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101.
Trevelyan J Brull DJ Needham EW Montgomery HE Morris A Mattu RK 《The American journal of cardiology》2004,94(5):564-569
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may have anti-inflammatory actions, an effect that could explain some of their beneficial effects on cardiovascular events in clinical trials. Coronary artery bypass grafting (CABG) is associated with a systemic inflammatory response and provides a convenient model to examine the effects of such agents. Genetic polymorphisms may be important in influencing the expression of cytokines, such as interleukin-6 (IL-6). We randomized men awaiting CABG to treatment with enalapril, losartan, or control for 2 months before surgery. Systemic IL-6, IL-8, IL-10, and IL-1 receptor agonists were measured before and after surgery, and genotypes for the -174 G/C and -572 G/C IL-6 gene polymorphisms were determined. Total release of the IL-1 receptor agonist was decreased 29% by enalapril and 31% by losartan (adjusted p = 0.041). IL-6 was decreased 17% by enalapril and 20% by losartan. Subjects possessing the -174 GG genotype produced 20% more IL-6 (adjusted p = 0.029). In these high producers of IL-6, release of IL-6 was decreased 51% by enalapril (adjusted p = 0.001) and 32% by losartan (adjusted p = 0.068). Release of IL-10 was nonsignificantly decreased 26% by enalapril and 21% by losartan, whereas IL-8 was not detected. In conclusion, enalapril and losartan significantly decreased release of the IL-1 receptor agonist after CABG. Enalapril produced a highly significant decrease of 51% in the release of IL-6 in patients identified as high producers of IL-6 by the -174 G/C polymorphism, whereas losartan has a similar but less marked effect. The production of IL-6 in this setting is influenced by the -174 G/C polymorphism. 相似文献
102.
We prospectively and blindly assessed the diagnostic and prognostic impact of implementation of the European Society of Cardiology/American College of Cardiology recommendations for redefinition of myocardial infarction (MI) in an unselected cohort of patients with suspected cardiac chest pain, with particular attention to prespecified clinical groups. All patients admitted to our institute with suspected cardiac chest pain were enrolled. Physicians provided usual care using serial electrocardiograms/creatine kinase (CK)/aspartate transaminase according to World Health Organization (WHO) criteria for MI, while blinded to additional measurements of cardiac troponin T (cTnT) and CK-MB mass. After discharge, diagnoses based on WHO and new criteria were compared, and major adverse cardiac events monitored for 6 months. Implementation of the new recommendations classified an additional 26.1% of patients as having MI compared with WHO criteria, and produced an overall diagnostic alteration in 11.5%. Two thirds of the additional patients with MI were previously diagnosed with unstable angina, whereas one third had "other cardiac" or "noncardiac" diagnoses. A similar MI cohort to the cTnT diagnosis was identified using a CK-MB mass discriminator value of 5 microg/L, but not 10 microg/L. The 6-month prognosis was similar in patients diagnosed with MI by new (cTnT) and WHO criteria, with the new criteria thus identifying a further high-risk cohort in the WHO negative group. In our cohort, the new Joint European Society of Cardiology/American College of Cardiology recommendations identify one fourth more patients as having MI. The 6-month prognosis of those patients reclassified as having MI was similar to those diagnosed with MI by both criteria. 相似文献
103.
Green JB Fricke B Chetty MC von Düring M Preston GF Stewart GW 《Blood cells, molecules & diseases》2004,32(3):411-422
The 32kD membrane protein stomatin was first studied because it is deficient from the red cell membrane in two forms of the class of haemolytic anaemias known as "hereditary stomatocytosis." The hallmark of these conditions is a plasma membrane leak to the monovalent cations Na+ and K+: the protein is missing only in the most severely leaky of these conditions. No mutation has ever been found in the stomatin gene in these conditions. Stomatin-like proteins have been identified in all three domains of biology, yet their function remains enigmatic. Although the murine knock-out is without phenotype, we have identified a family showing a splicing defect in the stomatin mRNA, in which affected children showed a catastrophic multisystem disease not inconsistent with the now-known wide tissue distribution of stomatin. We report here a study of strongly homologous stomatin-like genes in prokaryotes, which reveals a close connection with a never-studied gene erroneously known as "nfed." This gene codes for a hydrophobic protein with a probable serine protease motif. It is possible that these stomatin-like genes and those which are known as"nfed" form an operon, suggesting that the two protein products are aimed at a common function. The corollary is that stomatin could be a partner protein for a membrane-bound proteolytic process, in both prokaryotes and in eukaryotes generally: this idea is consistent with experimental evidence. 相似文献
104.
Angiotension-converting enzyme gene I/D polymorphism in patients with angina and normal coronary arteriograms 总被引:3,自引:0,他引:3
Vázquez-Rey E Montgomery HE Arroyo-Espliguero R Brown S Kaski JC 《International journal of cardiology》2005,98(2):339-340
A polymorphism of the human angiotensin-converting enzyme (ACE) gene has been identified in which the insertion (I) rather than the deletion (D) variant is associated with lower circulating and tissue ACE activity. ACE I allele is associated with resistance and endurance performance. Skeletal muscle metabolic efficiency is reduced in patients with heart failure and is improved by ACE inhibition. Profound muscle fatigue is a predominant and debilitating symptom in a proportion or patients with angina and normal coronary arteriograms (ANCA), and we postulated that the gene D allele might be associated with the presence of fatigue in ANCA patients. We studied 33 consecutive patients with typical ANCA who completed a validated fatigue questionnaire, and found an excess of the D allele frequency in patients with the highest fatigue scores compared to those with the lowest (64% vs. 36%; p=0.027). 相似文献
105.
Turner SM Moorghen M Probert CS 《European journal of gastroenterology & hepatology》2005,17(6):667-669
Coeliac disease is a T-cell-mediated enteropathy induced by gluten. A minority of patients who fail to respond to a gluten-free diet may require intervention with immunomodulating drugs. We report a case of refractory coeliac disease where remission was induced by the anti-tumour necrosis factor-alpha antibody infliximab and was maintained with prednisolone and azathioprine. 相似文献
106.
Pierre-Eric Juif Matthias Hoch Daniele D’Ambrosio Jasper Dingemanse 《Drugs in R&D》2015,15(2):203-210
Background
Ponesimod is a potent selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P1 receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis).Objectives
The aim of this study was to compare the relative bioavailability of two polymorphic forms of ponesimod in capsules (Form A versus Form C; Study 1) and the relative bioavailability of a capsule formulation and a tablet formulation (both polymorphic Form C; Study 2).Methods
Two open-label, randomized, two-way crossover studies in healthy subjects were performed. In Study 1, 12 male subjects received a single dose of 20 mg of polymorphic Form A or Form C of ponesimod in a capsule. In Study 2, 14 male and female subjects (ratio 1:1) received a single dose of 40 mg of polymorphic Form C of ponesimod in either a capsule or a tablet formulation. Pharmacokinetic and safety variables (clinical laboratory test results, vital signs, and an electrocardiogram) were assessed.Results
Comparison of the exposure to ponesimod following administration of the formulations in Study 1 showed that the 90 % confidence intervals of the geometric mean ratios for the area under the curve from time zero to infinity (AUC0–inf), the area under the curve from time zero to the time of the last measurable concentration (AUC0–t), the terminal half-life (t½), and the maximum plasma concentration (Cmax) were all within the 0.80–1.25 bioequivalence interval. In Study 2, more rapid absorption of ponesimod was observed from the tablet formulation than from the capsule formulation. There were no relevant differences in the safety and tolerability profiles between the different formulations.Conclusion
The two polymorphic forms of ponesimod and tablet versus capsule formulations were similar in terms of pharmacokinetics, safety, and tolerability. 相似文献107.
108.
Marie Pak Sue Wickner 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(10):4901-4906
ClpA, a newly discovered ATP-dependent molecular chaperone, remodels bacteriophage P1 RepA dimers into monomers, thereby activating the latent specific DNA binding activity of RepA. We investigated the mechanism of the chaperone activity of ClpA by dissociating the reaction into several steps and determining the role of nucleotide in each step. In the presence of ATP or a nonhydrolyzable ATP analog, the initial step is the self-assembly of ClpA and its association with inactive RepA dimers. ClpA-RepA complexes form rapidly and at 0°C but are relatively unstable. The next step is the conversion of unstable ClpA-RepA complexes into stable complexes in a time- and temperature-dependent reaction. The transition to stable ClpA-RepA complexes requires binding of ATP, but not ATP hydrolysis, because nonhydrolyzable ATP analogs satisfy the nucleotide requirement. The stable complexes contain approximately 1 mol of RepA dimer per mol of ClpA hexamer and are committed to activating RepA. In the last step of the reaction, active RepA is released upon exchange of ATP with the nonhydrolyzable ATP analog and ATP hydrolysis. Importantly, we discovered that one cycle of RepA binding to ClpA followed by ATP-dependent release is sufficient to convert inactive RepA to its active form. 相似文献
109.
Joseph E. Wagstaff Sue Klapholz Rochelle Easton Esposito 《Proceedings of the National Academy of Sciences of the United States of America》1982,79(9):2986-2990
Haploid yeast cells normally contain either the MATa or MATα mating-type allele and cannot undergo meiosis and spore formation. If both mating-type alleles are present as a consequence of chromosome III disomy (MATa/MATα), haploids initiate meiosis but do not successfully form spores, probably because the haploid chromosome complement is irregularly partitioned during meiotic nuclear division. We have demonstrated that the ochre-suppressible mutation spo13-1 enables haploid yeast cells disomic for chromosome III and heterozygous at the mating-type locus to complete meiosis and spore formation, yielding two haploid spores. Previous studies have shown that the absence of the wild-type SPO13 gene function permits diploid cells to bypass homologous chromosome segregation at meiosis I and proceed directly to meiosis II. During spo13-1 haploid meiosis, cells enter prophase of meiosis I. Genetic recombination, monitored on the chromosome III disome, occurs at levels similar to those seen in diploids, indicating that the level of exchange between homologs is an autonomous property of individual chromosomes and not dependent on exchange elsewhere in the genome. Exchange is then followed by a single meiosis II equational chromosome division. Recombination in spo13-1 haploids is blocked by the spo11-1 mutation, which also eliminates recombination between homologous chromosomes during conventional diploid meiosis. We conclude that Spo+ haploids expressing both a and α mating-type information attempt a SPO13-dependent meiosis I division, and that this division, in the absence of paired homologous chromosomes, is responsible for the failure of such haploids to complete normal gametogenesis. Our observations support the conclusion that initiation and completion of meiosis II and spore formation are not dependent on either completion of meiosis I or the presence of a diploid chromosome complement. 相似文献
110.
Benjamin F. Mundell Marianne T. Luetmer Hilal Maradit Kremers Sue Visscher Kurtis M. Hoppe Kenton R. Kaufman 《Journal of neuroengineering and rehabilitation》2018,15(1):58