the development of effective, safe therapies. Rodent models (rats and mice) have provided important information about the
pathogenic mechanisms. However, the evolutionary distance between rodents and humans hampers the translation of scientific
principles into effective therapies. The impact of the genetic distance between the species is especially seen with treatments
based on biological molecules, which are usually species-specific. The outbred nature and the closer anatomical, genetic,
microbiological, physiological, and immunological similarity of nonhuman primates to humans may help to bridge the wide gap
between inbred rodent strain models and the heterogeneous RA patient population. Here we review clinical, immunological and
pathological aspects of the rhesus monkey model of collagen-induced arthritis, which has emerged as a reproducible model of
human RA in nonhuman primates. 相似文献
56.
Calsequestrin (CSQ) concentrates in junctional sarcoplasmic reticulum (SR) where it functions in regulation of Ca2+ release. When purified from heart tissue, cardiac CSQ contains phosphate on a cluster of C-terminal serine residues, but little is known about the cellular site of kinase action, and the identity of the kinase remains uncertain. To determine basic features of the phosphorylation, we examined the reaction in canine heart preparations. CSQ phosphorylation was observed in [32P]metabolically-labeled heart cells after adenoviral overexpression, and its constitutive phosphorylation was limited to a CK2-sensitive C-terminal serine cluster. The CSQ kinase was oriented intralumenally, as was CSQ, inside membrane vesicles, such that exposure to each required detergent permeabilization. Yet even after detergent permeabilization, CSQ was phosphorylated much less efficiently by protein kinase CK2 in cardiac microsomes than was purified CSQ. Reduced phosphorylation was strongly dependent upon protein concentration, and phosphorylation time courses revealed a phosphatase activity that occurred constitutively as phosphorylated substrate accumulates. Evidence of selective dephosphorylation of CSQ glycoforms in heart homogenates was also seen by mass spectrometry analysis. Molecules with greater mannose content, a feature of early secretory pathway compartments, were more highly phosphorylated, while greater dephosphorylation was apparent in more distal compartments. Taken together, the analyses of CSQ phosphorylation in heart suggest that a constitutive process of phosphate turnover occurs for cardiac CSQ perhaps associated with its intracellular transport. 相似文献
57.
58.
P M Cala S E Anderson E J Cragoe 《Comparative biochemistry and physiology. A, Comparative physiology》1988,90(4):551-555
1. The role of Na/H exchange in cell volume and pH regulation is discussed. In addition the roles of Cl/HCO3 exchange and system buffers are evaluated as they relate to Na/H exchange-dependent changes in cell salt and water content and intracellular pH. 2. Data obtained from studies of Amphiuma red blood cells showed that in addition to previously reported Na/H exchange dependent volume regulation the pathway is also involved in regulating cell pH. 3. These data showed that in contrast to volume activated Na/H exchange, when the pathway is pH activated it does not deactivate as a function of cell volume. 4. Given what appeared to be mutually exclusive volume and pH regulatory functions of the Na/H exchange, we hypothesized that the pathway might play a role in hypoxic cell swelling (cytotoxic edema). 5. In studies performed on perfused rabbit hearts employing 23Na NMR we were able to observe that relative to normoxic controls hypoxic hearts exhibited a five-fold increase in intracellular Na content when the Na-K pump was inhibited by ouabain and/or K-free perfusate. 6. These studies lead us to conclude that hypoxia-induced Na uptake is the result of an increased inward Na leak as opposed to decreased Na pumping. 7. Based upon studies with a variety of inhibitors of dissipative Na transport, we conclude that the increased inward Na leak in hypoxic hearts is via Na/H exchange. 相似文献
59.
60.