Butyrate, Valerate, and Niacin Ameliorate Anaphylaxis by Suppressing IgE-Dependent Mast Cell Activation: Roles of GPR109A, PGE2, and Epigenetic Regulation.

Short-chain fatty acids (SCFAs) are produced by the intestinal microbiota during the fermentation of dietary fibers as secondary metabolites. Several recent studies reported that SCFAs modulate the development and function of immune-related cells. However, the molecular mechanisms by which SCFAs regulate mast cells (MCs) remain unclear. In the current study, we analyzed the function and gene expression of mouse MCs in the presence of SCFAs in vitro and in vivo. We found that the oral administration of valerate or butyrate ameliorated passive systemic anaphylaxis and passive cutaneous anaphylaxis in mice. The majority of SCFAs, particularly propionate, butyrate, valerate, and isovalerate, suppressed the IgE-mediated degranulation of bone marrow-derived MCs, which were eliminated by the Gi protein inhibitor pertussis toxin and by the knockdown of Gpr109a. A treatment with the HDAC inhibitor trichostatin A also suppressed IgE-mediated MC activation and reduced the surface expression level of FcεRI on MCs. Acetylsalicylic acid and indomethacin attenuated the suppressive effects of SCFAs on degranulation. The degranulation degree was significantly reduced by PGE2 but not by PGD2. Furthermore, SCFAs enhanced PGE2 release from stimulated MCs. The SCFA-mediated amelioration of anaphylaxis was exacerbated by COX inhibitors and an EP3 antagonist, but not by an EP4 antagonist. The administration of niacin, a ligand of GPR109A, alleviated the symptoms of passive cutaneous anaphylaxis, which was inhibited by cyclooxygenase inhibitors and the EP3 antagonist. We conclude that SCFAs suppress IgE-mediated activation of MCs in vivo and in vitro involving GPR109A, PGE2, and epigenetic regulation.

GPR55 contributes to neutrophil recruitment and mechanical pain induction after spinal cord compression in mice.

Pain transmission and processing in the nervous system are modulated by various biologically active substances, including lysophospholipids, through direct and indirect actions on the somatosensory pathway. Lysophosphatidylglucoside (LysoPtdGlc) was recently identified as a structurally unique lysophospholipid that exerts biological actions via the G protein-coupled receptor GPR55. Here, we demonstrated that GPR55-knockout (KO) mice show impaired induction of mechanical pain hypersensitivity in a model of spinal cord compression (SCC) without the same change in the models of peripheral tissue inflammation and peripheral nerve injury. Among these models, only SCC recruited peripheral inflammatory cells (neutrophils, monocytes/macrophages, and CD3+ T-cells) in the spinal dorsal horn (SDH), and GPR55-KO blunted these recruitments. Neutrophils were the first cells recruited to the SDH, and their depletion suppressed the induction of SCC-induced mechanical hypersensitivity and inflammatory responses in compressed SDH. Furthermore, we found that PtdGlc was present in the SDH and that intrathecal administration of an inhibitor of secretory phospholipase A2 (an enzyme required for producing LysoPtdGlc from PtdGlc) reduced neutrophil recruitment to compressed SDH and suppressed pain induction. Finally, by screening compounds from a chemical library, we identified auranofin as a clinically used drug with an inhibitory effect on mouse and human GPR55. Systemically administered auranofin to mice with SCC effectively suppressed spinal neutrophil infiltration and pain hypersensitivity. These results suggest that GPR55 signaling contributes to the induction of inflammatory responses and chronic pain after SCC via the recruitment of neutrophils and may provide a new target for reducing pain induction after spinal cord compression, such as spinal canal stenosis.

Metroplasty increases the take-home baby rate by reducing pregnancy loss without changing the chance of conception in women with septate uterus: a retrospective, single-center, observational study.

BACKGROUND: Although abdominal or hysteroscopic metroplasty for septate uterus is considered to reduce pregnancy loss and increase the take-home baby (THB) rate in women with a history of recurrent pregnancy loss, there exists an inherent risk of impaired fertility. This study aimed to clarify the reproductive outcomes of women with septate uterus who underwent abdominal and hysteroscopic metroplasty in a single center. METHODS: This retrospective observational study enrolled 27 women who underwent metroplasty between 2007 and 2019. The analysis included women with septate uterus [European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) type U2)] or septate-bicornuate uterus (ESHRE/ESGE type U3b) who underwent either abdominal or hysteroscopic metroplasty. Women who did not have an immediate desire to conceive were excluded from the analysis. As a rule, we recommended pregnancy without surgery for women who had not experienced repeated pregnancy loss. Abdominal metroplasty (ABM) was performed using the modified Tompkins' method and hysteroscopic metroplasty was performed using hysteroscopic transcervical resection of the septum [transcervical metroplasty (TCM)]. The conception ratio was calculated as the number of women who achieved ≥ 1 conception/total number of women, the pregnancy loss ratio was calculated as the number of women who experienced ≥ 1 pregnancy loss/the number of women who conceived, and the THB ratio was calculated as the number of women who achieved ≥ 1 THB/total number of women. RESULTS: Seventeen women underwent ABM and 10 women underwent TCM. Thirty-three conceptions and 26 babies were taken home after surgery. ABM did not change the ≥ 1 conception ratio (76% vs. 83% before and after surgery, respectively; RR = 1.08, p = 0.80). Meanwhile, ABM decreased the ≥ 1 pregnancy loss ratio (100% vs. 36%, RR = 0.36, p < 0.001) and increased the ≥ 1 THB ratio (12% vs. 71%, RR = 6.00, p < 0.01). Similarly, TCM did not change the ≥ 1 conception ratio, decreased the ≥ 1 pregnancy loss ratio, and increased the ≥ 1 THB ratio. CONCLUSIONS: Both abdominal and hysteroscopic metroplasty for septate uterus increased the THB rate by preventing pregnancy loss without affecting the chance of pregnancy. TRIAL REGISTRATION: Not applicable.

[Current issues related to education in the five core disciplines of public health at the school of public health in a private university].

Objectives　In Japan, schools of public health (SPH) have engaged in professional education focusing on five core disciplines: epidemiology, biostatistics, social and behavioral science, health policy and management, and occupational and environmental health. However, empirical information is lacking regarding the current state of this education and its associated challenges in Japan. In this article, we showcase this issue, using the master of public health (MPH) course at Teikyo University Graduate School of Public Health (Teikyo SPH) as an example.Methods　We summarized the current objectives and classes required to complete the MPH course at Teikyo SPH, using the course guideline published in 2022. Current issues and possible future directions in the course were summarized based on the opinions of Teikyo SPH faculty members.Results　For epidemiology, lectures and exercises were designed to focus on how to formulating public health issues, collecting and evaluating data, and causal inference. Issues related to the design included ensuring that students had the necessary skills to apply epidemiology to emerging issues, and catching the course up with evolving techniques. For biostatistics, lectures and exercise classes focused on understanding data and statistics, as well as performing analyses. Issues included the understanding of theories, setting the course level, and a lack of appropriate education materials for emerging analytical methods. For social and behavioral science, lectures and exercise classes focused on understanding human behaviors and actions for problem solving. Issues included learning various behavioral theories in a limited timeframe, the gap between the lectures and various needs, and nurturing professionals who had the skills to perform in practical settings. For health policy and management, lectures, exercise classes, and practical training classes focused on identifying and solving problems in the community and around the world, and on integrating the disparate viewpoints of health economics and policy. Issues included few alumni who actually found work globally, a lack of students working in local or central administrations, and insufficient perspectives on rational/economic thinking and macro-economic transitions. For occupational and environmental health, lectures, exercise classes, and practical training classes focused on learning the occupational and environmental impacts of public health issues, and their countermeasures. Challenges included enriching the topics with regard to advanced technologies, environmental health, and socially vulnerable populations.Conclusion　Through these reflections on MPH education at Teikyo SPH, the following recommendations are considered essential in order to prepare improvements to the program: reorganizing the curriculum to meet the needs of the day, accepting students with various backgrounds, addressing the increasing knowledge and skills that need to be acquired by the students, and enhancing the powers of professors to implement changes.

Control of naive and effector CD4 T cell receptor repertoires by rheumatoid-arthritis-risk HLA alleles.

OBJECTIVE: Human Leukocyte Antigen (HLA) alleles regulate susceptibility to rheumatoid arthritis (RA) and immune-mediated diseases. This study aims to elucidate the impact of HLA alleles to T cell subsets. METHODS: We performed genome-wide and HLA allele association analysis for T cell receptor (TCR) beta chain repertoire in 13 purified T cell subsets from the ImmuNexUT database, consisting of 407 donors with ten immune-mediated diseases and healthy controls. RESULTS: HLA class II alleles were associated with TRBV gene usage and the public clones of CD4 T cells, while HLA class I alleles were associated with CD8 T cells. RA-risk and immune-mediated diseases-risk HLA alleles were associated with TRBV gene usage of naive and effector CD4 T cell subsets and public clones accumulating in Th17. Clonal diversity was independent of HLA alleles and was correlated with transcriptome changes that reflect TCR signaling. CONCLUSION: This study revealed in vivo evidence that both HLA alleles and environmental factors shape naive and effector TCR repertoires in RA and immune-mediated diseases patients.

Association between maternal fermented food consumption and child sleep duration at the age of 3 years: the Japan Environment and Children's Study.

BACKGROUND: Using cohort data from the Japan Environment and Children's Study (JECS), we previously reported that the risk of sleep deprivation in 1-year-old children was reduced with a higher maternal intake of fermented foods, particularly miso. The present study, which evaluates children from the same cohort at 3 years of age, is a continuation of that work. METHODS: After applying exclusion criteria to 104,062 records in the JECS dataset, we evaluated 64,200 mother-child pairs in which the child was 3 years old. We examined the association of the dietary intake of fermented foods during pregnancy with child sleep duration < 10 h at the age of 3 years. RESULTS: Multivariable logistic regression analysis with the lowest quartile used as a reference revealed adjusted odds ratios (95% confidence intervals) for the second through fourth quartiles of 0.98 (0.90-1.06), 0.93 (0.85-1.01), and 0.85 (0.78-0.94) for cheese intake. CONCLUSIONS: The consumption of fermented foods during pregnancy is associated with reduced risk of sleep deprivation in 3-year-old children, albeit in a limited way.

Dietary intake of yogurt and cheese in children at age 1 year and sleep duration at age 1 and 3 years: the Japan Environment and Children's Study.

BACKGROUND: We previously reported that 1-year-old infants born to mothers who regularly consumed fermented food during pregnancy had a lower risk of sleep deprivation. However, it is not known if these positive effects are enhanced when infants themselves eat fermented foods or the long-term effects of such consumption. In this study, we examined the association between the frequency of fermented food intake during the child's weaning period and sleep deprivation at age 1 and 3 years. METHODS: This birth cohort study used data from a nationwide, government-funded study called the Japan Environment and Children's Study (JECS), covering 65,210 mother-child pairs. We examined the association between infants' consumption of fermented foods at 1 year of age and sleep deprivation at 1 and 3 years of age. RESULTS: There was no association between yogurt or cheese intake and sleep duration at age 1; at age 3, there was no group difference, although a trend test showed that yogurt intake at age 1 was significantly associated with sleep duration at age 3. There was also no association between the frequency of cheese intake and inadequate sleep duration at age 3. CONCLUSION: Frequency of children's yogurt and cheese intake at age 1 was not associated with sleep duration at age 1 or 3. However, a trend test showed a significant association between the frequency of yogurt intake at age 1 and sleep duration at age 3.

Effectiveness of self-managed continuous monitoring for maintaining high-quality early essential newborn care compared to supervision visit in Lao PDR: a cluster randomised controlled trial.

BACKGROUND: Thousands of neonatal deaths are expected to be averted by introducing the Early Essential Newborn Care (EENC) in the Western Pacific Region. In Lao People's Democratic Republic (Lao PDR), the government adopted the EENC programme and expanded it to district hospitals. With the expansion, maintaining the quality of EENC has become difficult for the government. METHODS: A cluster randomised controlled trial with four strata based on province and history of EENC coaching was implemented to evaluate the effectiveness of self-managed continuous monitoring compared with supervisory visit in Lao PDR between 20 July 2017 and 2 April 2019. Health workers who were routinely involved in maternity care were recruited from 15 district hospitals in Huaphanh (HP) and Xiangkhouang (XK) provinces. The primary endpoint was the score on the determinants of EENC performance measured by the Theory of Planned Behaviour (TPB). Secondary endpoints were set as the knowledge and skill scores. A linear mixed-effects model was applied to test the effects of intervention over time on the endpoints. RESULTS: Among 198 recruited health workers, 46 (23.2%) did not complete the final evaluation. TPB scores were 180.9 [Standard Deviation: SD 38.6] and 182.5 [SD 37.7] at baseline and 192.3 [SD 30.1] and 192.3 [SD 28.4] at the final evaluation in the intervention and control groups, respectively. There was no significant difference in changes between the groups in the adjusted model (2.4, p = 0.650). Interviews with participants revealed that district hospitals in HP regularly conducted peer reviews and feedback meetings, while few hospitals did in XK. Accordingly, in stratified analyses, the TPB score in the intervention group significantly increased in HP (15.5, p = 0.017) but largely declined in XK (- 17.7, p = 0.047) compared to the control group after adjusting for covariates. Skill scores declined sharper in the intervention group in XK (- 8.78, p = 0.026), particularly in the practice of managing nonbreathing babies. CONCLUSIONS: The study indicates that self-managed continuous monitoring is effective in improving behaviour among district health workers; however, additional measures are necessary to support its proper implementation. To maintain resuscitation skills, repeated practice is necessary. TRIAL REGISTRATION: This trial was registered at UMIN Clinical Trials Registry on 15/6/2017. Registration number is UMIN000027794 .

Apolipoprotein E is an HIV-1-inducible inhibitor of viral production and infectivity in macrophages.

Apolipoprotein E (ApoE) belongs to a class of cellular proteins involved in lipid metabolism. ApoE is a polymorphic protein produced primarily in macrophages and astrocytes. Different isoforms of ApoE have been associated with susceptibility to various diseases including Alzheimer's and cardiovascular diseases. ApoE expression has also been found to affect susceptibility to several viral diseases, including Hepatitis C and E, but its effect on the life cycle of HIV-1 remains obscure. In this study, we initially found that HIV-1 infection selectively up-regulated ApoE in human monocyte-derived macrophages (MDMs). Interestingly, ApoE knockdown in MDMs enhanced the production and infectivity of HIV-1, and was associated with increased localization of viral envelope (Env) proteins to the cell surface. Consistent with this, ApoE over-expression in 293T cells suppressed Env expression and viral infectivity, which was also observed with HIV-2 Env, but not with VSV-G Env. Mechanistic studies revealed that the C-terminal region of ApoE was required for its inhibitory effect on HIV-1 Env expression. Moreover, we found that ApoE and Env co-localized in the cells, and ApoE associated with gp160, the precursor form of Env, and that the suppression of Env expression by ApoE was cancelled by the treatment with lysosomal inhibitors. Overall, our study revealed that ApoE is an HIV-1-inducible inhibitor of viral production and infectivity in macrophages that exerts its anti-HIV-1 activity through association with gp160 Env via the C-terminal region, which results in subsequent degradation of gp160 Env in the lysosomes.

Spatial clustering of suicide mortality and associated community characteristics in Kanagawa prefecture, Japan, 2011-2017.

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.

Factors associated with discontinuation of glucocorticoids after starting biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients.

Objectives: Glucocorticoids (GCs) are effective treatments for rheumatoid arthritis (RA) but long-term use has adverse effects. This study aimed to elucidate whether GCs can be discontinued by introducing biological disease-modifying antirheumatic drugs (bDMARDs) and the factors influencing the outcome.Method: We included RA patients who had been orally taking GCs at the initiation of bDMARDs. The changes in GC dose after starting bDMARDs were evaluated and the GC discontinuation rate was analyzed using Kaplan-Meier analysis. The factors associated with discontinuation of GCs were assessed by Cox hazard models.Results: Eighty RA patients were included in the study. The dosage of oral prednisolone (PSL) was significantly reduced from 5.0 to 3.0 mg/day by 3 months (p = .013). GCs were discontinued in 31.3% of patients and the median time until GC discontinuation was 10.1 months. The GC discontinuation rate was significantly higher in patients with Class 1 and 2 (p = .024), with an initial PSL dose <5 mg/day (p = .040), and with low DAS28(ESR) (p = .038). In multivariate analyses, higher DAS28(ESR) (odds ratio, 0.200; p = .039), and higher PSL dose (odds ratio, 0.748; p = .029) were significantly associated with less frequent GC discontinuation.Conclusion: DAS28(ESR) high and PSL dose were factors associated with discontinuation of GC use after starting bDMARDs.

[The process of community building by Community Social Coordinators: The possibility of enhancing social capital in a disaster-affected city].

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.

Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-ß3 production.

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-ß3 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-ß3 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-ß3, 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-ß3-expressing vector. Intriguingly, latent TGF-ß binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-ß3 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-ß3 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.

Relation of High Social Capital to Preferable Emotional Response to News Media Broadcasting of Natural Disasters: A Nationwide Cross-Sectional Study in Japan.

Media coverage of disasters potentially damages mental health. Moreover, its effects may differ as recipients may have different emotional responses toward media. The present study examined whether social capital, known to be protective against mental problems, influences a recipient's emotional response toward news media broadcasting of natural disasters via newspapers, television and internet in Japan. Three social capital components, social participation, social support and cognitive social capital, were considered in the present study as each component reportedly had different effect on mental health. This nationwide cross-sectional survey was undertaken in 2015 among 1,200 Japanese citizens aged 15 to 79 years who were selected using the multi-stage sampling procedure. Data were collected via the drop-off pick-up method using a printed structured questionnaire. Negative and positive emotions were classified based on recipients' responses against news media. Among 1,190 participants who reported emotions toward news media, 30.9% (368) had experienced any natural disasters, 37.4% (445) belonged to at least one formal or informal organization (social participation), 40.2% (478) had high social support, and 68.8% (819) had high cognitive social capital. High social support was associated with both reduced negative emotional response (OR 0.66, 95% Confidence Interval (CI) 0.47-0.93) and increased positive emotional response (OR 1.48, 95% CI 1.04-2.12) in multivariate analyses, while high cognitive social capital was only associated with increased positive emotional response (OR 1.62, 95% CI 1.11-2.37). These results suggest protective effects of social support and cognitive social capital against news media coverage of natural disasters.

For making a declaration of countermeasures against the falling birth rate from the Japanese Society for Hygiene: summary of discussion in the working group on academic research strategy against an aging society with low birth rate.

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.

Direct ortho-C-H Aminoalkylation of 2-Substituted Pyridine Derivatives Catalyzed by Yttrium Complexes with N,N'-Diarylethylenediamido Ligands.

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 faster than that without HNBn2 due to acceleration of the product-eliminating step from complex 11 by HNBn2 to regenerate amidoyttrium complex 8 and the product. In addition, we determined that the catalytic reaction obeyed a first-order rate dependence on the catalyst concentration, independent of the imine concentration, and a second-order rate dependence on the concentration of the pyridine substrate in the reaction system, both with and without HNBn2. An enantiomerically pure N, N'-diaryl-1,2-diphenylethylenediamido ligand was applied for the C(sp2)-H aminoalkylation reaction in combination with Lu(CH2SiMe3)3(THF)2 to give chiral aminoalkylated products in moderate yield with good enantioselectivity.

Study protocol of a cluster randomized controlled trial to evaluate effectiveness of a system for maintaining high-quality early essential newborn care in Lao PDR.

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 .

Beneficial Roles of Social Support for Mental Health Vary in the Japanese Population depending on Disaster Experience: A Nationwide Cross-Sectional Study.

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.

Reevaluation of Pluripotent Cytokine TGF-ß3 in Immunity.

Transforming growth factor (TGF)-ßs are pluripotent cytokines with stimulatory and inhibitory properties for multiple types of immune cells. Analyses of genetic knockouts of each isoform of TGF-ß have revealed differing expression patterns and distinct roles for the three mammalian isoforms of TGF-ß. Considerable effort has been focused on understanding the molecular mechanisms of TGF-ß1-mediated immune regulation, given its pivotal role in prohibiting systemic autoimmune disease. In recent years, functional similarities and differences between the TGF-ß isoforms have delineated their distinct roles in the development of immunopathology and immune tolerance, with increased recent attention being focused on TGF-ß3. In addition to the characteristic properties of each TGF-ß 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-ßs in immunity. Controlling TGF-ß 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-ß3 with comparisons to other TGF-ß isoforms.

[Background factors contributing to over-consumption of alcohol and risk of lifestyle related diseases among middle-aged women on an isolated island].

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).