78 research outputs found

    Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine

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    Schizophrenia is a chronic psychiatric disorder with complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair of monozygotic twin cases with treatment-resistant schizophrenia, in which one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research

    Effects of raloxifene on the production of cytokines in stimulated whole blood in ex vivo and in vitro studies

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    Purpose : The aims of this study were to determine the effects of raloxifene therapy on production of cytokines and in vitro effects of raloxifene on production of cytokines by whole blood cultures. Methods :We obtained samples of peripheral blood from 6 postmenopausal women with osteopenia at baseline and after 3 and 6 months of raloxifene therapy and 10 postmenopausal women who did not receive raloxifene therapy. Whole blood from raloxifene-treated women was stimulated with lipopolysaccharide (LPS) or phytohemeagglutinin (PHA). Whole blood from postmenopausal women who were not treated with raloxifene was preincubated with raloxifene at concentrations of 10-10-10-7 M and then stimulated with LPS or PHA. Concentrations of IL-1β, IL-4, IL-6, IL-12p40, IL-12p70, TNF-α and IFN-γ in the supernatant were measured by respective ELISAs. Results : In ex vivo cultures, raloxifene therapy inhibited LPS-stimulated production of IL-1β, IL-6, IL-12p40, IL-12p70 and TNF-α, but not PHA-stimulated production of IL-4 and IFN-γ. In in vitro cultures, raloxifene at a concentration (10-9 M) inhibited LPS-stimulated production of IL-1β, IL-6 and IL-12p40 and PHA-stimulated production of IFN-γ. Conclusions : Raloxifene therapy decreases the production of IL-1β, IL-6, IL-12 and TNF-α but not that of IL-4 and IFN-γ, suggesting that modulation of cytokines could play a role in the mechanisms of the osteoprotective effect of raloxifene

    The effect of duration of illness and antipsychotics on subcortical volumes in schizophrenia: Analysis of 778 subjects

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    BackgroundThe effect of duration of illness and antipsychotic medication on the volumes of subcortical structures in schizophrenia is inconsistent among previous reports. We implemented a large sample analysis utilizing clinical data from 11 institutions in a previous meta-analysis.MethodsImaging and clinical data of 778 schizophrenia subjects were taken from a prospective meta-analysis conducted by the COCORO consortium in Japan. The effect of duration of illness and daily dose and type of antipsychotics were assessed using the linear mixed effect model where the volumes of subcortical structures computed by FreeSurfer were used as a dependent variable and age, sex, duration of illness, daily dose of antipsychotics and intracranial volume were used as independent variables, and the type of protocol was incorporated as a random effect for intercept. The statistical significance of fixed-effect of dependent variable was assessed.ResultsDaily dose of antipsychotics was positively associated with left globus pallidus volume and negatively associated with right hippocampus. It was also positively associated with laterality index of globus pallidus. Duration of illness was positively associated with bilateral globus pallidus volumes. Type of antipsychotics did not have any effect on the subcortical volumes.DiscussionA large sample size, uniform data collection methodology and robust statistical analysis are strengths of the current study. This result suggests that we need special attention to discuss about relationship between subcortical regional brain volumes and pathophysiology of schizophrenia because regional brain volumes may be affected by antipsychotic medication

    CNVs in Three Psychiatric Disorders

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    BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

    左前頭葉皮質下出血により環境依存症候群 (Lhermitte) を呈した一例

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    Quantitative estimation of the ecosystem services supporting the growth of Japanese chum salmon

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    Chum salmon (Oncorhynchus keta) are distributed widely in the subarctic North Pacific. The Japanese stock is maintained by artificial release procedures. Chum salmon, including the Japanese stock, provide important ecosystem services for humans that are related to provisioning, culture and support. These ecosystem services are supported by the supply of prey and habitat that the fish use. We regard the supply of prey and habitat as supporting services for salmon. We developed a procedure to estimate supporting services quantitatively, based on the prey biomass consumed by individual salmon, by coupling a bioenergetics model and a lower trophic level ecosystem model. Using this procedure, we estimated the prey biomass consumed by a cohort of Japanese chum salmon released in a single year. The phytoplankton biomass indirectly consumed by a cohort was also estimated and considered to be the primary production supporting the fish. The Japanese chum salmon cohort was estimated to consume ca. 4.2-4.7 x 10(9) kg wet weight of zooplankton, of which more than half is eaten in the Bering Sea. The Japanese chum salmon cohort is supported by an estimated primary production of 2.0-2.2 x 10(9) kg C, which amounts to 0.17%-0.19% of primary production in the areas and periods through which the fish migrate. We also attempted to calculate the monetary value of supporting services for the growth of Japanese chum salmon

    Menstruation, Hygiene Practice and Menstrual Distress in Female Undergraduate Students

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    Background: Currently, there is no up-to-date survey on actual menstruation, including recent changes in the amount of menstrual blood loss in women as the age of the first menstruation decreases in Japan. Also, few study has examined whether temperature in clothing reflecting with basal body temperature and other factors are related to menstruation-associated symptoms. Purpose: The study aimed to determine the actual menstruation, the change in the number of sanitary napkins and menstrual distress during one menstrual cycle, and the predictive factors of menstrual distress. Methods: The samples were eight university students over the age of 20. This study was conducted from the end of June to the end of September 2020. They were asked to undertake the following: menstrual cycle, length of menstruation; the amount of menstrual blood loss; changing sanitary napkins; the Japanese version of the Menstrual Distress Questionnaire (J-MDQ). The J-MDQ consists of 47 questions answered on a scale of 0 to 3, with a higher score indicating more severe menstruation-related symptoms, within a week before, during and a week after menstruation. Multiple liner regression and Friedman test were conducted as statistical analysis. Results: The volume of menstrual blood loss increased drastically on the second day of the menstruation, and rapidly decreased from the third day. Napkin changing was also most frequent on the second day, however there is no correlation between the volume of menstrual blood and the number of times changing sanitary napkins after the second day of menstruation. The total J-MDQ during menstruation was significantly higher than pre and after menstruation (P<0.05). The duration of blood flow were associated with J-MDQ. Conclusions: Appropriate changing sanitary napkins needs to be recommended to improve for vulvar hygiene. The menstrual distress was highest during menstruation
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