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Several epidemiologic studies have investigated the circulating levels of albumin, bilirubin, and uric acid (UA) in relation to cancer risk; however, they have provided equivocal evidence. In this prospective case-cohort study, we measured the plasma levels of albumin, bilirubin, and UA and investigated their association with cancer incidence in 3584 case patients and 4270 randomly selected participants with a median follow-up of 15.8 years. The adjusted hazard ratios (HRs) and 95% CIs of total cancer for the highest quartile (Q4) versus lowest quartile (Q1) was 0.77 (95% CI, 0.67-0.90; P <.001 for trend) for albumin. This association was attenuated after excluding liver cancer cases with lower plasma albumin levels. Plasma bilirubin levels were positively related to liver cancer but inversely to total cancer after excluding liver cancer with, for Q4 versus Q1, an adjusted HR of 0.86 (95% CI, 0.74-0.99; P = .015 for trend). Plasma UA levels were not dose-responsively associated with total cancer risk. Higher plasma bilirubin levels were associated with a decreased risk of total cancer after excluding liver cancer, which is likely attributed to the antioxidant properties of bilirubin., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Epidemiological studies have shown inconsistent results regarding the link between smoking and breast cancer risk, despite the biological plausibility of a positive association., Methods: Participants were 166 611 women from nine prospective cohort studies in Japan which launched in 1984-1994 and followed for 8-22 years. Information on smoking and secondhand smoke was obtained through self-administered baseline questionnaires. Breast cancer was defined as code C50 according to the International Classification of Diseases for Oncology, 3rd Edition or the International Classification of Diseases, 10th Revision. After adjusting for several potential confounders, relative risks for breast cancer were calculated in the individual studies according to the current or previous status of active and passive smoking using Cox regression, followed by a summary estimate of hazard ratios using random-effects meta-analyses., Results: Of the 60 441 participants who reported being premenopausal and 106 170 who reported being postmenopausal at baseline, 897 and 1168 developed breast cancer during follow-up, respectively. Compared with never smokers, current smokers had a higher risk of developing breast cancer before the age of 50 years. In addition, ever smokers who started smoking at 30 years of age or younger, or who started smoking before first childbirth, had a higher risk of developing breast cancer before the age of 50 years. No association between adulthood or childhood exposure to secondhand smoke and breast cancer was observed., Conclusion: Smoking may increase the risk of premenopausal breast cancer, and smoking earlier in life might be especially harmful. The impact of secondhand smoke needs further investigation., (© The Author(s) 2024; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objectives: The validity of prognostic nutritional index (PNI) as an index of incident bone fragility fracture (inc-BFF) in rheumatoid arthritis (RA) patients was investigated., Methods: RA patients whom continuously followed up for >3 years were picked up. Patients were classified in accordance with inc-BFF positivity (BFF+ and BFF-). Their clinical background including PNI was statistically examined for inc-BFF. The background factors were compared between the two groups. Patients were narrowed into subgroups according to the factor that showed a significant difference between the two groups, and they were statistically examined according to the PNI for the inc-BFF. The two groups were narrowed with propensity score matching and compared to the PNI., Results: A total of 278 patients with 44 BFF+ and 234 BFF- were recruited. In the background factors, the presence of prevalent BFF and the simplified disease activity index remission rate had a significantly higher risk ratio. In a subgroup who comorbid lifestyle-related diseases, PNI had a significantly higher risk ratio for the inc-BFF. After the propensity score matching, the PNI showed no significant difference between the two groups., Conclusions: PNI is available when patients with RA comorbid lifestyle-related diseases. PNI is not an independent key for the inc-BFF in RA patients., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Recent studies have found that long-term changes in weight during adulthood are associated with a high risk of mortality. The objective of this study was to characterize body mass index (BMI) trajectories during adulthood and to examine the association between BMI trajectories and risk of death in the Japanese population., Methods: The data were extracted from Japan Public Health Center-based Prospective Study-a population-based prospective cohort study in Japan with participants aged 40-69 years followed over 20 years. The participants were categorized into multiple BMI trajectory groups using the latent class growth model. The Cox proportional-hazards model was conducted using all-cause mortality and cause-specific mortality as outcomes and the identified BMI trajectory groups as a predictor. In total, 65 520 participants were included in the analysis., Results: Six BMI trajectory groups were identified: underweight stable (Group 1), low-to-high normal (Group 2), high-to-low normal (Group 3), normal to overweight (Group 4), overweight to normal (Group 5) and normal to obese (Group 6). Our Cox models showed a higher hazard (risk) of all-cause mortality among participants in the BMI-declining groups [Group 3, adjusted hazard ratio (aHR): 1.10, 95% CI: 1.05-1.16; Group 5, aHR: 1.16, 95% CI: 1.08-1.26], underweight stable group (Group 1, aHR: 1.27, 95% CI: 1.21-1.33) and normal to obese group (Group 6, aHR: 1.22, 95% CI: 1.13-1.33) than Group 2 (low-to-high normal BMI trajectory)., Conclusions: Stable underweight and weight loss were associated with a high risk of mortality, both of which were uniquely observed in a Japanese population., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Some aquatic invertebrates contain free d-alanine. We previously showed copious amounts of free d-glutamate, a novel d-amino acid, in the tissue of the male reproductive organs of Marsupenaeus japonicus. Herein, we clarified the distribution and potential role of d-glutamate and d-alanine in male reproductive tissues, namely the testis, vas deferens and seminal receptacle at different growth stages of M. japonicus. The percentage of d-glutamate to total glutamate was over 50% in these tissues. In particular, the content of d-glutamate was the most abundant in the vas deferens, the ratio of d-glutamate to total glutamate was approximately 80%. In contrast, d-alanine content was the lowest in the vas deferens among these tissues. d-Glutamate content was the highest when the prawn weighed 12 g, indicating that d-glutamate is actively synthesized in the younger stage. Our findings suggest that d-glutamate plays an important role in the reproductive functions of M. japonicus., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Background: Although studies have found an association between chronic kidney disease (CKD) and cancer incidence, the results are inconsistent., Methods: This study included participants in the Japan Public Health Center-based Prospective Study who had data on serum creatinine measurements. We assessed the association between estimated glomerular filtration rate (eGFR) and the risk of total and site-specific cancer incidence using a systematic survey in Japan. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for participant demographics and lifestyle factors., Results: A total of 21 978 participants who met the inclusion criteria were followed up for a mean period of 12.9 years, during which a total of 2997 incident cancer cases were reported. In the multivariable adjusted models, an eGFR of <45 mL/min/1.73 m2 was not significantly associated with total cancer incidence (adjusted HR 1.22, 95% CI 0.94-1.60), compared with an eGFR of 60-89 mL/min/1.73 m2 (reference). The HR among those with eGFRs of ≥90 mL/min/1.73 m2 was 1.10 (95% CI 1.00-1.22)., Conclusions: In this large prospective study, a low eGFR was not significantly associated with an increased risk of total cancer incidence in patients with CKD, which may be partly due to an underpowered sample size. This finding may be due to the many shared risk factors between CKD and cancer., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: The association between body mass index (BMI) and oesophageal cancer (OC) has been consistently negative among Asians, whereas different associations based on histological OC subtypes have been observed in Europeans and North Americans. We examined the association between BMI and OC mortality in the Asia Cohort Consortium., Methods: We performed a pooled analysis to evaluate the association between BMI and OC mortality among 842 630 Asians from 18 cohort studies. Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs., Results: A wide J-shaped association between BMI and overall OC mortality was observed. The OC mortality risk was increased for underweight (BMI <18.5 kg/m2: HR = 2.20, 95% CI 1.80-2.70) and extreme obesity (BMI ≥35 kg/m2: HR = 4.38, 95% CI 2.25-8.52) relative to the reference BMI (23-25 kg/m2). This association pattern was confirmed by several alternative analyses based on OC incidence and meta-analysis. A similar wide J-shaped association was observed in oesophageal squamous cell carcinoma (OSCC). Smoking and alcohol synergistically increased the OC mortality risk in underweight participants (HR = 6.96, 95% CI 4.54-10.67) relative to that in reference BMI participants not exposed to smoking and alcohol., Conclusion: Extreme obesity and being underweight were associated with an OC mortality risk among Asians. OC mortality and BMI formed a wide J-shaped association mirrored by OSCC mortality. Although the effect of BMI on OSCC and oesophageal adenocarcinoma mortality can be different in Asians, further research based on a large case-control study is recommended., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Increasing proportions of smokers in Japan smoke <10 cigarettes per day (CPD). Yet, the health risks of low-intensity smoking in Asia are poorly understood., Methods: We performed a pooled analysis of 410 294 adults from nine population-based prospective cohort studies participating in the Japan Cohort Consortium. Cigarette-use data were collected at each study baseline in 1983-1994. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality were calculated using multivariable-adjusted Cox regression by CPD among current smokers and by age at cessation among former smokers, with never smokers as the referent group. Pooled HRs and CIs were computed using a random-effect model., Results: The smoking prevalence was 54.5% in men and 7.4% in women. About 15.5% of male and 50.4% of female current smokers smoked 1-10 CPD (low-intensity). Both male and female low-intensity smokers had higher all-cause mortality risks than never smokers. Risks were further higher with increasing CPD in a dose-response manner. HRs (95% CIs) were 1.27 (0.97-1.66), 1.45 (1.33-1.59) and 1.49 (1.38-1.62) for 1-2, 3-5 and 6-10 CPD, respectively, in men; 1.28 (1.01-1.62), 1.49 (1.34-1.66) and 1.68 (1.55-1.81) for 1-2, 3-5 and 6-10 CPD, respectively, in women. Similar associations were observed for smoking-related causes of death. Among former low-intensity smokers, younger age at cessation was associated with lower mortality risk., Conclusions: Smoking very low amounts was associated with increased mortality risks in Japan. All smokers should quit, even if they smoke very few CPD., (Published by Oxford University Press on behalf of the International Epidemiological Association 2021. This work is written by US Government employees and is in the public domain in the US.)

Background: Several epidemiological studies have been conducted to draw consistent conclusions regarding the effect of dietary fibre on lung diseases and lung cancer. However, the effect of dietary fibre on the incidence of lung cancer remains unclear in an Asian population., Methods: We investigated the association between the intake of total dietary fibre and dietary fibre from different food sources and lung cancer incidence in a Japan public health centre-based prospective study (JPHC). A total of 73 405 participants (33 012 men and 40 393 women) aged 45-74 years were eligible for our study. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: During a median follow-up of 18.0 years, 1546 (1042 men and 504 women) newly diagnosed cases of lung cancer were ascertained. In the multivariable models, total dietary fibre intake was inversely associated with lung cancer risk in men, the HRs Q5 vs Q1 (95% CI) were 0.77 (0.62 to 0.94), P-trend = 0.020. Dietary fibre intake from vegetables was protectively associated with lung cancer risk in men [HR Q5 vs Q1 (95% CI): 0.80 (0.64 to 0.99), P-trend = 0.053]. However, no such association was observed in women., Conclusions: In men, a high intake of total dietary fibre may have preventive benefits for lung cancer incidence: dietary fibre intake from vegetables was associated with a lower incidence of lung cancer. However, similar associations did not appear in women. Further investigations are required to confirm the association between dietary fibre and lung cancer risk in women., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between coffee and tea consumption and mortality in Asian populations., Methods: We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model., Results: In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% [95% confidence interval (CI) 17%, 29%] and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption., Conclusions: In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objective: The association between adult-attained height and risk of colorectal cancer remains elusive among the Japanese population. We performed a systematic review and meta-analysis of epidemiological studies in Japan., Methods: We systematically searched the MEDLINE (PubMed) and Ichushi databases and complemented it with manual search to identify eligible studies. We extracted relative risks or odds ratios from the selected studies and conducted meta-analysis to estimate the summary relative risk with 95% confidence interval. We made the final judgment based on a consensus of the research group members considering both epidemiological evidence and biological plausibility., Results: This systematic review identified four cohort and one case-control studies among the Japanese. The meta-analysis of these five studies showed the summary relative risk of 1.21 (95% confidence interval: 1.07-1.35) of overall colorectal cancer for the highest vs. lowest categories of height. In the analysis by the cancer subsite, the association was significant for colon cancer with a summary relative risk of 1.26 (95% confidence interval: 1.10-1.45) but not for rectal cancer 1.05 (95% confidence interval: 0.71-1.54). In the analysis by sex, tall stature was associated with a significantly increased risk of overall colorectal cancer in both sexes; the summary relative risk was 1.21 (95% confidence interval: 1.04-1.41) in men and 1.20 (95% confidence interval: 1.00-1.44) in women, respectively., Conclusions: The evidence to support that adult-attained height is associated with increased risk of colorectal cancer (colon cancer) among the Japanese population is 'probable'., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In Japan, there are ongoing efforts to shift the gastric cancer prevention and control policy priorities from barium-based screening to Helicobacter pylori (H. pylori)-oriented primary prevention. A comprehensive summary of the evidence regarding the effects of H. pylori eradication on the risk of gastric cancer could inform policy decisions., Methods: We conducted a systematic review and meta-analysis of published studies evaluating the effectiveness of H. pylori eradication for the prevention of gastric cancer in otherwise healthy individuals (primary prevention) and early gastric cancer patients (tertiary prevention)., Results: In total, 19 studies were included. Three moderate-quality observational cohort studies showed that H. pylori eradication may be associated with a decreased risk of gastric cancer in healthy asymptomatic Japanese people. There is moderate certainty regarding the effectiveness of H. pylori eradication in patients with gastrointestinal diseases, such as peptic ulcers. A meta-analysis of 10 observational studies with otherwise healthy individuals (mainly peptic ulcer patients) yielded an overall odds ratio of 0.34 (95% CI: 0.25-0.46). Regarding tertiary prevention, the overall odds ratio for developing metachronous gastric cancer was 0.42 (95% CI: 0.35-0.51) in the eradication group in a meta-analysis of nine studies involving early gastric cancer patients who underwent endoscopic resection., Conclusion: H. pylori eradication is effective in preventing gastric cancer in the Japanese population, regardless of symptoms. Well-designed, large cohort studies are warranted to determine the long-term efficacy and safety of H. pylori eradication in the context of reducing the gastric cancer burden through population-based screening and treatment., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Increased arterial stiffness is one of the key mechanisms of heart failure with preserved ejection fraction (HFpEF). However, the possible association between arterial stiffness and subclinical left ventricular (LV) dysfunction and its sex-specific difference remains unclarified. LV strain is emerging as a highly sensitive tool to unmask early LV abnormalities., Methods and Results: We examined 1155 participants free of overt cardiovascular disease who underwent extensive cardiovascular examination. Speckle-tracking echocardiography was employed to assess LV global longitudinal strain (LVGLS) and circumferential strain (GCS), and arterial stiffness was assessed by cardio-ankle vascular index (CAVI). Mean age was 62 ± 12 years, and 56% were men. CAVI as continuous variable was associated with abnormal LVGLS (>-18.6%) independent of cardiovascular risk factors and echocardiographic parameters [adjusted odds ratio (OR) 1.23, P = 0.027] but not with LVGCS. In sex-stratified analysis, more pronounced association between quartiles of CAVI and abnormal LVGLS was observed in women than in men (unadjusted OR = 6.43 in women and 2.46 in men for upper quartile vs. lower quartile; both P < 0.01). CAVI was significantly associated with abnormal LVGLS independent of cardiovascular risk factors in both sexes. However, after further adjustment for LV mass index and diastolic parameters, the independent association persisted only in women (adjusted OR 1.67, P = 0.007), but not in men (adjusted OR 1.14, P = 0.227)., Conclusion: Increased arterial stiffness was independently associated with decreased LVGLS even without overt cardiovascular disease; a sex-specific pattern exists in the alteration of vascular-ventricular coupling, which might partially explain the greater susceptibility to HFpEF in women., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Purpose: Although subclinical hypothyroidism (SCH) is a common clinical entity and carries independent risk for incident heart failure (HF), its possible association with subclinical cardiac dysfunction is unclear. Left ventricular global longitudinal strain (LVGLS) and left atrial (LA) phasic strain can unmask subclinical left heart abnormalities and are excellent predictors for HF. This study aimed to investigate the association between the presence of SCH and subclinical left heart dysfunction in a sample of the general population without overt cardiac disease., Methods: We examined 1078 participants who voluntarily underwent extensive cardiovascular health check-ups, including laboratory tests and 2-dimensional speckle-tracking echocardiography to assess LVGLS and LA reservoir, conduit, and pump strain. SCH was defined as an elevated serum thyroid-stimulating hormone level with normal concentration of free thyroxine., Results: Mean age was 62 ± 12 years, and 56% were men. Seventy-eight (7.2%) participants exhibited SCH. Individuals with SCH had significantly reduced LA reservoir (37.1 ± 6.6% vs 39.1 ± 6.6%; P = 0.011) and conduit strain (17.3 ± 6.3% vs 19.3 ± 6.6%; P = 0.012) compared with those with euthyroidism, whereas there was no significant difference in left ventricular ejection fraction, LA volume index, LVGLS, and LA pump strain between the 2 groups. In multivariable analyses, SCH remained associated with impaired LA reservoir strain, independent of age, traditional cardiovascular risk factors, and pertinent laboratory and echocardiographic parameters. including LVGLS (standardized β -0.054; P = 0.032)., Conclusions: In an unselected community-based cohort, individuals with SCH had significantly impaired LA phasic function. This association may be involved in the higher incidence of HF in subjects with SCH., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Obesity carries significant risk for unfavorable ventricular remodeling and subsequent heart failure (HF) development, although the association between abdominal fat distribution and subclinical ventricular dysfunction is unclear. This study aimed to compare the subcutaneous and visceral abdominal adiposity with the risk of decreased ventricular strain., Methods: We included 340 participants without overt cardiac disease who underwent laboratory testing, abdominal computed tomographic examination, and speckle-tracking echocardiography. Abdominal adiposity was quantitatively assessed as visceral fat area (VFA) and subcutaneous fat area (SFA) at the level of the umbilicus. Speckle-tracking echocardiography was performed to assess left ventricular global longitudinal strain (LVGLS) and right ventricular free-wall longitudinal strain (RVLS)., Results: Mean age was 56 ± 9 years, and 244 of the participants (72%) were male. The mean LVGLS and RVLS were -19.1 ± 3.0% and -25.0 ± 4.1%, respectively. Both VFA and SFA correlated with LVGLS ( r  = 0.46 and r  = 0.15, both p  < 0.01) and RVLS ( r  = 0.38 and r  = 0.12, both p  < 0.05), demonstrating a stronger correlation between VFA and ventricular strain. Multivariable analysis showed that VFA was significantly associated with LVGLS and RVLS, independent of traditional cardiovascular risk factors as well as pertinent laboratory and echocardiographic parameters (both p  < 0.05), whereas SFA was not. Serum adiponectin level was correlated with LVGLS ( r  = -0.34, p  < 0.001) and RVLS ( r  = -0.25, p  < 0.001), although it lost statistical significance following multivariable adjustment., Conclusion: In a sample of the general population, VFA, but not SFA, accumulation was significantly associated with decreased LV and RV strain, an association that may be involved in the increased risk of HF in obese individuals.

Rhodococcus equi emerged as a zoonotic pathogen of human immunodeficiency virus-infected patients over the last three decades. Two virulence plasmid types of R. equi, pVAPA and pVAPB associated with equine and porcine isolates, have been recognized, and more recently, pVAPN, a novel host-associated virulence plasmid in R. equi, was found in bovine and caprine isolates. We reinvestigated 39 previously reported isolates of R. equi from patients with and without acquired immunodeficiency syndrome (AIDS) by detecting vapA, vapB and vapN using PCR and plasmid profiling. After excluding one isolate that could not be cultured from frozen storage, eight isolates carried a virulence plasmid encoding vapA (pVAPA), 10 carried a virulence plasmid encoding vapB (pVAPB), seven carried a virulence plasmid encoding vapN (pVAPN) and 13 were negative for those genes. Of the 29 isolates from patients with AIDS, 7, 10 and 5 harboured pVAPA, pVAPB and pVAPN respectively. Among nine isolates from patients without AIDS, one and two harboured pVAPA and pVAPN respectively. This study demonstrated that pVAPN-positive R. equi existed in human isolates before 1994 and reaffirmed that equine-associated pVAPA-positive, porcine-associated pVAPB-positive and bovine- or caprine-associated pVAPN-positive R. equi are widely spread globally. Because domestic animals might be major sources of human infection, further research is needed to reveal the prevalence of pVAPN-positive R. equi infection in cattle and goats., (© 2020 The Society for Applied Microbiology.)

Background: Although many epidemiological studies have reported the preventive effects of soy products and isoflavones on prostate cancer, our previous studies reported that the association between soy and isoflavones and prostate cancer incidence differed according to stage. It is more important to identify modifiable risk factors related to lethal prostate cancer. Here, we investigated the association between soy, soy products and isoflavones intake and prostate cancer mortality, in a prospective study in Japan., Methods: We conducted a population-based prospective study in 43 580 Japanese men with no history of cancer or cardiovascular disease (aged 45-74 years). Participants completed a validated questionnaire which included 138 food items. We followed participants from 1995 to 2016. Hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer mortality were calculated according to quintiles of soy products and isoflavones intake, using Cox hazard proportional hazards regression., Results: During 16.9 years follow-up, we registered 221 deaths from prostate cancer. Isoflavones and soy products intake was associated with an increased risk of prostate cancer death, with multivariate HRQ5 vs. Q1=1.39, 95% CI = 0.87-2.20, p for trend = 0.04 for isoflavones and multivariate HRQ5 vs. Q1=1.76, 95% CI = 1.10-2.82, p for trend = 0.04 for soy food., Conclusions: Our study suggested that high intake of soy and isoflavones might increase the risk of prostate cancer mortality., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Excess body weight is an established cause of postmenopausal breast cancer, but it is unknown if weight loss reduces risk., Methods: Associations between weight change and risk of breast cancer were examined among women aged 50 years and older in the Pooling Project of Prospective Studies of Diet and Cancer. In 10 cohorts, weight assessed on three surveys was used to examine weight change patterns over approximately 10 years (interval 1 median = 5.2 years; interval 2 median = 4.0 years). Sustained weight loss was defined as no less than 2 kg lost in interval 1 that was not regained in interval 2. Among 180 885 women, 6930 invasive breast cancers were identified during follow-up., Results: Compared with women with stable weight (±2 kg), women with sustained weight loss had a lower risk of breast cancer. This risk reduction was linear and specific to women not using postmenopausal hormones (>2-4.5 kg lost: hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70 to 0.96; >4.5-<9 kg lost: HR = 0.75, 95% CI = 0.63 to 0.90; ≥9 kg lost: HR = 0.68, 95% CI = 0.50 to 0.93). Women who lost at least 9 kg and gained back some (but not all) of it were also at a lower risk of breast cancer. Other patterns of weight loss and gain over the two intervals had a similar risk of breast cancer to women with stable weight., Conclusions: These results suggest that sustained weight loss, even modest amounts, is associated with lower breast cancer risk for women aged 50 years and older. Breast cancer prevention may be a strong weight-loss motivator for the two-thirds of American women who are overweight or obese., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear., Methods: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided., Results: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers., Conclusions: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract., (Published by Oxford University Press 2019. This work is written by US Government employees and is in the public domain in the United States.)

Background: Coffee and green tea, two popular drinks in the Japanese, have recently drawn much attention as potential protective factors against the occurrence of liver cancer., Methods: We systematically reviewed epidemiologic studies on coffee, green tea and liver cancer among Japanese populations. Original data were obtained by searching the MEDLINE (PubMed) and Ichushi databases, complemented with manual searches. The evaluation was performed in terms of the magnitude of association in each study and the strength of evidence ('convincing', 'probable', 'possible', or 'insufficient'), together with biological plausibility., Results: We identified four cohort and four case-control studies on coffee and liver cancer and six cohort and one case-control studies on green tea and liver cancer. All cohort and case-control studies on coffee reported a weak to strong inverse association, with a summary relative risk (RR) for one cup increase being 0.72 (95% confidence interval [CI] 0.66-0.79). Conversely, all studies but two cohort studies on green tea reported no association, with a corresponding summary RR of 0.99 (95% CI 0.97-1.01, P = 0.37)., Conclusion: Coffee drinking 'probably' decreases the risk of primary liver cancer among the Japanese population whereas the evidence on an association between green tea and liver cancer is 'insufficient' in this population., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 have been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31 230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (p-value < 5.0 × 10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5140 Japanese individuals (p-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2. Our study has confirmed that a functional ALDH2 variant, rs671, most strongly influences on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Background: There is a body of evidence to suggest that cigarette smoking increases the risk of cervical cancer in women, but no study has examined the magnitude of the association in Japanese women. Here, we evaluated the association between cigarette smoking and the risk of cervical cancer in Japanese women based on a systematic review of epidemiological evidence., Methods: Original data were obtained from a MEDLINE search using PubMed or from a search of the 'Ichushi' database, as well as by a manual search. Evaluation of associations was based on the strength of evidence and the magnitude of association, together with biological plausibility as evaluated previously by the International Agency for Research on Cancer. Meta-analysis of associations was also conducted to obtain a summarized overview of the data., Results: We identified two cohort studies and three case-control studies. All five studies had indicated strong positive associations between cigarette smoking and the risk of cervical cancer. Our summary estimate indicated that the relative risk (RR) for individuals who had ever-smoked relative to never-smokers was 2.03 (95% confidence interval: 1.49-2.57). Four studies had also demonstrated dose-response relationships between cigarette smoking and the risk of cervical cancer., Conclusion: We conclude that there is convincing evidence that cigarette smoking increases the risk of cervical cancer among Japanese women.

Background: The obesity-lung cancer association remains controversial. Concerns over confounding by smoking and reverse causation persist. The influence of obesity type and effect modifications by race/ethnicity and tumor histology are largely unexplored., Methods: We examined associations of body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR) with lung cancer risk among 1.6 million Americans, Europeans, and Asians. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. Analyses for WC/WHR were further adjusted for BMI. The joint effect of BMI and WC/WHR was also evaluated., Results: During an average 12-year follow-up, 23 732 incident lung cancer cases were identified. While BMI was generally associated with a decreased risk, WC and WHR were associated with increased risk after controlling for BMI. These associations were seen 10 years before diagnosis in smokers and never smokers, were strongest among blacks, and varied by histological type. After excluding the first five years of follow-up, hazard ratios per 5 kg/m2 increase in BMI were 0.95 (95% CI = 0.90 to 1.00), 0.92 (95% CI = 0.89 to 0.95), and 0.89 (95% CI = 0.86 to 0.91) in never, former, and current smokers, and 0.86 (95% CI = 0.84 to 0.89), 0.94 (95% CI = 0.90 to 0.99), and 1.09 (95% CI = 1.03 to 1.15) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Hazard ratios per 10 cm increase in WC were 1.09 (95% CI = 1.00 to 1.18), 1.12 (95% CI = 1.07 to 1.17), and 1.11 (95% CI = 1.07 to 1.16) in never, former, and current smokers, and 1.06 (95% CI = 1.01 to 1.12), 1.20 (95% CI = 1.12 to 1.29), and 1.13 (95% CI = 1.04 to 1.23) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Participants with BMIs of less than 25 kg/m2 but high WC had a 40% higher risk (HR = 1.40, 95% CI = 1.26 to 1.56) than those with BMIs of 25 kg/m2 or greater but normal/moderate WC., Conclusions: The inverse BMI-lung cancer association is not entirely due to smoking and reverse causation. Central obesity, particularly concurrent with low BMI, may help identify high-risk populations for lung cancer.

Background: Most previous studies evaluating the association between leisure-time physical activity (LTPA) and risk of death were conducted among generally healthy individuals of European ancestry. We investigated the association of LTPA with all-cause and cause-specific mortality among East Asian populations, including healthy individuals and those with existing chronic diseases, which has been less well characterized., Methods: We performed pooled analyses among 467 729 East Asian individuals recruited in nine prospective cohorts included in the Asia Cohort Consortium. Cox proportional hazards regressions were used to derive hazard ratios (HRs) and 95% confidence intervals (CIs) associated with LTPA after adjusting for age, sex, education and marital and smoking status., Results: During a mean follow-up period of 13.6 years, 65 858 deaths were identified. Compared with those who reported no or less than 1 h of LTPA per week, an inverse association was observed between the amount of LTPA and all-cause and cause-specific mortality (P for trend < 0.001). The strength of the inverse association was stronger for death due to cardiovascular diseases and causes other than cancer deaths. An inverse association of LTPA with total mortality was observed among individuals with a severe and often life-threatening disease: cancer, stroke or coronary heart disease [hazard ratio (HR) = 0.81, 95% CI = 0.73-0.89 for high vs low LTPA) and those with other chronic diseases such as diabetes or hypertension (HR = 0.86, 95% CI = 0.80-0.93 for high vs low LTPA). No clear modifying effects by sex, body mass index or smoking status were identified., Conclusions: Regular participation in LTPA is associated with reduced mortality in middle-aged and elder Asians regardless pre-existing health conditions., (© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

A comprehensive evidence-based cancer prevention recommendation for Japanese was developed. We evaluated the magnitude of the associations of lifestyle factors and infection with cancer through a systematic review of the literature, meta-analysis of published data, and pooled analysis of cohort studies in Japan. Then, we judged the strength of evidence based on the consistency of the associations between exposure and cancer and biological plausibility. Important factors were extracted and summarized as an evidence-based, current cancer prevention recommendation: 'Cancer Prevention Recommendation for Japanese'. The recommendation addresses six important domains related to exposure and cancer, including smoking, alcohol drinking, diet, physical activity, body weight and infection. The next step should focus on the development of effective behavior modification programs and their implementation and dissemination.

Autologous endothelial progenitor cell (EPC) therapy is commonly used to stimulate angiogenesis in ischemic repair and wound healing. However, low total numbers and functional deficits of EPCs make autologous EPC therapy ineffective in diabetes. Currently, no known ex vivo culture techniques can expand and/or ameliorate the functional deficits of EPCs for clinical usage. Recently, we showed that a quality-quantity culture (QQc) system restores the vasculogenic and wound-healing efficacy of murine diabetic EPCs. To validate these results and elucidate the mechanism in a translational study, we evaluated the efficacy of this QQc system to restore the vasculogenic potential of diabetic human peripheral blood (PB) CD34+ cells. CD34+ cells purified from PB of diabetic and healthy patients were subjected to QQc. Gene expression, vascular regeneration, and expression of cytokines and paracrine mediators were analyzed. Pre- or post-QQc diabetic human PB-CD34+ cells were transplanted into wounded BALB/c nude mice and streptozotocin-induced diabetic mice to assess functional efficacy. Post-QQc diabetic human PB-CD34+ cell therapy significantly accelerated wound closure, re-epithelialization, and angiogenesis. The higher therapeutic efficacy of post-QQc diabetic human PB-CD34+ cells was attributed to increased differentiation ability of diabetic CD34+ cells, direct vasculogenesis, and enhanced expression of angiogenic factors and wound-healing genes. Thus, QQc can significantly enhance the therapeutic efficacy of human PB-CD34+ cells in diabetic wounds, overcoming the inherent limitation of autologous cell therapy in diabetic patients, and could be useful for treatment of not only wounds but also other ischemic diseases. Stem Cells Translational Medicine 2018;7:428-438., (© 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Objectives: We aimed to investigate the frequency of moderate-to-severe sleep apnea syndrome (SAS) that possibly influences long-term prognosis in patients with rheumatoid arthritis (RA), and to analyze the risk factors for this group., Methods: We examined respiratory disturbance index (RDI) by polysomnography in 62 hospitalized RA patients. Risk factors of moderate-to-severe SAS (RDI ≥20) were analyzed using a multivariate logistic regression analysis., Results: RA was complicated by moderate-to-severe SAS in 13/62 (20.9%) cases. The highest stage of temporomandibular joint abnormality (TMJA) and a high value of health assessment questionnaire-disability index (HAQ-DI) were significant risk factors, according to the results of the multivariate logistic regression analysis (p < 0.0001 and p = 0.010, respectively). Contrary to these results, RDI was not related to the disease activity indexes of RA and other clinical characteristics., Conclusion: We clarified that the highest TMJA stage and a high value of HAQ-DI are novel important risk factors for moderate-to-severe SAS in RA patients.

Objective: It remains unclear whether coffee drinking is associated with colorectal cancer risk. We performed a systematic review and meta-analysis of epidemiologic studies on this issue among the Japanese population., Methods: Original data were obtained from MEDLINE searches using PubMed or from searches of the 'Ichushi' database, complemented with manual searches. Meta-analysis was performed by using the random effects model to estimate the summary relative risk with 95% confidence interval according to the study design. The final judgment was made based on a consensus of the research group members with consideration for both epidemiological evidence and biological plausibility., Results: We identified five cohort studies and nine case-control studies. Of these, one cohort study reported a strong inverse association (in women only), whereas three case-control studies reported a strong inverse association with colon or rectal cancer. In meta-analysis, high consumption of coffee was not appreciably associated with colorectal cancer risk among cohort studies, whereas it was associated with significantly lower risk of colorectal or colon cancer among case-control studies. The summary relative risk/odds ratio (95% confidence interval) for the highest versus lowest categories of coffee consumption was 0.95 (0.77-1.17) and 0.78 (0.65-0.95) for cohort and case-control studies, respectively., Conclusions: The evidence is insufficient to support that coffee drinking increases or decreases the risk of colorectal cancer among the Japanese population., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Although cigarette smoking is a well-established risk factor for head and neck cancer, the impact of smoking on head and neck cancer might vary among geographic areas. To date, however, no systematic review of cigarette smoking and head and neck cancer in the Japanese population has yet appeared., Methods: We conducted a systematic review of previous epidemiological studies for cigarette smoking and head and neck cancer among Japanese. Evaluation of associations was based on the strength of evidence ('convincing', 'probable', 'possible' or 'insufficient') and the magnitude of association ('strong', 'moderate', 'weak' or 'no association'), together with biological plausibility as previously evaluated by the International Agency for Research on Cancer. A meta-analysis was conducted to obtain summary estimates for the overall magnitude of association., Results: We identified five cohort studies and 12 case-control studies. Four of five cohort studies and 11 of 12 case-control studies showed a strong positive association between cigarette smoking and head and neck cancer. Nine of 12 studies indicated a dose-response relationship between cigarette smoking and the risk of head and neck cancer. Meta-analysis of 12 studies indicated that the summary relative risk for ever smokers relative to never smokers was 2.43 (95% confidence interval: 2.09-2.83). Summary relative risks for current and former smokers relative to never smokers were 2.68 (2.08-3.44) and 1.49 (1.05-2.11), respectively., Conclusions: Cigarette smoking is a convincing risk factor for head and neck cancer in the Japanese population., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort., Methods and Results: The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000-04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50-79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality.The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73-1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55-0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64-0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01-4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07-11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03-1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40-0.99), respectively., Conclusion: An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Objective: Although several epidemiological studies have demonstrated that cigarette smoking is an important risk factor for bladder cancer, no systematic review in the Japanese population has yet been performed. Accurate evaluation of bladder cancer risk in relation to smoking for Japanese populations can provide necessary information for Japanese policy-makers and doctors to enlighten the importance of smoking cessation. We reviewed epidemiologic data to estimate the strength of the association between cigarette smoking and bladder cancer in the Japanese population., Methods: We identified previous cohort and case-control studies, extracting data from databases in the MEDLINE (PubMed) and Ichushi. The magnitude of association and strength of evidence were evaluated in each study, and a meta-analysis was conducted to obtain summary estimates for the overall magnitude of association., Results: Three cohort and eight case-control studies were identified. Except for one case-control study, all studies showed a strong positive association between cigarette smoking and bladder cancer. The summary relative risk for ever smokers relative to never smokers was 2.14 (95% confidence interval 1.87-2.44) in a fixed-effect model., Conclusions: We conclude that cigarette smoking is a convincing risk factor for bladder cancer among Japanese., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Arterial occlusive disease is the leading cause of erectile dysfunction (ED). Using an established rat model we wanted to characterize the changes caused by atherosclerosis-induced chronic ischemia on penile structures and erectile function., Aim: To investigate the effect of melatonin on these parameters., Methods: Adult male Sprague-Dawley rats were divided into control, arterial injury (AI) and AI with melatonin treatment groups. AI and AI-melatonin groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI surgery for 8 weeks. AI-melatonin group rats received melatonin (20 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, erectile function was tested. Corpus cavernosum (CC) tissues were processed for pharmacological and immunohistochemical studies, histological examination, and Western blotting., Main Outcome Measures: Apomorphine test was performed to evaluate erectile function. Organ bath study was performed to measure the CC-contraction induced by KCl and phenylephrine, and relaxation induced by electrical field stimulation (EFS) and sodium nitroprusside (SNP)., Results: The number of erectile responses was significantly lower in the AI group (2.5 ± 0.5/hour) than in the control (5.0 ± 0.7/hour) and in the melatonin-treated groups (5.0 ± 0.3/hour). The responses to phenylephrine were lower in the AI-groups than in the controls, but there were no differences between control and AI-melatonin groups. SNP-induced relaxation in the AI-melatonin group was higher than in the AI, but lower than in control group. The EFS-elicited relaxation responses in the AI group were significantly lower than in the control and AI-melatonin groups. Compared to controls, CC tissues from the AI group showed significantly higher collagen content, and lower protein expression of eNOS and nNOS, and increased expression of iNOS. These changes were reduced or prevented by melatonin treatment., Conclusion: Treatment with melatonin reduced/prevented functional and morphological changes induced by chronic ischemia on penile structure and function., (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Leucine is known to increase mTOR-mediated phosphorylation of 4EBP. In this study, leucine was administered to skeletal muscle-PGC-1α knockout mice. We observed attenuated 4EBP phosphorylation in the skeletal muscle, but not in the liver, of the PGC-1α knockout mice. These data suggest that skeletal muscle-PGC-1α is important for leucine-mediated mTOR activation and protein biosynthesis.

Many potentially modifiable risk factors for prostate cancer are also associated with prostate cancer screening, which may induce a bias in epidemiologic studies. We investigated the associations of body mass index (weight (kg)/height (m)(2)), smoking, and alcohol consumption with risk of fatal prostate cancer in Asian countries where prostate cancer screening is not widely utilized. Analysis included 18 prospective cohort studies conducted during 1963-2006 across 6 countries in southern and eastern Asia that are part of the Asia Cohort Consortium. Body mass index, smoking, and alcohol intake were determined by questionnaire at baseline, and cause of death was ascertained through death certificates. Analysis included 522,736 men aged 54 years, on average, at baseline. During 4.8 million person-years of follow-up, there were 634 prostate cancer deaths (367 prostate cancer deaths across the 11 cohorts with alcohol data). In Cox proportional hazards analyses of all cohorts in the Asia Cohort Consortium, prostate cancer mortality was not significantly associated with obesity (body mass index >25: hazard ratio (HR) = 1.08, 95% confidence interval (CI): 0.85, 1.36), ever smoking (HR = 1.00, 95% CI: 0.84, 1.21), or heavy alcohol intake (HR = 1.00, 95% CI: 0.74, 1.35). Differences in prostate cancer screening and detection probably contribute to differences in the association of obesity, smoking, or alcohol intake with prostate cancer risk and mortality between Asian and Western populations and thus require further investigation., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Non-participants to psychosocial studies have been shown to have higher mortality, and mortality differs between partial and complete responders to psychosocial questionnaires. Yet, there is very little information available directly linking survey response status with completing suicide., Methods: The study population consisted of the participants of the Japanese Public Health Center-based prospective study. Ninety-nine thousand four hundred thirty-nine subjects who returned the 10-year follow-up questionnaire and 31 754 individuals who did not return the questionnaire were included in our analyses. The risk of dying by suicide according to response status was estimated by Cox regression models., Results: There were 358 suicides during 1 128 831 person-years of follow-up (mean follow-up time: 8.6 years). Of those who returned the questionnaire, 53.9% were full responders, 42.8% were partial non-responders, and 3.3% were complete non-responders. The risk of suicide was increased for both complete non-responders [hazard ratio (HR) = 1.84, 95% confidence interval (CI), 0.51, 6.64] and partial non-responders (HR = 1.36, 95% CI, 0.999, 1.84) to the questionnaire as a whole. The adjusting variables explained around 40% of the risk for complete non-responders whereas they did not explain the increased risk of suicide for partial non-responders. The risk of dying by suicide was significantly increased for partial non-responders to the subscale on coping (HR = 1.36, 95% CI, 1.01, 1.85) and for complete non-responders to questions on sleep (HR = 2.07, 95% CI, 1.03, 4.16)., Conclusions: Partial and complete non-responders have increased suicide risk compared with full responders. More than one non-responder category should therefore be considered when interpreting data pertaining to psychosocial questionnaires in longitudinal studies., (© The Author 2014. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

The Japan Public Health Center-based prospective Study conducted a baseline survey for 140 000 registered residents aged 40-69 years within 11 public health center areas nationwide in 1990-94. Five- and 10-year follow-up surveys were conducted to update information on lifestyle habits and health conditions. In total, 130 000 participants responded to at least one of the three questionnaire surveys, and 78 000 to all three. In addition, 60 000 participants provided blood samples on at least one of the two sampling times, and 23 000 on both. The subjects have been followed for vital status and the occurrence of cancer and other diseases. As of December 2011, 24 000 deaths have been documented, as well as 17 000 cases of cancer, 6000 cases of stroke and 1100 cases of myocardial infarction. We have tested the association between potential causal factors and the incidence of or mortality from cancer and other diseases, and published >250 papers to date. Typical dietary habits in Japan are high consumption of soy/isoflavones, fish/n-3 fatty acids, salt/salted foods and green tea, and low consumption of red meat and saturated fat. This paper briefly summarizes the observed associations of these foods/nutrients with cancer, cardiovascular diseases and diabetes. The Japan Public Health Center-based prospective Study is scheduled to conduct active follow-up for a total of 30 years, and we plan to publish additional evidence on the potential causes of a shorter life and major disease occurrence., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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

Objectives: Anti-cytokine therapy is reportedly useful in amyloid A (AA) amyloidosis complicating rheumatic diseases. However, to date no studies have directly compared the utility of tumour necrosis factor (TNF) inhibition to that of interleukin-6. The aim of our retrospective study was to compare the clinical utility of tocilizumab (TCZ) and anti-TNF (TNF inhibitor) therapy., Methods: We studied 42 patients treated with anti-cytokine agents at our hospital: 31 had received a single agent, ten had received two agents and one had received three agents. Patients were divided into a TCZ group (22 patients) and a TNF inhibitor group (32 patients). The main parameters compared were treatment retention rate, serum amyloid A (SAA) profile, renal function profile and clinical disease activity index., Results: The 5-year retention rates were 90.4 (TCZ group) and 34.3 % (TNF inhibitor group) (p = 0.0154, log-rank test). The median SAA fell from 219.2 μg/mL at treatment initiation to 5.0 μg/mL at last observation (TCZ), and from 143.6 to 38.1 μg/mL (TNF inhibitor) (p = 0.0194). Estimated glomerular filtration rate was improved in 72.7 (TCZ) and 34.4 % (TNF inhibitor) of patients (p = 0.0062). The rates of clinical remission or low disease activity at last observation for the TCZ and TNF inhibitor groups were 72.7 and 40.7 % (p = 0.0201), respectively., Conclusions: Based on these results, we conclude that TCZ was of greater clinical utility than anti-TNF therapy in our patients with AA amyloidosis complicating rheumatic diseases.

Objective: Clinical trials of β-carotene supplementation and recent large-scale prospective studies have called into question the protective effects of vegetable and fruit consumption against lung cancer. To re-assess this issue, we reviewed data from Japanese epidemiological studies., Methods: Original data were obtained from searches of MEDLINE and the Japana Centra Revuo Medicina (Ichushi) database. The associations were assessed based on their magnitude and the strength of the evidence, together with their biological plausibility as previously evaluated by the International Agency for Research on Cancer., Results: We identified six cohort studies and four case-control studies on the consumption of vegetables and/or fruit. We focused on fruit and green-yellow vegetables as food items, as they were included in more of the studies, and insufficient data were available on other types of vegetables. Among the three cohort and two case-control studies that reported on green-yellow vegetables, only one of each study type showed a weak inverse association between lung cancer risk and their consumption. Two of the four cohort studies and one (or possibly two) of the four case-control studies demonstrated a weak inverse correlation between lung cancer risk and fruit consumption. Meta-analysis for fruit consumption revealed a summary relative risk that was significantly smaller than unity., Conclusions: Our analysis of the Japanese epidemiological data showed that fruit consumption possibly decreased the risk of lung cancer, but found insufficient evidence of a link with vegetable consumption. Further prospective studies should assess the effects of consuming these food groups.

We report successful tocilizumab (TCZ) use in a patient with adult-onset Still's disease (AOSD) complicated by chronic hepatitis B (CHB) and AA amyloidosis (AAA). Treatments with corticosteroid and various types of immunosuppressants were unsuccessful. Aggravation of CHB ensued, and entecavir was started. Normalisation of liver function and hepatitis B virus (HBV) DNA were confirmed. TCZ was then started. His arthritis and AAA improved dramatically. TCZ is an excellent treatment for refractory AOSD and is feasible in an HBV-infected patient.

Peripheral arterial diseases are caused by arterial sclerosis and impaired collateral vessel formation, which are exacerbated by diabetes, often leading to leg amputation. We have reported that an activation of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway accelerated vascular regeneration and blood flow recovery in murine legs, for which ischemia had been induced by a femoral arterial ligation as a model for peripheral arterial diseases. In this study, ip injection of carperitide, a human recombinant atrial natriuretic peptide, accelerated blood flow recovery with increasing capillary density in ischemic legs not only in nondiabetic mice but also in mice kept upon streptozotocin-induced hyperglycemia for 16 wk, which significantly impaired the blood flow recovery compared with nondiabetic mice. Based on these findings, we tried to apply the administration of carperitide to the treatment of peripheral arterial diseases. The study group comprised a continuous series of 13 patients with peripheral arterial diseases (Fontaine's classification I, one; II, five; III, two; and IV, five), for whom conventional therapies had not accomplished appreciable results. Carperitide was administrated continuously and intravenously for 2 wk to Fontaine's class I-III patients and for 4 weeks to class IV patients. The dose was gradually increased to the maximum, with the patient's systolic blood pressure being kept above 100 mm Hg. Carperitide administration improved the ankle-brachial pressure index, intermittent claudication, rest pain, and ulcers. In conclusion, this study showed a therapeutic potential of carperitide to treat peripheral arterial diseases refractory to conventional therapies.

Porphyromonas gingivalis is a Gram-negative anaerobic oral black-pigmented bacterium closely associated with chronic periodontitis. Lipopolysaccharide (LPS) derived from P. gingivalis is shown to be unusual because the LPS contains a greater number of lipid A species, such as tri-, tetra-, and/or penta-acylated lipid As. In this study, a lipid A possessing penta-fatty acyl chains derived from P. gingivalis strain 381 (compound PG-381-5FA) was synthesized, and examined for its immunobiological activities, compared with a tri-acylated lipid A (compound PG-381-3FA) synthesized previously. Compound PG-381-5FA, similar to compound PG-381-3FA, demonstrated weaker activity in a Limulus test as compared with Escherichia coli-type synthetic lipid A (compound 506). Compound PG-381-5FA, followed by compound PG-381-3FA, induced KC, interleukin-6, and tumour necrosis factor-alpha production in peritoneal macrophages from LPS-responsive C3H/HeN mice, but not in those from LPS-hyporesponsive C3H/HeJ mice. Furthermore, compound PG-381-5FA, as well as compound PG-381-3FA, activated nuclear factor-kappaB via Toll-like receptor (TLR)4/mD-2, but not TLR2, in a manner similar to compound 506, and worked as an antagonist for compound 506-induced cell activation. In the case of human peripheral blood mononuclear cells, compound PG-381-5FA showed much stronger IL-6-inducing activity than compound PG-381-3FA. The present results demonstrate that the chemical synthesis of a penta-acylated lipid A, mimicking the natural lipid A portion of LPS from P. gingivalis, is attributable to immune cell activation through TLR4, similar to that of compound 506.

Adrenomedullin (AM) is a vasodilating hormone secreted mainly from vascular wall, and its expression is markedly enhanced after stroke. We have revealed that AM promotes not only vasodilation but also vascular regeneration. In this study, we focused on the roles of AM in the ischemic brain and examined its therapeutic potential. We developed novel AM-transgenic (AM-Tg) mice that overproduce AM in the liver and performed middle cerebral artery occlusion for 20 min (20m-MCAO) to examine the effects of AM on degenerative or regenerative processes in ischemic brain. The infarct area and gliosis after 20m-MCAO was reduced in AM-Tg mice in association with suppression of leukocyte infiltration, oxidative stress, and apoptosis in the ischemic core. In addition, vascular regeneration and subsequent neurogenesis were enhanced in AM-Tg mice, preceded by increase in mobilization of CD34(+) mononuclear cells, which can differentiate into endothelial cells. The vasculo-neuro-regenerative actions observed in AM-Tg mice in combination with neuroprotection resulted in improved recovery of motor function. Brain edema was also significantly reduced in AM-Tg mice via suppression of vascular permeability. In vitro, AM exerted direct antiapoptotic and neurogenic actions on neuronal cells. Exogenous administration of AM in mice after 20m-MCAO also reduced the infarct area, and promoted vascular regeneration and functional recovery. In summary, this study suggests the neuroprotective and vasculo-neuro-regenerative roles of AM and provides basis for a new strategy to rescue ischemic brain through its multiple hormonal actions.

We investigated the mechanism by which a GnRH agonist (GnRHa) affects ovarian vascularity, vascular permeability, and expression of the tight junction protein claudin-5 in a rat model of ovarian hyperstimulation syndrome (OHSS). Hyperstimulated rats received excessive doses of pregnant mare serum gonadotropin (PMSG; 50 IU/d) for 4 consecutive days, from d 25 to 28 of life, followed by 25 IU human chorionic gonadotropin (hCG) on d 29. Control rats received 10 IU PMSG on d 27 of life, followed by 10 IU hCG on d 29. GnRHa (leuprolide 100 microg/kg.d) was administered to some hyperstimulated rats either on d 29 and 30 (short-term GnRHa treatment) or from d 25 to 30 (long-term GnRHa treatment). Ovarian vascular density (vessels per 10 mm(2)) and vessel endothelial area (percent) were assessed by immunohistochemical analysis of the distribution of von Willebrand factor, whereas vascular permeability was evaluated based on leakage of Evans blue. High doses of PMSG and hCG significantly increased ovarian weight, vascular permeability, vascular density, and the vessel endothelial area and significantly reduced expression of claudin-5 protein and mRNA. All of these effects were significantly and dose-dependently inhibited by administration of GnRHa. This suggests that reduced expression of claudin-5 plays a crucial role in the increased ovarian vascular permeability seen in OHSS and that its expression can be modulated by GnRHa treatment. Indeed, preventing redistribution of tight junction proteins in endothelial cells and the resultant loss of endothelial barrier architecture might be the key to protecting patients against massive extravascular fluid accumulation in cases of OHSS.

Choline, a precursor of the neurotransmitter acetylcholine, is synthesized in only small amounts in the brain, so the choline concentration in the brain may vary depending on the plasma concentration and the transport rate across the blood-brain barrier. To elucidate the transport mechanism of choline, we carried out uptake experiments with mouse brain capillary endothelial cells in culture (MBEC4). [3H]Choline uptake was linear for up to 5 min. An examination of the concentration dependence of [3H]choline uptake revealed the operation of both saturable (Jmax = 423+/-27 pmol min(-1) (mg protein)(-1) and Kt = 20.0+/-3.1 microM) and non-saturable (kd = 1.23+/-0.045 microL min(-1)(mgprotein)-1) processes. The saturable process was independent of Na+ and pH, but was dependent on membrane potential as a driving force. Various basic drugs and endogenous substances, including substrates and inhibitors of the organic cation transporter, significantly inhibited the [3H]choline uptake. These data suggest that choline was taken up into the endothelial cells via two routes and that a membrane potential-dependent carrier-mediated transport system may participate in choline transport across the blood-brain barrier.

Induction of a microsomal Ca2+-dependent serine protease by hepatic tumor promoters was studied. Male F344 rats were fed a diet containing one of the following promoting agents: phenobarbital (CAS: 50-06-6), dichlorophenyltrichloroethane (CAS: 50-29-3), butylated hydroxytoluene, ethyl-alpha-chlorophenoxyisobutyrate (CAS: 128-95-0), or 17-alpha-ethynylestradiol (CAS: 57-63-6) or a nonpromoting agent, diphenylhydantoin (CAS: 57-41-0), for 1 week. By treatment with promoters, the protease activity in the microsomal fraction was increased to threefold to fivefold that of control, whereas only a slight increase of activity was found after diphenylhydantoin treatment. The Ca2+-dependent protease activity was determined with the use of N-benzoyl-L-tyrosine ethyl ester as the substrate in a medium containing 50 mM CaCl2 for its maximal activity. This protease was preferentially localized in the smooth microsomal membrane and strongly inhibited by diisopropyl phosphorofluoridate (CAS: 55-91-4), and the optimum pH of the activity was 7.8. It appears that the Ca2+-dependent serine protease measured by using a chymotrypsin substrate is a novel protease, and induction of its activity by hepatic tumor-promoting agents is a common and specific phenomenon.

Male inbred F344 rats weighing about 150 g were fed continuously a diet containing 0.02% N-2-fluorenylacetamide for 14-15 weeks. The presumptively preneoplastic hepatocytes were transferred to an in vitro system after dispersion by a collagenase-perfusion technique. Sensitivity to phalloidin in terms of formation of cytoplasmic blebs on the cell surface was less in the presumptively preneoplastic hepatocytes than in normal hepatocytes. Among the presumptively preneoplastic hepatocytes, the gamma-glutamyltransferase (GGT)-positive cells were less sensitive to phalloidin than GGT-negative cells, indicating a greater contribution to the decrease in the sensitivity to phalloidin of the presumptively preneoplastic cells.