Abstract Background Ethnic differences in prevalence and severity of coronary artery disease are well established and are usually attributed to risk factors variation. This study investigates the ...differences in coronary artery narrowing and coronary calcification between two age- and gender-matched cohorts of South Asian and Caucasian symptomatic angina patients. Methods We identified 101 symptomatic angina patients of South Asian origin who had undergone CT angiography and calcium scoring, and compared them with 101 age and gender matched Caucasian patients. Results South Asians had a greater mean number of arterial segments with both obstructive and non-obstructive plaque than Caucasians (p = 0.006 and p = 0.0003, respectively) and higher prevalence of triple-vessel disease (p = 0.0004). Similarly, South Asians had a higher mean CAC score (p < 0.0001) and the percentage of South Asians with CAC > 0 and in all categories of CAC score 100–1000 were also higher, as was the number of arterial segments with calcified and non-calcified plaque. These results were more marked in patients aged > 50 but in those ≤ 50, Caucasians showed a higher mean number of diseased segments (p = 0.019), with non-obstructive plaque (p = 0.02), possibly suggesting that Caucasians are likely to have more diffuse atherosclerosis at an earlier age. CAC prevalence and severity in this age-group were not significantly different between South Asians and Caucasians. Conclusion Despite similar conventional risk factors for CAD, symptomatic South Asians seem to have more aggressive and diffuse arterial calcification compared to Caucasians. These differences are more profound above the age of 50, suggesting potential genetic or other risk factors yet to be determined.
We present our analysis of Kepler observations of 29 RR Lyrae stars, based on 138 d of observation. We report precise pulsation periods for all stars. Nine of these stars had incorrect or unknown ...periods in the literature. 14 of the stars exhibit both amplitude and phase Blazhko modulations, with Blazhko periods ranging from 27.7 to more than 200 d. For V445 Lyr, a longer secondary variation is also observed in addition to its 53.2-d Blazhko period. The unprecedented precision of the Kepler photometry has led to the discovery of the the smallest modulations detected so far. Moreover, additional frequencies beyond the well-known harmonics and Blazhko multiplets have been found. These frequencies are located around the half-integer multiples of the main pulsation frequency for at least three stars. In four stars, these frequencies are close to the first and/or second overtone modes. The amplitudes of these periodicities seem to vary over the Blazhko cycle. V350 Lyr, a non-Blazhko star in our sample, is the first example of a double-mode RR Lyrae star that pulsates in its fundamental and second overtone modes.
Background Soy protein foods have attracted attention as useful plant protein foods with mild cholesterol-lowering effects that are suitable for inclusion in therapeutic diets. But on the basis of ...the lack of consistency in significant cholesterol reduction by soy in 46 randomized controlled trials, the US Food and Drug Administration (FDA) is reassessing whether the 1999 heart health claim for soy protein should be revoked. Methods and Results We have, therefore, performed a cumulative meta-analysis on the 46 soy trials identified by the FDA to determine if at any time, since the 1999 FDA final rule that established the soy heart health claim, the soy effect on serum cholesterol lost significance. The cumulative meta-analysis for both total cholesterol and low-density lipoprotein cholesterol demonstrated preservation of the small, but significant, reductions seen both before and during the subsequent 14 years since the health claim was originally approved. For low-density lipoprotein cholesterol, the mean reduction in 1999 was -6.3 mg/dL (95% CI, -8.7 to -3.9 mg/dL; P=0.00001) and remained in the range of -4.2 to -6.7 mg/dL ( P=0.0006 to P=0.0002, respectively) in the years after 1999. At no time point did the total cholesterol or low-density lipoprotein cholesterol reductions lose significance or were the differences at individual time points in the cumulative meta-analysis significantly different from those seen in 1999 when the health claim was approved. Conclusions A cumulative meta-analysis of the data selected by the FDA indicates continued significance of total cholesterol and low-density lipoprotein cholesterol reduction after soy consumption and supports the rationale behind the original soy FDA heart health claim.
Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has been implicated in both DNA damage induction and aberrant cell signalling in various tissue and cell backgrounds. We ...investigated here the role of iNOS and NO in DNA damage induction and nuclear factor-kappa B (NF-κB) signalling in esophageal cells in vitro. As esophageal adenocarcinoma develops in a background of Barrett's esophagus secondary to reflux disease, it is possible that inflammatory mediators like NO may be important in esophageal cancer development. We show that reflux components like stomach acid and bile acids deoxycholic acid (DCA) can induce iNOS gene and protein expression and produce NO generation in esophageal cells, using real-time PCR, western blotting and NO sensitive fluorescent probes, respectively. This up-regulation of iNOS expression was not dependent on NF-κB activity. DCA-induced DNA damage was independent of NF-κB and only partially dependent on iNOS and NO, as measured by the micronucleus assay. These same reflux constituents also activated the oncogenic transcription factor NF-κB, as measured by transcription factor enzyme-linked immunosorbent assay and gene expression studies with NF-κB linked genes (e.g. interleukin-8). Importantly, we show here for the first time that basal levels of NF-κB activity (and possibly acid and DCA-induced NF-κB) are dependent on iNOS/NO and this may lead to a positive feedback loop whereby induced iNOS is upstream of NF-κB, hence prolonging and potentially amplifying this signalling, presumably through NO activation of NF-κB. Furthermore, we confirm increased protein levels of iNOS in esophageal adenocarcinoma and, therefore, in neoplastic development in the esophagus.
Background
Zofenopril, a sulfhydrylated angiotensin‐converting enzyme inhibitor (ACEI), reduces mortality and morbidity in infarcted patients to a greater extent than do other ACEIs. Zofenopril is a ...unique ACEI that has been shown to increase hydrogen sulfide (H2S) bioavailability and nitric oxide (NO) levels via bradykinin‐dependent signaling. Both H2S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H2S and NO bioavailability and cardiac damage in murine and swine models of myocardial ischemia/reperfusion (I/R) injury.
Methods and Results
Zofenopril (10 mg/kg PO) was administered for 1, 8, and 24 hours to establish optimal dosing in mice. Myocardial and plasma H2S and NO levels were measured along with the levels of H2S and NO enzymes (cystathionine β‐synthase, cystathionine γ‐lyase, 3‐mercaptopyruvate sulfur transferase, and endothelial nitric oxide synthase). Mice received 8 hours of zofenopril or vehicle pretreatment followed by 45 minutes of ischemia and 24 hours of reperfusion. Pigs received placebo or zofenopril (30 mg/daily orally) 7 days before 75 minutes of ischemia and 48 hours of reperfusion. Zofenopril significantly augmented both plasma and myocardial H2S and NO levels in mice and plasma H2S (sulfane sulfur) in pigs. Cystathionine β‐synthase, cystathionine γ‐lyase, 3‐mercaptopyruvate sulfur transferase, and total endothelial nitric oxide synthase levels were unaltered, while phospho‐endothelial nitric oxide synthase1177 was significantly increased in mice. Pretreatment with zofenopril significantly reduced myocardial infarct size and cardiac troponin I levels after I/R injury in both mice and swine. Zofenopril also significantly preserved ischemic zone endocardial blood flow at reperfusion in pigs after I/R.
Conclusions
Zofenopril‐mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling.
Abstract Background and aim Compared to a DASH-type diet, an intensively applied dietary portfolio reduced diastolic blood pressure at 24 weeks as a secondary outcome in a previous study. Due to the ...importance of strategies to reduce blood pressure, we performed an exploratory analysis pooling data from intensively and routinely applied portfolio treatments from the same study to assess the effect over time on systolic, diastolic and mean arterial pressure (MAP), and the relation to sodium (Na+ ), potassium (K+ ), and portfolio components. Methods and results 241 participants with hyperlipidemia, from four academic centers across Canada were randomized and completed either a DASH-type diet (control n = 82) or a dietary portfolio that included, soy protein, viscous fibers and nuts (n = 159) for 24 weeks. Fasting measures and 7-day food records were obtained at weeks 0, 12 and 24, with 24-h urines at weeks 0 and 24. The dietary portfolio reduced systolic, diastolic and mean arterial blood pressure compared to the control by 2.1 mm Hg (95% CI, 4.2 to −0.1 mm Hg) (p = 0.056), 1.8 mm Hg (CI, 3.2 to 0.4 mm Hg) (p = 0.013) and 1.9 mm Hg (CI, 3.4 to 0.4 mm Hg) (p = 0.015), respectively. Blood pressure reductions were small at 12 weeks and only reached significance at 24 weeks. Nuts, soy and viscous fiber all related negatively to change in mean arterial pressure (ρ = −0.15 to −0.17, p ≤ 0.016) as did urinary potassium (ρ = −0.25, p = 0.001), while the Na+ /K+ ratio was positively associated (ρ = 0.20, p = 0.010). Conclusions Consumption of a cholesterol-lowering dietary portfolio also decreased blood pressure by comparison with a healthy DASH-type diet. Clinical Trial Reg. No. NCT00438425 , clinicaltrials.gov.
At 18 months, children engage in a variety of social behaviors that reflect their nascent ability to understand the intentions of other people (e.g. joint attention, empathy, cooperation and ...self‐recognition). Although numerous contextual factors have been shown to predict social cognition in young children, the genetic underpinnings of social‐cognitive traits has been understudied in this age group. Owing to the known effects of oxytocin on adult social cognition and psychopathology, this study hypothesized that variability in the oxytocin receptor gene (OXTR) would be associated with social cognition in children at 18 months. Participants consisted of 350 children (182 males; 168 females) who were part of an ongoing longitudinal study that aimed to assess environmental and genetic contributions to children's cognitive and socio‐emotional functioning. At 18 months, social cognition was measured using previously validated and developmentally sensitive tasks assessing children's joint attention, empathy, cooperation and self‐recognition. Five potentially functional OXTR variants were genotyped: rs1042778, rs2254298, rs11131149, rs237897 and rs237899. A family‐based association design was used to control for population admixture and stratification, and additional non‐genomic covariates were controlled. Results showed that variability in rs11131149 was significantly associated with social cognition (P = 0.009), with more copies of the major allele related to higher social cognition, and more copies of the minor (risk) allele associated with lower social cognition. A haplotype consisting of rs11131149–rs2254298 was also associated with social cognition (P = 0.020). Implications for normative and pathological development are discussed, and key areas for future research are proposed.
Variability in the oxytocin receptor (OXTR) gene is associated with social cognition at 18 months, the earliest known association in human children to date.
Paravalvular leaks (PVLs) are a well-recognized complication of prosthetic valves that are detected up to 18% of all implanted surgical valves. Perioperative morbidity is thought to be lower in ...percutaneous compared to surgical PVL repair. However, a direct comparison of PVL closure techniques has never been performed. Our study is the first to demonstrate that elective PVL closure with monitored anesthesia care can be achieved with high success and low complications rates resulting in short hospital stays.
This is a retrospective cohort of patients admitted electively for catheter-based treatment of symptomatic prosthetic paravalvular regurgitation from Jan 2013 to April 2018. Both mitral and aortic PVLs were included. Patients' demographics, risk factors, procedural outcomes, In-hospital and thirty-day mortality were all reported. We followed the Valve Academic Research Consortium (VARC) criteria to define device and procedural technical success. In-hospital and 30- day outcomes were assessed by retrospective chart review.
A total of 54 PVLs in thirty-seven patients were repaired (65% aortic & 35% mitral). The mean-age in the mitral cohort was lower than the aortic cohort (61 vs 72years, P<0.0001) but the two groups shared similar clinical risk factors (P>0.05). Average hospital stay was 1–2days (<1.5days overall cohort) which was significantly lower in the aortic compared to the mitral cohort (P=0.009). All procedures were guided by TEE under conscious sedation with monitored anesthesia care. Procedural technical success defined as any significant residual shunt was 81% in the overall cohort and 88% in the aortic group. No procedural deaths were reported. Short-term mortality during the first 30days was 5.4% (two patients).
Elective catheter-based repair of symptomatic prosthetic paravalvular regurgitation appears to be safe and effective. The use of conscious sedation with monitored anesthesia care resulted in short hospital stay.
•Describe current standard techniques for PVL closure•Discuss the role of conscious sedation in PVL closure•Comparison of different institutional published experiences in PVL closure and sedation•Summarize key points for successful PVL closure.
Our objective was to examine the value of phrenic nerve conduction studies (PNCS) in quantifying diaphragm dysfunction in ALS, as no ideal test of respiratory insufficiency exists in ALS. We ...prospectively recorded bilateral PNCS, forced vital capacity (FVC), maximum inspiratory pressure (MIP), sniff nasal inspiratory pressure (SNIP), respiratory rate, ALSFRS-R, and respiratory symptoms in 100 ALS patients attending our clinic over a nine-month period. Survival data were collected for two years. Results showed that PNCS were reproducible and well tolerated. When the Pamp was abnormal (<0.3 mV), the relative risk of a respiratory rate >18 was 7.2 (95% CI 2.2-37.2, p <0.01) compared with a Pamp ≥0.3 mV. Similarly, the relative risk of orthopnea was 3.5 (95% CI 1.6-8.7, p <0.01) and dyspnea 2.4 (95% CI 1.4-4.0, p <0.01). FVC had the strongest correlation with Pamp (R
2
= 0.48 (p <0.001)). Fourteen of 15 patients with a FVC <50% had a Pamp <0.3 mV. However, eight with a Pamp <0.3 had a FVC >80%. The median survival was 1.07 years when the Pamp was <0.3 mV and >2 years when the Pamp was >0.3 mV (p <0.001). In conclusion, the phrenic Pamp correlated closely with multiple symptoms, signs, and laboratory measures of respiratory insufficiency and may prove to be a useful biomarker of respiratory dysfunction in ALS.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Inflammasomes are important multiprotein regulatory complexes of innate immunity and have recently emerged as playing divergent roles in numerous inflammation-associated cancers. Among these include ...gastric cancer (GC), the third leading cause of cancer-associated death worldwide, and we have previously discovered a pro-tumorigenic role for the key inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) in the spontaneous genetic
mouse model for GC. However, the identity of the specific pattern recognition receptors (PRRs) that activate tumor-promoting inflammasomes during GC is unknown. Here, we investigated the role of the best-characterized inflammasome-associated PRR, nucleotide-binding domain, and leucine-rich repeat containing receptor, pyrin domain-containing (NLRP) 3, in GC. In gastric tumors of
mice, although NLRP3 expression was elevated at the mRNA (qPCR) and protein (immunohistochemistry) levels, genetic ablation of NLRP3 in
:
mice did not alleviate the development of gastric tumors. Similarly, cellular processes associated with tumorigenesis in the gastric mucosa, namely, proliferation, apoptosis, and inflammation, were comparable between
and
:
mice. Furthermore, inflammasome activation levels, determined by immunoblotting and immunohistochemistry for cleaved Caspase-1, which along with ASC is another integral component of inflammasome complexes, were unchanged in
and
:
gastric tumors. We also observed variable NLRP3 expression levels (mRNA and protein) among independent GC patient cohorts, and NLRP3 was not prognostic for survival outcomes. Taken together, these data suggest that NLRP3 does not play a major role in promoting inflammasome-driven gastric tumorigenesis, and thus pave the way for further investigations to uncover the key inflammasome-associated PRR implicated in GC.
PDF
