The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition.

Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 through genetic testing, which poses a significant clinical challenge because the contribution of these VUSs to cancer predisposition has not yet been determined. Here, we report 10 Japanese patients from seven families with breast or ovarian cancer harboring the BRCA2 c.7847C>T (p.Ser2616Phe) variant that was interpreted as a VUS. This variant recurs only in families from Japan and has not been reported in the global general population databases. A Japanese patient with Fanconi anemia with compound heterozygous variants c.7847C>T (p.Ser2616Phe) and c.475+1G>A in BRCA2 was reported. In silico predictions and quantitative cosegregation analysis suggest a high probability of pathogenicity. The clinical features of the variant carriers were not specific to, but were consistent with, those of patients with hereditary breast and ovarian cancer. A validated functional assay, called the mixed-all-nominated-in-one-BRCA (MANO-B) method and the accurate BRCA companion diagnostic (ABCD) test, demonstrated the deleterious effects of the variant. Altogether, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, this variant satisfied the "PS3," "PM2," "PM3," and "PP3" criteria. We thus conclude that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a "likely pathogenic" variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition.

Empathy experiences of Japanese certified genetic counselors: A qualitative investigation and proposed framework.

Empathy is an important element of genetic counseling. Most genetic counselors acknowledge the significance of empathically engaging clients. However, few empirical studies have focused on the empathy experience of genetic counselors, especially in non-Western countries. This study aimed to investigate Japanese genetic counselors' perspectives on the concept of empathy in clinical practice. The study conducted semi-structured interviews with Japanese certified genetic counselors who had approximately 10 years of clinical experience. Fourteen participants were interviewed about their thoughts on empathy and their experiences wherein they had deeply understood clients or felt closer to them. The interview data were analyzed using grounded theory. As a result, 17 categories were extracted, of which 13 were integrated into three themes of empathy: the empathic cycle in the relationships between genetic counselors and clients (cycling), the process of forming a deeper understanding of a client's perspectives (feeling), and the process of developing skills to understand clients with empathy (developing). The remaining four categories were grouped into the theme of "challenges of empathy." The categories included in the first three themes were similar to previous findings in Western countries, whereas some categories of challenges of empathy were unique to this study, which was conducted in a non-Western country. This might be attributed to the influence of Japanese culture, in which people emphasize self-regulation and an interdependent-self model. To our knowledge, this study is the first to report on Japanese certified genetic counselors' experiences of empathy. This study concludes with some suggestions for future research, including focusing on ways to overcome challenges of empathy in countries or healthcare systems.

Stool pattern is associated with not only the prevalence of tumorigenic bacteria isolated from fecal matter but also plasma and fecal fatty acids in healthy Japanese adults.

BACKGROUND: Colibactin-producing Escherichia coli containing polyketide synthase (pks+ E. coli) has been shown to be involved in colorectal cancer (CRC) development through gut microbiota analysis in animal models. Stool status has been associated with potentially adverse gut microbiome profiles from fecal analysis in adults. We examined the association between stool patterns and the prevalence of pks+ E. coli isolated from microbiota in fecal samples of 224 healthy Japanese individuals. RESULTS: Stool patterns were determined through factorial analysis using a previously validated questionnaire that included stool frequency, volume, color, shape, and odor. Factor scores were classified into tertiles. The prevalence of pks+ E. coli was determined by using specific primers for pks+ E. coli in fecal samples. Plasma and fecal fatty acids were measured via gas chromatography-mass spectrometry. The prevalence of pks+ E. coli was 26.8%. Three stool patterns identified by factorial analysis accounted for 70.1% of all patterns seen (factor 1: lower frequency, darker color, and harder shape; factor 2: higher volume and softer shape; and factor 3: darker color and stronger odor). Multivariable-adjusted odds ratios (95% confidence intervals) of the prevalence of pks+ E. coli for the highest versus the lowest third of the factor 1 score was 3.16 (1.38 to 7.24; P for trend = 0.006). This stool pattern exhibited a significant positive correlation with fecal isobutyrate, isovalerate, valerate, and hexanoate but showed a significant negative correlation with plasma eicosenoic acid and α-linoleic acid, as well as fecal propionate and succinate. No other stool patterns were significant. CONCLUSIONS: These results suggest that stool patterns may be useful in the evaluation of the presence of tumorigenic bacteria and fecal fatty acids through self-monitoring of stool status without the requirement for specialist technology or skill. Furthermore, it may provide valuable insight about effective strategies for the early discovery of CRC.

Mother-to-infant transmission of the carcinogenic colibactin-producing bacteria.

BACKGROUND: The Escherichia coli strain that is known to produce the genotoxic secondary metabolite colibactin is linked to colorectal oncogenesis. Therefore, understanding the properties of such colibactin-positive E. coli and the molecular mechanism of oncogenesis by colibactin may provide us with opportunities for early diagnosis or prevention of colorectal oncogenesis. While there have been major advances in the characterization of colibactin-positive E. coli and the toxin it produces, the infection route of the clb + strain remains poorly characterized. RESULTS: We examined infants and their treatments during and post-birth periods to examine potential transmission of colibactin-positive E. coli to infants. Here, analysis of fecal samples of infants over the first month of birth for the presence of a colibactin biosynthetic gene revealed that the bacterium may be transmitted from mother to infant through intimate contacts, such as natural childbirth and breastfeeding, but not through food intake. CONCLUSIONS: Our finding suggests that transmission of colibactin-positive E. coli appears to be occurring at the very early stage of life of the newborn and hints at the possibility of developing early preventive measures against colorectal cancer.

Comprehensive analysis of gut microbiota of a healthy population and covariates affecting microbial variation in two large Japanese cohorts.

BACKGROUND: Inter-individual variations in gut microbiota composition are observed even among healthy populations. The gut microbiota may exhibit a unique composition depending on the country of origin and race of individuals. To comprehensively understand the link between healthy gut microbiota and host state, it is beneficial to conduct large-scale cohort studies. The aim of the present study was to elucidate the integrated and non-redundant factors associated with gut microbiota composition within the Japanese population by 16S rRNA sequencing of fecal samples and questionnaire-based covariate analysis. RESULTS: A total of 1596 healthy Japanese individuals participated in this study via two independent cohorts, NIBIOHN cohort (n = 954) and MORINAGA cohort (n = 642). Gut microbiota composition was described and the interaction of these microorganisms with metadata parameters such as anthropometric measurements, bowel habits, medical history, and lifestyle were obtained. Thirteen genera, including Alistipes, Anaerostipes, Bacteroides, Bifidobacterium, Blautia, Eubacterium halli group, Faecalibacterium, Fusicatenibacter, Lachnoclostridium, Parabacteroides, Prevotella_9, Roseburia, and Subdoligranulum were predominant among the two cohorts. On the basis of univariate analysis for overall microbiome variation, 18 matching variables exhibited significant association in both cohorts. A stepwise redundancy analysis revealed that there were four common covariates, Bristol Stool Scale (BSS) scores, gender, age, and defecation frequency, displaying non-redundant association with gut microbial variance. CONCLUSIONS: We conducted a comprehensive analysis of gut microbiota in healthy Japanese individuals, based on two independent cohorts, and obtained reliable evidence that questionnaire-based covariates such as frequency of bowel movement and specific dietary habit affects the microbial composition of the gut. To our knowledge, this was the first study to investigate integrated and non-redundant factors associated with gut microbiota among Japanese populations.

Gut microbial composition in patients with atrial fibrillation: effects of diet and drugs.

Atrial fibrillation (AF) reduces the quality of life by triggering stroke and heart failure. The association between AF onset and gut metabolites suggests a causal relationship between AF and gut microbiota dysbiosis; however, the relationship remains poorly understood. We prospectively enrolled 34 hospitalized patients with AF and 66 age-, sex-, and comorbidity-matched control subjects without a history of AF. Gut microbial compositions were evaluated by amplicon sequencing targeting the 16S ribosomal RNA gene. We assessed differences in dietary habits by using a brief-type self-administered diet history questionnaire (BDHQ). Gut microbial richness was lower in AF patients, although the diversity of gut microbiota did not differ between the two groups. At the genus level, Enterobacter was depleted, while Parabacteroides, Lachnoclostridium, Streptococcus, and Alistipes were enriched in AF patients compared to control subjects. The BDHQ revealed that the intake of n-3 polyunsaturated fatty acids and eicosadienoic acid was higher in AF patients. Our results suggested that AF patients had altered gut microbial composition in connection with dietary habits.

[Investigation of the reproducibility and validity of a questionnaire on usual bowel movement patterns and stool characteristics compared to an evacuation diary].

Objective　Stool reflect our dietary and nutritional status as well as the characteristics of gut microbiota; thus, stool can be a convenient, noninvasive index for the evaluation of physical health and nutritional intake. However, there are few studies on appropriate tools for comprehensive and easy-to-perform objective assessments of stool. Therefore, there is a need for an effective questionnaire to accurately ascertain daily bowel movement patterns ("usual evacuation") and stool characteristics. Herein, we have created an assessment tool to determine stool characteristics (volume, color, form, etc.). To investigate the validity of this tool, we compared the results with evacuation diary data wherein the participants were asked to record the number of evacuations and stool characteristics.Methods　This study included 35 adult men and women, aged 22-78 years (45.2±17.1years). A questionnaire was administered to the subjects on usual stool characteristics for the most recent month, including the average number of evacuations, stool volume per evacuation, stool color and form, stool float, and abdominal bloating. To confirm the reproducibility of each item of this questionnaire, the survey was performed twice. Thereafter, an evacuation diary was used, wherein the subjects recorded the daily number of evacuations and stool characteristics for one week. Using the evacuation diary as the valid criterion for the number of evacuations and stool characteristics, we compared responses between the diary and the usual stool questionnaire. Additionally, the questionnaire had two types of responses for the number of evacuations, namely, multiple choice for categories indicating the number of evacuations and open answers using numerical values.Results　Assessment of the reproducibility of the questionnaire on usual stool by Spearman rank correlation coefficients showed a significant correlation (ρ=0.431-0.911) for all items. The weighted κ coefficient also showed high coincidence (weighted κ=0.348-0.841). Validity was assessed by comparing the number of evacuations per one-week period between the evacuation diary and the usual stool questionnaire. A higher correlation (ρ=0.855) was observed in the open responses for the number of evacuations per one-week period. Assessment of the correlations between median values for responses to stool characteristics in the one-week evacuation diary and the usual stool questionnaire showed significant correlation (ρ=0.429-0.800) for all items except for "stool float".Conclusion　We confirmed the high reproducibility and validity of the questionnaire created in this study for the assessment of usual bowel movement patterns and stool characteristics.

The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis.

PURPOSE: Iron is an important component of the oxygen-binding proteins and may be critical to optimal athletic performance. Previous studies have suggested that the G allele of C/G rare variant (rs1799945), which causes H63D amino acid replacement, in the HFE is associated with elevated iron indexes and may give some advantage in endurance-oriented sports. The aim of the present study was to investigate the association between the HFE H63D polymorphism and elite endurance athlete status in Japanese and Russian populations, aerobic capacity and to perform a meta-analysis using current findings and three previous studies. METHODS: The study involved 315 international-level endurance athletes (255 Russian and 60 Japanese) and 809 healthy controls (405 Russian and 404 Japanese). Genotyping was performed using micro-array analysis or by PCR. VO2max in 46 male Russian endurance athletes was determined using gas analysis system. RESULTS: The frequency of the iron-increasing CG/GG genotypes was significantly higher in Russian (38.0 vs 24.9%; OR 1.85, P = 0.0003) and Japanese (13.3 vs 5.0%; OR 2.95, P = 0.011) endurance athletes compared to ethnically matched controls. The meta-analysis using five cohorts (two French, Japanese, Spanish, and Russian; 586 athletes and 1416 controls) showed significant prevalence of the CG/GG genotypes in endurance athletes compared to controls (OR 1.96, 95% CI 1.58-2.45; P = 1.7 × 10-9). Furthermore, the HFE G allele was associated with high V̇O2max in male athletes [CC: 61.8 (6.1), CG/GG: 66.3 (7.8) ml/min/kg; P = 0.036]. CONCLUSIONS: We have shown that the HFE H63D polymorphism is strongly associated with elite endurance athlete status, regardless ethnicities and aerobic capacity in Russian athletes.

Effects of 1-year weight loss intervention on abdominal skeletal muscle mass in Japanese overweight men and women.

BACKGROUND AND OBJECTIVES: Limited information is available on how weight loss intervention programs affect skeletal muscle mass especially in trunk. METHODS AND STUDY DESIGN: A total of 235 overweight Japanese men and women aged 40-64 years with a body mass index of 28.0 to 44.8 kg/m2 participated in this randomized controlled intervention study. They were randomly divided into a lifestyle intervention group and control group. Before and after the one-year lifestyle intervention for weight loss an abdominal transverse image was acquired by computed tomography. The cross-sectional areas (CSAs) of visceral fat, subcutaneous fat, and skeletal muscle of rectus abdominis, abdominal oblique, iliopsoas, and erector spinae muscle were calculated. RESULTS: The body weight changed by approximately -5% in the intervention groups. The corresponding values for subcutaneous fat and visceral fat CSAs were -10.8 to -17.5% in both sexes. The reductions observed in skeletal muscle CSAs were significantly less (-6.0% and -7.2% in the men and women intervention groups respectively) than those in fat tissue CSAs. The CSA of each of the four skeletal muscle groups also significantly decreased; however, after adjustments for body weight at each time point, only reductions in the iliopsoas muscle in both sex and abdominal oblique muscles in men remained significant. CONCLUSIONS: The lifestyle weight loss intervention might reduce the relative amount of the abdominal skeletal muscles especially in iliopsoas muscle.

Simultaneous Validation of Seven Physical Activity Questionnaires Used in Japanese Cohorts for Estimating Energy Expenditure: A Doubly Labeled Water Study.

BACKGROUND: Physical activity questionnaires (PAQs) used in large-scale Japanese cohorts have rarely been simultaneously validated against the gold standard doubly labeled water (DLW) method. This study examined the validity of seven PAQs used in Japan for estimating energy expenditure against the DLW method. METHODS: Twenty healthy Japanese adults (9 men; mean age, 32.4 [standard deviation {SD}, 9.4] years, mainly researchers and students) participated in this study. Fifteen-day daily total energy expenditure (TEE) and basal metabolic rate (BMR) were measured using the DLW method and a metabolic chamber, respectively. Activity energy expenditure (AEE) was calculated as TEE - BMR - 0.1 × TEE. Seven PAQs were self-administered to estimate TEE and AEE. RESULTS: The mean measured values of TEE and AEE were 2,294 (SD, 318) kcal/day and 721 (SD, 161) kcal/day, respectively. All of the PAQs indicated moderate-to-strong correlations with the DLW method in TEE (rho = 0.57-0.84). Two PAQs (Japan Public Health Center Study [JPHC]-PAQ Short and JPHC-PAQ Long) showed significant equivalence in TEE and moderate intra-class correlation coefficients (ICC). None of the PAQs showed significantly equivalent AEE estimates, with differences ranging from -547 to 77 kcal/day. Correlations and ICCs in AEE were mostly weak or fair (rho = 0.02-0.54, and ICC = 0.00-0.44). Only JPHC-PAQ Short provided significant and fair agreement with the DLW method. CONCLUSIONS: TEE estimated by the PAQs showed moderate or strong correlations with the results of DLW. Two PAQs showed equivalent TEE and moderate agreement. None of the PAQs showed equivalent AEE estimation to the gold standard, with weak-to-fair correlations and agreements. Further studies with larger sample sizes are needed to confirm these findings.

Caffeine Consumption Is Associated With Higher Level of Physical Activity in Japanese Women.

Caffeine has been described as a sports performance-enhancing substance. However, it is unclear whether it can increase the level of physical activity (PA) in nonathletic individuals. This study investigates the relationship between daily caffeine consumption and (a) daily PA/fitness or (b) intervention-induced changes in PA in women and men. On the basis of responses to a dietary habit questionnaire, which included items on caffeinated beverages, 1,032 Japanese adults, were categorized into lower or higher caffeine consumption groups (relative to the median caffeine consumption). In each group, daily step count; sedentary time; and light, moderate, and vigorous PA outcomes were objectively measured. Physical fitness, including peak oxygen consumption, was also evaluated. The relationship between daily caffeine consumption and the change in the levels of PA was investigated in a subgroup of 202 subjects who participated in a 1-year PA counseling intervention. Women in the higher caffeine consumption group presented higher moderate-to-vigorous PA and step count compared with their counterparts in the lower consumption group (4.0 ± 2.1 vs. 3.3 ± 2.1 MET-hr/day, p < .001; 10,335 ± 3,499 vs. 9,375 ± 3,527 steps/day, p < .001). A significant positive correlation was noted between caffeine consumption and peak oxygen consumption among women (r = .15, p < .001). No caffeine-related effects were noted in men. The lower and higher caffeine consumption groups showed no significant differences in their levels of PA at the end of the 1-year intervention. Therefore, caffeine consumption appears to be associated with higher levels of PA in Japanese women. Further studies are needed to clarify this association.

AGTR2 and sprint/power performance: a case-control replication study for rs11091046 polymorphism in two ethnicities.

We aimed to replicate, in a specific athletic event cohort (only track and field) and in two different ethnicities (Japanese and East European, i.e. Russian and Polish), original findings showing the association of the angiotensin-II receptor type-2 gene (AGTR2) rs11091046 A>C polymorphism with athlete status. We compared genotypic frequencies of the AGTR2 rs11091046 polymorphism among 282 track and field sprint/power athletes (200 men and 82 women), including several national record holders and Olympic medallists (214 Japanese, 68 Russian and Polish), and 2024 control subjects (842 men and 1182 women) (804 Japanese, 1220 Russian and Polish). In men, a meta-analysis from the two combined cohorts showed a significantly higher frequency of the C allele in athletes than in controls (odds ratio: 1.62, P=0.008, heterogeneity index I 2 =0%). With regard to respective cohorts, C allele frequency was higher in Japanese male athletes than in controls (67.7% vs. 55.9%, P=0.022), but not in Russian/Polish male athletes (61.9% vs. 51.0%, P=0.172). In women, no significant results were obtained by meta-analysis for the two cohorts combination (P=0.850). The AC genotype frequency was significantly higher in Russian/Polish women athletes than in controls (69.2% vs. 42.1%, P=0.022), but not in Japanese women athletes (P=0.226). Our results, in contrast to previous findings, suggested by meta-analysis that the C allele of the AGTR2 rs11091046 polymorphism is associated with sprint/power track and field athlete status in men, but not in women.

Epistasis, physical capacity-related genes and exceptional longevity: FNDC5 gene interactions with candidate genes FOXOA3 and APOE.

BACKGROUND: Forkhead box O3A (FOXOA3) and apolipoprotein E (APOE) are arguably the strongest gene candidates to influence human exceptional longevity (EL, i.e., being a centenarian), but inconsistency exists among cohorts. Epistasis, defined as the effect of one locus being dependent on the presence of 'modifier genes', may contribute to explain the missing heritability of complex phenotypes such as EL. We assessed the potential association of epistasis among candidate polymorphisms related to physical capacity, as well as antioxidant defense and cardiometabolic traits, and EL in the Japanese population. A total of 1565 individuals were studied, subdivided into 822 middle-aged controls and 743 centenarians. RESULTS: We found a FOXOA3 rs2802292 T-allele-dependent association of fibronectin type III domain-containing 5 (FDNC5) rs16835198 with EL: the frequency of carriers of the FOXOA3 rs2802292 T-allele among individuals with the rs16835198 GG genotype was significantly higher in cases than in controls (P < 0.05). On the other hand, among non-carriers of the APOE 'risk' ε4-allele, the frequency of the FDNC5 rs16835198 G-allele was higher in cases than in controls (48.4% vs. 43.6%, P < 0.05). Among carriers of the 'non-risk' APOE ε2-allele, the frequency of the rs16835198 G-allele was higher in cases than in controls (49% vs. 37.3%, P < 0.05). CONCLUSIONS: The association of FDNC5 rs16835198 with EL seems to depend on the presence of the FOXOA3 rs2802292 T-allele and we report a novel association between FNDC5 rs16835198 stratified by the presence of the APOE ε2/ε4-allele and EL. More research on 'gene*gene' and 'gene*environment' effects is needed in the field of EL.

Appropriate control time constant in relation to characteristics of the baroreflex vascular system in 1/R control of the total artificial heart.

1/R control is a physiological control method of the total artificial heart (TAH) with which long-term survival was obtained with animal experiments. However, 1/R control occasionally diverged in the undulation pump TAH (UPTAH) animal experiment. To improve the control stability of the 1/R control, appropriate control time constant in relation to characteristics of the baroreflex vascular system was investigated with frequency analysis and numerical simulation. In the frequency analysis, data of five goats in which the UPTAH was implanted were analyzed with first Fourier transform technique to examine the vasomotion frequency. The numerical simulation was carried out repeatedly changing baroreflex parameters and control time constant using the elements-expanded Windkessel model. Results of the frequency analysis showed that the 1/R control tended to diverge when very low frequency band that was an indication of the vasomotion frequency was relative high. In numerical simulation, divergence of the 1/R control could be reproduced and the boundary curves between the divergence and convergence of the 1/R control varied depending on the control time constant. These results suggested that the 1/R control tended to be unstable when the TAH recipient had high reflex speed in the baroreflex vascular system. Therefore, the control time constant should be adjusted appropriately with the individual vasomotion frequency.

Association between ACTN3 R577X Polymorphism and Trunk Flexibility in 2 Different Cohorts.

α-Actinin-3 (ACTN3) R577X polymorphism is associated with muscular strength and power. This study was performed to investigate the association between ACTN3 R577X polymorphisms and flexibility as another component of fitness in 2 cohorts. Cohort 1 consisted of 208 men and 568 women (ages 23-88), while Cohort 2 consisted of 529 men and 728 women (ages 23-87). All participants were recruited from the Tokyo metropolitan area and underwent a battery of tests to assess their grip strength and sit-and-reach flexibility. Genotyping results were analyzed for ACTN3 (rs1815739) polymorphism using the TaqMan approach. In Cohort 1, sit-and-reach in the RR genotype (35.3±0.7 cm) was significantly lower than those in the RX and XX genotypes (37.2±0.3 cm) even after adjusting for sex, age, and exercise habit as covariates (P<0.01). In Cohort 2, sit-and-reach tended to be lower in RR (38.1±0.6 cm) than in RX and XX (39.1±0.3 cm), but the differences were not significant (P=0.114). Analysis in pooled subjects indicated that RR was associated with significantly lower flexibility than RX and XX (P=0.009). The RR genotype of ACTN3 R577X in the general Japanese population showed lower flexibility compared to the RX and XX genotypes.

The PtdIns(3,4)P(2) phosphatase INPP4A is a suppressor of excitotoxic neuronal death.

Phosphorylated derivatives of phosphatidylinositol, collectively referred to as phosphoinositides, occur in the cytoplasmic leaflet of cellular membranes and regulate activities such as vesicle transport, cytoskeletal reorganization and signal transduction. Recent studies have indicated an important role for phosphoinositide metabolism in the aetiology of diseases such as cancer, diabetes, myopathy and inflammation. Although the biological functions of the phosphatases that regulate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) have been well characterized, little is known about the functions of the phosphatases regulating the closely related molecule phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P(2)). Here we show that inositol polyphosphate phosphatase 4A (INPP4A), a PtdIns(3,4)P(2) phosphatase, is a suppressor of glutamate excitotoxicity in the central nervous system. Targeted disruption of the Inpp4a gene in mice leads to neurodegeneration in the striatum, the input nucleus of the basal ganglia that has a central role in motor and cognitive behaviours. Notably, Inpp4a(-/-) mice show severe involuntary movement disorders. In vitro, Inpp4a gene silencing via short hairpin RNA renders cultured primary striatal neurons vulnerable to cell death mediated by N-methyl-d-aspartate-type glutamate receptors (NMDARs). Mechanistically, INPP4A is found at the postsynaptic density and regulates synaptic NMDAR localization and NMDAR-mediated excitatory postsynaptic current. Thus, INPP4A protects neurons from excitotoxic cell death and thereby maintains the functional integrity of the brain. Our study demonstrates that PtdIns(3,4)P(2), PtdIns(3,4,5)P(3) and the phosphatases acting on them can have distinct regulatory roles, and provides insight into the unique aspects and physiological significance of PtdIns(3,4)P(2) metabolism. INPP4A represents, to our knowledge, the first signalling protein with a function in neurons to suppress excitotoxic cell death. The discovery of a direct link between PtdIns(3,4)P(2) metabolism and the regulation of neurodegeneration and involuntary movements may aid the development of new approaches for the treatment of neurodegenerative disorders.

Relationships between social factors and physical activity among elderly survivors of the Great East Japan earthquake: a cross-sectional study.

BACKGROUND: Physical inactivity is a health issue that often occurs after serious disaster. Social factors, which can be disrupted by disaster, are important determinants of physical activity levels in everyday living. This study was designed to confirm the association between social factors and physical activity among elderly survivors of the Great East Japan Earthquake. METHODS: From September 2011 to February 2012, 4316 males and females aged 65 or older participated in a health survey of Great East Japan Earthquake survivors. Multiple logistic regression analyses were performed with the dichotomous dependent variable of physical activity (high versus low) and working status, social network, and place of residence (one's own home versus elsewhere) as independent variables. RESULTS: Participants who had been displaced from their homes were more likely to have low physical activity (odds ratio [OR], 95% confidence interval [CI] for men: 1.37, 1.12 to 1.68; for women: 1.30, 1.09 to 1.55). Non-working status was significantly associated with low physical activity (men: 2.03, 1.65 to 2.49; women: 1.94, 1.60 to 2.34). Detriments to the social network were significantly associated with low physical activity (men: 1.71, 1.41 to 2.08; women: 1.79, 1.51 to 2.13). CONCLUSION: Place of residence and social factors were associated with physical activity levels in elderly survivors of the Great East Japan Earthquake. The findings suggest a need for improvement of social factors to encourage increases in physical activity for elderly persons after disaster.

Cross-sectional association of the number of neighborhood facilities assessed using postal code with objectively measured physical activity: the Saku cohort study.

Objectives The aim of this study was to examine the association between the number of neighborhood facilities that were assessed according to postal code and objectively measured physical activity by using an accelerometer in community-dwelling Japanese people.Methods The participants included 1,274 Japanese people aged 30-84 years from the Saku cohort study. As neighborhood facilities related to physical activity, we extracted information regarding train stations, supermarkets/convenience stores, postal offices/banks, hospitals/clinics, public offices/community centers, cultural facilities/public children's houses, parks, and sports facilities by using each participant's postal code from the online version of the iTownPages directory published by Nippon Telegraph and Telephone Corporation (NTT) and the official homepage of the Saku City Government Office. We measured each participant's physical activity level using an accelerometer, and calculated the average daily step count and the average weekly period of moderate-to-vigorous intensity (≥3 metabolic equivalents of tasks [METs]) physical activity. The association between two selected physical activity-related variables and the numbers of eight types of neighborhood facilities were analyzed by multivariate logistic regression analysis for people aged 30-64 years and for those aged over 65 years.Results On multivariate logistic regression analysis, meeting the 23 METs h/week of moderate-to-vigorous intensity physical activity was significantly and positively associated with the number of supermarkets/convenience stores in the neighborhood in both age groups. In addition, meeting the desired daily step count outlined in the Japanese National Health Promotion guidelines was positively related to the number of postal offices/banks for people aged over 65 years.Conclusion The results of this study suggest that a sufficient number of neighborhood facilities (i.e., stores, banks, and postal offices) is closely associated with the promotion of physical activity.

A missense single nucleotide polymorphism, V114I of the Werner syndrome gene, is associated with risk of osteoporosis and femoral fracture in the Japanese population.

Werner syndrome is a rare autosomal recessive disorder caused by mutations in the human WRN gene and characterized by the early onset of normal aging symptoms. Given that patients with this disease exhibit osteoporosis, the present study aimed to determine whether the WRN gene contributes to the etiology of osteoporosis. A genetic association study of eight non-synonymous polymorphisms in the WRN gene and the incidence of femoral fracture was undertaken in 1,632 consecutive Japanese autopsies in which 140 patients had experienced the fracture during their lifetime. The results were validated in 251 unrelated postmenopausal Japanese women with osteoporosis and 269 non-institutionalized, community-dwelling Japanese adults. A statistically significant association was observed between rs2230009 (c.340G > A)--which results in a Val to Ile substitution--and fracture risk; the incidence of femoral fracture increased dose-dependently with the number of A alleles (p = 0.0120). Femoral neck bone and whole bone densities were lower among postmenopausal women with osteoporosis and community-dwelling adults, respectively, if they were of the AG instead of the GG genotype. The results suggest that Japanese subjects bearing at least one A allele of rs2230009 of the WRN gene are at a significantly higher risk of femoral fracture, possibly due to decreased bone density.

Accuracy of segmental bioelectrical impedance analysis for predicting body composition in pre- and postmenopausal women.

This study aimed to compare the accuracy for predicting body composition using single-frequent segmental bioelectrical impedance analysis (BIA) between pre- and postmenopausal women. A total f 559 Japanese women aged 30-88yr were divided into 4 groups by questionnaire: natural menopause, pathological menopause, regular menstruation, or irregular menstruation. The measurement values by dual-energy X-ray absorptiometry were used as a reference of the body composition. In terms of the results, regardless of the menopausal status, BIA slightly but significantly overestimated the percentage of body fat (standard error of estimate: 5.3%-6.7%) and the leg lean soft tissue mass (LSTM; 5.1%-6.1%), and underestimated the LSTM in the whole body (6.2%-7.6%) and arm (2.8%-3.7%). The absolute values of the predictive error for leg LSTM were significantly higher in postmenopausal groups than in the premenopausal ones. The corresponding values for the whole body and arm LSTM, and the percentage of body fat were higher in premenopausal groups than in postmenopausal ones. In conclusion, the predictive accuracy of BIA for postmenopausal women is not inferior to that for premenopausal ones, unless we target the leg LSTM.