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1.
CYP2C9 gene polymorphisms are widely studied in several ethnic groups, however they are less known in the Roma population. The aim of this work was to study the ethnic differences of the CYP2C9 allele distribution in a healthy Roma population in order to compare them with a healthy Hungarian population. A total of 535 Hungarian and 465 Roma volunteers were genotyped for the CYP2C92 (Arg144Cys) and CYP2C93 (Ile359Leu) allelic variants by PCR-RFLP assay. The frequencies of the CYP2C91, 2 and 3 alleles in the Hungarian population were 0.787, 0.125, and 0.088 and in Roma 0.727, 0.118, and 0.155, respectively. We found a significant difference in CYP2C93 prevalence between the Hungarian and Roma populations, which have therapeutic consequences ( p < 0.005). The distribution of 1/1, 1/2, 1/3, 2/2, 2/3, and 3/3 genotypes in Hungarians were 0.620, 0.195, 0.139, 0.021, 0.015, and 0.011, while in Roma were 0.533, 0.168, 0.219, 0.011, 0.047, and 0.022, respectively. A significant difference was found between the Hungarian and Roma populations regarding the 1/1, 1/3 and the 2/3 ( p < 0.005) genotypes. This is the first study to investigate the polymorphisms of CYP2C9 gene in the two largest populations in Hungary, healthy Hungarians and Roma. The prevalence of variant CYP2C9 alleles in the Hungarian population is similar to that observed in other European populations. In contrast, the Roma population differs from Hungarians, from most of other Caucasian groups, and from Indians in the incidence of CYP2C9 common variants. The difference in allele distribution patterns between the two populations studied has therapeutic implications as it influences the optimization of therapies. 相似文献
2.
Currently used electrocardiographic criteria for identifying patients with ST-elevation myocardial infarction (STEMI) perform with high specificity but low sensitivity. Our aim was to enhance ischemia-detection ability of conventional STEMI criteria based on 12-lead electrocardiogram (ECG) by adding new criteria using 3 vessel-specific leads (VSLs) derived from 12-lead ECG. Study data consisted of 12-lead ECGs acquired during 99 ischemic episodes caused by balloon inflation in, respectively, left anterior descending coronary artery (LAD; n = 35), right coronary artery (RCA; n = 47), and left circumflex coronary artery (LCx; n = 17). ST deviation was measured at J point in 12 standard leads, and for 3 VSLs, its value was derived from 12-lead ECG by using 8 independent predictor leads or just a pair of precordial leads combined with a pair of limb leads. Mean values of sensitivity (SE) and specificity (SP) of ischemia detection achieved with conventional STEMI vs VSL criteria were then obtained from bootstrap trials. We found that the detection of ischemic state by conventional criteria achieved the mean SE/SP of 60%/96% in the total set of ischemic episodes, 74%/97% in the LAD subgroup, 60%/94% in the RCA subgroup, and 36%/100% in the LCx subgroup. In comparison, the mean SE/SP values of VSLs derived from 8 independent leads of 12-lead ECG were, at 125- μV threshold, 76% /96% in the total set, 91% /97% in the LAD subgroup, 70%/94% in the RCA subgroup, and 71% /100% in the LCx subgroup (with asterisk denoting a statistically significant increase). The mean SE/SP of VSLs derived from some of the 4-predictor lead sets (namely, those including lead V 3) matched or exceeded values achieved by VSLs derived from 8 predictors; for instance, with predictor leads I, II, V 3, V 6 derived VSLs attained at 125- μV threshold the mean SE/SP of 80% /95% in the total set, 91% /97% in the LAD subgroup, 74%/92% in the RCA subgroup, and 71% /100% in the LCx subgroup. Based on these results, we conclude that, in our data set, 3 VSLs derived from the complete standard 12-lead ECG—and even from its subsets—can identify acute ischemia better than existing STEMI criteria. 相似文献
3.
Folate supplementation improves endothelial function in patients with hyperhomocysteinemia. Mechanistic insights into potential benefits of folate on vascular function in general population however, remain mysterious. Expression of dihydrofolate reductase (DHFR) was markedly increased by folic acid (FA, 50 μmol/L, 24 h) treatment in endothelial cells. Tetrahydrofolate (THF) is formed after incubation of purified DHFR or cellular extracts with 50 μmol/L of substrate dihydrofolic acid. THF could then be detected and quantified by high performance liquid chromatography (HPLC) with a fluorescent detector (295/365 nm). Using this novel and sensitive assay, we found that DHFR activity was significantly increased by FA. Furthermore, FA improved redox status of Ang II treated cells by increasing H 4B and NO bioavailability while decreasing superoxide (O 2−) production. It however failed to restore NO levels in DHFR siRNA-transfected or methotrexate pre-treated cells, implicating a specific and intermediate role of DHFR. In mice orally administrated with FA (15 mg/kg/day, 16 days), endothelial upregulation of DHFR expression and activity occurred in correspondence to improved NO and H 4B bioavailability, and this was highly effective in reducing Ang II infusion (0.7 mg/kg/day, 14 days)-stimulated aortic O 2− production. 5′-methyltetrahydrofolate (5′-MTHF) levels, GTPCH1 expression and activity remained unchanged in response to FA or Ang II treatment in vitro and in vivo. FA supplementation improves endothelial NO bioavailability via upregulation of DHFR expression and activity, and protects endothelial cells from Ang II-provoked oxidant stress both in vitro and in vivo. These observations likely represent a novel mechanism (intermediate role of DHFR) whereby FA induces vascular protection. 相似文献
4.
We have recently shown that a novel endothelial mitogen netrin-1 potently stimulates nitric oxide (NO ) production via a DCC-ERK1/2 dependent mechanism. In view of the well-established cardioprotective role of NO , the present study investigated whether netrin-1 is cardioprotective via NO signaling in the heart. Netrin-1 receptor DCC was abundantly expressed in the C57BL/6J mouse hearts. Perfusion of heart with netrin-1 (100 ng/mL) using a Langendorff system significantly increased NO production. Under ischemia/reperfusion (I/R), netrin-1 induced a substantial reduction in infarct size (21.8 ± 4.9% from 42.5 ± 3.6% in the controls), which was accompanied by an augmented production of NO . Pre-perfusion with DCC-antibody, U0126 (MEK1/2 inhibitor), L-NAME or PTIO (NO scavenger) attenuated protective effects of netrin-1 on infarct size and NO production, indicating upstream roles of DCC and ERK1/2 in NO production, as well as an essential role of NO in cardioprotection. Netrin-1 induced reduction in infarct size was significantly attenuated in DCC+/− mice, confirming an intermediate role of DCC. In additional experiments we found netrin-1 increased ERK1/2 and eNOS s1177 phosphorylation, and DCC protein expression, which was diminished by I/R. Furthermore, netrin-1-induced DCC upregulation was NO and ERK1/2-dependent, implicating a feed-forward mechanism. DAF-AM staining revealed enhanced NO production in both cardiac endothelial cells (ECs) and myocytes. In primarily isolated cardiomyocytes, netrin-1 also increased NO production, DCC abundance and ERK1/2 phosphorylation. Of note, cardiac apoptosis was significantly attenuated by netrin-1, which was reversed by DCC-antibody, U0126, L-NAME or PTIO. In summary, our data clearly demonstrate that netrin-1 potently protects the heart from I/R injury by stimulating NO production from cardiac ECs and myocytes. This potent effect is mediated by a DCC/ERK1/2/eNOS s1177/NO /DCC feed-forward mechanism in both cell types. 相似文献
5.
Recent evidence has suggested that erythrocytes naturally deficient in glycophorin A (GPA) have a reduced Vmax for monovalent anion exchange. Unanswered is whether miss-folding of band 3 during biosynthesis, or the absence of GPA modulation of properly folded band 3 is responsible. Here, I determine the effect of selective depletion of GPA on the kinetics of reversible binding of the competitive transport inhibitor DIDS (4,4′-diisothiocyanato-2,2′-stilbenedisulfonate) to properly folded band 3. Reversible binding of DIDS follows biphasic kinetics: a fast phase {DIDS + band 3 (DIDS − band 3), k1, k− 1} and a slower phase {(DIDS − band 3) (DIDS − band 3), k2, k− 2}. Selective depletion of GPA was accomplished by pretreating membranes with Triton X-100, over a range where erythrocyte hemolysis is inhibited by the detergent (0% to 0.03%, v/v). Pretreatment with sublytic Triton X-100: (a) virtually completely depleted GPA, (b) did not deplete membrane-bound band 3, and (c) slowed the overall rate of reversible binding of DIDS to band 3. Data analysis and model simulation studies indicated that the decrease in the rate of binding of DIDS was due exclusively to a decrease in k− 2, with no change in the initial rate of binding. Thus, depletion of GPA does not alter the native conformation of band 3 at the DIDS binding site, but rather modulates a conformational equilibrium between two states of the binary complex formed by the competitive inhibitor DIDS, reversibly bound to properly folded band 3. 相似文献
6.
Maternal cocaine administration during gestation caused a down-regulation of PKC expression in the heart of adult offspring resulting in an increased sensitivity to ischemia and reperfusion injury. The present study investigated the direct effect of cocaine in epigenetic modification of PKC gene repression in the fetal heart. Hearts were isolated from gestational day 17 fetal rats and treated with cocaine in an ex vivo organ culture system. Cocaine treatment for 48 h resulted in significant decreases in PKC protein and mRNA abundance and increases in CpG methylation at two SP1 binding sites in the PKC promoter region (− 346 and − 268). Electrophoretic mobility shift assays demonstrated that CpG methylation of both SP1 sites inhibited SP1 binding. Consistently, chromatin immunoprecipitation assays showed that cocaine treatment significantly decreased binding of SP1 to the SP1 sites in the intact fetal heart. Reporter gene assays revealed that site-directed mutations of CpG methylation at both SP1 sites significantly reduced the PKC promoter activity while methylation of a single site at either − 346 or − 268 did not have a significant effect. The causal effect of increased methylation in the cocaine-induced down-regulation of PKC was demonstrated with the use of DNA methylation inhibitors. The presence of either 5-aza-2′-deoxycytodine or procainamide blocked the cocaine-induced increase in SP1 sites methylation and decrease in PKC mRNA. The results demonstrate a direct effect of cocaine in epigenetic modification of DNA methylation and programming of cardiac PKC gene repression linking prenatal cocaine exposure and pathophysiological consequences in the heart of adult offspring. 相似文献
7.
We investigated whether a combination of mild calorie restriction (MCR) and high-intensity interval walking (HIW) improved physical fitness more than HIW alone in middle-aged and older overweight Japanese (40–69 years old, BMI 23.6 kg/m 2). Forty-seven women and 16 men were divided into MCR + HIW and HIW groups. All subjects performed HIW: 5 sets of 3-min low-intensity walking (40% peak aerobic capacity for walking, VO 2peak) and 3-min high-intensity walking (70% VO 2peak) per day, 4 days per week, for 16 weeks while energy expenditure was monitored with a tri-axial accelerometer. The MCR + HIW group consumed meal replacement formula (240 kcal): a mixture of low-carbohydrates and -fat and high-protein, for either lunch or dinner everyday and therefore, had 87% of the energy intake of the HIW group during the intervention period. Although the HIW group showed improvements in BMI, blood pressure, and several blood chemicals, the MCR + HIW group had greater improvement. Moreover, the medical expenditure for the 6 months including the intervention period was 59% lower in the MCR + HIW group than in the HIW group. Our strategy of a short-term combination of MCR and HIW may thus prevent lifestyle-associated diseases and improve health in middle-aged and older overweight Japanese. 相似文献
8.
The sarcolemmal Na +/HCO 3− cotransporter (NBC) plays an important role in intracellular pH (pH i) regulation in the heart. In the present work we studied, in isolated cat ventricular myocytes, the role of Angiotensin II (Ang II) and reactive oxygen species (ROS) production as potential activators of the NBC. pH i was measured in single cells in a medium with HCO 3− using the fluorescent pH indicator BCECF. The NH 4+ pulse method was used to induce an intracellular acid load and the acid efflux ( JH) in the presence of the Na +/H + exchanger blocker HOE642 (10 μM) was calculated as indicator of NBC activity. The following JH data are presented at pH i of 6.8 ( and # indicate p < 0.05 after ANOVA vs. control and Ang II, respectively). The basal JH (1.03 ± 0.12 mM/min, n = 11) was significantly increased in the presence of 100 nM Ang II (1.70 ± 0.15 mM/min, n = 8 ). This effect of Ang II was abolished when we added to the extracellular solution 2 mM MPG (ROS scavenger; 0.80 ± 0.08 mM/min, n = 11 #), 300 μM apocynin (NADPH oxidase blocker; 0.80 ± 0.13 mM/min, n = 6 #), 500 μM 5-hydroxidecanoate (mitochondrial ATP dependent K + channel, mK ATP, blocker; 0.97 ± 0.21 mM/min, n = 9 #), or the inhibitor of the MAP kinase ERK pathway U0126 (10 μM; 0.56 ± 0.18 mM/min, n = 6 #). We also determined the phosphorylation of ERK during the first min of acidosis and we detected that Ang II significantly enhanced the ERK phosphorylation levels, an effect that was cancelled by scavenging ROS with MPG. In conclusion, we propose that Ang II enhances the production of ROS through the activation of the NADPH oxidase, which in turn triggers mK ATP opening and mitochondrial ROS production (“ROS-induced ROS-release mechanism”). Finally, these mitochondrial ROS stimulate the ERK pathway, leading to the activation of the NBC. 相似文献
9.
The adverse effects of iodine deficiency (ID) intellectual impairment, damaged reproduction, goiter and hypo- and hyperthyroidism are well known and easily corrected with salt iodization, but they continue to impair health and socioeconomic development, with more than two billion people at risk worldwide. During the major global expansion of salt iodization over the past four decades, much of Europe has remained iodine deficient. Although every European country endorsed the goal of eliminating iodine deficiency at the 1992 World Health Assembly, control of iodine deficiency has received low priority in much of Europe. However, there has been recent progress in the region and the number of children with low iodine intakes has decreased by ca. 30% since 2003. This paper presents an estimate of the prevalence of iodine deficiency in Europe in 2010, based on a systematic review to update the WHO Vitamin and Mineral Nutrition Information System (VMNIS) database. 相似文献
10.
The family of selenoproteins have a broad range of functions, including protection against oxidative damage. Previous studies have shown that elevated levels of oxidative damage can induce accelerated loss of telomeric DNA during proliferation of mammalian cells. The incorporation of selenocysteine (Sec) into proteins in mammalian cells requires the Sec insertion sequence (SECIS) binding protein 2 (SBP2). Thus in the present study we have assessed the effect of knocking down the expression of SBP2 on telomere length. Following knock-down of SBP2 expression in two different human cell lines, the MSTO mesothelioma cell line (5 Kb average telomere length) and SY5Y neuroblastoma cell line (4.2 Kb average telomere length), we observed a significant reduction (−0.6 to −1.1 Kb; P 0.01) in telomere length as compared to control cells. This reduction in telomere length was independent of affects on telomerase, since both telomerase activity levels and Tert mRNA expression levels were not altered by knock-down of SBP2 expression. Furthermore, telomeres were particularly sensitive to S1 nuclease digestion following SBP2 knock-down, indicating an increased frequency of oxidative damage-induced lesions in the telomeric DNA in these cells. Together, these observations imply that selenoproteins may help protect telomeric reserve in mammalian cells. 相似文献
11.
This study investigated the role of 5-HT 2Areceptors and α1 -adrenoceptors in the contractile response to 5-HT in the first branch pulmonary artery of the rat and their interaction with endogenous nitric oxide. 5-HT and phenylephrine induced concentration-dependent contractions. The α1 -adrenoceptor antagonists prazosin, HV723 and phentolamine produced concentration-dependent rightward shifts of the 5-HT concentration-response curves (CRC) consistent with an action at α1-adrenoceptors. The 5-HT 2receptor antagonists ritanserin, ketanserin and methysergide produced rightward shifts that were less than would have been predicted for an action solely at 5-HT 2Areceptors. 5-HT and phenylephrine CRCs were shifted to the left by
-NAME. Endothelium denudation also increased the tissue sensitivity to 5-HT. In the presence of
-NAME, ketanserin produced greater antagonism of the 5-HT CRC but not the phenylephrine CRC. Ketanserin also produced greater antagonism of the 5-HT CRC in endothelium denuded rings compared with endothelium intact rings. These findings indicate (a) that both the α1 -adrenoceptor class and the 5-HT 2Areceptor is involved in the contractile response to 5-HT; (b) in the presence of endogenous nitric oxide the contractile response to 5-HT is mediated predominently by α1 -adrenoceptors; (c) inhibition of endogenous nitric oxide potentiates the 5-HT 2Areceptor-mediated component of the contraction. 相似文献
12.
The site-specific phospholamban phosphorylation was studied with respect to the interplay of cAMP- and Ca 2+signaling in neonatal rat cardiomyocytes. To elucidate the signal pathway(s) for the activation of Ca 2+/calmodulin-dependent protein kinase (CaMKII) we studied Thr17 phosphorylation of phospholamban in dependence of Ca 2+channel activation by S(-)-Bay K8644 and in dependence of the depletion of the sarcoplasmic reticulum Ca 2+stores by ryanodine or thapsigargin in the absence or presence of β -adrenergic stimulation. The isoproterenol (0.1 μ
)-induced Thr17 phosphorylation was potentiated 2.5-fold in presence of 1 μ
S(-)-Bay K8644. Interestingly, S(-)-Bay K8644 alone was also able to induce Thr17 phosphorylation in a dose- and time-dependent fashion. Ryanodine (1.0 μ
) reduced both the isoproterenol (0.1 μ
) and S(-)-Bay K8644-(1 μ
) mediated Thr17 phosphorylation by about 90%. Thapsigargin (1 μ
) diminished the S(-)-Bay K8644 and isoproterenol-associated Thr17 phosphorylation by 53.5±6.3% and 92.5±11.1%, respectively. Ser16 phosphorylation was not affected under these conditions. KN-93 reduced the Thr17 phosphorylation by S(-)-Bay K8644 and isoproterenol to levels of 1.1±0.3% and 8.6±2.1%, respectively. However, the effect of KN-93 was attenuated (47.8±3.6%) in isoproterenol prestimulated cells. Protein phosphatase inhibition by okadaic acid increased exclusively the Ser16 phosphorylation. In summary, our results reflect a cross-talk between β -adrenoceptor stimulation and intracellular Ca 2+at the level of CaMKII-mediated phospholamban phosphorylation in neonatal rat cardiomyocytes. We report conditions which exclusively produce Thr17 or Ser16 phosphorylation. We postulate that Ca 2+transport systems of the sarcoplasmic reticulum are critical determinants for the activation of CaMKII that catalyzes phosphorylation of phospholamban. 相似文献
13.
A survey of the litterature was made to precise the characteristics of infectious endocarditis (IE) in the elderly as defined by the diagnostic criteria of Von Reyn. The IE presents at times with a fallacious symptomatology where fever and cardiac bruit are often lacking. With regard to the cardiac disease, there is an increase in the incidence of calcifying degenerative valvulopathy responsible for IE. On the bacteriological point of view, streptococcal infections are still predominent in etiologgy for endocarditis but opportunistic infections dues to other bacterial species are increasing in frequency. Lastly, on the therapeutical side, there is a new trend to reduce the proeminence of curative treatment with aminoglycoside agents in favor of the antibiotic prophylaxis. RésuméLe but de ce travail est de préciser, par une revue de la littérature, les particularités de l'endocardite infectieuse (El) du sujet âgé (critères diagnostiques de Von Reyn). L'El se distingue par une symptomatologie clinique trompeuse, où fièvre et souffle sont inconstants. Au plan cardiaque, les valvulopathies dégénératives calcifiantes responsables d'El sont à prendre en considération. Sur le plan bactériologique, si les El à streptocoques dominent, les greffes d'origine nosocomiale, provoquées par d'autres espèces bactériennes, sont en augmentation. Enfin, en matière de thérapeutique, on tend à restreindre la place des aminosides en traitement curatif, et à majorer celle de l'antibioprophylaxie. PDF (355 K)
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