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Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10

When two-frame apparent motion stimuli are presented with an appropriate inter-stimulus interval (ISI), motion is perceived in the direction opposite to the actual image shift. Herein, we measured a simple eye movement, ocular following responses (OFRs), in macaque monkeys to examine the ISI reversal effect on oculomotor. Two-frame movies with an ISI induced reversed OFRs. Without ISI, the OFRs to the two-frame movie were induced in the direction of the stimulus shift. However, with ISIs ≥10 ms, OFRs in the direction opposite to the phase shift were observed. This directional reversal persisted for ISIs up to 160 ms; for longer ISIs virtually no ocular response was observed. Furthermore, longer exposure to the initial image (Motion onset delay: MOD) reduced OFRs. We show that these dependences on ISIs/MODs can be explained by the motion energy model. Furthermore, we examined the dependence on ISI reversal using various spatial frequencies. To account for our findings, the optimal frequency of the temporal filters of the energy model must decrease between 0.5 and 1 cycles/°, suggesting that there are at least two channels with different temporal characteristics. These results are consistent with those from humans, suggesting that the temporal filters embedded in human and macaque visual systems are similar. Thus, the macaque monkey is a good animal model for the early visual processing of humans to understand the neural substrates underlying the visual motion detectors that elicit OFRs.

Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD., De novo mutations significantly contribute to autism spectrum disorders (ASD). Here, the authors demonstrate that ASD-associated de novo mutations in the POGZ gene, one of a high-confidence ASD gene, lead to ASD-related impaired neuronal development and disrupted mature cortical network function.

Pulmonary hypertension (PH) is a multicellular and progressive disease with a high mortality rate. Among many cell types, hematopoietic stem cells (HSCs) are incriminated in the pathogenesis of PH. However, our understanding of the mechanisms that increase HSCs in blood and lungs of hypertensive animals or patients and the role played by HSCs in the pathogenesis of PH remains elusive. Studies suggest that glycolysis is critical for the survival and growth of HSCs. In various cell types from hypertensive lungs of animals and patients, glycolysis and the glucose-6-phosphate dehydrogenase (G6PD) activity are increased. Herein, we demonstrated in mice that chronic hypoxia increased HSCs (CD34+, CD117+, CD133+, CD34+/CD117+, and CD34+/CD133+) in bone marrow and blood and around hypertensive pulmonary arteries in a time-dependent manner. Intriguingly, we found fewer CD133+ cells in the bone marrow of C57BL/6 mice compared with Sv129J mice, and C57BL mice developed less severe chronic hypoxia-elicited PH and heart failure than Sv129J mice. Similarly, the numbers of CD34+ and CD117+ cells in blood of patients with pulmonary arterial hypertension (PAH) were higher (>3-fold) compared with healthy individuals. By allogeneic bone marrow transplantation, we found that GFP+ bone marrow cells infiltrated the lungs and accumulated around the pulmonary arteries in lungs of hypoxic mice, and these cells contributed to increased α-adrenergic receptor-mediated contraction of the pulmonary artery cultured in hypoxia. Inhibition of G6PD activity with (3β,5α)-3,21-dihydroxypregnan-20-one, a novel and potent G6PD inhibitor, decreased HSCs in bone marrow, blood, and lungs of hypoxic mice and reduced α-agonist-induced contraction of the pulmonary artery and established hypoxia-induced PH. We did not observe CD133+ cells around the pulmonary arteries in the lungs of chronically hypoxic G6PD-deficient mice. Furthermore, knockdown of G6PD and inhibition of G6PD activity: 1) downregulated canonical and noncanonical Wnt and Fzd receptors genes; 2) upregulated Bmpr1a; 3) decreased Cxcl12, and 4) reduced HSC (CD117+ and CD133+) numbers. In all, our findings demonstrate unexpected function for bone marrow-derived HSCs in augmenting α-adrenergic receptor-mediated contraction of pulmonary arteries and remodeling of pulmonary arteries that contribute to increase pulmonary vascular resistance in PAH patients and hypoxic mice and suggest that G6PD, by regulating expression of genes in the WNT and BMPR signaling, contributed to increase and release of HSCs from the bone marrow in response to hypoxic stimuli.

Background Patients with schizophrenia show various trajectories in intelligence. However, whether the degree of IQ decline is associated with functional outcomes remains unclear. The purposes of the study were 1) to determine whether IQ decline was related with work outcome, and 2) to perform predictions for attaining a certain amount of work measured by work hours. Methods One hundred and forty patients with schizophrenia and 156 healthy volunteers enrolled in the study. The patients were classified into the deteriorated group or preserved group based on the degree of IQ decline. In addition to current and premorbid intelligence, functional outcomes and clinical conditions were also evaluated. Those variables were compared among the patient groups and healthy adults to select independent variables for logistic regression analyses. Four separate logistic regression analyses were conducted with work hours dichotomized by four criteria (0, 10, 20, or 30 h per week) as dependent variables. Results IQ decline remained significant in all regression models except the model with the 30 h per week criterion. Social function and psychiatric symptoms were also prominent factors in most models. Predictions were more accurate in the models with higher criteria. Individual probabilities to exceed each criterion were presented based on the equations derived from the regression models. Conclusion Intellectual deterioration, in addition to impaired social function and psychiatric symptoms, may play a key role in work disturbances in patients with schizophrenia. Probability models presented here have strengths in evaluating the ability to work from statistical, clinical, and theoretical viewpoints.

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (P(best) = 4.1 × 10(−10)), SLC38A3 (P(best) = 5.7 × 10(−10)), and CABP1-ACADS (P(best) = 9.8 × 10(−9)). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (P(best) = 4.0 × 10(−11)) and between SCZ and BD in the JPN population (P ~ 10(−40)); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, r(g) = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ “risk” effect is shared with other psychiatric disorders even across populations.

The Raman spectra of twenty-two chemical warfare agents (CWAs) were measured: eleven nerve agents and their precursor, five blister agents, three lachrymators, one choking agent, and one vomit agent, in liquid or solid state in colorless transparent vials were analyzed using a portable Raman spectrometer, Xantus-2 from Rigaku Corporation, equipped with selectable excitation lasers (785 nm and 1064 nm). With 785 nm excitation, characteristic Raman spectra composed of many sharp peaks were observed for twenty CWAs, but nitrogen mustard 3 (HN3) and adamsite (DM) did not show particular peaks owing to broad and intense mountain-like baselines. With 1064 nm excitation, Raman spectra similar to those with 785 nm excitation were observed for the twenty CWAs, where the wavenumbers of the peak tops and comparative heights were similar to those with 785 nm excitation. Characteristic Raman spectra with several sharp peaks could be even obtained for HN3 and DM with 1064 nm excitation. The resolutions of the peaks in the spectral region below 1000 cm−1 were higher with 785 nm excitation than those with 1064 nm excitation. In contrast, those above 1000 cm−1 were almost compatible with both excitations. The heights of the peaks in the spectral region lower than 1000 cm−1 were significantly higher with 785 nm excitation than those with 1064 nm excitation, but those higher than 1000 cm−1 were almost compatible with both excitations. The CWAs could be discriminated based on the Raman spectra showing respective unique fingerprint patterns, even among six alkyl methylphosphonofluoridate congeners. Structural assignment to Raman bands observed in the spectra was also proposed. The influence of mixing with gasoline to match the quality of library search was examined for seven representative CWAs. With 785 nm excitation, the hit quality index (HQI) of sarin was higher than 50% when the concentration (V/V) was higher than 25%. Meanwhile, with 1064 nm excitation, HQI of sarin was higher than 50% even when the concentration was as low as 15%. With 785 nm excitation, the HQI of L1 was higher than 50% when the concentration was higher than 80%. However, with 1064 nm excitation, the HQI of L1 was higher than 50% when the concentration was 20%. Measurements with 1064 nm excitation seemed superior in identifying CWAs in a gasoline mixture using the library search. The Raman spectra with 785 nm and 1064 nm excitation were compared in the measurement in the amber glass containers.

Summary: Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders. : Kushima et al. perform comparative analyses of CNVs in ASD and SCZ in a Japanese population. They identify pathogenic CNVs and biological pathways in each disorder with significant overlap. Patients with pathogenic CNVs have a higher prevalence of intellectual disability. Disease-relevant genes are detected in eight well-known ASD/SCZ-associated CNV loci. Keywords: autism spectrum disorder, schizophrenia, copy-number variation, array comparative genomic hybridization, genetic overlap, Japanese population, oxidative stress response, genome integrity, lipid metabolism, gene ontology

The current study aimed to examine the outcomes of pharmacists' involvement with elderly people in special nursing homes. We analyzed 58 cases involving regular visits by community pharmacists to 41 residents. The residents' mean age was 87.8±6.9 years, and 68.3% were prescribed 6 or more types of medication. Antipsychotic and insomnia medication was taken by 24.4% and 31.8% of residents, respectively. Pharmaceutical consultation following medication use accounted for 60.3% of pharmacists' involvement with residents. The outcomes of these consultations included improvements in prescription content; the identification and prevention of adverse drug events; improvement in activities of daily living; and improvement in test results, sleep, and urination/bowel control. The results also suggested that pharmacists' intervention reduced drug costs. Information that facilitated involvement was most frequently acquired via conversations (67.2%) and conferences (24.1%) in the facilities. The most common information sources were care workers (72.4%), followed by nurses (37.9%), physicians (6.9%), and functional training instructors (6.9%). Information was also acquired from patients (3.4%) and their family members (5.2%). The findings indicated that regular visits by pharmacists to facilities for elderly people and conversations between residents, their family members, and physicians, nurses and various other professionals improved various pharmacotherapy outcomes.

Eye movements are considered endophenotypes of schizophrenia. However, the genetic factors underlying eye movement are largely unknown. In this study, we explored the susceptibility loci for four eye movement scores: the scanpath length during the free viewing test (SPL), the horizontal position gain during the fast Lissajous paradigm of the smooth pursuit test (HPG), the duration of fixations during the far distractor paradigm of the fixation stability test (DF) and the integrated eye movement score of those three scores (EMS). We found 16 SNPs relevant to the HPG that were located in 3 genomic regions (1q21.3, 7p12.1 and 20q13.12) in the patient group; however, these SNPs were intronic or intergenic SNPs. To determine whether these SNPs occur in functional non-coding regions (i.e., enhancer or promoter regions), we examined the chromatin status on the basis of publicly available epigenomic data from 127 tissues or cell lines. This analysis suggested that the SNPs on 1q21.3 and 20q13.12 are in enhancer or promoter regions. Moreover, we performed an analysis of expression quantitative trait loci (eQTL) in human brain tissues using a public database. Finally, we identified significant eQTL effects for all of the SNPs at 1q21.3 and 20q13.12 in particular brain regions.

Aim To explore the characteristics of psychiatric morbidity in chronic pain patients who present with or without fibromyalgia. Methods Patients are referred to our chronic pain clinic from primary medical institutions, as we are a secondary medical institution. Although some patients have chronic pain, they have no clear organic disorder such as rheumatoid arthritis to account for the pain. Among the 367 new patients seen during the period from March 2009 to August 2012, 347 patients underwent psychiatric evaluation in face‐to‐face interviews with mental health specialists before a physical examination. Results Of the 347 patients examined, at least one psychiatric diagnosis was made for 94.6%. The average number of DSM‐IV‐TR diagnoses was 1.46 in the 330 chronic pain patients who had at least one psychiatric diagnosis. The breakdown of the number of psychodiagnoses was one in 60.8%, two in 27.1%, three in 4.9%, and more than three in 2.3% chronic pain patients with or without fibromyalgia. In fibromyalgia patients, the highest relative frequencies were found for somatoform disorders (76%), followed by dysthymic disorder (17%) and major depressive disorder (15%). In patients without fibromyalgia, the highest relative frequencies were found for somatoform disorders (64%), followed by major depressive disorder (15%) and dysthymic disorder (14%). Psychiatric disorders were found in 96.9% of fibromyalgia patients, and in 93.5% of chronic pain patients without fibromyalgia in Japan (no significant difference using chi‐square test). Conclusion Results show that chronic pain patients with or without fibromyalgia are extremely likely to be diagnosed with a psychiatric disorder., Psychodiagnoses of fibromyalgia patients and chronic pain patients without fibromyalgia.

We demonstrate a highly scalable subsystem-modular optical cross-connect (OXC) that uses sub-OXCs based on a newly developed single-module 6 × 6 wavelength-selective switch (WSS). Network simulations in dynamic-traffic scenarios assure the good routing performance of the architecture. Its technical feasibility is confirmed by transmission experiments using 96-wavelength 32-Gbaud dual-polarization quadrature phase-shift keying (DP-QPSK) signals. The developed 6 × 6 WSS allows each DP-QPSK signal to traverse 12 nodes when the internode distance is 100 km.

Background An imbalance in the inflammatory tumor necrosis factor system, including soluble tumor necrosis factor receptor 2 (sTNFR2), may contribute to the pathophysiology of schizophrenia. Methods We measured the plasma levels of sTNFR2 in 256 healthy controls and 250 patients with schizophrenia including antipsychotic drug-free patients and treatment-resistant patients. We also explored the possible association between plasma sTNFR2 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition, the Wechsler Memory Scale-Revised, and the Rey Auditory Verbal Learning Test. An association between plasma sTNFR2 levels and hippocampal volume in controls and patients with schizophrenia was also investigated via MRI. Results We found that the plasma levels of sTNFR2 were significantly higher in patients with schizophrenia, including both antipsychotic drug-free patients and treatment-resistant patients. We found a significant negative association between plasma sTNFR2 levels and cognitive performance in controls and patients with schizophrenia. Hippocampal volume was also negatively associated with plasma sTNFR2 levels in patients with schizophrenia. Conclusion Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased sTNFR2 levels are associated with a smaller hippocampal volume and cognitive impairment.

Background The 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. Methods Imaging 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. Results Daily 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. Discussion A 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., Graphical abstract Image 2, Highlights • The imaging data as well as prescription data and demographics from 778 patients with schizophrenia from 11 institutions were included. • The effect of protocol was cooperated as random-effect in the linear mixed-effect model. • Significant positive association were found between daily dose of antipsychotics and left globus pallidus volume. • Significant negative association was found between daily dose of antipsychotics and right hippocampus volume. • Significant positive associations were found between duration of illness and bilateral volumes of globus pallidus.

Memory performance is severely impaired in individuals with schizophrenia. Although several studies have reported a relationship between memory performance and hippocampal volume, only a few structural magnetic resonance imaging (MRI) studies have investigated the relationship between memory performance and subcortical structures other than hippocampus in patients with schizophrenia. We investigated the relationship between memory performance and subcortical regional volumes in a large sample of patients with schizophrenia. Participants included 174 patients with schizophrenia and 638 healthy comparison subjects (HCS). The Wechsler Memory Scale-Revised (WMS-R) has three memory indices (verbal immediate recall, visual immediate recall, and delayed recall (verbal plus visual)) and one control neurocognitive index (attention/concentration). We obtained T1-weighted MRI data and measured the bilateral volumes of the hippocampus, amygdala, thalamus, nucleus accumbens (NA), caudate, putamen, and globus pallidus. Patients with schizophrenia had significantly lower scores for all of the indices of the WMS-R than the HCS. They had more severe impairments in verbal immediate recall and delayed recall than in visual immediate recall and attention/concentration. Verbal immediate recall/delayed recall scores in patients with schizophrenia were significantly correlated not only with hippocampal volume (left: r = 0.34; right: r = 0.28/left: r = 0.33; right: r = 0.31), but also with NA volume (left: r = 0.24; right: r = 0.25/left: r = 0.26; right: r = 0.27). The present investigation with a large sample size did not only replicate hippocampal volume and memory association, but also found that NA volume is associated with memory performances in schizophrenia.

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.

Graphical abstract, Only a few bone marrow-derived macrophages (BM-MΦ) are positive for macrophage colony-stimulating factor receptor (M-CSFR). Thus, a method is needed to increase the proportion of BM-MΦ that are positive for M-CSFR to facilitate the investigation of the effects of M-CSFR downregulation on various diseases. We used mouse primary BM-MΦ to evaluate the expression of M-CSFR on the cytoplasmic membrane using flow cytometry. Treatment with a reducing agent, dithiothreitol (DTT), increased the proportion of BM-MΦ that were positive for M-CSFR, and this increase was time dependent. We next determined whether DTT-treated BM-MΦ can lead to the downregulation of M-CSFR. Treatment with lipopolysaccharide (LPS) for 24 h. decreased the proportion of DTT-treated BM-MΦ that were positive for M-CSFR. These results suggest that DTT treatment increases the proportion of BM-MΦ that are positive for M-CSFR and that the upregulation of M-CSFR on BM-MΦ can be abrogated by treatment with LPS. Here, we propose a simple method to increase the number of M-CSFR-positive BM-MΦ using the reducing agent DTT, which could be useful in investigations of the relationship between the downregulation of M-CSFR and some diseases. • The proportion of BM-MΦ that expresses M-CSFR on the membrane increases by approximately twice following DTT treatment.

Patients with schizophrenia can exhibit intelligence decline, which is an important element of cognitive impairment. Previous magnetic resonance imaging (MRI) studies have demonstrated that patients with schizophrenia have altered gray matter structures and functional connectivity associated with intelligence decline defined by a difference between premorbid and current intelligence quotients (IQs). However, it has remained unclear whether white matter microstructures are related to intelligence decline. In the present study, the indices of diffusion tensor imaging (DTI) obtained from 138 patients with schizophrenia and 554 healthy controls were analyzed. The patients were classified into three subgroups based on intelligence decline: deteriorated (94 patients), preserved (42 patients), and compromised IQ (2 patients) groups. Given that the DTI of each subject was acquired using either one of two different MRI scanners, we analyzed DTI indices separately for each scanner group. In the comparison between the deteriorated IQ group and the healthy controls, differences in some DTI indices were noted in three regions of interest irrespective of the MRI scanners, whereas differences in only one region of interest were noted between the preserved IQ group and the healthy controls. However, the comparisons between the deteriorated and preserved IQ groups did not show any reproducible differences. Together with the previous findings, it is thought that gray matter structures and functional connectivity are more promising as markers of intelligence decline in schizophrenia than white matter microstructures.

Cryopreservation of whole blood is useful for DNA collection, and clinical and basic research. Blood samples in ethylenediaminetetraacetic acid disodium salt (EDTA) tubes stored at − 80 °C are suitable for DNA extraction, but not for high-quality RNA extraction. Herein, a new methodology for high-quality RNA extraction from human blood samples is described. Quickly thawing frozen whole blood on aluminum blocks at room temperature could minimize RNA degradation, and improve RNA yield and quality compared with thawing the samples in a 37 °C water bath. Furthermore, the use of the NucleoSpin RNA kit increased RNA yield by fivefold compared with the PAXgene Blood RNA Kit. Thawing blood samples on aluminum blocks significantly increased the DNA yield by ~ 20% compared with thawing in a 37 °C water bath or on ice. Moreover, by thawing on aluminum blocks and using the NucleoSpin RNA and QIAamp DNA Blood kits, the extraction of RNA and DNA of sufficient quality and quantity was achieved from frozen EDTA whole blood samples that were stored for up to 8.5 years. Thus, extracting RNA from frozen whole blood in EDTA tubes after long-term storage is feasible. These findings may help advance gene expression analysis, as well as biomarker research for various diseases.

In this paper, the shortening of the development length of mortar-filled joints that connect precast concrete members is studied focusing on the use of expansion fillers and headed rebars. Rebars with a diameter of 13 mm are used. First, specimens are prepared with different dosages of lime-based expansive additive containing calcium oxide as the main component in commercial high-strength-non-shrink mortar or low-viscosity grout. It is found that the load-bearing performance of the mortar-filled joint is improved when the expansive additive is added to the high-strength-non-shrink mortar. However, in all cases, pullout failure occurs and rebar failure cannot be achieved. Second, a cement-based-highly-expansive filler mainly composed of calcium oxide and silicate with a swelling pressure of 40 N/mm 2 or more at 3 days is employed. As a result, it is found that the rebar failure can be achieved for a development length of 4 d (52 mm). To further shorten the development length, headed rebar is then used as an inserted rebar. The test results show that rebar failure can be achieved when using a comparatively short development length of 3.5 d (45.5 mm). It is concluded that the use of a cement-based-highly-expansive filler and a headed rebar is effective in shortening the development length of mortar-filled joints.

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric disorders. We examined serum GDNF levels in bipolar disorder (BD) patients and major depressive disorder (MDD) patients and their association with response to lithium therapy. We used a multicenter (six sites), exploratory, cross-sectional case-control design and recruited 448 subjects: 143 BD patients, 116 MDD patients, and 158 healthy controls (HCs). We evaluated the patients' clinical severity using the Clinical Global Impression (CGI), and responses to lithium therapy using the Alda scale. The serum GDNF levels were significantly decreased in the BD and MDD groups compared to the HCs, with no significant difference between the BD and MDD groups. After adjustment, the serum GDNF levels in the BD and MDD patients in remission or depressive states were decreased compared to the HC values. Lower serum GDNF levels in BD patients were associated with higher CGI and Alda scores (i.e., severe illness and good response to lithium therapy, respectively). Our findings suggest that the serum GDNF level may be a biomarker for both BD and MDD in remission or depressive states. The serum GDNF level may be associated with the lithium response of BD patients.

Bone marrow stromal cells (BMSCs) are common progenitors of both adipocytes and osteoblasts. We recently suggested that increased [Ca2+]o caused by bone resorption might accelerate adipocyte accumulation in response to treatment with both insulin and dexamethasone. In this study, we investigated the mechanism by which high [Ca2+]o enhances adipocyte accumulation. We used primary mouse BMSCs and evaluated the levels of adipocyte accumulation by measuring Oil Red O staining. CaSR agonists (both Ca2+ and Sr2+) enhanced the accumulation of adipocytes among BMSCs in response to treatment with both insulin and dexamethasone. We showed that high [Ca2+]o decreases the concentration of cAMP using ELISA. Real-time RT-PCR revealed that increasing the intracellular concentration of cAMP (both chemical inducer (1μM forskolin and 200nM IBMX) and a cAMP analog (10μM pCPT-cAMP)) suppressed the expression of PPARγ and C/EBPα. In addition, forskolin, IBMX, and pCPT-cAMP inhibited the enhancement in adipocyte accumulation under high [Ca2+]o in BMSCs. However, this inhibited effect was not observed in BMSCs that were cultured in a basal concentration of [Ca2+]o. We next observed that the accumulation of adipocytes in the of bone marrow of middle-aged mice (25-40 weeks old) is higher than that of young mice (6 weeks old) based on micro CT. ELISA results revealed that the concentration of cAMP in the bone marrow mononuclear cells of middle-aged mice is lower than that of young mice. These data suggest that increased [Ca2+]o caused by bone resorption might accelerate adipocyte accumulation through CaSR following a decrease in cAMP.

Background and aims Lipopolysaccharide (LPS) is a main component of the Gram-negative bacterial cell wall and is associated with a greater risk of atherosclerosis development in periodontal disease. LPS has been reported to increase both CD36 and CD204 expression and enhance the uptake of modified low-density lipoprotein (LDL). However, the signaling pathways by which LPS enhances these expression levels and function have not been fully elucidated, although the clarification of these signaling pathways is important for identifying therapeutic targets for atherosclerosis. Methods and results We have shown here that LPS activated the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, increased both CD204 and CD36 expression, and enhanced the uptake of acetylated-LDL (Ac-LDL) in mouse bone marrow macrophages. The MAPK/ERK kinase (MEK) inhibitors, U0126 (1 μM) and PD0325901 (10 nM), did not affect the expression of either CD36 or CD204 or the uptake of Ac-LDL under normal conditions (no treatment with LPS). In contrast, U0126 (1 μM) and PD0325901 (10 nM) blocked the LPS-induced increase in Ac-LDL uptake and CD204 expression but not CD36 expression. Conclusions These results suggest that LPS may increase Ac-LDL uptake and enhance CD204 expression through MAPK/ERK activation and CD36 expression through an ERK-independent pathway. Since MEK inhibitors block CD204 expression in mouse BM macrophages only under LPS treatment but not under normal conditions, a MEK inhibitor might be a good candidate compound for the treatment of LPS-induced atherosclerosis.

Fibromyalgia is a refractory disease characterized by chronic intractable pain and psychological suffering, the cause of which has not yet been elucidated due to its complex pathology. Activation of immune cells in the brain called microglia has attracted attention as a potential underlying pathological mechanism in chronic pain. Until recently, however, technological and ethical considerations have limited the ability to conduct research using human microglia. To overcome this limitation, we have recently developed a technique to create human-induced microglia-like (iMG) cells from human peripheral blood monocytes. In this study, we created the iMG cells from 14 patients with fibromyalgia and 10 healthy individuals, and compared the activation of iMG cells between two groups at the cellular level. The expression of tumor necrosis factor (TNF)-α at mRNA and protein levels significantly increased in ATP-stimulated iMG cells from patients with fibromyalgia compared to cells from healthy individuals. Interestingly, there was a moderate correlation between ATP-induced upregulation of TNF-α expression and clinical parameters of subjective pain and other mental manifestations of fibromyalgia. These findings suggest that microglia in patients with fibromyalgia are hypersensitive to ATP. TNF-α from microglia may be a key factor underlying the complex pathology of fibromyalgia.

We have recently demonstrated that disruption of the murine cytochrome P-450 2c44 gene ( Cyp2c44) exacerbates chronic hypoxia-induced pulmonary artery remodeling and hypertension in mice. Subsequently, we serendipitously found that Cyp2c44 gene disruption also increases hematopoietic stem cell (HSC) numbers in bone marrow and blood. Therefore, the objective of the present study was to investigate whether CYP2C44-derived eicosanoids regulate HSC proliferation/cell growth and whether increased HSCs contribute to chronic hypoxia-induced remodeling of pulmonary arteries in Cyp2c44 knockout mice. Our findings demonstrated that lack of CYP2C44 epoxygenase, which catalyzed the oxidation of arachidonic acid to epoxyeicosatrienoic (EETs) and hydroxyeicosatetraenoic (HETE) acids, increases the numbers of 1) HSCs (CD34+, CD117+, and CD133+), 2) proangiogenic (CD34+CD133+and CD34+CD117+CD133+) cells, and 3) immunogenic/inflammatory (CD34+CD11b+, CD133+CD11b+, F4/80+, CD11b+, and F4/80+CD11b+) macrophages in bone marrow and blood compared with wild-type mice. Among the various CYP2C44-derived arachidonic acids, only 15-HETE decreased CD117+cell numbers when applied to bone marrow cell cultures. Interestingly, CD133+and von Willebrand factor-positive cells, which are derived from proangiogenic stem cells, are increased in the bone marrow, blood, and lungs of mice exposed to chronic hypoxia and in remodeled and occluded pulmonary arteries of CYP2C44-deficient mice. In conclusion, our results demonstrate that CYP2C44-derived 15-HETE plays a critical role in downregulating HSC proliferation and growth, because disruption of the Cyp2c44 gene increased HSCs that potentially contribute to chronic hypoxia-induced pulmonary arterial remodeling and occlusion.NEW & NOTEWORTHY This study demonstrates that cytochrome P-450 2C44 plays a critical role in controlling the phenotype of hematopoietic stem cells and that when this enzyme is knocked out, stem cells are differentiated. These stem cells give rise to increased circulating monocytes and macrophages and contribute to the pathogenesis of chronic hypoxia-induced pulmonary artery remodeling and hypertension.

Background and Objectives: Diclofenac (DIC) is metabolized to reactive metabolites such as diclofenac acyl-β-d-glucuronide (DIC-AG). It is possible that such reactive metabolites could cause tissue damage by formation of covalent protein adducts and other modification of cellular proteins or by induction of immune responses against its covalent protein adducts. However, the detailed mechanisms of idiosyncratic drug-induced liver injury (DILI) have been unclear. The objective is to clarify the involvement of DIC-AG and 4′hydroxydiclofenac (4′OH-DIC) in acute DILI. Methods: We examined the effects of inhibiting DIC-AG and 4′OH-DIC production on covalent protein adduct formation and lactate dehydrogenase leakage using sandwich-cultured rat hepatocytes (SCRHs). Results: After pretreatment of SCRH with (−)-borneol (BOR, a uridine diphosphate (UDP)-glucuronosyltransferase inhibitor) or sulfaphenazole (SUL, a cytochrome P450 2C9 inhibitor) for 30 minutes, intracellular concentrations of DIC, DIC-AG, and 4′OH-DIC were determined after further treating cells with 300 μM DIC for 3 hours. The decreased levels of reactive metabolites caused by BOR or SUL pretreatment resulted in decreased lactate dehydrogenase leakage from SCRH, although the formation of covalent protein adducts was not affected. Conclusion: These results suggested that both DIC-AG and 4′OH-DIC may be involved in acute cytotoxicity by DIC.

The coupled numerical manifold method (NMM) and discontinuous deformation analysis (DDA) are enhanced to simulate deformations of continuous soil and discontinuous masonry structures. An elasto-plastic NMM-DDA is formulated that incorporates elasto-plastic constitutive laws into incremental forms of the equation of motion. A node-based uniform strain element is applied to avoid volumetric locking, which often occurs in conventional NMM-DDA. The proposed method is applied to three fundamental boundary value problems: a beam bending problem, a bearing capacity problem of a footing, and a bearing capacity problem of a masonry structure. The method is verified through comparisons with conventional solutions.

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10−9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (P best=5.8 × 10−10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (P best=1.9 × 10−9), TRANK1 (P best=2.1 × 10−9) and ODZ4 (P best=3.3 × 10−9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for ‘within Japanese comparisons’, Pbest~10−29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for ‘trans-European-Japanese comparison,’ Pbest~10−13, R2~0.27%). This ‘trans population’ effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD ‘risk’ effect are shared between Japanese and European populations.

Background In previous studies of eye movement abnormalities, it was showed that patients with schizophrenia had significant abnormalities in saccade control and smooth pursuit, suggesting that eye movement abnormalities are useful as a biomarker. However, many patients participating in clinical trials are receiving antipsychotic treatment and it is important to examine the effects. Methods Eighty-five patients with schizophrenia were recruited and free-viewing, fixation stability and smooth pursuit tests were performed. First, multiple regression analysis was performed using the obtained parameters as the dependent variables, antipsychotics, illness severity, and duration of illness as independent variables. Secondly, patients were grouped into tertiles by antipsychotic dose (CPZ equivalents), then we conducted a group comparison with each parameter between the three groups. Results A multiple linear regression was calculated to predict each parameter based on CPZ equivalents, illness severity and duration of illness. There was no significance in the free-viewing and fixation stability test after Bonferroni correction. In smooth pursuit test, a significant regression equation was found with the horizontal gain (F (1,81) = 15.1, p < 0.00, R2 = 0.15) and vertical gain (F (1,81) = 12.5, p = 0.02, R2 = 0.12), and both were accounted only for CPZ equivalents. In a group comparison, there were significant effects of the horizontal gain (F (2,80) = 5.32, p = 0.07) and the vertical gain (F (2,80) = 3.31, p = 0.41), but both did not survive Bonferroni correction. Discussion It was found that antipsychotic treatment affects smooth pursuit eye movement. Eye movement abnormalities in schizophrenia can be a useful biomarker from previous studies, but the effects of antipsychotics must be considered.

Aim Studies have reported that cognitive decline occurs after the onset of schizophrenia despite heterogeneity in cognitive function among patients. The aim of this study was to investigate the degree of estimated cognitive decline in patients with schizophrenia by comparing estimated premorbid intellectual functioning and current intellectual functioning. Methods A total of 446 patients with schizophrenia (228 male, 218 female), consisting of three sample sets obtained from 11 psychiatric facilities, and 686 healthy controls participated in this study. The Wechsler Adult Intelligence Scale-III (WAIS-III) was used to measure the participants’ current full-scale IQ (FSIQ). The premorbid IQ was estimated using the Japanese Adult Reading Test-25. Estimated cognitive decline (difference score) was defined as the difference between the estimated premorbid IQ and the current FSIQ. Results Patients with schizophrenia showed greater estimated cognitive decline, a lower FSIQ, and a lower premorbid IQ compared with the healthy controls. The mean difference score, FSIQ, and estimated premorbid IQ were −16.3, 84.2, and 100.5, respectively, in patients with schizophrenia. Furthermore, 39.7% of the patients had a difference score of 20 points or greater decline. A discriminant analysis showed that the difference score accurately predicted 81.6% of the patients and healthy controls. Conclusion These results show the distribution of difference score in patients with schizophrenia. These findings may contribute to assessing the severity of estimated cognitive decline and identifying patients with schizophrenia who suffer from cognitive decline.

Our blood serum Ca

Our blood serum Ca2+ levels are maintained within a narrow range (Ca2+ homeostasis) through a complex feedback system. However, local bone marrow Ca2+ levels can reach high concentrations, at least transiently, due to bone resorption, which is one of the notable features of the bone marrow stroma. Bone homeostasis is maintained by both the balance between osteoblastic bone formation and osteoclastic bone resorption and the balance of mesenchymal stem cell differentiation into osteoblasts and adipocytes. It has been reported that under culture conditions of infrequent adipocyte differentiation (no treatment with insulin or dexamethasone), high extracellular Ca2+ enhances osteoblast but not adipocyte accumulation in bone marrow stromal cells. In contrast, under culture conditions of predominant adipocyte differentiation (treatment with insulin and dexamethasone), high extracellular Ca2+ enhances adipocyte but not osteoblast accumulation in bone marrow stromal cells. Thus, the increased extracellular Ca2+ caused by bone resorption might enhance osteoblast development to reform missing bone under conditions of infrequent adipocyte differentiation (such as the normal physiological state) and might accelerate adipocyte accumulation instead of osteoblastic bone formation under conditions of predominant adipocyte differentiation (such as aging, obesity, use of glucocorticoids, and postmenopause). Moreover, increased adipocyte accumulation in bone marrow suppresses lymphohematopoiesis and contributes to a dysfunction of osteogenesis.

Prostaglandin E

In atherosclerosis progression, atherosclerotic plaques develop upon accumulated foam cells derived from macrophages that take up modified low-density lipoprotein (LDL). CD36 and CD204 are the principal scavenger receptors responsible for the uptake of modified LDL. Lipopolysaccharide (LPS) exacerbates atherosclerosis by enhancing the expression of scavenger receptors and thus increasing the uptake of modified LDL into macrophages. However, the signaling pathways that mediate LPS and scavenger receptor expression have not been fully elucidated. We used mouse bone marrow-derived macrophages and investigated the effects of LPS in vitro. LPS enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription-1 (STAT-1). Inhibitors of the mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) pathway (U0126 and PD0325901) suppressed the uptake of acetylated-LDL (Ac-LDL) and the expression of CD204 but not CD36 in LPS-activated macrophages. Inhibitors of the Janus tyrosine kinase (JAK)-STAT pathway (ruxolitinib and tofacitinib) suppressed the uptake of Ac-LDL and the expression of both CD36 and CD204 in LPS-activated macrophages. We next injected LPS into the peritoneal cavity of mice and analyzed the effects of LPS. MEK inhibitor U0126 suppressed the uptake of Ac-LDL and the expression of CD204 but not CD36 in LPS-activated macrophages. JAK inhibitor ruxolitinib suppressed the uptake of Ac-LDL and the expression of both CD36 and CD204 in LPS-activated macrophages. These results suggest that scavenger receptors in LPS-activated mouse macrophages are regulated through a JAK-STAT-dependent pathway. Although further evaluation is necessary, JAK-STAT inhibition could be useful in atherosclerosis therapy, at least for atherosclerosis exacerbated by LPS.

We analyzed the genomic architecture of neuroanatomical diversity using magnetic resonance imaging and single nucleotide polymorphism (SNP) data from >26 000 individuals from the UK Biobank project and 5 other projects that had previously participated in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our results confirm the polygenic architecture of neuroanatomical diversity, with SNPs capturing from 40% to 54% of regional brain volume variance. Chromosomal length correlated with the amount of phenotypic variance captured, r ~ 0.64 on average, suggesting that at a global scale causal variants are homogeneously distributed across the genome. At a local scale, SNPs within genes (~51%) captured ~1.5 times more genetic variance than the rest, and SNPs with low minor allele frequency (MAF) captured less variance than the rest: the 40% of SNPs with MAF

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder, characterized by impaired social interaction, repetitive behavior and restricted interests. Although the molecular etiology of ASD remains largely unknown, recent studies have suggested that de novo mutations are significantly involved in the risk of ASD. We and others recently identified spontaneous de novo mutations in PKD2, a protein kinase D family member, in sporadic ASD cases. However, the biological significance of the de novo PKD2 mutations and the role of PKD2 in brain development remain unclear. Here, we performed functional analysis of PKD2 in cortical neuron development using in utero electroporation. PKD2 is highly expressed in cortical neural stem cells in the developing cortex and regulates cortical neuron development, including the neuronal differentiation of neural stem cells and migration of newborn neurons. Importantly, we determined that the ASD-associated de novo mutations impair the kinase activity of PKD2, suggesting that the de novo PKD2 mutations can be a risk factor for the disease by loss of function of PKD2. Our current findings provide novel insight into the molecular and cellular pathogenesis of ASD.

Eye movements are indispensable for the collection of visual information in everyday life. Many findings regarding the neural basis of eye movements have been accumulated from neurophysiological and psychophysical studies. In the field of psychiatry, studies on eye movement characteristics in mental illnesses have been conducted since the early 1900s. Participants with schizophrenia are known to have characteristic eye movements during smooth pursuit, saccade control, and visual search. Recently, studies evaluating eye movement characteristics as biomarkers for schizophrenia have attracted considerable attention. In this article, we review the neurophysiological basis of eye movement control and eye movement characteristics in schizophrenia. Furthermore, we discuss the prospects for eye movements as biomarkers for mental illnesses., In this paper, we review recent research on eye movements in schizophrenia and discuss the prospects for eye movements as biomarkers for mental illnesses.

Aim We investigated the outcomes of interdisciplinary drug therapy interventions by pharmacists among older residents of special elderly nursing homes. Methods The study was designed as a non-randomized, parallel-group, controlled study. Four nursing homes were allocated in a 1:1 ratio to an intervention group (IG) or control group (CG). The participants of the study were residents taking five or more medications. The nursing homes in the IG were each visited by one pharmacist, who was charged with looking for potential problems in drug therapy. Activities in the CG were carried out as usual. The intervention period was 6 months. The primary end-points were the incidences of potentially inappropriate medication (PIM) and falls. The mean difference and proportion of participants were compared between groups. Results Data from 28 participants in the IG and 27 participants in the CG were analyzed. The number of PIM decreased from 2.64 at baseline to 2.39 after 6 months in the IG (P = 0.032). The proportion of participants in whom the use of PIM was reduced without problems was 17.9% in the IG and 3.7% in the CG (P = 0.094). The mean number of falls was 0.04 in the IG and 0.41 in the CG (P = 0.033). Falls occurred in 3.6% of participants in the IG and 22.2% of participants in the CG (P = 0.043). Conclusions The results suggested a trend toward fewer PIM and falls in the IG. Geriatr Gerontol Int 2019; ••: ••-••.

Basophils have nonredundant roles in various immune responses that require Ca2+ influx. Here, we examined the role of two Ca2+ sensors, stromal interaction molecule 1 and 2 (STIM1 and STIM2), in basophil activation. We found that loss of STIM1, but not STIM2, impaired basophil IL-4 production after stimulation with immunoglobulin E (IgE)-containing immune complexes. In contrast, when basophils were stimulated with IL-3, loss of STIM2, but not STIM1, reduced basophil IL-4 production. This difference in STIM proteins was associated with distinct time courses of Ca2+ influx and transcription of the Il4 gene that were elicited by each stimulus. Similarly, basophil-specific STIM1 expression was required for IgE-driven chronic allergic inflammation in vivo, whereas STIM2 was required for IL-4 production after combined IL-3 and IL-33 treatment in mice. These data indicate that STIM1 and STIM2 have differential roles in the production of IL-4, which are stimulus dependent. Furthermore, these results illustrate the vital role of STIM2 in basophils, which is often considered to be less important than STIM1.

BACKGROUND: Quality of life (QOL) has come to be emphasized as an important measure of recovery in patients with schizophrenia. Accordingly, work outcome, a component of self-efficacy or self-esteem, has also been attracting interest in the association with QOL (Fujino et al., 2016). It is likely that maintaining work status during a certain period is important to improve QOL. The purpose of this study was to investigate this issue by examining the longitudinal relationship between work status and improvement of QOL in patients with schizophrenia. METHODS: Subjects: Sixty-five patients meeting DSM-IV-TR criteria for schizophrenia entered the study. They were recruited at the Department of Psychiatry, Osaka University Hospital, and the study was approved by the Ethics Committee of Osaka University. Assessment: Patients were assessed at baseline (T1) and approximately 1.5-years later (T2) (mean period between T1 and T2 = 1.71 ± 0.79 years). The following variables were assessed: 1) psychiatric symptoms, the Positive and Negative Syndrome Scale; 2) intellectual ability, the Wechsler Adult Intelligence Scale-Third Edition; 3) daily-living skills, the UCSD Performance-Based Skills Assessment-Brief version; 4)social function, the Social Functioning Scale Individuals’ version Modified for MATRICS-PASS; 5) work status (hours worked per week), the Social Activity Assessment. QOL was assessed by the Schizophrenia Quality of Life Scale (Wilkinson et al., 2000; Kaneda et al., 2002). Analyses: Differences between T2 and T1 (Δ) were calculated subtracting scores at T1 from T2. To examine the effect of work status, patients were classified based on Δ of hours worked per week (Δ Work). Group comparisons were conducted by the t-tests for the following variables: Age, Education, Onset, Duration, Premorbid IQ, ΔCurrent IQ, ΔPsychiatric symptoms, ΔDaily-living skills, ΔSocial function. Improvement in QOL (ΔQOL) was compared using the Mann-Whitney test. RESULTS: Only a few patients recorded negative ΔWork (mean=3.1, SD=12.4), suggesting that a majority preserved or improved their work status during the follow-up period. Most patients elicited a very small change of work hours. Therefore, The median (0.0 hours/week, no change in work hours) was used as a cut-off point for classifying patients into either the Improved group (ΔWork > 0) or the Preserved group (ΔWork < 0).The Improved grouped showed significantly higher ΔQOL compared to the Preserved group. There were no significant differences in other variables although a moderately higher increase was observed in the Improved groups in the functional domain (i.e., ΔDaily-living skills and ΔSocial function). DISCUSSION: The results revealed that improved work status is associated with better QOL in patients with schizophrenia. It is noteworthy that the ‘increase’, rather than the ‘length’, of work hours was related with self-reported QOL. This finding underscores work functioning in patients with schizophrenia (Sumiyoshi et al., 2018) in the course of recovery. Also, the current study may support the idea that subjective QOL should be included in the full concept of recovery in patients with schizophrenia. References: Fujino, H., et al. Schizophrenia Research: Cognition 2016:3, 20–25 Kaneda, Y., et al. Psychiatry Res 2002:113, 107–13 Sumiyoshi, C., et al. Schizophrenia Research 2018: 201, 172–179 Wilkinson, G., et al. Br. J. Psychiatry 2000:177, 42–46

We have previously reported that increased extracellular and intracellular Ca

Minds (Medical Information Network Distribution Service) is an information service provided by the Japan Council for Quality Health Care (JCQHC), a public interest incorporated foundation. The Minds guide for developing clinical practice guidelines was published in 2014. The aim of the Minds project is to help medical practitioners fully utilize information related to evidence-based medicine (EBM) in their practice. Minds also provides patients and the public with information to help understand the basics of diseases and share up-to-date evi- dence with doctors, on which modern medical practices are based. Overall, clinical practice guidelines are made up as follows : 1) a three-layered structure of guideline committees con- sisting of a managing committee, guideline creation team, and a systematic review team, 2) a clear description of the basis for an individual's judgment and COI, 3) evaluation of the body of evidence summarized for every outcome and study design in all selected research reports for each Clinical Question (CQ), and 4) not only the "benefit" but also the "harm" in the patient outcome caused by intervention are to be included in the evaluation. According to the Minds method, the Japanese Society of Neuropsychopharmacology has created a "Guidelines for Pharmacological Therapy of Schizophrenia." These guidelines were introduced to explain the characteristics of the Minds method in this paper. The Effectiveness of GUIdelines for Dissemination and Education in psychiatric treatment project (EGUIDE proj- ect) was also introduced to disseminate and evaluate these guidelines.

The problem of high-dose psychotropic polypharmacy has been pointed out for a longtime in schizophrenia, being referred to at the Annual Meeting of the Society in 2011. The fre- quency of high-dose psychotropic polypharmacy is much higher in Japan compared with other countries. The polypharmacy rate is about 65% for anti-psychotic drugs, and rates of high- dose antipsychotics are 30% or higher. The rates of combination therapy using anti-Parkinson drugs, anti-anxiety drugs/sleeping pills, and mood stabilizers with antipsychotics have also been reported to be 30-80% or higher. In 2014, a reduction of medical fees for multi-drug prescriptions of psychotropic drugs was made, but it is still too early to assess its impact. Against this background, we introduced the Guidelines for Pharmacological Therapy of Schizophrenia, created by The Japanese Society of Neuropsychopharmacology. We describe how high-dose psychotropic polypharmacy has been used to treat schizophrenia in Japan in these guidelines, being the first evidence-based guidelines using the Minds method. Further- more, a schizophrenic case with cognitive decline who received polypharmacy is presented. In addition, the EGUIDE project for the purpose of education and dissemination of these guide- lines is considered. It is our hope that patients with schizophrenia can receive more appropriate treatment.