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Objectives: We investigated the effects of fatigue on NK cell function and lymphocyte subpopulations in nurses performing shift work using a longitudinal design. Methods: Fifty-seven female nurses engaged in shift work at a hospital in Japan were selected for our study cohort. The hospital used a counterclockwise rotating three-shift system. Night shifts followed day shifts after a seven-hour interval. Immune parameters measured at the beginning of the day shift through to the end of the night shift were compared between two groups stratified by their level of fatigue. Statistical differences were evaluated after adjusting for baseline immune values and other demographic features. Results: Subjective feelings of fatigue increased progressively from the beginning of day shifts to the end of night shifts. From the beginning of day shifts to the end of night shifts, NK cell activity and CD16+CD56+ lymphocytes decreased, while CD3+ and CD4+ lymphocytes increased. The group with the greater increase in fatigue showed a larger decrease in NK cell activity and a larger increase in CD4+lymphocytes when compared with the group reporting less fatigue. These findings did not change after adjusting for demographic factors and sleep hours. Conclusion: Our data suggest that shift work has deleterious effects on NK cell function and that the effects depend on the degree of fatigue. Proper management of shift work may lessen fatigue in workers and also ameliorate many health problems experienced by shift workers.

Influenza A virus RNA genome exists as eight-segmented ribonucleoprotein complexes containing viral RNA polymerase and nucleoprotein (vRNPs). Packaging of vRNPs and virus budding take place at the apical plasma membrane (APM). However, little is known about the molecular mechanisms of apical transport of newly synthesized vRNP. Transfection of fluorescent-labeled antibody and subsequent live cell imaging revealed that punctate vRNP signals moved along microtubules rapidly but intermittently in both directions, suggestive of vesicle trafficking. Using a series of Rab family protein, we demonstrated that progeny vRNP localized to recycling endosome (RE) in an active/GTP-bound Rab11-dependent manner. The vRNP interacted with Rab11 through viral RNA polymerase. The localization of vRNP to RE and subsequent accumulation to the APM were impaired by overexpression of Rab binding domains (RBD) of Rab11 family interacting proteins (Rab11-FIPs). Similarly, no APM accumulation was observed by overexpression of class II Rab11-FIP mutants lacking RBD. These results suggest that the progeny vRNP makes use of Rab11-dependent RE machinery for APM trafficking.

A 9-y follow-up study of 3,178 persons who lived in a cadmium-polluted area was conducted to assess the influence of environmental cadmium exposure on long-term outcome. The standardized mortality ratios of the urinary beta 2-microglobulin-positive subjects (> 1,000 micrograms/g creatinine) of both sexes were higher than those of the general Japanese population, whereas the cumulative survival curves were lower than those of the urinary beta 2-microglobulin-negative group. A significant association was also found between urinary beta 2-microglobulin and mortality, using a Cox's proportional hazards model. Moreover, mortality rates increased in proportion to increases in the amount of urinary beta 2-microglobulin excreted. These results suggest that the prognosis for cadmium-exposed subjects with proximal tubular dysfunction is unfavorable. The mortality rate tended to become higher as the severity of renal dysfunction progressed.

This cohort study investigated the association between dietary glycemic index (GI), glycemic load (GL), and the incidence of type 2 diabetes mellitus in middle-aged Japanese men, and the effect of insulin resistance and pancreatic B-cell function on the association. Participants were 1995 male employees of a metal products factory in Japan. Dietary GI and GL were assessed using a self-administered diet history questionnaire. The incidence of diabetes was detected in annual medical examinations over a 6-year period. The association between GI, GL, and the incidence of diabetes was evaluated using Cox proportional hazards models. During the study, 133 participants developed diabetes. Age- and body mass index-adjusted hazard ratios across the GI quintiles were 1.00 (reference), 1.62, 1.50, 1.68, and 1.80; and those of GL were 1.00 (reference), 1.07, 1.48, 0.95, and 0.98. The hazard ratio for the highest GI quintile was significantly greater than that for the lowest quintile. The influence of GI was more pronounced in the lowest insulin resistance subgroups. GI and pancreatic B-cell function were independently associated with the incidence of type 2 diabetes mellitus; participants with low B-cell function and the highest tertile of GI had the highest risk of diabetes. Dietary GI is associated with the incidence of diabetes in middle-aged Japanese men. GI and B-cell function were independently associated with incidence of diabetes. © 2012 Elsevier Inc. All rights reserved.

Human immunodeficiency virus (HIV) Gag precursor protein is cleaved by viral protease (PR) within GagPol precursor protein to produce the mature matrix (MA), capsid, nucleocapsid, and p6 domains. This processing is termed maturation and required for HIV infectivity. In order to understand the intracellular sites and mechanisms of HIV maturation, HIV molecular clones in which Gag and GagPol were tagged with FLAG and hemagglutinin epitope sequences at the C-termini, respectively were made. When coexpressed, both Gag and GagPol were incorporated into virus particles. Temporal analysis by confocal microscopy showed that Gag and GagPol were relocated from the cytoplasm to the plasma membrane. Mature cleaved MA was observed only at sites on the plasma membrane where both Gag and GagPol had accumulated, indicating that Gag processing occurs during Gag/GagPol assembly at the plasma membrane, but not during membrane trafficking. Fluorescence resonance energy transfer imaging suggested that these were the primary sites of GagPol dimerization. In contrast, with overexpression of GagPol alone an absence of particle release was observed, and this was associated with diffuse distribution of mature cleaved MA throughout the cytoplasm. Alteration of the Gag-to-GagPol ratio similarly impaired virus particle release with aberrant distributions of mature MA in the cytoplasm. However, when PR was inactive, it seemed that the Gag-to-GagPol ratio was not critical for virus particle release but virus particles encasing unusually large numbers of GagPol molecules were produced, these particles displaying aberrant virion morphology. Taken together, it was concluded that the Gag-to-GagPol ratio has significant impacts on either intracellular distributions of mature cleaved MA or the morphology of virus particles produced.

Aims: This study investigated the association between dietary glycemic index (GI)/glycemic load (GL) and serum lipids in middle-aged Japanese men and women.Methods: The study participants were employees of a metal products factory in Japan: 2,257 men and 1,598 women aged 35 years or older. Dietary GI and GL were assessed using a self-administered diet history questionnaire. Serum lipid levels, adjusted for age, body mass index, alcohol consumption, smoking, physical activity, menopause status, and dietary intake of total energy, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, cholesterol and fiber, were compared among GI/GL quintiles for each gender.Results: No significant associations were observed between GI and adjusted serum lipids in men or women. In contrast, GL was inversely associated with HDL-cholesterol in men and women (p for trend=0.001 for men and < 0.001 for women), and positively associated with non-HDL-cholesterol (p for trend=0.010), LDL-cholesterol (p for trend=0.035) and triglycerides (p for trend=0.011) in women; however, alcohol drinking affected these associations; there was no association between GL and serum lipids in male nondrinkers and between GL and LDL-cholesterol in female nondrinkers.Conclusion: GL was inversely associated with HDL-cholesterol and positively associated with non-HDL-cholesterol in Japanese women. These associations in men were not observed in nondrinkers. A high-GL diet for women may have an atherogenic effect through these serum lipid abnormalities.

Since there is little information derived from prospective studies on the amount of alcohol drinking required to induce hyperuricaemia, we attempted to address this issue in a Japanese population.A total of 3310 Japanese men aged 20-54 years that were free of hyperuricaemia were classified according to their alcohol intake per week at baseline. Incident hyperuricaemia, defined as7.0 mg/dl and/or taking medication for hyperuricaemia, was assessed through annual heath examinations for 6 years after the baseline examination. During follow-up, 529 incident cases of hyperuricaemia occurred. There was a positive, dose-response relationship between alcohol intake and the risk of incident hyperuricaemia. The hazard ratio (95% confidence interval) for hyperuricaemia in drinkers compared with non-drinkers was 1.10 (0.85-1.42) for10.0 drinks/week, 1.40 (1.07-1.84) for 10.0-19.9 drinks/week, 1.64 (1.23-2.21) for 20.0-29.9 drinks/week and 1.98 (1.40-2.80) for ≥30.0 drinks/week (one drink contained 11.5 g of ethanol) after adjusting for age, baseline serum uric acid, body mass index, smoking habits, exercise habits, serum creatinine, blood pressure, serum cholesterol and blood glucose. The fraction of hyperuricaemia in the population attributable to alcohol intake was 21.6%. A clear dose-response pattern was observed for both beer and sake, when the consumption of these two beverages was analysed separately.Habitual alcohol intake significantly contributed to the development of hyperuricaemia in Japanese men, regardless of type of alcoholic beverage consumed. Therefore, it is essential to reduce excessive alcohol intake to prevent and manage hyperuricaemia.

Aim: We investigated the individual and population impacts of mild abnormalities associated with metabolic syndrome (blood pressure, lipids and glucose) and abdominal obesity, for which lifestyle modification is initially applicable, on cardiovascular disease risk.Methods: Using a cohort study of 2,685 Japanese men aged 35 to 59 years with an 11-year follow-up period, we calculated the relative risks for cardiovascular diseases due to mild metabolic abnormalities that included at least one of the following three conditions: 1) systolic blood pressure 130-139 mmHg and/or diastolic blood pressure 85-89 mmHg; 2) triglycerides 150-299 mg/dL and/or high-density lipoprotein cholesterol 35-39 mg/dL; and 3) fasting plasma glucose 110-125 mg/dL and/or abdominal obesity. Participants with a mild metabolic abnormality were compared to participants with no metabolic abnormality or abdominal obesity. The population attributable fraction of these abnormalities for cardiovascular diseases was also estimated.Results: At baseline, 9.8% and 21.8% of the total population had a mild metabolic abnormality with or without abdominal obesity, respectively, while 7.5% had isolated abdominal obesity without any metabolic abnormality. A mild metabolic abnormality with or without abdominal obesity and isolated abdominal obesity increased the risk of cardiovascular disease by 2.68-fold, 1.49-fold, and 2.36-fold, respectively. Approximately 20% of cardiovascular diseases in the total population were attributable to either mild metabolic abnormalities or isolated abdominal obesity.Conclusion: The importance of lifestyle modification should be acknowledged, especially in cases of mild metabolic abnormality and/or abdominal obesity, which may contribute to approximately 20% of the population burden for cardiovascular diseases.

We investigated whether occupational class affects the incidence of cardiovascular events in Japanese factory workers. We prospectively evaluated 1,794 male workers aged 40-59, including 632 non-manual and 1,162 manual workers, employed in a metal products factory in Japan. The hazard ratios of stroke, myocardial infarction (MI) and cardiovascular events (combined stroke, MI and sudden cardiac death) for manual workers were compared with non-manual workers as estimated by the Cox proportional hazards regression model. Among the 1,794 workers, there were 60 cardiovascular events (32 cases of stroke, 23 cases of MI and 5 cases of sudden cardiac death) with an incidence rate of 3.14 per 1,000 person-years for cardiovascular events; 1.68 for stroke and 1.20 for MI. Blood pressure and HbA1c significantly increased the risk of stroke. Body mass index and total cholesterol significantly increased the risk of MI. However, occupational class was determined not to be a risk factor for cardiovascular events. The hazard ratios of stroke, MI and cardiovascular events for manual workers compared with non-manual workers were 0.97 (95%CI, 0.45-2.08), 0.73 (95%CI, 0.30-1.79) and 0.92 (95%CI, 0.53-1.61), respectively. Our study did not reveal significant occupational class inequalities in the rate of cardiovascular events. These findings are not in accordance with studies from other industrialized countries.

The purpose of this study is to examine the association between long work hours and sleep disturbance among white-collar workers. We evaluated 1510 male white-collar full-time employees, between the ages of 18 and 59 years, using a comprehensive sleep quality questionnaire, the Pittsburgh Sleep Quality Index (PSQI). All subjects worked in a light metal products factory in Japan. The mean number of monthly overtime work hours was determined using data from the previous 6 months from timecard records. Subjects were divided into five groups based on quintiles of the mean number of monthly overtime work hours:26 h month(-1); ≥26 but40; ≥40 but50; ≥50 but63; and63. Leisure time physical activity, drinking habits just before sleep, presence of family/partner and health status were used as confounding factors in the multiple regression model. The prevalence of short sleep hours, impairment of sleep efficiency and daytime dysfunction among seven components of PSQI increased, in a dose-response relationship, with overtime work hours. The prevalence of high global score (5.5 points) was highest in workers with overtime hours ≥50 h week(-1). The odds ratios after adjustment for confounding factors for high global score using less than 26 h as a reference group were 1.67 for workers with ≥50 h and63 h, and 1.87 for workers with 63 h and more. To conclude, the present results suggest that long work hours correlate with reduced sleep quality in a dose-response manner.

The genome of influenza type A virus consists of single-stranded RNAs of negative polarity. Progeny viral RNA (vRNA) replicated in the nucleus is nuclear-exported, and finally transported to the budding site beneath the plasma membrane. However, the precise process of the membrane targeting of vRNA is unclear, although viral proteins and cytoskeleton are thought to play roles. Here, we have visualized the translocation process of progeny vRNA using fluorescence in situ hybridization method. Our results provide an evidence of the involvement of vesicular trafficking in membrane targeting of progeny vRNA independent of that of viral membrane proteins.

A cell clone, L-2, which produces non-infectious doughnut-shaped human immunodeficiency virus type 1 (HIV-1) particles, was permissive for HIV-1 superinfection, which resulted in the production of infectious particles. The superinfection showed slow kinetics compared with primary HIV-1 infection of M10 cells, the parent of the L-2 cell clone. Inhibition studies on the superinfection of L-2 cells using several CD4-related reagents showed that the CD4 molecule was an essential component of the receptor for superinfection. Strong inhibitory effects were obtained using CD4 peptides such as CD4(68-130), which includes a portion homologous to the immunoglobulin third complementarity-determining region (CDR3), as well as recombinant soluble CD4. In contrast, a CD4(45-60) peptide, which includes most of the CDR2-related region, was not effective, although the Leu-3a monoclonal antibody (MAb), which recognizes a site near the CDR2-related region, did slightly, but significantly, delay the superinfection kinetics. Comparative flow cytometry of L-2 and M10 cells revealed that the cell surface of L-2 cells despite expressing HIV-1 env protein, reacted slightly with OKT4 or anti-CD4(68-130) MAb, but not with Leu-3a or OKT4A MAb. In contrast, no reaction was detected with any of these anti-CD4 MAbs on the surface of another HIV-1 superinfection-resistant cell clone, MOLT-#8IIIB-14, which expresses HIV-1 env proteins but does not produce infectious HIV-1 particles. These results strongly suggest that expression of the CD4 major receptor site for primary HIV-1 infection is preferentially decreased on the surface of L-2 cells, but that the OKT4 epitope and the nearby region corresponding to immunoglobulin CDR3 remain exposed on the cell surface. Consequently, the CD4 CDR3-related region could play a major role as the receptor for the superinfection reported here.

The mortality rates and causes of death among elderly people aged sixty five and over were compared between China and Japan. The data used for comparison was China's 1990 and Japan's 1990 vital statistics. It appears that the mortality rate in China was higher than Japan. Comparing the causes of death, it was found that the death rates involving cerebrovascular diseases, malignant neoplasms and heart diseases in urban districts of China was higher than those in Japan. Also the death rate of people with bronchitis in rural districts was significantly higher in China than Japan. Comparing the death rates resulting from malignant neoplasms by each organ, the death rates of lung cancer and esophageal cancer were higher in China than Japan. With regard to heart diseases, the urban district death rate of ischemic heart disease was higher in China than Japan. The differences in the medical systems and life styles in China and Japan were suspected as the reasons for the differences of death rates and causes of death in China and Japan. Further study will be needed to clarify the reasons.

BackgroundIt has been accepted that HIV buds from the cell surface in T lymphocytes, whereas in macrophages it buds into intracellular endosomes. Recent studies, on the other hand, suggest that HIV preferentially buds from the cell surface even in monocytic cells. However, most studies are based on observations in acutely infected cells and little is known about HIV budding concomitant with reactivation from latency. Such studies would provide a better understanding of a reservoir for HIV.ResultsWe observed HIV budding in latently infected T lymphocytic and monocytic cell lines following TNF-α stimulation and examined the upregulation of host factors that may be involved in particle production. Electron microscopy analysis revealed that reactivation of latently infected J1.1 cells (latently infected Jurkat cells with HIV-1) and U1 cells (latently infected U937 cells with HIV-1) displayed HIV particle budding predominantly at the plasma membrane, a morphology that is similar to particle budding in acutely infected Jurkat and U937 cells. When mRNA expression levels were quantified by qRT-PCR, we found that particle production from reactivated J1.1 and U1 cells was accompanied by CD44 upregulation. This upregulation was similarly observed when Jurkat and U937 cells were acutely infected with HIV-1 but not when just stimulated with TNF-α, suggesting that CD44 upregulation was linked with HIV production but not with cell stimulation. The molecules in endocytic pathways such as CD63 and HRS were also upregulated when U1 cells were reactivated and U937 cells were acutely infected with HIV-1. Confocal microscopy revealed that these upregulated host molecules were recruited to and accumulated at the sites where mature particles were formed at the plasma membrane.ConclusionOur study indicates that HIV particles are budded at the plasma membrane upon reactivation from latency, a morphology that is similar to particle budding in acute infection. Our data also suggest that HIV expression may lead to the upregulation of certain host cell molecules that are recruited to sites of particle assembly, possibly coordinating particle production.

Genome-wide screening of host factors that regulate HIV-1 replication has been attempted using numerous experimental approaches. However, there has been limited success using T cell-based cDNA library screening to identify genes that regulate HIV-1 replication. We have established a genetic screening strategy using the human T cell line MT-4 and a replication-competent HIV-1. With this system, we identified the C-terminal domain (CTD) of SEC14-like 1a (SEC14L1a) as a novel inhibitor of HIV-1 replication. Our T cell-based cDNA screening system provides an alternative tool for identifying novel regulators of HIV-1 replication.

The RNase H activity associated with human immunodeficiency virus type 1 (HIV-1) is an attractive target for an antiretroviral drug development. We screened 20000 small-molecular-weight compounds for RNase H inhibitors and identified a novel RNase H-inhibiting structure characterized by a 5-nitro-furan-2-carboxylic acid carbamoylmethyl ester (NACME) moiety. Two NACME derivatives, 5-nitro-furan-2-carboxylic acid adamantan-1-carbamoylmethyl ester (compound 1) and 5-nitro-furan-2-carboxylic acid [[4-(4-bromo-phenyl)-thiazol-2-yl]-(tetrahydro-furan-2-ylmethyl)-carbamoyl]-methyl ester (compound 2), effectively blocked HIV-1 and MLV RT-associated RNase H activities with IC(50)s of 3-30 microM but had little effect on bacterial RNase H activity in vitro. Additionally, 20-25 microM compound 2 effectively inhibited HIV-1 replication. An in silico docking simulation indicated that the conserved His539 residue, and two metal ions in the RNase H catalytic center are involved in RNase H inhibition by NACME derivatives. Taken together, these data suggest that NACME derivatives may be potent lead compounds for development of a novel class of antiretroviral drugs.

The role of selected glycosylation sites in the ability of the envelope glycoprotein of HIV-2 (gp105) to bind to CD4 has been investigated. Loss of glycosylation sites at amino acids 410 and 447 did not affect the CD4 binding ability of gp105 even when removed in pair combination. Loss of a single glycosylation site at amino acid 400, however, was sufficient to cause a reduction of at least 50-fold in the efficiency of receptor binding. These data support the hypothesis that some of the carbohydrate side chains on gp106 have a profound effect on biological activity.

Suppressor of cytokine signaling 1 (SOCS1) is a recently identified host factor that positively regulates the intracellular trafficking and stability of HIV-1 Gag. We here examine the molecular mechanism by which SOCS1 regulates intercellular Gag trafficking and virus particle production. We find that SOCS1 colocalizes with Gag along the microtubule network and promotes microtubule stability. SOCS1 also increases the amount of Gag associated with microtubules. Both nocodazole treatment and the expression of the microtubule-destabilizing protein, stathmin, inhibit the enhancement of HIV-1 particle production by SOCS1. SOCS1 facilitates Gag ubiquitination and the co-expression of a dominant-negative ubiquitin significantly inhibits the association of Gag with microtubules. We thus propose that the microtubule network plays a role in SOCS1-mediated HIV-1 Gag transport and virus particle formation.Structured summaryMINT-7014185: Gag (uniprotkb:P05888) and SOCS1 (uniprotkb:O15524) colocalize (MI:0403) by cosedimentation (MI:0027)MINT-7014239: Cullin 2 (uniprotkb:Q13617) physically interacts (MI:0218) with RelA (uniprotkb:Q04206), RBX1 (uniprotkb:P62877), SOCS1 (uniprotkb:O15524), elongin B (uniprotkb:Q15369) and elongin C (uniprotkb:Q15370) by pull-down (MI:0096)MINT-7014046: gag (uniprotkb:P05888), SOCS1 (uniprotkb:O15524) and tubulin alpha (uniprotkb:Q13748) colocalize (MI:0403) by fluorescence microscopy (MI:0416)MINT-7014269: tubulin alpha (uniprotkb:Q13748) physically interacts (MI:0218) with Gag (uniprotkb:P05888) by anti tag coimmunoprecipitation (MI:0007)MINT-7014036: tubulin alpha (uniprotkb:Q13748) and SOCS1 (uniprotkb:O15524) colocalize (MI:0403) by fluorescence microscopy (MI:0416)MINT-7014201: Cullin 2 (uniprotkb:Q13617) physically interacts (MI:0218) with RBX1 (uniprotkb:P62877), SOCS1 (uniprotkb:O15524), elongin B (uniprotkb:Q15369) and elongin C (uniprotkb:Q15370) by pull-down (MI:0096)MINT-7014257: Gag (uniprotkb:P05888) physically interacts (MI:0218) with Ubiquitin (uniprotkb:P62988) by anti tag coimmunoprecipitation (MI:0007)MINT-7014221: Cullin 2 (uniprotkb:Q13617) physically interacts (MI:0218) with Gag (uniprotkb:P05888), elongin C (uniprotkb:Q15370), elongin B (uniprotkb:Q15369), SOCS1 (uniprotkb:O15524) and RBX1 (uniprotkb:P62877) by pull-down (MI:0096)

The purpose of this study was to investigate the effect of designating a medical school environment as smoke-free on the smoking behavior of medical students.The total environment of a medical school in Japan was designated as smoke-free in 2004. Smoking behavior was surveyed among approximately 640 students in each year during the period 2001-2007 (response rate 91.2%). Smoking rates were also monitored among each year's freshmen during their time at the school, before and after 2004. Attitudes to smoking among both current smokers and those who had quit smoking were also investigated. RESULTED: Smoking rates among all students declined after the medical school was declared smoke-free in 2004; the rates were highest in 2002 (41.2%) and lowest in 2007 (22.1%) among men. Smoking rates among each year's freshmen tended to increase as the school year progressed before 2004, but they tended to decrease after 2004. Comparison of smoking rates among identical students showed a decline from 36.0% in 2003 to 25.6% in 2004 (P0.05). The rate of smokers wishing to quit smoking increased significantly from 39.1% in 2003 to 60.2% in 2004 (P0.01). 20.8% of students who had quit smoking and 50.0% of students who had continued to smoke felt that they would not be confident about educating their patients in smoking cessation (P0.01).Making a medical school environment smoke-free could be very effective means to motivating medical students to change their attitudes to smoking and to quit.

This study investigated the relationship between changes in lipoprotein particle size and body weight change over a 9-year period in Japanese adult men and women.Among 299 INTERMAP Toyama Study participants aged 40-59 in 1997, 260 were followed up in 2006 (129 men and 131 women). Their body weight and lipoprotein particle sizes were measured in 1997 and 2006. Nuclear Magnetic Resonance spectroscopy was used for the measurement of lipoprotein particle size.The number of small LDL particles decreased from 774.3 to 617.4 nmol/L in men (p=0.005) while the number increased from 353.2 to 414.5 nmol/L in women (p=0.028) over this period. No significant changes in mean body weight were noted in either sex. Nine-year body weight change was positively associated with changes in the numbers of small LDL particles (men, r=0.37, p0.001; women, r=0.21, p=0.018), but inversely associated with changes in LDL particle size (men, r=-0.30, p=0.001; women, r=-0.16, p=0.066) and HDL particle size (men, r=-0.42, p0.001; women, r=-0.42, p0.001). These relationships were similar even when adjusted for age, baseline body mass index, baseline values for LDL and HDL particle sizes, and other factors. The number of small LDL particles increased in both men and women in the body weight gain group. In the body weight loss group, the number of small LDL particles decreased in men but did not decrease in women.This 9-year observational study showed that the number and size of lipoprotein particles were strongly influenced by long-term body weight change.

Dendritic cells (DCs) are professional antigen-presenting cells that possess a unique capacity to cross-present exogenous antigens efficiently to CD8 + T cells. We previously demonstrated that monocyte-derived DCs (MDDCs) pulsed with yeast-derived HIV-1 Gag virus-like particles (VLPs) were able to activate Gag-specific CD8 + T cells from HIV-1-infected individuals. Yeast VLPs are abundantly mannosylated (high-mannose type: HmVLPs) and are highly immunogenic. Because lectin receptors are shown to negatively regulate Th1 responses, we investigated the relationship between VLP mannosylation level and MDDC cross-presentation activity. Poorly mannosylated VLPs (low-mannose type: LmVLPs) were prepared using a yeast mnn9 mutant strain that lacks a core mannosylation enzyme. We found that MDDCs pulsed with LmVLPs activated Gag-specific T cells more strongly than those pulsed with HmVLPs. However, MDDCs showed similar antigen uptake and intracellular transport of both types of VLPs. Interestingly, LmVLPs induced IL-12 production slightly more than HmVLPs (yet statistically significant). Furthermore, the level of LPS-induced IL-10 production was enhanced by pulsing with HmVLPs, but not with LmVLPs. These results indicate that lectin receptors recognizing mannose may influence the Th1/Th2 balance of the immune response, resulting in reduced efficiency of CD8 + T cell activation by a heavily mannosylated antigen presented by DCs.

Objectives This study examined the effect of changes in psychosocial workplace characteristics on weight gain and abdominal obesity. Methods Twice, at an interval of 6 years, the authors conducted examinations of job demand–control–support and measurements of body mass index and waist circumference among 2200 men and 1371 women aged 30–53 years and working in a factory. The scores of the psychosocial work characteristics in each examination were dichotomized at the median values for the men and women separately and then categorized into three groups as follows: group I: low score in both the first and second examinations, group II: low score in the first examination and high score in the second (or high at the first and low at the second), and group III: high in both the first and second examinations. Results Although there was no statistically significant association between psychosocial work characteristics and the change in body mass index, for both genders, the change in waist circumference increased more in group III than in group I. Similarly, the odds ratios for the change in waist circumference above the 75th percentile for groups II and III increased more than in group I, being 1.13 [95% confidence interval (95% CI) 0.87–1.46 and 1.39 (95% CI 1.07–1.79) for the men in groups II and III, respectively, and 1.27 (95% CI 0.90–1.78) and 1.78 (95% CI 1.26–2.52) for the women in groups II and III, respectively. Conclusions The results suggest that high job strain is a risk factor for increased abdominal obesity.

We conducted a phenotypic cDNA screening using a T cell line-based assay to identify human genes that render cells resistant to human immunodeficiency virus type 1 (HIV-1). We isolated potential HIV-1 resistance genes, including the carboxy terminal domain (CTD) of bromodomain-containing protein 4 (Brd4). Expression of GFP-Brd4-CTD was tolerated in MT-4 and Jurkat cells in which HIV-1 replication was markedly inhibited. We provide direct experimental data demonstrating that Brd4-CTD serves as a specific inhibitor of HIV-1 replication in T cells. Our method is a powerful tool for the identification of host factors that regulate HIV-1 replication in T cells.

The positive transcription elongation factor b complexes comprise CDK9 and a C-type cyclin, required for the efficient expression of both eukaryotic and primate lentivirus-encoded genes. Cyclin K/CPR4 is the least studied of the positive transcription elongation factor b-forming cyclins. Here, we demonstrate that cyclin K/CPR4-containing positive transcription elongation factor b complexes are unresponsive to Tat and HEXIM1-mediated inactivation. Enhancing expression of cyclin K/CPR4 inhibited the human and simian immunodeficiency viral replication. These data indicate that cyclin K/CPR4 functions as a natural inhibitor of primate lentiviruses.

We studied the synthetic modification of structurally similar N-mercaptoacyl- l -proline and (4R)-N-mercaptoacylthiazolidine-4-carboxylic acid to obtain potent leukotriene A4 (LTA4) hydrolase inhibitors. An N-mercaptoacyl group, (2S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a large substituent such as 4-isopropylbenzylthio (3f), 4-tert-butylbenzylthio (3l) or 4-cyclohexylbenzylthio group (3m) with (S)-configuration at the C4 position of proline yielded much more potent LTA4 hydrolase inhibitors (IC50; 52, 31, and 34 nM, respectively) than captopril (IC50; 630,000 nM).

There have been few large-scale nationwide studies investigating both the prognosis and the prognostic factors of idiopathic dilated cardiomyopathy (IDC). A predictive score that can be used in clinical practice has not been established.A nationwide epidemiological study of the prognosis of IDC was conducted in 1999 among randomly selected hospitals in Japan, and 147 departments participated in the present 5-year follow-up survey. The vital status of 1,554 IDC patients was collected in 2004 using medical records and residence-based registers. The crude 5-year survival rate for those diagnosed in 1998 was 78.6%. Cox's regression model selected 5 independent predictors of mortality: male sex, higher age, higher New York Heart Association functional class, higher left ventricular diameter index, and lower left ventricular ejection fraction. A predictive score using these 5 variables effectively predicted prognosis; 5-year survival rates were 90.6% in patients with a score of 4 or less and 49.0% in patients with a score of 9 or 10.This nationwide survey revealed the present prognostic status of IDC in Japan and 5 independent predictors of prognosis that can be used in clinical practice as a predictive score.

Human immunodeficiency virus type 1 (HIV-1) utilizes the macromolecular machinery of the infected host cell to produce progeny virus. The discovery of cellular factors that participate in HIV-1 replication pathways has provided further insight into the molecular basis of virus–host cell interactions. Here, we report that the suppressor of cytokine signaling 1 (SOCS1) is an inducible host factor during HIV-1 infection and regulates the late stages of the HIV-1 replication pathway. SOCS1 can directly bind to the matrix and nucleocapsid regions of the HIV-1 p55 Gag polyprotein and enhance its stability and trafficking, resulting in the efficient production of HIV-1 particles via an IFN signaling-independent mechanism. The depletion of SOCS1 by siRNA reduces both the targeted trafficking and assembly of HIV-1 Gag, resulting in its accumulation as perinuclear solid aggregates that are eventually subjected to lysosomal degradation. These results together indicate that SOCS1 is a crucial host factor that regulates the intracellular dynamism of HIV-1 Gag and could therefore be a potential new therapeutic target for AIDS and its related disorders.

Antibody and cytotoxic T lymphocyte (CTL) responses to the haemagglutinin (HA) of human H3N2 influenza virus were analysed, using recombinant vaccinia viruses containing the influenza HA gene inserted into the HA gene locus of vaccinia virus. The recombinant vaccinia viruses elicited a high haemagglutination inhibiting (HI) antibody response to the homologous influenza virus in mice. In addition, HI antibody generated by the recombinant vaccinia virus reacted with antigenic variants of human H3N2 influenza virus in a manner similar to that elicited by the HA vaccine. Mice with a high response to influenza virus HA vaccine were highly responsive to the HA expressed from the recombinant vaccinia virus, as measured by HI antibody production. The immunogenicity of the influenza virus HA expressed by the recombinant seems to be attributable to the intrinsic immunogenicity of the HA molecule. The recombinants primed mice for an influenza virus H3-specific CTL response and primed CTLs recognized the target cells in a subtype-specific manner. The results indicate that a recombinant vaccinia virus derived by the insertion of a foreign gene into its HA gene locus is a potent live vaccine not only for eliciting a high antibody response but also for priming a specific CTL response.

A follow-up study was conducted from 1967 to 1987 for patients diagnosed as having itai-itai disease, subjects who were suspected of having the disease, and controls. Ninety-five subjects per category were selected after matching for age, sex, and residential area. The cumulative survival rate of the patients who had a definite diagnosis of itai-itai disease was significantly lower than that of the control group in every period after the first 3 y. The cumulative survival rate of the subjects who were suspected of having itai-itai disease and who had severe renal dysfunction due to cadmium pollution was significantly lower than that of the control group. These results demonstrate (1) the enduring negative influence of itai-itai disease on prognosis and (2) that the cadmium pollution-induced renal disorder adversely affects the health of the inhabitants of a cadmium-polluted area.

Plasmid vectors were constructed to facilitate the insertion and expression of a foreign gene in the haemagglutinin (HA) gene locus of vaccinia virus. Five unique cloning sites adjacent to the P7.5 promoter of vaccinia virus permit the rapid insertion of a foreign sequence coding for a protein into these plasmids. This vector system provides a simple procedure to select recombinant viruses because they can be readily identified on the basis of their HA-defective phenotype. Recombinant vaccinia viruses expressing influenza virus HA were constructed to characterize the possible use of this system. The recombinant viruses did express the influenza HA through the authentic pathway of biosynthesis. In addition to having immunological characteristics similar to the authentic influenza HA, the expressed HA was found to possess haemagglutinating, haemadsorption and acid-inducible fusion activities. These findings demonstrate the usefulness of this eukaryotic vector system.

The soluble domains of the envelope glycoprotein of HIV-1 (gp120) and human CD4 (sCD4) have been individually expressed in insect cells using recombinant baculoviruses. Each product is secreted from infected cells and accumulates in the surrounding media to levels of 1-2 mg/liter of 2 x 10(9) cells. Both molecules have full biological activity, and conditioned media from infected cells have been used to establish a simple assay for gp120-sCD4 interaction that is highly specific and amenable to mass screening. The crystallization of sCD4 purified from this source is reported.

A follow-up study was carried out from January 1967 to December 1986 on 148 patients with Itai-itai disease, 130 suspected patients (persons requiring observation), and 212 controls who were living in the same community as patients with Itai-itai disease. The relative survival rates for the three groups were calculated from a life expectancy table. Except for 1973 data, comparison of the annual data from 1968 to 1986 showed that the relative survival rates in the patient group were significantly lower than those in the control group. The relative survival rates in the suspected patient group were significantly lower than those in the control group between 1981 and 1986. Recently the differences of the relative survival rates between the patient group and the suspected patient group have become smaller and are not significant. These results show the long-lasting influence of Itai-itai disease on the prognoses of patients and suspected patients.

To study diffrences in dietary factors among communities with different living environments, we carried out a survey by the Cardiac Study method in 241 people (106 men and 135 women) aged between 50 and 54 years who were selected by random sampling from a total of 37, 000 inhabitants in a small city. The city was geographically divided into town, flatland farming area, and mountainous farming area, and the results of the survey were compared among these areas.The mean Na excretion in 24-hour specimens of urine was slightly higher in the mountainous farming area than in the other two-areas. The mean serum total cholesterol was higher in men in the town than in those in the other areas.Factor analysis of the data for nutrient intake patterns revealed a lower fat intake in the two farming areas than in the town in the men, and a higher intake of animal foods in the town and a lower fat intake in the mountainous area in the women.These results show that risk factors for circulatory diseases such as urinary Na excretion, serum cholesterol level, and nutrient intake patterns differ even among small areas if the living environment differs.

A high-throughput crystallization-to-structure pipeline for structural genomics was recently developed at the Advanced Protein Crystallography Research Group of the RIKEN SPring-8 Center in Japan. The structure determination pipeline includes three newly developed technologies for automating X-ray protein crystallography: the automated crystallization and observation robot system “TERA”, the SPring-8 Precise Automatic Cryosample Exchanger “SPACE” for automated data collection, and the Package of Expert Researcher’s Operation Network “PERON” for automated crystallographic computation from phasing to model checking. During the 5 years following April, 2002, this pipeline was used by seven researchers to determine 138 independent crystal structures (resulting from 437 purified proteins, 234 cryoloop-mountable crystals, and 175 diffraction data sets). The protocols used in the high-throughput pipeline are described in this paper.

Background: The relationship between glycated hemoglobin A1c (HbA1c) and stroke has not been fully elucidated. In addition, there have been few reports from Asia, and few trials have been conducted for each stroke subtype. Methods: A prospective cohort study was performed involving 32,726 participants (9,558 men and 23,168 women) aged 40–79 years at baseline with approximately 6 years of follow-up in a general population of Japan. The end points included the incidence of all, ischemic and hemorrhagic strokes. Multivariate-adjusted hazard ratios by 6 HbA1c categories were calculated using a Cox proportional hazard model. Results: During the follow-up, 393 participants developed a stroke, including 240 ischemic and 139 hemorrhagic stroke cases. The adjusted hazard ratios of all strokes and ischemic stroke showed tendencies to increase with HbA1c level, and the relationships were independent of other confounders. The adjusted hazard ratios of ischemic stroke incidence showed an apparent and graded increase from a relatively mild HbA1c level (≧6.0%); the HRs (95% CI) were 1.79 (1.10–2.93) for HbA1c 6.0–6.4%, 2.20 (1.21–4.00) for HbA1c 6.5–6.9% and 2.91 (1.91–4.44) for HbA1c ≧7.0% compared with the category of HbA1c 5.0–5.4%. For hemorrhagic stroke incidence, no significant increase due to rises in HbA1c level was observed. Conclusions: The relationship of the risk of stroke, especially ischemic stroke, to HbA1c in the general population appears to be graded without any apparent threshold. The ischemic stroke risk would increase from a relatively mild HbA1c level of ≧6.0%.

BACKGROUND: Inflammation has been established as a risk factor for cardiovascular diseases. The relationships of polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids to inflammation are still controversial in Western populations. The relationships are not clear in Japanese whose intake of seafood-based long-chain n-3 PUFAs is high.METHODS: We conducted a cross-sectional epidemiologic study in the Japanese population (1,556 men and 1,461 women aged 35-60). Serum high sensitivity C-reactive protein (CRP) was measured, and intakes of 7 specific fatty acids (% of energy) were evaluated by a validated self-administered dietary history questionnaire.RESULTS: CRP was significantly and inversely related to the intakes of oleic acid (p=0.008) and α-linolenic acid (p=0.026) in women after adjustment for confounding factors. A multiple regression analysis showed that, especially in the middle tertile of long-chain n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) intake, CRP was inversely related to the intake of oleic acid and linoleic acid in both sexes and to the intake of α-linolenic acid in women.CONCLUSION: Intakes of oleic acid, linoleic acid, and α-linolenic acid would reduce serum CRP, especially when the intake of long-chain n-3 PUFAs is at a moderate level in Japanese.J Epidemiol 2007; 17:86-92.

The relationship between the G-protein beta3 subunit variant C825T and risk of hypertension was examined in a prospective cohort study of Japanese workers. This study included observations over a 5-year period from 1997 to 2002 on 878 males and 692 females who were normotensive at entry. Hypertension was defined as systolic blood pressure > or =140 mmHg and/or diastolic blood pressure > or =90 mmHg, or taking antihypertensive medication. Pooled logistic regression analyses were performed using C825T genotype, age, body mass index, lifestyle, and the result of blood chemistries as the covariates. Multivariate pooled logistic regression analysis showed the risk of hypertension was 2.31 times higher in females with the TT genotype than in females with the CC genotype (95% confidence interval: 1.07-4.96), after adjustment for the effects of other potential covariates. In contrast, no significant risk of hypertension was observed with the TT genotype in male subjects. This study indicates that the 825T allele is an independent risk factor for hypertension in Japanese females, and suggests that this polymorphism may be a beneficial prognostic marker for hypertension in the general Japanese female population.

A non-randomized controlled trial was conducted to evaluate the effectiveness of three lifestyle modification programs to reduce blood pressure: individual counseling only; counseling using group dynamics; and individual support using mail.We enrolled men and women ages 20-69 with a systolic blood pressure (SBP) of 130-159 mmHg and/or a diastolic blood pressure of 85-99 mmHg (high-normal or mild hypertension). Participants were assigned to one of 4 groups: individual counseling (n = 134); group counseling (n = 79); mailing support (n = 127); and controls (with usual care) (n = 178). The three intervention programs included behavioral support for each person's lifestyle problems once a month for 6 months. Sex and age adjusted net blood pressure change (and 95% confidence intervals [CIs]) compared with the control group was calculated for each of the intervention groups.Net SBP change was the largest for the group counseling group: sex and age adjusted net SBP change was -6.5 mmHg (95% CI: -10.0, -3.0). Net SBP change for the mailing support group was also significant (-4.3 mmHg [95% CI: -7.3, -1.3]). Net SBP change for the individual counseling group was -2.5 mmHg (95% CI: -5.5, 0.5). Looking at the results separately by sex, net SBP reduction was also largest in women of the group counseling group, whereas improvement in men was similar among 3 groups (approximately 4 mmHg). Body weights were reduced by about 1 kg in all 3 groups.Lifestyle modification programs using group dynamics or using individual support by mail, in addition to individual behavioral support, appear to be effective for blood pressure reduction. Group counseling may be more effective in women.

To investigate which of four anthropometric variables of obesity has the strongest association with blood pressure (BP), and to investigate whether there are gender differences in these relationships in Asian adults, we evaluated the associations of four anthropometric variables, body mass index (BMI), waist circumference, waist-to-hip ratio and waist-to-height ratio, with BP and the prevalence of hypertension in a cross-sectional study. A total of 4,557 employees of a metal-products factory in Toyama, Japan (2,935 men and 1,622 women, aged 35 to 59 years) were included in the study. Waist circumference in men and BMI in women had the strongest associations with BP. As for the age-adjusted rate ratio (RR) of the prevalence of hypertension for one standard deviation increase in each anthropometric variable, RR was the highest for waist circumference in men (RR, 1.44; 95% confidence interval [CI], 1.31-1.58), and for BMI in women (RR, 1.61; 95% CI, 1.38-1.88). The associations of waist circumference in men and BMI in women remained significant after adjustment for each of the other variables. The associations of waist-to-height ratio with BP and the prevalence of hypertension were a little weaker than those of waist circumference for both men and women. In conclusion, among four anthropometric variables of obesity--i.e., BMI, waist circumference, waist-to-hip ratio, and waist-to-height ratio-waist circumference had the strongest association with BP and the prevalence of hypertension in men and BMI had the strongest association with BP and hypertension in women. Waist circumference in men and BMI in women should be given more importance in the screening of and guidelines on hypertension in Asians.

The C825T variant of the G-protein beta3 subunit (GNB3) gene has attracted renewed attention as a candidate gene for obesity, hypertension and hyperuricemia. The main role of G-protein is to translate signals from the cell surface into a cellular response. The 825T allele is associated with a splice variant of GNB3 protein and enhanced G-protein activation. We examined the relationship between this variant and the risk of hyperuricemia in Japanese workers. The study subjects were 1,452 men and 1,169 women selected from 3,834 men and 2,591 women in 1997. On the basis of common clinical criteria, hyperuricemia I was defined as serum uric acid >or= 7.0 mg/dl in men and 6.0 mg/dl in women or taking antihyperuricemic medication. The hyperuricemia I group consisted of 186 men and 20 women and its control of 1,266 men and 1,149 women. Hyperuricemia II was defined as serum uric acid > 5.7 mg/dl (median) in men and 3.9 mg/dl (median) in women or taking antihyperuricemic medication. The hyperuricemic II group consisted of 684 men and 570 women and its control of 768 men and 599 women. To replicate previous significant results in young Caucasian men, we selected these criteria because the authors of the study in young Caucasian men adopted the median in their subjects as a cut-off. The statistical power was estimated as 99% based on the significant results in Caucasians. Genotype and allele distributions in men and women with hyperuricemia I and II were not significantly different from those in the corresponding control groups. Logistic regression analysis on hyperuricemia I and II, and multiple regression on serum uric acid level demonstrated no significant effect of the C825T genotype. Despite the sufficient statistical power, this study could not demonstrate the significant influence of C825T on hyperuricemia or serum uric acid. The targeting of this polymorphism is unlikely to be beneficial in the prevention of hyperuricemia in the general Japanese population.

To clarify the causes of death of residents with renal tubular dysfunction induced by cadmium (Cd) in the environment.A 15 year follow up study was performed with the inhabitants living in the Cd polluted Kakehashi River basin in Japan. Standardised mortality ratios (SMRs) for causes of death, classified by ICD-9, were computed using the person-years method to investigate the excess mortality of subjects with urinary beta2-MG (microglobulin)or =1000 microg/gCr. Mortality risk analysis was performed using Cox's proportional model to compare mortality between subjects with urinary beta2-MGor =1000 and1000 microg/gCr, and to investigate the relationship between the degree of urinary beta2-MG and mortality.Excess mortality due to heart failure and cerebral infarction in both sexes, and nephritis and nephrosis in men, was observed among subjects with urinary beta2-MGor =1000 microg/gCr. Significant increases in mortality risk for cerebral infarction in men and for malignant neoplasms in women with urinary beta2-MGor =1000 microg/gCr were observed during the first five year observation period. For nephritis and nephrosis, the mortality risks for men and women with urinary beta2-MGor =1000 microg/gCr significantly increased over the 15 year observation period. The mortality risks for heart failure and cerebral infarction increased in proportion to the increased urinary beta2-MG in both sexes. Increased mortality risks for nephritis and nephrosis were identified in the subjects with urinary beta2-MGor =10000 microg/gCr in both sexes.Renal tubular dysfunction induced by Cd affected the causes of death, and mortality for heart failure, cerebral infarction, and nephritis and nephrosis was increased among inhabitants living in a Cd polluted area in Japan. In women, cancer mortality may have been increased while Cd pollution was ongoing.

We investigated the association between hypercholesterolemia or serum total cholesterol level and the C825T polymorphism in the G-protein ss3 subunit gene in Japanese workers using multivariate analysis to control possible confounding factors. The study subjects were 1,452 males and 1,169 females selected from 3,834 males and 2,591 females. Hypercholesterolemia was classified as either a total serum cholesterol $5.7 mmol/L (220 mg/dL) or taking lipid-lowering medication. The statistical power of the study was estimated as 99.9% based on total cholesterol levels of previous significant studies in Caucasians and Japanese. The genotype distributions in males with hypercholesterolemia (CC = 78, CT = 154, TT = 78) and females (CC = 60, CT = 137, TT = 52) were not significantly different from normal males (CC = 280, CT = 595, TT = 267) or females (CC = 234, CT = 501, TT = 185). Allele distributions also were not significantly different in either sex. Logistic regression analysis of hypercholesterolemia data and analysis of variance, t-test and multiple regression of serum total cholesterol data demonstrated no significant relationship with the C825T genotype. Despite sufficient statistical power, this study did not demonstrate a significant influence of C825T on hypercholesterolemia or serum total cholesterol level. The targeting of this polymorphism therefore is unlikely to be beneficial in preventing hypercholesterolemia in the general Japanese population.

This prospective cohort study in Japanese workers examined the relationship between the -1438A/G polymorphism in the 5-hydroxytryptamine receptor 2A gene and the development of positive findings for various life-style-related disorders. This study over the 5-year period, 1997-2002, included observations of several disorders in cohorts ranging between 560-1023 for males and 477-735 for females who had negative findings for each disorder at baseline. The criteria for development of the disorders were: hypertension, systolic blood pressure > or =140 mmHg or dia-stolic blood pressure > or =90 mmHg or taking antihypertensive medication; overweight, body mass index (BMI) > or =25 kg/m(2); obesity, BMI > or =30 kg/m(2); new onset of cerebral stroke; metabolic abnormalities, glycosylated hemoglobin A1c >6.0%, total cholesterol > or =240 mg/dl, high-density lipoprotein cholesterol 7.0 mg/dl, gamma-glutamyl transpeptidase > or =60 IU/l in males and > or =30 IU/l in females. Pooled logistic regression analyses were performed using the -1438A/G genotype and other potential factors as covariates. The odds ratios to AA genotype were significant for uric acid (GG, 0.52; AG, 0.59), obesity (AG, 0.24) in males and for high-density lipoprotein cholesterol (GG, 0.11; AG, 0.36), gamma-glutamyl transpeptidase (GG, 0.53; AG, 0.62) and total cholesterol (GG, 1.84) in females. The present study is the first prospective cohort investigation to demonstrate that the -1438G allele has a protective effect against the development of a range of cardiovascular and metabolic disorders. This study indicates that the -1438A/G polymorphism is an independent factor for various disorders in the general Japanese population and suggests that targeting of this polymorphism may be beneficial for preventing these disorders in Japan.

This prospective cohort study in Japanese workers examined the relationship between the -1438A/G polymorphism in the 5-hydroxytryptamine receptor 2A gene and the development of positive findings for various life-style-related disorders. This study over the 5-year period, 1997-2002, included observations of several disorders in cohorts ranging between 560-1023 for males and 477-735 for females who had negative findings for each disorder at baseline. The criteria for development of the disorders were: hypertension, systolic blood pressureor =140 mmHg or dia-stolic blood pressureor =90 mmHg or taking antihypertensive medication; overweight, body mass index (BMI)or =25 kg/m(2); obesity, BMIor =30 kg/m(2); new onset of cerebral stroke; metabolic abnormalities, glycosylated hemoglobin A1c6.0%, total cholesterolor =240 mg/dl, high-density lipoprotein cholesterol40 mg/dl, uric acid7.0 mg/dl, gamma-glutamyl transpeptidaseor =60 IU/l in males andor =30 IU/l in females. Pooled logistic regression analyses were performed using the -1438A/G genotype and other potential factors as covariates. The odds ratios to AA genotype were significant for uric acid (GG, 0.52; AG, 0.59), obesity (AG, 0.24) in males and for high-density lipoprotein cholesterol (GG, 0.11; AG, 0.36), gamma-glutamyl transpeptidase (GG, 0.53; AG, 0.62) and total cholesterol (GG, 1.84) in females. The present study is the first prospective cohort investigation to demonstrate that the -1438G allele has a protective effect against the development of a range of cardiovascular and metabolic disorders. This study indicates that the -1438A/G polymorphism is an independent factor for various disorders in the general Japanese population and suggests that targeting of this polymorphism may be beneficial for preventing these disorders in Japan.

We examined the relationship between the C825T, C1429T, and A-350G variants in the G-protein beta 3 subunit (GNB3) gene, the A1330V and Q89R variants in the low-density lipoprotein receptor-related protein 5 (LRP5) gene, and the risk of hypercholesterolemia in a prospective study in Japanese workers. This study included observations over a 5-year period from 1997 to 2002 on 936 males and 662 females who were not hypercholesterolemic on entry. Hypercholesterolemia was defined as a serum total cholesterol level of 240 mg/dL or higher. Pooled logistic regression analyses were performed using either of the gene variants with age, body mass index, smoking, alcohol consumption, and habitual exercise as the covariates. The risk of the development of hypercholesterolemia was 2.27 times higher in males with the TT genotype of GNB3/C1429T than in males with the CC genotype (95% confidence interval, 1.04-4.94), after adjustment for the effects of other potential covariates. Simultaneously, the risk was 1.49 times higher in males with the AV genotype of LRP5/A1330V than in males with the AA genotype (95% confidence interval, 1.04-2.12) after adjustment for the effects of other potential covariates. This study indicates the GNB3/C1429T and LRP5/A1330V are independent risk factors for hypercholesterolemia in Japanese males and suggests that targeting these polymorphisms may be beneficial when attempting to prevent hypercholesterolemia in the general Japanese male population.

Objectives This study investigated whether shift work is a risk factor for the development of diabetes mellitus. Methods The workers, 2860 men in a sash and zipper factory in the Toyama prefecture of Japan, were followed for 8 years, and the incidence rate of diabetes mellitus was determined. The cohort contained fixed daytime blue-collar workers, shift blue-collar workers, and white-collar workers. The workers were considered to have diabetes mellitus if, in their annual health examination, they had a glycated hemoglobin level of ≥6.1 or if the diagnosis had been made by a hospital physician. The relative risks were estimated by Cox’s proportional hazards regression model. Results Among the 2860 workers, there were 87 cases of new-onset diabetes mellitus, resulting in an incidence rate of 4.41 per 1000 person-years. The age-adjusted incidence was highest for the two-shift workers and lowest for the white-collar workers. The relative risk of diabetes mellitus for the two-shift workers and the three-shift workers compared with the fixed daytime workers was 1.73 and 1.33, respectively, after adjustment for all the confounding factors, but these values were not statistically significant. When the white-collar workers were used as a reference group, a significantly increased risk of diabetes mellitus was found for the two-shift workers (relative risk was 2.01 after adjustment for all confounding factors), but not for the three-shift workers or the fixed daytime blue-collar workers. Conclusions The study suggests that shift work is a risk factor for the onset of diabetes mellitus and that there is a different risk associated with different shift schedules.

A 15-year follow-up study of 3178 inhabitants (1424 men and 1754 women) living in the cadmium (Cd) polluted Kakehashi River basin was conducted. The results clarified effects on mortality of renal dysfunction induced by Cd indicated by urinary beta-2-microglobulin (beta2-MG), total protein, glucose, and total amino acids. This study used Cox's proportional hazard model. The mortality risk ratio of urinary beta2-MG positive (= 1000 microg/gCr) subjects was significantly increased in both sexes: 1.35 for men and 1.73 for women. The increased mortality ratio of the urinary protein positive (= 10 mg/dl) subjects was also significant for both sexes, with risk ratios of 1.82 for men and 2.01 for women. Only the women showed significantly increased mortality of the urinary glucose positive (= 20 mg/dl) subjects and amino acids positive (= 300 microg/gCr) subjects. When the subjects were divided into four categories according to urinary beta2-MG,300, 300-1000, 1000-10000,= 10000 microg/gCr, the mortality risk ratios were increased in proportion to the increase of urinary beta2-MG in both sexes. These results suggest that mortality of Cd-exposed subjects increased with increasing excretion of four urinary markers of renal tubular dysfunction, and in proportion to increases in the amount of urinary beta2-MG excretion including under 1000 microg/gCr.