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We examined the association of serum s-adenosylmethionine (SAM), s-adenosylhomocysteine (SAH) (methionine metabolites), and their ratio on the risk of dementia and death in a community-dwelling population of older Japanese individuals. 1371 residents of Hisayama, Japan, aged 65 years or older and without dementia, were followed for a median of 10.2 years (2007–2017). We divided serum SAM, SAH, and SAM/SAH ratio into quartiles. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) of serum SAM, SAH, and SAM/SAH ratio levels on the risk of a composite outcome of all-cause dementia or death, and each outcome. During the follow-up, 635 participants developed all-cause dementia and/or died, of which 379 participants developed dementia and 394 deaths occurred. The multivariable-adjusted HRs of the composite outcome decreased significantly with increasing serum SAM levels (P for trend = 0.01), while they increased significantly with higher serum SAH levels (P for trend = 0.03). Higher serum SAM/SAH ratio levels were significantly associated with a lower risk of the composite outcome (P for trend = 0.002), as well as with lower risk of each outcome. Our findings suggest that the balance of methionine metabolites may closely associate with the risk of dementia and death. [ABSTRACT FROM AUTHOR]

Background: A nationwide survey of autoimmune hepatitis (AIH) patients was performed in Japan in 2015. The aims of this study were to elucidate the trends and characteristics of AIH in Japan, in addition to identifying differences in AIH between acute hepatitis and chronic hepatitis.Methods: Questionnaires about patients with AIH diagnosed from 2009 to 2013 were sent to 437 hospitals or clinics with hepatology specialists.Results: A total of 1682 patients were enrolled. The mean age at diagnosis was 60.0 years, and 87.1 % of patients were female. Serum immunoglobulin G levels were high, peaking at 1.5-2.0 g/dL. Histological diagnoses of chronic hepatitis, acute hepatitis, and cirrhosis were seen in 79.6, 11.7, and 6.7 % of patients respectively. In addition to elevation of aminotransferase levels, the frequencies of emperipolesis and human leukocyte antigen (HLA)-DR2 positivity were higher in patients with acute hepatitis than in those with chronic hepatitis. Approximately 80 % of patients were treated with corticosteroids, and in 97.7 % of them, their condition improved. Steroid pulse therapy was more frequently given to patients with acute hepatitis than to those with chronic hepatitis.Conclusions: In the present nationwide survey of AIH patients in Japan, patients with acute hepatitis had clinical features different from those of patients with chronic hepatitis. [ABSTRACT FROM AUTHOR]

Background: This study aimed to examine the associations between time spent in prolonged and non-prolonged sedentary bouts and the development of metabolic syndrome.Methods: We used data from a prospective study of Japanese workers. Baseline examination was conducted between 2010 and 2011. A total of 430 office workers (58 women) aged 40-64 years without metabolic syndrome were followed up by annual health checkups until 2014. Metabolic syndrome was defined as having ≥ 3 out of 5 diagnostic criteria from the Joint Interim Statement 2009 definition. Sedentary time was assessed using a tri-axial accelerometer. Time spent in total, prolonged (accumulated ≥ 30 min) and non-prolonged sedentary bouts (accumulated < 30 min) was calculated. Cox proportional hazards models were used to estimate the risk of developing metabolic syndrome.Results: During a median follow-up of 3 years, 83 participants developed metabolic syndrome. After adjustment for age, sex, education, smoking, and family income, positive associations were observed between time spent in prolonged sedentary bouts and the development of metabolic syndrome. After additional adjustment for moderate-to-vigorous physical activity, those in the three highest quartiles of time spent in prolonged sedentary bouts showed higher risk of metabolic syndrome compared to the lowest quartile group, with adjusted hazard ratios (95 % confidence intervals) of 2.72 (1.30 - 5.73), 2.42 (1.11 - 5.50), and 2.85 (1.31 - 6.18), respectively. No associations were seen for time spent in total and non-prolonged sedentary bouts.Conclusions: Sedentary behavior accumulated in a prolonged manner was associated with an increased risk of metabolic syndrome. In devising public health recommendations for the prevention of metabolic disease, the avoidance of prolonged uninterrupted periods of sedentary behavior should be considered. [ABSTRACT FROM AUTHOR]

Introduction: Lumbar spinal stenosis (LSS) is a lumbar spinal disorder that causes leg symptoms and intermittent claudication. It is reported that the risk factors for low back pain include age, family history, smoking, obesity, work-related physical load, exercise, and depression. This was a multicenter, cross-sectional survey, and the aim of this study was to investigate the prevalence of LSS by age and the relationships between LSS and psychosocial factors and job satisfaction.Methods: This study enrolled subjects aged 50 years and over from a survey of LSS in 2177 hospitals and general practices nationwide. The clinical characteristics of the LSS and non-LSS groups were compared using the χ2 test, and the multivariate logistic regression analysis was performed to examine associations between exercise, perceived stress, strenuous use of the low back or legs, job satisfaction, and LSS.Results: In total, 18,642 patients (8338 males, 10,267 females) were analyzed. The rate of LSS was 38.3% and it increased with age. Regular exercise was less common among those in the LSS group than those in the non-LSS group (p<0.001). Satisfaction in all job-related items was less in the LSS group than in the non-LSS group (p<0.001). The odds for having LSS were higher in subjects having perceived stress and strenuous use of the low back or legs (p=0.001). The odds ratios of heart diseases and hypertension (p<0.001) were higher in the LSS group.Conclusion: This study investigated factors associated with LSS. The prevalence of LSS increased with age. Perceived stress and strenuous use of the low back or legs might be associated with LSS, and job satisfaction was lower with LSS. [ABSTRACT FROM AUTHOR]

Background: To. our knowledge, there are no previous reports that assessed the association between dietary patterns and risk of dementia in Asian populations. Objective: We investigated dietary patterns and their potential association with risk of incident dementia- in a general Japanese population. Design: A total of 1006 community-dwelling Japanese subjects without dementia, aged 60-79 y, were followed up for a median of 15 y. The reduced rank regression procedure was used to efficiently determine their dietary patterns. Estimated risk conferred by a particular dietary pattern on the development of dementia was computed by using a Cox proportional hazards model. Results: Seven dietary patterns were extracted; of these, dietary pattern I was correlated with high, intakes of soybeans and soybean products, vegetables, algae,, and milk and dairy products and a low intake of rice. During the follow-up, 271 subjects developed all-cause, dementia. Of these individuals, 144 subjects had Alzheimer disease (AD), and' 88 subjects had vascular dementia (VaD). After adjustment for potential confounders, risks of development of all-cause dementia, AD, and VaD. were reduced by 0.66 (95% CI: 0.46, 0.95), 0.65 (95% CI: 0:40, 1.06), and 0:45 (95% CI: 0.22, 0,91), respectively, in subjects in the highest quartile of score for dietary pattern. 1. compared with, subjects, in the lowest quartile. Conclusion:. Our findings suggest that a higher adherence to a dietary pattern characterized by a high intake of soybeans and soybean products, vegetables, algae, and milk and dairy products and a low intake of rice is associated with reduced risk of dementia in the general Japanese population. [ABSTRACT FROM AUTHOR]

The authors examined the association between white blood cell (WBC) count and the development of gastric cancer in a 19-year follow-up study of 2,558 Japanese subjects aged ≥40 years (1988–2007). The subjects were stratified into 4 groups according to baseline WBC quartile (≤4.4, 4.5–5.2, 5.3–6.3, or ≥6.4 × 103 cells/μL). During follow-up, 128 subjects developed gastric cancer. The age- and sex-adjusted incidence of gastric cancer increased linearly with higher WBC level: 1.7, 2.6, 3.9, and 5.4 per 1,000 person-years, respectively, for the 4 quartile groups (P for trend < 0.01). The risk of gastric cancer was 2.22-fold (95% confidence interval: 1.19, 4.14) higher in the highest WBC quartile group than in the lowest group after adjustment for confounding factors. With respect to Helicobacter pylori infection status, H. pylori-seropositive subjects in the highest WBC quartile group showed a significantly greater risk of gastric cancer than those in the lower 3 quartile groups, whereas such an association was not observed in H. pylori-seronegative subjects. There was no evidence of heterogeneity in the association (P for heterogeneity = 0.65). The study findings suggest that higher WBC levels are a risk factor for gastric cancer, especially in subjects with H. pylori infection. [ABSTRACT FROM PUBLISHER]

Background. Chronic kidney disease (CKD) is increasingly recognized as a leading public health issue. However, there are limited data assessing secular trends in the prevalence of CKD in general Asian communities. [ABSTRACT FROM PUBLISHER]

Recent genome-wide association study using four prospective population-based cohorts identified two single-nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579, to be significantly associated with the incidence of atherothrombotic stroke. To examine the association of these SNPs with atherothrombotic stroke in the Japanese population, we carried out a case–control association study using a total of 3784 cases and 3102 controls. We also examined the effect of these SNPs on the subtypes of ischemic stroke. Association analysis was carried out using logistic regression model after adjustment of age, sex and cardiovascular risk factors. Rs12425791 was significantly associated with atherothrombotic stroke (P=0.0084, odds ratio (OR)=1.15). When we analyzed effects of rs12425791 on ischemic stroke subtypes, rs12425791 was significantly associated with both small-artery occlusion (P=0.015, OR=1.15) and large-artery atherosclerosis (P=0.024, OR=1.19). Rs11833579 showed no association with atherothrombotic stroke or its subtypes in our population. Our data suggest that rs12425791 on chromosome 12p13 is a genetic marker for atherothrombotic stroke in multiethnic population. [ABSTRACT FROM AUTHOR]

Background: A previous study showed the relationship between the intake of dairy products and periodontitis, but the types of dairy products that confer a benefit on periodontal health status have not been determined. Methods: We analyzed 942 subjects aged 40 to 79 years as part of a comprehensive health examination of Hisayama Town, Fukuoka, Japan. Probing depth (PD) and clinical attachment loss (CAL) were used as the periodontal parameters. The dietary survey was conducted using a semiquantitative food frequency method. We examined the relationship between the intake of dairy products, such as milk, cheese, and lactic acid foods (yogurt and lactic acid drinks), and periodontal condition. Results: The daily intake of lactic acid foods in subjects with generalized deep PD or severe CAL was significantly lower than that in subjects with localized deep PD or slight CAL. In multivariate linear regression analysis, the increased intake of lactic acid foods was associated significantly with lower mean PD (P = 0.002) and lower mean CAL (P = 0.003). In multivariate logistic regression analysis, the subjects eating ≥55 g lactic acid foods per day had a significantly lower prevalence of deep PD and severe CAL compared to those not eating the se foods after adjusting for confounding variables; the odds ratios for generalized deep PD and severe CAL were 0.40 (95% confidence interval [CI]: 0.23 to 0.70) and 0.50 (95% CI: 0.29 to 0.87), respectively. Conclusion: The routine intake of lactic acid foods may have a beneficial effect on periodontal disease. [ABSTRACT FROM AUTHOR]

The article discusses the results of a study on the relationship between liver enzymes and the development of diabetes in Hisayama, Japan. It mentions that connections of serum γ-glutamyltransferase (GGT) and alanine aminotransferase (ALT) with diabetes were found within each stratified category of risk factors. It says that GGT and ALT concentrations can be considered as strong predictors of the disease.

The authors examined whether a serum pepsinogen test (SPT) based on the combination of the serum pepsinogen I level and pepsinogen I/II ratio is a good predictor of gastric cancer occurrence in a general Japanese population. A total of 2,446 subjects aged ≥40 years were classified into negative, positive, and strong-positive SPT groups and were followed prospectively for 14 years (1988–2002). Compared with that for the negative SPT group (26 men, 10 women), gastric cancer incidence increased significantly for both men (n = 17; age-adjusted hazard ratio = 4.56, 95% confidence interval: 2.42, 8.60) and women (n = 6; age-adjusted hazard ratio = 5.84, 95% confidence interval: 2.00, 17.11) in the strong-positive SPT group. It was also significantly higher in the positive SPT group for men (n = 23; age-adjusted hazard ratio = 3.91, 95% confidence interval: 2.23, 6.86). These associations did not attenuate even after adjustment for other comprehensive risk factors. Stratified analysis revealed significant associations between the SPT and development of intestinal-type gastric cancer as well as of cancer in both Helicobacter pylori–negative and –positive subjects. These findings suggest that the SPT can serve as a predictor of intestinal-type gastric cancer, irrespective of H. pylori infection. [ABSTRACT FROM AUTHOR]

Background: Diagnostic support tools for lumbar spinal stenosis such as the Self-administered, Self-reported History Questionnaire have been developed in Japan, but no report has demonstrated the diagnostic accuracy of this questionnaire in Japanese primary care settings. This multicenter, cross-sectional survey was performed to evaluate and improve the diagnostic accuracy of this questionnaire for lumbar spinal stenosis patients in Japanese primary care settings.Methods: The lumbar spinal stenosis diagnosis support tool project was conducted in 1657 hospitals to evaluate the diagnostic accuracy of the Self-administered, Self-reported History Questionnaire in Japan from 2011 to 2012. Consecutive adults (≥50 years old) from physicians, including non-orthopedic general practitioners and orthopedic general practitioners, were considered for enrollment. Consecutive adults (≥50 years old) with low back pain from hospital-based orthopedic surgeons were also considered for enrollment. The diagnostic accuracy of the Self-administered, Self-reported History Questionnaire with initial and several new cutoff points in classifying patients according to the presence of lumbar spinal stenosis was assessed in terms of sensitivity, specificity and negative predictive values.Results: Among the 33,545 patients, 10,199 (30.4 %) were diagnosed with lumbar spinal stenosis by the physicians. The Self-administered, Self-reported History Questionnaire version 1.1 with a new cutoff point was more sensitive than the Self-administered, Self-reported History Questionnaire version 1.0 with the initial cutoff point (79.8 vs. 68.3 %) and less specific (68.8 vs. 75.1 %) for lumbar spinal stenosis diagnosis. The respective negative predictive values were 88.5 and 84.3 %.Conclusions: The Self-administered, Self-reported History Questionnaire version 1.1 with the new cutoff was more sensitive and had higher negative predictive value than version 1.0 with the initial cutoff. Therefore, the improved Self-administered, Self-reported History Questionnaire version 1.1 can be used for lumbar spinal stenosis screening, and its use may improve the quality of lumbar spinal stenosis diagnostic practice in Japanese primary care settings. [ABSTRACT FROM AUTHOR]

Background: The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction., Methods: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses., Results: The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9% were male. The prevalence of dementia at baseline was 8.5% in overall participants. However, it was 16.4% among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer's disease., Conclusions: The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan.

Background: The reference values of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) in patients with lumbar spinal stenosis (LSS) are still unknown. This multicenter cross-sectional survey was performed to determine the reference values and disease-specific characteristics of deterioration of QOL caused by LSS itself, not by aging, through comparison of patients with and without LSS who had an outpatient visit for low back pain by age and sex groups., Methods: The present study was performed at 564 medical centers and clinics. The JOABPEQ was measured for 8338 patients aged 20 years or over who came to an outpatient clinic for low back pain (LBP) and were examined for whether they had LSS using the LSS diagnosis support tool (LSS-DST). Scores in the five JOABPEQ domains were compared between the LSS group and the LBP without LSS group (LBP group) for each age and sex group., Results: Scores for Pain-related disorder, Gait disturbance, Social life disturbance, and Psychological disorders were significantly lower in the LSS group than in the LBP group., Conclusion: The percentiles of JOABPEQ scores in patients with LSS were clarified and could be used as reference values. Deterioration of QOL caused by LSS itself, not by aging, are characterized by Pain-related disorder, Gait disturbance, Social life disturbance, and Psychological disorders., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The purpose of this study was to describe changes in physical activity volumes and sedentary time over 3 years in the middle-aged and older Japanese population., Methods: Study participants included 1151 Japanese community-dwelling residents aged ≥40 years in 2009 who underwent 2 sets of health examinations (2009 and 2012). Using a triaxial accelerometer, longitudinal changes in sedentary time, light physical activity volume, moderate to vigorous physical activity volume, number of steps, and total physical activity volume were evaluated according to sex, age (40-49, 50-59, 60-69, 70-79, and ≥80 y), and obese (nonobese and obese) categories., Results: Sedentary time significantly increased, and all physical activity volumes significantly decreased among all participants. Although most variables did not change significantly in the 40-49 and 50-59 year age categories, similar changes as all participants were observed across all other categories. In the correlation analyses, changes in sedentary time correlated, at most, only modestly for each change in physical activity volumes, indicating that increased physical activity volume does not always lead to decreased sedentary time, and vice versa., Conclusions: Strategies to reduce sedentary time and promote physical activity are needed in Japan, particularly for people aged ≥60 years.

Background: There have been very few reports of risk score models for the development of gastric cancer. The aim of this study was to develop and validate a risk assessment tool for discerning future gastric cancer risk in Japanese., Methods: A total of 2444 subjects aged 40 years or over were followed up for 14 years from 1988 (derivation cohort), and 3204 subjects of the same age group were followed up for 5 years from 2002 (validation cohort). The weighting (risk score) of each risk factor for predicting future gastric cancer in the risk assessment tool was determined based on the coefficients of a Cox proportional hazards model in the derivation cohort. The goodness of fit of the established risk assessment tool was assessed using the c-statistic and the Hosmer-Lemeshow test in the validation cohort., Results: During the follow-up, gastric cancer developed in 90 subjects in the derivation cohort and 35 subjects in the validation cohort. In the derivation cohort, the risk prediction model for gastric cancer was established using significant risk factors: age, sex, the combination of Helicobacter pylori antibody and pepsinogen status, hemoglobin A1c level, and smoking status. The incidence of gastric cancer increased significantly as the sum of risk scores increased (P trend < 0.001). The risk assessment tool was validated internally and showed good discrimination (c-statistic = 0.76) and calibration (Hosmer-Lemeshow test P = 0.43) in the validation cohort., Conclusions: We developed a risk assessment tool for gastric cancer that provides a useful guide for stratifying an individual's risk of future gastric cancer.

Background: Hyperuricemia (HU) may enhance susceptibility to hypertensive renal damage via disrupted autoregulation of glomerular hemodynamics. The effect of HU on the association between blood pressure (BP) and proteinuria remains unknown in patients with chronic kidney disease (CKD)., Methods: In total, 109 patients with nonnephrotic CKD (55 men and 54 females) who underwent renal biopsy were recruited. Arteriolar hyalinosis was semiquantitatively assessed via arteriole grading. Correlation between BP and urine protein (UP) level was examined based on the presence of HU, which was defined as the use of urate-lowering drugs or serum uric acid levels of ≥7 and ≥5 mg/dl in males and females, respectively, which were associated with increased risks of hyalinosis in our previous study., Results: Median age, BP, estimated glomerular filtration rate, and UP level were 38 years, 124/74 mm Hg, 82 ml/min/1.73 m2, and 0.8 g/gCr, respectively. In patients with HU (n = 59), log-transformed systolic BP (SBP) was significantly correlated with log-transformed UP level (r = 0.49, P < 0.0001); this was not observed in patients without HU (n = 50). Multiple regression analysis (R2 = 0.21, P = 0.0001) revealed that the interaction between HU and log-transformed SBP with respect to proteinuria was significantly correlated with log-transformed UP level (β = 7.0, P = 0.03), independent of age, sex, and potential confounding factors; however, this statistical significance was completely eliminated after adjustment for the arteriolar hyalinosis index., Conclusions: HU potentiates susceptibility to hypertensive glomerular damage via disrupted autoregulation in patients with nonnephrotic CKD.

Purpose: The objective of this multicenter cross-sectional study was to investigate the relationship of nocturnal polyuria in patients with common lifestyle related diseases and overactive bladder, with special attention to hypertension., Materials and Methods: After baseline assessment, patients recorded 24-hour urinary frequency/volume, blood pressure and heart rate for 3 days. They were stratified into 4 groups based on mean blood pressure, including no hypertension, and controllable, untreated and uncontrolled hypertension, respectively., Results: The 2,353 eligible patients, who had urinary urgency once or more per week and 1 or more nocturnal toilet visits, were enrolled from 543 sites in Japan. Of these patients complete data, including the 24-hour frequency volume chart, were collected from 1,271. Multivariable analyses showed a statistically significant association of nocturnal polyuria with increasing age (OR 1.04, 95% CI 1.02-1.05, p <0.001) and gender (women vs men OR 0.75, 95% CI 0.59-0.96, p = 0.02), and for controllable (OR 1.10, 95% CI 0.83-1.460), untreated (OR 2.62, 95% CI 1.55-4.45) and uncontrolled (OR 1.15, 95% CI 0.81-1.62) hypertension vs no hypertension (p = 0.005). However, when assessed separately in men and women, hypertension and heart rate were significantly associated with nocturnal polyuria in women alone (p = 0.01 and 0.03, respectively). Lower urinary tract symptoms suggestive of benign prostatic hyperplasia were significantly associated with nocturnal polyuria in men alone (p <0.001)., Conclusions: The current study demonstrates that nocturnal polyuria was significantly associated with age, male gender, and untreated hypertension in patients with lifestyle related diseases and overactive bladder. The association between hypertension and nocturnal polyuria was significant in women alone., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: There is little information regarding whether the combination of Helicobacter pylori (H. pylori) antibody and serum pepsinogen (sPG), which is a marker of the degree of atrophic gastritis, has a discriminatory ability for detecting incident gastric cancer. We examined this issue in a long-term prospective cohort study of a Japanese population., Methods: A total of 2446 Japanese community-dwelling individuals aged ≥40 years were stratified into four groups according to baseline H. pylori serological status and sPG: Group A (H. pylori[-], sPG[-]), Group B (H. pylori[+], sPG[-]), Group C (H. pylori[+], sPG[+]), and Group D (H. pylori[-], sPG[+]), and participants were followed up prospectively for 20 years., Results: During the follow-up, 123 subjects developed gastric cancer. Compared with that in Group A, the cumulative incidence of gastric cancer was significantly increased in Groups B, C, and D, whereas no significant difference was found between Groups C and D. The multivariable-adjusted risk of gastric cancer was significantly increased in Group B (hazard ratio [HR], 4.08; 95% confidence interval [CI], 1.62-10.28) and in Groups C and D combined (HR 11.1; 95% CI, 4.45-27.46). When the multivariable model with H. pylori antibody was changed into that with the combination of H. pylori antibody and sPG, the C statistics for developing gastric cancer increased significantly (0.773 vs 0.732, P = 0.005), and the continuous net reclassification improvement value was 0.591 (P < 0.001)., Conclusions: Our findings suggest that the combination of H. pylori antibody and sPG is a useful tool for predicting the development of gastric cancer.

Aim: To determine the optimal cut-off value of serum total adiponectin for managing the risk of developing metabolic syndrome (MetS) in male Japanese workers., Methods: A total of 365 subjects without MetS aged 20-60 years were followed up prospectively for a mean of 3.1 years. The accelerated failure-time model was used to estimate time ratio (TR) and cut-off value for developing MetS., Results: During follow-up, 45 subjects developed MetS. Age-adjusted TR significantly declined with decreasing total adiponectin level (≤ 4.9, 5.0-6.6, 6.7-8.8 and ≥ 8.9 μg/ml, P for trend = 0.003). In multivariate analyses, TR of MetS was 0.12 (95% CI 0.02-0.78; P = 0.03) in subjects with total adiponectin level of 5.0-6.6 μg/ml, and 0.15 (95% CI 0.02-0.97; P = 0.047) in subjects with total adiponectin level ≤ 4.9 μg/ml compared with those with total adiponectin level ≥ 8.9 μg/ml. The accelerated failure-time model showed that the optimal cut-off value of total adiponectin for managing the risk of developing MetS was 6.2 μg/ml. In the multivariate-adjusted model, the mean time to the development of MetS was 78% shorter for total adiponectin level ≤ 6.2 μg/ml compared with > 6.2 μg/ml (TR 0.22, 95% CI: 0.08-0.64, P = 0.005)., Conclusion: Our findings suggest that the cut-off value for managing the risk of developing MetS is 6.2 μg/ml in male Japanese workers. Subjects with total adiponectin level ≤ 6.2 μg/ml developed MetS more rapidly than did those with total adiponectin level > 6.2 μg/ml.

Aim: The angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism has been reported to be implicated in susceptibility to coronary heart disease (CHD). However, this association remains inconclusive. The purpose of this study was to clarify the association between the I/D polymorphism of the ACE gene and the development of CHD in a Japanese general population and investigate whether the effects of traditional risk factors on the risk of CHD are heterogeneous among ACE genotypes., Methods: The subjects included 2,125 community-dwelling individuals 40 years of age or older without cardiovascular disease for whom genetic information was available. All patients were prospectively followed for 19 years, and the association between the ACE polymorphism and the incidence of CHD was examined based on the interactions with traditional risk factors, such as hypercholesterolemia, hypertension, diabetes and smoking., Results: A total of 161 CHD events occurred during the follow-up period. The age- and sex-adjusted incidence of CHD was not significantly different among the genotypes (5.8, 5.2, and 6.9 per 1,000person-years for genotypes II, ID and DD, respectively). In a stratified analysis, however, the ACE DD genotype was found to significantly accelerate the risk of developing CHD by hypercholesterolemia (hazard ratio [HR]=4.50, 95% confidence interval=2.02-10.04 for hypercholesterolemia with the DD genotype; HR=1.48, 95% CI=1.04-2.12 for hypercholesterolemia with the ID＋II genotype; P for interaction=0.01), even after adjusting for other confounding factors, whereas no such associations were observed for hypertension, diabetes or smoking., Conclusions: The current findings suggest that the ACE DD genotype enhances the effect of hypercholesterolemia on the development of CHD in the general Japanese population.

Background: Lumbar spinal stenosis (LSS) is a major clinical problem associated with back pain, intermittent claudication, leg pain, and leg numbness. Diagnostic support tools for LSS such as the self-administered, self-reported history questionnaire (SSHQ) and developmental clinical diagnosis support tool (ST) have been validated in Japan. However, the degree of awareness and use of these two diagnostic support tools for LSS in Japan has not been clarified. The aims of the current study were to determine the degree of awareness and use of these two diagnostic support tools by Japanese physicians. Furthermore, we compared these results among nonorthopedic general practitioner (GP), orthopedic GP, and hospital-based orthopedic physicians., Methods: The LSS Diagnosis Support Tool (DISTO) Project was conducted to evaluate the degree of awareness and use of these two diagnostic support tools in Japan from 2011 to 2012. A total of 1,811 answers were obtained from physicians including nonorthopedic general practitioners (GP), orthopedic GPs, and hospital-based orthopedic physicians. Questions were (1) Do you know about these two diagnostic tools? and (2) If you know about these two diagnostic tools, have you used them?, Results: The degree of awareness of ST and SSHQ was about 30 and 26 % by nonorthopedic GPs, 70 and 46 % by orthopedic GPs, and 68 and 41 % by hospital-based orthopedic physicians. The degree of awareness of ST and SSHQ by nonorthopedic GPs was significantly lower than by orthopedic GPs or hospital-based orthopedic physicians (p < 0.001). For physicians who were aware of ST and SSHQ, the degree of use of ST or SSHQ was <50 % by nonorthopedic GPs, orthopedic GPs, and hospital-based orthopedic physicians., Conclusions: We expect that use of the ST or SSHQ tools in primary care will improve the accuracy of diagnosis and lead to improved quality of patient care. The low proportion of awareness by nonorthopedic GPs (<30 %) and use by all physicians (<50 %) indicate a need to encourage physicians to use ST and SSHQ more frequently.

Introduction: Chronic pain is a significant health problem worldwide, with a prevalence in the general population of approximately 40%. Alexithymia -- the personality trait of having difficulties with emotional awareness and self-regulation -- has been reported to contribute to an increased risk of several chronic diseases and health conditions, and limited research indicates a potential role for alexithymia in the development and maintenance of chronic pain. However, no study has yet examined the associations between alexithymia and chronic pain in the general population., Methods: We administered measures assessing alexithymia, pain, disability, anxiety, depression, and life satisfaction to 927 adults in Hisayama, Japan. We classified the participants into four groups (low-normal alexithymia, middle-normal alexithymia, high-normal alexithymia, and alexithymic) based on their responses to the alexithymia measure. We calculated the risk estimates for the criterion measures by a logistic regression analysis., Results: Controlling for demographic variables, the odds ratio (OR) for having chronic pain was significantly higher in the high-normal (OR: 1.49, 95% CI: 1.07-2.09) and alexithymic groups (OR: 2.56, 95% CI: 1.47-4.45) compared to the low-normal group. Approximately 40% of the participants belonged to these two high-risk groups. In the subanalyses of the 439 participants with chronic pain, the levels of pain intensity, disability, depression, and anxiety were significantly increased and the degree of life satisfaction was decreased with elevating alexithymia categories., Conclusions: The findings demonstrate that, in the general population, higher levels of alexithymia are associated with a higher risk of having chronic pain. The early identification and treatment of alexithymia and negative affect may be beneficial in preventing chronic pain and reducing the clinical and economic burdens of chronic pain. Further research is needed to determine if this association is due to a causal effect of alexithymia on the prevalence and severity of chronic pain.

Background:  Recent evidence indicates that vitamin D deficiency is associated with an increased risk of renal impairment, but studies addressing the influence of vitamin D deficiency on the development of chronic kidney disease (CKD) in the general Asian population have been few., Methods and Results:  A total of 2,417 community-dwelling individuals without CKD stage 3-5 aged ≥40 years were followed for 5 years (mean age, 60 years; women, 59.1%). The cumulative incidence of CKD stage 3-5, defined as estimated glomerular filtration rate (eGFR) <60ml·min(-1)·1.73m(-2), and the rate of decline in eGFR according to quartile of serum 1,25-dihydroxyvitamin D (1,25(OH)2D), were estimated. During follow-up, 378 subjects experienced CKD stage 3-5. The age- and sex-adjusted incidence of CKD stage 3-5 increased significantly with decreasing serum 1,25(OH)2D (P for trend <0.001). Compared with the highest quartile, the multivariate-adjusted odds ratio for the development of CKD stage 3-5 was 1.90 in the lowest quartile and 1.74 in the second lowest quartile, after adjusting for confounding factors. Additionally, lower serum 1,25(OH)2D was significantly associated with a greater change in eGFR (-0.10ml·min(-1)·1.73m(-2)·year(-1) per 10-pg/ml decrement in serum 1,25(OH)2D)., Conclusions:  Lower serum 1,25(OH)2D is a significant risk factor for the development of CKD stage 3-5 in the general Asian population.

Background: Uncertainty still surrounds the association between metabolic syndrome (MetS) and depression. We aimed to evaluate the association between MetS and elevated depressive symptoms in a general Japanese population., Methods: This is a cross-sectional survey of 3,113 community-dwelling individuals aged 40 years or over. MetS was defined according to the joint interim statement. MetS was diagnosed when a subject had three or more of the following components: 1) central obesity (waist circumference ≥ 90 cm for men, ≥ 80 cm in for women); 2) elevated blood pressure (≥ 130/85 mmHg or current use of antihypertensive medication); 3) hypertriglyceridemia (≥ 1.7 mmol/L); 4) low HDL cholesterol (< 1.0 mmol/L for men, < 1.3 mmol/L for women); and 5) elevated fasting plasma glucose (≥ 5.55 mmol/L or current use of antidiabetic medication). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The age- and multivariable-adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated using a logistic regression model., Results: Elevated depressive symptoms were observed in 4.3% of male and 6.3% of female participants. In men, the age-adjusted prevalence of elevated depressive symptoms was significantly higher in subjects with MetS than in those without (7.1% versus 3.6%, p = 0.04). The prevalence of elevated depressive symptoms rose progressively as the number of MetS components increased (3.5%, 3.6%, 5.8%, and 9.2% in male subjects with 0-1, 2, 3, and ≥ 4 components, respectively; p = 0.02 for trend). This association remained significant even after adjustment for age, marital status, history of cardiovascular disease, smoking habit, alcohol intake, and regular exercise. In women, on the other hand, there was no clear association between MetS and depressive symptoms., Conclusions: MetS was associated with elevated depressive symptoms in a general population of Japanese men.

Background: Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan., Methods and Results: We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply., Conclusions: Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors.

Background: Serum pepsinogen (sPG) levels have been established as a good marker of chronic atrophic gastritis and the sequential occurrence of gastric cancer. However, there have been few prospective investigations which investigated the predictive performance of sPG for future gastric cancer incidence., Subjects and Methods: We prospectively followed-up a total of 2446 community-dwelling Japanese aged ≥ 40 years for 10 years and used the Youden's index to determine the cutoff values of the pepsinogen I level and pepsinogen I/II ratio to accurately discriminate gastric cancer events. Predictive performance of sPG was assessed by ROC curve., Results: During the follow-up, 69 subjects developed gastric cancer. The most predictive sPG test criteria were determined to be a pepsinogen I level ≤ 59 ng/ml and pepsinogen I/II ratio ≤ 3.9. The sensitivity and specificity of these criteria to discriminate the actual occurrence of gastric cancer were 71.0% and 69.2%, respectively. The area under the ROC curve for gastric cancer occurrence increased significantly by adding the sPG test to the model that included the status of Helicobater pylori infection and other potential risk factors (from 0.742 to 0.809; p for difference in the area < 0.001)., Conclusions: This study determined the optimal sPG test criteria for predicting gastric cancer occurrence over 10 years in a general Japanese population. These criteria would be effective to screen for individuals at high risk of this disease.

Objectives: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) defined blood pressure (BP) levels of 120-139/80-89  mmHg as prehypertension. The objective of the present analysis was to examine the impact of prehypertension and its population-attributable fraction for development of cardiovascular events in a general Japanese population., Methods: Two thousand, six hundred and thirty-four residents of the town of Hisayama aged at least 40 years without cardiovascular disease were followed up for 19 years. BP categories were defined using JNC7, and prehypertension was divided into the lower (120-129/80-84  mmHg) and higher ranges (130-139/85-89  mmHg). During the follow-up period, 449 participants developed cardiovascular disease (305 strokes and 187 coronary heart diseases)., Results: The frequencies of normal BP, prehypertension, and stages 1 and 2 hypertension were 24.9, 37.7, 23.8, and 13.6%, respectively. The age and sex-adjusted incidence of cardiovascular disease rose progressively with elevation of BP levels (P < 0.001 for trend). The risks of cardiovascular disease in lower and higher ranges of prehypertension were 58% [95% confidence interval (CI) 11-126%] and 70% (95% CI 18-144%) higher than normal BP even after controlling for other cardiovascular risk factors. The population-attributable fraction of prehypertension was 13.2%, which was similar to those of stages 1 and 2 hypertension., Conclusions: The risks of cardiovascular disease increased significantly from the lower range of prehypertension in a general Japanese population. Approximately one-third of excess cardiovascular events attributable to elevated BP levels were estimated to occur among individuals with prehypertension.

Background and Aim: Type 1 autoimmune pancreatitis (AIP) is characterized by the increase of serum immunoglobulin (Ig)G4 and abundant IgG4 plasma cell infiltration in the pancreas and various extrapancreatic lesions (EPL), which are proposed as IgG4-related disease. We assessed the correlation between serum IgG4 and the number of EPL, and the association between serum IgG4 and the distribution of EPL in type 1 AIP patients., Methods: Serum IgG4 was measured in 35 type 1 AIP patients and 71 non-AIP patients. The clinical characteristics and distribution of eight EPL were determined in 35 type 1 AIP patients., Results: Serum IgG4 in type 1 AIP was significantly higher than in non-AIP (P < 0.001). A total of 33 patients had EPL among 35 patients with type 1 AIP (94.3%). There was a significant correlation between serum IgG4 and the number of EPL (ρ = 0.75, P < 0.001). Further, to assess the association between serum IgG4 and the distribution of EPL, type 1 AIP patients were divided into two groups: as abdominal localized EPL and systemic EPL. Both serum IgG4 and total numbers of EPL in systemic EPL were remarkably higher than those in abdominal localized EPL. Serum IgG4 cut-off value was 346 mg/dL to distinguish between abdominal localized EPL and systemic EPL according to the receiver-operator characteristic curve data., Conclusions: Our findings indicated that serum IgG4 was useful in both the diagnosis of type 1 AIP and the detection of systemic EPL. Our finding may help the concept and diagnostic criteria of IgG4-related disease with type 1 AIP., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Purpose: To examine the prevalence of retinal vein occlusion (RVO) and its systemic relevant factors in a general Japanese population aged 40 years or older., Methods: In 1998, 1775 Hisayama residents consented to participate in the study. Each participant underwent a comprehensive examination that included ophthalmic testing. RVO was determined by grading color fundus photographs. Logistic regression analysis was performed to determine risk factors for RVO., Results: Of the 1775 subjects examined, 38 had RVO. The prevalence of RVO was 2.1% (2.0% for branch RVO and 0.2% for central RVO). After adjustment for age and sex, it was found that systolic and diastolic blood pressures, hypertension, and hematocrit were significantly associated with RVO. In multivariate analysis, age (per 10 years; odds ratio [OR], 1.47; 95% confidence interval [CI], 1.04-2.08), hypertension (OR, 4.25; 95% CI, 1.82-9.94), and hematocrit (per 10%; OR, 3.09; 95% CI, 1.10-1.22) remained independently significant risk factors for RVO. Both high-normal blood pressure and hypertension were significantly associated with RVO. Furthermore, compared with normotensive subjects without high hematocrit, the likelihood of RVO was markedly high in subjects having both high blood pressure and high hematocrit (age- and sex-adjusted OR, 36.0; 95% CI, 4.43-292)., Conclusions: The findings suggest that the prevalence of RVO is higher in the Japanese than in other Asians or Caucasians and that older age, higher hematocrit, and both hypertension and high-normal blood pressure are significant risk factors for RVO in the Japanese.

Although stroke is a common cause of death and a major cause of disability all over the world, genetic components of common forms of ischemic stroke are largely unknown. To identify susceptibility genes of atherothrombotic stroke, we performed a large case-control association study and a replication study in a total of 2775 cases with atherothrombotic stroke and 2839 controls. Through the analysis in 860 cases and 860 age- and sex-matched controls, we found that a single-nucleotide polymorphism (SNP), rs2280887, in the ARHGEF10 gene was significantly associated with atherothrombotic stroke even after the adjustment of multiple testing by a permutation test [unadjusted P = 1.2 x 10(-6), odds ratio = 1.80, 95% confidence interval (CI) = 1.42-2.28]. This association was replicated in independent 1915 cases and 1979 controls. Subsequent fine mapping found another three SNPs which showed similar association due to strong linkage disequilibrium to rs2280887 (r(2) > 0.95). In the functional analyses of these four highly associated SNPs, using luciferase assay and electrophoretic mobility shift assay we found that rs4376531 affected ARHGEF10 transcriptional activity due to the different Sp1-binding affinity. In small GTPase activity assay, we found that a gene product of ARHGEF10 specifically activated RhoA. A population-based cohort study revealed the subjects with rs4376531 CC or CG to increase the incidence of ischemic stroke (P = 0.033, hazard ratio = 1.79, 95% CI = 1.05-3.04). Our data suggest that the functional SNP of ARHGEF10 confers the susceptibility to atherothrombotic stroke.

Background and Purpose: Few studies have shown the association between glucose tolerance status defined by a 75-g oral glucose tolerance test and the development of different types of cardiovascular disease., Methods: A total of 2421 community-dwelling Japanese subjects aged 40 to 79 years who underwent the oral glucose tolerance test were followed up for 14 years., Results: In multivariable analysis, the risks of ischemic stroke in both sexes and coronary heart disease (CHD) in women were significantly higher in subjects with diabetes determined by the World Health Organization criteria than in those with normal glucose tolerance even after adjustment for other confounding factors, but such association was not seen for CHD in men (ischemic stroke: adjusted hazard ratio [HR]=2.54, P=0.002 in men; adjusted HR=2.02, P=0.03 in women; CHD: adjusted HR=1.26, P=0.47 in men; adjusted HR=3.46, P=0.002 in women). Similar associations were observed for fasting plasma glucose levels of >or=7.0 mmol/L (ischemic stroke: adjusted HR=2.15, P=0.03 in men; adjusted HR=2.10, P=0.045 in women; CHD: adjusted HR=1.29, P=0.47 in men; adjusted HR=3.83, P=0.003 in women) and for 2-hour postload glucose levels of >or=11.1 mmol/L (ischemic stroke: adjusted HR=2.71, P=0.003 in men; adjusted HR=2.19, P=0.03 in women; CHD: adjusted HR=1.58, P=0.16 in men; adjusted HR=4.44, P<0.001 in women). The age-adjusted incidences of ischemic stroke and CHD did not significantly increase in subjects with impaired fasting glycemia or impaired glucose tolerance in either sex., Conclusions: Our findings suggest that diabetes is an independent risk factor for ischemic stroke in both sexes and CHD in women in the Japanese population.

The objective of this paper is to develop a new risk prediction model of cardiovascular disease and to validate its performance in a general population of Japanese. The Hisayama study is a population-based prospective cohort study. A total of 2634 participants aged 40 years or older were followed up for 14 years for incident cardiovascular disease (stroke and coronary heart disease (myocardial infarction, coronary revascularization and sudden cardiac death)). We used data among a random two-thirds (the derivation cohort, n=1756) to develop a new risk prediction model that was then tested to compare observed and predicted outcomes in the remaining one-third (the validation cohort, n=878). A multivariable cardiovascular risk prediction model was developed that incorporated age, sex, systolic blood pressure, diabetes, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and smoking. We assessed the performance of the model for predicting individual cardiovascular event among the validation cohort. The risk prediction model demonstrated good discrimination (c-statistic=0.81; 95% confidence interval, 0.77 to 0.86) and calibration (Hosmer-Lemeshow chi(2)-statistic=6.46; P=0.60). A simple risk score sheet based on the cardiovascular risk prediction model was also presented. We developed and validated a new cardiovascular risk prediction model in a general population of Japanese. The risk prediction model would provide a useful guide to estimate absolute risk of cardiovascular disease and to treat individual risk factors.

Objective: Clinical uncertainty remains whether the blood pressure classification and risk stratifications recommended by the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009) are useful in predicting the risks of stroke and its subtypes in the general Japanese population., Methods: A total of 1621 stroke-free residents of a Japanese community aged at least 40 years were followed up for 32 years. Outcomes were total and cause-specific stroke (lacunar infarction, atherothrombotic infarction, cardioembolic infarction, cerebral haemorrhage and subarachnoid haemorrhage). Incidence was calculated by the pooling of repeated observations method., Results: The age-adjusted incidence of total stroke rose progressively with higher blood pressure levels in both sexes (both P for trend <0.0001). A similar pattern was observed for lacunar infarction in both sexes and for cerebral haemorrhage in men: the differences were significant between optimal blood pressure and grades 1-3 hypertension (all P < 0.05). The age-adjusted incidence of atherothrombotic infarction in either sex and that of cardioembolic infarction and subarachnoid haemorrhage in women significantly increased in grade 3 hypertension (all P < 0.05). These associations remained substantially unchanged even after adjustment for other risk factors. In regard to risk stratification, the age-adjusted incidence of stroke significantly increased with the level of risk in both sexes., Conclusion: Our findings suggest that the blood pressure classification and risk stratifications recommended by the JSH 2009 guidelines are useful in predicting the risk of stroke in a general Japanese population, but the magnitude and patterns of the impact of blood pressure categories are different among stroke subtypes.

Background: Resistin, secreted from adipocytes, causes insulin resistance in mice. The relationship between resistin and coronary artery disease is highly controversial, and the information regarding resistin and ischemic stroke is limited. In the present study, the association between serum resistin concentration and cardiovascular disease (CVD) was investigated in a general Japanese population., Methods: A total of 3,201 community-dwelling individuals aged 40 years or older (1,382 men and 1,819 women) were divided into quintiles of serum resistin, and the association between resistin and CVD was examined cross-sectionally. The combined effect of either diabetes or hypertension and high serum resistin was also assessed. Serum resistin was measured using ELISA., Results: Compared to those without CVD, age- and sex-adjusted mean serum resistin concentrations were greater in subjects with CVD (p = 0.002) or ischemic stroke (p < 0.001), especially in those with lacunar and atherothrombotic infarction, but not elevated in subjects with hemorrhagic stroke or coronary heart disease. When analyzed by quintile of serum resistin concentration, the age- and sex-adjusted odds ratio (OR) for having CVD and ischemic stroke increased with quintile of serum resistin (p for trends, 0.02 for CVD, < 0.001 for ischemic stroke), while such associations were not observed for hemorrhagic stroke or coronary heart disease. Compared to the first quintile, the age- and sex-adjusted OR of ischemic stroke was greater in the third (OR = 3.54; 95% confidence interval [CI], 1.17-10.67; p = 0.02), fourth (OR = 4.48; 95% CI, 1.53-13.09; p = 0.006), and fifth quintiles (OR = 4.70; 95% CI, 1.62-13.61; p = 0.004). These associations remained substantially unchanged even after adjustment for other confounding factors including high-sensitivity C-reactive protein. In the stratified analysis, the combination of high serum resistin and either diabetes or hypertension markedly increased the risk of ischemic stroke., Conclusion: Elevated serum resistin concentration appears to be an independent risk factor for ischemic stroke, especially lacunar and atherothrombotic infarction in the general Japanese population. The combination of high resistin and the presence of either diabetes or hypertension increased the risk of ischemic stroke.

Purpose: To estimate the 9-year incidence and risk factors for age-related macular degeneration (AMD) in a general Japanese population., Design: Population-based, cohort study., Participants: In 1998, a total of 1775 Hisayama residents aged >or=40 years underwent a baseline eye examination. Of those, 1401 subjects (78.9%) took part in the follow-up eye examination in 2007 and were enrolled in the present study., Methods: At both time points, the characteristics of AMD were determined by grading color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System., Main Outcome Measures: Incident early and late AMD., Results: The age-standardized, 9-year cumulative incidence of early AMD was 10.0%, and that of late AMD was 1.4%. Men were found to have a significantly higher incidence of late AMD than women (age-adjusted odds ratio [OR], 2.97; 95% confidence interval [CI], 1.25-7.09). The incidence of both early and late AMD increased significantly with age. Multiple logistic regression analysis showed that older age (per 1 year; OR, 1.10; 95% CI, 1.05-1.16), smoking habits (OR, 3.98; 95% CI, 1.07-14.7), and higher circulating white blood cell (WBC) count (per 1000 cells/mm(3)) (OR, 1.38; 95% CI, 1.07-1.79) were significantly associated with the development of late AMD., Conclusions: Our findings suggest that the 9-year incidences of late AMD are lower among the Japanese than among white people in Western countries, and it is higher than among black people. Smoking habits and higher circulating WBC count are significant risk factors for the development of late AMD in the Japanese.

Background and Purpose: The current criteria of metabolic syndrome (MetS) are not based on evidence derived from prospective studies on cardiovascular disease (CVD)., Methods: In a 14-year follow-up study of 2452 community-dwelling Japanese individuals aged >or=40 years, we examined which of the MetS criteria are most predictive for the development of CVD. During the follow-up, 246 first-ever CVD events occurred., Results: An optimal cutoff point of waist circumference for predicting CVD was 90 cm in men (age-adjusted hazard ratio=1.81; 95% CI, 1.19 to 2.74; P=0.005) and 80 cm in women (age-adjusted hazard ratio=1.46; 95% CI, 0.99 to 2.16; P=0.05). A comparison of MetS criteria showed that the modified Japanese criteria using this cutoff point instead of the original definition were the strongest predictor of CVD events in both sexes (men: age-adjusted hazard ratio=2.58; 95% CI, 1.65 to 4.02; P<0.001; women: age-adjusted hazard ratio=2.39; 95% CI, 1.65 to 3.48; P<0.001). These observations remained robust even after adjustment for other confounding factors. According to this criteria set, only in the presence of central obesity, the hazard ratios for future CVD increased significantly as the number of MetS components increased, and a significant relationship was identified from 2 or more MetS components compared with individuals who had no MetS component., Conclusions: Our findings suggest that the optimal cutoff point of waist circumference is 90 cm in men and 80 cm in women and that the modified Japanese criteria of MetS with this cutoff point as an essential component better predict CVD in the general Japanese population.

Background & Aims: Although diabetes mellitus and hyperglycemia are considered to be possible risk factors for various types of malignancy, the epidemiologic evidence concerning gastric cancer is scarce. The aim of this study was to evaluate the impact of hemoglobin A1c (HbA1c) levels on gastric cancer occurrence and their interaction with Helicobacter pylori infection., Methods: A total of 2603 Japanese subjects aged>or=40 years were stratified into 4 groups according to baseline HbA1c levels (or=7.0%) and followed up prospectively for 14 years., Results: During the follow-up, 97 subjects developed gastric cancer. The age- and sex-adjusted incidence of gastric cancer significantly increased in the 6.0%-6.9% (5.1 per 1000 person-years; P<.05) and >or=7.0% groups (5.5 per 1000 person-years; P<.05) compared with the 5.0%-5.9% group (2.5 per 1000 person-years), whereas it was slightly but not significantly high in the or=7.0% group). Among subjects who had both high HbA1c levels (>or=6.0%) and Helicobacter pylori infection, the risk of gastric cancer was dramatically elevated (interaction term, P=.004)., Conclusions: Our findings suggest that casual hyperglycemia is a risk factor for gastric cancer and is a possible cofactor increasing the risk posed by Helicobacter pylori infection.

Background and Purpose: After the first genomewide association study of ischemic stroke identified PDE4D as a susceptible gene, many replication studies have been conducted. However, the validity of the association has remained controversial because of the heterogeneity of both genetic markers and phenotypes., Methods: We investigated the association between variations of PDE4D and ischemic stroke by 3 methods: single-marker, haplotype, and tag-single nucleotide polymorphism (SNP) analyses. In the single-marker analysis, we evaluated the association using 2 large case-control samples (1112 cases and 1112 control subjects in a sample obtained from Kyushu, Japan, and 1711 cases and 1786 control subjects in BioBank Japan) and a prospective cohort with 14 years of follow-up. These samples were analyzed both separately and pooled. Haplotype and tag-SNP analyses were performed using the 2 case-control samples together., Results: In single-marker association tests, we found no significant association in the same direction among the 6 SNP reported in the initial study and ischemic stroke subtypes. Haplotype analysis revealed no significant association between the region around the 5'-end of the gene and combined atherothrombotic and cardioembolic infarction. Rs7730070, a SNP located around the 3'-end of PDE4D, showed the lowest nominal probability value by tag-SNP analysis but was not significant after adjustment for multiple testing (adjusted probability value =0.36)., Conclusions: These results suggest that variations in PDE4D are not associated with ischemic stroke risk in the Japanese population.

Background and Purpose: Although the relation between serum LDL cholesterol level and coronary heart disease (CHD) is well established, its relation with stroke subtypes is less clear., Methods: A total of 2351 inhabitants age >or=40 years in a Japanese community were followed up for 19 years., Results: During follow-up, 271 subjects developed stroke and 144 developed CHD. Whereas the age- and sex-adjusted incidences of CHD significantly increased with increasing LDL cholesterol levels (P for trend <0.001), the associations between LDL cholesterol level and the incidences of ischemic or hemorrhagic stroke were not significant. The age- and sex-adjusted incidences of atherothrombotic infarctions (ATIs) and lacunar infarctions (LIs) significantly increased with increasing LDL cholesterol level (P for trend=0.03 for ATIs and=0.02 for LIs), but no such association was observed for cardioembolic infarction. After multivariate adjustment, the positive associations of LDL cholesterol level with the risks of ATI and CHD remained significant (P for trend=0.02 for ATIs and=0.03 for CHD), whereas the association with LIs was not significant. The risk of ATI significantly increased in the fourth quartile of LDL cholesterol compared with the first quartile (multivariate-adjusted hazard ratio=2.84; 95% CI, 1.17 to 6.93). The multivariate-adjusted risks for developing nonembolic infarction (ATIs and LIs) and CHD were significantly elevated in the groups with elevated LDL cholesterol values with and without the metabolic syndrome., Conclusions: Our findings suggest that an elevated LDL cholesterol level is a significant risk factor for developing ATI as well as CHD, and these associations are independent of the metabolic syndrome.

Background: There have been few population-based studies of the seroprevalence and correlates of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in Japan., Methods: We enrolled a total of 1244 adults, aged 18-59 years, from a population-based cohort in southern Japan, and tested their serum samples using an ELISA kit containing HSV type-specific antigens to glycoproteins G1 and G2., Results: The seroprevalence of HSV-1 and HSV-2 was 55.4% and 7.4% in men and 63.3% and 9.3% in women, respectively. Overall, 4 percent of the participants (2.3% of men and 5.0% of women) were co-infected with HSV-1 and HSV-2. The seroprevalences of both HSV-1 and HSV-2 increased with age in both sexes, and were always higher among women than among men in each age bracket. The prevalence of HSV-2 infection among HSV-1 infected individuals was lower than that among uninfected individuals, both in men and women. Male current drinkers, and male and female current smokers, were more likely to be infected with HSV-1 and HSV-2, as compared to never drinkers and never smokers, respectively., Conclusion: It is hoped that the estimates produced in this study will help in understanding the burden of these infections in Japan.

The authors assessed the separate and joint influences of cigarette smoking and Helicobacter pylori infection on the development of gastric cancer in a population-based prospective study. A total of 1,071 Japanese men aged > or =40 years were followed up prospectively for 14 years (1998-2002). Compared with that for current nonsmokers, the multivariate-adjusted hazard ratios of gastric cancer for smokers of 1-9, 10-19, and > or =20 cigarettes per day were 1.36 (95% confidence interval (CI): 0.50, 3.71), 1.93 (95% CI: 1.01, 3.67), and 1.88 (95% CI: 1.02, 3.43), respectively. The risk of gastric cancer increased steeply for subjects who had both a smoking habit and H. pylori infection compared with those who did not have both risk factors (hazard ratio = 11.41, 95% CI: 1.54, 84.67). If causal, the estimated population attributable fraction of gastric cancer for cigarette smoking was approximately half that for H. pylori infection (28.4% vs. 56.2%). The overlap of the population attributable fractions for the 2 factors was 49.6%. Findings suggest that cigarette smoking and H. pylori infection are significant risk factors for gastric cancer in Japanese men, and the magnitude of their combined influence is considerable.

Objective: We examined the relationship between fasting plasma glucose (FPG) and 2-h post-load glucose (PG) levels, and the optimal FPG cutoff level to correspond to a 2-h PG of 11.1 mmol/liter, the gold standard diagnostic criterion, in a general Japanese population., Design: Cross-sectional study populations of 2421 subjects in 1988 and 2698 subjects in 2002, aged 40-79 yr and without antidiabetic medication, were tested with an oral glucose tolerance test. The relationship between FPG and 2-h PG was investigated by various regression models and a receiver operating characteristic curve., Results: The best-fit model for the relationship between FPG and 2-h PG was a quadratic regression model. The FPG cutoff levels corresponding to the 2-h PG of 11.1 mmol/liter by this model were 6.2 mmol/liter in 1988 and 6.3 mmol/liter in 2002. In the combined populations, the FPG cutoff point was 6.3 mmol/liter; the sensitivity and specificity of this cutoff point for detecting a 2-h PG of 11.1 mmol/liter were 75.2 and 88.6%, respectively. The receiver operating characteristic curve analysis confirmed that the corresponding FPG point was 6.2 mmol/liter in both the 1988 and 2002 populations. In a stratified analysis, the FPG cutoff level increased with increasing body mass index levels; however, even in subjects with body mass index more than or equal to 30 kg/m2, the FPG cutoff level was lower than 7.0 mmol/liter., Conclusions: Our findings suggest that the FPG cutoff level corresponding to the 2-h PG of 11.1 mmol/liter in the general Japanese population is lower than the current diagnostic criterion.

A methodology for modeling covariate effects on the time-to-event data is developed. The covariates are allowed to be time dependent and their effects are modeled using polynomial splines in order to account for possibly non-linear effects. The methodology is applied to examine the effects on the incidence brain infarction based on a cohort study in Hisayama, Japan. The results indicate that at least two non-linear effects are significant (body mass index and systolic blood pressure) and there is a time-varying drug effect. The resulting significant risk factors are assessed by the proposed method that is more flexible and hence less biased than the traditional procedures where linear effects are imposed. These results are extremely important to the local medical investigation. In particular, more insight has been gained by examining the non-linear effects., (2008 John Wiley & Sons, Ltd)

Objective: The purpose of this study was to investigate the effects of high-sensitivity C-reactive protein (hs-CRP) on the risks of coronary heart disease (CHD) in a general population of Japanese., Methods and Results: The Hisayama study is a population-based prospective cohort study. A total of 2589 participants aged 40 years or older were followed up for 14 years. Outcomes are incident CHD (myocardial infarction, coronary revascularization, and sudden cardiac death). The median hs-CRP level was 0.43 mg/L at baseline. During the follow-up period, 129 coronary events were observed. Age- and sex-adjusted annual incidence rates of CHD rose progressively with higher hs-CRP levels: 1.6, 3.3, 4.5, and 7.4 per 1000 person-years for quartile groups defined by hs-CRP levels of <0.21, 0.21 to 0.43, 0.44 to 1.02, and >1.02 mg/L, respectively (P<0.0001 for trend). The risk of CHD in the highest quartile group was 2.98-fold (95% CI, 1.53 to 5.82) higher than that in the lowest group even after controlling for other cardiovascular risk factors., Conclusions: hs-CRP levels were clearly associated with future CHD events in a general population of Japanese. In Japanese populations, the hs-CRP cut-off point for high-risk of future development of CHD is likely to be >1.0 mg/L, which is much lower than that for Western populations.

The results of prospective studies that have examined the association between serum cholesterol levels and the incidence of gastric cancer remain controversial. To examine this issue in a general population, a total of 2,604 subjects aged 40 years or older were followed up prospectively for 14 years. During the follow-up period, gastric cancer developed in 97 subjects. The age- and sex-adjusted incidence of gastric cancer by quartiles of serum cholesterol level, namely, <4.06, 4.06-5.32, 5.33-6.04 and >or=6.05 mmol/L, were 3.9, 3.3, 3.1 and 2.1 per 1,000 person-years, respectively. The risk of gastric cancer increased with decreasing cholesterol level (age- and sex-adjusted hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.01-1.49; p = 0.04 for a decrease of 1 mmol/L in serum cholesterol level). This inverse association remained unchanged even after adjustment for other confounding factors, namely, Helicobacter pylori infection, atrophic gastritis, family history of malignant neoplasm, smoking habits, body mass index, hemoglobin A1c, white blood cell count and dietary factors (adjusted HR, 1.28; 95% CI, 1.03-1.58; p = 0.02). This association was significant for intestinal-type gastric cancers, but not for diffuse-type. As regards cancer stage, the inverse cholesterol-cancer association was marginally significant for early gastric cancer after multivariate-adjustment (adjusted HR, 1.25; 95% CI, 0.97-1.61; p = 0.09), but was not for advanced gastric cancer probably due to the small number of cases. In conclusion, our findings suggest that low serum cholesterol levels are an independent risk factor for developing gastric cancer, especially intestinal-type gastric cancer., ((c) 2007 Wiley-Liss, Inc.)

Objective: The association between the E23K polymorphism of ATP-sensitive K(+) channel subunit Kir6.2 and diabetes has been reported in Caucasians but not in Asians. We examined this issue in follow-up and cross-sectional studies in a general Japanese population., Research Design and Methods: In a 14-year follow-up study of 976 subjects aged 40-79 years with normal glucose tolerance (NGT), we investigated the impact of the E23K polymorphism on change of glucose tolerance status using a 75-g oral glucose tolerance test. Additionally, we confirmed this association in a cross-sectional survey of 2,862 subjects., Results: In the follow-up study, the frequencies of the K/K genotype or K-allele were significantly higher in subjects with conversion from NGT to diabetes than in those in whom NGT was maintained (genotypes, P = 0.01; alleles, P = 0.008). In multivariate analysis, the risk for progression to diabetes was significantly higher in subjects with the E/K (odds ratio 2.10 [95% CI 1.16-3.83]) and K/K (2.40 [1.01-5.70], P for trend = 0.01) genotypes than in those with the E/E genotype after adjustment for confounding factors, namely, age, sex, fasting plasma glucose, family history of diabetes, BMI, physical activity, current drinking, and current smoking. In the cross-sectional study, the frequencies of the K/K genotype or K-allele were also significantly higher in those with diabetes than in those with NGT (genotypes, P = 0.006; alleles, P = 0.001)., Conclusions: Our findings suggest that the Kir6.2 E23K polymorphism is an independent genetic risk factor for diabetes in the general Japanese population.

Background and Purpose: The metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease (CVD) events in general populations. However, well-designed prospective studies in Asian populations are very limited., Methods: We prospectively evaluated a total of 2452 community-dwelling Japanese individuals aged 40 years or older from 1988 to 2002 and examined the effects of MetS defined by the modified National Cholesterol Education Program Adult Treatment Panel III criteria on incident CVD., Results: The prevalence of the MetS was 21% in men and 30% in women at baseline. During the follow up, 307 CVD events occurred. Compared with those without MetS, the age-adjusted incidence of CVD (per 1000 person-years) was significantly higher in subjects with the MetS in both men (21.8 versus 11.6, P<0.01) and women (12.9 versus 6.5, P<0.01). The risk of CVD events was significantly higher even after adjusting for the following confounding factors: age, proteinuria, electrocardiographic abnormalities, serum total cholesterol, smoking habits, alcohol intake, and regular exercise (hazard ratio, 1.86; 95% CI, 1.32 to 2.62 in men and hazard ratio, 1.70; 95% CI, 1.22 to 2.36 in women). The risk of incident CVD was found to increase with the number of components of MetS and became significantly predictive when the number of components reached 3. Similar associations were also observed when CVD was divided into coronary heart disease and stroke., Conclusions: Our findings suggest that MetS is a significant risk factor for the development of CVD in the Japanese middle-aged population.

Brain infarction is one of the common causes of death and also a major cause of severe disability. To identify a gene(s) susceptible to brain infarction, we performed a large-scale association study of Japanese patients with brain infarction, using 52608 gene-based single nucleotide polymorphism (SNP) markers. Comparison of allele frequencies between 1112 cases with brain infarction and age- and sex-matched control subjects of the same number found an SNP in the 5'-flanking region of angiotensin receptor like-1 (AGTRL1) gene (rs9943582, - 154G/A) to have a significant association with brain infarction [odds ratio = 1.30, 95% confidence interval (CI) = 1.14-1.47, P = 0.000066]. We also found the binding of Sp1 transcription factor to the region including the susceptible G allele, but not the non-susceptible A allele. Luciferase assay and RT-PCR analysis demonstrated that exogenously introduced Sp1 induced transcription of AGTRL1 and its ligand, apelin, as well, indicating direct regulation of apelin/APJ pathway by Sp1. Furthermore, a 14 year follow-up cohort study in a Japanese community in Hisayama town, Japan revealed that the homozygote of the susceptible G allele of this particular SNP had significantly higher risk of brain infarction (hazard ratio = 2.00, 95% CI = 1.22-3.29, P = 0.006). Our results indicate that the SNP in the AGTRL1 gene is associated with the susceptibility to brain infarction.

The results of prospective studies of the association between dietary salt intake and gastric cancer occurrence remain controversial. To examine this issue in a cohort study of a general population, 2,476 subjects aged 40 years or older were stratified into 4 groups according to the amount of daily salt intake: namely, <10.0, 10.0-12.9, 13.0-15.9, and > or = 16.0 per day and were followed up prospectively for 14 years. During the follow-up period, 93 subjects developed gastric cancer. The age- and sex-adjusted incidence was significantly higher in the second to fourth groups than in the first group (age- and sex-adjusted hazard ratio [95% confidence interval], 2.42 [1.24-4.71] for the second group; 2.10 [1.03-4.30] for the third group; 2.98 [1.53-5.82] for the fourth group). This association remained substantially unchanged even after adjusting for other confounding factors such as age, sex, Helicobacter pylori infection, atrophic gastritis, medical history of peptic ulcer, family history of cancer, body mass index, diabetes, total cholesterol, physical activity, alcohol intake, smoking habit and other dietary factors. In the stratified analysis, a significant salt-cancer association was observed only in subjects who had both Helicobacter pylori infection and atrophic gastritis (age- and sex-adjusted hazard ratio, 2.87 [1.14-7.24]). Our findings suggest that high dietary salt intake is a significant risk factor for gastric cancer; moreover, this association was found to be strong in the presence of Helicobacter pylori infection with atrophic gastritis.