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Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

This follow-up study was conducted over 30 years in a cadmium-polluted area of Japan. Urinary cadmium (U-Cd) concentration decreased by nearly half from 1986 to 2008 in men and women. However, it increased from 2008 to 2014 and maintained similar levels in 2016. Because renal atrophy may induce an increase in U-Cd, kidney volumes were determined using magnetic resonance imaging (MRI) scans in 2018. Based on the MRI results, we divided the participants into two groups, namely the normal group (n = 6, three men and three women) and the lesion group (n = 6, three men and three women). The level of urinary N-acetyl-β-d-glucosaminidase/creatinine (U-NAG/Cr) in the lesion group was significantly higher than in the normal group. The level of serum alkaline phosphatase (Al-P) was positively associated with U-Cd. Age and renal cortex volumes showed significantly negative associations. However, U-Cd and renal cortex and kidney volumes showed no significant associations. These results suggest that U-NAG and serum Al-P were sensitive biomarkers to reflect renal tubular dysfunction and bone damage caused by cadmium poisoning. Individuals chronically exposed to Cd should be observed carefully, due to the increased effect of aging on renal cortex volumes.

The relationship between cadmium exposure, exposure-related renal tubular dysfunction, and mortality have been reported, mainly in the residents of Cd-contaminated areas in Japan. The aim of this study was to establish the cause-effect relationship between renal tubular dysfunction and cancer mortality in the general population in non-contaminated areas. A 19-year cohort study was conducted in 1110 men and 1703 women in 1993 or 1994, who lived in three cadmium-non-contaminated areas. Mortality risk ratios of urinary β2-microglobulin (β2MG) and N-acetyl-β-glucosaminidase (NAG) for all malignant neoplasms and specific cancers were estimated using the Fine and Gray competing risks regression model. Significant hazard ratios (HRs) for liver and pancreas cancer were observed for NAG (liver: HR corresponding to an increase of 1 IU/g cr, 1.10, 95%CI, 1.02-1.19, pancreas: HR, 1.10, 95%CI, 1.02-1.19) in men. In women, a negative HR was observed for NAG (lung cancer: HR 0.80, 95% CI, 0.67-0.96) and for β2MG (all malignant neoplasms: HR, 0.97, 95% CI, 0.93-1.00). The present study indicated that renal tubular dysfunction was significantly related to mortality in the general population of cadmium-non-contaminated areas in Japan.

OBJECTIVES We investigated the support environments in companies in Ishikawa prefecture that aim to maintain a balance between work and treatment of their employees' diseases. The relationships between these strategies, company size, and type of industry were examined. METHODS In 2016, as a part of a survey, questionnaires were sent to 1,491 companies with ≥ 50 employees. Of the 688 companies who responded (response rate, 46.1%), 624 companies who provided complete main survey data were included in the final analysis. The questionnaire acquired responses on systems for arranging working hours and sick leave, the role of occupational health physicians, and the outcomes of support that was offered over the last 3 years. The targeted diseases were mental health problems, such as depression, and physical diseases. Responses were compared according to the size of the company and type of industry. RESULTS A total of 409 companies (65.5%) reported their experiences of helping employees maintain a balance between treatment and work over the last 3 years. Employees with depression received the most support. In 36.7% of the companies, some employees had retired due to their disease over the last 3 years, with the highest proportion in medical care and welfare businesses. Further, 66% of the companies had a support system to help employees with diseases, and the proportion of companies with flexible working hours and sick leave increased with the number of employees. The proportion of companies with shorter working hours and hourly paid leave was lower in the manufacturing industry and transportation/traffic business. The proportion of companies in which an occupational health physician interviewed employees who took sick leave and returned to work was 22%. CONCLUSIONS Almost 70% of the companies reported supporting workers during their disease treatment. There were some differences in arranging these support systems between companies of varying sizes and type of industry. The enablement of companies to support workers with diseases so that they keep working and receive treatment requires consideration of company characteristics.

Dementia that occurs before age 65 years is defined as young-onset dementia (YOD). YOD develops during the prime of a person's working life and has a major impact on not only work but life in general. Therefore, Japan is promoting measures to support work and social participation, taking into account the characteristics of people living with YOD. Given the rarity of YOD, few studies have examined the difficulties faced by people living with YOD during this life stage or the kinds of support they require. We believe that studying these difficulties and support requirements will contribute to prolonging the careers of people living with YOD and to providing them support during social, emotional and economic crises. This qualitative study aims to clarify the experiences of working-age Japanese people living with YOD to examine, from their perspective, possibilities for employment support. For this study, people living with YOD who were currently working were recruited by snowball sampling. This study was conducted in Japan between September 2018 and February 2019. A semi-structured interview was conducted, and the contents were transcribed and analysed using Colaizzi's qualitative methodology. Four categories were derived: (a) crisis from continuing to work, (b) seeking support, (c) overcoming challenges to work and (d) reaffirming a sense of purpose by resuming work and social participation. Participants were able to continue working and socialising by letting others know about their illness and seeking support. In the process of reaffirming a sense of purpose by resuming work and social participation, participants continued working or transitioned to socially active lives after leaving their job thanks to the support of work colleagues and medical and healthcare/welfare professionals who understand YOD. The results indicate a need for awareness raising in the workplace to promote understanding of such professional support and its significance.

The aim of the present study was to evaluate the effect of environmental cadmium (Cd) exposure indicated by urinary Cd (U-Cd) on cancer mortality in the general Japanese population. A 19-year cohort study was conducted in 1107 men and 1697 women who lived in three Cd non-polluted areas in Japan. Mortality risk ratio and 95% confidence interval (95%CI) for continuous U–Cd were estimated for all malignant neoplasms and specific cancers using a Fine and Gray competing risks regression model. The all-cause, including cancer and non-cancer mortality rates per 1000 person-years were 29.8 and 13.9 in men and women, respectively. By using Fine and Gray's method, continuous U–Cd adjusted for creatinine (+1 μg/g cre) was significantly related to mortalities for all malignant neoplasms (risk ratio = 1.06, 95%CI: 1.02–1.11) and pancreas (risk ratio = 1.13, 95%CI: 1.03–1.24) in women. In the present study, U–Cd was significantly associated with increased cancer mortality in the general Japanese population, indicating that environmental Cd exposure adversely affects the life prognosis in Cd non-polluted areas in Japan.

A small fraction of HIV-1-infected T cells forms populations of latently infected cells when they are a naive T-cell subset or in transit to a resting memory state. Latently HIV-1-infected cells reside in lymphoid tissues and serve as viral reservoirs. However, whether they systemically recirculate in the body and re-enter the lymphoid nodes are unknown. Here, we employed two in-vitro cell coculture systems mimicking the lymphatic endothelium in lymph nodes and investigated the homing potential, specifically the transendothelial migration (TEM), of two latently HIV-1-infected cell lines (J1.1 and ACH-2). In trans-well coculture systems, J1.1 and ACH-2 showed higher TEM efficiencies than their parental uninfected and acutely infected cells. The efficiency of TEM was enhanced by the presence of stromal cells, such as HS-5 and fibroblastic reticular cells. In an in-vitro reconstituted, three-dimensional coculture system in which stromal cells are embedded in collagen matrices, J1.1 showed slightly higher TEM efficiency in the presence of HS-5. In accordance with these phenotypes, latently infected cells adhered to the endothelial cells more efficiently than uninfected cells. Together, our study showed that latently HIV-1-infected cells enhanced cell adhesion and TEM abilities, suggesting their potential for efficient homing to lymph nodes.

We evaluated the association between urinary cadmium concentration (uCd, μg/g Cr) and risk of cause-specific mortality according to urinary β2-microglobulin (MG) concentration. Participants were 1383 male and 1700 female inhabitants of the Cd-polluted Kakehashi River basin. The uCd and β2-MG were evaluated in a survey in 1981–1982, where those participants were followed-up over 35 years later. Among the participants with a urinary β2-MG < 1000, the hazard ratios (HRs) (95% confidence interval) for mortality were significantly higher in those with a uCd of ≥10.0 compared with

Objective This study investigated associations between three indices of obesity-the body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR)-and the incidence of chronic kidney disease (CKD). Methods The employees of a company in Japan (1,725 men, 1,186 women; aged 35-55 years) had BMI, WC, and WHtR measured in health examinations. The incidence of CKD was determined at annual medical examinations over a six-year period. The hazard ratios for CKD were calculated using proportional hazard models, and the χ2 statistic was used to compare the strengths of the associations. Results The mean BMI (kg/m2), WC (cm), and WHtR were 23.6, 84.3, and 0.49 for men and 22.3, 79.7, and 0.50 for women, respectively. The incidence of CKD (/1,000 person-years) was 18.1 for men and 8.4 for women. In men, positive linear associations were observed between the BMI, WC, and WHtR and the risk of CKD, even after adjusting for the presence of metabolic abnormalities (p for trend

Aims/Introduction This cohort study assessed the risk for bodyweight gain and development of glucose intolerance based on the frequency of consumption of balanced meals including grain, fish or meat and vegetables. Materials and Methods The participants (8,573 men, 3,327 women) were employees of a company in Japan. A self‐administered questionnaire was used to evaluate the frequency of balanced meal consumption. Bodyweight changes and the incidence of glucose intolerance (glycated hemoglobin >6.0%) during the 3‐year follow‐up period were determined through annual health examinations. Results The mean bodyweight change over a period of 3 years was 0.78 kg for men and 0.84 kg for women. A lower frequency of balanced meals was associated with a higher bodyweight gain for men (P for trend = 0.004), but not for women. During the study, 464 men and 115 women developed glucose intolerance. Overall, the frequency of balanced meals was not associated with the risk of glucose intolerance in either sex. However, the interaction between the frequency of balanced meals and degree of obesity had a significant effect on the incidence of glucose intolerance in men (P = 0.005), with less frequent consumption of balanced meals being associated with a higher risk for glucose intolerance among men with a BMI ≥25.0 kg/m2 (P for trend = 0.007). Conclusions A higher frequency of balanced meals, including grain, fish or meat and vegetable dishes – important components of healthy Japanese food – was associated with a lower risk of glucose intolerance in obese men, but not in non‐obese men and women., We evaluated the risk for development of glucose intolerance based on the frequency of consumption of balanced meals including grain, fish and meat, and vegetable dishes. A lower frequency of balanced meals was associated with a higher risk of glucose intolerance in obese men.

The objective of this study was to assess the effect of environmental cadmium exposure according to urinary cadmium concentration (U-Cd) on noncancer mortality in a general Japanese population. We conducted a longitudinal study for 19 years in 2804 inhabitants (1107 men and 1697 women) in some cadmium nonpolluted regions in Japan. The participants were classified into quartiles based on U-Cd (μg/g cre) adjusted for urinary creatinine. Hazard ratio (HR) and 95% confidence interval (95% CI) for continuous U-Cd or the quartiles of U-Cd were calculated for noncancer mortality. By applying a Fine and Gray competing risk model, continuous U-Cd (+1 μg/g cre) showed significant HR for cardiocerebrovascular diseases (HR 1.05, 95% CI: 1.00-1.11), cerebrovascular diseases (HR 1.08, 95% CI: 1.01-1.16), and cerebral infarction (HR 1.11, 95% CI: 1.04-1.20) in men. However, notable significant HR for continuous and quartered U-Cd were not observed in women. In this study, U-Cd was associated with increased cardiocerebrovascular mortality in a general Japanese population, suggesting that environmental cadmium exposure is detrimental to the life prognosis in cadmium nonpolluted regions in Japan.

The relationship between urinary β

HIV reactivation from latency is induced by cytokines but also by cell contact with other cells. To better understand this, J1.1 cells, a latent HIV-1-infected Jurkat derivative, were cocultured with its parental Jurkat. J1.1 cells became p17MA-positive and produced a high level of HIV p24CA antigen, only when they were cocultured with stimulated Jurkat with cell-to-cell contact. In contrast, very little p24CA was produced when they were cocultured without cell contact. Similar results were obtained when latent ACH-2 and its parental A3.01 cells were cocultured. Confocal microscopy revealed that not only HIV-1 p17MA and gp120Env but also LFA-1, CD81, CD59, and TCR CD3 accumulated at the cell contact site, suggesting formation of the virological synapse-like structure. LFA-1&ndash, ICAM-1 interaction was involved in the cell-to-cell contact. When J1.1 was cocultured with TCR-deficient Jurkat, the p17MA-positive rate was significantly lower, although the cell-to-cell contact was not impaired. Quantitative proteomics identified 54 membrane molecules, one of which was MHC class I, that accumulated at the cell contact site. Reactivation from latency was also influenced by the presence of stromal cells. Our study indicated that latent HIV-1 in J1.1/ACH-2 cells was efficiently reactivated by cell-to-cell contact with stimulated parental cells, accompanying the virological synapse-like structure.

Dioxin concentrations remain elevated in the environment and humans residing near the former US Air Force base in Bien Hoa city, South Vietnam. We recruited 210 mother-infant pairs for whom breast milk dioxin levels were reported in our previous study. Cord blood samples were collected from 162 mother-infant pairs. We selected 16 cord blood samples with a volume over 20mL and fat content of ≥0.03g. Toxic equivalent levels of polychlorinated dibenzodioxins and polychlorinated dibenzofurans (TEQ-PCDD/Fs) and concentrations of 17 congeners, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), in cord blood were measured and compared with levels in breast milk (Study 1). Levels of 2,3,7,8-TCDD and TEQ-PCDD/Fs in cord blood samples were highly and significantly correlated with those in breast milk samples in the same pairs. This suggests dioxins in breast milk reflect prenatal dioxin exposure. Estradiol (E2) and testosterone (TS) were measured in cord blood serum from 162 samples. Associations between dioxins in breast milk and cord blood sex hormones were analyzed by infant sex, after adjusting for confounding factors (Study 2). Increased levels of TEQ-PCDD/Fs in breast milk were associated with decreased cord blood TS in girls. In boys, a significant reduction of cord blood TS was observed in those exposed to 2,3,7,8-TCDD at high levels (≥5.5pg/g lipid). There was no significant association between E2 and dioxins in breast milk in either sex. These results suggest increased prenatal dioxin exposure is associated with decreased cord TS, but in boys, only high level of 2,3,7,8-TCDD influence cord blood TS.

Objectives The increasing number of working elderly people has enhanced the importance of workplace health promotion activities. We investigated the association between the health status of workers approximately 60 years of age and the risk of all‐cause mortality after compulsory retirement in Japan. Methods The 2026 participants (1299 males and 727 females) had retired from a metal‐products factory at ≥60 years of age. Baseline health examinations were conducted at 60 years of age and included questions about medical history and lifestyle factors; the participants also underwent a physical examination. The participants were followed up annually by mail for an average of 7.4 years. The association between health status at age 60 years and the risk of all‐cause mortality was assessed by Cox proportional hazards regression analysis. Results During the study, 71 deaths were reported. The age‐ and sex‐adjusted hazard ratio (HR [95% confidence interval]) for all‐cause mortality was higher for males (HR, 3.41 [1.73‐6.69]) compared with females, participants with a low body mass index (

OBJECTIVES This study aimed to clarify workplace recognition regarding working continuation of employees with early onset dementia. METHODS An anonymous self-administrated questionnaire was emailed to a prefecture consisting of 1,293 workplaces with 50 or more employees. Survey items assessed demographics, workplace regulations supporting employees, coworker acceptance of employees with early onset dementia, and recognition and dealing with employees with early onset dementia. The possibility of employees with early onset dementia continuing work was compared for demographics, workplace regulations supporting employees, and cooperation in the workplace. RESULTS Responses were received from 375 workplaces, and 273 valid responses were analyzed. In total, 133 workplaces (48.7%) answered that there was a high possibility of continuing employment for employees with early onset dementia and 135 workplaces (49.5%) were aware of early onset dementia. Less than 10% of workplaces reported examination of managing employees with early onset dementia, implementation/planning of training and information dissemination to managers or employees. Factors related to the possibility of continuing employment were number of employees (< 100, p = .015, odds ratio = 2.02), workplace regulations supporting employees with early onset dementia (p = .011, odds ratio = 2.22), and workplace coordination with occupational health staff (p = .004, odds ratio = 2.16). CONCLUSIONS There is a general need for training and information regarding early onset dementia in the workplace. For smaller companies, external advice and support in providing systems suitable to each workplace is necessary.

Objectives: The present cohort study investigated the relationship between serum ferritin levels and indices of insulin resistance and β-cell dysfunction in a normoglycemic population without iron overload disorders. Methods: The study participants included 575 normoglycemic Japanese men aged 35–57 years with serum ferritin levels of 400 μg/L or less. Insulin resistance and β-cell dysfunction were estimated at baseline and after 3 years by the homeostasis model assessments of insulin resistance and β-cell function (HOMA-IR and HOMA-β, respectively). To compare the subsequent changes in HOMA-IR and HOMA-β over a 3-year follow-up period among 3 groups based on tertiles of baseline serum ferritin levels (4.9–87.1, 87.2–140.5, and 140.6–396.8 μg/L), the geometric mean HOMA-IR and HOMA-β values at year 3 were calculated for each group using analysis of covariance, incorporating the respective log-transformed parameters at baseline in addition to age, body mass index and major confounding factors. Results: The multivariate-adjusted geometric mean HOMA-IR at year 3 was significantly higher in those in the highest and middle serum ferritin tertiles (1.24 and 1.22, respectively), compared with the lowest tertile (1.07) (p=0.009). When the total study participants were stratified by median body mass index (22.72 kg/m2), similar positive relationships were observed between serum ferritin levels and HOMA-IR for both obese and non-obese participants. However, the adjusted geometric mean HOMA-β at year 3 was similar among the 3 serum ferritin groups. Conclusions: Elevated serum ferritin levels predicted a subsequent increase in HOMA-IR in normoglycemic Japanese men without iron overload disorders.

Background We previously reported that perinatal dioxin exposure increased autistic traits in children living in dioxin-contaminated areas of Vietnam. In the present study, we investigated the impact of dioxin exposure on children’s eating behavior, which is often altered in those with developmental disorders. Methods A total of 185 mother-and-child pairs previously enrolled in a birth cohort in dioxin-contaminated areas participated in this survey, conducted when the children reached 3 years of age. Perinatal dioxin exposure levels in the children were estimated using dioxin levels in maternal breast milk after birth. Mothers were interviewed using the Children’s Eating Behaviour Questionnaire (CEBQ). A multiple linear regression model was used to analyze the association between dioxin exposure and CEBQ scores, after controlling for covariates such as location, parity, maternal age, maternal education, maternal body mass index, family income, children’s gestational age at delivery, and children’s age at the time of the survey. A general linear model was used to analyze the effects of sex and dioxin exposure on CEBQ scores. Results There was no significant association between most dioxin congeners or toxic equivalencies of polychlorinated dibenzo-p-dioxins/furans (TEQ-PCDDs/Fs) and CEBQ scores in boys, although significant associations between some eating behavior sub-scores and 1,2,3,4,6,7,8,9-octachlorodibenzofuran were observed. In girls, there was a significant inverse association between levels of TEQ-PCDFs and enjoyment of food scores and between levels of TEQ-PCDFs and TEQ-PCDDs/Fs and desire to drink scores. Two pentachlorodibenzofuran congeners and 1,2,3,6,7,8-hexachlorodibenzofuran were associated with a decreased enjoyment of food score, and seven PCDF congeners were associated with a decreased desire to drink score. The adjusted mean enjoyment of food score was significantly lower in children of both sexes exposed to high levels of TEQ-PCDFs. There was, however, a significant interaction between sex and TEQ-PCDF exposure in their effect on desire to drink scores, especially in girls. Conclusions Perinatal exposure to dioxin can influence eating behavior in children and particularly in girls. A longer follow-up study would be required to assess whether emotional development that affects eating styles and behaviors is related to dioxin exposure. Electronic supplementary material The online version of this article (10.1186/s12887-018-1171-2) contains supplementary material, which is available to authorized users.

Background Exposure to cadmium (Cd) via food is supposed to affect life prognosis of inhabitants of Cd-polluted area in Japan. However, there have been few reports demonstrating a significant relationship between the amount of Cd intake and mortality. We aimed to investigate the relationship between mortality and individual lifetime Cd intake (LCd) in inhabitants of the polluted Jinzu River basin, Toyama, Japan. Methods We conducted a 26-year follow-up survey in 2407 inhabitants (1208 men and 1199 women) who participated in health examinations for screening of renal dysfunction from 1979 to 1984. The calculation of LCd in each inhabitant was based on the formula of Nogawa (Nogawa et al., 1989): (mean Cd concentration in rice of the present hamlet × 333.5 g/day + 34 μg/day) × 365 days/year × number of years of residence in the present hamlet + 50 μg/day × 365 days/year × number of years living in Cd non-polluted regions. In this formula, 333.5 g/day is the 1970 average daily intake of rice in this area, 34 µg/day is the Cd intake from foods other than rice in this area, and 50 μg/day is the average intake of Cd in non-polluted areas in Japan. Mortality risk ratios of LCd for all and specific causes were estimated after adjustments for age at baseline, smoking status, and history of hypertension using a Cox hazard model or Fine and Gray competing risks regression model. Results The mortality risk ratios of LCd (+ 1 g) for all causes in women were significantly dose-dependently increased (risk ratio: 1.08). Relative risk of LCd for kidney and urinal tract disease, renal diseases, renal failure and toxic effects of cadmium were significantly higher in women. Conclusions The present study documents that individual LCd dose-dependently decreased life prognosis over long-term observation in women. LCd was significantly related to the increased mortality for renal disease and toxic effect of Cd in women. The result provides clear evidence that life prognosis was adversely affected by Cd-exposure, especially in women.

The present cohort study assessed the risk among Japanese men for developing type 2 diabetes, based on the percentage of energy intake from carbohydrates and degree of obesity. Participants and Methods: The participants were 2,006 male factory employees, and the macronutrient intake of each patient was measured using a self-administered diet history questionnaire. The incidence of diabetes was determined in annual blood examinations over a 10-year period. Results: During the study, 232 participants developed diabetes. The crude incidence rates (/1,000 person-years) for different levels of carbohydrate intake as a percentage of calories consumed (65.0% of energy intake) were 16.5, 14.4, 12.7 and 17.6. Overall, carbohydrate intake was not associated with the risk of diabetes. However, there was significant interaction between carbohydrate intake and degree of obesity on the incidence of diabetes (P for interaction = 0.024). Higher carbohydrate intake was associated with elevated risk for diabetes among participants with a body mass index ≥25.0 kg/m2 (P for trend = 0.034). For obese participants, the multivariate-adjusted hazard ratio for those with carbohydrate intakes >65% energy was 2.01 (95% confidence interval 1.08-3.71), which was significantly higher than that of participants with carbohydrate intakes 50.0-57.4% energy. Conclusions: Higher carbohydrate intake was associated with higher risk of diabetes in obese participants, but not in non-obese participants. Obese participants with carbohydrate intakes >65% energy should reduce their intakes to levels within the desirable carbohydrate energy proportion for Japanese (50-65% energy) to prevent development of type 2 diabetes. © 2016 Asian Association for the Study of Diabetes and John Wiley & Sons Australia, Ltd.

The aim of this study was to investigate the relationship between mortality and rice cadmium (Cd) concentration in inhabitants of a polluted area in Japan. The target subjects were inhabitants of the Jinzu River basin who participated in health examinations for screening of renal dysfunction from 1979 to 1984. The mean rice Cd concentration in each hamlet was used as an index of the Cd exposure. We conducted a 26 year follow-up survey in 3281 inhabitants (1544 men and 1737 women) whose data regarding the rice Cd concentration were available. Mortality risk ratios for all and specific causes were estimated after adjustments for age at baseline, smoking status and history of hypertension using a Cox hazard model or Fine and Gray competing risks regression model. The mortality risk ratios of rice Cd concentration (+0.1 ppm) for all causes in women were significantly increased (risk ratio: 1.04). Furthermore, the relative risks of rice Cd concentration for kidney and urinary tract disease, renal diseases, renal failure and toxic effects of cadmium were significantly increased in both sexes. These findings indicated that increased rice Cd concentration decreased the prognosis for life over a long-term observation in women. This result provides important information for determining the worldwide standard for allowable rice Cd concentration.

Aims To examine the relation of insulin resistant status determined by homeostasis model assessment of insulin resistance (HOMA-IR) with the risk of incident hyperuricemia. Methods The study participants included 2071 Japanese men without hyperuricemia and diabetes, aged 35–54 years. The participants had undergone annual heath examinations for 6 years to compare incident hyperuricemia (serum uric acid >416.4 μmol/L (7.0 mg/dL) and/or taking medication for hyperuricemia) in four groups based on quartiles of baseline HOMA-IR. Results During follow-up there were 331 incident cases of hyperuricemia. The hazard ratios for hyperuricemia, compared with HOMA-IR ≤0.66, were 1.42 (95% confidence interval 1.02–1.98) for HOMA-IR 0.67–0.98, 1.20 (0.86–1.68) for HOMA-IR 0.99–1.49 and 1.44 (1.04–1.98) for HOMA-IR ≥1.50 after adjustment for baseline serum uric acid, creatinine, hypercholesterolemia and hypertension status, age, alcohol intake, and smoking and exercise habits. The hazard ratio associated with an increase of one standard deviation in lnHOMA-IR (1.85 as one geometric standard deviation of HOMA-IR) was 1.14 (1.03–1.28) ( p for trend = 0.02). Conclusions Increased HOMA-IR independently predicted the subsequent development of hyperuricemia. Insulin resistance itself or compensatory hyperinsulinemia may contribute to the development of hyperuricemia.

In polarized epithelial cells, influenza A virus hemagglutinin (HA) and neuraminidase (NA) are intrinsically associated with lipid rafts and target the apical plasma membrane for viral assembly and budding. Previous studies have indicated that the transmembrane domain (TMD) and cytoplasmic tail (CT) of HA and NA are required for association with lipid rafts, but the raft dependencies of their apical targeting are controversial. Here, we show that coexpression of HA with NA accelerated their apical targeting through accumulation in lipid rafts. HA was targeted to the apical plasma membrane even when expressed alone, but the kinetics was much slower than that of HA in infected cells. Coexpression experiments revealed that apical targeting of HA and NA was accelerated by their coexpression. The apical targeting of HA was also accelerated by coexpression with M1 but not M2. The mutations in the outer leaflet of the TMD and the deletion of the CT in HA and NA that reduced their association with lipid rafts abolished the acceleration of their apical transport, indicating that the lipid raft association is essential for efficient apical trafficking of HA and NA. An in situ proximity ligation assay (PLA) revealed that HA and NA were accumulated and clustered in the cytoplasmic compartments only when both were associated with lipid rafts. Analysis with mutant viruses containing nonraft HA/NA confirmed these findings. We further analyzed lipid raft markers by in situ PLA and suggest a possible mechanism of the accelerated apical transport of HA and NA via clustering of lipid rafts. IMPORTANCE Lipid rafts serve as sites for viral entry, particle assembly, and budding, leading to efficient viral replication. The influenza A virus utilizes lipid rafts for apical plasma membrane targeting and particle budding. The hemagglutinin (HA) and neuraminidase (NA) of influenza virus, key players for particle assembly, contain determinants for apical sorting and lipid raft association. However, it remains to be elucidated how lipid rafts contribute to the apical trafficking and budding. We investigated the relation of lipid raft association of HA and NA to the efficiency of apical trafficking. We show that coexpression of HA and NA induces their accumulation in lipid rafts and accelerates their apical targeting, and we suggest that the accelerated apical transport likely occurs by clustering of lipid rafts at the TGN. This finding provides the first evidence that two different raft-associated viral proteins induce lipid raft clustering, thereby accelerating apical trafficking of the viral proteins.

We investigated the relation between overall sleep status based on the modified Pittsburgh Sleep Quality Index (PSQI) global score and subsequent changes in serum high-sensitivity C-reactive protein (hsCRP) in a population of Japanese factory workers, who were predominantly female. A total of 991 Japanese with inflammation classified as low cardiovascular risk (baseline hsCRP 1.0 mg L(-1) ) were grouped according to the presence or absence of unfavourable sleep, defined as a modified PSQI global score 5.5 points. The subsequent changes in hsCRP after 3 years were then compared in the two groups. Analysis of covariance incorporating log-transformed baseline hsCRP, age, sex, lifestyle and physical and biochemical profiles was used to compare the geometric means of hsCRP at year 3 in each sleep status group. A logistic regression model incorporating the same variables was used to calculate the odds ratios for development of inflammation with a medium-to-high cardiovascular risk (hsCRP at year 3 ≥ 1.0 mg L(-1) ) comparing the presence or absence of unfavourable sleep habits. The multivariate-adjusted geometric mean of hsCRP at year 3 was significantly higher in subjects with unfavourable sleep habits compared with those with a normal pattern (0.275 versus 0.242 mg L(-1) ). The multivariate-adjusted odds ratio for developing increased and potentially pathogenic levels of inflammation due to unfavourable sleep was 2.08 (95% confidence interval = 1.29-3.35). There was a significant linear trend for the development of increased inflammation across the modified PSQI global scores (P = 0.04). Unfavourable sleep is associated with activation of low-grade systemic inflammation.

The aim of this study was to establish the cause-effect relationship between renal tubular dysfunction and mortality. A 19-year cohort study was conducted in 900 men and 1313 women in 1993 or 1994 who lived in two cadmium non-polluted areas in Japan. Hazard ratio (HR) and 95% confidence interval (95% CI) of urinary β2-microglobulin (β2-MG) and N-acetyl-β-glucosaminidase (NAG) for mortality were calculated using a proportional hazard regression. Forward stepwise model selection was applied to the potential covariates such as age, body mass index, mean arterial pressure, various lifestyle factors and present illness. Simultaneously, the dose-effect relationship between renal tubular markers and urinary cadmium at baseline was evaluated using multiple regression analyses. In men, HR was significant for β2-MG (HR corresponding to an increase of 100 μg/g cre: 1.02) and NAG (HR corresponding to an increase of 1 IU/g cre: 1.05). In women, a significant HR was observed for β2-MG (HR corresponding to an increase of 100 μg/g cre: 1.01) and NAG (HR corresponding to an increase of 1 IU/g cre: 1.02). Dose-effect relationships were significant for urinary cadmium and all renal tubular markers in men and women. The present study indicated that renal tubular dysfunction was significantly related to mortality in the general population of cadmium non-polluted areas in Japan.

Dioxin levels in the breast milk of mothers residing near a contaminated former airbase in Vietnam remain much higher than in unsprayed areas, suggesting high perinatal dioxin exposure for their infants. The present study investigated the association of perinatal dioxin exposure with autistic traits in 153 3-year-old children living in a contaminated area in Vietnam. The children were followed up from birth using the neurodevelopmental battery Bayley-III. The high-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposed groups (⩾3.5 pg per g fat) showed significantly higher Autism Spectrum Rating Scale (ASRS) scores for both boys and girls than the mild-TCDD exposed groups, without differences in neurodevelopmental scores. In contrast, the high total dioxin-exposed group, indicated by polychlorinated dibenzo-p-dioxins/furans (PCDDs/Fs)--the toxic equivalents (TEQ) levels⩾17.9 pg-TEQ per g fat, had significantly lower neurodevelopmental scores than the mild-exposed group in boys, but there was no difference in the ASRS scores. The present study demonstrates a specific impact of perinatal TCDD on autistic traits in childhood, which is different from the neurotoxicity of total dioxins (PCDDs/Fs).

Aims: The aim of this study was to investigate age-related differences in the relationship between work-related factors and heavy drinking. METHODS: This study in 3398 male workers at a factory in Japan examined data on heavy drinking, defined as an alcohol consumption >40 g/day, and work-related factors including occupation, shift work, and job stress evaluated using the Japanese version of the Karasek's Job Content Questionnaire (JCQ). In the present cross-sectional study, alcohol consumption was assessed using a self-administered diet history questionnaire (DHQ). RESULTS: The prevalence of heavy drinkers in the study population was 15.5% and rose with increasing age. An increase in the odds ratio (OR) for heavy drinking was observed consistently in blue-collar workers compared with white-collar workers in all age groups. In subjects aged 20-29 years, shift work had also increased the OR for heavy drinking. In subjects aged 40-49 years, the two groups with a lower decision latitude had an increased OR compared with the highest group. The adjusted OR for individuals who received the lowest level of social support in the workplace was increased significantly compared with the highest group (4.22 [95%CI, 1.07-16.62]). On the other hand, social support showed a positive association with heavy drinking in subjects aged 40-49 and 50-59 yr. Job demand was not related to heavy drinking in any of the age groups. CONCLUSION: Our findings suggest that occupation and work schedule are related to alcohol use more apparently in a younger age group and that psychosocial factors are related to enhancement or prevention of alcohol use. Language: en

Objective This cross-sectional study investigated the associations between the serum thyroid-stimulating hormone (TSH) concentration and indices of obesity in middle-aged Japanese men and women. Methods The participants were 2,037 employees (1,044 men and 993 women; age, 36-55 yr) of a metal products factory in Japan. Clinical examinations were conducted in 2009. We obtained a medical history and anthropometric measurements (body weight, body mass index [BMI] and waist circumference) and measured the serum TSH concentrations. The anthropometric indices were compared across serum TSH quartiles. The associations were evaluated separately according to the smoking status in men. Results The mean body weight (kg), BMI (kg/m(2)) and waist circumference (cm) were 69.2, 23.7 and 83.2 in men and 55.3, 22.3 and 74.3 in women, respectively. Men with a higher TSH concentration had higher body weight and BMI values (p for trend=0.016 and 0.019, respectively), and these significant associations were observed even after adjusting for age, smoking status and other potential confounders. The TSH level was not associated with waist circumference. We found a significant interaction between the TSH level and the smoking status on body weight (p for interaction=0.013) and a significant association between the TSH level and body weight in nonsmokers, but not in current smokers. No significant associations were observed between the TSH level and the anthropometric indices in women. Conclusion Significant positive associations between the serum TSH concentration, body weight and BMI were detected in men only, and an interaction with the smoking status was observed for this association.

Although glucocorticoids are effective for patients with IgG4-related disease, the treatment has not yet been standardized. Therefore, the treatment strategy should be established.Patients who fulfilled the comprehensive diagnostic criteria for definite IgG4-related disease were started on prednisolone (0.6 mg/kg body weight) with the dose reduced every two weeks. The subsequent maintenance dose and need for prednisolone were determined for individual patients. The primary endpoint was the complete remission (CR) rate at one year. Secondary endpoints included overall response rate (ORR), the maintenance dose, the relapse rate, and adverse events.This study enrolled 61 patients. After clinicopathological review, three patients were excluded, and one, 13, and 44 patients were diagnosed with probable, possible, and definite IgG4-related disease, respectively. Of the 44 patients with definite IgG4-RD, 29 (65.9%) achieved CR, and the ORR was 93.2%. No patient was refractory to primary treatment. The most frequent adverse events were glucose intolerance. Six patients relapsed.Glucocorticoid treatment is usually effective for patients with IgG4-RD, and we should examine the possibility of other disorders when a patient is glucocorticoid refractory. Some patients are misdiagnosed, making central clinicopathological review of diagnosis very important in conducting clinical studies.

Efavirenz (EFV), a nonnucleoside reverse transcriptase (RT) inhibitor, also inhibits HIV-1 particle release through enhanced Gag/Gag-Pol processing by protease (PR). To better understand the mechanisms of the EFV-mediated enhancement of Gag processing, we examined the intracellular localization of Gag/Gag-Pol processing products and their precursors. Confocal microscopy revealed that in the presence of EFV, the N-terminal p17 matrix (p17MA) fragment was uniformly distributed at the plasma membrane (PM) but the central p24 capsid (p24CA) and the Pol-encoded RT antigens were diffusely distributed in the cytoplasm, and all of the above were observed in puncta at the PM in the absence of EFV. EFV did not impair PM targeting of Gag/Gag-Pol precursors. Membrane flotation analysis confirmed these findings. Such uniform distribution of p17MA at the PM was not seen by overexpression of Gag-Pol and was suppressed when EFV-resistant HIV-1 was used. Forster's fluorescence resonance energy transfer assay revealed that Gag-Pol precursor dimerization occurred mainly at the PM and that EFV induced a significant increase of the Gag-Pol dimerization at the PM. Gag-Pol dimerization was not enhanced when HIV-1 contained the EFV resistance mutation in RT. Bacterial two-hybrid assay showed that EFV enhanced the dimerization of PR-RT fragments and restored the dimerization impaired by the dimerization-defective mutation in the RT tryptophan repeat motif but not that impaired by the mutation at the PR dimer interface. Collectively, our data indicate that EFV enhances Gag-Pol precursor dimerization, likely after PM targeting but before complete particle assembly, resulting in uniform distribution of p17MA to and dissociation of p24CA and RT from the PM.

The aim of this study was to identify psychosocial work characteristics associated with long sick leave in a large population of male Japanese employees in multiple workplaces. We ex- amined various psychosocial work characteristics (job overload, job control, supervisor support, coworker support, support by family and friends, role ambiguity, role conflict, intragroup conflict and intergroup conflict) of employees in six factories at the base line. We then conducted a follow- up survey on the recorded long sick leaves of ≥30 continuous days taken by the employees due to any medical condition. We found 574 cases of long sick leave out of 15,531 subjects during an aver- age 5.07-yr follow-up. The results showed that high supervisor support was significantly associated with a decrease in the hazard ratio (HR) of long sick leave after adjustment for several confounding factors (95%CI; 0.69-0.97). High role ambiguity also tended to increase HR, but without reaching significance (95%CI; 0.99-1.41). The results suggest that supervisor support in the workplace may be important to reduce long sick leave in Japanese male employees.

Aims: To investigate the effects of shift work on increased alcohol intake associated with poor sleep quality. Methods: This cross-sectional survey evaluated the correlation between work schedule, poor sleep quality and heavy drinking among 909 factory workers aged 35-54 years in Japan. Subjects included 530 day workers, 72 shift workers who did not work at night and 290 shift workers who engaged in night work. Heavy drinking was defined as a mean volume of alcohol consumption exceeding 60 g/day. Results: Compared with other workers, night-shift workers who suffered poor sleep quality exhibited the highest frequency of heavy drinking (17.6%). Multiple logistic regression analysis demonstrated that compared with day workers with good sleep, night-shift workers who experienced poor sleep had more than twice the odds of heavy alcohol consumption (odds ratio 2.17 [95% confidence interval (CI), 1.20-3.93]). Shift workers who did not work at night and day workers with poor sleep were not at increased odds of heavy drinking. Conclusion: Shift workers who engage in night work may try to modify their health behavior to cope with sleep problems. Such modification may be a risk factor for heavy drinking. Language: en

Objective: This cohort study investigated the association between eating speed and the incidence of type 2 diabetes in middle-aged Japanese men. Materials/Methods: Participants were 2,050 male employees of a metal products factory in Japan. We measured self-reported categorical eating speed. The incidence of diabetes was determined in annual medical examinations over a 7-year period. The association between eating speed and the incidence of diabetes adjusted for multiple variables (age, family history of diabetes, smoking, alcohol drinking, habitual exercise, and presence of hypertension and hyperlipidemia) was evaluated using Cox proportional hazards models. Results: The prevalence of obesity (BMI ≥ 25 kg/m 2) across the categories of eating speed (slow, medium, and fast) was 14.6, 23.3, and 34.8%, respectively, and a faster eating speed was associated with a higher prevalence of obesity. During the study, 177 participants developed diabetes. Crude incidence rates (/1,000 person-years) across the three categories of eating speed were 9.9, 15.6, and 17.3, respectively. Multivariate-adjusted hazard ratios (95% CI) across the categories were 1.00 (reference), 1.68 (0.93-3.02), and 1.97 (1.10-3.55), respectively, and eating speed was associated with the risk of diabetes (p for trend = 0.030). After further adjustment for BMI, a significant association was not observed. Conclusions: Eating speed was associated with the incidence of diabetes. Since these associations were not significant after adjusting for BMI, eating speed may act via its effect on body weight. Eating speed is a controllable risk factor, and eating slowly could be an acceptable lifestyle intervention for the prevention of diabetes mellitus. © 2012 Elsevier Inc. All rights reserved.

Measles virus (MV) infection in children harboring human immunodeficiency virus type 1 (HIV-1) is often fatal, even in the presence of neutralizing antibodies; however, the underlying mechanisms are unclear. Therefore, the aim of the present study was to examine the interaction between HIV-1 and wild-type MV (MVwt) or an MV vaccine strain (MVvac) during dual infection. The results showed that the frequencies of MVwt- and MVvac-infected CD4 + T cells within the resting peripheral blood mononuclear cells (PBMCs) were increased 3- to 4-fold after HIV-1 infection, and this was associated with a marked upregulation of signaling lymphocytic activation molecule (SLAM) expression on CD4 + T cells but not on CD8 + T cells. SLAM upregulation was induced by infection with a replication-competent HIV-1 isolate comprising both the X4 and R5 types and to a lesser extent by a pseudotyped HIV-1 infection. Notably, SLAM upregulation was observed in HIV-infected as well as -uninfected CD4 + T cells and was abrogated by the removal of HLA-DR + cells from the PBMC culture. Furthermore, SLAM upregulation did not occur in uninfected PBMCs cultured together with HIV-infected PBMCs in compartments separated by a permeable membrane, indicating that no soluble factors were involved. Rather, CD4 + T cell activation mediated through direct contact with dendritic cells via leukocyte function-associated molecule 1 (LFA-1)/intercellular adhesion molecule 1 (ICAM-1) and LFA-3/CD2 was critical. Thus, HIV-1 infection induces a high level of SLAM expression on CD4 + T cells, which may enhance their susceptibility to MV and exacerbate measles in coinfected individuals.

Background: The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. Methods: We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies. Results: For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Conclusion: Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved.

Human immunodeficiency virus (HIV) Gag protein targets to the plasma membrane and assembles into viral particles. In the next round of infection, the mature Gag capsids disassemble during viral entry. Thus, Gag plays a central role in the HIV life cycle. Using a yeast membrane-associated two-hybrid assay based on the SOS-RAS signaling system, we developed a system to measure the Gag-Gag interaction and isolated 6 candidates for Gag assembly inhibitors from a chemical library composed of 20,000 small molecules. When tested in the human MT-4 cell line and primary peripheral blood mononuclear cells, one of the candidates, 2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine (BMMP), displayed an inhibitory effect on HIV replication, although a considerably high dose was required. Unexpectedly, neither particle production nor maturation was inhibited by BMMP. Confocal microscopy confirmed that BMMP did not block Gag plasma membrane targeting. Single-round infection assays with envelope-pseudotyped and luciferase-expressing viruses revealed that BMMP inhibited HIV replication postentry but not simian immunodeficiency virus (SIV) or murine leukemia virus infection. Studies with HIV/SIV Gag chimeras indicated that the Gag capsid (CA) domain was responsible for the BMMP-mediated HIV postentry block. In vitro studies indicated that BMMP accelerated disassembly of HIV cores and, conversely, inhibited assembly of purified CA protein in a dose-dependent manner. Collectively, our data suggest that BMMP primarily targets the HIV CA domain and disrupts viral infection postentry, possibly through inducing premature disassembly of HIV cores. We suggest that BMMP is a potential lead compound to develop antiretroviral drugs bearing novel mechanisms of action.

Objectives Although previous epidemiological studies have investigated the relationship between sleep duration and various cardiovascular events, the results have been inconsistent. Accordingly, we conducted a follow-up survey to investigate the relationship between sleep duration and cardiovascular events among male workers, accounting for occupational factors that might confound the true relationship. Methods A total of 2282 male employees aged 35–54 years based in a factory in Japan were followed for 14 years. The risk of cardiovascular events was compared among 4 groups stratified based on sleep duration at baseline (

In an operation by United States Armed Forces during 1961 to 1971, large quantities of herbicides were sprayed in South Vietnam. These herbicides contained 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-tetraCDD), the most toxic congener of dioxins. Several decades after the herbicide spraying ceased, dioxin concentrations in the environment and human remained elevated in the sprayed areas. Breast milk samples from 520 nursing mothers residing in areas including the hot spots as well as the sprayed and unsprayed areas were collected to quantify the levels of dioxins. The total toxic equivalents of 2,3,7,8-substitued PCDDs/PCDFs in breast milk of mothers living in the hot spots, and the sprayed and unsprayed areas were 14.10 pg/g lipid, 10.89 pg/g lipid, and 4.09 pg/g lipid for primiparae and 11.48 pg/g lipid, 7.56 pg/g lipid, and 2.84 pg/g lipid for multiparae, respectively, with significant differences in the values among the three areas. In the hot spots, dioxin levels were highly correlated with the residency of mothers after adjustment for their age and parity.

Like all viruses, HIV-1 requires cellular host factors for replication. The mechanisms for production of progeny virions involving these host factors, however, are not fully understood. To better understand these mechanisms, we used a yeast ( Saccharomyces cerevisiae ) genetic screen to identify mutant strains in which HIV-1 Gag targeting to the plasma membrane was aberrant. Of the 917 mutants identified, we selected 14 mutants whose missing genes had single orthologous counterparts in human and tested them for Gag-induced viruslike particle (VLP) release in yeast cells. We found that the Vps18 and Mon2 proteins were important for HIV-1 Gag-induced VLP release in yeast. In eukaryote cells, these host proteins are highly conserved and function in protein trafficking. Depletion of hVps18 or hMon2 reduced the efficient production of infectious HIV-1 virions in human cells. Our data suggest that these cellular factors play an important role in the efficient production of infectious HIV-1 virion particles.

Integration, an indispensable step for retrovirus replication, is executed by integrase (IN), which is expressed as a part of a Gag-Pol precursor. Although mechanistic detail of the IN-catalyzed integration reaction is well defined, numerous evidence have demonstrated that IN is involved in multiple steps of retrovirus replication other than integration. In this study, Huwe1, a HECT-type E3 ubiquitin ligase, was identified as a new cellular interactor of human immunodeficiency virus type 1 (HIV-1) IN. The interaction was mediated through the catalytic core domain of IN and a wide-range region of Huwe1. Interestingly, although depletion of Huwe1 in target cells did not affect the early phase of HIV-1 infection in a human T cell line, we found that infectivity of HIV-1 released from the Huwe1 knockdown cells was significantly augmented more than that of virus produced from control cells. The increase in infectivity occurred in proviral DNA synthesis. Further analysis revealed that Huwe1 interacted with HIV-1 Gag-Pol precursor protein through an IN domain. Our results suggest that Huwe1 in HIV-1 producer cells has a negative impact on early post-entry events during the next round of virus infection via association with an IN region of Gag-Pol.

Little is known about the relationship between the HOMA of insulin resistance (HOMA-IR) and the risk of cardiovascular events in Asian populations, which have lower levels of HOMA-IR than Western populations. Accordingly, we determined the predictive value of HOMA-IR for cardiovascular risk in a Japanese population that was apparently free of diabetes, addressing whether insulin resistance itself increases cardiovascular risk independently of other relevant metabolic disorders.We followed 2,548 non-diabetic men aged 35 to 59 years for 11 years. The hazard ratios for the incidence of cardiovascular events due to increased HOMA-IR were estimated using a Cox proportional hazards model that was adjusted for potential confounding factors.The multivariate-adjusted hazard ratio for cardiovascular events compared with the first quartile of HOMA-IR (or=0.66) was 1.07 (95% CI 0.44-2.64) for the second (HOMA-IR 0.67-1.01), 1.36 (0.56-3.28) for the third (HOMA-IR 1.02-1.51) and 2.50 (1.02-6.10) for the fourth quartile (HOMA-IRor=1.52). The hazard ratio associated with a one SD (0.61) increment in log-transformed HOMA-IR was 1.51 (1.13-2.02). A similar positive relationship was observed for coronary events and stroke. In addition, the relationship between HOMA-IR and cardiovascular risk was broadly similar in participants with and without hypertension, dyslipidaemia (elevated triacylglycerol and/or reduced HDL-cholesterol), abdominal obesity and current smoking.Increased HOMA-IR predicted subsequent cardiovascular events in non-diabetic Japanese men. The association was independent of traditional cardiovascular risk factors and other relevant metabolic disorders.

金沢大学医薬保健研究域医学系, 金沢医科大学健康増進予防医学（公衆衛生学）, Aims This study investigated the relationship between waist circumference and the subsequent incidence of Type 2 diabetes and the association with insulin resistance and pancreatic B-cell function in relatively lean Japanese individuals. Methods The study participants were 3992 employees (2533 men and 1459 women, aged 35-55 years) of a metal-products factory in Japan. The incidence of diabetes was determined in annual medical examinations during an 8-year follow-up. We calculated age- and sex-adjusted hazard ratios (HRs) according to the sex-specific quintile of waist circumference at baseline. Differences in baseline insulin resistance [homeostatis model assessment (HOMA)-IR] and pancreatic B-cell function (HOMA-B) were compared between participants who developed diabetes and those who did not. Results During the follow-up, 218 participants developed diabetes. Age- and sex-adjusted HRs across the quintiles of waist circumference were 1.78, 1.00 (reference), 1.59, 3.11 and 3.30, respectively (P for trend, < 0.0001). The HR for the lowest quintile was significantly higher than that for the second quintile. Among participants with waist circumference of the lowest quintile, HOMA-B was lower in those who developed diabetes than in those who did not [33.1 (24.1-45.0) vs. 54.3 (37.9-74.6) median (interquartile range), P < 0.0001], but HOMA-IR did not differ between these groups. Conclusions There was a J-shaped relationship between waist circumference and subsequent risk for Type 2 diabetes in relatively lean Japanese individuals; lower pancreatic B-cell function may also increase the risk of diabetes in very lean Japanese people. © 2009 Diabetes UK.

Aim The purpose of this study was to examine the relationship between stress coping and burnout in Japanese hospital nurses. Background Findings on effective stress management training are required in order to reduce nurse’s stress and prevent it from becoming chronic. Methods The study included 1291 nurses who completed the General Coping Questionnaire and the Japanese version of the Maslach Burnout Inventory-General Survey. The data were analysed using structural equation modelling. Results In women, a frequent use of cognitive reinterpretation predicted low exhaustion and cynicism and high professional efficacy. In men, a frequent use of problem solving predicted low cynicism and high professional efficacy. Although for women, a frequent use of problem solving predicted high professional efficacy that was similar to men, there was also a concurrent high exhaustion. Conclusion These findings suggested that enhancement of cognitive coping skills for women and problem-solving skills for men could contribute to a reduction of burnout in nurses. Implications for nursing management Our findings suggested that effective intervention strategies in order to prevent hospital nurse’s stress from becoming chronic might be different between men and women. This difference should be taken into account in nursing management.

Objectives: The purpose of this longitudinal study was to investigate the effects of burnout on risk factors for arteriosclerotic disease. Methods: Baseline data were collected from 442 male middle managers working for a manufacturing company in Japan. All participants had a physical health check-up and completed the Japanese Maslach Burnout Inventory-General Survey. We calculated the Japanese-specific cut-off points of the MBI-GS and applied "exhaustion +1" criterion to define subjects as healthy or burnout at baseline. Follow-up measures were collected 4-5 yr later for 383 middle managers. Changes in the subjects' waist circumference, body weight, body mass index (BMI), blood pressure, total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, fasting blood sugar, fasting insulin, HOMA-R, and HbA1c over a time period of 4 to 5 yr were compared between the healthy and burnout groups. New cases of large waist circumference, high BMI, metabolic syndrome, hypertension, hypercholesterolemia, high triglycerides, low HDL cholesterol, high LDL cholesterol, and impaired fasting glucose were detected at follow-up. Results: Changes in waist circumference, body weight, and BMI were significantly greater in burned-out managers than in healthy managers. Furthermore, compared to other variables (age and health behaviors such as smoking), burnout was a significant explanatory variable. The odds ratio of the burnout group was 2.80 for hypercholesterolemia with statistical significance after adjusting for age. After adjusting for age, health behaviors, and baseline total cholesterol, the results were similar. Conclusions: Burnout, which results from prolonged exposure to chronic work stress, may be associated with risk factors for arteriosclerotic disease.

The matrix domain (MA) of human immunodeficiency virus type 1 Pr55Gagis covalently modified with a myristoyl group that mediates efficient viral production. However, the role of myristoylation, particularly in the viral entry process, remains uninvestigated. This study replaced the myristoylation signal of MA with a well-studied phosphatidylinositol 4,5-biphosphate-binding plasma membrane (PM) targeting motif, the phospholipase C-δ1 pleckstrin homology (PH) domain. PH–Gag–Pol PM targeting and viral production efficiencies were improved compared with Gag–Pol, consistent with the estimated increases in Gag–PM affinity. Both virions were recovered in similar sucrose density-gradient fractions and had similar mature virion morphologies. Importantly, PH–Gag–Pol and Gag–Pol pseudovirions had almost identical infectivity, suggesting a dispensable role for myristoylation in the virus life cycle. PH–Gag–Pol might be useful in separating the myristoylation-dependent processes from the myristoylation-independent processes. This the first report demonstrating infectious pseudovirion production without myristoylated Pr55Gag.

Background: Mikulicz’s disease (MD) has been considered as one manifestation of Sjogren’s syndrome (SS). Recently, it has also been considered as an IgG 4 -related disorder. Objective: To determine the differences between IgG 4 -related disorders including MD and SS. Methods: A study was undertaken to investigate patients with MD and IgG 4 -related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG 4 -positive multiorgan lymphoproliferative syndrome (IgG 4 +MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG 4 (>135 mg/dl) and infiltration of IgG 4 + plasma cells in the tissue (IgG 4 +/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG 4 +MOLPS and 31 patients with typical SS were compared. Results: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG 4 +MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG 2 , IgG 4 and IgE levels were significantly increased in IgG 4 +MOLPS. Histological specimens from patients with IgG 4 +MOLPS revealed marked IgG 4 + plasma cell infiltration. Many patients with IgG 4 +MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG 4 + cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG 4 +MOLPS treated with glucocorticoids showed marked clinical improvement. Conclusion: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG 4 +MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG 4 +MOLPS.

Myristoylation of human immunodeficiency virus (HIV) Gag protein is essential for membrane targeting of Gag and production of viral particles. We show here that coexpression of wild-type and nonmyristoylated forms of HIV Gag resulted in severe inhibition of viral particle production, indicating that the nonmyristoylated counterpart had a dominant negative effect on particle release. When coexpressed, the nonmyristoylated Gag partially incorporated into membrane and lipid raft fractions, likely through coassembly with the wild-type Gag. The membrane and raft associations of the wild-type Gag appeared unaffected, and yet particle production was severely impaired. When viral particles produced from the coexpressing cells were analyzed, the wild-type Gag was more abundant than the nonmyristoylated Gag. Confocal microscopy showed that both forms of Gag were diffusely distributed in the cytoplasm of coexpressing cells but that a portion of the wild-type Gag population was accumulated in EEA1- and CD63-positive endosomes. The intracellular accumulation of Gag was more frequently observed at late time points. The Gag accumulation was also observed on the cell surface protrusion. Electron microscopy of the coexpressing cells revealed budding arrest phenotypes, including the occurrence of interconnected virions on the plasma membrane, and intracellular budding. We also show that the inhibition of particle production and the Gag accumulation to endosomes were suppressed when the nucleocapsid (NC) domain was deleted from the nonmyristoylated Gag, although the NC-deleted Gag was still capable of coassembly. Overall, our data indicate that coassembly with the nonmyristoylated Gag impairs HIV particle release, a phenomenon that may involve NC-mediated Gag-Gag interaction.

The aim of this study was to investigate the effects of shift work on nutrient intakes, including macronutrient intake and micronutrient intake, in a large sample size. The study population included 2,254 male manual workers, 20-59 yr of age, employed in a factory. A self-administered diet history questionnaire was used. The subjects were classified into 3 groups according to their work schedule: (i) fixed day workers; (ii) shift workers without midnight shifts; and (iii) shift workers with midnight shifts. The nutrient intakes of the groups were compared by age group. There was a significant difference in nutrient intakes between subjects aged 20-29 yr and those aged 30 yr and over. Among subjects aged 20-29 yr, the energy density value for saturated fat and the energy adjusted intakes of calcium, potassium, vitamin A, and vitamin B1 were the lowest among shift workers with midnight shifts. Among subjects aged 30 yr and over, the total energy intake was the highest among shift workers with midnight shifts; the difference was significant compared to fixed day workers. Shift workers with midnight shifts had the highest intake of cereals among subjects 30 yr of age and older. In conclusion, there were no significant differences in nutrient intakes between fixed day workers and shift workers without midnight shift. Shift work, particularly midnight shift work, affected nutrient intake. The impact of shift work on nutrient intakes differed by age and the type of shift work.

We developed a unique monoclonal antibody, mAb61A5, using the nucleoprotein (NP) of influenza virus A/Puerto Rico/8/34 (PR8) strain. Truncation and alanine substitution experiments showed that mAb61A5 recognized the NP fragment with residues 17 to 123 in which a conformational epitope formed by the beta1 sheet and the linker region between the alpha1 and alpha2 helices. Variations in the epitope or nearby can partly account for the poor mAb61A5 reactivity with the NP of A/Aichi/2/68 or A/duck/Pennsylvania/10128/84 strains. Interestingly, immunoprecipitation analysis revealed that mAb61A5 preferentially interacted with viral ribonucleoprotein complexes, composed of RNA polymerase, negative/positive sense RNA and NP, rather than exogenously added NP. Immunofluorescence microscopy using mAb61A5 showed a punctate staining in the cytoplasm during the late phase of infection. The punctate NPs accumulated at the microtubule organizing center and co-localized with microtubules. The treatment with leptomycin B to block a CRM1-dependent nuclear export failed to produce the punctate NP. The treatment with nocodazole, a microtubule-depolymerizing agent, showed random distribution of the punctate NP in the cytoplasm. These results suggest that microtubule networks, although were not required for the formation of punctate structures, were responsible for the polarized distribution of the punctate NP antigens, most likely viral progeny ribonucleoprotein complexes.

We have previously shown that the expression of human immunodeficiency virus type 1 (HIV-1) Gag protein in Saccharomyces cerevisiae spheroplasts produces Gag virus-like particles (VLPs) at the plasma membrane, indicating that yeast has all the host factors necessary for HIV-1 Gag assembly. Here we expand the study by using diverse primate lentiviral Gags and show that yeast does not support the production of HIV-2 or simian immunodeficiency virus SIVmac Gag VLPs but allows the production of SIVagm and SIVmnd Gag VLPs. Particle budding was observed at the surfaces of cells expressing SIVagm and SIVmnd Gags, but cells expressing HIV-2 and SIVmac Gags showed only membrane-ruffling structures, although they were accompanied with electron-dense submembrane layers, suggesting arrest at an early stage of particle budding. Comparison of HIV-1 and HIV-2 Gag expression revealed broadly equivalent levels of intracellular Gag expression and Gag N-terminal myristoylation in yeast. Both Gags showed the same membrane-binding ability and were incorporated into lipid raft fractions at a physiological concentration of salt. HIV-2 Gag, however, failed to form a high-order multimer and easily dissociated from the membrane, phenomena which were not observed in higher eukaryotic cells. A series of chimeric Gags between HIV-1 and HIV-2 and Gag mutants with amino acid substitutions revealed that a defined region in helix 2 of HIV-2 MA (located on the membrane-binding surface of MA) affects higher-order Gag assembly and particle production in yeast. Together, these data suggest that yeast may lack a host factor(s) for HIV-2 and SIVmac Gag assembly.