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Lawrence A. Leiter Deepak L. Bhatt Darren K. McGuire Hwee Teoh Kim Fox Tabassome Simon Shamir R. Mehta Eli I. Lev Róbert G. Kiss Anthony J. Dalby Héctor Bueno Wilhelm Ridderstråle Anders Himmelmann Jayne Prats Yuyin Liu Jane J. Lee John Amerena Mikhail N. Kosiborod Philippe Gabriel Steg 《Journal of the American College of Cardiology》2021,77(19):2366-2377
BackgroundTHEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n = 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA1c 7.1%) and stable coronary artery disease without prior myocardial infarction (MI) or stroke, that ticagrelor plus aspirin (compared with placebo plus aspirin) produced a favorable net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding) if the patients had a previous percutaneous coronary intervention.ObjectivesIn these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events [MACE]), primary safety outcome (Thrombolysis In Myocardial Infarction–defined major bleeding) and net clinical benefit varied with diabetes-related factors.MethodsOutcomes were analyzed across baseline diabetes duration, HbA1c, and antihyperglycemic medications.ResultsIn THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for ≤5 years, 11.1% for >20 years) and HbA1c (6.4% for ≤6.0%, 11.8% for >10.0%). The relative benefits of ticagrelor plus aspirin on 3-point MACE reduction (hazard ratio [HR]: 0.90; p = 0.04) were generally consistent across subgroups. Major bleeding event rate (overall: 1.6%) did not vary by diabetes duration or HbA1c and was increased similarly by ticagrelor across all subgroups (HR: 2.32; p < 0.001). These findings were mirrored in THEMIS-PCI. The efficacy and safety of ticagrelor plus aspirin did not differ by baseline antihyperglycemic therapy. In THEMIS-PCI, but not THEMIS, ticagrelor generally produced favorable net clinical benefit across diabetes duration, HbA1c, and antihyperglycemic medications.ConclusionTicagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors in THEMIS-PCI but not in the overall THEMIS population. 相似文献
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Lev EI Kornowski R Vaknin-Assa H Brosh D Fuchs S Battler A Assali A 《The American journal of cardiology》2008,101(4):435-439
Pretreatment with clopidogrel before elective primary percutaneous coronary intervention (PCI) has been shown to reduce ischemic complications. There are limited data about the value of clopidogrel pretreatment in the setting of PCI for ST-elevation myocardial infarction (STEMI). We aimed to examine the effect of clopidogrel preloading on angiographic and clinical outcomes in patients with STEMI who were treated with PCI. We conducted a prospective registry of all patients treated with primary PCI for STEMI from March 2003 to June 2006. Excluded were patients with cardiogenic shock. For the current analysis, patients (n = 292) were allocated into 2 groups. One group received clopidogrel loading dose before PCI (in the emergency department or coronary care unit, n = 165); the other,immediately after PCI (n = 127). TIMI myocardial perfusion (TMP) grade at the end of PCI and 30-day and 6-month clinical outcomes were assessed. Clinical characteristics were similar among the groups. However, patients pretreated with clopidogrel were more likely to receive aspirin and beta blockers before the current admission. TMP grade 3 occurred in a higher proportion of patients in the clopidogrel pretreatment group than in the no-pretreatment group (85% vs 71%, p = 0.01). Multivariate logistic regression analysis showed that clopidogrel pretreatment was associated with an odds ratio of 2.2 for TMP grade 3 (1.2 to 3.9, p = 0.01). Furthermore, the incidence of reinfarction at 30 days was lower in the pretreatment group (0% vs 3.2%, respectively, p = 0.04). In conclusion, these findings support the early use of clopidogrel in patients with STEMI who are treated with primary PCI. 相似文献
76.
Van Hare GF Javitz H Carmelli D Saul JP Tanel RE Fischbach PS Kanter RJ Schaffer M Dunnigan A Colan S Serwer G;Pediatric Electrophysiology Society 《Journal of cardiovascular electrophysiology》2004,15(7):759-770
INTRODUCTION: A multicenter prospective study was designed and implemented to assess the short- and longer-term results and risks associated with radiofrequency (RF) ablation in children. METHODS AND RESULTS: Patients recruited for the study were aged 0 to 16 years with supraventricular tachycardia due to accessory pathways or AV nodal reentrant tachycardia (AVNRT), excluding patients with nontrivial congenital heart disease. A national registry also was established, and contributing centers were encouraged to enroll all pediatric patients, aged 0 to 21 years, undergoing ablation at their center. This report summarizes acute results of these procedures. For analysis, subjects were divided into three groups: the prospective cohort (n = 481), cohort-eligible registry participants (n = 504), and not cohort eligible registry participants (n = 1,776). Prospectively enrolled cohort patients were similar to cohort-eligible patients in terms of demographic and other patient characteristics. Overall success rates for RF ablation were high (95.7%), with higher success rates for left-sided and particularly left free-wall pathways (97.8%) than right free-wall pathways (90.8%). Complications of both electrophysiologic study and RF ablation were infrequent (4.2% and 4.0%, respectively), and there were no deaths. AV block was uncommon overall (1.2%) and was limited to ablation in AVNRT (2.1%) and septal accessory pathways (3.0%). CONCLUSION: Despite the multicenter and prospective design, the study demonstrates high success rates and low complication rates, which are comparable to prior single-center retrospective studies. These results may serve as the current best benchmark for expected results in the pediatric population, aged 0 to 16 years, both in terms of acute success rates and the occurrence of complications. 相似文献
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Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study
Zelber-Sagi S Nitzan-Kaluski D Goldsmith R Webb M Zvibel I Goldiner I Blendis L Halpern Z Oren R 《Hepatology (Baltimore, Md.)》2008,48(6):1791-1798
Physical activity (PA) is commonly recommended for nonalchoholic fatty liver disease (NAFLD) patients. However, there is limited evidence on the independent role of PA in NAFLD. The aim of this study was to examine the association between PA and NAFLD. We conducted a cross-sectional study of a subsample (n = 375) of the Israeli National Health and Nutrition Survey. Exclusion criteria were any known etiology for liver disease. Participants underwent an abdominal ultrasound examination; biochemical tests, including leptin, adiponectin, and resistin; and the noninvasive biomarker SteatoTest and anthropometric evaluations. A semiquantitative food frequency questionnaire and a detailed PA questionnaire were administered. Three hundred forty-nine patients (52.7% men, 30.9% primary NAFLD) were included. The NAFLD group engaged in less aerobic, resistance, or other kinds of PA (P = 0.03). The SteatoTest was significantly lower among subjects engaging in any PA or resistance PA at least once a week (P = 0.01). PA at least once a week in all categories was associated with a reduced risk for abdominal obesity. Adjusting for sex, engaging in any kind of sports (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.44-0.96 per 1 standard deviation increment in PA score) and resistance exercise (OR 0.61, 95% CI 0.38-0.85) were inversely associated with NAFLD. These associations remained unchanged after adjusting for homeostasis model assessment, most nutritional factors, adiponectin, and resistin. Only the association with resistance PA remained significant with further adjustment for body mass index (OR 0.61, 95% CI 0.44-0.85). Adding leptin or waist circumference to the model eliminated the statistical significance. Conclusion: Habitual leisure-time PA, especially anaerobic, may play a protective role in NAFLD. This association appears to be mediated by a reduced rate of abdominal obesity. 相似文献
79.
Phenotype-genotype studies in kuru: Implications for new variant Creutzfeldt–Jakob disease
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Larisa Cervenkov Lev G. Goldfarb Ralph Garruto Hee-Suk Lee D. Carleton Gajdusek Paul Brown 《Proceedings of the National Academy of Sciences of the United States of America》1998,95(22):13239-13241
The PRNP polymorphic (methionine/valine) codon 129 genotype influences the phenotypic features of transmissible spongiform encephalopathy. All tested cases of new variant Creutzfeldt–Jakob disease (nvCJD) have been homozygous for methionine, and it is conjectural whether different genotypes, if they appear, might have distinctive phenotypes and implications for the future “epidemic curve” of nvCJD. Genotype-phenotype studies of kuru, the only other orally transmitted transmissible spongiform encephalopathy, might be instructive in predicting the answers to these questions. We therefore extracted DNA from blood clots or sera from 92 kuru patients, and analyzed their codon 129 PRNP genotypes with respect to the age at onset and duration of illness and, in nine cases, to detailed clinical and neuropathology data. Homozygosity at codon 129 (particularly for methionine) was associated with an earlier age at onset and a shorter duration of illness than was heterozygosity, but other clinical characteristics were similar for all genotypes. In the nine neuropathologically examined cases, the presence of histologically recognizable plaques was limited to cases carrying at least one methionine allele (three homozygotes and one heterozygote). If nvCJD behaves like kuru, future cases (with longer incubation periods) may begin to occur in older individuals with heterozygous codon 129 genotypes and signal a maturing evolution of the nvCJD “epidemic.” The clinical phenotype of such cases should be similar to that of homozygous cases, but may have less (or at least less readily identified) amyloid plaque formation. 相似文献
80.
Dorit Trudler Kristopher L. Nazor Yvonne S. Eisele Titas Grabauskas Nima Dolatabadi James Parker Abdullah Sultan Zhenyu Zhong Marshall S. Goodwin Yona Levites Todd E. Golde Jeffery W. Kelly Michael R. Sierks Nicholas J. Schork Michael Karin Rajesh Ambasudhan Stuart A. Lipton 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(15)
Parkinson’s disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn–antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.Parkinson’s disease (PD) is characterized by accumulation of α-synuclein (αSyn; encoded by the SNCA gene) (1). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal cell death in part via microglial activation (2, 3). Moreover, misfolded proteins in general are thought to interact with brain microglia, triggering microglial activation that contributes to neurodegenerative disorders, although microglial phagocytosis may also initially clear aberrant proteins to afford some degree of protection (2, 4). Additionally, in Alzheimer’s disease (AD), amyloid-β peptide (Aβ) is thought to trigger similar processes in microglia (5–7); however, the mechanism for this trigger is still poorly understood.Microglial cells contribute to neuroinflammation, specifically that mediated by the inflammasome. In particular, the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome has been associated with several neurodegenerative disorders, although other types of inflammation may also be important in this regard (8). The NLRP3 inflammasome is a multiprotein complex that responds to cell stress and pathogenic stimuli to promote activation of caspase-1, which in turn mediates maturation and release of proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-18 (9–11). NLRP3 inflammasome activation is a two-step process, involving an initial priming step and a secondary trigger. Priming involves a proinflammatory stimulus, such as endotoxin, a ligand for Toll-like receptor 4 (TLR4), that increases the abundance of NLRP3 and promotes de novo synthesis of pro–IL-1β via nuclear factor κB (11). The secondary trigger promotes inflammasome complex assembly and caspase-1 activation that in turn mediates the cleavage of pro–IL-1β and subsequent release of mature IL-1β. There are various secondary triggers, including adenosine triphosphate (ATP), microparticles, and bacterial toxins, all of which somehow lead to mitochondrial damage and release of oxidized mitochondrial DNA (11). Neuroinflammation has been reported in both human PD and AD brains (12–15), and NLRP3 inflammasome activation in particular has been observed in mouse models of PD and AD (7, 16). Importantly, in these PD models, dopaminergic (DA) neurons in the substantia nigra are resistant to damage in NLRP3-deficient mice compared with wild-type (WT) mice (16). Interestingly, a recent report identified an NLRP3 polymorphism that confers decreased risk in PD (17). Several groups have reported that fibrillar αSyn can activate the NLRP3 inflammasome in mice and in human monocytes (18–22), but it remains unknown if human brain microglia can be activated in this manner. Critically, antibodies targeting misfolded proteins are being tested in human clinical trials for several neurodegenerative diseases, including AD and PD; however, it is still unclear how antibodies to αSyn might affect this inflammatory response. In this study, we characterized the response of human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) to oligomeric/fibrillar αSyn in vitro and in vivo, using engraftment of hiMG in humanized mice. We used these immunocompromised mice because they prevent human cell rejection and express three human genes that support human cell engraftment (23). We show that αSyn and, even more so, αSyn–antibody complexes activate the NLRP3 inflammasome. Moreover, this process is further sensitized by the presence of Aβ and its cognate antibodies. These observations are of heightened interest because recent studies have shown that both misfolded Aβ and αSyn are present in several neurodegenerative disorders such as AD and Lewy body dementia (LBD), a form of dementia that can occur in the setting of PD (24–26). 相似文献