上村 浩一

Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) have been shown to accumulate in the human body. The purpose of the present study was to examine the factors associated with the blood levels of PFOS and PFOA. Methods: A cross-sectional study was performed on 307 men and 301 women (aged 16-76 years) living in 15 prefectures in Japan. Blood levels of PFOS and PFOA were measured by liquid chromatography-mass spectrometry. Hepatic enzymes (γ -GTP, GOT, and GPT) and ω -3 polyunsaturated fatty acids (DHA and EPA) levels in serum were also measured. Associations between the levels of PFOS and PFOA in blood and the intake frequency of 41 kinds of dishes, foods and beverages and the serum levels of liver enzymes and ω -3 polyunsaturated fatty acids were examined using rank correlations. Results: Frequency of intake of boiled fish in broth, sliced raw fish and coastal fish showed significant positive correlations with PFOS concentrations in blood after adjustments for potential confounders. Serum levels of GOT, GPT, DHA and EPA showed significant positive correlations with PFOS and PFOA in blood. There was also a significant regional difference in the blood levels of PFOS and 2013PFOA, with medians being highest in the Tokai/Hokuriku/Kinki region. Conclusions: These findings suggest that the concentrations of PFOS in blood were mainly associated with fish consumption and that the levels of PFOS and PFOA were associated with the serum levels of liver enzymes in Japanese populations. Further investigations are required to clarify the reason for the regional differences in blood levels of PFOS and PFOA in Japan.

Background: Estrogen deficiency due to natural menopause or surgical menopause has been suggested to have an adverse effect on insulin resistance. Testosterone and sex hormone-binding globulin (SHBG) as well as estrogen are also associated with insulin resistance in women. However, to date, the associations of estradiol, testosterone and SHBG with insulin resistance according to estrogen level have not been clarified. Objectives: We examined the associations of estradiol, testosterone and SHBG with insulin resistance in pre- and in postmenopausal women and postmenopausal women who had received hormone therapy to clarify whether the associations differ depending on the estrogen status. Patients and Methods: Twenty premenopausal women and thirty-two postmenopausal women were enrolled in this study. Fifteen postmenopausal women received oral conjugated equine estrogen (CEE) (0.625 mg) everyday for 12 months. Serum levels of estradiol, testosterone, SHBG and insulin and plasma levels of glucose were measured. Results: Serum estradiol levels tended to have a negative correlation with homeostasis model assessment of insulin resistance (HOMA-IR) in premenopausal women but not in postmenopausal women. On the other hand, free testosterone levels tended to have a positive correlation with HOMA-IR in postmenopausal women but not in premenopausal women. Serum SHBG levels showed significant negative correlations with HOMA-IR in both pre- and postmenopausal women. SHBG level was significantly increased, free testosterone level was significantly decreased and HOMA-IR was significantly decreased at 12 months after CEE administration. However, there were no significant correlations of changes between estradiol, SHBG or free testosterone and HOMA-IR. Conclusions: The associations of sex steroid hormones with insulin resistance are different depending on the estrogen status. © 2013, Research Institute For Endocrine Sciences and Iran Endocrine Society.

The purpose of this study was to evaluate the associations between dietary factors and sleep-wake regularity in the Japanese population. We analyzed 1368 eligible subjects (931 men and 437 women) aged 35-69 years who had participated in the baseline survey of a cohort study in Tokushima Prefecture, Japan. Information on individual lifestyle characteristics, including dietary habits and sleep-wake regularity, was obtained by a self-administrated questionnaire. Logistic regression analyses were performed to evaluate adjusted associations of the intake energy ratios of macronutrients, as well as intake frequency, and the amount of staple foods with sleep-wake regularity. The lowest quartile of protein intake as well as the highest quartile of carbohydrates showed significantly higher multivariable-adjusted odds ratios of 2.1 (95% confidence interval, 1.3-3.3) and 2.1 (1.3-3.5), respectively, for poor sleep-wake regularity compared with the respective second quartile that is thought to be moderate intake. Regarding intake of staple foods, low weekly intake frequency at breakfast (<5 times/week), the lowest intake amount (<1 bowl or slice/roll) at breakfast, and the highest intake amount (>= 2 bowls or slices/rolls) at lunch and dinner exhibited significantly high adjusted odds ratios for poor sleep-wake regularity. Additionally adjusting for sleep duration, these results did not substantially alter. Our results suggested that low intake energy ratio of proteins and high intake energy ratio of carbohydrates, skipping intake of the staple foods at breakfast, and excessive intake amount of the staple foods at lunch and dinner may be associated with poor sleep-wake regularity.

「食品交換表に基づく新たなカーボカウント法」（黒田ら，糖尿病2010）に基づいて糖尿病食1食に含まれる糖質量を算出する場合，1食を主食と副食にわけ，副食は一律20 gと概算する．しかし，小児期は必要エネルギー量や栄養素バランスが食品交換表とは異なる．よって本研究では，小児期の副食糖質量を検討することを目的とした．学校給食摂取基準に基づく学校給食42食分を小学校の学年別に検討した．その結果，1食のエネルギーは670±44～752±50（平均値±標準偏差）kcalと学年が上がるに従い増加したが，副食糖質量は29.7±7.5～31.2±8.1 gであり，エネルギー量にかかわらず副食糖質量を約30 gに概算できた．学校給食では糖質約10 gの牛乳が毎食提供されるため糖尿病食や病院普通食に比較して副食糖質量が10 g増加すると考えられた．以上より，小学校給食では副食糖質量を30 gとしてカーボカウントを指導できることが明らかとなった．<br>

Objective: We examined (1) the change in circulating adiponectin in women during the menopausal transition and (2) the associations of adiponectin levels with estrogen, androgen and sex hormone-binding globulin (SHBG) in women during the menopausal transition. Methods: We conducted a cross-sectional study in 235 healthy women and divided them into 7 stages by menstrual regularity and follicle-stimulating hormone (FSH) level. Serum levels of adiponectin, estradiol, total testosterone, dehydroepiandrosterone-sulfate (DHEA-S) and SHBG were measured. Levels of free and bioavailable testosterone were calculated by using total testosterone, albumin and SHBG. Results: Serum adiponectin levels showed a U-curve, levels being low in early and late menopausal transition and gradually becoming higher after menopause. Adiponectin levels were negatively correlated with levels of free testosterone, bioavailable testosterone and DHEA-S and were positively correlated with SHBG in postmenopausal women for whom more than 1 year had passed since menopause. Adiponectin level was not correlated with estradiol level. Conclusion: Circulating adiponectin level shows a U-curve during the menopausal transition and adiponectin level is associated with levels of free and bioavailable testosterone and DHEA-S in post-menopause. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

Background: Although the peroxisome proliferator-activated receptor-gamma 2 (PPARG2) Pro12Ala gene variant is associated with diabetes mellitus, the associations and interactions of this polymorphism and known clinical risk factors with glycated hemoglobin (HbA1c) remain poorly understood. We investigated if carrying the Ala allele was inversely associated with HbA1c level and examined possible interactions. Methods: This cross-sectional analysis used data collected from 1281 men and 1356 women aged 40 to 69 years who completed the baseline survey of the japan Multi-Institutional Collaborative Cohort Study. PPARG2 polymorphism was determined by multiplex polymerase chain reaction (PCR)-based Invader assay. Multiple linear regression and ANCOVA were used to control for confounding variables (age, body mass index [BMI], energy intake, alcohol, smoking, physical activity, and family history of diabetes) and examine possible interactions. Results: After adjustment, the Ala allele was significantly inversely associated with HbA1c in women but not in men. Older age, BMI, and family history of diabetes were associated with higher HbA1c in both sexes. When stratified by PPARG2 genotype, these associations were observed in subjects with the Pro12Pro genotype but not in Ala allele carriers. A significant interaction of genotype and BMI on HbA1c was observed in women. Older age, BMI, and family history of diabetes were significantly associated with high-normal HbA1c (&gt;= 5.7% NGSP), whereas PPARG2 polymorphism was not. Conclusions: Although PPARG2 Pro12Ala polymorphism might attenuate associations between known risk factors and HbA1c level, it had a small effect on high-normal HbA1c, as compared with clinical risk factors, in the general population.

This study examined the associations of the APOA5 T-1131C (rs662799), G553T (Cys185Gly, rs2075291), GCK G-30A (rs1799884), GCKR A/G at intron 16 (rs780094) and T1403C (Leu446Pro, rs1260326) polymorphisms with scrum lipid and glucose levels in Japanese, considering lifestyle factors. Study subjects were 2,191 participants (aged 35-69 years, 1,159 males) enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. Dyslipidemia was defined as fasting serum triglycerides (FTG) &gt;= 150 mg/dL and/or HDL-cholesterol (HDL-C) &lt;40 mg/dL, while dysglycemia was as fasting blood sugar (FBS) &gt;= 110 mg/dL. When those with APOA5 -1131 T/Tor 553 G/G were defined as references, those with APOA5 -1131 TIC, C/C or 553 G/T, T/T demonstrated significantly elevated risk of dyslipidemia (age- and sex-adjusted odds ratio: 1.77 [95% confidence interval:1.39-2.27], 3.35 [2.41-4.65], 2.23 [1.64-3.02] and 13.78 [3.44-55.18], respectively). Evaluation of FTG, HDL-C or FBS levels according to the genotype revealed that FIG and HDL-C levels were significantly associated with the APOA5T-1131C and G553Tpolymorphisms, FIG with the GCKR rs780094 and rs1260326 polyrnorphisms, and FBS with the GCICR rs780094 and rs1260326 polymorphisms. Moreover, a significant positive interaction between APOA5 553 G/T+T/T genotypes and fat intake &gt;= 25% of total energy for the risk of dyslipidemia was observed. Our cross-sectional study confirmed the essential roles of the polymorphisms of the APOA5, GCK and GCKR in the lipid or glucose metabolism disorders, and suggested the importance of fat intake control in the individualized prevention of dyslipidemia.

Objective: The purpose of this study was to determine (1) the influence of estrogen deficiency induced by gonadotropin-releasing hormone (GnRH) agonist administration on insulin sensitivity as well as hormones and factors related to insulin resistance and (2) the differences in the influence for these parameters by the degree of basal insulin sensitivity. Methods: Thirty-five women diagnosed with leiomyoma were enrolled in this study. Serum levels of fasting glucose, insulin, sex steroid hormones, sex hormone-binding globulin (SHBG), vascular inflammatory markers and cytokines before and at 6 months after commencement of GnRH agonist administration were examined. Results: In all women, levels of insulin, glucose and homeostasis model assessment of insulin resistance (HOMA-IR) were not significantly changed. However, in women who had a low HOMA-IR before treatment, levels of insulin, glucose and HOMA-IR showed significant increases and total testosterone level showed a significant decrease. In women who had a high HOMA-IR, levels of insulin, HOMA-IR and SHBG were significantly decreased and levels of highly sensitive C-reactive protein, soluble intercellular adhesion molecule-1, E-selectin and monocyte chemoattractant protein-1 were significantly increased. Conclusion: Change in insulin sensitivity caused by GnRH agonist administration for premenopausal women with leiomyoma differs depending on baseline insulin sensitivity before treatment. (C) 2012 Elsevier B.V. All rights reserved.

Persistent organic pollutants (POPs) are a group of chemical substances that have the common properties of resistance to biodegradation, wide-range transportation, high lipophilicity, bioaccumulation in fat, and biomagnification in the food chain. POPs are persistent in the environment worldwide and have potential adverse impacts on human health and the environment. Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) are well known chemicals that are considered as POPs.<br> The association between high-level exposure to dioxins and type 2 diabetes among U.S. Air Force veterans who had been exposed to Agent Orange contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during the Vietnam War was reported in the late 1990s. This association has been supported by similar epidemiologic studies, whose subjects were exposed to high doses of dioxins in their places of work involving phenoxyacid herbicide production and spraying, and in the industrial accident in Seveso, Italy.<br> Recently, low-level exposure to dioxins and PCBs has been reported to be linked to type 2 diabetes. Cross-sectional studies in the U.S. general population and Japanese general population showed that body burden levels of some dioxins and PCBs were strongly associated with the prevalence of type 2 diabetes. Very recently, following these cross-sectional studies, several prospective studies have suggested that low-level exposure to some PCBs predicted the future risk of type 2 diabetes in the general population. Environmental exposure to some dioxins and PCBs, which mainly accumulate in adipose tissue, may play a role in the development of type 2 diabetes.<br>

In our previous proteomic study in rat liver damaged by carbon tetrachloride, soluble catechol-O-methyltransferase (COMT) increased as a phosphorylated form and decreased as a dephosphorylated form. This finding raised the possibility that the COMT protein is associated with liver function. Thus, we hypothesized that (1) the COMT gene contributes to liver homeostasis and (2) a COMT polymorphism (rs4680: Val158Met) causing thermolability of enzymatic activity affects liver enzymes (e.g., aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (gamma-GT)) in serum. To investigate (2), we statistically analyzed the association between COMT genotypes and serum ALT activity in a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. We conducted a multiple logistic regression analysis for males (n = 838) and females (n = 970). Those participants having missing values or a past history of liver cirrhosis or liver cancer were excluded. ALT values were divided into two; elevated (30 IU/L &lt;=; males n = 239, females n = 90) and normal (&lt;30 IU/L; males n = 599, females n = 880). In females, non-adjusted and adjusted odds ratios for ALT values in the rs4680 A/A homozygote (n = 126) compared with the wild-type G/G homozygote (n = 397) were 0.37 (95% CI 0.14-0.96) and 034 (95% CI 0.13-0.93), respectively. In males, an analysis of the population aged 35-69 did not reveal any significant difference, but the population aged 45-54 had a significant difference in the non-adjusted and adjusted odds ratio in the G/A heterozygote (n = 89) (0.50 (95% CI 0.27-0.92) and 0.35 (95% CI 0.18-0.71)) and in the A/A homozygote (n = 22) (0.34 (95% CI 0.11-0.99) and 0.22 (95% CI 0.07-0.72)), compared with the G/G homozygote (n = 88). These data suggest that the COMT polymorphism affects serum ALT activity to maintain liver function. (C) 2012 Elsevier B.V. All rights reserved.

Objectives: Timing of menopause affects postmenopausal health risks. The objective of this study was to evaluate the associations of the single nucleotide polymorphisms (SNPs) in peroxisome proliferator-activated receptor (PPAR)-related genes (PPARD, PPARG, and PPARGC1A) and environmental factors with timing of natural menopause among the general Japanese population. Study design: We analyzed cross-sectional data from 1758 women aged 40-69 years who were enrolled in the baseline surveys of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. Main outcome measures: Associations of timing of natural menopause with its probable covariates and with target gene variants were evaluated by univariate and multivariate Cox proportional hazards models. Results: Lower body mass index and later age at menarche were significantly associated with earlier natural menopause. Women with minor alleles at T-48444C in PPARD showed a significantly higher adjusted hazard ratio of 1.57 (95% confidence interval: 1.18-2.10) for earlier natural menopause. In contrast, women with minor alleles at Thr394Thr in PPARGC1A showed a significantly lower adjusted hazard ratio of 0.86 (0.76-0.97) for earlier natural menopause. These associations did not substantially alter when re-analyzed after excluding the subjects who self-reported a history of diabetes or the subjects whose age was more than 65 years. Conclusions: Gene variants in PPARD and PPARGC1A might be associated with timing of natural menopause, probably through direct actions on the ovaries, among the general Japanese population. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Uncovering population structure is important for properly conducting association studies and for examining the demographic history of a population. Here, we examined the Japanese population substructure using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC), which covers all but the northern region of Japan. Using 222 autosomal loci from 4502 subjects, we investigated population substructure by estimating FST among populations, testing population differentiation, and performing principal component analysis (PCA) and correspondence analysis (CA). All analyses revealed a low but significant differentiation between the Amami Islanders and the mainland Japanese population. Furthermore, we examined the genetic differentiation between the mainland population, Amami Islanders and Okinawa Islanders using six loci included in both the Pan-Asian SNP (PASNP) consortium data and the J-MICC data. This analysis revealed that the Amami and Okinawa Islanders were differentiated from the mainland population. In conclusion, we revealed a low but significant level of genetic differentiation between the mainland population and populations in or to the south of the Amami Islands, although genetic variation between both populations might be clinal. Therefore, the possibility of population stratification must be considered when enrolling the islander population of this area, such as in the J-MICC study.

The purpose of the present study was to investigate the factors associated with blood levels of each congener of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (DL-PCBs) in the Japanese population. A cross-sectional study was performed on 1,656 subjects (755 men and 901 women) aged 15-73 years, who were living in 90 different areas of 30 prefectures in Japan. Blood levels of 29 PCDD, PCDF, and DL-PCB congeners were determined by high-resolution gas chromatography/mass spectrometry. In addition, a questionnaire survey on life style, including dietary habit, was carried out. The median total toxicity equivalent (TEQ) was 17 pgTEQ/g lipid. After adjustment for age, sex, body mass index, smoking habit, and consumption of other food groups, six PCDDs/PCDFs with 4-6 substituted chlorine atoms and 10 DL-PCBs, but not HeptaCDD/F or OctaCDD, showed significant positive correlations with the frequency of intake of fish and shellfish. Furthermore, significant positive relationships were also found between plasma levels of docosahexaenoic acid (DHA), a biomarker of fish intake, and 10 PCDDs/PCDFs with 4-6 chlorine atoms and 10 DL-PCBs. The partial correlation coefficients with plasma DHA were significantly higher for DL-PCBs than for PCDDs/PCDFs, and partial correlation coefficients for PCDDs/PCDFs significantly decreased with increasing number of chlorine atoms (Spearman r = -0.80, P = 0.001). Blood levels of PCDDs/PCDFs with 4-6 chlorine atoms and DL-PCBs were positively associated with fish intake in the Japanese population. These results may be explained by the higher degree of bioaccumulation of these congeners in fish and shellfish in the ecosystem, and the high consumption of fish among the Japanese population.

Objective: The objective of this study was to examine the influence of twin pregnancy on calcium metabolism, including bone turnover markers and calcium-regulating factors, by comparison between singleton pregnancy and twin pregnancy in women during pregnancy and puerperium in cross-sectional and longitudinal studies. Methods: Women with singleton and twin pregnancies were recruited from the outpatient clinic of Tokushima University Hospital. In both cross-sectional and longitudinal studies, bone formation and resorption markers, mineral metabolism and calcium-regulating factors were measured at 10, 25, 30 and 36 weeks of pregnancy and at 4 days and 1 month postpartum in women with singleton and twin pregnancies. Results: Urinary levels of cross-linked type I collagen N-telopeptides and C-terminal telopeptides of type I collagen in women with twin pregnancy were significantly higher than those in women with singleton pregnancy and those high levels were observed earlier than those in women with singleton pregnancy. In the cross-sectional study, serum levels of bone-specific alkaline phosphatase, calcium and phosphate in women with twin pregnancy were higher and the levels of 1,25-(OH)(2) vitamin D and 25-(OH) vitamin Din women with twin pregnancy were lower than those in women with singleton pregnancy. Conclusion: Changes in bone metabolism in women with twin pregnancy are different from those in women with singleton pregnancy. Early and large increases in bone turnover markers allow women with twin pregnancy to meet high fetal demand for calcium during pregnancy. (C) 2011 Elsevier Inc. All rights reserved.

The aim of the present study was to determine the influence of acute estrogen deficiency induced by administration of a gonadotropin-releasing hormone (GnRH) agonist on circulating levels of cytokines and chemokines. Eighty-three women with uterine leiomyoma were assigned in open, parallel-group fashion to a no-treatment (control) group and a GnRH-agonist group. Serum levels of nine cytokines and chemokines as well as vascular inflammatory markers were measured. Serum levels of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor-alpha (TNF alpha) in the GnRH-agonist group were increased significantly at 6 months. There were also significant differences in percentage changes in interleukin (IL)-6, IL8, MCP1, and macrophage inflammatory protein-1 beta (MIP1 beta) between the control and GnRH agonist groups. Soluble intercellular adhesion molecule-1 (sICAM1) and E-selectin levels showed significant increases in the GnRH agonist group at 6 months. Serum MCP1 concentrations showed weak correlations with levels of sICAM and E-selectin. We conclude that a hypo-estrogenic state due to administration of a GnRH agonist increases circulating levels of cytokines and chemokines, especially MCP1. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Background: Most diseases are thought to arise from interactions between environmental factors and the host genotype. To detect gene-environment interactions in the development of lifestyle-related diseases, and especially cancer, the Japan Multi-institutional Collaborative Cohort (J-MICC) Study was launched in 2005. Methods: We initiated a cross-sectional study to examine associations of genotypes with lifestyle and clinical factors, as assessed by questionnaires and medical examinations. The 4519 subjects were selected from among participants in the J-MICC Study in 10 areas throughout Japan. In total, 108 polymorphisms were chosen and genotyped using the Invader assay. Results: The study group comprised 2124 men and 2395 women with a mean age of 55.8 +/- 8.9 years (range, 35-69 years) at baseline. Among the 108 polymorphisms examined, 4 were not polymorphic in our study population. Among the remaining 104 polymorphisms, most variations were common (minor allele frequency &gt;= 0.05 for 96 polymorphisms). The allele frequencies in this population were comparable with those in the HapMap-JPT data set for 45 Japanese from Tokyo. Only 5 of 88 polymorphisms showed allele-frequency differences greater than 0.1. Of the 108 polymorphisms, 32 showed a highly significant difference in minor allele frequency among the study areas (P &lt; 0.001). Conclusions: This comprehensive data collection on lifestyle and clinical factors will be useful for elucidating gene environment interactions. In addition, it is likely to be an informative reference tool, as free access to genotype data for a large Japanese population is not readily available.

Purpose: The aims of this study were to determine the effects of raloxifene therapy on production of cytokines and in vitro effects of raloxifene on production of cytokines by whole blood cultures. Methods: We obtained samples of peripheral blood from 6 postmenopausal women with osteopenia at baseline and after 3 and 6 months of raloxifene therapy and 10 postmenopausal women who did not receive raloxifene therapy. Whole blood from raloxifene-treated women was stimulated with lipopolysaccharide (LPS) or phytohemeagglutinin (PHA). Whole blood from postmenopausal women who were not treated with raloxifene was preincubated with raloxifene at concentrations of 10-10-10-7 M and then stimulated with LPS or PHA. Concentrations of IL-1β, IL-4, IL-6, IL-12p40, IL-12p70, TNF-α and IFN-γ in the supernatant were measured by respective ELISAs. Results: In ex vivo cultures, raloxifene therapy inhibited LPS-stimulated production of IL-1β, IL-6, IL-12p40, IL-12p70 and TNF-α, but not PHA-stimulated production of IL-4 and IFN-γ. In in vitro cultures, raloxifene at a concentration (109 M) inhibited LPS-stimulated production of IL-1β, IL-6 and IL-12p40 and PHA-stimulated production of IFN-γ. Conclusions: Raloxifene therapy decreases the production of IL-1β, IL-6, IL-12 and TNF-α but not that of IL-4 and IFN-γ, suggesting that modulation of cytokines could play a role in the mechanisms of the osteoprotective effect of raloxifene.

Objective: The effects of the Japanese traditional medicines keishibukuryogan and kamishoyosan on circulating cytokines were examined to clarify the difference in the actions of Japanese traditional medicines in women with hot flashes. Methods: Seven premenopausal, 51 perimenopausal, 45 spontaneously postmenopausal and 17 surgically postmenopausal women who had complained of hot flashes were enrolled in this study. Eighty women who hoped to receive Japanese traditional medicines were randomly assigned in open, parallel-group fashion to a keishibukuryogan group or kamishoyosan group. Forty women who did not want any treatment for hot flashes were followed up for 6 months as a control group. Serum levels of cytokines were measured using a multiplexed human cytokine assay. Results: The proportions of responders in women treated with keishibukuryogan and kamishoyosan were 73.7% and 69.2%, respectively. Serum monocyte chemotactic protein-1 level in women treated with keishibukuryogan decreased significantly (P = 0.0037). On the other hand, concentrations of interleukin (IL)-6 and macrophage inflammatory protein-1 beta in women treated with kamishoyosan decreased significantly (P = 0.019 and P = 0.039, respectively). In both keishibukuryogan and kamishoyosan responder groups, serum IL-8 concentrations were reduced significantly (P = 0.021 and P = 0.014, respectively). Conclusions: Both treatments with keishibukuryogan and kamishoyosan reduce the circulating IL-8 level, which is involved in thermoregulation in perimenopausal women with hot flashes. In addition, keishibukuryogan decreases circulating monocyte chemotactic protein-1 level in postmenopausal women.

The association between dietary patterns and blood dioxin levels has not been fully investigated. The present study population consisted of 755 men and 901 women (aged 15-73 years) living in 90 different areas of 30 prefectures of japan. Dietary habits were assessed by inquiring about the consumption frequency of 28 foods, food groups and beverages. In addition, the blood levels of 29 polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzo-furans (PCDFs), and dioxin-like polychlorinated biphenyl (DL-PCBs) congeners were determined by high-resolution gas chromatography/mass spectrometry. The median total toxicity equivalent (TEQ) in the blood, which was calculated on the basis of the toxicity equivalency factors of WHO (2005), was 16 pg TEQ g(-1) lipid. Principal component analysis identified five dietary patterns: Healthy diet (high intake of vegetables and fruits); Meat/High fat intake (high intake of meat, meat products, and eggs); Seafood and Alcohol (high intake of fish, shellfish, and alcoholic beverages); Miscellaneous; and Milk products and Alcohol intake (high intake of milk, Milk products, and alcoholic beverages). After adjusting for sex, age, body mass index, and smoking habits, the Seafood and Alcohol pattern scores were significantly related to higher blood levels of total TEQ and PCDDs/PCDFs/DL-PCBs, and the Milk products and Alcohol pattern scores were correlated with higher blood levels of DL-PCBs. More detailed analysis showed that the intake frequencies for alcoholic beverages and seafood were independently and positively associated with total TEQ and the TEQ of PCDFs and DL-PCBs. The association between alcoholic beverage intake and PCDDs was also significant. Analysis of dietary patterns may be useful for identifying the dietary characteristics of individuals with a high dioxin body burden. (C) 2010 Elsevier Ltd. All rights reserved.

Purpose: The aim of this study was to clarify the role of blood in the early stage of development of endometriotic lesions by developing a syngeneic transplantation model using immunocompetent mice. Methods: Endometriotic lesions were induced in C57BL/6 mice by an intraperitoneal injection of endometrial fragments plus saline or endometrial fragments plus blood. Some endometrial fragments plus blood were injected with heparin, hirudin or tissue plasminogen activator (tPA). Endometriotic lesions on days 1, 3 and 5 were evaluated by gross and microscopic findings. Results: The areas of endometriotic lesions in the blood group (6.4 ± 1.7 mm2) were significantly larger than those in the saline group (0.5 ± 0.3 mm2). The areas of endometriotic lesions were significantly reduced by the addition of heparin, hirudin or tPA. On day 1, endometriotic lesions in the blood group were observed on the peritoneum in five of the six mice. Endometriotic lesions on days 3 and 5 were significantly larger than those on day 1. On day 5, endometriotic lesions appeared cystic in all the mice. Conclusions: Blood accelerates the early stage of development of endometriotic lesions when endometrial fragments plus blood are injected. Blood property might be involved in early endometrial-peritoneal interactions. © 2010 Japan Society for Reproductive Medicine.

Objective: Our objective was to investigate congener-specific body burden levels and possible determinants of polybrominated diphenyl ethers (PBDEs) in the Japanese human population. Methods: We conducted a cross-sectional study on 72 participants aged 15-74 years; subjects were not occupationally exposed to PBDEs or dioxin-like polychlorinated biphenyls (DL-PCBs). Participants lived in two urban areas and two fishing villages. Twenty-seven PBDE congeners, PCB-126, PCB-118, PCB-156, and biochemical factors were determined in fasting blood. A questionnaire survey on life-style was also conducted. Results: More than half of the PBDE values for 14 congeners were below the levels of detection (LODs). The median concentration of total PBDEs was 3.6 ng g(-1) lipid. The most abundant congener was BDE-209 (median concentration, 0.90 ng g(-1) lipid), followed by BDE-153, BDE-207, and BDE-47 in the given order. Most PBDE congeners with &lt;= 6 bromine atoms had significant positive associations with the concentrations of the three DL-PCBs (suggesting common routes of exposure) and with plasma concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DNA), biological markers of fish intake. These associations did not change substantially after adjustment for age, sex, and log(body mass index). These positive associations with the concentrations of DL-PCBs or EPA/DHA were not found in analyses of high-brominated PBDE congeners with &gt;= 8 bromine atoms. Conclusions: Fish consumption may be a major contributor to the accumulation of PBDE congeners with &lt;= 6 bromine atoms among the general Japanese population. In contrast, the main exposure routes to high-brominated PBDEs in humans are probably not associated with fish consumption. (C) 2010 Elsevier Ltd. All rights reserved.

Background: The relationships between N-terminal fragment proBNP (B-type natriuretic peptide) (NT-proBNP) and sex steroid hormones have not been fully elucidated. We examined these associations in pre-, peri- and postmenopausal women without known cardiovascular disease. We also examined the change in circulating NT-proBNP caused by a gonadotrophin-releasing hormone (GnRH) agonist in order to clarify the effect of acute hormone deficiency on NT-proBNP. Methods: Forty-nine premenopausal women, 101 perimenopausal women and 108 postmenopausal women were enrolled in one study. Forty-four premenopausal women with leiomyoma were recruited for another study, and 22 of those women were treated with a GnRH agonist. Serum levels of NT-proBNP, estradiol, testosterone and sex hormone-binding globulin (SHBG) were measured. Results: NT-proBNP concentrations showed significant inverse correlations with body mass index (BMI) in peri- and postmenopausal women. Serum NTproBNP concentrations showed significant positive correlations with SHBG in peri- and postmenopausal women. These significant correlations remained after adjustment for age and BMI. Serum NT-proBNP concentration was significantly decreased after GnRH agonist administration. while NT-proBNP concentration in the control group did not change significantly. Serum SHBG level was also significantly decreased after GnRH agonist administration. Conclusion: Circulating NT-proBNP levels are positively associated with SHBG levels in non-obese peri- and postmenopausal women, and this relationship was found under the condition of acute hormone deficiency induced by GnRH agonist treatment. (C) 2009 Elsevier B.V. All rights reserved.

The Barthel Index (BI) cannot be used to measure initial stroke severity or by extension, to stratify patients by severity in acute stroke trials because most patients are bedbound in the first few hours after stroke, either by their deficit or by medical directive. Our objectives were to clarify the threshold of acute BI for use in the prediction of subsequent independence in activities of daily living (ADL) and to assist in the definition of acute stroke rehabilitation goals. Subjects comprised 78 patients out of 191 inpatients admitted with acute stroke at our hospital during 2006-2007. The BI ADL score was divided into 2 ranges (BI ≧ 60 and ≧ 40), in a process similar to previous studies. During the acute period (from onset to approximately 3 weeks), all patients with a BI ≧ 40 could improve their ADL in 6 months. Patients with a BI ≧ 40 exhibited two ADL recovery outcomes (improved and no change) at 6 months. We also found that the skill level of basic activities related to standing was significant indicator of BI improvement (P&lt 0.001). BI scores determined at approximately 3 weeks were reliable predictors of ADL disabilities at 6 months.

This study aimed to clarify the therapeutic effects of postoperative ambulation after total knee arthroplasty (TKA) on deep venous thrombosis (DVT) in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) after TKA. Subjects of this study were thirty-seven inpatients (21 inpatients : OA, 16 inpatients : RA) undergoing TKA (32 female and 5 male). Subjects were divided into two groups, deep venous thrombosis (DVT) group (n=25) and non-DVT group (N group, n=12). The cutoff value was 10.0 μg/ml plasma D-dimer level measured on 7th postoperative day. The N group was below the cutoff value. Another cutoff value divided into two groups, ambulatory group (n=26) and non-ambulatory group (n=11). Ambulatory group was the date of ambulation beginning below 7th day. Statistical analysis confirmed that all subjects showed a significant correlation to the date of ambulation. Postoperative ambulation beginning had strong association with the level of D-dimer (r=0.71). Group comparison showed that the non-ambulatory group had significant higher values of D-dimer than ambulatory group (P=0.022). Typical case supported these results. Postoperative early ambulation within a week after TKA kept patients with OA and RA after TKA lower level of D-dimer.

Osteoporosis is a chronic skeletal condition characterized by impaired bone strength and increased risk of fracture. This disorder causes notable morbidity, deterioration in quality of life （QOL）and mortality in the elderly due to associated with fragility fractures of the spine, hip and wrist. Moreover, the treatment of osteoporotic fractures is also associated with a huge economic cost for society. To avoid the fragility fracture, prevention of osteoporosis and fall down are of great importance. For that purpose, not only pharmacological therapy（mainly by antiresorptive medications） in middle-aged and elderly individuals but also non-pharmacological intervention through lifestyle modification will become important in adolescents and young adults from the early life. Lifestyle modification emphasizing bone health such as adequate calcium, vitamin D and vitamin K nutrition, restriction of caffeine and alcohol consumption, and avoidance of tobacco are essential to the management of osteoporosis risk. Balance and strength training also play important roles in the improvement of bone strength. Most of the risk and preventive factors of osteoporosis are common to those of other lifestylerelated diseases. Therefore, lifestyle modification emphasizing bone health from the early life will contribute to avoid not only fragility fracture but also other lifestyle-related diseases, and will contribute to maintenance or improvement of QOL.

Objective: The aim of the present study was to determine the different effects of oral estrogen therapy (ET) and transdermal ET on changes in circulating levels of cytokines and chemokines in relationship to changes in markers of inflammation in postmenopausal women with hysterectomy Methods: Fifty-live post menopausal women with hysterectomy were randomly assigned ill open. parallel-group fashion to an oral ET group and a transdermal ET group. Serum levels of cytokines and chemokines were simultaneously measured using a multiplexed human cytokine assay. Serum concentrations of high-sensitive C-reactive protein, Soluble vascular Cell adhesion molecule-1. Soluble intercellular adhesion molecule-1, and E-selectin were measured as vascular inflammation markers. Results: Both oral ET and transdermal ET significantly decreased serum interleukin (IL)-7 concentrations at 12 months (P=0.020 and P=0.015 respectively). Transdermal ET decreased serum concentrations of IL-8, monocyte chemoattractant protein (MCP-1), and macrophage inflammatory protein (MIP)-1 beta (P=0.05, P=0.019. and P=0.029), but oral ET increased IL-8 level (P=0.025). There were significant differences in percentage changes in IL-18 and MIP-1 beta between the oral and transdermal ET groups. Oral ET significantly decreased E-selectin level after 12 months. Conclusion: Transdermal ET reduces circulating levels of IL-8, MCP-1, and MIP-1 beta, while both oral ET and transdermal ET reduce circulating level of IL-7.

Interleukin (IL-7), which is a regulator of development and homeostatic maintenance of T and B cells, is implicated in the induction of leukocyte-endothelial cell adhesion during inflammatory events. We hypothesized that circulating IL-7 is associated with cytokines and chemokines, vascular inflammatory markers and lipid profiles involved in regulating cell adhesion in postmenopausal women. Serum levels of 8 cytokines and chemokines were simultaneously measured in 200 post-menopau sal women using a multiplexed human cytokine assay. C-reactive protein, soluble vascular cell adhesion molecule, soluble intercellular adhesion molecule and soluble E-selectin were measured as inflammatory markers. Serum IL-7 concentration was significantly correlated with serum MCP-1 concentration and the correlation remained after adjustment for age and body mass index (BMI). Serum IL-7 levels also showed significant positive correlations with serum levels of IL-10 and IL-6. In addition, the serum IL-7 concentration showed significant positive correlations with levels of soluble E-selectin and triglyceride after adjustment for age and BMI We conclude that there is a relationship between circulating IL-7, MCP-1 and soluble E-selectin, and that IL-7 may be involved in regulating inflammatory cell adhesion together with MCP-1 and E-selectin in post-menopausal women. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Objective: The aim of the present study was to determine the effects of raloxifene on changes in circulating levels of cytokines and chemokines in relation to changes in lipid profiles and markers of inflammation in postmenopausal women. Methods: Fifty-three postmenopausal women aged 45-65 years old were randomly assigned in open, parallel-group fashion to a control group or raloxifene group. Twenty-six women received oral administration of 60 mg raloxifene every day and 27 women did not receive any drugs for 12 months. Serum cytokines levels were simultaneously measured using a multiplexed human cytokine assay. Results: Serum IL-7 concentrations in women who received raloxifene were decreased significantly (p = 0.014), and serum monocyte chemoattractant protein (MCP)-1 concentrations in women who received raloxifene were decreased significantly (p = 0.0003) at 12 months. In the control group, serum levels of MCP-1 and IL-7 did not show significant changes. There were significant differences (p = 0.032 and p = 0.0024, respectively) in percentage changes in IL-7 and MCP-1 in the control group and in the raloxifene group. Levels of low-density lipoprotein cholesterol (LDL-C) and E-selectin were decreased significantly in women who received raloxifene, but the percentage changes in LDL-C and E-selectin over a period of 12 months were not significantly correlated with percentage changes in IL-7 and MCP-1 over the same period. Conclusion: Circulating levels of IL-7 and MCP-1 decrease in postmenopausal women who received raloxifene. © 2008 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND: Environmental exposure to some persistent organic pollutants has been reported to be associated with metabolic syndrome in the U.S. population. OBJECTIVES: We evaluated the associations of body burden levels of dioxins and related compounds with the prevalence of metabolic syndrome among the general population in Japan. METHODS: We conducted a cross-sectional study with 1,374 participants not occupationally exposed to these pollutants, living throughout Japan during 2002-2006. In fasting blood samples, we measured biochemical factors and determined lipid-adjusted concentrations of 10 polychlorinated dibenzo-p-dioxins (PCDDs), 7 polychlorinated dibenzofurans (PCDFs), and 12 dioxin-like polychlorinated biphenyls (DL-PCBs) all of which have toxic equivalency factors. We also performed a questionnaire survey. RESULTS: The toxic equivalents (TEQs) of PCDDs, PCDFs, and DL-PCBs and total TEQs had significant adjusted associations with metabolic syndrome, whether or not we excluded diabetic subjects. By analyzing each component of metabolic syndrome separately, the DL-PCB TEQs and total TEQs were associated with all components, and the odds ratios (ORs) in the highest quartile of DL-PCB TEQs in four of the five components were higher than those for PCDDs or PCDFs. We also found congener-specific associations with metabolic syndrome; in particular, the highest quartiles of PCB-126 and PCB-105 had adjusted ORs of 9.1 and 7.3, respectively. compounds. CONCLUSIONS: These results suggest that body burden levels of dioxins and related particularly those of DL-PCBs, are associated with metabolic syndrome. Of the components, high blood pressure, elevated triglycerides, and glucose intolerance were most closely associated with these pollutants.

The objective of this study was to examine the effects of environmental cadmium (Cd) exposure on the gene expression profile of peripheral blood cells, using an original oligoDNA microarray. The study population consisted of 20 female residents in a Cd-polluted area (Cd-exposed group) and 20 female residents in a non-Cd-polluted area individually matched for age (control group). The mRNA levels in Cd-exposed subjects were compared with those in respective controls, using a microarray containing oligoDNA probes for 1867 genes. Median Cd concentrations in blood (3.55 mu g/l) and urine (8.25 mu g/g creatinine) from the Cd-exposed group were 2.4- and 1.9-times higher than those of the control group, respectively. Microarray analysis revealed that the Cd-exposed group significantly up-regulated 137 genes and down-regulated 80 genes, compared with the control group. The Ingenuity Pathway Analysis Application (IPA) revealed that differentially expressed genes were likely to modify oxidative stress and mitochondria-dependent apoptosis pathways. Among differentially expressed genes, the expression of five genes was positively correlated with Cd concentrations in blood or urine. Quantitative real-time PCR (RT-PCR) analysis validated the significant up-regulation of CASP9, TNFRSF1B, GPX3, HYOU1, SLC3A2, SLC19A1, SLC35A4 and ITGAL, and down-regulation of BCL2A1 and COX7B. After adjustment for differences in the background characteristics of the two groups, we finally identified seven Cd-responsive genes (CASP9, TNFRSF1B, GPX3, SLC3A2, ITGAL, BCL2A1, and COX7B), all of which constituted a network that controls oxidative stress response by IPA. These seven genes may be marker genes useful for the health risk assessment of chronic low level exposure to Cd. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Objective: The aim of the present study was to compare the effects on serum cytokine concentrations of paroxetine, a selective serotonin re-uptake inhibitor, and kamishoyosan, a Japanese traditional medicine, in midlife women with psychological symptoms. Methods: Seventy-six women with psychological symptoms such as anxiety and mild depression as menopausal symptoms were enrolled in this study. Thirty-eight women received oral administration of 10 mg paroxetine every day, and 38 women received oral administration of kamshoyosan every day for 6 months. Overall climacteric symptoms were assessed using Greene&apos;s climacteric scale. Serum levels of cytokines were measured using a multiplexed human cytokine assay. Results: Greene&apos;s total scores in both women treated with paroxetine and in women treated with kamishoyosan decreased significantly. Percentage decreases in Greene&apos;s total, psychological and vasomotor scores during the 6-month period in the paroxetine group were significantly greater than those in the kamishoyosan group. Serum IL-6 concentration in women treated with paroxetine decreased significantly. Serum concentrations of IL-8, IL-10, macrophage inflammatory protein (MIP)-1 beta and monocyte chemoattractant protein-1 in women treated with paroxetine decreased significantly. On the other hand, serum IL-6 concentration in women treated with kamishoyosan decreased significantly, but other serum concentrations did not change significantly. Conclusion: Decrease in IL-6 concentration may be involved in the mechanism of the actions of both paroxetine and kamishoyosan in women with psychological symptoms, and IL-6 may therefore be useful as a marker of treatment. The action of paroxetine may also be associated with decreases in IL-8, IL-10, MIP-1 beta. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Carbon tetrachloride (CCl4) is known to induce liver damage. Animal experiments with CCl4 injections have revealed many findings, especially mechanisms of liver damage and liver regeneration. Recently. proteomic approaches have been introduced in various studies to evaluate the quantitative and qualitative changes in the comprehensive proteome level. The aim of this research is to elucidate the key protein for liver damage, liver protection and liver regeneration by using proteomic techniques. 50% (V/V) CCl4 in corn oil was administered intraperitoneally to adult male rats at a dose of 4 ml/kg body weight. Approximately 24 h after the injection, the liver was removed and extracted proteins were analyzed with cleavable isotope coded affinity tag (cICAT) reagents, two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS). A twelvefold increase in D-dopachrome tautomerase (DDT) was indicated. This enzyme has been reported to be involved in the biosynthesis of melanin, an antioxidant. According to the histological analysis, melanin levels were increased in un-damaged hepatocytes of CCl4-treated rats. These results suggest that the increase in DDT is a response to liver damage, accelerates melanin biosynthesis and protects the liver from oxidative stress induced by CCl4. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

OBJECTIVE: The aim of the present study was to determine the effects of raloxifene on changes in circulating levels of cytokines and chemokines in relation to changes in lipid profiles and markers of inflammation in postmenopausal women. METHODS: Fifty-three postmenopausal women aged 45-65 years old were randomly assigned in open, parallel-group fashion to a control group or raloxifene group. Twenty-six women received oral administration of 60mg raloxifene every day and 27 women did not receive any drugs for 12 months. Serum cytokines levels were simultaneously measured using a multiplexed human cytokine assay. RESULTS: Serum IL-7 concentrations in women who received raloxifene were decreased significantly (p=0.014), and serum monocyte chemoattractant protein (MCP)-1 concentrations in women who received raloxifene were decreased significantly (p=0.0003) at 12 months. In the control group, serum levels of MCP-1 and IL-7 did not show significant changes. There were significant differences (p=0.032 and p=0.0024, respectively) in percentage changes in IL-7 and MCP-1 in the control group and in the raloxifene group. Levels of low-density lipoprotein cholesterol (LDL-C) and E-selectin were decreased significantly in women who received raloxifene, but the percentage changes in LDL-C and E-selectin over a period of 12 months were not significantly correlated with percentage changes in IL-7 and MCP-1 over the same period. CONCLUSION: Circulating levels of IL-7 and MCP-1 decrease in postmenopausal women who received raloxifene.

Background: The associations of endogenous estrogen with lipid profiles and insulin resistance were conflicting in both men and women. We determined the associations of serum estradiol level and free estradiol index (FEI) with lipid profiles and insulin resistance in aged Japanese men and women. Methods: One hundred seventy-four men and 208 postmenopausal women aged from 50 to 85 y were included in this study. Lipid profiles, fasting glucose and insulin as well as estradiol, testosterone, dehydroepiandrosterone-sulfate (DHEA-S) and sex hormone-binding globulin (SHBG) in serum were measured. Results: Serum estradiol concentration in men showed a significant and negative correlation with high density lipoprotein-cholesterol (HDL-C) concentration and a significant and positive correlation with triglyceride (TG) after adjustment for age and body mass index (BMI). In addition, estradiol level was positively correlated with insulin and HOMA index. In women, serum levels of estradiol and testosterone were not correlated with lipid profiles and insulin resistance. SHBG concentration was negatively correlated with TG after adjustment for age and BMI in women. Conclusion: Endogenous estradiol level is associated with unfavorable lipid profiles and insulin resistance in aged men. In aged women, SHBG level is associated with favorable lipid profiles. (C) 2008 Elsevier B.V. All rights reserved.

Dietary intake of dioxins was estimated by duplicate portion analysis of consecutive 3-day food samples among 86 men and 288 women (aged 17-72 years), who were living in 75 different areas of 25 prefectures in Japan. The mean (median) intake of PCDDs+PCDFs, coplanar PCBs (co-PCBs), and total dioxins, expressed on the basis of toxicity equivalents (TEQ), was 0.46 (0.34), 0.59 (0.39), and 1.06 (0.79) pg/kg body weight/day, respectively. Dietary intake was highest in fishing areas, followed by farming and urban areas. In multiple regression analysis, TEQs of PCDDs+PCDFs, co-PCBs, and total dioxins were positively associated with age and intake amount of fish and shellfish, and milk and dairy products, and negatively associated with survey year. There were significant positive correlations between dietary intake and blood levels for TEQs of PCDDs+PCDFs, co-PCBs, and total dioxins (Pearson r = 0.35-0.36). The proportion of those whose dietary intake exceeded the tolerable daily intake (TDI), set by the World Health Organization (4 pg TEQ/kg/day) and European Union (2 pg TEQ/kg/day), was estimated at 2.1% and 10.4%, respectively. However, these proportions were considered to be overestimated because of the effect of day-to-day within-person variation. Therefore, the ratio of within- and between-person variance was estimated by applying random effects one-way analysis of variance to repeated measurements for another group of 35 persons. When the effect of within-person variation of dietary intake was accounted for, the proportion of subjects whose long-term intake exceeded the TDI of WHO and EU decreased to 0.06% and 2.9%, respectively. (C) 2008 Elsevier Inc. All rights reserved.

The aim of this study was to evaluate the associations of environmental exposure to dioxins with diabetes among general inhabitants in Japan. A cross-sectional study was performed on 1374 participants, who were not occupationally exposed to dioxins, aged 15-73 years, living widely in 75 different residential areas of 25 prefectures in Japan through 2002-2006. Seven polychlorinated dibenzo-p-dioxins (PCDDs), 10 polychlorinated dibenzofurans (PCDFs), 12 dioxin-like polychlorinated biphenyls (PCBs), which are assigned a toxic equivalency factor, and biochemical factors were determined in fasting blood. A questionnaire survey on life-style including past history of diseases and treatments was also performed. We examined the associations of the accumulated toxic equivalents (TEQs) of PCDDs+PCDFs, dioxin-like PCBs and total dioxins with prevalent diabetes. Simple and partial correlation analyses revealed that HbA1c correlated with the accumulated TEQs of PCDDs+PCDFs, dioxin-like PCBs and total dioxins. In logistic regression analyses, the third and the highest quartiles of dioxin-like PCBs had adjusted odds ratios (ORs) of 3.07 (95% CI 1.16-8.81) and 6.82 (95% CI 2.59-20.1) compared to the reference (first plus second quartiles). On the other hand, the highest but not the third quartiles of PCDDs+PCDFs and total dioxins had significantly higher adjusted ORs compared to the respective references. These associations persisted when the subjects with poor liver or poor renal function were removed from the analysis. This recent representative data from general inhabitants in Japan showed associations of environmental exposure to dioxins, especially dioxin-like PCBs, with diabetes. (C) 2008 Elsevier Inc. All rights reserved.

Objective: The objective was to grasp the recent body burden levels of polychlorinated dibenzo-p-dioxin. (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (DL-PCBs) and to investigate their determinants among general inhabitants in Japan. This study was performed on 1374 participants aged 15-73 years, who were not occupational exposure to PCDDs/PCDFs and DL-PCBs, living widely in 75 different residential areas of 25 prefectures in Japan. Sever PCDDs, ten PCDFs, twelve DL-PCBs, which are assigned a toxicity equivalent factor, and biochemical factors were determined in fasting blood. A questionnaire survey on life-style was also performed. The median of total toxicity equivalent (TEQ) was 20 pg TEQ/g lipid. The TEQs of PCDDs/PCDFs, DL-PCBs and total TEQ increased with age. The intake frequency of fish-and-shellfish was positively associated with the TEQ of DL-PCBs in both sexes. Current smoking was negatively related to the TEQ of DL-PCBs in male subjects but not in female subjects. Feeding status was significantly related to the TEQs of PCDDs/PCDFs, DL-PCBs and total TEQ being lowest in breast feeding and highest in never and bottle feeding. According to the results of subgroup analysis, parity was not associated with the TEQs. The fish-and-shellfish consumption may contribute to the accumulation of DL-PCBs. and smoking may induce some biological action for the elimination of DL-PCBs from the human body. Breast feeding is considered to be one of the major excretory pathways of PCDDs/PCDFs and DL-PCBs in women, while parity may not largely contribute to the elimination of these pollutants. (c) 2008 Elsevier Ltd. All rights reserved.

Objective: The aim of the present study was to clarify the association of serum adiponectin concentrations with serum 17 beta-estradiol concentrations in pre-, peri-, and postmenopausal women. In addition, the associations of serum adiponectin with serum concentrations of proinflammatory and anti-inflammatory cytokines were examined in women during the menopausal transition. Design: A total of 197 women were enrolled in this study: 33 premenopausal women, 80 perimenopausal women, and 84 postmenopausal women. Serum adiponectin concentration was measured by an enzyme-linked immunosorbent assay. Serum concentrations of the proinflammatory cytokines interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha, anti-inflammatory cytokine IL-10, and the chemokines IL-8, macrophage inflammatory protein 1 beta and monocyte chemotactic protein-1 were measured by using a multiplexed human cytokine assay. Results: Serum adiponectin concentration showed a significant negative correlation with serum estradiol concentration (r = -0.400, P = 0.001) in postmenopausal women but not in pre- and perimenopausal women, and this correlation was significant after adjustment for age and body mass index. Serum adiponectin concentration also showed a significant negative correlation with serum monocyte chemotactic protein-1 concentration (r = -0.244, P = 0.05) in postmenopausal women. Conclusion: An increase in adiponectin level due to a decrease in estradiol results in a reduction in monocyte chemotactic protein-1 level in postmenopausal women, suggesting that adiponectin may be associated with a protective role against insulin resistance and atherosclerosis, which occur in the postmenopausal stage.

Objective: The aim of the present study was to determine the associations of interleukin (IL)-6 with other cytokines and chemokines and to compare these associations in peri- and postmenopausal women. Methods: Ninety-nine perimenopausal and 92 postmenopausal women were enrolled in this study. Serum concentrations of IL-6, IL-1 beta, IL-2, IL-4, IL-5, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, tumor necrosis factor (TNF)-alpha, interferon gamma, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, macrophage inflammatory protein (MIP)-1 beta and monocyte chemotactic protein (MCP)-1 were measured simultaneously using a multiplexed cytokine assay. Results: Among the 17 cytokines, IL-6, IL-1 beta, IL-5, IL-7, IL-8, IL-10, MCP-1 and MIP-1 beta were detected in serum in more than 50% of the women. Serum levels of IL-4 and MCP-1 in postmenopausal women were significantly higher than those in perimenopausal women. Serum IL-6 concentrations showed significant and positive correlations with serum concentrations of IL-1 beta, IL-8, MIP-1 beta, IL-7 and MCP-1 in women regardless of menopausal status, and these correlations were still significant after adjustment for age and body mass index. Conclusion: Serum IL-6 concentration was found to be closely associated with serum concentrations of IL-1 beta, IL-8, MIP-1 beta, IL-7 and MCP-1 in women regardless of menopausal status, suggesting that these cytokines act in concert with the progression of several symptoms and various diseases. (c) 2007 Elsevier Ltd. All rights reserved.

Objective: The aim of this study was to elucidate the detail profiles of circulating osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappa B ligand (sRANKL) in post-menopausal women. Methods: Eighty Japanese post-menopausal women were enrolled in this cross-sectional study. Circulating OPG and free fraction of sRANKL (free sRANKL), PTH, calcium and phosphorus, age, years since menopause, body mass index, bone mineral density of the vertebral bodies (LBMD) and bone turnover markers were determined in each subject. Results: In rank order correlation analysis, serum OPG concentrations had a significant positive correlation with age (r=0.291, p=0.024) and a marginal significant negative correlation with LBMD (r=-0.247, p=0.062). However they did not have correlations with LBMD or other parameters after adjustment for age. Serum free sRANKL concentrations had a significant positive correlation with age (r=0.332, p=0.010) and a significant negative correlation with LBMD (r=-0.608, p &lt; 0.001). This correlation with LBMD persisted after adjustment for age. In a multiple regression analysis with a stepwise model, the main determinants of LBMD were age and serum free sRANKL (p=0.015 and p=0.006, respectively). Conclusions: We found the increase in circulating OPG and sRANKL with age and a robust negative correlation between circulating free sRANKL and LBMD after adjustment for age. The increase in circulating free sRANKL may reflect directly or indirectly the conditions coexistent with bone loss in post-menopausal women.

OBJECTIVE: The aim of this study was to elucidate the detail profiles of circulating osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappaB ligand (sRANKL) in post-menopausal women. METHODS: Eighty Japanese post-menopausal women were enrolled in this cross-sectional study. Circulating OPG and free fraction of sRANKL (free sRANKL), PTH, calcium and phosphorus, age, years since menopause, body mass index, bone mineral density of the vertebral bodies (LBMD) and bone turnover markers were determined in each subject. RESULTS: In rank order correlation analysis, serum OPG concentrations had a significant positive correlation with age (r=0.291, p=0.024) and a marginal significant negative correlation with LBMD (r=-0.247, p=0.062). However they did not have correlations with LBMD or other parameters after adjustment for age. Serum free sRANKL concentrations had a significant positive correlation with age (r=0.332, p=0.010) and a significant negative correlation with LBMD (r=-0.608, p&lt;0.001). This correlation with LBMD persisted after adjustment for age. In a multiple regression analysis with a stepwise model, the main determinants of LBMD were age and serum free sRANKL (p=0.015 and p=0.006, respectively). CONCLUSIONS: We found the increase in circulating OPG and sRANKL with age and a robust negative correlation between circulating free sRANKL and LBMD after adjustment for age. The increase in circulating free sRANKL may reflect directly or indirectly the conditions coexistent with bone loss in post-menopausal women.

Objective: Osteoprotegerin (OPG), an inhibitor of osteoclastogenesis and osteoclast activation, has been reported to be linked to vascular biology. The aim of this study was to clarify the relationships between circulating OPG and the risk factors for vascular disorders in postmenopausal women. Design: Eighty Japanese postmenopausal women were enrolled in this cross-sectional study. Clinical parameters (age, number of years since menopause, body mass index, systolic and diastolic blood pressure); serum concentrations of OPG, creatinine, calcium, and phosphorus; serum lipid profile; plasma glucose; and bone mineral density of the L2-4 vertebral bodies were determined for each woman. Results: In rank-order correlation analysis, serum OPG concentrations had significant positive correlations with age (r = 0.29, P = 0.03), systolic blood pressure (r = 0.45, P &lt; 0.01), diastolic blood pressure (r = 0.34, P &lt; 0.01), and serum creatinine (r = 0.29, P = 0.04). Serum OPG concentration also had a marginally significant negative correlation with bone mineral density of the L2-4 vertebral bodies (r = -0.25, P = 0.06). However, serum OPG did not correlate with body mass index, serum lipid profile, or plasma glucose. The correlation of serum OPG with systolic blood pressure persisted after adjustment for both age and serum creatinine. Conclusions: These results suggest that increased circulating OPG in postmenopausal women is closely related to higher systolic blood pressure, which could cause atherosclerosis.

Background: Sensitivity to cold is associated with several factors, such as aging, sex, and body composition. However, no previous studies have examined the differences in sensitivity to cold in men and women or the association of hormonal levels with sensitivity to cold. Objective: The aim of the present study was to clarify both the change in sensitivity to cold with aging and the difference in sensitivity to cold between men and women. Associations were also examined between circulating hormonal concentrations and the changes with aging and differences in sensitivity. Methods: This population-based cohort study enrolled healthy Japanese men and women aged &gt;= 50 years. A standardized 210-item health questionnaire was used to obtain information on symptoms of sensitivity to cold. Serum concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), estradiol, testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin (SHBG) were measured. Results: Of the 154 men and 180 women enrolled in this study, more women than men had sensitivity to cold. Whereas the percentage of men who had sensitivity to cold significantly increased with aging (P &lt; 0.05), the percentage of women who had sensitivity to cold was already high (23.7%) at 50 to 60 years of age and did not change with aging. In men, advancing age and low body mass index (BMI) were significantly associated with sensitivity to cold (P &lt; 0.05); however, age and BMI in women were not similarly associated. In addition, the effect of sex after adjustment for age was significant (P &lt; 0.05), and there was also a numeric but nonsignificant effect of sex after adjustment for BMI. In men, low serum levels of the gonadal hormone FSH were significantly associated with sensitivity to cold in logistic analysis, but this association was nonsignificant after multivariate analysis. Serum concentrations of gonadal hormones and SHBG in women were not associated with sensitivity to cold. Conclusions: The association of age with sensitivity to cold was different in men and women; the association of BMI with sensitivity to cold might be different in men and women. In addition, these changes in sensitivity to cold were not associated with circulating hormonal concentrations. (Gend Med. 2007;4:359-366) Copyright (c) 2007 Excerpta Medica, Inc.

Background: Changes with aging in serum gonadal hormones, sex hormone-binding globulin (SHBG) and adiponectin, which are involved in insulin resistance and metabolic syndrome, are different in men and women. We examined the relationships of serum adiponectin concentrations with serum concentrations of hormones and SHBG in men and women. Methods: One hundred fifty-four men and 180 women aged from 50 to 85 years were included in the cross-sectional study. Serum concentrations of testosterone, estradiol, dehydroepiandrosterone-sulfate, SHBG and adiponectin were measured in men and women. Results: Serum adiponectin concentration showed a significant positive correlation with serum SHBG concentration in men and women (r = 0.404, p &lt; 0.0001 and r = 0.348, p &lt; 0.0001, respectively). Multiple regression analysis also showed that SHBG was the significant predictor for adiponectin in men and women. Serum adiponectin concentration in men showed a significant positive correlation with total testosterone concentration, but that in women was not significantly correlated with total testosterone concentration. Both adiponectin and SHBG concentrations in men (r = -0.222, p = 0.0051 and r = -0.334, p &lt; 0.0001, respectively) and women (r = -0.281, p = 0.0014 and r = -0.251, p = 0.0048, respectively) showed significant negative correlations with the homeostasis model assessment (HOMA) index. Conclusion: Correlations between adiponectin and SHBG were significantly positive in both men and women, and both adiponectin and SHBG might be involved in insulin resistance in both sexes. (C) 2007 Elsevier B.V. All rights reserved.

A longitudinal study was performed to investigate the associations of exposure to environmental cadmium (Cd) with cause-specific mortality and cancer incidence rates. The study population comprised 275 adults living in a Cd-polluted area, Nagasaki Prefecture, Japan. The follow-up period extended from 1982 to 2005 for the analysis of cancer mortality, and from 1985 to 2002 for the analysis of cancer incidence. In the study area, the daily Cd intake from foods had decreased after 1980-1983 because of the restoration of Cd-polluted rice fields. The mortality rate among those with urinary beta 2-microglobulin (U-beta 2M) &gt;= 1000 mu g/g creatinine was significantly higher than that of the Japanese population for death from causes other than cancer, but not for cancers (177 at the 95% confidence interval [CI] 94-303). From analysis within the Cd-polluted area, the age-adjusted rate ratio of cancer deaths associated with increased U-beta 2M was 2.58 (95% CI 1.25-5.36). The incidence rate of cancer among those with U-beta 2M &gt;= 1000 mu g/g creatinine was 1.38 (95% CI 0.69-2.47) times that of the regional reference rate. Within the Cd-polluted area, the age-adjusted rate ratio of developing cancer associated with high U-beta 2M was 1.79 (95% CI 0.84-3.82). In summary, there was a significant association between U-beta 2M excretion and cancer mortality. However, there was neither a significantly increased standardized incidence ratio of cancer, nor significant relationship between U-beta 2M and cancer incidence rate, though the point estimates were higher than unity. Continued follow-up and investigation of a larger cohort may be required before drawing a conclusion for the association between exposure to environmental Cd and cancer risk. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

Objective: The purpose of the present study was to clarify the association of serum cytokine concentrations, determined using a multiplexed cytokine assay, with psychological symptoms in midlife women. Methods: Fifty-three peri- and post-menopausal women with and without psychological symptoms in Greene's climacteric scale were enrolled in this study. Level, of 17 cytokines in serum samples were measured simultaneously using a multiplexed human cytokine assay. Results: Serum interleukin (IL)-6 concentration in women with psychological symptoms (2.71 +/- 047 pg/ml) was significantly (p = 0.009) higher than that in women without psychological symptoms (0.98 +/- 0.18 pg/ml). Serum IL-8 concentration in women with psychological symptoms(33.4 +/- 8.17 pg/ml) was also significantly (p = 0.048) higher than that in women without psychological symptoms (7.87 +/- 1.64 pg/ml), In addition, serum IL-10 concentration in women with psychological symptoms (0.74 +/- 0.26 pg/ml) was significantly (p = 0.048) higher than that in women without psychological symptoms (0.07 +/- 0.04 pg/ml). Tumor necrosis factor (TNF)-alpha in serum was detected only in women with psychological symptoms. Serum IL-2 concentration in women with psychological symptoms tended (p = 0.066) to be higher than that in women without psychological symptoms. No significant differences were found between levels of other cytokines in women with and without psychological symptoms. Conclusion: Psychological stress manifested as climacteric symptoms in midlife women may be associated with increases in serum concentrations of IL-6, IL-8, IL-10, and TNF-alpha. (c) 2007 Elsevier Ireland Ltd. All rights reserved.