Objective— Nitroglycerine-induced vasodilation has been used as a control test for flow-mediated vasodilation (FMD) to differentiate endothelium-dependent from endothelium-independent response when evaluating endothelial function in humans. Recently, nitroglycerine-induced vasodilation has also been reported to be impaired in patients with atherosclerosis. The purpose of this study was to determine the relationships between nitroglycerine-induced vasodilation and cardiovascular risk factors. Approach and Results— We measured nitroglycerine-induced vasodilation and FMD in 436 subjects who underwent health examinations (mean age, 53±19 years; age range, 19–86 years), including patients with cardiovascular diseases. There was a significant relationship between nitroglycerine-induced vasodilation and FMD ( r =0.42; P <0.001). Univariate regression analysis revealed that nitroglycerine-induced vasodilation correlated with age ( r =−0.34; P <0.001), systolic blood pressure ( r =−0.32; P <0.001), diastolic blood pressure ( r =−0.24; P <0.001), heart rate ( r =−0.21; P <0.001), glucose ( r =−0.23; P <0.001), and smoking pack-year ( r =−0.12; P =0.01), as well as Framingham risk score ( r =−0.30; P <0.001). Nitroglycerine-induced vasodilation was significantly smaller in patients with cardiovascular disease than in both subjects with and without cardiovascular risk factors (10.5±5.6% versus 13.7±5.4% and 15.3±4.3%; P <0.001, respectively), whereas there was no significant difference in nitroglycerine-induced vasodilation between subjects with and without cardiovascular risk factors. Multivariate analysis revealed that male sex, body mass index, hypertension, diabetes mellitus, baseline brachial artery diameter, and FMD were independent predictors of nitroglycerine-induced vasodilation. Conclusions— These findings suggest that nitroglycerine-induced vasodilation may be a marker of the grade of atherosclerosis. FMD should be interpreted as an index of vascular function reflecting both endothelium-dependent vasodilation and endothelium-independent vasodilation in subjects with impaired nitroglycerine-induced vasodilation.

Objective: To estimate total numbers of undiagnosed carriers of hepatitis C virus (HCV) and hepatitis B virus (HBV) in Japan. Methods: Area- and age-specific prevalence of HCV as well as HBV was determined in the first-time blood donors [20–39 years (n = 2,429,364)] and examinees of periodical health check-ups [40–74 years (6,204,968 for HCV and 6,228,967 for HBV)] in Japan. Prevalence in adolescents [5–19 years (79,256 for HCV and 68,792 for HBV)] was determined in a single prefecture, and that of HCV in the elderly (≧75 years) was estimated by the exponential model. HBV infection was determined by the detection of hepatitis B surface antigen, and HCV infection by either the algorithm or assuming persistent infection in 70% of the individuals with antibody to HCV. Results: Of the total population of 127,285,653 in 2005, 807,903 (95% CI 679,886–974,292) were estimated to be infected with HCV at a carrier rate of 0.63%, and 903,145 (837,189–969,572) with HBV at that of 0.71%. Conclusion: Accurate estimation of undiagnosed HCV and HBV carriers in the general population would help to predict the future burden of liver disease, and take appropriate measures for improving healthcare.

Decreased total adiponectin is an independent risk factor for the progression to type 2 diabetes in Japanese-Americans. Moreover, HMW adiponectin more closely associates with the progression to type 2 diabetes when compared with total adiponectin.

DEC1 suppresses CLOCK/BMAL1-enhanced promoter activity, but its role in the circadian system of mammals remains unclear. Here we examined the effect of Dec1 overexpression or deficiency on circadian gene expression triggered with 50% serum. Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions, whereas it had little effect on the circadian phase of Per2 and Cry1 carrying CACGTT E boxes. In contrast, Dec1 deficiency advanced the phase of the E-box-containing clock genes but not that of the E-box-containing clock genes. Accordingly, DEC1 showed strong binding and transrepression on the E box, but not on the E box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Dec1 ؊/؊ mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle. Knockdown of Dec2 with small interfering RNA advanced the phase of Dec1 and Dbp expression, and double knockdown of Dec1 and Dec2 had much stronger effects on the expression of the E-box-containing clock genes. These findings suggest that DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock.The mammalian molecular clock system consists of various clock genes and their protein products involved in interlocked feedback loops of transcriptional and translational regulation through clock elements such as CACGTG E-box, D-box, and ROR/REV-ERB binding elements (RORE) (18,24). Among these regulatory sequences, the E box is thought to be the most important element in the molecular oscillatory system, since it is the binding site for the CLOCK/BMAL1 heterodimer, which up-regulates various clock genes, including Dec1, Dec2, Per1, Dbp, and Rev-erb␣. In this regulatory system, PER, CRY, and DEC serve as negative factors for transcription from E-boxdriven promoters, and the E-box-like element EЈ box (CAC GTT) was recently shown to be involved in the direct regulation of Per2 and Cry1 genes by CLOCK/BMAL1 (1, 31, 34). RORE, on the other hand, is a clock element to which the transcriptional activators-ROR␣/ROR␤/ROR␥-and repressors-REV-ERB␣/REV-ERB␤-bind, and ROR and REV-ERB regulate the circadian expression of Bmal1, Clock, Npas2, and Cry1 via RORE (31).In the mammalian clock system, DEC1 (also known as BHLHB2, STRA13, or SHARP2) and DEC2 (BHLHB3 or SHARP1) serve as transcriptional repressors for CLOCK/ BMAL1-enhanced promoter activity, through binding to E boxes or interaction with BMAL1 (12,14,18,26). Among suppressive factors for E boxes, DEC1 and DEC2 can bind directly to E boxes through their basic helix-loop-helix DNA binding domains (18,26), although it remains unclear whether DEC1 and DEC2 also bind to the EЈ boxes. In contrast, PER and CRY interact with the CLOCK/BMAL1 heterodimer but cannot bind directly to E/EЈ boxes, since they have no DNA binding domain.Dec1 expression shows...

Testosterone deficiency is a common finding among male ESRD patients, and it is independently associated with inflammation, cardiovascular co-morbidity and outcome. Future studies are needed to determine the potential adverse effects of male hypogonadism in ESRD and the possibility of improving risk profile, quality of life, and ultimately outcome with testosterone supplementation in these patients.

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that have regenerative capability and exert paracrine actions on damaged tissues. Since peritoneal fibrosis is a serious complication of peritoneal dialysis, we tested whether MSCs suppress this using a chlorhexidine gluconate model in rats. Although MSCs isolated from green fluorescent protein–positive rats were detected for only 3 days following their injection, immunohistochemical staining showed that MSCs suppressed the expression of mesenchymal cells, their effects on the deposition of extracellular matrix proteins, and the infiltration of macrophages for 14 days. Moreover, MSCs reduced the functional impairment of the peritoneal membrane. Cocultures of MSCs and human peritoneal mesothelial cells using a Transwell system indicated that the beneficial effects of MSCs on the glucose-induced upregulation of transforming growth factor-β1(TGF-β1) and fibronectin mRNA expression in the human cells were likely due to paracrine actions. Preincubation in MSC-conditioned medium suppressed TGF-β1-induced epithelial-to-mesenchymal transition, α-smooth muscle actin, and the decrease in zonula occludens-1 in cultured human peritoneal mesothelial cells. Although bone morphogenic protein 7 was not detected, MSCs secreted hepatocyte growth factor and a neutralizing antibody to this inhibited TGF-β1 signaling. Thus, our findings imply that MSCs ameliorate experimental peritoneal fibrosis by suppressing inflammation and TGF-β1 signaling in a paracrine manner.

Background and objectives: The soluble receptor of advanced glycation end products (sRAGE) may exert anti-inflammatory protective roles on the vasculature. In contrast, the RAGE ligand S100A12 (also known as EN-RAGE) contributes to inflammation and the development of atherosclerosis in animal models. Whether alterations at this level contribute to the increased mortality observed in patients on dialysis is currently unknown.Design, setting, participants, & measurements: Prospective study including 184 prevalent hemodialysis patients and 50 healthy controls matched for age and gender. Plasma concentrations of S100A12 and sRAGE were studied in relation to risk profile and mortality after a median follow-up period of 41 months.Results: S100A12 and sRAGE levels were significantly elevated in hemodialysis patients compared with healthy controls. S100A12 had a strong positive correlation with C-reactive protein and IL-6, whereas sRAGE negatively associated with C-reactive protein. S100A12, but not sRAGE, was independently and positively associated with clinical cardiovascular disease (CVD). During follow-up, 85 (33 cardiovascular-related) deaths occurred. Whereas sRAGE did not predict mortality, S100A12 was associated with both all-cause (per log 10 ng/ml hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.18 to 3.15) and CVD-related (HR 3.23, 95% CI 1.48 to 7.01) mortality, even after adjustment for age, sex, vintage, and comorbidities. Further adjustment for inflammation made the predictive value of S100A12 disappear for all-cause mortality, but still persisted in CVD-related mortality.Conclusions: Circulating S100A12 and sRAGE are both elevated in hemodialysis patients. However, only S100A12 associates with mortality, partly explained by its links with inflammation.

ObjectiveTo determine the relationships between flow-mediated vasodilation (FMD) and cardiovascular risk factors, and to evaluate confounding factors for measurement of FMD in a large general population in Japan.MethodsThis was a cross-sectional study. A total of 5314 Japanese adults recruited from people who underwent health screening from 1 April 2010 to 31 August 2012 at 3 general hospitals in Japan. Patients’ risk factors (age, Body Mass Index, blood pressure, cholesterol parameters, glucose level and HbA1c level) and prevalence of cardiovascular disease (coronary heart disease and cerebrovascular disease) were investigated.ResultsUnivariate regression analysis revealed that FMD correlated with age (r=−0.27, p<0.001), Body Mass Index (r=−0.14, p<0.001), systolic blood pressure (r=−0.18, p<0.001), diastolic blood pressure (r=−0.13, p<0.001), total cholesterol (r=−0.07, p<0.001), triglycerides (r=−0.10, p<0.001), high-density lipoprotein cholesterol (r=0.06, p<0.001), low-density lipoprotein cholesterol (r=−0.04, p=0.01), glucose level (r=−0.14, p<0.001), HbA1c (r=−0.14, p<0.001), and baseline brachial artery diameter (r=−0.43, p<0.001) as well as Framingham Risk score (r=−0.29, p<0.001). Multivariate analysis revealed that age (t value=−9.17, p<0.001), sex (t value=9.29, p<0.001), Body Mass Index (t value=4.27, p<0.001), systolic blood pressure (t value=−2.86, p=0.004), diabetes mellitus (t value=−4.19, p<0.001), smoking (t value=−2.56, p=0.01), and baseline brachial artery diameter (t value=−29.4, p<0.001) were independent predictors of FMD.ConclusionsFMD may be a marker of the grade of atherosclerosis and may be used as a surrogate marker of cardiovascular outcomes. Age, sex, Body Mass Index, systolic blood pressure, diabetes mellitus, smoking and, particularly, baseline brachial artery diameter are potential confounding factors in the measurement of FMD.