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Background: Relocation following a disaster can impact the psychological well-being of evacuees. This study investigated the associations between residence-related factors and psychological distress among evacuees living in temporary housing after the Fukushima Daiichi Nuclear Power Plant accident., Methods: Data from 525 participants living in temporary housing were collected. Associations between residence-related factors (frequent relocation, dissatisfaction with the residence, and plan to move to permanent housing) and psychological distress were measured. The psychological distress of evacuees was measured using the Japanese version of the 6-item Kessler scale (K6). We used a cut-off score of five to identify cases with psychological distress, the basis of Kessler's 6 items for psychological distress., Results: Multivariate logistic regression analysis (n = 418) showed that frequent relocation (OR = 2.05, 95% CI: 1.14-3.66, p = 0.016) and dissatisfaction with the residence (OR = 2.48, 95% CI: 1.60-3.83, p < 0.001) was significantly associated with psychological distress. After stratifying by gender, dissatisfaction with the residence was associated with psychological distress, and a plan to move to permanent housing was significantly associated with psychological distress in women (OR = 1.93, 95% CI: 1.03-3.63, p = 0.041)., Conclusions: Frequent relocation and dissatisfaction with the residence were associated with psychological distress among evacuees following the Fukushima nuclear disaster. Evacuees should be provided with comfortable living spaces, and steps should be taken to reduce repeated relocation of evacuees. Thus, particular attention should be paid to women with a plan to move to permanent housing within this context.

Linear accelerator-based radiotherapy has little effect on the majority of locally advanced neoplasms. Thus, the novel radiosensitizer Kochi Oxydol Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), which contains hydrogen peroxide and sodium hyaluronate, was developed. The effectiveness of KORTUC II for the treatment of chemotherapy-resistant supraclavicular lymph node metastases has been previously demonstrated. The present study evaluated the safety and effectiveness of KORTUC II in patients with recurrent breast cancer. A total of 20 patients (age range, 39-84 years) were enrolled in the study. The majority of patients underwent positron emission tomography (PET)-computed tomography (CT) examinations prior to and 1-7 months following KORTUC II treatment, and every 6 months thereafter when possible. The radiotherapy regimen was 2.75 Gy/fraction, 5 fractions/week, for 16-18 fractions, with a total radiation dose of 44.00-49.50 Gy (X-ray irradiation), or 4.00 Gy/fraction, 3 fractions/week, for 10-12 fractions, with a total radiation dose of 40.00-48.00 Gy (electron beam irradiation). The injection of 3-6 ml of the KORTUC II agent was initiated at the fifth radiotherapy fraction, and was performed twice/week under ultrasonographic guidance. The therapeutic effects were evaluated by PET-CT examinations prior and subsequent to KORTUC II treatment, which was observed to be well tolerated with minimal adverse effects. Of the 24 lesions presented by the 20 patients, 18 exhibited complete response, 5 partial response, 0 stable disease and 1 progressive disease. The overall survival rate was 100% at 1 year and 95% at 2 years. The mean duration of follow-up at the end of June 2014 was 51 months. Based on the results of the PET-CT studies conducted, KORTUC II treatment demonstrated marked therapeutic effects, with satisfactory treatment outcomes and acceptable adverse events.

Transcriptional co-activator with PDZ-binding motif (TAZ) plays versatile roles in cell proliferation and differentiation. It is phosphorylated by large tumor suppressor kinases, the core kinases of the tumor-suppressive Hippo pathway. Phosphorylation induces the cytoplasmic accumulation of TAZ and its degradation. In human cancers, the deregulation of the Hippo pathway and gene amplification enhance TAZ activity. TAZ interacts with TEA domain family members (TEAD), and upregulates genes implicated in epithelial-mesenchymal transition. It also confers stemness to cancer cells. Thus, TAZ activation provides cancer cells with malignant properties and worsens the clinical prognosis. Therefore, TAZ attracts attention as a therapeutic target in cancer therapy. We applied 18 606 small chemical compounds to human osteosarcoma U2OS cells expressing GFP-fused TAZ (GFP-TAZ), monitored the subcellular localization of GFP-TAZ, and selected 33 compounds that shifted GFP-TAZ to the cytoplasm. Unexpectedly, only a limited number of compounds suppressed TAZ-mediated enhancement of TEAD-responsive reporter activity. Moreover, the compounds that weakened TEAD reporter activity did not necessarily decrease the unphosphorylated TAZ. In this study, we focused on three compounds that decreased both TEAD reporter activity and unphosphorylated TAZ, and treated several human cancer cells with these compounds. One compound did not show a remarkable effect, whereas the other two compounds compromised the cell viability in certain cancer cells. In conclusion, the GFP-TAZ-based assay can be used as the first screening for compounds that inhibit TAZ and show anticancer properties. To develop anticancer drugs, we need additional assays to select the compounds., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Humans have 10 genes that belong to the Ras association (RA) domain family (RASSF). Among them, RASSF7 to RASSF10 have the RA domain in the N-terminal region and are called the N-RASSF proteins. In contradistinction to them, RASSF1 to RASSF6 are referred to as the C-RASSF proteins. The C-RASSF proteins have the RA domain in the middle region and the Salvador/RASSF/Hippo domain in the C-terminal region. RASSF6 additionally harbors the PSD-95/Discs large/ZO-1 (PDZ)-binding motif. Expression of RASSF6 is epigenetically suppressed in human cancers and is generally regarded as a tumor suppressor. RASSF6 induces caspase-dependent and -independent apoptosis. RASSF6 interacts with mammalian Ste20-like kinases (homologs of Drosophila Hippo) and cross-talks with the Hippo pathway. RASSF6 binds MDM2 and regulates p53 expression. The interactions with Ras and Modulator of apoptosis 1 (MOAP1) are also suggested by heterologous protein-protein interaction experiments. RASSF6 regulates apoptosis and cell cycle through these protein-protein interactions, and is implicated in the NF-κB and JNK signaling pathways. We summarize our current knowledge about RASSF6 and discuss what common and different properties RASSF6 and the other C-RASSF proteins have.

Aims: Prevention of depressive symptoms is an essential issue with regard to the promotion of healthy lifestyles in older people. To date, few studies have examined the relation between fluctuations in physical activity and depression among older individuals. We thus conducted a longitudinal survey of older adults to examine the effect of long-term fluctuating physical activity on the incidence of depressive symptoms., Methods: A 3-year prospective cohort study was performed in a community-based environment. A total of 680 individuals (291 men and 389 women) aged 65 years and over at the baseline assessment participated. The 15-item Geriatric Depression Scale was used to assess depressive symptoms, with scores of ≥6 indicative of depression. Participants were categorized into the following four groups based on change in physical activity status between 2002 and 2003: sedentary, cessation, initiation, and maintenance., Results: The incidence of depressive symptoms was 16.9% (16.8% in men and 17.0% in women) at the 3-year follow up (in 2006). Multiple logistic regression analyses showed that physical activity maintenance (odds ratio, 0.50; 95% confidence interval, 0.30-0.83) only reduced the incidence of depressive symptoms at the 3-year follow up after adjusting for confounding variables., Conclusions: Continuous physical activity may be a valuable and simple way to prevent depressive symptoms in community-dwelling older people. Therefore, it is necessary to implement interventions that teach older adults how to integrate physical activity into their daily lives., (© 2015 The Authors. Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology.)

Transcriptional co-activator with PSD-95/Dlg-A/ZO-1 (PDZ)-binding motif (TAZ) regulates in cell proliferation and differentiation. In mesenchymal stem cells it promotes osteogenesis and myogenesis, and suppresses adipogenesis. TAZ activators are expected to prevent osteoporosis, obesity and muscle atrophy. TAZ activation induces epithelial-mesenchymal transition, confers stemness to cancer cells and leads to poor clinical prognosis in cancer patients. In this point of view, TAZ inhibitors should contribute to cancer therapy. Thus, TAZ attracts attention as a two-faced drug target. We screened for TAZ modulators by using human lung cancer A549 cells expressing the fluorescent reporter. Through this assay, we obtained TAZ activator candidates. We unexpectedly found that ethacridine, a widely used antiseptic and abortifacient, enhances the interaction of TAZ and protein phosphatases and increases unphosphorylated and nuclear TAZ. Ethacridine inhibits adipogenesis in mesenchymal C3H10T1/2 cells through the activation of TAZ. This finding suggests that ethacridine is a bona fide TAZ activator and supports that our assay is useful to discover TAZ activators., (© The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Improvement in the health of older people and changes in their lifestyles necessitate a scale that can better measure their competence at a higher level. This study describes the development process of the Japan Science and Technology Agency Index of Competence (JST-IC) by (a) refining conceptual definitions and developing preliminary items and (b) examining the basic properties of the items. Participants were 1,253 septuagenarians (539 men and 714 women) living in communities, who were asked to judge whether they were independent via 88 items. To examine the basic properties of the preliminary items, five different analyses were conducted. Thirty-four items were considered as inappropriate (6 overlapped between the analyses): (a) 9 due to very high or low ratios of responders who answered "yes," (b) 4 due to gender or regional differences, (c) 5 due to their weak association with health status, (d) 9 due to low communalities in factor analysis, and (e) 13 due to redundancy of meaning with other items. Conceptual definitions and preliminary items were developed, and the basic properties of the items were examined to create the JST-IC. The next step would be to screen the remaining 54 items to create the final version of the scale., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The development of the efficient screening system of detecting compounds that promote myogenesis and prevent muscle atrophy is important. Mouse C2C12 cells are widely used to evaluate myogenesis but the procedures of the assay are not simple and the quantification is not easy. We established C2C12 cells expressing the N-terminal green fluorescence protein (GFP) and the C-terminal GFP (GFP1-10 and GFP11 cells). GFP1-10 and GFP11 cells do not exhibit GFP signals until they are fused. The signal intensity correlates with the expression of myogenic markers and myofusion. Myogenesis-promoting reagents, such as insulin-like growth factor-1 (IGF1) and β-guanidinopropionic acid (GPA), enhance the signals, whereas the poly-caspase inhibitor, z-VAD-FMK, suppresses it. GFP signals are observed when myotubes formed by GFP1-10 cells are fused with single nuclear GFP11 cells, and enhanced by IGF1, GPA, and IBS008738, a recently-reported myogenesis-promoting reagent. Fusion between myotubes formed by GFP1-10 and GFP11 cells is associated with the appearance of GFP signals. IGF1 and GPA augment these signals, whereas NSC23766, Rac inhibitor, decreases them. The conditioned medium of cancer cells suppresses GFP signals during myogenesis and reduces the width of GFP-positive myotubes after differentiation. Thus the novel split GFP-based assay will provide the useful method for the study of myogenesis, myofusion, and atrophy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We report on the clinical, neuropathological, and genetic findings of a Japanese case with myocerebrohepatopathy spectrum (MCHS) disorder due to polymerase gamma (POLG) mutations. A girl manifested poor sucking and failure to thrive since 4 months of age and had frequent vomiting and developmental regression at 5 months of age. She showed significant hypotonia and hepatomegaly. Laboratory tests showed hepatocellular dysfunction and elevated protein and lactate levels in the cerebrospinal fluid. Her liver function and neurologic condition exacerbated, and she died at 8 months of age. At autopsy, fatty degeneration and fibrosis were observed in the liver. Neuropathological examination revealed white matter-predominant spongy changes with Alzheimer type II glia and loss of myelin. Enzyme activities of the respiratory chain complex I, III, and IV relative to citrate synthase in the muscle were normal in the biopsied muscle tissue, but they were reduced in the liver to 0%, 10%, and 14% of normal values, respectively. In the liver, the copy number of mitochondrial DNA compared to nuclear DNA was reduced to 3.3% of normal values as evaluated by quantitative polymerase chain reaction. Genetic analysis revealed compound heterozygous mutations for POLG (I1185T/A957V). This case represents the differential involvement of multiple organs and phenotype-specific distribution of brain lesions in mitochondrial DNA depletion disorders., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objectives: Several studies have explored the prevalence and risk factors of sarcopenia, but they have been based on cross-sectional data. The objective of this study was to determine the incidence and predictors of the onset of sarcopenia over 4 years in community-dwelling elderly women., Design: Four-year longitudinal follow-up study., Setting: Urban community in Tokyo, Japan., Participants: A total of 538 nonsarcopenic women older than 75 years., Measurements: Body composition was determined by bioelectrical impedance analysis. Functional fitness measurements, including grip strength, usual walking speed, timed up and go (TUG), and interview surveys were conducted at baseline and 4-year follow-up. Blood samples were obtained to analyze serum albumin and hemoglobin A1c, and kidney function was analyzed using serum creatinine and cystatin C. Sarcopenia was defined based on the criteria suggested by the European Working Group on Sarcopenia in Older People, and the development of all stages, that is, presarcopenia, sarcopenia, and severe sarcopenia as well as the components of sarcopenia skeletal muscle index (SMI), grip strength, and walking speed, were analyzed., Results: The incidence of total sarcopenia was 39.6% (presarcopenia 23.8%, sarcopenia 11.2%, severe sarcopenia 4.6%). Older age was significantly predictive of the development of presarcopenia and severe sarcopenia. Body mass index (BMI) lower than 21.0 kg/m(2) was significantly predictive of the development of all stages of sarcopenia, as well as declines in SMI, grip strength, and walking speed. Slow TUG was a predictor of the development of presarcopenia and severe sarcopenia. Increased calf circumference showed protective effects from the development of all stages of sarcopenia. Greater albumin levels also showed lower risk of declines in SMI, walking speed, and development of presarcopenia. Cystatin C was positively associated with the development of severe sarcopenia (odds ratio 1.83, 95% confidence interval 1.08-3.12). Heart disease and hyperlipidemia history were associated with presarcopenia and sarcopenia, respectively., Conclusion: Age, BMI, calf circumference, and TUG were consistent predictors of the various stages and components of sarcopenia. The data also suggest that cystatin C was associated with higher odds of incident severe sarcopenia, and further study into kidney function and onset of sarcopenia in large populations is needed., (Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Unhappiness at school is one of the main reasons for truancy among adolescents. In order to assess this problem more thoroughly in the context of Japanese adolescents, the present study examined the associations between feelings of unhappiness at school and lifestyle habits, school life realities, and mental health status., Method: This study was designed as a cross-sectional survey. A self-administered questionnaire was provided to students enrolled in randomly selected junior and senior high schools throughout Japan. We calculated the percentages of both junior and senior high school students who felt unhappy at school based on factors related to school life, lifestyle habits, and mental health status. Multiple logistic regression analyses were performed in order to examine the associations between those factors and students' feelings of unhappiness at school., Results: A total of 98,867 valid responses were analysed, 7.9% (Boys: 8.4%, Girls: 7.4%) of which came from students who responded that they felt unhappy at school. For both junior and senior high school students, the percentages of those who felt unhappy at school were significantly higher among those who had not yet decided on their future life course, who did not participate in extracurricular activities, did not eat breakfast every day, went to bed late, had used tobacco or alcohol in the previous 30 days, and had poor mental health compared with others. The results of multiple logistic regression analyses indicated that the adjusted odds ratios for feeling unhappy at school with regard to the above-mentioned factors were significantly high for both junior and senior high school students., Conclusions: The present results suggest that school employees and administrators must provide health guidance to students, considering that irregular lifestyle habits, lower school engagement, smoking, drinking alcohol, and poor mental health status are all associated with maladaptation to school among adolescents.

The transcriptional coactivator with a PDZ-binding motif (TAZ) cooperates with various transcriptional factors and plays various roles. Immortalized human mammalian epithelial MCF10A cells form spheres when TAZ is overexpressed and activated. We developed a cell-based assay using sphere formation by TAZ-expressing MCF10A cells as a readout to screen 18,458 chemical compounds for TAZ activators. Fifty compounds were obtained, and 47 were confirmed to activate the TAZ-dependent TEAD-responsive reporter activity in HEK293 cells. We used the derived subset of compounds as a TAZ activator candidate minilibrary and searched for compounds that promote myogenesis in mouse C2C12 myoblast cells. In this study, we focused on one compound, IBS008738. IBS008738 stabilizes TAZ, increases the unphosphorylated TAZ level, enhances the association of MyoD with the myogenin promoter, upregulates MyoD-dependent gene transcription, and competes with myostatin in C2C12 cells. TAZ knockdown verifies that the effect of IBS008738 depends on endogenous TAZ in C2C12 cells. IBS008738 facilitates muscle repair in cardiotoxin-induced muscle injury and prevents dexamethasone-induced muscle atrophy. Thus, this cell-based assay is useful to identify TAZ activators with a variety of cellular outputs. Our findings also support the idea that TAZ is a potential therapeutic target for muscle atrophy.

Neoadjuvant chemotherapy (NACT) is a widely accepted therapeutic option for patients with breast cancer. Although NACT produces good results for breast cancer patients, it has the potential to delay effective treatment in patients with chemotherapy-resistant breast cancer. The purpose of the present study was to evaluate the utility of the pretreatment apparent diffusion coefficient (ADC), which is calculated from diffusion-weighted imaging (DWI), the change in ADC after first administration of NACT, and the change in tumor greatest diameter on ultrasonography in the early prediction of the tumor response to NACT. The response rate of breast tumors to NACT was calculated by the greatest diameter measured by contrast-enhanced MRI obtained before and after NACT. Only the change in ADC was significantly correlated with the response rate. The area under the curve of the change in ADC was sufficiently high (0.90, 95% confidence interval, 0.760-1.040) to discriminate between responders and non-responders. Calculation of the ADC from DWI-MRI was found to be useful for predicting breast tumor response to NACT. Further studies are required to investigate the benefit of changing systemic therapy for breast cancer based on the prediction of the response to NACT by DWI-MRI.

Background: Although mitochondrial respiratory chain disorders (MRCD) are one of the most common congenital metabolic diseases, there is no cumulative data on enzymatic diagnosis and clinical manifestation for MRCD in Japan and Asia., Methods: We evaluated 675 Japanese patients having profound lactic acidemia, or patients having symptoms or signs of multiple-organ origin simultaneously without lactic acidemia on respiratory chain enzyme activity assay and blue native polyacrylamide gel electrophoresis. Quantitative polymerase chain reaction was used to diagnose mitochondrial DNA depletion syndrome (MTDPS). Mutation analysis of several genes responsible for MTDPS was also performed., Results: A total of 232 patients were diagnosed with a probable or definite MRCD. MRCD are common, afflicting one in every several thousand people in Japan. More than one in 10 of the patients diagnosed lacked lactic acidemia. A subsequent analysis of the causative genes of MTDPS identified novel mutations in six of the patients. A 335 bp deletion in deoxyguanosine kinase (DGUOK; g.11692&#95;12026del335 (p.A48fsX90)) was noted in two unrelated families, and may therefore be a common mutation in Japanese people. The proportion of all patients with MTDPS, and particularly those with recessive DNA polymerase γ (POLG) mutations, appears to be lower in Japan than in other studies. This is most likely due to the relatively high prevalence of ancient European POLG mutations in Caucasian populations. No other significant differences were identified in a comparison of the enzymatic diagnoses, disease classifications or prognoses in Japanese and Caucasian patients with MRCD., Conclusion: MTDPS and other MRCD are common, but serious, diseases that occur across all races., (© 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.)

Background: Cognitive function is an important contributor to health among elderly adults. One reliable measure of cognitive functioning is information processing speed, which can predict incident dementia and is longitudinally related to the incidence of functional dependence. Few studies have examined the association between information processing speed and mortality. This 8-year prospective cohort study design with mortality surveillance examined the longitudinal relationship between information processing speed and all-cause mortality among community-dwelling elderly Japanese., Methods: A total of 440 men and 371 women aged 70 years or older participated in this study. The Digit Symbol Substitution Test (DSST) was used to assess information processing speed. DSST score was used as an independent variable, and age, sex, education level, depressive symptoms, chronic disease, sensory deficit, instrumental activities of daily living, walking speed, and cognitive impairment were used as covariates., Results: During the follow-up period, 182 participants (133 men and 49 women) died. A multivariate Cox proportional hazards model showed that lower DSST score was associated with increased risk of mortality (hazard ratio [HR] = 1.62, 95% CI = 0.97-2.72; HR = 1.73, 95% CI = 1.05-2.87; and HR = 2.55, 95% CI = 1.51-4.29, for the third, second, and first quartiles of DSST score, respectively)., Conclusions: Slower information processing speed was associated with shorter survival among elderly Japanese.

The co-chaperonin GroES (Hsp10) works with chaperonin GroEL (Hsp60) to facilitate the folding reactions of various substrate proteins. Upon forming a specific disordered state in guanidine hydrochloride, GroES is able to self-assemble into amyloid fibrils similar to those observed in various neurodegenerative diseases. GroES therefore is a suitable model system to understand the mechanism of amyloid fibril formation. Here, we determined the cytotoxicity of intermediate GroES species formed during fibrillation. We found that neuronal cell death was provoked by soluble intermediate aggregates of GroES, rather than mature fibrils. The data suggest that amyloid fibril formation and its associated toxicity toward cell might be an inherent property of proteins irrespective of their correlation with specific diseases. Furthermore, with the presence of anthocyanins that are abundant in bilberry, we could inhibit both fibril formation and the toxicity of intermediates. Addition of bilberry anthocyanins dissolved the toxic intermediates and fibrils, and the toxicity of the intermediates was thus neutralized. Our results suggest that anthocyanins may display a general and potent inhibitory effect on the amyloid fibril formation of various conformational disease-causing proteins.

Ras association domain family (RASSF) 6 is a member of the C-terminal RASSF proteins such as RASSF1A and RASSF3. RASSF6 is involved in apoptosis in various cells under miscellaneous conditions, but it remains to be clarified how RASSF6 exerts tumor-suppressive roles. We reported previously that RASSF3 facilitates the degradation of MDM2, a major E3 ligase of p53, and stabilizes p53 to function as a tumor suppressor. In this study, we demonstrate that RASSF6 overexpression induces G1/S arrest in p53-positive cells. Its depletion prevents UV- and VP-16-induced apoptosis and G1/S arrest in HCT116 and U2OS cells. RASSF6-induced apoptosis partially depends on p53. RASSF6 binds MDM2 and facilitates its ubiquitination. RASSF6 depletion blocks the increase of p53 in response to UV exposure and up-regulation of p53 target genes. RASSF6 depletion delays DNA repair in UV- and VP-16-treated cells and increases polyploid cells after VP-16 treatment. These findings indicate that RASSF6 stabilizes p53, regulates apoptosis and the cell cycle, and functions as a tumor suppressor. Together with the previous reports regarding RASSF1A and RASSF3, the stabilization of p53 may be the common function of the C-terminal RASSF proteins.

Background: Multilevel and multimodal interventions have been suggested for suicide prevention. However, few studies have reported the outcomes of such interventions for suicidal behaviours., Methods: We examined the effectiveness of a community-based multimodal intervention for suicide prevention in rural areas with high suicide rates, compared with a parallel prevention-as-usual control group, covering a total of 631,133 persons. The effectiveness was also examined in highly populated areas near metropolitan cities (1,319,972 persons). The intervention started in July 2006, and continued for 3.5 years. The primary outcome was the incidence of composite outcome, consisting of completed suicides and suicide attempts requiring admission to an emergency ward for critical care. We compared the rate ratios (RRs) of the outcomes adjusted by sex, age group, region, period and interaction terms. Analyses were performed on an intention-to-treat basis and stratified by sex and age groups., Findings: In the rural areas, the overall median adherence of the intervention was significantly higher. The RR of the composite outcome in the intervention group decreased 7% compared with that of the control group. Subgroup analyses demonstrated heterogeneous effects among subpopulations: the RR of the composite outcome in the intervention group was significantly lower in males (RR = 0.77, 95% CI 0.59-0.998, p = 0.0485) and the RR of suicide attempts was significantly lower in males (RR = 0.39, 95% CI 0.22-0.68, p = 0.001) and the elderly (RR = 0.35, 95% CI 0.17-0.71, p = 0.004). The intervention had no effect on the RR of the composite outcome in the highly populated areas., Interpretation: Our findings suggest that this community-based multimodal intervention for suicide prevention could be implemented in rural areas, but not in highly populated areas. The effectiveness of the intervention was shown for males and for the elderly in rural areas., Trial Registration: ClinicalTrials.gov NCT00737165 UMIN Clinical Trials Registry UMIN000000460.

Objective: We sought to examine the longitudinal relationship between cognitive function and all-cause mortality among Japanese community-dwelling older adults, using an 8-year prospective cohort study design with mortality surveillance., Methods: A total of 454 men and 386 women, aged 70 years and older, participated in the study. The Mini Mental State Examination (MMSE) was administered to assess global cognition. The total MMSE score and subscale scores were used as independent variables, and age, gender, education level, chronic disease, sensory deficit, depressive symptoms, and instrumental activities of daily living were used as covariates., Results: During the follow-up period, 191 subjects (139 men and 52 women) died, and 64 subjects (31 men and 33 women) moved to a different region of Japan and were lost to follow-up. Use of the multivariate Cox proportional hazards model, adjusted for potential confounders, showed that global cognition was significantly and independently associated with mortality (hazard ratio [HR] = 1.59, 95% confidence interval [CI]: 1.14-2.23 and HR = 2.81, 95% CI: 1.77-4.36 for the middle [24-27 points] and lowest [0-23 points] categories, respectively). Among the MMSE subscales, place orientation (HR = 1.57, 95% CI: 1.09-2.25), calculation (HR = 1.67, 95% CI: 1.18-2.35), and delayed recall (HR = 1.42, 95% CI: 1.03-1.96), were also significantly and independently associated with mortality., Conclusions: Our study suggests that among older individuals, those with lower levels of cognitive function are more likely to have a shorter lifespan compared with those with higher cognitive functioning., (Copyright © 2012 John Wiley & Sons, Ltd.)

The mammalian Hippo pathway comprises mammalian Ste20-like kinases (MST1/2) and large tumor suppressor kinases (LATS1/2). LATS1/2, which are activated by MST1/2, phosphorylate a transcriptional co-activator, yes-associated protein (YAP), and induce the recruitment of YAP by 14-3-3 to cytoplasm, so that the TEAD-dependent gene transcriptions are turned off. Although the core components of the Hippo pathway are well conserved in metazoans, it has been discussed that Caenorhabditis elegans lacks YAP ortholog, we found that F13E6.4 gene encodes a protein that shows sequence similarities to YAP in the N-terminal TEAD-binding domain and in the WW domain. We designated this gene as yap-1. YAP-1 is widely expressed in various cells such as epithelial cells, muscles, hypodermal cells, gonadal sheath cells, spermatheca, and hypodermal cells. YAP-1 is distributed in cytoplasm and nuclei. wts-1 (LATS ortholog) and ftt-2 (14-3-3 ortholog) knockdowns cause nuclear accumulation of YAP-1, supporting that the subcellular localization of YAP-1 is regulated in a similar way as that of YAP. Heat shock also causes the nuclear accumulation of YAP-1 but after heat shock, YAP-1 translocates to cytoplasm. Knockdowns of DAF-21 (HSP90 ortholog) and HSF-1block the nuclear export of YAP-1 during this recovery. YAP-1 overexpression is beneficial for thermotolerance, whereas YAP-1 hyperactivity induced by wts-1 and ftt-2 knockdowns is deleterious on thermal response and yap-1 deficiency promotes health aging. In short, YAP-1 partially shares basal characters with mammalian YAP and plays a role in thermal stress response and healthy aging., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Mammals have 10 RASSF proteins, which are characterized by the Ras-association (RA) domain. Among them, RASSF1 to RASSF6 have the Salvador/RASSF/Hippo (SARAH) domain and form the subclass C-terminal RASSF proteins. Drosophila genome has a single C-terminal RASSF, dRASSF. All these RASSF proteins are related to the tumor suppressive Hippo pathway, and are considered to function as tumor suppressors. Caenorhabditis elegans T24F1.3 encodes a protein with the RA and the SARAH domains. The amino acid sequences are 40% and 55% similar to those of RASSF1 in the RA and the SARAH domains, respectively. We have characterized T24F1.3 gene product and named it RSF-1 as RASSF1 homolog. RSF-1 is widely expressed in epithelial cells. About 14% rsf-1 mutants exhibit defects in embryonal morphogenesis and the actin disorganization. The combinatorial synthetic lethal analysis demonstrates that the lethality is enhanced to more than 80% in rsf-1 mutants with the WASP-family verprolin homologous protein complex-related gene depletions and corroborates the implication of RSF-1 in the regulation of actin cytoskeleton. In rsf-1 mutants, the structures of muscle actin are preserved, but the swimming ability is impaired. Although we could not detect the direct physical interaction of LET-60 with RSF-1, rsf-1 mutants suppress the multivulva phenotype of the active let-60 mutants, suggesting that rsf-1 genetically interacts with the Ras signaling., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Peroxisomes are subcellular organelles involved in lipid metabolic processes, including those of very-long-chain fatty acids and branched-chain fatty acids, among others. Peroxisome matrix proteins are synthesized in the cytoplasm. Targeting signals (PTS or peroxisomal targeting signal) at the C-terminus (PTS1) or N-terminus (PTS2) of peroxisomal matrix proteins mediate their import into the organelle. In the case of PTS2-containing proteins, the PTS2 signal is cleaved from the protein when transported into peroxisomes. The functional mechanism of PTS2 processing, however, is poorly understood. Previously we identified Tysnd1 (Trypsin domain containing 1) and biochemically characterized it as a peroxisomal cysteine endopeptidase that directly processes PTS2-containing prethiolase Acaa1 and PTS1-containing Acox1, Hsd17b4, and ScpX. The latter three enzymes are crucial components of the very-long-chain fatty acids β-oxidation pathway. To clarify the in vivo functions and physiological role of Tysnd1, we analyzed the phenotype of Tysnd1(-/-) mice. Male Tysnd1(-/-) mice are infertile, and the epididymal sperms lack the acrosomal cap. These phenotypic features are most likely the result of changes in the molecular species composition of choline and ethanolamine plasmalogens. Tysnd1(-/-) mice also developed liver dysfunctions when the phytanic acid precursor phytol was orally administered. Phyh and Agps are known PTS2-containing proteins, but were identified as novel Tysnd1 substrates. Loss of Tysnd1 interferes with the peroxisomal localization of Acaa1, Phyh, and Agps, which might cause the mild Zellweger syndrome spectrum-resembling phenotypes. Our data established that peroxisomal processing protease Tysnd1 is necessary to mediate the physiological functions of PTS2-containing substrates., Competing Interests: The authors have declared that no competing interests exist.

The diagnosis of ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy is of great interest to breast physicians. The present study compared the utility of gray-scale sonography standardized by a breast imaging reporting and data system (BI-RADS) and power Doppler sonography for differentiating between benign scar formation and IBTR after breast-conserving therapy. Gray-scale sonography detected 83 solid breast lesions classified as BI-RADS categories 3-5 in 272 patients after breast-conserving therapy, and these lesions were entered into the study (53 lesions as category 3, probably benign; 30 lesions as categories 4-5, suspected malignancy). Power Doppler sonography revealed intratumoral flow in 19 of 83 solid breast lesions. BI-RADS category 3 was accepted as probably benign and BI-RADS categories 4-5 were considered as suspicious for breast tumor recurrence in the gray-scale ultrasound criteria. Positive and negative intratumoral flow were employed as suspicious for breast tumor recurrence and probably benign, respectively, in the power Doppler sonography criteria. Sensitivity was higher for power Doppler sonography (94.7±10.0%) than for gray-scale sonography (57.9±22.2%). Specificity was also higher for power Doppler sonography (98.4±3.0%) than for gray-scale sonography (70.3±0.6%). These results suggest that power Doppler sonography can complement gray-scale sonography standardized by BI-RADS in differentiating between IBTR and benign scar lesions.

Co-chaperonin GroES from Escherichia coli works with chaperonin GroEL to mediate the folding reactions of various proteins. However, under specific conditions, i.e. the completely disordered state in guanidine hydrochloride, this molecular chaperone forms amyloid fibrils similar to those observed in various neurodegenerative diseases. Thus, this is a good model system to understand the amyloid fibril formation mechanism of intrinsically disordered proteins. Here, we identified a critical intermediate of GroES in the early stages of this fibril formation using NMR and mass spectroscopy measurements. A covalent rearrangement of the polypeptide bond at Asn(45)-Gly(46) and/or Asn(51)-Gly(52) that eventually yield β-aspartic acids via deamidation of asparagine was observed to precede fibril formation. Mutation of these asparagines to alanines resulted in delayed nucleus formation. Our results indicate that peptide bond rearrangement at Asn-Gly enhances the formation of GroES amyloid fibrils. The finding provides a novel insight into the structural process of amyloid fibril formation from a disordered state, which may be applicable to intrinsically disordered proteins in general.

Background: Improving Maternal and Child Health (MCH) is a prioritized global agenda in achieving the United Nations Millennium Development Goal 5. In this challenge, involving males has been an important agenda, and a program with such intent was conducted in Alfonso Lista, Ifugao, of the Philippines. The objectives of this study were: (1) to evaluate the effectiveness in knowledge, attitude, and practice before and after a MCH session; (2) to evaluate the session's effectiveness in relation to socio-demographic characteristics; and (3) to examine if males who have learned about MCH topics can teach another group of males., Methods: A male community representative who received a lecture from the health office staff was assigned to teach a group of community males [Group 1, N = 140] in 5 sessions, using educational materials. 10 male volunteers from Group 1 then taught a different group of males [Group 2, N = 105] in their own barangays (villages). To evaluate its effectiveness, a self-administered questionnaire survey pertaining knowledge, attitude and practice regarding MCH was conducted at three different time points: before the session (Time 1, T1), after the session (Time 2, T2), and 3 months following the session (Time 3, T3). A repeated measures analysis of variance was conducted to test for changes over time and its interaction effect between specific socio-demographic variables., Results: In Group 1, there was a significant positive increase in knowledge score over time at T1-T2 and T1-T3 (p < 0.001). For attitude, the score increased only at T1-T2 (p = 0.027). The effectiveness in knowledge and attitude did not vary by socio-demographic characteristics. As for practice, majority of the participants reported that they had talked about MCH topics in their community and assisted a pregnant woman in some ways. A comparison between Group 1 and Group 2 revealed that Group 2 had similar effectiveness as Group 1 in knowledge improvement immediately after the session (p < 0.001), but no such improvement in the attitude score., Conclusion: Although the change in attitude needs further assessment, this strategy of continuous learning and teaching of MCH topics within community males is shown to improve knowledge and has a potential to uplift the MCH status, including the reduction of maternal deaths, in Alfonso Lista, Ifugao, Philippines.

Background: Few studies have examined whether declines over time in hand-grip strength (HGS) and fast walking speed (FWS) differ by sex and age among non-Western community-dwelling older adults. This study aimed to quantify changes in HGS and FWS over the 6-year period from 1994 to 2000 and examine whether these changes differed by sex and baseline age among older individuals in a Japanese community., Methods: We conducted a community-based prospective cohort study. The participants were 513 nondisabled men and women aged 67 to 91 years at the 1994 survey. Independent variables regarding time since baseline, in addition to various time-dependent and time-independent covariates, were obtained in 1994, 1996, 1998, and 2000. The outcome variables were HGS and FWS assessed at each survey. All data on independent and dependent variables that were collected at each survey were simultaneously analyzed using a linear mixed-effects model., Results: The linear mixed-effects model revealed significant declines in both HGS (-0.70 kg/year, P < 0.001) and FWS (-0.027 m/sec/year, P < 0.001) among nondisabled older participants who had analyzable data in any survey during the 6-year period. Sex was significantly associated with the rate of decline in HGS (P < 0.001), but not FWS (P = 0.211)., Conclusions: In this analysis of nondisabled older Japanese, a mixed-effects model confirmed a significant effect of aging on declines in HGS and FWS and showed that men had a significantly steeper decline in HGS than did women during a 6-year period.

Inflammatory cytokines may contribute to lower physical function in elderly. The purpose of this study was to clarify the relation between circulating level of C-reactive protein (CRP) and physical performance among the community-dwelling elderly in Japan. Participants were 803 (329 men and 474 women) aged 65 years and over. Four physical performances were assessed using hand-grip strength, length of time standing on one leg, and walking speed (usual and maximal). Low physical performance was defined as the lowest 25% of study sample in each sex. Multiple logistic regression analysis showed that CRP was negatively associated with physical performance in hand-grip strength (odds ratio=OR=1.86, 95% confidence interval=95% CI=1.32-3.05, OR=2.92, 95% CI=1.53-5.58, for the middle and highest, respectively), time of one leg standing (OR=1.96, 95% CI=1.28-3.00, OR=2.16, 95% CI=1.19-3.92, for the middle and highest, respectively) and maximal walking speed (OR=2.46, 95% CI=1.23-4.93, for the highest) when adjusted for the confounding factors. The results showed the negatively associated between CRP level and physical performance when adjusted for the confounding factors. CRP level may be a useful indicator for detecting the lower physical performance in elderly., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Improving health of the rapidly growing aging population is a critical medical, social, and economic goal. Identification of genes that modulate healthspan, the period of mid-life vigor that precedes significant functional decline, will be an essential part of the effort to design anti-aging therapies. Because locomotory decline in humans is a major contributor to frailty and loss of independence and because slowing of movement is a conserved feature of aging across phyla, we screened for genetic interventions that extend locomotory healthspan of Caenorhabditis elegans. From a group of 54 genes previously noted to encode secreted proteins similar in sequence to extracellular domains of insulin receptor, we identified two genes for which RNAi knockdown delayed age-associated locomotory decline, conferring a high performance in advanced age phenotype (Hpa). Unexpectedly, we found that hpa-1 and hpa-2 act through the EGF pathway, rather than the insulin signaling pathway, to control systemic healthspan benefits without detectable developmental consequences. Further analysis revealed a potent role of EGF signaling, acting via downstream phospholipase C-gammaplc-3 and inositol-3-phosphate receptor itr-1, to promote healthy aging associated with low lipofuscin levels, enhanced physical performance, and extended lifespan. This study identifies HPA-1 and HPA-2 as novel negative regulators of EGF signaling and constitutes the first report of EGF signaling as a major pathway for healthy aging. Our data raise the possibility that EGF family members should be investigated for similar activities in higher organisms.

Aim: The Montreal Cognitive Assessment (MoCA), developed by Dr Nasreddine (Nasreddine et al. 2005), is a brief cognitive screening tool for detecting older people with mild cognitive impairment (MCI). We examined the reliability and validity of the Japanese version of the MoCA (MoCA-J) in older Japanese subjects., Methods: Subjects were recruited from the outpatient memory clinic of Tokyo Metropolitan Geriatric Hospital or community-based medical health check-ups in 2008. The MoCA-J, the Mini-Mental State Examination (MMSE), the revised version of Hasegawa's Dementia Scale (HDS-R), Clinical Dementia Rating (CDR) scale, and routine neuropsychological batteries were conducted on 96 older subjects. Mild Alzheimer's disease (AD) was found in 30 subjects and MCI in 30, with 36 normal controls., Results: The Cronbach's alpha of MoCA-J as an index of internal consistency was 0.74. The test-retest reliability of MoCA, using intraclass correlation coefficient between the scores at baseline survey and follow-up survey 8 weeks later was 0.88 (P < 0.001). MoCA-J score was highly correlated with MMSE (r = 0.83, P < 0.001), HDS-R (r = 0.79, P < 0.001) and CDR (r = -0.79, P < 0.001) scores. The areas under receiver-operator curves (AUC) for predicting MCI and AD groups by the MoCA-J were 0.95 (95% confidence interval [CI] = 0.90-1.00) and 0.99 (95% CI = 0.00-1.00), respectively. The corresponding values for MMSE and HDS-R were 0.85 (95% CI = 0.75-0.95) and 0.97 (95% CI = 0.00-1.00), and 0.86 (95% CI = 0.76-0.95) and 0.97 (95% CI = 0.00-1.00), respectively. Using a cut-off point of 25/26, the MoCA-J demonstrated a sensitivity of 93.0% and a specificity of 87.0% in screening MCI., Conclusion: The MoCA-J could be a useful cognitive test for screening MCI, and could be recommended in a primary clinical setting and for geriatric health screening in the community.

Purpose: To investigate the effects of genetic polymorphisms on morphine-induced adverse events in cancer patients., Methods: We examined the relation of morphine-related adverse events to polymorphisms in UDP-glucuronosyltransferase (UGT) 2B7, ATP-binding cassette, sub-family B, number 1 (ABCB1), and μ-opioid receptor 1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets., Results: The T/T genotype at 1236 or TT/TT diplotype at 2677 and 3435 in ABCB1 was associated with significantly lower frequency of fatigue (grades 1-3) (P = 0.012 or 0.011, Fisher’s exact test). The UGT2B7*2 genotype was associated with the frequency of nausea (grades 1-3) (P = 0.023). The frequency of nausea was higher in patients without UGT2B7*2 allele than others. The diplotype at 2677 and 3435 in ABCB1 was associated with the frequency of vomiting (grades 1-3) (P = 0.011). No patient whose diplotype was consisted of no GC allele at 2677 and 3435 suffered from vomiting., Conclusion: Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.

Objective: This study aimed to examine a longitudinal relationship between depression status and functional decline among Japanese community-dwelling older adults, using a 12-year population-based, prospective cohort study design., Method: A total of 710 men and women, aged 65 years and over, participated in the study. Katz's Index and the Tokyo Metropolitan Institute of Gerontology Index of Competence were used to measure the functional capacities of basic activities of daily living (BADL) and higher-level competence, respectively. For the purpose of analysis, a decline in each subscale of functional capacity during the follow-up period were used as outcome variables; depression status assessed by the Japanese version of the 30-item Geriatric Depression Scale (GDS), with a cut-off of 11, was used as an independent variable; and age, gender, education level, history of chronic disease, hospitalization, smoking, physical activity, living alone, hearing problems, physical pain, dietary habits, and usual walking speed at baseline were used as covariates., Results: Use of the multivariate Cox proportional hazards model adjusted for potential confounders showed that depression status was significantly and independently associated with BADL decline (risk ratio (RR) = 1.46, 95% confidence interval (CI): 1.13-1.89) and with higher-level competence decline (RR = 1.56, 95% CI: 1.18-2.04)., Conclusion: Our study found an independent relationship between depression status and longitudinal change in functional capacity among community-dwelling older individuals, suggesting that depression status is a reliable predictor of functional decline (both of BADL decline and higher-level competence decline) in older adults., (Copyright 2009 John Wiley & Sons, Ltd.)

Various fatty acids (FAs) are involved as an energy source in many different functions in the organism. They are also essential ingredients of membranous lipids and act as intracellular signaling molecules. Intracellular fatty-acid-binding proteins (FABPs) comprise a family of soluble lipid-binding proteins with low molecular masses and solubilize long-chain FAs to allow intracellular translocation in the aqueous cytosol. To clarify the functions of FABPs in the retina, which is remarkably rich in polyunsaturated FAs, we have investigated the localization of B (brain type)-, H (heart type)-, E (epidermal type)-, and A (adipocyte type)-FABPs in adult mouse retinae by immunohistochemistry. In order to determine the possible involvement of FABPs in retinal degenerative diseases, we have also examined changes in FABP expression in light-induced photoreceptor cell degeneration (photic injury). The discrete localization of B-, H-, E-, and A-FABP species in various cell populations of the retina has been clarified: B-FABP is mainly localized in the cone photoreceptor cells, H-FABP in some populations of amacrine/bipolar/horizontal interneurons, and E-FABP in ganglion cells, with A-FABP-like immunoreactivity being located in resident microglia of normal retinae. E-FABP has further been localized in invasive macrophages in damaged retinae following photic injury, allowing discrete identification of the resident microglia and invasive macrophages by A- and E-FABP immunoreactivity, respectively.

Background/aims: To describe the clinical and biological findings of two Japanese siblings with novel MPV17 gene mutations (c.451insC/c.509C > T) manifesting hepatic mitochondrial DNA depletion syndrome., Methods: We observed these brothers and sought to determine the efficacy of treatment targeting respiratory chain complex II for the younger brother., Results: A 3-month-old boy had presented with profound liver dysfunction, failure to thrive, and watery diarrhea. Although he was then placed on a carbohydrate-rich diet, his liver function thereafter fluctuated greatly in association with viral infections, and rapidly deteriorated to liver failure. He underwent liver transplantation at 17 months of age but died at 22 months of age. The younger brother, aged 47 months at the time of this writing, presented with liver dysfunction from 8 months of age. His transaminase levels also fluctuated considerably fluctuations in association with viral infections. At 31 months of age, treatment with succinate and ubiquinone was initiated together with a lipid-rich diet using ketone milk. Thereafter, his transaminase levels normalized and never fluctuated, and the liver histology improved., Conclusions: These cases suggested that the clinical courses of patients with MPV17 mutations are greatly influenced by viral infections and that dietary and pharmaceutical treatments targeting the mitochondrial respiratory chain complex II may be beneficial in the clinical management of MPV17 mutant patients.

Objective: The aim of this study is to examine the relationship between personality traits and participation in mass health checkups among Japanese community-dwelling elderly., Methods: A data set of 327 men and 519 women aged 70 years and over was used in the analysis. The NEO Five-Factor Inventory was administered to assess the "big five" personality traits: neuroticism, extraversion, openness, agreeableness, and conscientiousness., Results: In multivariate logistic regression analysis adjusted for gender, age, number of years of education, living alone, presence of psychiatric diseases, presence of chronic diseases, and history of hospitalization during a 1-year period, openness was independently associated with participation in mass health checkups [odds ratio (OR)=1.51, 95% confidence interval (CI)=1.08-2.12, P<.01 and OR=1.38, 95% CI=0.96-1.97, P=.07 for the middle and highest tertile, respectively]. No other domains of personality were related to participation in the checkups., Conclusions: The results of the present study suggest that older individuals high in openness are likely to take part in checkups for the elderly. Our findings could help improve the participation rate in mass health checkups for the prevention of long-term care dependence in later life.

Despite the continuous development and release of new anti-epileptic drugs (AEDs), almost one in four patients are resistant to AED therapy. Current therapy requires trial and error to determine the most effective AED and dosage for a patient. The development of individualized medicine for epilepsy is critical for improving AED treatment, particularly that based on genetic information. However, several crucial issues remain to be resolved before the development of AED therapy can proceed further. The epilepsy genes responsible for common phenotypes have not yet been identified and ongoing pharmacogenetic studies continue to search for an explanation as to why 20-25% of patients do not respond to AEDs. There is no convincing clinical evidence that P-glycoprotein at the blood-brain barrier limits the uptake of AEDs into the brain of epileptic patients and contributes to the development of the drug-resistant phenotype. This article provides a critical review of the status and perspectives for the development of individualized medicine for epilepsy, based on genetic polymorphisms/mutations in relation to three major components: the pharmacodynamic pathway, the pharmacokinetic pathway and the mechanisms of action of AEDs. The development of multiplex assay technologies, together with the generation of epilepsy animal models bearing human epilepsy genes, are also discussed.

Previous studies have shown that low serum 25-hydroxyvitamin D [25(OH)D] level is a risk factor for falls among the elderly in European and North American populations. We used a cross-sectional community-based survey to study the association of serum 25(OH)D level and falls among Japanese community-dwelling elderly. A total of 2957 elderly persons (950 men and 2007 women) 65-92 yr of age who participated in mass health examinations for the prevention of geriatric syndrome for the elderly underwent an interview, blood analysis, and physical performance testing. Experience of falls over the previous year was assessed in an interview. Physical performance tests of handgrip strength, stork standing time with the eyes open, and normal waking speed as risk factors for falls among the elderly were conducted. Serum albumin and 25(OH)D concentrations were analyzed. Mean 25(OH)D concentration was significantly lower in women than in men (p < 0.001). Women showed a significant decline of 25(OH)D level with increased age (p < 0.001). There was also a significant difference in the prevalence of 25(OH)D insufficiency [25(OH)D level < 20 ng/ml] between the sexes (p < 0.001). The rate of falls was significantly higher in the lowest quartile of 25(OH)D level in women (p = 0.02) and in women with 25(OH)D insufficiency (p = 0.001). Women also showed significant declines in all three fall-related physical performance tests. Multiple logistic regression analysis showed significant and independent associations between 25(OH)D level and experience of falls in women only (p = 0.01). Low 25(OH)D level was significantly associated with a high prevalence of falls in Japanese elderly women because of their inferior physical performance. Low serum 25(OH)D levels appear preventable and easily treated; there is an evident need for greater awareness to screen and thus prevent this condition.

This study longitudinally examined the relationships between the specific domains of cognitive performance and functional decline among the community elderly. The study population was 119 men and 194 women aged 70-84 at baseline, who were examined at both baseline and in a 4-year follow-up survey. Katz's Index and the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) were used for measuring the functional capacities of basic activities of daily living (BADL) and higher-level competence, respectively. For the purpose of analyses, declines in each subscale of functional capacity during the follow-up period were used as outcome variables; and specific domains of cognitive performances, including information processing speed, executive function, orientation, and episodic memory at baseline, were used as independent variables. Multiple logistic regression analyses, adjusted for the potential confounders, showed that information processing speed and orientation were associated independently and inversely with BADL decline, and that information processing speed and executive function were related independently and inversely to higher-level competence decline. These results suggested that information processing speed and orientation are reliable predictors for decline in BADL, and information processing speed and executive function are also reliable predictors for decline in higher-level competence among the community elderly.

Purpose: The present study was conducted to identify the characteristics of non-participants in secondary comprehensive health examinations among community-dwelling elderly., Methods: The subjects were 728 men and 984 women aged 70 years and over who had participated in comprehensive health examinations in 2002. Multiple logistic regression analysis was performed to assess the characteristics associated with non-participation in comprehensive health examinations after 2 years (in 2004)., Results: The rates of participation in follow-up health examinations were 66.3% for men and 67.3% for women. Logistic regression analysis showed that male non-participants had low cognitive function (odds ratio (OR) = 2.19, 95% confidence interval (CI) = 1.07-4.49), low education (OR = 1.58, 95% CI = 1.22-2.22), and suffered from health problems (OR = 1.82, 95% CI = 1.27-2.59), and that female non-participants had low cognitive function (OR = 2.01, 95% CI 1.13-3.59), tended to be smokers (OR = 2.05, 95%, CI = 1.13-3.72), and had no hobby (OR = 0.68, 95% CI = 0.50-0.92)., Conclusion: Poor cognitive function, health problems, and unfavorable lifestyle factors are related to non-participation in comprehensive health examinations., Proposal: It is necessary to devise various approaches to encourage participation of such individuals.

In conventional transmission electron microscopy (EM), thinly sectioned specimens embedded in epoxy resin are observed. However, because of a substantial level of electron density of epoxy resin, the possibility cannot be ruled out that bio-structures having electron density similar to that of epoxy resin are not clearly recognized and thus are neglected or misinterpreted in conventional EM. This was the reason to require for embedment-free EM. Embedment-free sections have already been made available reliably by transient embedding in polyethylene glycol (PEG) and subsequent de-embedding through immersion in water, and further by critical-point drying, and this embedment-free EM is thus termed PEG-EM. However, this PEG-EM has not been successful to attract reasonable attention from electron microscopists and instead been misunderstood as a non-reliable method. In this paper, the remarkably enhanced contrast and electron translucency of any observation targets in PEG-EM are clearly demonstrated by comparing with images in conventional EM of adipocytes and neural myelin as examples. These features of PEG-EM, together with faithful correspondence in EM images of any individual substructures between the two methods, confirm the reliability of PEG-EM. Furthermore, the much higher thickness of embedment-free sections together with these features makes the PEG-EM more advantageous than the conventional EM for three-dimensional appreciation of structural elements, which is made by stereo-viewing of sections or by EM tomography. Therefore, the PEG-EM is regarded as an important adjunct to the conventional EM for histological studies and wide application of this method may unravel a new level of histology.

Background and Aims: Recent studies have revealed that there are critical differences between participants and non-participants in health examinations. The aim of this study was to examine mortality differences between participants and non-participants in a comprehensive health examination for prevention of geriatric syndromes among community-dwelling elderly people, using a three-year prospective cohort study., Methods: The study population included 854 adults aged 70 to 84 at baseline. The following items were all studied: the status of participation in the comprehensive health examination as an independent variable, age, gender, number of years of education, living alone, presence of chronic diseases, experience of falls over one year, history of hospitalization over one year, self-rated health, body mass index, instrumental activities of daily living, and subjective well-being as covariates; and all-cause mortality during a three-year follow-up as a dependent variable., Results: In an adjusted Cox's proportional hazard regression model, the mortality risk for participants in the comprehensive health examination was significantly lower than that of non-participants (Risk Ratio (for participants)= 0.44, 95% confidence interval=0.24 to 0.78)., Conclusions: The present study shows that there is a large mortality difference between participants and non-participants. Our findings suggest two possible interpretations: 1) There is a bias due to self-selection for participation in the trial, which was not eliminated by adjustment for the covariates in the statistical model; 2) There is an intervention effect associated with participation in the comprehensive health examination which reduces the mortality risk.

A promising strategy for identifying disease susceptibility genes for both single- and multiple-gene diseases is to search patients' autosomes for shared chromosomal segments derived from a common ancestor. Such segments are characterized by the distinct identity of their haplotype. The methods and algorithms currently available have only a limited capability for determining a high-resolution haplotype genomewide. We herein introduce the homozygosity haplotype (HH), a haplotype described by the homozygous SNPs that are easily obtained from high-density SNP genotyping data. The HH represents haplotypes of both copies of homologous autosomes, allowing for direct comparisons of the autosomes among multiple patients and enabling the identification of the shared segments. The HH successfully detected the shared segments from members of a large family with Marfan syndrome, which is an autosomal dominant, single-gene disease. It also detected the shared segments from patients with model multigene diseases originating with common ancestors who lived 10-25 generations ago. The HH is therefore considered to be useful for the identification of disease susceptibility genes in both single- and multiple-gene diseases.

Objectives: This study was conducted in order to examine the prevalence of geriatric syndrome (falls, incontinence, depression, and under-nutrition) in community-dwelling elderly people, and to analyze the health status of the elderly with geriatric syndrome risk compared to those of a group not at risk., Methods: The subjects comprised 1,784 residents (769 men and 1,015 women) aged 70 years or more living in Itabashi-ku, Tokyo, who took part in the study. For this study, we divided the subjects into two groups: those with geriatric syndrome (n=688) and those without (n=1,096)., Results: It was found that 33.6% of men and 42.4% of women had geriatric syndrome. Elderly with geriatric syndrome in both men and women had a significantly lower the proportion of subjects who perceived as 'healthy' in terms of the self-rated health, the higher-level functional capacity, higher prevalence of fear of falling, and decreased physical performance including handgrip strength and usual.maximal walking speed than those in the group who did not have geriatric syndrome. Logistic regression analysis showed that geriatric syndrome was associated with poor perceived self-rated health, a lower hemoglobin level and a slower usual walking speed in men, whereas in women it was associated with poor perceived self-rated health and fear of falling., Conclusion: Elderly individuals with geriatric syndrome have significantly decreased health status and physical performance compared to those without geriatric syndrome.

Background: The present study was conducted to identify the characteristics of non-participants in intervention for geriatric syndrome among community-dwelling elderly., Methods: The subjects were 208 men and 399 women aged 70 years and over who were eligible for participation in intervention programs for geriatric syndrome (falls, urinary incontinence, depression, and malnutrition) after recruitment based on a baseline health examination survey in 2002. Multiple logistic regression analysis was performed to assess non-participation in the intervention program as a dependent variable, and the relevant characteristics for participation in the baseline survey as the independent variables., Results: The rates of participation in the intervention were 16.8% for men and 32.6% for women. Logistic regression analysis showed that male non-participants had not participated in group social activity (odds ratio (OR)=2.46, 95% confidence interval (CI) 1.08-5.59), and had no medical history of heart disease (OR=0.38, 95%CI 0.17-0.89), whereas female non-participants had not lived alone (OR=0.53, 95%CI 0.34-0.83), and had no medical history of hyperlipemia (OR=0.54, 95% CI 0.34-0.84)., Conclusion: Social activity, living arrangement, and medical history are related to non-participation in intervention for geriatric syndrome. It is necessary to devise various intervention programs and approaches to encourage participation.

Objectives: To investigate the association between change in bone mineral density (BMD) and change in usual walking speed in elderly community-living Japanese women during 2 years of follow-up., Design: Longitudinal cohort study., Setting: Community-based., Participants: A total of 182 women aged 70 to 84 who completed a baseline survey and a follow-up survey 2 years later., Measurements: An interview, anthropometric measurements, blood analysis, and physical performance tests were performed at baseline and at follow-up 2 years later. BMD was evaluated using dual-energy X-ray absorptiometry measured at the forearm. Annual percentage changes in BMD and usual walking speed during the 2-year follow-up period were calculated; annual percentage changes in BMD were summarized in quartiles. The association between annual bone loss rate and decline in usual walking speed was analyzed using multiple linear regression adjusted for changes in muscle strength, balance capability, and other potential confounders., Results: Change in BMD was significantly related to change in usual walking speed during the 2-year follow-up. After multivariate adjustment, usual walking speed declined significantly more in elderly women whose BMD decreased (-3.5% change in walking speed in the first quartile of percentage change in BMD and -3.1% in the second quartile) than in women whose BMD increased (+1.5% in fourth quartile)., Conclusion: Elderly women whose BMD decreased had a significantly greater decline in usual walking speed than women whose BMD increased, even after multivariate adjustment of potential confounders.

Objective: The present study was performed to comprehensively investigate the prevalence of multiple symptoms of the geriatric syndrome, characteristics and related factors in urban community-dwelling elderly women., Methods: Among 669 women aged 70 years and above living in 5 areas of Itabashi-ku, who attended the Otassha Kenshin (comprehensive health check for the elderly) in November 2004 and gave consent to participate in this study, 668 had no missing data and their interview and physical fitness data were analyzed. The criteria for the geriatric syndrome were: (1) functional decline: a score of 10 points or below for the 13 items of the Tokyo Metropolitan Institute of Gerontology (TMIG) index of competence; (2) falls: "have fallen" once or more in the last year; and (3) urinary incontinence: frequency of urine leakage of "1 to 3 times in a month" in daily life. The interview and physical fitness data were compared between healthy persons, persons with one symptom and persons with multiple symptoms. Multiple logistic regression models were used to analyse related factors., Results: The prevalence of multiple geriatric syndromes was 15.3%; comprising 2.2% with "functional decline+falls", 6.0% with "functional decline+urinary incontinence", 5.1% with "falls+urinary incontinence", and 2.0% with "functional decline+falls+urinary incontinence". The group reporting multiple symptoms had poor self-rated health, had a high percentage currently taking three or more medications, had a fear of falling and had a significantly (P < 0.05) higher likelihood of a history of stroke and urinary disease. In addition, the group with multiple symptoms were older, and had significantly (P < 0.05) poorer results for grip strength, usual walking speed, maximum walking speed, functional reach, knee extension strength, and one leg standing time with eyes open. Within this group, the "functional decline+falls" subgroup had the lowest level of physical fitness. Analysis of factors related to the presence (1) or absence (0) of multiple symptoms identified fear of falling and usual walking speed as two significant variables., Conclusion: This study showed that: (1) physical fitness is significantly lower in the group with multiple symptoms of the geriatric syndrome compared with healthy persons, and was the lowest in the subgroup with "functional decline+falls"; and (2) fear of falling and usual walking speed were two factors related to multiple geriatric syndromes. These results suggest directions for future intervention strategies.

Background: Previous studies have shown that serum albumin or vitamin D is associated with physical performance. We hypothesized that older adults with concomitant lower serum albumin and vitamin D (25-hydroxyvitamin D, 25OHD) levels are associated with decreased physical performance compared to those with 1 or none of the 2 risk factors., Objective: To investigate the association of combined serum albumin and 25OHD levels with physical performance (muscle strength and balance capability) in community-dwelling elderly., Methods: A cross-sectional study in a community-based population in the province of Tokyo, Japan, was performed. For the study, 1,094 community-dwelling people aged 70 and older underwent an interview, anthropometric measurements, blood analysis and physical performance testing. The subjects were classified into 4 types by combining serum albumin and 25OHD levels: lower albumin only, lower vitamin D only, lower albumin and lower vitamin D, higher albumin and higher vitamin D., Results: Men with concomitant lower albumin and lower 25OHD levels had significantly decreased knee extension power, usual timed Up & Go and maximal timed Up & Go, even after adjusting for age and body mass index (BMI). In women, concomitant lower albumin and lower vitamin D was associated with significantly decreased handgrip strength and functional reach, even after adjusting for age and BMI. Subjects with combined lower albumin and lower vitamin D levels showed a significant decline in muscle strength and balance capability compared to higher albumin and higher vitamin D, even after adjusting for age, current drinking or smoking status, physical activity, history of chronic disease, basic activities of daily living, instrumental activities of daily living, BMI and bone mineral density., Conclusion: Concomitant lower serum albumin and lower vitamin D levels are associated with decreased muscle strength and balance capability in both men and women. These results suggest that serum albumin and 25OHD together may be an important target for strategies aiming to achieve a healthy life and prevent loss of independence in community-dwelling elderly.

Aim: We examined the prevalence and characteristics of urinary incontinence in community-dwelling elderly individuals., Methods: The participants were 1,783 individuals (768 men and 1,015 women) aged over 70 years who participated in a comprehensive health examination involving a medical examination and interview, plus physical performance tests. Differences in characteristics between individuals with and without urinary incontinence were examined, and multivariate logistic regression models were used to describe the characteristics associated with urinary incontinence., Results: The prevalence of urinary incontinence was 13.4% in men and 23.3% in women. Urinary incontinence was significantly associated with a lower level of physical fitness. Multivariate logistic regression showed that urinary incontinence was significantly associated with a slower walking speed (Odds Ratio (OR) = 0.19, 95% Confidence Intervals (CI) 0.08-0.48) and lower serum albumin level (OR = 0.40, 95% CI 0.16-0.99) in men, and with a slower walking speed (OR = 0.29, 95% CI 0.15-0.56), a higher BMI (OR = 1.09, 95% CI 1.04-1.14), depression (OR = 3.06, 95% CI 1.40-6.69), and lack of physical activity (OR = 0.70, 95% CI 0.50-0.98) in women., Conclusion: The characteristics of urinary incontinence in this cohort of community-dwelling elderly individuals were a low level of physical fitness and poor nutritional state in men, and a low level of physical fitness, a tendency to be obese, a poor mental health state, and lack of physical activity in women.

Purpose: We explored correlates of change in cognitive function during a two-year follow-up period among the community-dwelling elderly in Japan, using a population-based prospective approach., Method: The participants analyzed in the present study were 260 men and 222 women aged 70 to 84 years at baseline, living in an urban Japanese community. Data such as change in cognitive function during two years (calculated by subtracting baseline Mini-Mental State Examination [MMSE] score from follow-up MMSE score: a negative value means a decrease in MMSE scores during the two-year period) as an outcome variable, age, education, hearing and vision problems, IADL deficit (measured by the Tokyo Metropolitan Institute of Gerontology of Index of Competence), problems related to memory complaint, living alone, hemoglobin level, as explanatory variables, and the baseline MMSE score, depressive status (measured by the Mini-International Neuropsychiatric Interview), chronic conditions (hypertension, stroke, and diabetes mellitus) as covariates, were collected during a comprehensive health examination survey for the elderly., Results and Conclusion: We conducted multivariate regression analysis by genders to explore correlates of change in cognitive function. The results showed that higher age (beta = -0.18), presence of hearing problem (beta = -0.21), presence of IADL deficit (beta = -0.15), and memory complaint (beta = -0.20) in men, and higher age (beta = -0.27), low education level (beta = -0.25) and lower hemoglobin level (beta = 0.16) in women, were significantly associated with change in cognitive function when adjusting for the potential confounders. These factors may be reliable predictors for cognitive decline.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to cause a multitude of detrimental effects to developing zebrafish (Danio rerio). Previously, we demonstrated that jaw growth was impaired by TCDD exposure, but the exact mechanism underlying these malformations remained unknown. In the present study, we investigated the involvement of hedgehog genes and their downstream signaling in TCDD-mediated jaw malformation. We demonstrate that the developing lower jaw expresses sonic hedgehog a (shha), sonic hedgehog b (shhb) and their receptors, patched1 (ptc1) and patched2 (ptc2), as well as the downstream transcription factors, gli1 and gli2a. Loss of Hh signaling in mutants (sonic you) and larvae treated with a Hh inhibitor (cyclopamine), resulted in similar effects as those caused by TCDD. Moreover, TCDD exposure caused downregulation of shha and shhb in a manner dependent on aryl hydrocarbon receptor 2 (ahr2). Although this suggested an involvement of Hh signaling in TCDD-mediated impairment of jaw growth, we did not observe downregulation of ptc1 and ptc2, receptors dependent on Hh signaling. Furthermore, while the overall occurrence of apoptosis in the developing jaw was minimal, it was significantly increased in larvae treated with cyclopamine. In contrast, both TCDD and cyclopamine markedly reduced immunoreactivity against phosphorylated histone 3, a cell proliferation marker in the developing jaw. Taken together, our data suggest that Ahr2-mediated downregulation of Hh signaling, leading to a failure of cell proliferation, contributes to TCDD induced inhibition of lower jaw growth. TCDD may impair jaw growth through other pathway(s) in addition to Hh signaling.