Association between DNA methylation levels of thioredoxin-interacting protein (TXNIP) and changes in glycemic traits: a longitudinal population-based study.

Thioredoxin-interacting protein (TXNIP) plays an important role in glucose metabolism, and its expression is regulated by DNA methylation (DNAm). Although the association between TXNIP DNAm and type 2 diabetes mellitus has been demonstrated in studies with a cross-sectional design, prospective studies are needed. We therefore examined the association between TXNIP DNAm levels and longitudinal changes in glycemic traits by conducting a longitudinal study involving 169 subjects who underwent two health checkups in 2015 and 2019. We used a pyrosequencing assay to determine TXNIP DNAm levels in leukocytes (cg19693031). Logistic regression analyses were performed to assess the associations between dichotomized TXNIP DNAm levels and marked increases in glycemic traits. At four years, the TXNIP DNA hypomethylation group had a higher percentage of changes in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) compared to those in the hypermethylation group. The adjusted odds ratios for FPG and HbA1c levels were significantly higher in the TXNIP DNA hypomethylation group than in the hypermethylation group. We found that TXNIP DNA hypomethylation at baseline was associated with a marked increase in glycemic traits. Leukocyte TXNIP DNAm status could potentially be used as an early biomarker for impaired glucose homeostasis.

Serum carotenoid levels are positively associated with DNA methylation of thioredoxin-interacting protein.

Background: Carotenoids have been reported to exert protective effects against age-related diseases via changes in DNA methylation. Although lower thioredoxin-interacting protein (TXNIP) DNA methylation is associated with age-related diseases, only a few studies have investigated the factors influencing TXNIP DNA methylation. Carotenoids may be a factor linking TXNIP to specific pathophysiological functions. The aim of this study was to examine whether serum carotenoid levels are associated with TXNIP DNA methylation levels. Methods: We conducted a cross-sectional study using 376 health examination participants (169 men). DNA methylation levels were determined using a pyrosequencing assay. Serum carotenoid levels were determined by high-performance liquid chromatography. Multivariable regression analyses were performed to examine the associations between TXNIP DNA methylation levels and serum carotenoid levels with adjustment for age, BMI, HbA1c, CRP, smoking habits, alcohol consumption, exercise habits, and percentage of neutrophils. Results: Multiple linear regression analyses showed that TXNIP DNA methylation levels were positively associated with serum levels of zeaxanthin/lutein (ß [95%CI]: 1.935 [0.184, 3.685]), ß-cryptoxanthin (1.447 [0.324, 2.570]), α-carotene (1.061 [0.044, 2.077]), ß-carotene (1.272 [0.319, 2.226]), total carotenes (1.255 [0.040, 2.469]), total xanthophylls (2.133 [0.315, 3.951]), provitamin A (1.460 [0.402, 2.519]), and total carotenoids (1.972 [0.261, 3.683]) in men (all p<0.05). Of these, provitamin A showed the stronger association (standardized ß=0.216). No significant association of TXNIP DNA methylation and serum carotenoid was observed in women. Conclusions: The findings of this study suggest that carotenoid intake may protect against age-related diseases by altering TXNIP DNA methylation status in men.

Maternal fructose intake predisposes rat offspring to metabolic disorders via abnormal hepatic programming.

Given that fructose consumption has increased by more than 10-fold in recent decades, it is possible that excess maternal fructose consumption causes harmful effects in the next generation. This study attempted to elucidate the mechanism of the harmful effects of excessive maternal fructose intake from the perspective of offspring liver function. Female rats during gestation and lactation were fed water containing fructose, and their offspring were fed normal water. We attempted to elucidate the mechanism of fructose-induced transgenerational toxicity by conducting a longitudinal study focusing on hepatic programming prior to disease onset. Impaired Insulin resistance and decreased high-density lipoprotein-cholesterol levels were observed at 160 days of age. However, metabolic disorders were not observed in 60-day-old offspring. Microarray analysis of 60-day-old offspring livers showed the reduction of hepatic insulin-like growth factor-1 (Igf1) mRNA expression. This reduction continued until the rats were aged 160 days and attenuated Igf1 signaling. Hepatic microRNA-29 (miR-29a) and miR-130a, which target Igf1 mRNA, were also found to be upregulated. Interestingly, these miRNAs were upregulated in the absence of metabolic disorder. In this study, we found that maternal fructose intake resulted in dysregulated expression of Igf1 and its target miRNAs in the offspring liver, and that these offspring were more likely to develop metabolic disorders. Abnormal hepatic programming induced by an imbalanced maternal nutritional environment is maintained throughout life, implying that it may contribute to metabolic disorders.

Circulating microRNA-27a and -133a are negatively associated with incident hypertension: a five-year longitudinal population-based study.

BACKGROUND: Previous cross-sectional studies have shown that several circulating microRNA levels are associated with hypertension, but there are no prospective studies among general populations. OBJECTIVE: We evaluated the impact of circulating inflammatory- and oxidative stress-responsive microRNAs on changes in blood pressure and the development of hypertension in normotensive Japanese. METHOD: The study subjects were 84 normotensive participants (33 men and 51 women) who were given a health examination in both 2012 and 2017. In five years, 29 participants developed hypertension. Serum levels of miRNAs (miR-21, miR-27a, and miR-133a) were measured using qRT-PCR. Odds ratios (ORs) and 95% confidence intervals (CIs) for incident hypertension were estimated by logistic regression analysis. RESULTS: Serum miR-27a and -133a levels were lower in newly hypertensive subjects compared with normotensive subjects. With 1-unit lower serum miR-27a and -133a, the confounders adjusted ORs and 95% CI for incident hypertension were 0.84 (0.72-0.96) and 0.75 (0.58-0.91), respectively. The group with high levels of serum miR-27a and -133a had lower ORs than the group with low levels of these miRNAs (OR and 95% CI of miR-27a: 0.29, 0.08-0.91; miR-133a: 0.08, 0.01-0.37, respectively). CONCLUSIONS: Circulating miR-27a and -133a are potential biomarkers for the prediction and prevention of hypertension.

A Nationwide Epidemiological Survey of Adolescent Patients With Diverse Symptoms Similar to Those Following Human Papillomavirus Vaccination: Background Prevalence and Incidence for Considering Vaccine Safety in Japan.

BACKGROUND: Since June 2013, Japan has suspended proactive recommendation of human papillomavirus (HPV) vaccination due to self-reported diverse symptoms, including pain and motor dysfunction, as possible serious adverse events following immunization. Although these symptoms may be seen in adolescents without HPV vaccination, their frequency, taking into account disease severity, has not been examined. METHODS: A two-stage, descriptive, nationwide epidemiological survey was conducted in 2016, with a 6-month target period from July 1 to December 31, 2015, to estimate the prevalence and incidence of diverse symptoms among Japanese adolescents without HPV vaccination. Participants were 11,037 medical departments in hospitals selected nationwide by stratified random sampling. Eligible patients had to satisfy four criteria: (1) aged 12-18 years upon visiting hospital; (2) having at least one of four symptoms/disorders (pain or sensory dysfunction, motor dysfunction, autonomic dysfunction, or cognitive impairment); (3) symptoms/disorders persisting for at least 3 months; and (4) both criteria (2) and (3) influence attendance at school or work. We then extracted data of patients with diverse symptoms similar to those after HPV vaccination while considering opinions of doctors in charge. RESULTS: Estimated 6-month period prevalence of diverse symptoms among girls aged 12-18 years without HPV vaccination was 20.2 per 100,000. Annual incidence was estimated to be 7.3 per 100,000. CONCLUSION: Adolescent Japanese girls without HPV vaccination also visited hospitals with diverse symptoms similar to those following HPV vaccination. Our findings predict the medical demands for coincident diverse symptoms, which are temporally associated with but not caused by HPV vaccination of Japanese adolescents.

DNA methylation level of the gene encoding thioredoxin-interacting protein in peripheral blood cells is associated with metabolic syndrome in the Japanese general population.

Metabolic syndrome (MetS) is cluster of metabolic diseases, including abdominal obesity, hyperglycemia, high blood pressure, and dyslipidemia, that directly escalate the risk of type 2 diabetes, heart disease, and stroke. Thioredoxin-interacting protein (TXNIP) is a binding protein for thioredoxin, a molecule that is a key inhibitor of cellular oxidation, and thus regulates the cellular redox state. Epigenetic alteration of the TXNIP-encoding locus has been associated with components of MetS. In the present study, we sought to determine whether the level of TXNIP methylation in blood is associated with MetS in the general Japanese population. DNA was extracted from the peripheral blood cells of 37 subjects with and 392 subjects without MetS. The level of TXNIP methylation at cg19693031 was assessed by the bisulfite-pyrosequencing method. We observed that TXNIP methylation levels were lower in MetS subjects (median 74.9%, range 71.7-78.4%) than in non-MetS subjects (median 77.7%, range 74.4-80.5%; p = 0.0024). Calculation of the confounding factor-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for hypomethylation revealed that subjects with MetS exhibited significantly higher ORs for hypomethylation than did those without MetS (OR, 2.92; 95% CI, 1.33-6.62; p = 0.009). Our findings indicated that lower levels of TXNIP methylation are associated with MetS in the general Japanese population. Altered levels of DNA methylation in TXNIP at cg19693031 might play an important role in the pathogenesis of MetS.

Association between the Extent of Peripheral Blood DNA Methylation of HIF3A and Accumulation of Adiposity in community-dwelling Women: The Yakumo Study.

INTRODUCTION: DNA methylation in the CpG sites of intron 1 of HIF3A is associated with body mass index (BMI). This cross-sectional study investigated correlations between DNA methylation of HIF3A and BMI or adiposity parameters in the Japanese population. METHOD: DNA methylation of HIF3A was quantified via pyrosequencing. RESULT: DNA methylation of HIF3A differed only in women; DNA methylation level at cg27146050 was associated with visceral adipose tissue thickness and correlated with BMI and percent (%) body fat after excluding smokers. CONCLUSION: Peripheral blood DNA methylation at the CpG site (cg27146050) of HIF3A correlated with VAT thickness in Japanese women.

Association of drinking behaviors with TXNIP DNA methylation levels in leukocytes among the general Japanese population.

Background: Thioredoxin-interacting protein (TXNIP) controls the cellular redox balance by binding to and inhibiting the expression and function of thioredoxin. DNA methylation of the TXNIP gene is involved in the regulation of TXNIP mRNA expression. Changes in TXNIP DNA methylation levels are associated with the development of various diseases such as type 2 diabetes mellitus (T2DM). However, few studies have focused on the influence of lifestyle factors such as alcohol intake on TXNIP DNA methylation.Objectives: This research examines the association of drinking behaviors with TXNIP DNA methylation levels in the general Japanese population.Methods: We conducted a cross-sectional study of 404 subjects (176 males and 228 females) who were divided into non-, moderate and heavy drinkers based on self-reported drinking behaviors. TXNIP DNA methylation levels in leukocytes were determined using a pyrosequencing assay.Results: The mean TXNIP DNA methylation level in heavy drinkers (74.2%) was significantly lower than that in non- and moderate drinkers (non: 77.7%, p < .001; moderate: 76.6%, p = .011). Multivariable linear regression analysis showed that log-transformed values of daily (b = -1.34; p < .001) and cumulative (b = -1.06; p = .001) alcohol consumption were associated with decreased TXNIP DNA methylation levels.Conclusion: TXNIP DNA methylation levels in heavy drinkers was lower than in non- and- moderate drinkers. Decreased TXNIP DNA methylation level increases the expression of TXNIP and elevates the risk of developing of diseases such as T2DM. Therefore, decreasing alcohol use in heavy drinkers may lessen the likelihood of some alcohol-related illnesses moderated through TXNIP DNA methylation.

Time Course of Coronary Artery Aneurysms in Kawasaki Disease.

OBJECTIVES: To determine the timeframe in which coronary artery aneurysms (CAAs) caused by Kawasaki disease reach their maximum diameter, the timeframe in which they regress to normal size, and the cutoff point of the diameter for CAA regression. STUDY DESIGN: We reviewed 195 CAAs of the right coronary artery, left anterior descending artery, and left coronary artery measured by 2-dimensional echocardiography ≥5 times for 1 year after Kawasaki disease in 84 patients using medical records from 1995. The maximum diameters of CAAs were investigated retrospectively. The time to CAA regression using both absolute diameter and Z score were investigated. The cutoff points of the diameter of CAA regression in the 2 classifications were identified using receiver operator characteristic curve analysis. One year after Kawasaki disease, a CAA of <3.0 mm in absolute diameter and a Z score of <2.5 were defined as CAA regression. RESULTS: The time when CAAs reached their maximum diameter ranged from 11 days to 87 days, with a median of 35 days (n = 195). The time to CAA regression ranged from 41 to 386 days, with a median of 136 days in the absolute diameter classification (n = 92); 78% of CAA regression regressed by 200 days. The cutoff point for CAA regression at one year was 5.7 mm for the absolute diameter (area under the curve, 0.887; P < .0001; n = 190) and 9.5 for the Z score (area under the curve, 0.815; P < .0001; n = 195). CONCLUSIONS: CAAs with a smaller diameter regressed earlier, and most CAAs of <6 mm regressed by 6 months after Kawasaki disease.

Study Profile of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study.

BACKGROUND: The Japan Multi-institutional Collaborative Cohort (J-MICC) study was launched in 2005 to examine gene-environment interactions in lifestyle-related diseases, including cancers, among the Japanese. This report describes the study design and baseline profile of the study participants. METHODS: The participants of the J-MICC Study were individuals aged 35 to 69 years enrolled from respondents to study announcements in specified regions, inhabitants attending health checkup examinations provided by local governments, visitors at health checkup centers, and first-visit patients at a cancer hospital in Japan. At the time of the baseline survey, from 2005 to 2014, we obtained comprehensive information regarding demographics, education, alcohol consumption, smoking, sleeping, exercise, food intake frequency, medication and supplement use, personal and family disease history, psychological stress, and female reproductive history and collected peripheral blood samples. RESULTS: The baseline survey included 92,610 adults (mean age: 55.2 [standard deviation, 9.4] years, 44.1% men) from 14 study regions in 12 prefectures. The participation rate was 33.5%, with participation ranging from 19.7% to 69.8% in different study regions. The largest number of participants was in the age groups of 65-69 years for men and 60-64 years for women. There were differences in body mass index, educational attainment, alcohol consumption, smoking, and sleep duration between men and women. CONCLUSIONS: The J-MICC Study collected lifestyle and clinical data and biospecimens from over 90,000 participants. This cohort is expected to be a valuable resource for the national and international scientific community in providing evidence to support longer healthy lives.

Impact of musculoskeletal disorders on healthy life expectancy in Japan.

BACKGROUND: Musculoskeletal disorders are a key cause of morbidity in elderly people. How musculoskeletal disorders relate to healthy life expectancy remain elusive. Hence, we aimed to estimate gains in healthy life expectancy from the elimination of musculoskeletal diseases and injuries by using recent national health statistics data in Japan. METHODS: Mortality data were taken from Japanese national life tables and death certificates in 2016. Information on medical diagnoses, injuries, and activity were obtained from the 2016 Comprehensive Survey of Living Conditions. We examined five disorders: rheumatoid arthritis, arthrosis, low back pain, osteoporosis, and fracture. The prevalence of limitations in activities of daily living (ADL) in the population after eliminating the disorder was estimated as the proportion of outpatients without the disorder and ADL limitations, inpatients without the disorder in hospitals and clinics, and people without the disorder who reside in long-term elderly care facilities. RESULTS: There were small gains in life expectancy from elimination of all selected musculoskeletal disorders (0.0-0.1 years). Elimination of rheumatoid arthritis, osteoporosis, and fracture slightly increased the expected years without activity limitation (0.1-0.4) and slightly decreased years with activity limitation (0.1-0.4 years). Meanwhile, elimination of arthrosis, low back pain, and arthrosis and low back pain moderately increased expected years without activity limitation (0.3-1.5 years) and decreased years with activity limitation (0.3-1.5 years). In addition, elimination of rheumatoid arthritis, arthrosis, low back pain, osteoporosis, and fracture decreased expected years with ADL limitations (0.0-0.8 years) and non-ADL limitations (0.0-0.3 years). A combination of arthrosis and low back pain showed a moderate decrease in expected years with both ADL limitations (0.7-1.1 years) and non-ADL limitations (0.3-0.4). CONCLUSIONS: These findings provide clinical evidence that among the musculoskeletal disorders low back pain and arthrosis are the key factors for the elongation of healthy life expectancy.

Changes in Coronary Aneurysm Diameters After Acute Kawasaki Disease from Infancy to Adolescence.

We clarified the changes in coronary artery diameters based on the degree of coronary artery involvement immediately after acute Kawasaki disease (KD). Two hundred sixteen coronary arteries in 85 patients after KD examined by two-dimensional echocardiography were reviewed from 1995. The maximal internal diameters were measured at 2 months, 1 year, 3 years, 10 years and 15 years after KD. The coronary arteries were divided into five groups based on the absolute diameter at 2 months, as well as six groups based on the Z score at 2 months. The maximum diameters were compared at 2 months with those during follow-up in each group. The numbers of right coronary, left anterior descending, left coronary, and left circumflex arteries were 84, 73, 55 and 4, respectively. There was a significant relationship between the maximum internal diameter at 2 months and subsequent changes in the maximum diameters after KD in the late period in both groups (p < 0.0001). The maximum diameters of coronary artery aneurysms (CAAs) ≥ 8.0 mm at 2 months did not change significantly after 1 year, however, the maximum diameter of CAAs < 8.0 mm was significantly smaller in the late period (p < 0.05). Coronary arteries without dilatation at 2 months after KD grew normally. CAAs with a maximum diameter ≥ 6.0 mm and Z score ≥ 7.5 at 2 months after KD persisted in adolescents, whereas coronary arteries with diameters < 6.0 mm and Z score < 7.5 could be within normal ranges in the late period.

Characteristics of coronary flow velocity reserve on transthoracic Doppler echocardiography in patients with a history of Kawasaki disease.

Whether the acute inflammation caused by Kawasaki disease will have an effect on the endothelial function of coronary arteries in the future is unknown. METHODS: The coronary flow velocity reserve of the left anterior descending artery was examined by transthoracic Doppler echocardiography in 189 patients (male 125, female 64) with a history of Kawasaki disease and 10 volunteers (control). Their ages ranged from 6 to 40 years (median 22 years). The patients were divided into nine groups based on the left anterior descending artery lesions. The coronary flow velocity reserve was measured by intravenous administration of adenosine triphosphate (0.15 mg/kg/minute) while fasting. The coronary flow velocity reserve was calculated as the ratio of hyperaemic to basal mean diastolic flow velocities. The respective groups were as follows: control, no coronary artery lesions (n = 39), no coronary artery lesions in the right coronary artery (n = 29), regression (n = 11), aneurysm at the bifurcation of the left coronary artery (n = 26), aneurysm of the left anterior descending artery (n = 15), localised stenosis <75% (n = 12), localised stenosis ≥75% (n = 17), segmental stenosis (n = 5) and coronary artery bypass grafting (n = 36). One-factor ANOVA followed by Tukey's test was used to compare the coronary flow velocity reserve among the groups. RESULTS: The coronary flow velocity reserve was significantly lower in the localised stenosis ≥75%, segmental stenosis and coronary artery grafting groups than in the other groups (p < 0.05). CONCLUSIONS: The endothelial function in the epicoronary artery was preserved in patients with a history of Kawasaki disease and dilated coronary artery lesions.

Maternal fructose-induced oxidative stress occurs viaTfam and Ucp5 epigenetic regulation in offspring hippocampi.

Fructose consumption is rising globally, but maternal high fructose intake might adversely affect offspring. Our previous report demonstrated that excess maternal fructose intake impairs hippocampal function in offspring, indicating that the hippocampi of offspring are highly sensitive to maternal fructose. Here, we examined the effect of maternal high fructose on mitochondrial physiology and uncoupling protein (UCP) expression. Rat dams received a 20% fructose solution during gestation and lactation. Immediately after weaning, offspring hippocampi were isolated. Maternal high fructose consumption attenuated the mitochondrial O2 consumption rate and stimulated lipid hydroperoxide production in the hippocampi of offspring. Reduced Ucp5 and mitochondrial transcription factor A (Tfam) mRNA levels were also observed after maternal exposure to fructose. We assessed the promoter regions of both genes and found that this treatment enhanced DNA methylation levels. In addition, luciferase assays showed that this DNA methylation could reduce the transcription of both genes. Chromatin immunoprecipitation analysis demonstrated that specificity protein 1 binding to the Ucp5 promoter regions was reduced by DNA methylation. In addition, Ucp5 knockdown induced the up-regulation of reactive oxygen species levels in a rat brain glioma cell line, whereas reduced O2 consumption was observed with Tfam knockdown. Maternal high fructose intake thus induces reduced O2 oxygen consumption and increases oxidative stress in offspring, at least partly through epigenetic mechanisms involving Ucp5 and Tfam.-Yamada, H., Munetsuna, E., Yamazaki, M., Mizuno, G., Sadamoto, N., Ando, Y., Fujii, R., Shiogama, K., Ishikawa, H., Suzuki, K., Shimono, Y., Ohashi, K., Hashimoto, S. Maternal fructose-induced oxidative stress occurs viaTfam and Ucp5 epigenetic regulation in offspring hippocampi.

Estimating nationwide cases of sexually transmitted diseases in 2015 from sentinel surveillance data in Japan.

BACKGROUND: The rates of newly diagnosed cases of sexually transmitted diseases, including genital chlamydial infection and gonorrhea, are important for prevention and control of these diseases. However, nationwide rates are not reported in Japan. METHODS: We used the number of cases of sexually transmitted diseases reported by nationwide sentinel surveillance in 2015, together with the number of all disease outpatients in September 2014 at all medical institutions, drawn from the Survey of Medical Institutions of Japan. The number of cases of sexually transmitted diseases in the total population was estimated using the ratio estimation method with the number of all disease outpatients as auxiliary information. This method is currently used for estimating influenza cases from sentinel surveillance data in Japan. RESULTS: The estimated number of newly diagnosed cases per 100,000 population in 2015 in Japan was 244 (95% confidence interval 211-277) for genital chlamydial infection, 87 (95% confidence interval 74-100) for genital herpes, 61 (95% confidence interval 29-93) for condyloma acuminatum, and 89 (95% confidence interval 64-113) for gonorrhea. CONCLUSION: We estimated the nationwide number of newly diagnosed cases of sexually transmitted diseases in Japan from sentinel surveillance data. This provides useful information for public health policy-making.

Associations of Circulating MicroRNAs (miR-17, miR-21, and miR-150) and Chronic Kidney Disease in a Japanese Population.

BACKGROUND: MicroRNAs (miRNAs) play crucial roles in the development of various diseases, including chronic kidney disease (CKD). Although previous studies in clinically severe patients have investigated associations between CKD and miRNAs, with particular attention on renal fibrosis, relationships in a general population have yet to be established. The aim of this study was to examine the relationship between expression level of circulating miRNAs and CKD in a middle-aged Japanese population. METHODS: A final total of 513 individuals (216 men and 297 women) who participated in the health check-up program in 2012 were included in our analysis. Quantitative real-time polymerase chain reaction was used to determine expression levels of 22 miRNAs. Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine level, sex, and age. Participants with eGFR <60 mL/min/1.73 m2 were defined as having CKD. RESULTS: Three different miRNAs (miR-17, miR-21, and miR-150) showed significant correlations with eGFR after Bonferroni correction and were selected for further analyses. Expression levels of miR-17, miR-21, and miR-150 miRNAs were positively associated with eGFR after adjusting for potential confounders (P = 0.004, 0.002, and 0.004, respectively). Logistic regression analyses showed significantly lower odds ratios for CKD (eGFR <60 mL/min/1.73 m2) in the highest tertile of all three miRNAs (miR-17, miR-21, and miR-150) compared with the lowest tertile (P = 0.003, 0.01, and 0.02, respectively). CONCLUSIONS: We found that three circulating miRNAs were significantly associated with CKD in a general Japanese population, which suggested that these miRNAs may be biomarkers for CKD among general adults.

Excess maternal fructose consumption impairs hippocampal function in offspring via epigenetic modification of BDNF promoter.

Recent increases in fructose consumption have raised concerns about the potential adverse intergenerational effects of excess fructose intake. In the present study, we investigated whether excess maternal fructose intake affects hippocampal function in offspring. Female Sprague-Dawley rats were divided into 3 experimental groups: one group received distilled water, one group received 20% fructose water, and one group received 20% glucose water in addition to standard chow during gestation and lactation. Hippocampal function of offspring was evaluated by using novel object recognition and fear conditioning tests. Impaired cognitive performance was observed in the offspring of fructose-fed dams at postnatal d 60, potentially a result of decreased hippocampal neurogenesis. Real-time PCR analysis demonstrated that offspring from fructose-fed dams exhibited decreased brain-derived neurotrophic factor ( BDNF) gene expression, whereas pyrosequencing assays revealed increased DNA methylation at the BDNF promoter. The potential association between BDNF transcription and levels of DNA methylation was confirmed on the basis of luciferase activity. Furthermore, longitudinal analysis revealed that increased methylation of the BDNF promoter region was maintained at least until rats reached maturity. These results indicate that epigenetic changes associated with BDNF may underlie hippocampal dysfunction that is induced by early-life exposure to excess maternal fructose consumption.-Yamazaki, M., Yamada, H., Munetsuna, E., Ishikawa, H., Mizuno, G., Mukuda, T., Mouri, A., Nabeshima, T., Saito, K., Suzuki, K., Hashimoto, S., Ohashi, K. Excess maternal fructose consumption impairs hippocampal function in offspring via epigenetic modification of BDNF promoter.

Congenital limb deficiency in Japan: a cross-sectional nationwide survey on its epidemiology.

BACKGROUND: Congenital limb deficiency is a rare and intractable disease, which impairs both function and appearance of the limbs. To establish adequate medical care, it is necessary to reveal the actual conditions and problems associated with this disease. However, there have been no extensive epidemiological surveys in Japan addressing this disease. This is the first nationwide epidemiological survey of congenital limb deficiency in this country. METHODS: With the cooperation of epidemiology experts, we performed a two-stage nationwide survey to estimate the number of patients with congenital limb deficiency and reveal basic patient features. We targeted orthopaedic surgery, paediatric, and plastic surgery departments. Hospitals were categorized according to the institution type and the number of hospital beds; hospitals were randomly selected from these categories. We selected 2283 departments from a total 7825 departments throughout Japan. In this study, we defined congenital limb deficiency as partial or total absence of the limbs, proximal to the proximal interphalangeal joint of the fingers/lesser toes or interphalangeal joint of the thumb/great toe. We distributed the first survey querying the number of initial patient visits from January 2014 to December 2015. Targets of the second survey were departments that reported one or more initial patient visits in the first survey. RESULTS: In the first survey, 1767 departments responded (response rate: 77.4%). Among them, 161 departments reported one or more initial patient visits. We conducted the second survey among these 161 departments, of which 96 departments responded (response rate: 59.6%). The estimated number of initial visits by patients with congenital limb deficiency was 417 (95% confidence interval: 339-495) per year in 2014 and 2015. The estimated prevalence of congenital limb deficiency in Japan was 4.15 (95% confidence interval: 3.37-4.93) per 10,000 live births. The sex ratio was 1.40. Upper limbs were more affected than lower limbs. CONCLUSIONS: We revealed the estimated number of initial patient visits per year and birth prevalence of congenital limb deficiency in Japan. Our results will contribute to establishing the disease concept and grades of severity of congenital limb deficiency.

Association of Primary Hemodilution and Retrograde Autologous Priming with Transfusion in Cardiac Surgery: Analysis of the Perfusion Case Database of the Japanese Society of Extra-Corporeal Technology in Medicine.

It is important to avoid unnecessary blood cell transfusion. However, the associations of hemodilution and retrograde autologous priming with red blood cell transfusion during and after cardiopulmonary bypass (CPB) in cardiac surgery in Japan are currently unclear. We analyzed these associations using data for 3,090 adults from the Perfusion Case Database of the Japanese Society of Extra-Corporeal Technology in Medicine. Percent hemodilution was calculated by total priming volume and weight. Logistic regression models were used to adjust for covariates including type of surgery, gender, age, hemoglobin concentration before CPB, CPB time, urine volume during CPB, and institution. The percentages of red blood cell transfusions during CPB for patients with <15, 15 to <20, 20 to <25, 25 to <30, and ≥30% hemodilution were 43.0, 51.5, 68.9, 77.3, and 87.7%, respectively. This increase in line with increasing dilution was significant after adjusting for covariates. The percentage of red blood cell transfusion after CPB also increased slightly between 39.0 and 49.4% with percent hemodilution, but the trend after adjusting for covariates was not significant. Use of retrograde autologous priming was significantly associated with blood cell transfusion during CPB after adjusting for covariates, but was not significantly related to blood cell transfusion after CPB. These results suggest that optimizing the percent hemodilution and use of retrograde autologous priming might reduce the use of red blood cell transfusion during CPB in clinical practice in Japan.

[The number of deaths by suicide after the Great East Japan Earthquake based on demographic statistics in the coastal and non-coastal areas of Iwate, Miyagi, and Fukushima prefectures].

Objective　The number of deaths by suicide after the Great East Japan Earthquake was surveyed based on demographic statistics. In particular, this study examined whether or not there were excessive deaths due to suicide (excluding people who were injured in the earthquake) after the Great East Japan Earthquake disaster. This examination surveyed municipalities in coastal and non-coastal areas of Iwate, Miyagi, and Fukushima prefectures (referred to below as the "three prefectures").Methods　The demographic statistics questionnaire survey information supplied by Article 33 of the Statistics Act (Ministry of Health, Labour and Welfare's published statistics Vol. 0925 No.4, September 25th, 2014) were used as the basic data with particular reference to the information on the deaths from January 1st, 2010 to March 31st, 2013. The information obtained included the date of death, the municipality where the address of the deceased was registered, the gender of the deceased, age at the time of death, and cause of death codes (International Classification of Disease Codes 10th revision: ICD-10). Additionally, information was gathered about the population based on the resident register from 2009 to 2013 and the 2010 National Census; the number of deaths by suicide was then totalled by period and area. The areas were classified as municipalities within three prefectures and those located elsewhere using the municipality where the address of the deceased was registered.Results　The SMR for suicides did not show a tendency to increase for coastal or non-coastal areas throughout the two-year period after the earthquake disaster (from March 2011 to February 2013).　The SMR for the three prefectures 0-1 years after the disaster compared with the year before the disaster was 0.92 and for 1-2 years after the disaster was 0.93. Both these values were significantly low. Looking at both the non-coastal and coastal areas from each of the three prefectures, the SMR for suicides for 0-1 and 1-2 years after the disaster compared with the year before the disaster ranged from 0.73 to 1.07. None were significantly high.Conclusion　The above results indicate that there was no increase in deaths by suicide in these three prefectures in the two years following the earthquake disaster.