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Aim The risk factors for ischemic heart disease (IHD) or cerebrovascular accident (CVA) in elderly diabetic individuals with type IIb dyslipidemia are not fully known. Therefore, we investigated the relationship between lipid levels and IHD and CVA in diabetic individuals with type IIb dyslipidemia. Method The Japan Cholesterol and Diabetes Mellitus Study is a prospective cohort study of 4014 type 2 diabetic patients (1936 women; age 67.4 ± 9.5 years). The primary end-points were the onset of IHD or CVA. Lipid and glucose levels, and other factors were investigated in relation to the occurrence of IHD or CVA. A total of 462 participants were included in the group of patients with type IIb dyslipidemia. Results The 462 diabetic participants with type IIb dyslipidemia were divided into those who were aged 75 years (n = 168, 190 and 104, respectively). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol/HDL-C were significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged more...

Chemical dry etching of Si was performed using the reaction of F2 + NO → F + FNO at an elevated temperature. The etched profile, surface morphology, and surface chemical bonding structures, measured by a scanning electron microscope, X-ray photoelectron spectroscopy (XPS), and a Fourier transform infrared spectrometer (FT-IR), were significantly changed when the substrate was heated at 27 and 300 °C. Differences in total energies of Si before and after the chemical reaction with gas molecules in the etching apparatus were theoretically calculated by the density functional theory (DFT) using CAM-B3LYP/6-311G+(d,p) in Gaussian 09. The possible change in chemical bonding structures during and after the Si etching was considered by correlating the measured XPS and FT-IR spectra and the DFT calculation results. When the Si sample was heated at 27∼60 °C, the nanoporous features were observed since molecules present in the gas phase remained in the condensed layer near the Si surface and they reacted with the Si... more...

We have been investigating a plasmaless Si chemical dry etching in NO/F2 gas mixtures using the F produced by the exothermic reaction of F2 + NO → FNO + F at room temperature. The effect of the change in the flow rate ratio of NO and F2, fNO/fF2, on the etch rate, the chemical bonding structures, and the surface morphology was measured by laser microscopy, Fourier transform infrared spectrometer, scanning electron microscopy, and scanning white light interferometry and results were compared with the calculated F flux. Total energy variations and their changes in chemical bonding structures before and after the reactions of molecules in the gas phase and the Si surface were considered using the molecular orbital (MO) method. On the basis of the MO calculation using a Si(100)-2×1 cluster model, F was necessary to form a dangling bond at the surface of Si that would trigger subsequent chemical reactions of Si with F2, NO, F, or FNO. The etch rate and surface roughness increased with the addition of NO up to ... more...

Objective There is little evidence showing that inhabitants of urban areas engage in more physical activity than do rural ones, although accumulating evidence concerning the best neighborhood environments conducive to physical activity supports the idea. This study sought to fill the research gap by examining the association between city scale and daily steps using data from Japan's National Health and Nutrition Survey (NHNS).Methods We analyzed data from 15,763 men and 18,479 women aged 20 years and older who participated in a one-day pedometer measurement during any part of the NHNS between 2006 and 2010. The data obtained for these years were combined into a single data set. City scale was categorized into 5 groups based on population: 1) 12 large cities and 23 wards, 2) population greater than 150,000, 3) population 50,000-150,000, 4) population less than 50,000, and 5) towns and villages. Differences in daily steps among city scale groups were analyzed using an ANCOVA, adjusting for age by gender. The Bonferroni method was employed for multiple comparisons, and linear regression was used to test for linear trends. Subgroup analyses were performed by age (20-39, 40-64, older than 64), and job status. The study was approved by the Tokyo Medical University ethics committee, and use of these data complied with the Statistics Act of Japan.Results The steps per day for men after adjusting for age were Group 1 : 7,494±4,429 (mean±SD), Group 2 : 7,407±4,428, Group 3 : 7,206±4,428, Group 4 : 6,911±4,428, and Group 5 : 6,715±4,429. Women's daily steps according to city scale group were 6,767±3,648, 6,386±3,647, 6,062±3,646, 6,069±3,649, and 6,070±3,649 for Groups 1 through 5, respectively. There were overall statistically significant differences (ANCOVA, P0.001) between both genders. The larger the city scale, the more mean daily steps that were taken by both men and women (P values for both trends0.001). Subgroup analyses revealed significant differences in the mean daily steps by city scale, regardless of age or job status for both genders. There were no significant differences among Groups 3, 4, or 5 among unemployed men, men older than 64, or overall women, which differed from the results for men with jobs, who took fewer steps in smaller cities.Conclusions Our study showed that men and women living in larger cities took more steps compared to those living in smaller cities. Subgroup analyses further revealed that the associations between city scale and physical activity differed according to gender, age, and job status. more...

We investigated the effects of combining 1 g of l-citrulline and 1 g of l-arginine as oral supplementation on plasma l-arginine levels in healthy males. Oral l-citrulline plus l-arginine supplementation more efficiently increased plasma l-arginine levels than 2 g of l-citrulline or l-arginine, suggesting that oral l-citrulline and l-arginine increase plasma l-arginine levels more effectively in humans when combined. more...

Nitric oxide (NO) plays a key role in the maintenance of vascular tone, contributing to the functional regulation of arterial stiffness. Although oral L-citrulline could become the effective precursor of L-arginine (substrate for endothelial NO synthase) via the L-citrulline/ L-arginine pathway, little is known about the efficacy of L-citrulline application on arterial stiffness.We examined the short-term effects of L-citrulline supplementation on arterial stiffness in humans.In a double-blind, randomized, placebo-controlled parallel-group trial, 15 healthy male subjects (age: 58.3 ± 4.4 years) with brachial-ankle pulse wave velocity (baPWV; index of arterial stiffness1400 cm/sec) were given 5.6g/day of L-citrulline (n=8) or placebo (n=7) for 7 days. baPWV and various clinical parameters were measured before (baseline) and after oral supplementation of L-citrulline or placebo.Compared with the placebo group, baPWV was significantly reduced in the L-citrulline group (p0.01). No significant differences in blood pressure (BP) were found between the two groups, and no correlation was observed between BP and baPWV. The serum nitrogen oxide (NOx, the sum of nitrite plus nitrate) and NO metabolic products were significantly increased only in the L-citrulline group (p0.05). Plasma citrulline, arginine and the ratio of arginine/asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (arginine/ADMA ratio) were significantly increased in the L-citrulline group compared with the placebo group (p0.05, p0.01, p0.05, respectively). Moreover, there was a correlation between the increase of plasma arginine and the reduction of baPWV (r=-0.553, p0.05).These findings suggest that short-term L-citrulline supplementation may functionally improve arterial stiffness, independent of blood pressure, in humans. more...

Both type I and type V hyperlipoproteinemia are characterized by severe hypertriglyceridemia due to an increase in chylomicrons. Type I hyperlipoproteinemia is caused by a decisive abnormality of the lipoprotein lipase (LPL)- apolipoprotein C-II system, whereas the cause of type V hyperlipoproteinemia is more complicated and more closely related to acquired environmental factors. Since the relationship of hypertriglyceridemia with atherosclerosis is not as clear as that of hypercholesterolemia, and since type I and V hyperlipoproteinemia are relatively rare, few guidelines for their diagnosis and treatment have been established; however, type I and V hyperlipoproteinemia are clinically important as underlying disorders of acute pancreatitis, and appropriate management is necessary to prevent or treat such complications. Against such a background, here we propose guidelines primarily concerning the diagnosis and management of type I and V hyperlipoproteinemia in Japanese. more...

A decrease in high density lipoprotein-cholesterol (HDL-C) is a strong risk factor for atherosclerotic disorders in Japan, probably more important than an increase in low density lipoprotein-cholesterol (LDL-C). While there are rational grounds for the argument that elevation of HDL-C leads to decreased risk, there has as yet been no direct evidence of such an effect. If elevation of HDL-C decreases the risk, this effect is expected throughout the normal range of HDL-C or perhaps even higher than that. Simulation based on epidemiological data indicated that it may eventually reduce the incidence of ischemic heart disease by 60-70% in Japan. In the risk management guideline, "low" HDL-C is presently defined as 40 mg/dL or below. While there is no evidence that strongly urges a change in this definition, the results of epidemiological studies support "The higher the HDL-C level, the lower the risk,"even in the "normal range". Elevation of the HDL-C level may reduce the risk, probably at least up to 70 mg/dL; however, there are no supportive data for this effect still being obtained over 80 mg/dL. Patients with homozygous CETP deficiency should be followed-up while controlling other risk factors, so as not to dismiss the possibility of a risk increase with an extremely elevated HDL-C level. more...

The purpose of this study was to examine the prevalence of screening-detected depression and the association of depression with QoL in community-dwelling postmenopausal women living in three Asian countries. We examined self-reported questionnaires and conducted the study. A total of 698 community-dwelling postmenopausal women living in three Asian countries participated in this study. The mean age was 59.4±6.6 years (±SD) Depressive symptoms were assessed using a 15-item geriatric depression scale (GDS-15). Using the cut-off of 5/6 for the GDS-15, the percentages of subjects with depression were 39.0% of the Korean subjects, 29.2% of the Chinese subjects, and 33.9% of the Japanese subjects. For the assessment of QoL, we used the EQ-5D of the EuroQoL Group. The following five dimensions were assessed: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The proportions of subjects reporting problems for each dimension were examined. Subjects with depression had significantly lower levels of some dimensions of QoL than those without depression in all three countries. In all three countries, 29.2-39.0% of community-dwelling postmenopausal women had screening-detected depression, which was significantly associated with a lower level of some dimensions of QoL. These results suggest that clinicians should pay more attention to depression in community-dwelling postmenopausal women. more...

Objectives A comparison between the atheroprotective and osteoprotective effects of the selective estrogen receptor modulator (SERM) raloxifene and those of hormone replacement therapy (HRT) has not been made in elderly women. Methods A randomized prospective controlled trial was performed in a cohort of 32 elderly Japanese women with osteoporosis receiving HRT (estriol plus medroxyprogesterone) for more than 1 year. In 16 randomly selected subjects, HRT was changed to raloxifene therapy (60 mg/day, 71.4 ± 3.4 years, SERM group). The other 16 patients were continued on HRT (71.8 ± 2.9 years, HRT group). As a control group, 14 subjects were enrolled, did not take any medications and were age-matched to experimental patients (72.5 ± 3.3 years, control group). Plasma lipids, TNFα, adiponectin, NO metabolites (NOx: NO 2 - and NO 3 - ), cyclicGMP and bone-mineral density (BMD) were evaluated at baseline and at 26 and 52 weeks after enrollment. Results SERM (Raloxifene) increased high-density-lipoprotein cholesterol levels and tended to decrease low-density-lipoprotein cholesterol levels (P = 0.058) compared with baseline. Adiponectin, NOx and cGMP levels were significantly increased after 6 months compared with baseline or the HRT group. TNFα was decreased by raloxifene. In control subjects, no significant changes were observed in any of these markers. Bone-mineral density was higher at baseline in the raloxifene and HRT groups than in the control group, and BMD increased 12 months after baseline in the HRT and control group. Conclusion SERM improved BMD and endothelial function in elderly postmenopausal women with osteoporosis who had received HRT, and these effects were comparable to or slightly stronger than those of HRT. Changes in adiponectin and TNFα may underlie the improvements in endothelial function, such as NO signaling. more...

Atherosclerosis-related diseases are leading causes of morbidity among patients undergoing hemodialysis. The effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) on the endothelial function of hemodialyzed patients are not known.For 16 weeks, we prescribed simvastatin (low dose: 5 mg or moderate dose: 10 mg) to 28 patients (low dose: n=14, 61.2 ± 8.6 years, moderate dose: n=14, 60.8 ± 10.2 years) and chose 9 patients (61.5 ± 5.2 years) without prescriptions as controls. We compared the effects of statin on lipids, flow-mediated endothelium-dependent and nitroglycerin-induced endothelium-independent dilatation (%FMD, %NTD), and markers of oxidant stress and atherosclerosis. Serum HDL-cholesterol and triglycerides did not change significantly in any of the three groups; however, LDL-cholesterol was decreased at 16 weeks in both simvastatin groups. The %FMD and plasma NOx increased at 1 and 16 weeks in both statin groups, but not in the control group (P0.01). The %NTD did not change. Oxidized LDL, VCAM-1, and 8-isoprostane decreased significantly after 16 weeks in both statin groups; however, TNF-α and interleukin 6 did not change. In the control group, no significant changes in these parameters were observed. Multiple regression analyses showed that the (short) period of hemodialysis and (young) age are significant factors associated with %FMD improvement.A statin improved impaired endothelial function in the arteries of chronic dialysis patients, in part by enhancing NO bioavailability within one week. Improved endothelial function is in line with the anti-atherosclerotic effects observed in patients undergoing chronic hemodialysis. more...

Glucagon-like peptide-1 (GLP-1), a member of the proglucagon-derived peptide family, was seen to exert favourable actions on cardiovascular function in preclinical and clinical studies. The mechanisms through which GLP-1 modulates cardiovascular function are complex and incompletely understood. We thus investigated whether the GLP-1 analogue, liraglutide, which is an acylated GLP-1, has protective effects on vascular endothelial cells. Nitrite and nitrate were measured in medium with an automated nitric oxide detector. Endothelial nitric oxide synthase (eNOS) activation was assessed by evaluating the phosphorylation status of the enzyme and evaluating eNOS activity by citrulline synthesis. Nuclear factor κB (NF-κB) activation was assessed by reporter gene assay. Liraglutide dose-dependently increased nitric oxide production in HUVECs. It also caused eNOS phosphorylation, potentiated eNOS activity and restored the cytokine-induced downregulation of eNOS (also known as NOS3) mRNA levels, which is dependent on NF-κB activation. We therefore examined the effect of liraglutide on TNFα-induced NF-κB activation and NF-κB-dependent expression of proinflammatory genes. Liraglutide dose-dependently inhibited NF-κB activation and TNFα-induced IκB degradation. It also reduced TNFα-induced MCP-1 (also known as CCL2), VCAM1, ICAM1 and E-selectin mRNA expression. Liraglutide-induced enhancement of nitric oxide production and suppression of NF-κB activation were attenuated by the AMP-activated protein kinase (AMPK) inhibitor compound C or AMPK (also known as PRKAA1) small interfering RNA. Indeed, liraglutide induced phosphorylation of AMPK, which occurs through a signalling pathway independent of cyclic AMP. Liraglutide exerts an anti-inflammatory effect on vascular endothelial cells by increasing nitric oxide production and suppressing NF-κB activation, partly at least through AMPK activation. These effects may explain some of the observed vasoprotective properties of liraglutide, as well as its beneficial effects on the cardiovascular system. more...

Quadruple mass spectrometric measurements of CH3 density during radical-injection plasma-enhanced chemical vapor deposition to consider the sp2 fraction of amorphous carbon (a-C) films were performed. The sp2 fraction of the a-C films reached a minimum of 46%, where the CH3 density was maximum for a residence time of 6 ms. The sp2 fraction of the a-C films was tailored with the gaseous phase CH3 density during the deposition. This knowledge is useful for understanding the formation mechanism of bonding structures in the a-C films, which enables the precise control of their electronic properties. more...

Background and purpose: Hyperglycaemia is known to reduce nitric oxide (NO) bioavailability by modulating endothelial NO synthase (eNOS) activity, and polyphenols are believed to have cardiovascular benefit. One possible mechanism could be through interaction with eNOS. more...

Nanoparticles were prepared by the thermosensitive aggregation of the elastin model polypeptide, (GVGVP)251, and gamma-ray crosslinking. Three different heating processes, “slow heating,” “fast heating,” and “heat shock,” were used for the aggregation of the peptide, followed by gamma-ray crosslinking. Only the “heat shock” process successfully yielded stable nanoparticles with diameters of less than ca. 150 nm and a narrow size distribution. Circular dichroism (CD) spectrometry showed that this polypeptide formed a type-II β-turn structure when the temperature was increased to above the cloudy point in the case of the “heat shock” process; suggesting that this structure might contribute to stable nanoparticle formation by gamma-rays. CD spectrometry also suggested that this structure would be affected during the formation of stable crosslinked particles. more...

The ecology of the Japanese Green Pheasant Phasianus versicolor should be elucidated for proper game bird population management. Individual discrimination is essential to elucidate its sociality. A method for individual discrimination that is reliable, feasible, and minimizes the burden to birds is needed for further research. Each characteristic distinguished by listening to their crow calls in the field seemed to be the clue to discriminate individuality of male pheasants. I visually analyzed sonograms, and observations of the shape, number, and distribution of high sound pressure level (SPL) frequencies distinguished differences of crow calls among birds. Then, I quantitatively analyzed sonograms by performing principal component analysis (PCA) using six parameters. The discriminative acoustic structure of crow calls were selected as six parameters. The crow calls of each bird were clustered closely and did not overlap with those of other birds. These analyses confirmed that there is more inte... more...

Background The respective incidences of ischemic heart and cerebrovascular disease (IHD, CVD) are high in diabetic individuals. Complications of dyslipidemia increase the risk, but direct evidence is limited, so a cohort prospective study (Japan-CDM) was conducted. Methods and Results The study group comprised 4,014 subjects with type 2 diabetes (1,936 women, 2,078 men; mean age 67.4±9.5 years) who were divided into dyslipidemic patients (79.1%) with or without medication (medicated, 50.9%; not medicated, 28.2%) and normo-lipidemic patients (20.9%). The incidence of IHD, CVD, arteriosclerosis obliterans (ASO), congestive heart failure (CHF) and death was assessed. IHD and CVD occurred in 0.82 and 0.67%, respectively, during the first year following registration. CHF, ASO and sudden death occurred in 0.27%, 0.12% and 0.12%, respectively. There was a significant statistical difference in the relation of elevated levels of high-density lipoprotein-cholesterol to lower rates of IHD and CVD. IHD and CVD in males were dependent on the level of low-density lipoprotein-cholesterol (LDL-C): 0.45%, 1.56%, 1.78%, 1.91% and 2.34% were observed in less than 2.11, 2.11-2.62, 2.63-3.15, 3.16-3.67, and more than 3.68 mol/L of LDL-C. In the lowest LDL-C group, death other than from vascular diseases was increased. Age, sex (male) and complicated hypertension increased the risk of events. Patients who were prescribed antihyperlipidemic agents suffered less events than patients who were not being treated, which suggests direct effects of therapy. Conclusion Strict lipid control may be effective for reducing the incidence of vascular events in Japanese diabetic individuals. (Circ J 2008; 72: 218 - 225) more...

The objective of this study was to assess the capacity of different criteria of metabolic syndrome (MetS) to identify risks of coronary heart diseases (CHDs) and related changes of adipocytokines in postmenopausal women. A cross-sectional study was carried out in 225 community-dwelling, elderly postmenopausal Chinese women (age, 66.77±5.09 years) without hormone replacement therapy (HRT). Baseline data such as blood pressure, body mass index (BMI), serum lipid profiles, and fasting glucose were analyzed, and insulin sensitivity was estimated via the homeostasis model assessment for insulin resistance. Serum tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and adiponectin were measured simultaneously. The prevalence of MetS identified by the Third Report of the National Cholesterol Education Programme Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, the International Diabetes Federation (IDF), the Chinese Diabetes Society (CDS), and the Japanese Society of Internal Medicine (JPN) were 27.31%, 37.34%, 23.29%, and 13.65%, respectively. No significant differences of baseline data were found among different MetS groups, except for a significant higher waist circumference in the JPN-MetS group as compared with other MetS groups. The prevalence of confirmed CHD in the four MetS groups were 26.2%, 18.6%, 26.9%, and 32%, respectively. Odds ratios for CHD were 1.905 (95% CI=1.273–2.851), 1.208 (95% CI=0.778–1.876), 1.997 (95% CI=1.238–3.221), and 2.336 (95% CI=1.119–4.876), respectively. The JPN-MetS group had higher levels of TNFα and IL-6, whereas the CDS-MetS group correlated better with lower adiponectin levels. The IDF definition for MetS is the most sensitive one with regard to metabolic disorders, whereas JPN and CDS definitions correlate better with CHD and changes of adipocytokines among the four criteria studied. more...

OBJECTIVES: To assess the efficacy of various vascular endocrinological substances, such as plasma nitric oxide metabolites (NOx), as surrogate markers of survival in older patients. DESIGN: Prospective cohort, observational. SETTING: Nagoya University Hospital and related hospitals, Japan. PARTICIPANTS: One hundred fifty patients aged 70 and older, recruited consecutively from the outpatient clinics of Nagoya University Hospital and related hospitals. MEASUREMENT: Serum biochemical analyses such as albumin and total cholesterol, various prognostic markers, such as tumor necrosis factor (TNF)-α, NOx, activities of daily living (ADLs), and instrumental ADLs (IADLs) were evaluated on enrollment. ADLs, IADLs, and comorbidities, especially depression and impaired cognition, were evaluated on enrollment. The main outcome was survival rate over 2.75 years. RESULTS: Forty-nine patients died during the follow-up period. Mann-Whitney U-test showed that hemoglobin, total protein, serum albumin, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high sensitive c-reactive protein, NOx, B-type natriuretic peptide, interleukin-6, and TNF-α levels; ADLs; cognitive impairment; and depressive status were significantly different for subjects who survived and those who died. Of the dependent variables in the Cox proportional hazards regression analyses, only ADLs, NOx, and albumin were significantly different. In the Kaplan-Meier analyses of mortality, the prognosis of patients in the third and fourth quartiles of NOx was significantly worse than that of patients in the first or second quartile. The prognosis of patients with impaired ADLs was worse than that of other patients for the overall period. CONCLUSION: Lower levels of NOx may be associated with survival in older patients. It may be an effective marker, like ADLs, which is a well-known marker. more...

Objective— When the availability of tetrahydrobiopterin (BH4) is deficient, endothelial nitric oxide synthase (eNOS) produces superoxide rather than NO (uncoupled eNOS). We have shown that the atherosclerotic lesion size was augmented in apolipoprotein E–deficient (ApoE-KO) mice overexpressing eNOS because of the enhanced superoxide production. In this study, we addressed the specific importance of uncoupled eNOS in atherosclerosis, and the potential mechanistic role for specific versus nonspecific antioxidant strategies in restoring eNOS coupling. Methods and Results— We crossed mice overexpressing eNOS in the endothelium (eNOS-Tg) with mice overexpressing GTP-cyclohydrolase I (GCH), the rate-limiting enzyme in BH4 synthesis, to generate ApoE-KO/eNOS-Tg/GCH-Tg mice. As a comparison, ApoE-KO/eNOS-Tg mice were treated with vitamin C. Atherosclerotic lesion formation was increased in ApoE-KO/eNOS-Tg mice compared with ApoE-KO mice. GCH overexpression in ApoE-KO/eNOS-Tg/GCH-Tg mice increased vascular BH4 levels and reduced plaque area. This reduction was associated with decreased superoxide production from uncoupled eNOS. Vitamin C treatment failed to reduce atherosclerotic lesion size in ApoE-KO/eNOS-Tg mice, despite reducing overall vascular superoxide production. Conclusion— In contrast to vitamin C treatment, augmenting BH4 levels in the endothelium by GCH overexpression reduced the accelerated atherosclerotic lesion formation in ApoE-KO/eNOS-Tg mice, associated with a reduction of superoxide production from uncoupled eNOS. more...

The long-term benefits of nitroglycerin therapy are limited by tolerance development. Understanding the precise nature of mechanisms underlying nitroglycerin-induced endothelial cell dysfunction may provide new strategies to prevent tolerance development. In this line, we tested interventions to prevent endothelial dysfunction in the setting of nitrate tolerance. When bovine aortic endothelial cells (BAECs) were continuously treated with nitric oxide (NO) donors, including nitroglycerin, over 2–3 days, basal production of nitrite and nitrate (NOx) was diminished. The diminished basal NOx levels were mitigated by intermittent treatment allowing an 8-h daily nitrate-free interval during the 2- to 3-day treatment period. Addition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin restored the basal levels of NOx that were decreased by continuous nitroglycerin treatment of BAECs. Apocynin caused significant improvement of increased mRNA and protein levels of endothelial nitric oxide synthase (eNOS) in BAECs given nitroglycerin continuously over the treatment period. Apocynin also reduced endothelial production of reactive oxygen species (ROS) after continuous nitroglycerin treatment. These results showed an essential similarity to the effects of a nitrate-free interval. Application of the NOS inhibitor Nω-nitro- l-arginine methyl ester caused a recovery effect on basal NOx and eNOS expression but was without effect on ROS levels in continuously NO donor-treated BAECs. In conclusion, the present study characterized abnormal features and functions of endothelial cells following continuous NO donor application. We suggest that inhibition of NADPH oxidase, by preventing NO donor-induced endothelial dysfunction, may represent a potential therapeutic strategy that confers protection from nitrate tolerance development. more...

A disadvantage of ICP type plasma etching method compared with CCP one is low selectivity to photo resist. So a novel etching method was developed to obtain high selectivity to photo resist by incorporating a sputtering method, in which a target was placed on the opposite side of the substrate. Satisfactory results were obtained for a continuous gas feeding treatment and also for a gas modulating treatment. more...

Background For elderly patients, the consideration of prognostic factors is very important, but there have been few reports about the potential use of vasoactive substances as prognostic markers in the elderly. Objective We assessed endocrinological substances, such as plasma NO x (metabolites of NO), as the prognostic marker in elderly. We compared their efficacy with that of such well-known markers as albumin and pro-inflammatory cytokines such as IL-6. Methods The patients were recruited consequently from the clinics of Nagoya University Hospital or related home care services facilities. One hundred and twenty seven elderly aged 65 and older were registered. Biochemical analyses such as albumin, total cholesterol, BNP, and NO x were measured upon enrollment. The main outcome was the survival rate. Results Forty-six patients died during the follow-up period. Mann–Whitney’s U -test showed that the levels of age, hemoglobin, total protein, serum albumin, serum creatinine, total cholesterol, HDL-cholesterol, LDL-cholesterol, high sensitive CRP, NO x , IL-6, and TNF-α were significantly different between the living and deceased subjects. Among the dependent variables in the logistic regression analyses, only albumin and NO x were significantly different. In the Kaplan–Meier analyses of mortality, the prognosis of patients in 3rd and 4th quartile of NO x was significantly worse than that in 1st or 2nd quartile. Conclusion NO x has potential both as a vascular marker and as a marker for predicting survival in elderly. In the latter role, it may be as effective as albumin. more...

Metformin is a biguanide family member used in the treatment of type 2 diabetes and one of the most widely prescribed antidiabetes drugs. This drug increases the peripheral uptake of glucose, decreases hepatic glucose production, and reduces insulin resistance in liver and skeletal muscle. The exact molecular mechanisms responsible for its effect on glucose homeostasis are still not completely understood but may include the triggering of the AMPK pathway (1), although it has been indicated that the acute inhibitory effects of high doses of metformin on hepatic gluconeogenesis are independent of AMPK activation (2). Interestingly, experimental and clinical studies have shed new light on an array of potential benefits of metformin, not only in the treatment of diabetes. Notably, accumulating evidence suggests that the cardiovascular protective role of metformin is largely beyond its hypoglycemic action and is ascribed to pleiotropic effects (3–5). Previous studies have described the anti-inflammatory effects of metformin on different types of cells, including human vascular endothelial cells and smooth muscle cells (6,7). Recent reports have also demonstrated that metformin can attenuate lipopolysaccharide (LPS)-induced or oxidized LDL–induced proinflammatory responses in monocytes and macrophages (8,9). Although the crucial mechanisms underlying the anti-inflammatory effects of metformin remain to be fully elucidated, the current concept of atherosclerosis as an inflammatory disorder may imply that such anti-inflammatory properties could contribute, at least in part, to the anti-atherosclerotic … more...

An one-step selective oxidation of primary alcohol to carboxylic ester took place in liquid-phase over nano-gold particles supported on metal oxides by means of molecular oxygen. Furthermore, it was found that the oxidation of a mixture of ethylene glycol and methanol produced methyl glycolate selectively with a small amount of methyl formate. The substrate-selectivity was observed clearly with Au catalyst, not with a typical Pd or Ru catalyst, which is also capable of catalyzing the oxidative esterification of alcohol. more...

Chemically modified cellulase treatment on ramie fabric under neutral condition with air jet treatment machine was studied. After glue was removed from the fabric with amylase, fluff arose on the surface of ramie fabric. Fluff was removed from the surface of ramie fabric with cellulase treatment under the neutral condition and the fabric softened. The mechanical strength of the fabric treated with chemically modified cellulase was not severely damaged compared with that of with native cellulase. more...

The objective of this study was to evaluate the influence of ingested l -arginine, l -citrulline, and antioxidants (vitamins C and E) on the progression of atherosclerosis in rabbits fed a high-cholesterol diet. The fatty diet caused a marked impairment of endothelium-dependent vasorelaxation in isolated thoracic aorta and blood flow in rabbit ear artery in vivo , the development of atheromatous lesions and increased superoxide anion production in thoracic aorta, and increased oxidation-sensitive gene expression [Elk-1 and phosphorylated cAMP response element-binding protein]. Rabbits were treated orally for 12 weeks with l -arginine, l -citrulline, and/or antioxidants. l -arginine plus l -citrulline, either alone or in combination with antioxidants, caused a marked improvement in endothelium-dependent vasorelaxation and blood flow, dramatic regression in atheromatous lesions, and decrease in superoxide production and oxidation-sensitive gene expression. These therapeutic effects were associated with concomitant increases in aortic endothelial NO synthase expression and plasma \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{N}}{\mathrm{O}}_{2}^{-}+{\mathrm{N}}{\mathrm{O}}_{3}^{-}\end{equation*}\end{document} and cGMP levels. These observations indicate that ingestion of certain NO-boosting substances, including l -arginine, l -citrulline, and antioxidants, can abrogate the state of oxidative stress and reverse the progression of atherosclerosis. This approach may have clinical utility in the treatment of atherosclerosis in humans. more...

Background Approximately 80% of cases of ischemic heart disease (IHD) occur in patients with nonstenotic coronary arteries, and few studies have systematically assessed exercise testing (TMT) as a predictor of risk in the elderly. Methods TMT was carried out using a protocol for the independent and active elderly ( n =176). After 4.1±0.5 years follow-up, logistic regression analysis was performed for each coronary risk factor such as diabetes mellitus (DM) and hypercholesterolemia (HC). According to the results, patients were divided into Gp HC, hypercholesterolemic patients; Gp DM, diabetics; Gp HC+DM, hypercholesterolemic diabetics; and Gp C, nonhyperlipidemic and nondiabetics. Sensitivity and specificity of TMT for IHD (significant stenosis or acute coronary syndrome) were analyzed. Results Odds ratios for each risk factors are as follows: DM, 4.167; HC, 4.485; and DM+HC, 8.652. Notably, TMT was 17.59. Age was a significant risk, but hypertension was not. Positive ischemic signs in TMT were observed in 52.7%, 28.6%, 33.3%, and 16.3% in the Gp HC+DM, HC, DM, and C groups, respectively. Only three participants complained of chest pain during the TMT. Significant stenosis was observed in 75.0%, 71.4%, 69.2%, and 60.0% of coronary angiography (CAG)-receiving patients of Gp HC, DM, HC+DM, and C. During the observation term, acute coronary syndromes occurred in 4.7%, 3.3%, 5.5%, and 0% of patients in the Gp HC, DM, HC+DM, and C groups, respectively. The sensitivity of TMT for IHD was higher than 66.7% and specificity was higher than 94.1% in each group. Conclusion An exercise tolerance test in the elderly, especially for diabetics and hypercholesterolemic patients, is useful for the diagnosis of IHD. more...

2,4,6-Trinitrotoluene (TNT), which is widely used in explosives, is an important occupational and environmental pollutant. Human exposure to TNT has been reported to be associated with cardiovascular dysfunction, but the mechanism is not well understood. In this study, we examine the endothelial nitric oxide synthase (eNOS) activity and blood pressure value following TNT exposure. With a crude enzyme preparation, we found that TNT inhibited the enzyme activity of eNOS in a concentration-dependent manner (IC50 value = 49.4 microM). With an intraperitoneal administration of TNT (10 and 30 mg/kg) to rats, systolic blood pressure was significantly elevated 1 h after TNT exposure (1.2- and 1.3-fold of that of the control, respectively). Under the conditions, however, experiments with the inducible NOS inhibitor aminoguanidine revealed that an adaptive response against hypertension caused by TNT occurs. These results suggest that TNT is an environmental chemical that acts as an uncoupler of constitutive NOS isozymes, resulting in decreased nitric oxide formation associated with hypertension in rats. more...

Objective We investigated the effect of apocynin, an NADPH oxidase inhibitor, in the impairment of vascular responses in Otsuka Long-Evans Tokushima Fatty (OLETF) rats (type 2 diabetic rat model) with or without (w/wo) N-nitro-l-arginine methyl ester treatment. Methods Male OLETF and littermate Long-Evans Tokushima Otsuka (LETO) (28 weeks old) rats were separated as follows: LETO w/wo apocynin (Gp C, Gp C-apo), OLETF w/wo apocynin (Gp DM, Gp DM-apo) and OLETF plus l-nitro arginine acetate ester w/wo apocynin (Gp DMLN, Gp DMLN-apo). Five days after, peritoneal macrophages were stimulated with thioglycolate. Two days after, they were evaluated. Results Plasma glucose and lipid levels remained unchanged. Acetylcholine-induced nitric oxide-dependent (NO-dependent) relaxation and nitroglycerin-induced NO-independent relaxation were improved in the Gp DMLN-apo, compared with that in Gp DMLN. Tone-related basal NO release and plasma NO(2) (-) and NO(3) (-) tended to be lower in Gp DM and Gp DMLN groups. The increased amount of superoxide anion released from macrophages in Gp DM and Gp DMLN was restored by apocynin. Intimal thickening was observed in aortae of Gp DM and Gp DMLN animals; however, there was little in aortae of Gp DM-apo and Gp DMLN(-) apo rats. Increased tumour necrosis factor-alpha (TNF-alpha) in the Gp DM and Gp DMLN was also restored by apocynin treatment. Conclusion Apocynin restores the impairment of endothelial and non-endothelial function in diabetic angiopathy in OLETF without changing plasma glucose and lipid levels. NO and O(2) (-) may play a role in this process by decreasing TNF-alpha levels. more...

Background: The purpose of the present study is to clarify the target criteria for care in long-term health care facilities for the elderly in Japan and to investigate the relationship between changes in basic activities of daily living (BADL) over 1 year and the comprehensive geriatric assessment (CGA) scale. Methods: An observational study was conducted in a facility in Nagoya, Japan. The participants consisted of 54 residents. The following four scales of comprehensive geriatric assessment were administered to the residents in both 2000 and 2001: Barthel index (BI), Lawton scale, mini-mental state examination and geriatric depression scale 15. Results: The Barthel index was significantly improved in 2001 compared with 2000 (P= 0.007). The Lawton scale was significantly lower in 2001 (P= 0.029). Neither the mini-mental state examination nor geriatric depression scale 15 scores changed significantly. To determine the factors that influenced the change in BADL, logistic regression analyses were performed using the above four scales as independent variables and the BI change as a dependent variable. In multivariate analysis, a BI score of less than 75 approached significance for improvement in BADL (P = 0.094, odds ratio = 2.79). Other logistic regression analyses were also performed using each ADL task in BI as an independent variable and the change in BI as a dependent variable. In multivariate analysis, bowel incontinence was a significant independent variable (P = 0.006, odds ratio = 10.9). Conclusion: As bridging facilities between acute-care hospitals and home, long-term health care facilities are a reasonable choice for the elderly with bowel incontinence. more...

Human inducible nitric oxide synthase (iNOS) is most readily observed in macrophages from patients with inflammatory diseases like atherosclerosis. The aim of the present study was to find out the combined effect of male sex hormone; testosterone and apocynin (NADPH oxidase inhibitor) on cytokine-induced iNOS production. THP-1 cells were differentiated into macrophages by phorbol myristate acetate (PMA). Expression of iNOS was induced by the addition of cytokine mixture? Testosterone was added at different concentrations (10(-6)-10(-12) M) with apocynin (1 mM). Testosterone (10(-8), 10(-10) M) inhibited NOx production in cytokine-added THP-1 cells which was further confirmed by quantikine assay of iNOS protein and RT-PCR analysis. Testosterone treatment decreased 40% of superoxide anion production. Testosterone showed inhibition of NADPH oxidase, especially expression of p67phox and p47phox (cytosol subunits). Addition of testosterone with apocynin further decreased the expression of p67phox and p47phox subunits of NADPH oxidase. The findings of the present study suggest that, testosterone; the male androgen plays an important role in the prevention of atherogenesis. Even though apocynin does not have any role on NO production, addition of apocynin together with testosterone is effective in suppressing iNOS activity. more...

Background: It has been widely accepted that control of serum cholesterol levels is effective for prevention of cardiovascular events. Recent data have suggested that this is also the case in the elderly. Methods: A research group (chaired by T. Kita) was organized as part of the Comprehensive Research on Aging and Health conducted by the Japanese Ministry for Health, Labour, and Welfare in 1999–2002 to determine the best strategy for control of cholesterol levels in elderly Japanese with hypercholesterolemia. In order to do this a review of the literature was conducted. Conclusion: The research group concluded: (i) Japanese patients aged 65–74 years with hypercholesterolemia should be treated by following the Guideline for Diagnosis and Treatment of Atherosclerotic Cardiovascular Diseases by the Japan Atherosclerosis Society (2002), as cholesterol-lowering therapy would bring a similar, or even larger, preventive effect to the elderly, whose absolute risk of cardiovascular events is higher than that in the younger population; (ii) target cholesterol levels in elderly Japanese aged ≥ 75 years with hypercholesterolemia should be determined individually according to their physical activities. It is noted that the elderly are more susceptible to drug-related adverse effects than the younger since renal and liver functions, required for metabolizing drugs, in the elderly are relatively weaker. more...

We occasionally found that poly (α- l -glutamate) showed a superior protective effect on enzymes against UV and 60 Co-γ irradiation. We selected papain and α-amylase as a model enzyme and irradiated the aqueous solution (10 mg/ml) of each enzyme with UV and 60 Co-γ rays in the presence of poly (α- l -glutamate) (α-PGA), poly (glucosyl oxyethyl methacrylate (GEMA)), and glucose (1.25% w/v each). The mixture of the three compounds has a significant protective effect on the activity of papain solution showing 40% of remaining activity twice as much as the control containing no additive at the dose of 15 kGy. Among them, α-PGA showed the highest protecting effect on the both papain and α-amylase even after 10-kGy irradiation at which 50% of the activity was retained. α-PGA also showed significant protective activity on α-amylase against UV both in solution and under dried state. more...

During the last 3 years, especially in the last year following the publication of Women's Health Initiative, WHI, many papers reported the ineffectiveness or risk of side effects of hormone replacement therapy (HRT), which is the opposite of previous papers. I have categorized my topic into four parts: (1) megaclinical studies such as PEPI, Nurse's Health Study (NHS), HERS and WHI, (2) the effect of HRT on ischemic cardiovascular disease, (3) the effect of HRT on breast cancer, and (4) the effect of HRT on other disorders such as dementia, quality of life (QOL) and diabetes. Conclusion: Usual HRT using premalin and medroxyprogesterone is not recommended in general (for Asians). more...

The commercial cellulase was chemically modified with a water soluble polymer with the aim of increasing molecular weight of the enzyme. Maleic acid methylvinylether copolymer was used as a water soluble polymer. Avicelase activity, the optimal pH of the chemically modified cellulase shifted to the alkali side compared with native cellulase. However, the avicelase activity of the modified enzyme at pH 7 showed 80% of the maximum activity in borate buffer. On the contrary, the activity of native enzyme showed only 30% of the maximum one. The results showed that activation of the modified enzyme occurred in the presence of borate ion. Using the effect, the biopolishing of cellulosic fiber might possible. The decline of breaking strength of ramie yarns was improved, when the modified enzyme was used. more...

Deep plasma etching technology of quartz has been applied to the fabrication of a microcapillary with a depth of over 20 µm. In this deep etching, defects of abnormal shape were observed on the etched surface. The shape of the defect was conelike and the defects were randomly distributed. The diameters of the defects were the same and linearly increased with etching time. Simulations were carried out using micromasks and the same defects with the same shape and expansion rate of diameter were generated on the etched surface. This implied that the micromask was the origin of the conelike defects. These defects were eliminated with the newly proposed high-bias cleaning process of only 2 min duration performed in an early period before the deep etching. This result indicated that the origin of the conelike defects were particles that fell to the surface of the quartz before deep etching. more...

A–B–A type tri-block copolymer consisting of N -hydroxypropyl- l -glutamine as the A component and l -alanine as the B component as well as the corresponding random copolymers and homopolymers were prepared by carrying out an aminoalcoholysis reaction with 3-amino-1-propanol, together with a crosslinking reaction with 1,8-octamethylenediamine on membranes of the starting polymer membranes including γ-methyl- l -glutamate residue. It was shown that the effective crosslink density was proportional to the percent crosslinker in the reaction mixture. The relation between their bulk structure and membrane properties were investigated, such as the swelling ratio in water ( q ), tensile properties, and enzymatic degradation behavior of the membranes in a pseudo-extracellular fluid (PECF). The tensile properties of the hydrophilic membranes were highly dependent on q in PECF, and on the hydrophobic portions in molecular chains, whose behavior was typical of an elastomer. Biodegradation of the membranes in vitro by bromelain indicated that the degradation took place in bulk rather than on the surface, and that the rate of degradation was also highly dependent on q in the samples as well as on the hydrophobic portion of the membranes in PECF. more...

Many harmful effects of nitric oxide are caused by the reaction of NO with superoxide anion. The present study was carried out to find out the concomitant production of superoxide and to investigate a suitable inhibitor of NO, which is produced by iNOS. THP-1 cells were differentiated into macrophages by PMA and cytokine. Addition of L-NAME showed decrement in superoxide production. Addition of apocynin, aminoguanidine or ONO 1714 brought about a significant reduction in superoxide production. The expressions of p67 and p47(phox) were reduced by the addition of apocynin, aminoguanidine or ONO 1714 whereas xanthine oxidase and cyclooxygenase did not have a major role in superoxide production. The results of the present study show that iNOS and NADPH oxidase play an important role in superoxide release. It suggests that addition of iNOS inhibitor together with apocynin may be more effective in case of therapeutic application in disease conditions like atherosclerosis. more...