Bowel movement frequency, stool consistency, and risk of disabling dementia: a population-based cohort study in Japan.

OBJECTIVES: This population-based study aimed to evaluate the association between bowel habits from midlife and dementia. STUDY DESIGN: This was a cohort study using certification records for national long-term care insurance in Japan. METHODS: Participants aged 50 to 79 years who reported bowel habits from eight districts within the Japan Public Health Center-based Prospective Study (JPHC Study) were followed from 2006 to 2016 for incident dementia. Hazard ratio (HR) and 95% confidence interval (CI) were estimated for men and women separately using Cox proportional hazards models accounting for various lifestyle factors and medical histories. RESULTS: Among 19,396 men and 22,859 women, 1889 men and 2685 women were diagnosed with dementia. In men, the multivariable-adjusted HRs compared with bowel movement frequency (BMF) of once/day were 1.00 (95% CI: 0.87-1.14) for twice/day or more, 1.38 (1.16-1.65) for 5-6 times/week, 1.46 (1.18-1.80) for 3-4 times/week, and 1.79 (1.34-2.39) for <3 times/week (P for trend <0.001). In women, the corresponding HRs were 1.14 (0.998-1.31), 1.03 (0.91-1.17), 1.16 (1.01-1.33), and 1.29 (1.08-1.55) (P for trend = 0.043). Harder stool was associated with higher risk (P for trend: 0.0030 for men and 0.024 for women), with adjusted HRs compared to normal stool of 1.30 (1.08-1.57) for hard stool and 2.18 (1.23-3.85) for very hard stool in men, and 1.15 (1.002-1.32) and 1.84 (1.29-2.63) in women. CONCLUSIONS: Lower BMF and harder stool were each associated with higher risk of dementia.

Selective release of miRNAs via extracellular vesicles is associated with house-dust mite allergen-induced airway inflammation.

BACKGROUND: MicroRNAs (miRNAs) may facilitate cell-to-cell communication via extracellular vesicles (EVs). The biological roles of miRNAs in EVs on allergic airway inflammation are unclear. METHODS: Airway-secreted EVs (AEVs) were isolated from bronchoalveolar lavage fluid (BALF) of control and house-dust mite (HDM) allergen-exposed HDM-sensitized mice. The expression of miRNAs in AEVs or miRNAs and mRNAs in lung tissue was analysed using miRNA microarray. RESULTS: The amount of AEV increased 8.9-fold in BALF from HDM-exposed mice compared with that from sham-control mice. HDM exposure resulted in significant changes in the expression of 139 miRNAs in EVs and 175 miRNAs in lung tissues, with 54 miRNAs being common in both samples. Expression changes of these 54 miRNAs between miRNAs in AEVs and lung tissues after HDM exposure were inversely correlated. Computational analysis revealed that 31 genes, including IL-13 and IL-5Ra, are putative targets of the miRNAs up-regulated in AEVs but down-regulated in lung tissues after HDM exposure. The amount of AEV in BALF after HDM exposure was diminished by treatment with the sphingomyelinase inhibitor GW4869. The treatment with GW4869 also decreased Th2 cytokines and eosinophil counts in BALFs and reduced eosinophil accumulation in airway walls and mucosa. CONCLUSION: These results indicate that selective sorting of miRNA including Th2 inhibitory miRNAs into AEVs and increase release to the airway after HDM exposure would be involved in the pathogenesis of allergic airway inflammation.

Expression of Periostin in Normal, Atopic, and Nonatopic Chronically Inflamed Canine Skin.

In humans, periostin plays a critical role in the enhancement and chronicity of allergic skin inflammation; however, whether it is involved in the pathogenesis of canine dermatitis remains unknown. The aim of this study was to examine the expression patterns of periostin in healthy, atopic, and nonatopic chronically inflamed canine skin. Biopsy specimens from 47 dogs with skin disease and normal skin tissue from 5 adult beagles were examined by light microscopy, immunohistochemistry, and in situ hybridization. In normal skin, periostin was localized just beneath the epidermis and around the hair follicles. In chronically inflamed skin, periostin expression was most intense in the dermis with inflammatory cell infiltrates. In contrast, low levels of periostin were detected in acutely inflamed and noninflamed skin. Conversely, all canine atopic dermatitis tissues characteristically showed the most intense expression of periostin in the superficial dermis, particularly at the epidermal-dermal junction. In situ hybridization showed that periostin mRNA was broadly expressed in the basal epidermal keratinocytes, outer root sheath cells, and dermal fibroblasts in normal dog skin. High expression of periostin mRNA was observed in fibroblasts in dog skin with chronically inflamed dermatitis. Moreover, in some chronically inflamed skin specimens, periostin mRNA expression was increased in basal keratinocytes. The severity score of chronic pathologic changes and CD3+ cell number in the dermis were correlated with distribution pattern of periostin in the atopic skin. These data suggest that periostin could play a role in the pathophysiology of chronic dermatitis, including atopic dermatitis, in dogs.

Expressions of local renin-angiotensin system components in chondrocytes.

In 2013, we reported that local renin-angiotensin system (local RAS) components express during the hypertrophic differentiation of chondrocytes and can modulate it, using ATDC5 cell line that involves differentiation from mesenchymal stem cells to calcified hypertrophic chondrocytes. However, the expressions of local RAS components in normal chondrocytes have not been revealed yet. The purpose of this study is to examine the expression of the local RAS components in chondrocytes in vivo and the conditions allowing the expression. We stained five major regions of 8-week-old C57BL/6 adult mice in which chondrocytes exist, including epiphyseal plates and hyaline cartilages, with antibodies to local RAS components. We also examined the expression of local RAS components in the cultured bovine's articular cartilage chondrocytes using quantitative reverse transcription polymerase chain reaction and western blot analysis. In result, hypertrophic chondrocytes of epiphyseal plates included in the tibia and the lamina terminals expressed local RAS components. However, hyaline chondrocytes, including the knee articular cartilages, the parenchyma of nasal septums and of the tracheal walls, did not express local RAS components. Cultured bovine's articular cartilage chondrocytes also did not express local RAS components. However, inducing hypertrophy by administering interleukin-1ß or tumor necrosis factor-α, the cultured articular chondrocytes also expressed angiotensin II type 1 receptor and angiotensin II type 2 receptor. In conclusion, local RAS components express particularly in chondrocytes which occur hypertrophy and do not in hyaline chondrocytes. The results are in accord with our previous in vitro study. We think this novel knowledge is important to investigate cartilage hypertrophy and diseases induced by hypertrophic changes like osteoarthritis.

Modification of the excess risk of coronary heart disease due to smoking by seafood/fish intake.

Seafood/fish intake has been regarded as a protective factor for coronary heart disease (CHD), while smoking is a strong risk factor. To examine whether associations between smoking and risk of CHD are modified by seafood/fish intake, we studied 72,012 Japanese men and women aged 45-74 years who completed 2 food frequency questionnaires, 5 years apart, during the period 1995-2009. After 878,163 person-years of follow-up, 584 incident cases of CHD (101 fatal and 483 nonfatal), including 516 myocardial infarctions, were documented. There was a clear dose-response association between smoking and CHD risk among subjects with a low seafood/fish intake (<86 g/day) but not among those with a high seafood/fish intake (≥86 g/day). Compared with never smokers, the multivariable hazard ratios in light (1-19 cigarettes/day), moderate (20-29 cigarettes/day), and heavy (≥30 cigarettes/day) smokers were 2.39 (95% confidence interval (CI): 1.60, 3.56), 2.74 (95% CI: 1.90, 3.95), and 3.24 (95% CI: 2.12, 4.95), respectively, among low seafood/fish eaters and 1.13 (95% CI: 0.64, 1.99), 1.29 (95% CI: 0.95, 2.04), and 2.00 (95% CI: 1.18, 3.51), respectively, among high seafood/fish eaters. Compared with heavy smokers with a low seafood/fish intake, light smokers with a high seafood/fish intake had substantially reduced risk of CHD (hazard ratio = 0.57, 95% CI: 0.32, 0.98). High seafood/fish intake attenuated the positive association between smoking and risk of CHD.

Meat consumption in relation to mortality from cardiovascular disease among Japanese men and women.

BACKGROUND/OBJECTIVES: Although high or low (no) meat consumption was associated with elevated or reduced mortality from cardiovascular disease, respectively, few studies have investigated the association between moderate meat consumption and cardiovascular disease. We aimed to evaluate the associations between moderate meat consumption and cardiovascular disease mortality. SUBJECTS/METHODS: We conducted a prospective cohort study of 51,683 Japanese (20,466 men and 31,217 women) aged 40-79 years living in all of Japan (The Japan Collaborative Cohort Study; JACC Study). Consumptions of meat (beef, pork, poultry, liver and processed meat) were assessed via a food frequency questionnaire administrated at baseline survey. Hazard ratios (HRs) of mortality from cardiovascular disease were estimated from Cox proportional hazards regression models according to quintiles of meat consumption after adjustment for potential confounding variables. RESULTS: During 820,076 person-years of follow-up, we documented 2685 deaths due to total cardiovascular disease including 537 ischemic heart diseases and 1209 strokes. The multivariable HRs (95% confidence interval) for the highest versus lowest quintiles of meat consumption (77.6 versus 10.4 g/day) among men were 0.66 (0.45-0.97) for ischemic heart disease, 1.10 (0.84-1.43) for stroke and 1.00 (0.84-1.20) for total cardiovascular disease. The corresponding HRs (59.9 versus 7.5 g/day) among women were 1.22 (0.81-1.83), 0.91 (0.70-1.19) and 1.07 (0.90-1.28). The associations were similar when the consumptions of red meat, poultry, processed meat and liver were examined separately. CONCLUSION: Moderate meat consumption, up to ~100 g/day, was not associated with increased mortality from ischemic heart disease, stroke or total cardiovascular disease among either gender.

Dietary fiber intake and risk of cardiovascular disease in the Japanese population: the Japan Public Health Center-based study cohort.

BACKGROUND/OBJECTIVES: There has been no study with regard to the association between dietary fibers and the incidence of stroke and coronary heart disease (CHD) in Asia. We investigated the association between dietary fiber and the risk of cardiovascular disease (CVD), which we defined as stroke or CHD, in a Japanese population. SUBJECTS/METHODS: We studied 86 387 Japanese subjects (age 45-65 years, without CVD or cancer in 1995 as Cohort I and in 1998 as Cohort II) and used a self-administered questionnaire to follow-up the participants until the end of 2004. Dietary fiber intake was estimated from food-frequency questionnaires comprising 138 food items. RESULTS: After 899 141 person-years of follow-up, we documented the incidence of 2553 strokes and 684 cases of CHD. Multivariable-adjusted hazard ratios (95% confidence intervals (CIs)) of CVD for the third to fifth quintiles of total fiber were 0.79 (0.63-0.99), 0.70 (0.54-0.89) and 0.65 (0.48-0.87) in women, respectively, compared with the lowest quintile. Total fiber intake was inversely associated with the incidence of stroke, either cerebral infarction or intracerebral hemorrhage in women. The results for insoluble fiber in women were similar to those for total fiber, whereas those for soluble fiber were weak. An inverse association of total fiber with CVD was observed primarily in non-smokers (P for trend=0.045 and 0.001) and not in smokers (probability values for interaction between total fiber and smoking were 0.06 and 0.01 in men and women, respectively). CONCLUSIONS: Higher total dietary fiber was associated with reduced risk of CVD in Japanese non-smokers.

Cross-cultural comparison of the sleep-disordered breathing prevalence among Americans and Japanese.

The aim of the present study was to compare the prevalence of sleep-disordered breathing among Hispanic and white Americans and Japanese. A 1-night sleep study using a single-channel airflow monitor was performed on 211 Hispanics and 246 Whites from the Minnesota field centre (St Paul, MN, USA) of the Multi-Ethnic Study of Atherosclerosis (MESA), and 978 Japanese from three community-based cohorts of the Circulatory Risk in Communities Study (CIRCS) in Japan. The respiratory disturbance index and sleep-disordered breathing, defined as a respiratory disturbance index of > or =15 events x h(-1), were estimated. The prevalence of sleep-disordered breathing was higher in males (34.2%) than females (14.7%), and among Hispanics (36.5%) and Whites (33.3%) than among Japanese (18.4%), corresponding to differences in body mass index. Within body mass index strata, the race difference in sleep-disordered breathing was attenuated. This was also true when body mass index was adjusted for instead of stratification. The strong association between body mass index and sleep-disordered breathing was similar in Japanese and Americans. The prevalence of sleep-disordered breathing was lower among Japanese than among Americans. However, the association of body mass index with sleep-disordered breathing was strong, and similar among the race/ethnic groups studied. The majority of the race/ethnic difference in sleep-disordered breathing prevalence was explained by a difference in body mass index distribution.

Nocturnal intermittent hypoxia and the development of type 2 diabetes: the Circulatory Risk in Communities Study (CIRCS).

AIMS/HYPOTHESIS: Although the associations between obstructive sleep apnoea and type 2 diabetes mellitus have been reported in cross-sectional design studies, findings on the prospective association between the two conditions are limited. We examined prospectively the association between nocturnal intermittent hypoxia as a surrogate marker of obstructive sleep apnoea and risk of type 2 diabetes. METHODS: A total of 4,398 community residents aged 40 to 69 years who had participated in sleep investigation studies between 2001 and 2005 were enrolled. Nocturnal intermittent hypoxia was assessed by pulse-oximetry and defined by the number of oxygen desaturation measurements < or =3% per h, with five to <15 per h corresponding to mild and 15 events or more per h corresponding to moderate-to-severe nocturnal intermittent hypoxia, respectively. The development of type 2 diabetes was defined by: (1) fasting serum glucose > or =7.00 mmol/l (126 mg/dl); (2) non-fasting serum glucose > or =11.1 mmol/l (200 mg/dl); and/or (3) initiation of glucose-lowering medication or insulin therapy. Multivariable model accounted for age, sex, BMI, smoking status, current alcohol intake, community, borderline type 2 diabetes, habitual snoring, excessive daytime sleepiness, sleep duration and (for women) menopausal status. RESULTS: By the end of 2007, 92.2% of participants had been followed up (median follow-up duration [interquartile range] 3.0 [2.9-4.0] years) and 210 persons identified as having developed diabetes. The multivariable-adjusted hazard ratio (95% CI) for developing type 2 diabetes was 1.26 (0.91-1.76) among those with mild nocturnal intermittent hypoxia and 1.69 (1.04-2.76) among those with moderate-to-severe nocturnal intermittent hypoxia (p = 0.03 for trend). CONCLUSIONS/INTERPRETATION: Nocturnal intermittent hypoxia was associated with increased risk of developing type 2 diabetes among middle-aged Japanese.

Associations between weight change since 20 years of age and sleep-disordered breathing among male truck drivers.

BACKGROUND: Limited evidence for association of weight gain with sleep-disordered breathing (SDB) has been produced for Asian populations whose body mass index (BMI) levels are lower than in western countries. OBJECTIVE: The aim of this study was to examine weight change since 20 years of age and risk of SDB among Japanese. DESIGN: Retrospective cohort study. SUBJECTS: This study includes a large sample of 5320 male Japanese truck drivers aged 30-69 years. MEASUREMENTS: The respiratory disturbance index (RDI) was selected as an indicator of SDB, and it was estimated with a one-night sleep test using an airflow monitor, and the Epworth Sleepiness Scale (ESS) was used to estimate excessive daytime sleepiness. RESULTS: Respiratory disturbance and sleepiness were more prevalent among men with BMI of 25.0-29.9 and > or =30.0 kg/m(2) than among those with BMI of 18.5-24.9; multivariable odds ratios (ORs) were 1.8(1.5-2.0), P<0.001 and 4.4(3.5-5.5), P<0.001 for RDI > or =10, and 1.2(0.9-1.4), P=0.18 and 1.5(1.1-2.1), P=0.02 for ESS > or =11, respectively. Compared with men showing BMI changes within +/-1.0, the respective multivariable ORs for those with BMI changes of 3.0-4.9 and > or =5.0 were 1.4(1.2-1.6), P<0.001 and 2.4(2.0-2.9), P<0.001 for RDI > or =10, and 1.2(0.9-1.6), P=0.22 and 2.0(1.5-2.6), P<0.001 for ESS > or =11. The corresponding ORs for weight gain of > or =10.0 kg compared with weight change less than +/-5.0 kg were 2.0(1.7-2.4), P<0.001 for RDI > or =10 and 1.5(1.2-2.0), P=0.002 for ESS > or =11. Similar trends were observed for RDI > or =20. CONCLUSION: Our results suggest that an increase in BMI of > or =5 kg/m(2) or weight gain of > or =10 kg is a risk factor for SDB and excessive daytime sleepiness among Japanese truck drivers.

Low protein C and incidence of ischemic stroke and coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Protein C is an important plasma natural anticoagulant. Although protein C deficiency increases risk of venous thrombosis, it remains uncertain whether low protein C increases risk of atherothrombosis. OBJECTIVE: To examine whether low protein C may be a risk factor for ischemic stroke or coronary events in a prospective population-based study. PATIENTS/METHODS: The Atherosclerosis Risk in Communities Study assessed protein C antigen by ELISA at baseline in 1987-89 and followed participants (n = 13 879) for incident ischemic stroke or coronary events through 2005. RESULTS: Over a median of 16.9 years of follow-up, 613 ischemic strokes and 1257 coronary heart disease events occurred. Protein C was inversely associated with incidence of ischemic stroke. Adjusted for multiple risk factors, the rate ratios (95% CIs) from highest to lowest quintiles were 1.0, 1.16 (0.90-1.50), 1.22 (0.94-1.58), 1.18 (0.90-1.55) and 1.52 (1.17-1.98). This inverse association was stronger for non-lacunar and cardioembolic stroke than for lacunar stroke. In contrast, there was a positive association between protein C and coronary heart disease in incompletely adjusted models, but no association after adjustment for plasma lipids. CONCLUSIONS: In this cohort study, low protein C was a risk factor for incident ischemic stroke but not coronary heart disease. Levels of protein C associated with stroke risk were not restricted to the traditional 'deficient' range for protein C (< 0.5 percentile), suggesting that other etiologies for a lower protein C, or genetic variants associated with more subtle changes in protein C, are playing a role in disease pathogenesis.

Modulation of gonadotrophin-releasing hormone pulse generator activity by the pheromone in small ruminants.

In small ruminants, such as goats and sheep, a primer pheromone produced by males induces an out-of-seasonal ovulation in anoestrous females, a phenomenon known as the male effect. The male effect is unique in that an external chemical stimulus can immediately modulate the activity of the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator. We have established a monitoring method of the GnRH pulse generator activity in Shiba goat. Using this method as a sensitive bioassay to assess the male effect pheromone activity, we have shown that the male effect pheromone is synthesised in an androgen-dependent manner in the sebaceous glands or their vicinity in specific body regions in goats. Although chemical identity of the pheromone is yet to be determined, analyses of male goat hair extracts by gas chromatography fractionation suggest that the male effect pheromone is a volatile substance with relatively small molecular weight. From morphological and molecular biological studies in goats, it is suggested that the pheromone molecule is detected by a member of the V1R family located on both the olfactory neurones and the vomeronasal sensory neurones, and the pheromone signal is conveyed to the medial nucleus of amygdala via the main olfactory and vomeronasal pathways and, subsequently, to the hypothalamic GnRH pulse generator to enhance its activity.

Living arrangement and coronary heart disease: the JPHC study.

BACKGROUND: Previous studies have suggested that living in a multi-generational household (a type of family structure prevalent in Japan) confers mixed health benefits and stresses, especially for women who report such living arrangements. OBJECTIVE: To examine, in a prospective cohort study, the impact of living arrangements on the incidence of coronary heart disease (CHD) and mortality as well as all-cause mortality in a large prospective cohort of the Japanese population. METHODS: The association between living arrangements and risk of CHD and mortality was examined prospectively within a cohort of 90 987 Japanese women and men aged 40-69 years, free of prior diagnosis of cancer and cardiovascular disease. A total of 671 cases of newly diagnosed CHD, 339 CHD deaths and 6255 all-cause deaths occurred between the baseline questionnaire (1990-4) and the end of follow-up in January 2004. RESULTS: After adjustment for potentially confounding variables, women living in multi-generational households (ie, with spouse-children-parents; or spouse-parents) had a two- to threefold higher risk of CHD than women living with spouses only. Women living with spouses and children also had a 2.1-fold higher risk of CHD incidence compared with married women living without children. CONCLUSIONS: Women in a multi-generational family had a higher risk of CHD, probably due to stress from multiple family roles.

Body mass index and weight change since 20 years of age and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based Study.

BACKGROUND: Obesity and weight gain are associated with increased risk of coronary heart disease in Western countries. However, their impact is not well elucidated in Asia, where body mass index (BMI) levels are generally lower than in Western countries. We examined associations of BMI (kg/m(2)) and weight change with risk of coronary heart disease in Japanese people. METHODS AND RESULTS: A total of 43 235 men and 47 444 women aged 40-69 years living in communities were followed up from 1990 to 2001 in the Japan Public Health Center-based (JPHC) prospective study . During 879 619 person-years of follow-up, we documented 399 cases of coronary heart disease (334 myocardial infarction and 65 sudden cardiac death) for men and 119 (95 myocardial infarction and 24 sudden cardiac death) for women. Compared with persons with BMI 23.0-24.9, men, but not women, with BMI >/=30.0 had higher risk of coronary heart disease and myocardial infarction; the multivariable relative risks for men were 1.8 (1.1-3.0) and 1.9 (1.1-3.2), respectively. When weight change was examined according to BMI at age 20 years, men with initial BMI <21.7 who gained more than 10 kg compared with men of no weight change had a twofold higher risk of coronary heart disease. Both men and women with initial BMI >/=21.7 showed no association between weight loss and the risk. CONCLUSIONS: High BMI was associated with increased risk of coronary heart disease among men. Also, weight gain was associated with increased risk among lean men.

Parasitism, development and adult longevity of the egg parasitoid Telenomus nawai (Hymenoptera: Scelionidae) on the eggs of Spodoptera litura (Lepidoptera: Noctuidae).

When Telenomus nawai Ashmead or Trichogramma ostriniae Pang & Chen (Hymenoptera: Trichogrammatidae) was inoculated into intact egg masses of Spodoptera litura (Fabricius) that were covered with a scale-hair layer, T. nawai emerged from 76% of the eggs, while emergence of T. ostriniae was from only 3% of the eggs. When the hair layer was removed before inoculation, the rate by the latter increased to 21%. These observations confirmed that the hair layer effectively protects S. litura egg masses from attack by T. ostriniae, and that T. nawai parasitism is more effective. In order to assess the feasibility of T. nawai as a biological control agent for S. litura, parasitism rate, development time and adult longevity were examined in the laboratory. Emergence of T. nawai was observed in more than 95% of 0- and 1-day-old separated eggs of S. litura, but the rate decreased to 60% and 0% for 2- and 3-day-old eggs, respectively. The emergence rates of T. nawai were near 95% for temperatures in a range from 25 degrees C to 35 degrees C, but decreased to 80% at 20 degrees C. No parasitoids emerged at 15 degrees C. The developmental periods decreased as temperature increased from 20 degrees C to 35 degrees C. The developmental threshold occurred at 13.7 degrees C and 13.9 degrees C, and the effective accumulative temperatures from egg to adult emergence were 149.3 and 147.1 degree-days for females and males, respectively. Mean longevity of the adult females decreased with increasing temperature; 87.0 days at 15 degrees C and 9.5 days at 35 degrees C. The feasibility of the use of T. nawai for controlling S. litura is discussed.

G-protein beta-3 subunit C825T polymorphism, sodium and arterial blood pressure: a community-based study of Japanese men and women.

Epidemiological evidence on gene-environment effects of the G-protein beta-3 subunit C825T polymorphisms and sodium on blood pressure in the free-living general population is limited. We examined the associations between the C825T polymorphism and blood pressure levels, stratified by the sodium variables estimated by 24-h urinary sodium excretion and a dietary questionnaire, among 1,471 men and women aged 30-74 from a community in Japan. Our a priori hypothesis was that individuals with the 825T allele have elevated blood pressure among subjects with a high sodium intake. Among the whole group, the systolic blood pressure level was +2.2 mmHg (p = 0.10) higher in TT than CC genotype individuals after adjustment for sex, age, antihypertensive medication use, body mass index, and alcohol consumption. This difference was more evident among individuals with low sodium excretion (+4.5 mmHg, p = 0.01), low present sodium intake (+3.2 mmHg, p = 0.11), and low past sodium intake (+4.8 mmHg, p = 0.02). No associations were observed among those with high sodium variables. Our results indicate that the G-protein beta-3 subunit C825T polymorphism is associated with higher systolic blood pressure levels in a large free-living Japanese population, and more specifically in women with a low sodium intake. This finding helps to explain part of the discrepancy between the previously reported genetic association among different ethnic groups.

The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population.

Proteinuria, high serum creatinine, and reduced glomerular filtration rate (GFR) have been associated with increased mortality from cardiovascular disease (CVD) and all causes. However, the combined effect of proteinuria with serum creatinine and GFR on CVD or all-cause mortality has not been well investigated. We conducted a 10-year prospective cohort study of 30,764 men and 60,668 women aged 40-79 years who participated in annual health checkups in 1993. The Cox proportional hazards model was used to estimate the relative risk (RR) after adjusting for age, smoking, and other cardiovascular risk factors. The multivariable RR (95% confidence interval (CI)) of CVD death for positive vs negative proteinuria was 1.38 (1.05-1.79) among men and 2.15 (1.64-2.81) among women. The respective RR for the highest vs lowest creatinine groups (> or = 1.3 vs < or = 0.8 mg/dl for men and > or = 1.1 vs < or = 0.6 mg/dl for women) was 1.56 (1.19-2.04) among men and 2.15 (1.58-2.93) among women. The respective RR for GFR < 60 vs > r = 100 ml/min/1.73 m2 was 1.65 (1.25-2.18) among men and 1.81 (1.39-2.36) among women. For individuals with proteinuria combined by hypercreatininemia or reduced GFR, the risk of CVD death was two-fold higher in men and 4-6-fold higher in women compared to those without proteinuria and with normal creatinine level or GFR. Similar associations were observed for stroke, coronary heart disease, and all-cause mortality. Proteinuria, and hypercreatininemia or reduced GFR and their combination were significant predictors of CVD and all-cause mortality.

Type 2 diabetes and risk of non-embolic ischaemic stroke in Japanese men and women.

AIMS/HYPOTHESIS: The aim of this study was to examine the relationship between type 2 diabetes and risk of ischaemic stroke in Asian populations. METHODS: We conducted a 17-year prospective cohort study in 10,582 Japanese individuals (4287 men and 6295 women) aged 40-69 years living in five communities in Japan. All subjects were free of stroke and CHD at baseline. Diabetes was defined as a fasting glucose level of >/=7.0 mmol/l, a non-fasting glucose of >/=11.1 mmol/l, or receiving medication for diabetes. RESULTS: The risk of non-embolic ischaemic stroke was approximately two-fold higher in diabetic subjects than in subjects with normal glucose levels. The multivariate relative risk after adjustment for age, community, hypertensive status, BMI, triceps and subscapular skinfold thickness (TSF and SSF), and other known cardiovascular risk factors was 1.8 (95% CI 1.0-3.2) for men and 2.2 (1.2-4.0) for women. This excess risk was primarily observed among non-hypertensive subjects and individuals with higher values for measures of adiposity (BMI, TSF and SSF values above the median), particularly those with higher values for SSF. The association between non-embolic ischaemic stroke and glucose abnormality was particularly strong among non-hypertensive subjects with higher SSF values: the multivariate relative risk was 1.9 (1.0-3.7) for borderline diabetes and 4.9 (2.5-9.5) for diabetes. CONCLUSIONS/INTERPRETATION: In this cohort, type 2 diabetes was a significant risk factor for non-embolic ischaemic stroke, particularly in non-hypertensive and non-lean individuals. Due to the nationwide decrease in blood pressure and increase in mean BMI among the Japanese population, with current levels approaching those observed in Western countries, the impact of glucose abnormalities on risk of ischaemic stroke represents a forthcoming public health issue in Japan.

Endogenous melanin-concentrating hormone receptor SLC-1 in human melanoma SK-MEL-37 cells.

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that regulates several physiological functions. The orphan G protein-coupled receptors SLC-1 and MCHR2 were recently found to bind MCH with high affinity. We show here that the human melanoma cell line SK-MEL-37 expresses SLC-1 mRNA but not MCHR2 by RT-PCR analysis and immunofluorescence studies. Using Chinese hamster ovary cells and 293 cells overexpressing SLC-1 by cDNA transfection, it was shown that SLC-1 coupled to both G alpha(i)/G alpha(o) and G alpha(q) proteins. In SK-MEL-37 cells, MCH inhibited forskolin-stimulated cyclic AMP accumulation and induced mitogen-activated protein kinase (MAPK) in a pertussis toxin-(PTX)-sensitive manner. The MAPK activity leads to the production of phosphorylated forms of p42/p44 MAPK. However, an increase in the intracellular free Ca(2+) concentration was not elicited by MCH in SK-MEL-37 cells. These results show that SLC-1 is coupled only to PTX-sensitive G alpha(i)/G alpha(o) in SK-MEL-37 cells. This study provides for the first time a skin-derived cellular model to analyze the molecular mechanism of the MCH signaling pathway.