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Activation of lysolipid-sensitive G protein-coupled receptors (GPCR) depends not only on lysolipid class but also on the length and degree of saturation of their respective hydrophobic tails. Positive regulation of these signaling networks caused by the lipid chain length specificity of upstream phospholipases is firmly established. Nonagonistic lysolipid homologues, featuring incompatible lipid tails, have been suggested to indirectly modulate GPCR signaling by delaying agonist catabolism. Nonetheless, recent results seem inconsistent with this hypothesis. Utilizing a simplified lysolipid-GPCR signaling assay based on the established lysophosphatidylglucoside-GPR55 signaling axis in primary sensory neurons, we demonstrate that short-chain ligand homologues directly modulate receptor activation via a potent competitive antagonistic activity. Considering the well-documented tissue-specific concentration of lysolipid homologues, we propose that endogenous lysolipids with insufficient chain length for stable receptor activation exert an antagonistic activity, effectively representing a negative control mechanism for GPCR-associated lysolipid signaling.

Objectives To build a healthy and safe community, it is important to provide direct services, such as health, medical, and social welfare services. However, it is also crucial to enhance the community's social capital by promoting self-help and mutual aid within the community. The development and utilization of resources/networks as well as community empowerment are possible methods to enhance social capital, but there is no conclusive method to facilitate effective coordination within the community. The purpose of this study is to clarify the community building process. This is achieved through qualitative research on community social coordinators (CSCs) who worked in an area that was significantly damaged by the Great East Japan Earthquake.Methods A qualitative approach was employed to assess 10 individuals who worked as CSCs in a city within Miyagi Prefecture. Semi-structured interviews were conducted, which were between 40-90 minutes in length. A modified grounded theory approach (M-GTA) was used to analyze the data obtained from the interviews.Results The CSCs "built a relationship with the community," "assessed the community," and "intervened in the community." While assessing the community, they considered both its strengths and weaknesses, not limiting the fields it covered. To "solve the issues in the community," the CSCs "intervened in the community by themselves," "supported the autonomy of the residents," and "connected the residents to resources." This intervention was facilitated through "cooperation with the community" or "cooperation with other supporters."Conclusion Three stages were observed in the community building process. First, the CSCs built a relationship with the community. They then assessed the community, and intervened as required. It was found that the intervention-which was based on the CSCs' assessment of the community's strengths and weaknesses-was facilitated by the cooperation of the community or that of other supporters. Additionally, the CSCs aimed to promote the autonomy of the residents.

Summary During neurodevelopment, the growth cone deciphers directional information from extracellular guidance cues presented as shallow concentration gradients via signal amplification. However, it remains unclear how the growth cone controls this amplification process during its navigation through an environment in which basal cue concentrations vary widely. Here, we identified inositol 1,4,5-trisphosphate (IP3) receptor type 3 as a regulator of axonal sensitivity to guidance cues in vitro and in vivo. Growth cones lacking the type 3 subunit are hypersensitive to nerve growth factor (NGF), an IP3-dependent attractive cue, and incapable of turning toward normal concentration ranges of NGF to which wild-type growth cones respond. This is due to globally, but not asymmetrically, activated Ca2+ signaling in the hypersensitive growth cones. Remarkably, lower NGF concentrations can polarize growth cones for turning if IP3 receptor type 3 is deficient. These data suggest a subtype-specific IP3 receptor function in sensitivity adjustment during axon navigation., Graphical Abstract, Highlights • IP3 receptor type 3 (IP3R3) controls axonal sensitivity to IP3-based guidance cues • IP3R3−/− growth cones are not attracted to NGF due to global Ca2+ responses • Lower NGF concentrations can polarize IP3R3−/− growth cones for attractive turning • NGF knockdown in vivo can revert abnormal trajectory of IP3R3−/− axons, Biological Sciences; Neuroscience; Molecular Neuroscience; Cellular Neuroscience

Background Suicide mortality is high in Japan and early interventional strategies to solve that problem are needed. An accurate evaluation of the regional status of current suicide mortality would be useful for community interventions. A few studies in Kanagawa prefecture, located next to Tokyo and with the second largest population in Japan, have identified spatial clusters of suicide mortality at regional levels. This study examined spatial clustering and clustering over time of such events using spatial data from regional statistics on suicide deaths. Methods Data were obtained from regional statistics (58 regions in Kanagawa prefecture) of the National Vital Statistics of Japan from 2011 to 2017. The standardized mortality ratio (SMR) and Empirical Bayes estimator for the SMR (EBSMR) were used as measures. Spatial clusters were examined by Kulldorff’s circular spatial scan statistic, Tango-Takahashi’s flexible spatial scan statistic and Tango’s test. Linear regression and conditional autoregressive (CAR) models were used not only to adjust for covariates but also to estimate regional effects. The analyses were conducted for each year, inclusive. Results Among male suicide deaths, being unemployed (50%) was most frequently related to suicide while among female health problem (50%) were frequent. Spatial clusters with significance detected by FlexScan, SatScan and Tango’s test were few and varied somewhat according to the method used. Spatial clusters were detected in some regions including Kawasaki ward after adjustment by covariates. By the linear regression models, selected variables with significance were different between the sexes. For males, unemployment, family size, and proportion of higher education were detected for several of the years studied while for females, family size and divorce rate were detected over this period. These variables were also observed by the CAR model with 5 covariates. Regional effects were much clearer by considering the spatial parameter for both males and females and especially, Kawasaki ward was detected as a high risk region in many years. Conclusion The present results detected some spatial clustering of suicide deaths within certain regions. Factors related to suicide deaths were also indicated. These results would provide important information in policy making for suicide prevention.

ObjectivesWomen and men might experience psychological distress differently during a disaster. This study investigated gender differences in the factors associated with psychological distress among working-age people 1 to 2 years after the Great East Japan Earthquake.MethodsA cross-sectional household survey of victims who remained living in their homes was conducted between May and December 2012 in Ishinomaki City, Japan. Psychological distress was defined as a Kessler Psychological Distress Scale ≥5, and gender differences were examined using a logistic regression analysis.ResultsData were obtained from 2593 individuals, and 1537 participants were included in the analyses. Psychological distress was observed in 28.0% of the participants. Living in a household without a salaried income and a low frequency of leaving the house were associated with psychological distress among women. Young age, lack of occupation and no informational support were associated with psychological distress among men. Income change due to the disaster and health complaints were associated with psychological distress in both genders.ConclusionsFor women, stable household income and frequently leaving the house can be protective factors. For men, intervention focusing on young people, occupational support, and informational support may be useful. Income change after the disaster and health complaints may be risk factors in both genders. (Disaster Med Public Health Preparedness. 2019;13:487-496)

A mixed ligated amidoyttrium complex, Y(NBn2)(L1)(THF)2 (8, L1 = N,N’-bis(2,6-diisopropylphenyl)ethylenediamine), served as a catalyst for addition of the ortho-pyridyl C(sp2)—H bond of 2-substituted pyridines to nonactivated imines; complex 8 showed superior catalytic performance compared with Y[N(SiMe3)2]3 (1) and Y[N(SiMe3)2]2(NBn2)(THF) (2). Concerning the reaction mechanism, we conducted a stoichiometric reaction of an alkylyttrium complex, Y(CH2SiMe3)(L1)(THF)2 (7), with 2-ethylpyridine (4e), giving a mixture of (η3-pyridylmethyl)yttrium complex 9 and (η2-pyridyl)yttrium complex 10 along with elimination of SiMe4. Furthermore, addition of N-(tert-butyl)-2-methylpropan-1-imine (5i) to the mixture of 9 and 10 afforded (pyridylmethylamido)yttrium complex 11 as a single product, and the catalytic activity of 11 was comparable to that of complex 8. Kinetic analysis of the aminoalkylation reaction in the presence/absence of HNBn2 revealed that the reaction rate in the presence of HNBn2 was four times fast...

Programmed death ligand 1 (PD-L1)-mediated induction of immune tolerance has been vigorously investigated in autoimmunity and anti-tumor immunity. However, details of the mechanism by which PD-L1 is induced in CD4+ T cells are unknown. Here, we revealed the potential function of Klf1 and Egr2-mediated induction of PD-L1 in CD4+ T cells. We focused on the molecules specifically expressed in CD4+CD25−LAG3+ regulatory T cells (LAG3+ Tregs) highly express of PD-L1 and transcription factor Egr2. Although ectopic expression of Egr2 induced PD-L1, a deficiency of Egr2 did not affect its expression, indicating the involvement of another PD-L1 induction mechanism. Comprehensive gene expression analysis of LAG3+ Tregs and in silico binding predictions revealed that Krüppel-like factor 1 (Klf1) is a candidate inducer of the PD-L1 gene (Cd274). Klf1 is a transcription factor that promotes β-globin synthesis in erythroid progenitors, and its role in immunological homeostasis is unknown. Ectopic expression of Klf1 induced PD-L1 in CD4+ T cells through activation of the PI3K-mTOR signaling pathway, independent of STATs signaling and Egr2 expression. Our findings indicate that Klf1 and Egr2 are modulators of PD-L1-mediated immune suppression in CD4+ T cells and might provide new insights into therapeutic targets for autoimmune diseases and malignancies.

In this paper, we examine the trend in Japan towards nonregular employment and its effects on marriage, childbirth, and childcare from the viewpoint of a decreasing societal birthrate. Although the decision to marry includes personal values and preferences, socioeconomic status factors such as income and employment type are also associated with the determinants of marriage. Nonregular employment workers have a lower rate and motivation for marriage than regular workers. Thus, socioeconomic disparity caused by employment needs to be minimized through governmental measures and policies. Nonregular employment is increasing among younger generations, and for them, maternity and childcare leave are especially vital. Employee insurance coverage should be expanded to function as a form of income security during these leaves of absence, such that nonregular workers are also covered. During the childcare period, which lasts more than 10 years, it is necessary to cover childrearing costs and also the time required to spend with children. If a single working parent is involved in childcare alone, there is the burden of both work and childcare. Additionally, long work hours can also impact workers that are not involved in childcare. This is a dilemma: a stable and regular employment is often necessary to achieve a higher education; however, it is difficult for nonregular employees to take care of and prepare children for higher education owing to limited financial means. Properly designed measures and policies are necessary to break this chain. Importantly, considerations about life and work are important for all workers, including nonregular workers, who are especially affected in terms of marriage, childbirth, and childcare.

To investigate associations between socioeconomic status (SES) and prevalence, awareness, treatment, and control of hypertension in Japan's general population.In 2010, we established a cohort of participants in the National Health and Nutrition Survey of Japan. The cohort included 2623 adults from 300 randomly selected areas across Japan. Using baseline data, four cross-sectional analyses were performed: association of SES with prevalent hypertension in 2623 participants; association of SES with unawareness of hypertension and with no treatment in 1282 hypertensive patients; and association of SES with uncontrolled hypertension in 720 treated hypertensive patients. SES was classified according to employment status, length of education, marital and living status, and household expenditure.The overall prevalence of hypertension was 48.9%. Among hypertensive participants, the proportions of unawareness and no treatment were 33.1 and 43.8%, respectively. Target blood pressure levels were not achieved among 61.2% of treated hypertensive patients. Hypertension was more prevalent in the unmarried and living alone group than in the married group (odds ratio 1.76; 95% confidence interval 1.26-2.44), after adjustment for age, sex, BMI, smoking, alcohol consumption, habitual exercise, history of cardiovascular diseases, diabetes mellitus, hypercholesterolemia, dietary sodium, and potassium intake. SES was not clearly associated with unawareness, no treatment, nor poor control of hypertension.Being unmarried and living alone was associated with increased prevalence of hypertension. There was no clear association of SES with unaware, untreated, and uncontrolled hypertension.

Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as ‘selective insulin resistance'. Here, we show that ‘selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop ‘selective insulin resistance', whereas mice lacking in Irs1, or both Irs1 and Irs2, develop ‘total insulin resistance'. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that ‘selective insulin resistance' is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression., Type 2 diabetes and obesity are associated with increased hepatic gluconeogenesis and lipogenesis, known as selective insulin resistance. Here Kubota et al. explain selective insulin resistance in the liver with the zonal distribution and selective insulin-mediated regulation of Irs1 and Irs2.

TGF-β family members are multipotent cytokines that are involved in many cellular processes, including cell differentiation, organ development, wound healing and immune regulation. TGF-β has pleiotropic effects on adaptive immunity, especially in the regulation of CD4(+) T cell and B cell responses. Furthermore, identification of CD4(+) T cell subsets that produce TGF-β3 revealed unexpected roles of TGF-β3 in the control of adaptive immunity. In contrast to TGF-β1, which induces extensive fibrosis, TGF-β3 induces non-scarring wound healing and counteracts tissue fibrosis. Recent progress in the understanding of the activation mechanism of TGF-β may enable us to develop novel biologic therapies based on advanced protein engineering.

The participation of women in the Japanese labor force is characterized by its M-shaped curve, which reflects decreased employment rates during child-rearing years. Although, this M-shaped curve is now improving, the majority of women in employment are likely to fall into the category of non-regular workers. Based on a review of the previous Japanese studies of the health of non-regular workers, we found that non-regular female workers experienced greater psychological distress, poorer self-rated health, a higher smoking rate, and less access to preventive medicine than regular workers did. However, despite the large number of non-regular workers, there are limited researches regarding their health. In contrast, several studies in Japan concluded that regular workers also had worse health conditions due to the additional responsibility and longer work hours associated with the job, housekeeping, and child rearing. The health of non-regular workers might be threatened by the effects of precarious employment status, lower income, a lower safety net, outdated social norm regarding non-regular workers, and difficulty in achieving a work-life balance. A sector wide social approach to consider life course aspect is needed to protect the health and well-being of female workers' health; promotion of an occupational health program alone is insufficient.

Objectives This study aimed to identify social factors that contribute to harmful alcohol use, defined as consuming more than 20 g of ethanol per day and raising the risk of lifestyle-related diseases, among women living on an isolated island, which has a culture that tolerates heavy drinking.Methods The participants were residents of Yoron Island, Kagoshima prefecture, aged 20-64 years (393 women and 419 men). A survey that included general questions about health was conducted as part of the Health Yoron 21 (second term) survey in July 2016. The outcome was presence or absence of harmful alcohol use, and the predictors were social factors. Multiple logistic regression analysis was conducted to assess the association between harmful alcohol use and social factors. Age, presence or absence of child, and the length of time living on the island were also entered into the model as control variables.Results Analysis of data from 309 women showed that 46 women (14.8%) engaged in harmful alcohol use, and five significant factors were identified: restaurant and tourist industry workers (OR 6.73, 95%CI 1.13-39.98); smoking (OR 4.47, 95%CI 1.36-14.63); participation in recreational activities (OR 4.47, 95%CI 1.93-10.39); depressed within the past 2 weeks (OR 2.47, 95%CI 1.08-5.68); and drinking at home (OR 16.52, 95%CI 6.77-40.29).Conclusion This study identified negative aspects of social interactions in women engaged in harmful alcohol use. Additionally, depression within the previous 2 weeks was associated with harmful alcohol use. Given the island culture, drinking is expected to contribute to forming and maintaining better human relationships. However, drinking should be moderated in the interest of health. The results of this study will be used for Health Yoron 21 (second term).

The purpose of the present study was to assess the effects of social capital on mental health among the Japanese population with or without natural disaster experience. A nationwide cross-sectional study was performed in the population aged 15 to 79 years old. We collected data on psychological status, social capital, disaster experience in ten years prior to the survey, and socio-demographic information. We assessed cognitive social capital (perceptions of support, reciprocity and trust), social support (support from individuals in the community), and social participation (participation in social activities) as components of social capital. The study outcome was mild mood or anxiety disorder (hereafter mood/anxiety disorder), defined as the score of 5 or higher in the Kessler Psychological Distress Scale (K6). Using logistic regression models, we tested whether each component of social capital was associated with mood/anxiety disorder with or without disaster experience. Out of 1,200 participants, 1,183 had available K6 score data and were considered. Among three components of social capital, only social support significantly interacted with disaster experience (p = 0.019). In the population without disaster experience, those with high social support were less likely to have mood/anxiety disorder (OR 0.45, 95% Cl 0.28-0.73); however, no such association was observed among those with disaster experience (OR 1.11, 95% CI 0.64-1.90). Thus, the protective effects of social support against mood/anxiety disorder vary in the Japanese population depending on disaster experience. The present study provides important insight into the role of social capital on mental health after natural disaster.

In 1952, the Japanese Society for Hygiene had once passed a resolution at its 22nd symposium on population control, recommending the suppression of population growth based on the idea of cultivating a healthier population in the area of eugenics. Over half a century has now passed since this recommendation; Japan is witnessing an aging of the population (it is estimated that over 65-year-olds made up 27.7% of the population in 2017) and a decline in the birth rate (total fertility rate 1.43 births per woman in 2017) at a rate that is unparalleled in the world; Japan is faced with a “super-aging” society with low birth rate. In 2017, the Society passed a resolution to encourage all scientists to engage in academic researches to address the issue of the declining birth rate that Japan is currently facing. In this commentary, the Society hereby declares that the entire text of the 1952 proposal is revoked and the ideas relating to eugenics is rejected. Since the Society has set up a working group on the issue in 2016, there have been three symposiums, and working group committee members began publishing a series of articles in the Society’s Japanese language journal. This commentary primarily provides an overview of the findings from the published articles, which will form the scientific basis for the Society’s declaration. The areas we covered here included the following: (1) improving the social and work environment to balance between the personal and professional life; (2) proactive education on reproductive health; (3) children’s health begins with nutritional management in women of reproductive age; (4) workplace environment and occupational health; (5) workplace measures to counter the declining birth rate; (6) research into the effect of environmental chemicals on sexual maturity, reproductive function, and the children of next generation; and (7) comprehensive research into the relationship among contemporary society, parental stress, and healthy child-rearing. Based on the seven topics, we will set out a declaration to address Japan’s aging society with low birth rate.

Objective Biologic disease-modifying antirheumatic drugs (bDMARDs) used for rheumatoid arthritis (RA) treatment have several mechanisms of action. Interleukin-6 inhibitors (IL-6i) block the production of acute-phase reactants (APRs), which are some of the composite measures of disease activity. We undertook this study to examine the agreement between the European League Against Rheumatism (EULAR) response based on the erythrocyte sedimentation rate (ESR) or C-reactive protein level, the Simplified Disease Activity Index 50% response measure (SDAI50), and the Clinical Disease Activity Index 50% response measure (CDAI50) in patients treated with IL-6i and other bDMARDs. Methods We enrolled 306 patients with RA who started or switched bDMARDs. Treatment response at 6 months was analyzed. Kappa statistics were used to evaluate the agreement between different response measures. The contribution of APRs to improvement in disease activity scores was examined. The change of Health Assessment Questionnaire (HAQ) score was analyzed in IL-6i-treated patients. Results Good agreement was achieved between response measures, with κ >0.6 in patients treated with tumor necrosis factor inhibitors or cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin fusion protein. In IL-6i-treated patients, the agreement was low between the EULAR response (ESR) and the SDAI50 or the CDAI50 (κ = 0.43 and 0.37, respectively). Under IL-6i treatment, APR improvement accounted for 56.0% of total improvement of the Disease Activity Score in 28 joints (DAS28) using the ESR. When discordance was found between the CDAI50 and EULAR response in IL-6i-treated patients, all patients were classified as EULAR-only responders; there was no HAQ improvement in EULAR-only responders. Conclusion EULAR response criteria overestimate the response under IL-6i treatment because the APR improvement largely contributes to the DAS28 improvement.

M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood. Herein, we demonstrate that, the IL-4/Irs2/Akt pathway is selectively impaired, along with decreased macrophage Irs2 expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specific Irs2-deficient mice show impairment of IL-4-induced M2a-subtype macrophage activation, as a result of stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex, resulting in insulin resistance under the HF diet condition. Moreover, the reduction of macrophage Irs2 expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell-specific IR-deficient mice, the IL-4/Irs2 pathway is preserved in the macrophages, which results in a reduced degree of insulin resistance, because of the lack of IR-mediated downregulation of Irs2. We conclude that downregulation of Irs2 in macrophages caused by hyperinsulinemia is responsible for systemic insulin resistance via impairment of M2a-subtype macrophage activation in obesity., Obesity is associated with low-grade chronic inflammation. Here the authors show that the activation of anti-inflammatory M2a-subtype macrophages requires the IL4/Irs2/Akt pathway. Due to decreased Irs2 expression this pathway is impaired in obese mice thus leading to a defect in M2a activation.

Angewandte Chemie. International Edition, 57 (44), ISSN:1433-7851, ISSN:1521-3773, ISSN:0570-0833

Transforming growth factor (TGF)-βs are pluripotent cytokines with stimulatory and inhibitory properties for multiple types of immune cells. Analyses of genetic knockouts of each isoform of TGF-β have revealed differing expression patterns and distinct roles for the three mammalian isoforms of TGF-β. Considerable effort has been focused on understanding the molecular mechanisms of TGF-β1-mediated immune regulation, given its pivotal role in prohibiting systemic autoimmune disease. In recent years, functional similarities and differences between the TGF-β isoforms have delineated their distinct roles in the development of immunopathology and immune tolerance, with increased recent attention being focused on TGF-β3. In addition to the characteristic properties of each TGF-β isoform, recent progress has identified determinants of context-dependent functionality, including various cellular targets, cytokine concentrations, tissue microenvironments, and cytokine synergy, which combine to shape the physiological and pathophysiological roles of the TGF-βs in immunity. Controlling TGF-β production and signaling is being tested as a novel therapeutic strategy in multiple clinical trials for several human diseases. This review highlights advances in the understanding of the cellular sources, activation processes, contextual determinants, and immunological roles of TGF-β3 with comparisons to other TGF-β isoforms.

Introduction: M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood. Methods: We found that the phosphorylation levels of Irs2 by IL-4 were significantly reduced along with decreased Irs2 expression in macrophages of high-fat (HF) diet-fed mice. To investigate the role of Irs2 in the macrophages, we then generated myeloid cell-specific Irs2-deficient (MIrs2KO) mice. Results: HF diet-fed MIrs2KO mice showed impairment of IL-4-induced M2a-subtype macrophage activation, resulting in insulin resistance. Expressions of the maker genes for M2a-subtype macrophages were downregulated by stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex via impairment of the IL-4/Irs2 pathway. Furthermore, Irs2 expression was significantly suppressed by insulin treatment in macrophages, suggesting that chronic hyperinsulinemia downregulates macrophage Irs2 expression via insulin receptor (IR). Indeed, in myeloid cell-specific IR-deficient mice, the IL-4-Irs2 pathway was preserved in the macrophages due to the lack of IR-mediated downregulation of Irs2, resulting in a reduced degree of inflammation and insulin resistance. Conclusion: These data suggest that in obesity, downregulation of macrophage Irs2 is induced by hyperinsulinemia, resulting in impaired IL-4-induced M2a-subtype macrophage activation, and insulin resistance. Disclosure T. Kubota: None. M. Inoue: None. N. Kubota: None. I. Takamoto: None. K. Ueki: Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Novo Nordisk Inc., Mitsubishi Tanabe Pharma Corporation, Kyowa Hakko Kirin Co., Ltd., Takeda. Research Support; Self; Takeda, Astellas, Novo Nordisk Inc. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

Background Reduction in neonatal deaths has been a major challenge globally. To prevent neonatal deaths, improvements in newborn care have been promoted worldwide. The World Health Organization Western Pacific Regional Office has been promoting the Early Essential Newborn Care (EENC), a package of specific simple and cost-effective interventions, in their region. However, mere introduction of EENC cannot reduce neonatal deaths unless quality of care is ensured. In Lao PDR, the government introduced self-managed continuous monitoring as a sustainable way to improve the quality of care described in the EENC. Methods A clustered randomized controlled trial was designed to compare the effectiveness of self-managed continuous monitoring with external supervisory visits to monitor health workers’ satisfactory EENC performance and their knowledge and skills related to the EENC in Lao PDR. Determinants of EENC performance will be measured with a structured questionnaire developed based on the Theory of Planned Behaviour, which predicts future behaviour. During self-managed continuous monitoring activities, health workers in each district hospital will conduct periodical peer reviews and feedback sessions. Fifteen district hospitals will be randomly allocated into the self-managed continuous monitoring (intervention) and the supervision (control) groups. Fifteen health workers routinely involved in maternity and newborn care including physicians, midwives and other health staff will be recruited from each hospital (effect size 0.6, intra-cluster correlation coefficient 0.06, 5% alpha error and 80% power). We will compare the change in the mean score of the determinants before and one year after randomisation between the two groups. We will also compare the retention of knowledge and skills related to the EENC between the two groups. The expected enrolment period is July 20th, 2017 to July 20th, 2018. Discussion This is the first cluster randomized trial to evaluate a self-managed continuous monitoring system for quality maintenance of newborn care in a resource-limited country. This research is conducted in collaboration with the Ministry of Health and international organizations; therefore, if effective, this intervention would be applied in larger areas of the country and the region. Trial registration This trial was registered at UMIN-CTR on 15th of June, 2017. Registration number is UMIN000027794. Electronic supplementary material The online version of this article (10.1186/s12913-018-3311-7) contains supplementary material, which is available to authorized users.

In this paper, we examine the trend in Japan towards nonregular employment and its effects on marriage, childbirth, and childcare from the viewpoint of a decreasing societal birthrate. Although the decision to marry includes personal values and preferences, socioeconomic status factors such as income and employment type are also associated with the determinants of marriage. Nonregular employment workers have a lower rate and motivation for marriage than regular workers. Thus, socioeconomic disparity caused by employment needs to be minimized through governmental measures and policies. Nonregular employment is increasing among younger generations, and for them, maternity and childcare leave are especially vital. Employee insurance coverage should be expanded to function as a form of income security during these leaves of absence, such that nonregular workers are also covered. During the childcare period, which lasts more than 10 years, it is necessary to cover childrearing costs and also the time required to spend with children. If a single working parent is involved in childcare alone, there is the burden of both work and childcare. Additionally, long work hours can also impact workers that are not involved in childcare. This is a dilemma: a stable and regular employment is often necessary to achieve a higher education; however, it is difficult for nonregular employees to take care of and prepare children for higher education owing to limited financial means. Properly designed measures and policies are necessary to break this chain. Importantly, considerations about life and work are important for all workers, including nonregular workers, who are especially affected in terms of marriage, childbirth, and childcare.

Axon paths in developing spinal cords Sensory neurons entering the spinal cord take different paths as inputs for pain and proprioception diverge. Working with chick and mouse embryos, Guy et al. found that glycerophospholipids produced by radial glial cells guide these neural fibers, or axons, in the developing spinal cord. A soluble glycerophospholipid released by the cells provided an inhibitory signal to the pain-sensitive axons, keeping them on their own unique pathway. Science , this issue p. 974

ObjectivesThe role of the community is becoming increasingly recognized as a crucial determinant of human health, particularly during a disaster and during disaster recovery. To identify disaster-vulnerable communities, we sought factors related to communities in need of support by using census information from before the Great East Japan Earthquake.MethodsWe identified vulnerable communities by using a needs-assessment survey conducted 6 to 12 months after the Great East Japan Earthquake in Ishinomaki City, Miyagi Prefecture, as indicated by higher proportions of households with at least 1 of 3 major support needs (medical, elderly, psychological, and dwelling environment). The associations between the need for support and 9 demographic characteristics of the community from census data prior to the Great East Japan Earthquake were examined for 71 communities by use of logistic regression analysis.ResultsThe need for elderly support was positively associated with the proportions of aged people (odds ratio [OR]=1.5; 95% confidence interval [CI]: 1.2–1.8) and one-person households (OR=1.3; 95% CI: 1.0–1.7), whereas the need for psychological support was associated with the proportion of people engaged in agriculture (OR=4.6; 95% CI: 1.0–20.7). The proportion of fisheries was negatively associated with the need for dwelling environment support (OR=0.5; 95% CI: 0.3–0.9).ConclusionsThe consideration of simple demographic characteristics from the census may be useful for identifying vulnerable communities and preparing for future disasters. (Disaster Med Public Health Preparedness. 2015;9:19-28)

The Great East Japan Earthquake (GEJE) and subsequent tsunamis that occurred in 2011 caused extensive and severe structural damage and interrupted numerous research activities; however, the majority of such activities have been revived, and further public health researches and activities have started to follow the population affected by the disaster. In this mini-review, we overview our recent activities regarding epidemiologic studies in Miyagi Prefecture, the region most affected by the GEJE. Through our study processes, we were able to identify the particular characteristics of vulnerable populations, and provide ideas that may help save lives and reduce the amount of damage caused by a future disaster. Long-term follow-up and care of survivors is essential in affected areas, and health professionals should pay particular attention to various diseases, e.g., cardiovascular complications and mental disorders. Furthermore, building up resilience and social relationships in the community is beneficial to survivors. Ongoing cohort studies conducted before disasters can help minimize biases regarding the survivors’ pre-disaster information, and emerging cohort studies after disasters can find potential helpful novel indices. To identify characteristics of vulnerable populations, save lives, and reduce the amount of damage caused by a future disaster, constant research that is consistently improved by new data needs to be performed.

This study reports on an experimental class on water holding capacity in forestry, involving the use of a handmade and low-cost sprinkling instrument by vocational high school students to detect Hortonian overland flow, as proposed by Tanaka and Kuraji (2016). The low-cost sprinkling instrument consists of three plastic garden stakes, an iron flower-pot holder, a two-liter plastic bottle with a hole in the bottom, and a shower nozzle attached to the plastic bottle-goods can be bought at u201c100-yen shopsu201d (a dollar store). Using the proposed instrument, students examined thrice whether Hortonian overland flow occurred at the forest plantations at school. These experimental classes were conducted in 2017 and 2018 in Kimitsu City, Japan.No flow or a few flows were observed during the first experiment. A leaf lodged against the shower nozzle restricted the water flow at the time of the second experiment; as a result, the drop of water was big, and Hortonian flow was observed in the ground. No leaves affected the water flow from the shower nozzle in the third experiment; as a result, the drop of water was small, and the flow was low in the ground. Thus, the students could consider the relationship between water-holding capacity and rainfall in a forest plantation.

OBJECTIVES The aim of this study was to examine whether the association between employment contract and self-rated health differs by household structure in a representative sample of employees in Japan. METHODS The participants were 81,441 male and 64,471 female employees aged 18-59 years who had participated in the 2010 Comprehensive Survey of Living Conditions. We assessed the interactive effect of employment contract (permanent or precarious) and household structure (couple only, couple with children, single parent, single person, or other multi-person) on fair/poor health, adjusting for covariates by using logistic regression. We then calculated the relative poverty rate by employment contract and household structure. RESULTS The interaction effect was significant for women (p

Purpose Interleukin-32 (IL-32) is an inflammatory cytokine that is associated with the pathogenesis of several connective tissue diseases. We measured serum IL-32γ concentrations of systemic lupus erythematosus (SLE) patients. Methods Serum samples were obtained from SLE patients ( n = 51), and healthy controls ( n = 15). Serum IL-32 concentrations were measured using ELISA. Clinical information was obtained from medical records. Results Serum IL-32γ was detectable in three cases of SLE patients, whereas it was not detected in any healthy controls. Case 1: a 44-year-old female with lupus nephritis (LN) (Class II) and antiphospholipid antibody syndrome. Serum IL-32γ was 5.1 pg/ml. Case 2: a 30-year-old female with a history of diffuse proliferative LN (Class IV G (A/C)) and pulmonary hemorrhage. Serum IL-32γ was 8.9 pg/ml. Case 3: a 45-year-old female with chronic LN. Serum IL-32γ was 9.1 pg/ml. All three cases of IL-32γ-detectable patients had histories of LN and one had an active disease. In the context of LN, serum IL-32γ was detectable in 18.8% (three of 16) of SLE patients with histories of LN. Conclusion We suppose that IL-32γ could contribute to the pathogenesis of renal diseases in some LN patients.

Common genetic variations of the transcription factor 7-like 2 gene (encoded by TCF7L2), one of the T cell factor/lymphoid enhancer-binding factor transcription factors for the converging wingless-type MMTV integration site family (Wnt)/β-catenin signalling pathway, are known to be associated with type 2 diabetes. Individuals with at-risk alleles of TCF7L2 exhibit impaired insulin secretion. Although previous studies using animal models have revealed the existence of a relationship between the Wnt/β-catenin signalling pathway and glucose homeostasis, it remains unclear whether TCF7L2 in the pancreatic beta cells might be causally involved in insulin secretion in vivo. In this study, we investigated the role of TCF7L2 expressed in the pancreatic beta cells in glucose homeostasis. Three independent groups of genetically engineered mice (DN mice) were generated, in which expression of the dominant-negative form of Tcf7l2 was driven under a rat insulin promoter. Phenotypes of both adult and newborn mice were evaluated. The levels of genes and proteins expressed in isolated islets were determined by reverse transcription-quantitative PCR and western blot analysis, respectively. Adult DN mice showed impaired glucose tolerance and decreased insulin secretion in both oral and intraperitoneal glucose tolerance tests. Marked reduction of the beta cell area and whole-pancreas insulin content was observed in both the adult and newborn DN mice. Islets from the DN mice showed decreased gene expressions of Ccnd1, Ccnd2, Irs1, Irs2, Ins1, Ins2 and Mafa, consistent with the deleterious effects of the dominant-negative form of Tcf7l2 on beta cell proliferation and insulin production. TCF7L2 expressed in the pancreatic beta cells plays a crucial role in glucose metabolism through regulation of the beta cell mass.

Pioglitazone (PIO) is widely used as an insulin-sensitizing agent in the treatment of type 2 diabetes, but it also causes an increase in body weight in a dose-dependent manner. Beraprost sodium (BPS), a stable prostaglandin I2 analog, is used clinically for the treatment of peripheral arterial disease and primary pulmonary hypertension. BPS has recently been demonstrated to promote insulin-induced glucose uptake by skeletal muscle. In this study, we examined whether low-dose PIO (PIO-L; 3 mg/kg/day) plus BPS treatment might exert antidiabetic effects without causing body weight gain in obese/diabetic KKAy mice. Treatment with PIO-L plus BPS tended to improve the hepatic insulin resistance and significantly improved the skeletal muscle insulin resistance, yielding a similar degree of hyperglycemia improvement to that obtained with high-dose PIO (PIO-H; 30 mg/kg/day) treatment. Moreover, the increase in body weight observed following PIO-H treatment was not observed following PIO-L plus BPS treatment. An increase in plasma adiponectin levels, which have been shown to be negatively correlated with hepatic glucose production, but not with the glucose disappearance rate during hyperinsulinemic-euglycemic clamp, was observed in the animals treated with PIO-L, PIO-L plus BPS, and PIO-H. This suggests that the improvement in hepatic insulin resistance was associated, at least in part, with an increase in the plasma adiponectin levels observed during PIO treatment. In contrast, treatment with BPS, which failed to increase the plasma adiponectin levels, ameliorated skeletal, but not hepatic insulin resistance. PIO-L plus BPS treatment may represent efficacious treatment for insulin resistance and type 2 diabetes without causing body weight gain.

公共施設を中高生の「地域の居場所」として活用する方策を考えるため、中高生を対象に調査を実施し、公共施設の利用実態と意識、中高生対象事業の参加実態と意識について検討した結果、以下のことが明らかになった。1）調査対象の中高生の生活実態をみると、放課後の生活パタンから居場所所有にやや問題があると考えられる中高生、本音で話し合える人がいない中高生、居心地の良い場所をもたない中高生がそれぞれ1割程度存在することが明らかになった。2）公共施設の利用実態では、あまり利用していない施設が多いが、中でも青少年施設の利用度は特に低く、希望も低い。また、居場所提供や居場所事業を行っている公共施設についての中高の認知度も低い。公共施設の利用条件として、中高生は無料で利用できること、利用しやすい場所にあり、施設内の自由度が高いことを求めている。また、自由に使える空間があり、中高生利用できる時間帯に開館していることを求めている。3）中高生対象事業については、不特定多数が参加する事業には多くの参加者があるが、個人での参加が基本となる事業への参加は非常に少ない。しかし、個人的な趣味・興味に関わる事業では希望が大きく増加しており、中高生が希望する事業と実際に行われている事業とが一致していない部分が大きい。また参加している中高生の参加の仕方としては受動的な参加がほとんどであるが、希望ではもっと主体的な参加をしたいと考えている中高生が多い。不参加者がその理由とするのは興味の持てる事業がないことと、この年代に特徴的な対人的な問題であり、施設利用以前の問題が大きい。4）中高生は、公共施設に対して「社会的な居場所」とともに「個人的な居場」を同程度に求めているが、公共施設側は「個人的な居場所」に対する必要性意識は非常に低い。「個人的な居場所」に対する必要性意識に中高生と施設側に大きな隔たりがあり、これが中高生の公共施設利用や事業への参加を妨げる大きな原因になっていると考えられる。

In Tokyo, the annual average suspended particulate matter (SPM) and PM2.5 concentrations have decreased in the past two decades. The present study quantitatively evaluated these decreasing trends using data from air-pollution monitoring stations. Annual SPM and PM2.5 levels at 83 monitoring stations and hourly SPM and PM2.5 levels at four monitoring stations in Tokyo, operated by the Tokyo Metropolitan Government, were used for analysis, together with levels of co-pollutants and meteorological conditions. Traffic volume in Tokyo was calculated from the total traveling distance of vehicles as reported by the Ministry of Land, Infrastructure, Transport, and Tourism. High positive correlations between SPM levels and nitrogen oxide levels, sulfur dioxide levels, and traffic volume were determined. The annual average SPM concentration declined by 62.6%from 59.4 microg/m3 in 1994 to 22.2 microg/m3 in 2010, and PM2.5 concentration also declined by 49.8% from 29.3 microg/m3 in 2001 to 14.7 microg/m3 in 2010. Likewise, the frequencies of hourly average SPM and PM2.5 concentrations exceeding the daily guideline values have significantly decreased since 2001 and the hourly average SPM or PM2.5 concentrations per traffic volume for each time period have also significantly decreased since 2001. However SPM and PM2.5 concentrations increased at some monitoring stations between 2004 and 2006 and from 2009 despite strengthened environmental regulations and improvements in vehicle engine performance. The annual average SPM and PM2.5 concentrations were positively correlated with traffic volumes and in particular with the volume of diesel trucks. These results suggest that the decreasing levels of SPM and PM2.5 in Tokyo may be attributable to decreased traffic volumes, along with the effects of stricter governmental regulation and improvements to vehicle engine performance, including the fitting of devices for exhaust emission reduction.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4+ regulatory T cells, CD4+CD25−LAG3+ cells, that characteristically express both Egr2 and LAG3 and control mice model of lupus via TGF-β3 production. However, due to the mild phenotype of lymphocyte-specific Egr2-deficient mice, the presence of an additional regulator has been speculated. Here, we show that Egr2 and Egr3 expressed in T cells cooperatively prevent humoral immune responses by supporting TGF-β3 secretion. T cell-specific Egr2/Egr3 double-deficient (Egr2/3DKO) mice spontaneously developed an early onset lupus-like disease that was more severe than in T cell-specific Egr2-deficient mice. In accordance with the observation that CD4+CD25−LAG3+ cells from Egr2/3DKO mice completely lost the capacity to produce TGF-β3, the excessive germinal center reaction in Egr2/3DKO mice was suppressed by the adoptive transfer of WT CD4+CD25−LAG3+ cells or treatment with a TGF-β3–expressing vector. Intriguingly, latent TGF-β binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-β3 production from CD4+CD25−LAG3+ cells. Because Egr2 and Egr3 did not demonstrate cell intrinsic suppression of the development of follicular helper T cells, Egr2- and Egr3-dependent TGF-β3 production by CD4+CD25−LAG3+ cells is critical for controlling excessive B-cell responses. The unique attributes of Egr2/Egr3 in T cells may provide an opportunity for developing novel therapeutics for autoantibody-mediated diseases including SLE.

ObjectiveWe aimed to investigate the influence of social factors, especially social support, on psychological distress and the prevalence of health problems (HPs) among victims living in their homes 14 to 21 months after the Great East Japan Earthquake and tsunami.MethodsA subgroup analysis was performed for elderly participants of a cross-sectional household survey in Ishinomaki area, Japan. The prevalence of psychological HPs was assessed by using a psychological distress questionnaire (K6) and by recording the number of subjective HPs. Perceived social support was assessed in 3 dimensions: informational, emotional, and instrumental support. Univariate and multivariate logistic regression models were used to examine the association between social factors and psychological health.ResultsAn elderly subgroup with 879 participants was used for analyses. Psychological distress (K6 score≥9) was observed in 6.8% of the participants aged 65 to 74 years and in 8.0% of those aged ≥75 years. Receiving a long-term care service was associated with having HPs, and discontinuation of attendance at a hospital as an outpatient was associated with psychological distress. Receiving emotional support was associated with lower psychological distress and not having HPs.ConclusionsEmotional support was found to be an important factor for promoting health among elderly disaster victims. (Disaster Med Public Health Preparedness. 2017;11:64–71)

The aim of this study is to elucidate to what degree adiponectin is involved in TZD-mediated amelioration of neointimal formation. We investigated the effect of 3- or 8-weeks’ pioglitazone on cuff-induced neointimal formation in adiponectin-deficient (APN-KO) and wild-type (WT) mice. Pioglitazone for 3 weeks reduced neointimal formation in the WT mice with upregulation of the plasma adiponectin levels, but failed to reduce neointimal formation in the APN-KO mice, suggesting that pioglitazone suppressed neointimal formation by adiponectin-dependent mechanisms. Pioglitazone for 3 weeks suppressed vascular smooth muscle cell (VSMC) proliferation and increased AdipoR2 expression in the WT mice. In vitro, globular adiponectin activated AMPK through both AdipoR1 and AdipoR2, resulting in the inhibition of VSMC proliferation. Interestingly, 8-weeks’ pioglitazone was reduced neointimal formation in APN-KO mice to degree similar to that seen in the WT mice, suggesting that pioglitazone can also suppress neointimal formation via a mechanism independent of adiponectin. Pioglitazone for 8 weeks completely abrogated the increased VSMC proliferation, along with a reduction of cyclin B1 and cyclin D1 expressions and cardiovascular risk profile in the APN-KO mice. In vitro, pioglitazone suppressed these expressions, leading to inhibition of VSMC proliferation. Pioglitazone suppresses neointimal formation via both adiponectin-dependent and adiponectin-independent mechanisms.

TGF-β is a pleotropic cytokine involved in various biological processes. Of the three isoforms of TGF-β, TGF-β1 has long been recognized as an important inhibitory cytokine in the immune system and has been reported to inhibit B cell function in both mice and humans. Recently, it has been suggested that TGF-β3 may play an important role in the regulation of immune system in mice. Murine CD4+CD25-LAG3+ regulatory T cells suppress B cell function through the production of TGF-β3, and it has been reported that TGF-β3 is therapeutic in a mouse model of systemic lupus erythematosus. The effect of TGF-β3 on human B cells has not been reported, and we herein examined the effect of TGF-β3 on human B cells. TGF-β3 suppressed B cell survival, proliferation, differentiation into plasmablasts, and antibody secretion. Although the suppression of human B cells by TGF-β1 has long been recognized, the precise mechanism for the suppression of B cell function by TGF-β1 remains elusive; therefore, we examined the effect of TGF-β1 and β3 on pathways important in B cell activation and differentiation. TGF-β1 and TGF-β3 inhibited some of the key molecules of the cell cycle, as well as transcription factors important in B cell differentiation into antibody secreting cells such as IRF4, Blimp-1, and XBP1. TGF-β1 and β3 also inhibited B cell receptor signaling. Our results suggest that TGF-β3 modifying therapy might be therapeutic in autoimmune diseases with B cell dysregulation in humans.