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Motoyasu Kato,1,2 Fumiyuki Takahashi,1,2 Tadashi Sato,1,2 Yoichiro Mitsuishi,1,2 Ken Tajima,1,2 Hiroaki Ihara,1,2 Fariz Nurwidya,1,2 Hario Baskoro,1,2 Akiko Murakami,1,2 Isao Kobayashi,1,2 Moulid Hidayat,1,2 Naoko Shimada,1– 3 Shinichi Sasaki,1,2 Reiko Mineki,4 Tsutomu Fujimura,5 Toshio Kumasaka,6 Shin-ichiro Niwa,7 Kazuhisa Takahashi1– 3 1Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; 2Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan; 3Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; 4Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; 5Laboratory of Bioanalytical Chemistry, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan; 6Department of Pathology, Japanese Red Cross Medical Center, Tokyo, Japan; 7Link Genomics, Incorporated, Tokyo, JapanCorrespondence: Motoyasu KatoDepartment of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Bunkyo-Ku, Tokyo 113-8431, JapanTel +81-3-5802-1063Fax +81-3-5802-1617Email mtkatou@juntendo.ac.jpPurpose: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix (ECM) protein in the lungs. Transforming growth factor (TGF) β-induced ECM protein synthesis contributes to the development of IPF. Tranilast, an anti-allergy drug, suppresses TGFβ expression and inhibits interstitial renal fibrosis in animal models. However, the beneficial effects of tranilast or its mechanism as a therapy for pulmonary fibrosis have not been clarified.Methods: We investigated the in vitro effect of tranilast on ECM production and TGFβ/SMAD2 pathway in TGFβ 2-stimulated A549 human alveolar epithelial cells, using quantitative polymerase chain reaction, Western blotting, and immunofluorescence. In vitro observations were validated in the lungs of a murine pulmonary fibrosis model, which we developed by intravenous injection of bleomycin.Results: Treatment with tranilast suppressed the expression of ECM proteins, such as fibronectin and type IV collagen, and attenuated SMAD2 phosphorylation in TGFβ 2-stimulated A549 cells. In addition, based on a wound healing assay in these cells, tranilast significantly inhibited cell motility, with foci formation that comprised of ECM proteins. Histological analyses revealed that the administration of tranilast significantly attenuated lung fibrosis in mice. Furthermore, tranilast treatment significantly reduced levels of TGFβ, collagen, fibronectin, and phosphorylated SMAD2 in pulmonary fibrotic tissues in mice.Conclusion: These findings suggest that tranilast inhibits pulmonary fibrosis by suppressing TGFβ/SMAD2-mediated ECM protein production, presenting tranilast as a promising and novel anti-fibrotic agent for the treatment of IPF.Keywords: tranilast, idiopathic pulmonary fibrosis, TGFβ, SMAD2

Akira Wada,1,2 Yasuto Kunii,1 Jyunya Matsumoto,1 Mizuki Hino,1 Atsuko Nagaoka,1 Shin-ichi Niwa,3 Hirooki Yabe1 1Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, 2Department of Neuropsychiatry, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, 3Department of Psychiatry, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu City, Fukushima, Japan Background: The calcineurin (CaN) inhibitor, tacrolimus, is widely used in patients undergoing allogeneic organ transplantation and in those with certain allergic diseases. Recently, several reports have suggested that CaN is also associated with schizophrenia. However, little data are currently available on the direct effect of tacrolimus on the human brain.Case: A 23-year-old Japanese female experienced severe delusion of persecution, delusional mood, suspiciousness, aggression, and excitement. She visited our hospital and was diagnosed with schizophrenia. When she was 27 years old, she had severe general fatigue, persistent fever, systemic joint pain, gingival bleeding, and breathlessness and was diagnosed with acute myelomonocytic leukemia. Later she underwent bone marrow transplantation (BMT), she was administered methotrexate and cyclosporin A to prevent graft versus host disease (GVHD). Three weeks after BMT, she showed initial symptoms of GVHD and was prescribed tacrolimus instead of cyclosporin A. Seven months after BMT at the age of 31 years, she died of progression of GVHD. Pathological anatomy was examined after her death, including immunohistochemical analysis of her brain using anti-CaN antibodies. For comparison, we used our previous data from both a schizophrenia group and a healthy control group. No significant differences were observed in the percentage of CaN-immunoreactive neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-immunoreactive neurons in layers III–VI of the BA46 and the putamen tended to be lower in the tacrolimus case.Conclusion: Tacrolimus may decrease CaN immunoreactivity in some regions of the human brain. Thus, tacrolimus may introduce side effects such as cognitive dysfunction and extrapyramidal symptoms. In addition, we also found that the effect of tacrolimus on CaN immunoreactivity in human brain was stronger than the effect of schizophrenia. Keywords: calcineurin, calcineurin inhibitors, schizophrenia, postmortem brain, immuno­histochemistry

Introduction: Nociplastic pain (NP), classified as a third type of pain alongside nociceptive and neuropathic pain, is chronic pain arising from the amplification of nociceptive stimuli through central sensitization, despite the absence of tissue damage, sensory nerve damage, or disease. An important clinical feature of NP is that it is not only associated with pain but also with sensory hypersensitivity to sound and light and cognitive dysfunction, including mood and attention disorders. Recent studies have suggested that depression and developmental disorders, such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), coexist with NP at high frequency. Additionally, cognitive impairment in individuals with NP may be associated with these psychiatric comorbidities. However, to our knowledge, there are no reports on (1) multidimensional evaluation and diagnostic details of abdominal NP in adults with ADHD/ASD; (2) how ADHD drugs and antidepressants are administered when ADHD and depression coexist with NP; and (3) how central sensitization, brain function, and family relationship problems underlying NP are altered by treatments of ADHD and depression., Case Presentation: Herein, we present the case of a 51-year-old woman with abdominal NP. She developed severe right lower abdominal pain and underwent a thorough medical examination; however, the physical, medical cause remained unknown, making treatment challenging. Additionally, she took time off work as she began to complain of insomnia and anxiety. She was referred to our pain center, where a diagnosis of depression, ADHD, and ASD was confirmed, and treatment with ADHD medication was initiated. While ADHD medications alone did not yield sufficient improvement, a combination of methylphenidate and the antidepressant venlafaxine eventually led to improvements in abdominal NP, depression, ADHD symptoms, central sensitization, and family relationship issues. During treatment, cerebral blood flow in the anterior cingulate, prefrontal, and parietal cortices also improved., Conclusion: The treatment of comorbid depression is important while treating NP, and venlafaxine may be effective, especially in cases of comorbid ADHD/ASD. Screening for developmental disorders and depression is required in patients with abdominal NP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Kasahara, Takahashi, Takahashi, Morita, Matsudaira, Sato, Momose, Niwa and Uchida.)

Aims: Schizophrenia is a chronic relapsing psychiatric disorder that is characterized by many symptoms and has a high heritability. There were studies showing that the phospholipid abnormalities in subjects with schizophrenia (Front Biosci, S3, 2011, 153; Schizophr Bull, 48, 2022, 1125; Sci Rep, 7, 2017, 6; Anal Bioanal Chem, 400, 2011, 1933). Disturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in subjects with schizophrenia (Sci Rep, 7, 2017, 6; Anal Bioanal Chem, 400, 2011, 1933; Schizophr Res, 215, 2020, 493; J Psychiatr Res, 47, 2013, 636; Int J Mol Sci, 22, 2021). For exploring the signaling pathways contributing to the lipid changes in previous study (Sci Rep, 7, 2017, 6), we performed two types of transcriptome analyses in subjects with schizophrenia: an unbiased transcriptome analysis solely based on RNA-seq data and a correlation analysis between levels of gene expression and lipids., Methods: RNA-Seq analysis was performed in the postmortem prefrontal cortex from 10 subjects with schizophrenia and 5 controls. Correlation analysis between the transcriptome and lipidome from 9 subjects, which are the same samples in the previous lipidomics study (Sci Rep, 7, 2017, 6)., Results: Extraction of differentially expressed genes (DEGs) and further sequence and functional group analysis revealed changes in gene expression levels in phosphoinositide 3-kinase (PI3K)-Akt signaling and the complement system. In addition, a correlation analysis clarified alterations in ether lipid metabolism pathway, which is not found as DEGs in transcriptome analysis alone., Conclusions: This study provided results of the integrated analysis of the schizophrenia-associated transcriptome and lipidome within the PFC and revealed that lipid-correlated alterations in the transcriptome are enriched in specific pathways including ether lipid metabolism pathway., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Objective: This study aimed to assess the efficacy and safety of quadripulse transcranial magnetic stimulation-50 (QPS-50) in patients with intractable epilepsy., Methods: Four patients were included in the study. QPS-50, which induces long-term depression in healthy subjects, was administered for 30 min on a weekly basis for 12 weeks. Patients' clinical symptoms and physiological parameters were evaluated before, during, and after the repeated QPS-50 period. We performed two control experiments: the effect in MEP (Motor evoked potential) size after a single QPS-50 session with a round coil in nine healthy volunteers, and a follow-up study of physiological parameters by repeated QPS-50 sessions in four other healthy participants., Results: Motor threshold (MT) decreased during the repeated QPS-50 sessions in all patients. Epileptic symptoms worsened in two patients, whereas no clinical worsening was observed in the other two patients. In contrast, MT remained unaffected for 12 weeks in all healthy volunteers., Conclusions: QPS-50 may not be effective as a treatment for intractable epilepsy., Significance: In intractable epilepsy patients, administering repeated QPS-50 may paradoxically render the motor cortex more excitable, probably because of abnormal inhibitory control within the epileptic cortex. The possibility of clinical aggravation should be seriously considered when treating intractable epilepsy patients with non-invasive stimulation methods., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with primary chronic pain syndromes, such as fibromyalgia, migraine, and chronic low back pain. Although idiopathic orofacial pain (IOP) is classified as burning mouth syndrome or persistent idiopathic facial or dentoalveolar pain and as a primary chronic pain, the association between IOP and ADHD has not been investigated. This retrospective cohort study investigated the severity of ADHD symptoms measured using the ADHD scale and the effects of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole. The participants were 25 consecutive patients with refractory IOP referred to a psychiatrist and diagnosed with coexisting ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5. The ADHD scale scores were higher in patients with intractable IOP than those in the general population. Pharmacotherapy used in this study led to clinically significant improvements in pain, anxiety/depression, and pain catastrophizing. Intractable IOP and ADHD were shown to be associated. In the future, screening and pharmacotherapy for ADHD should be considered in the treatment of intractable IOP., (© 2023. The Author(s).)

Background: Systemic sclerosis (SSc) is a collagen disease that exhibits intractable fibrosis and vascular injury of the skin and internal organs. Transforming growth factor-β (TGF-β)/Smad signaling plays a central role in extracellular matrix (ECM) production by α-SMA-positive myofibroblasts. Myofibroblasts may be partially derived from various precursor cells in addition to resident fibroblasts. Recently, our high-throughput in vitro screening discovered a small compound, LG283, that may disrupt the differentiation of epithelial cells into myofibroblasts. This compound was originally generated as a curcumin derivative., Methods: In this study, we investigated the effect of LG283 on inhibiting fibrosis and its mechanism. The action of LG283 on TGF-β-dependent fibrogenic activity and epithelial-mesenchymal transition (EMT) was analyzed in vitro. The effects of LG283 were also examined in a bleomycin-induced skin fibrosis mouse model., Results: LG283 suppressed TGF-β-induced expression of ECM, α-SMA, and transcription factors Snail 1 and 2, and Smad3 phosphorylation in cultured human dermal fibroblasts. LG283 was also found to block EMT induction in cultured human epithelial cells. During these processes, Smad3 phosphorylation and/or expression of Snail 1 and 2 were inhibited by LG283 treatment. In the bleomycin-induced skin fibrosis model, oral administration of LG283 efficiently protected against the development of fibrosis and decrease of capillary vessels without significantly affecting cell infiltration or cytokine concentrations in the skin. No apparent adverse effects of LG283 were found. LG283 treatment remarkably inhibited the enhanced expression of α-SMA and phosphorylated Smad3, as well as those of Snail 1 and 2, in the bleomycin-injected skin., Conclusions: The LG283 compound exhibits antagonistic activity on fibrosis and vascular injury through inhibition of TGF-β/Smad/Snail mesenchymal transition pathways and thus, may be a candidate therapeutic for the treatment of SSc. Although the involvement of EMT in the pathogenesis of SSc remains unclear, the screening of EMT regulatory compounds may be an attractive approach for SSc therapy., (© 2022. The Author(s).)

Aim: Clozapine is currently the only effective drug for treatment-resistant schizophrenia; nonetheless, its pharmacological mechanism remains unclear, and its administration is limited because of severe adverse effects. By comparing the binding proteins of clozapine and its derivative olanzapine, which is safer but less effective than clozapine, we attempted to clarify the mechanism of action specific to clozapine., Methods: First, using the polyproline rod conjugates attached with clozapine or olanzapine, clozapine-binding proteins in extracts from the cerebra of 7-week-old ICR mice were isolated and separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify proteins. Second, the effect of clozapine on tubulin polymerization was determined turbidimetrically. Finally, the cellular effects of clozapine were observed in HeLa cells by immunofluorescence microscopy., Results: Alpha and β tubulins were the most abundant clozapine-binding proteins. We also found that clozapine directly binds with α and β tubulin heterodimers to inhibit their polymerization to form microtubules and disturbs the microtubule network, causing mitotic arrest in HeLa cells., Conclusion: These results suggest that α and β tubulin heterodimers are targeted by the clozapine and the microtubules are involved in the etiology of schizophrenia., (© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

This study was a systematic review of research using the Wechsler Intelligence Scale for Children (WISC) with Autism Spectrum Disorder (ASD) to examine cognitive characteristics of children with ASD beyond the impact of revisions based on WISC and diagnostic criteria changes. The classic "islets of ability" was found in individuals with full-scale IQs < 100. The "right-descending profiles" were observed among high IQ score individuals. High levels on the Block Design and low Coding levels were consistently found regardless of the variation in intellectual functioning or diagnosis. This review identified patterns of cognitive characteristics in ASD individuals using empirical data that researchers may have previously been aware of, based on their experiences, owing to the increased prevalence of ASD., (© 2021. The Author(s).)

Background: Associations between attention-deficit/hyperactivity disorder (ADHD) and chronic pain disorders, such as fibromyalgia, have been reported. However, associations between persistent chronic nonspecific low back pain (CNLBP) and ADHD have not yet been investigated., Objectives: This study aimed to investigate the positive rates of possible ADHD, as assessed by self-reported ADHD scales, in patients with persistent CNLBP, using data from self-reported questionnaires completed by patients and their families. This study also aimed to compare the self-reported scores obtained from existing standardized data for healthy individuals, and to examine whether the ADHD scale scores of patients with persistent CNLBP are associated with pain variables., Study Design: Cross-sectional study., Setting: The specialized pain clinic at our university hospital., Methods: This cross-sectional study included 60 consecutive patients with persistent CNLBP who were diagnosed with a possible somatic symptom disorder and were referred to a psychiatrist in our pain clinic. The Conners' Adult ADHD Rating Scales (CAARS) self-report (CAARS-S) and observer-rated (CAARS-O) questionnaires were utilized. We investigated the CAARS scores, and the association between the CAARS subscale scores and pain variables (pain duration and pain Numeric Rating Scale) in patients with persistent CNLBP., Results: Of the 60 patients, 19 (31.7%) were positive on both CAARS-S and CAARS-O questionnaires (T-score > 65). The ADHD indices, which comprised subscales of the CAARS estimating the necessity of treatment for ADHD, were significantly higher in both male and female patients with persistent CNLBP than in the Japanese standardized sample (P < 0.005). CAARS-S hyperactivity/restlessness, CAARS-O hyperactivity/restlessness, and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition hyperactive-impulsive symptom subscale scores also correlated with the pain intensity (P < 0.05)., Limitations: In this study, ADHD tendency was evaluated using only a self-reported questionnaire. Hence in the future, accurate and precise assessments of ADHD symptoms using structured clinical interviews conducted by ADHD experts are warranted. Additionally, the study only included patients with persistent CNLBP. Therefore in the future, it will be valuable to investigate ADHD scale scores (e.g., CAARS) among patients with CNLBP and nonspecific low back pain with larger sample sizes., Conclusions: Our findings revealed that the subscale scores on an ADHD scale were considerably high in patients with persistent CNLBP. As a previous study of our clinical experience indicates that persistent CNLBP can be substantially relieved by administering ADHD medications, ADHD screening is warranted in the treatment of persistent CNLBP.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.

Background: Suicide is a major concern after the 2011 earthquake and nuclear accident in Fukushima. Aims: This study delineates characteristics of the disaster-related suicides in Fukushima. Method: Data provided by the Fukushima Prefectural Police and data published by the Fukushima or Japanese Government were analyzed. Numbers of disaster-related suicides and evacuees were compared among the three prefectures affected. Age, sex, occupation, and means for disaster-related suicides in Fukushima were compared with overall suicides in Fukushima or Japan. History of medical treatment, changes in job and family structure after the disaster, and signs of contemplation were examined within the disaster-related suicides of Fukushima. Results: While other prefectures have experienced a drop in disaster-related suicides, Fukushima has not. Age-standardized disaster-related suicide rates were remarkably higher in men than in women. Moreover, disaster-related suicide rates in Fukushima were higher in women in their 50s and 80s as compared with overall suicide rates in Fukushima or Japan. Limitations: No detailed comparisons were made between disaster-related and non-disaster-related suicides. Conclusion: Disaster-related suicide rates were higher in men than in women. Also, it was found that the disaster-related suicide rates of elderly women were higher compared with overall suicide rates in Japan and Fukushima. In addition, many who died by suicide showed signs of contemplation before the attempt and had started psychiatric treatment. Improvement of suicide risk assessment skills for mental health professionals and gatekeeper training among residents will be essential to prevent disaster-related suicides.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder. Recent studies have suggested that epithelial-mesenchymal transition (EMT) of alveolar epithelial cells influences development of pulmonary fibrosis, which is mediated by transforming growth factor β (TGF-β). Tumor necrosis factor α (TNF-α), an important proinflammatory cytokine in IPF, has been shown to enhance TGF-β-induced EMT. Nintedanib, a multiple tyrosine kinase inhibitor that is currently used to treat IPF, has been shown to suppress EMT in various cancer cell lines. However, the mechanism of EMT inhibition by nintedanib and its effect on TGF-β and TNF-α signaling pathways in alveolar epithelial cells have not been fully elucidated., Methods: A549 alveolar epithelial cells were stimulated with TGF-β2 and TNF-α, and the effects of nintedanib on global gene expression were evaluated using microarray analysis. Furthermore, Smad2/3 phosphorylation was assessed using western blotting., Results: We found that in A549 cells, TGF-β2 and TNF-α treatment induces EMT, which was inhibited by nintedanib. Gene ontology analysis showed that nintedanib significantly attenuates the gene expression of EMT-related cellular pathways and the TGF-β signaling pathway, but not in the TNF-α-mediated signaling pathway. Furthermore, hierarchical cluster analysis revealed that EMT-related genes were attenuated in nintedanib-treated cells. Additionally, nintedanib was found to markedly suppress phosphorylation of Smad2/3., Conclusion: Nintedanib inhibits EMT by mediating EMT-related gene expression and the TGF-β/Smad pathway in A549 alveolar epithelial cells., Competing Interests: Declaration of Competing Interest Kazuhisa Takahashi (K.T.) received research funding from Chugai Pharm, Ono Pharma, Taiho Pharm, Nippon Boehringer Ingelheim, AstraZeneca, Pfizer, MSD, and Lilly Japan. Motoyasu Kato (M.K.) received speaker honoraria from Nippon Boehringer Ingelheim. The remaining authors declare no conflict of interest., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Individuals with schizophrenia exhibit cognitive impairments, which are related to impairments in social functions. This study investigated the effects of cognitive remediation on cognitive, social, and daily living impairment. Participants were individuals with schizophrenia between 20 and 60 years old ( N  = 44). Participants were randomly assigned to two groups: a cognitive remediation intervention group and a non-intervention control group. The control group was provided with conventional drug therapy and either day care or occupational therapy. The intervention group was provided with the "neuropsychological educational approach to cognitive remediation" developed by Medalia and co-workers. We assessed cognitive functions using the brief assessment of cognition in schizophrenia (BACS), and evaluated social and daily living functions using the global assessment of functioning (GAF) scale. Significant group by time interaction effects indicated that verbal memory, working memory, attention, and executive function showed significantly greater improvement at post-intervention for the intervention group than the control group. Social and daily living function also improved in the intervention group and improvements were maintained one year after intervention. These preliminary findings indicate that the combination of cognitive remediation and psychiatric rehabilitation is effective for facilitating improvements in cognitive function and social and daily living functions in individuals with schizophrenia.

Aim: Tissue pH and RNA integrity are crucial quality-control indicators of human post-mortem brain tissues in the identification of the pathogeneses of neuropsychiatric disorders, but pH has not been measured as often due to limitations in the amount of tissue available. This study was designed to develop and validate a protocol for tissue pH evaluation using a minimal amount of human post-mortem tissues., Methods: A procedure that included a proper ratio of brain tissue weight to water for homogenization and the duration of homogenization was designed based on preliminary experiments using mouse brain tissues. The minimal (10 mg) and typical (100 mg) amounts of post-mortem brain tissue from 52 subjects were homogenized in 5 volumes (50 μL/10 mg tissue) and 10 volumes (1000 μL/100 mg tissue) of nuclease-free water and subjected to pH measurements using an InLab Ultra micro pH electrode., Results: The pH values based on the new protocol using a minimal amount of tissue significantly correlated with measurements of the standard protocol (r 2 = 0.86). The correlation coefficients of the pH values between gray and white matter of the same brain region, and the values between different brain regions were 0.73 and 0.54, respectively., Conclusion: The proposed protocol used one-tenth of the tissue amount of current standard protocol and enabled us to evaluate the exact quality of post-mortem brain tissue subjected to subsequent analyses. The application of this protocol may improve the detection of biological phenomena of interest in post-mortem brain studies by diminishing confounding factors., (© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology.)

L-Type amino acid transporter 1 (LAT1) disulfide linked to CD98 heavy chain (hc) is highly expressed in most cancer cells, but weakly expressed in normal cells. In the present study, we developed novel anti-LAT1 mAbs and showed internalization activity, inhibitory effects of amino acid uptake and cell growth and antibody-dependent cellular cytotoxicity, as well as in vivo antitumor effects in athymic mice. Furthermore, we examined the reactivity of mAbs with LAT1 of Macaca fascicularis to evaluate possible side-effects of antihuman LAT1 mAbs in clinical trials. Antihuman LAT1 mAbs reacted with ACHN human and MK.P3 macaca kidney-derived cells, and this reactivity was significantly decreased by siRNAs against LAT1. Macaca LAT1 cDNA was cloned from MK.P3, and only two amino acid differences between human and macaca LAT1 were seen. RH7777 rat hepatoma and HEK293 human embryonic kidney cells expressing macaca LAT1 were established as stable transfectants, and antihuman LAT1 mAbs were equivalently reactive against transfectants expressing human or macaca LAT1. Dual (high and low) avidity modes were detected in transfectants expressing macaca LAT1, MK.P3, ACHN and HCT116 human colon cancer cells, and K A values were increased by anti-CD98hc mAb, suggesting anti-LAT1 mAbs detect an epitope on LAT1-CD98hc complexes on the cell surface. Based on these results, LAT1 may be a promising anticancer target and Macaca fascicularis can be used in preclinical studies with antihuman LAT1 mAbs., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The present adjunct study of the Japan Environment and Children's Study (JECS) aimed to determine the occurrence of developmental disorders in Fukushima Prefecture, which was exposed to low-dose radiation. At two medical institutions in Fukushima City, we enrolled 339 pregnant women from September 2013 through May 31, 2014, who delivered 335 neonates (174 male, including one set of twins) between November 4, 2013 and November 11, 2014. The parents of four neonates declined to participate in the present study and one neonate died. Therefore, 334 families agreed to participate in additional surveys until March 2017. Child Behavior Checklists (CBCL) were mailed to all 334 families during the month of their infant's second birthday and we received 236 responses (response rate, 70%). All responses were below the 69 th percentile in the CBCL, and no responses indicated significant problem behaviors. Boys tended to have higher values for items associated with developmental problems, but symptoms of autism were not evident. The mental health of the mothers indicated in the previous study might not have influenced the children. Autism spectrum disorder (ASD) is not obvious by the age of three years and thus it might become apparent as the children grow older.

In children, storytelling provides many psychological and educational benefits, such as enhanced imagination to help visualize spoken words, improved vocabulary, and more refined communication skills. However, the brain mechanisms underlying the effects of storytelling on children are not clear. In this study, the effects of storytelling on the brains of children were assessed by using near-infrared spectroscopy (NIRS). Results indicated significant decreases of the blood flow in the bilateral prefrontal areas during picture-book reading when the subjects were familiarized in comparison to the cases of the subject naïve to the stories. However, no significant differences in the blood flow were found during storytelling between the subjects naïve and familiarized to the stories. The results indicated more sustained brain activation to storytelling in comparison with picture-book reading, suggesting possible advantages of storytelling as a psychological and educational medium in children.

Perineuronal nets comprise chondroitin sulfate moieties and their core proteins, and their neuropathological alterations have been implicated in schizophrenia. To explore the molecular mechanism of the perineuronal net impairments in schizophrenia, we measured the immunoreactivity of chondroitin sulfate moieties, major components of perineuronal nets, in three brain regions (postmortem dorsolateral prefrontal cortex, caudate nucleus, and hippocampus) of schizophrenia patients and control subjects. Immunoblotting for chondroitin 4-sulfate and chondroitin 6-sulfate moieties revealed a significant increase in intensity of a 180 kD band of chondroitin 4-sulfate immunoreactivity in the hippocampus of patients, although we detected no significant alteration in their immunoreactivities with any other molecular sizes or in other brain regions. The levels of immunoreactivity were not correlated with postmortem interval, age, or storage time. We failed to find such an increase in a similar molecular range of the chondroitin 4-sulfate immunoreactivity in the hippocampus of the rats chronically treated with haloperidol. These results suggest that the level alteration of the chondroitin 4-sulfate moiety might contribute to the perineuronal net abnormality found in patients with schizophrenia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Transforming growth factor β (TGFβ)-mediated epithelial-mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGFβ1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo., Methods: TGFβ1-stimulated human alveolar epithelial (A549) and bronchial epithelial (BEAS-2B) cells were treated with or without DAS in vitro. Murine pulmonary fibrosis model was generated by injection of bleomycin (BLM)., Results: A549 and BEAS-2B cells exposed to TGFβ1 underwent EMT, as indicated by downregulation of epithelial protein E-cadherin and induction of the mesenchymal proteins, fibronectin and type I and type IV collagen. These effects were dramatically suppressed by DAS treatment, which also prevented Smad2 and Smad3 phosphorylation. DAS inhibited TGFβ1-induced cell motility and migration. Furthermore, DAS administration significantly attenuated lung fibrosis in mice by histological analysis. Treatment with DAS also significantly reduced the levels of collagen and fibronectin and phosphorylation of Smad2 in the lung tissues of the murine model., Conclusions: These findings suggest that DAS inhibited TGFβ-mediated EMT of alveolar and bronchial epithelial cells and attenuated BLM-induced lung fibrosis in mice by suppressing the TGFβ/Smad pathway. DAS may be a promising and novel anti-fibrotic agent for preventing lung fibrosis.

Background: Men score higher on mental rotation tasks compared to women and suffer from depression and anxiety at half the rate of women. The objective of this study was to confirm the gender-specific effects of depression and anxiety on mental rotation performance., Methods: We collected data in non-experimental conditions from 325 university students at three universities. Participants completed rating scales of depressive and anxiety symptoms, and then simultaneously performed a mental rotation task using tablet devices., Results: We observed no significant difference between men and women in the depressive and anxiety symptoms and task response time. Men had a significantly higher correct answer rate compared with women. The scores of depression and anxiety of all participants were positively correlated. Task response time correlated positively with intensity of depressive symptoms and anxiety in women, but not in men. Women with high depressive symptoms had significantly longer response times than did women with low depressive symptoms, while men had no differences due to depressive symptoms., Limitations: We did not directly examine brain functions; therefore, the underlying neurobiological results are only based on previous knowledge and action data., Conclusions: The pathology of depression and anxiety was reflected in the correct answer rate and response time in relation to the gender difference of brain function used in mental rotation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The relationships between -141C insertion/deletion (Ins/Del) polymorphisms in the dopamine D2 receptor gene and the two dopamine system integrators, i.e., dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN), are still unclear. In this study, we assessed the effect of this polymorphism on DARPP-32 and CaN protein expression in the postmortem striatum of patients with schizophrenia and control individuals. The expression levels of truncated DARPP and CaN were lower in Del allele carriers. These findings provide important insights into the mechanism by which this genotype could result in a poor response to antipsychotic drugs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Using near-infrared spectroscopy, we examined changes in the concentration of oxygenated hemoglobin ([oxy-Hb]) in the frontal lobe during a verbal fluency task in 20 patients with schizophrenia (10 patients each receiving olanzapine [OLZ] and risperidone [RIS]) and 10 healthy controls. We found that [oxy-Hb] levels in the prefrontal region were higher in the patients receiving OLZ than in those receiving RIS. These results suggest that antipsychotic drugs have different effects on cerebral hemodynamic patterns, which may reflect frontal lobe function. Further studies with a larger sample size are needed to verify our preliminary findings., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Transforming growth factor-β (TGF-β)/Smad signaling is well known to play a critical role in the pathogenesis of systemic sclerosis (SSc). We previously developed an artificial molecule, the histidine-pyridine-histidine ligand derivative HPH-15, which may have an antifibrotic effect. The purpose of the present study was to clarify the effects of this drug in human skin fibroblasts and in a preclinical model of SSc., Methods: The effects of HPH-15 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. The antifibrotic properties of HPH-15 and its mechanisms were also examined in a bleomycin-induced skin fibrosis mouse model., Results: HPH-15 suppressed the TGF-β-induced phosphorylation of Smad3 and inhibited the expression of collagen I, fibronectin 1, connective tissue growth factor, and α-smooth muscle actin induced by TGF-β in cultured human skin fibroblasts. In the bleomycin-induced skin fibrosis model, oral administration of HPH-15 protected against the development of skin fibrosis and ameliorated established skin fibrosis. Additionally, HPH-15 suppressed the phosphorylation of Smad3 in various cells, including macrophages in the bleomycin-injected skin. Further, in the treated mice, dermal infiltration of proinflammatory macrophages (CD11b + Ly6C hi ) and M2 profibrotic macrophages (CD11b + CD204 + or CD11b + CD206 + ) was significantly decreased during the early and late stages, respectively. HPH-15 treatment resulted in decreased messenger RNA (mRNA) expression of the M2 macrophage markers arginase 1 and Ym-1 in the skin, whereas it inversely augmented expression of Friend leukemia integration 1 and Krüppel-like factor 5 mRNAs, the transcription factors that repress collagen synthesis. No apparent adverse effects of HPH-15 were found during the treatment., Conclusions: HPH-15 may inhibit skin fibrosis by inhibiting the phosphorylation of Smad3 in dermal fibroblasts and possibly in macrophages. Our results demonstrate several positive qualities of HPH-15, including oral bioavailability, a good safety profile, and therapeutic effectiveness. Thus, this TGF-β/Smad inhibitor is a potential candidate therapeutic for SSc clinical trials.

The discovery of a novel series of β-methyltryptophan (β MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A, β-MeTrp derivative with highly potent and selective SSTR2 agonistic activity IC 50 (SSTR2/SSTR5)=0.3/>100 (nM), was identified asa drug candidate for treatment of Type 2 diabetes which lowers significantly plasma glucose level in Wistar fatty rats in its oral administrations. However, as serious increase in AUC and phospholipidosis (PLsis) were observed in its toxicological studies in rats, follow-up compounds were searched to avoid risk of PLsis with reference to their in vitro PLsis potentials evaluated on the basis of accumulation of phospholipids in HepG2 cells exposed to the compounds. It has been found that introduction of a carbonyl group onto the piperidine and piperazine or aniline moiety of compounds A and B reduced markedly the in vitro PLsis potentials. And further modification of the compounds and their evaluation led to a discovery of compounds 3k with lower in vitro PLsis potentials exhibiting lowering effect of hypoglycemia-induced glucagon secretion in SD rats (ED 50 =1.1mg/kg) and glucose excursion in meal tolerance test in Wistar fatty diabetic rats (MED=3.0mg/kg) in oral administrations. Compound 3k was selected asa new drug candidate of selective and orally active non-peptide SSTR2 agonists for treatment of Type 2 diabetes with low in vivo PLsis potential., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

ObjectivesThe purpose of this study was to develop a comprehensive back school program that included elements of CBT (Cognitive Behavioral Therapy), implement this through multidisciplinary collaboration, and ascertain its effectiveness as a pilot study. DesignThis school was implemented in the form of five 90-minute group sessions held every other week.MethodsParticipants comprised 7 chronic low back pain patients with poor improvement in the usual treatment. Practitioners were orthopaedic surgeon, physical therapist, and a clinical psychologist. This school contents were patient education, self-monitoring, back exercise, relaxation, stress management, cognitive restructuring, activity pacing, and exposure. ResultsFrom the Wilcoxon signed-rank test, each score of four scales or items (sense of control, PCS (pain catastrophizing), PASS-20 (escape/avoidance), FFD (finger-floor distance)) after this program significantly improved. Results of calculating the effect size, sense of control (d=0.55) is 'moderate', the PCS (d=1.12) and the PASS-20 (d=1.64) were 'large'.ConclusionsThis back school may be useful for physical function and psychological variables which much related to pain management and daily disabilities in patients with poor respond to standard orthopaedic treatment.

Schizophrenia is a disabling mental illness associated with dysfunction of the prefrontal cortex, which affects cognition and emotion. The purpose of the present study was to identify altered molecular networks in the prefrontal cortex of schizophrenia patients by comparing protein expression levels in autopsied brains of patients and controls, using a combination of targeted and focused quantitative proteomics. We selected 125 molecules possibly related to schizophrenia for quantification by knowledge-based targeted proteomics. Among the quantified molecules, GRIK4 and MAO-B were significantly decreased in plasma membrane and cytosolic fractions, respectively, of prefrontal cortex. Focused quantitative proteomics identified 15 increased and 39 decreased proteins. Network analysis identified "GNA13-ERK1-eIF4G2 signaling" as a downregulated network, and proteins involved in this network were significantly decreased. Furthermore, searching downstream of eIF4G2 revealed that eIF4A1/2 and CYFIP1 were decreased, suggesting that downregulation of the network suppresses expression of CYFIP1, which regulates actin remodeling and is involved in axon outgrowth and spine formation. Downregulation of this signaling seems likely to impair axon formation and synapse plasticity of neuronal cells, and could be associated with development of cognitive impairment in the pathology of schizophrenia., Biological Significance: The present study compared the proteome of the prefrontal cortex between schizophrenia patients and healthy controls by means of targeted proteomics and global quantitative proteomics. Targeted proteomics revealed that GRIK4 and MAOB were significantly decreased among 125 putatively schizophrenia-related proteins in prefrontal cortex of schizophrenia patients. Global quantitative proteomics identified 54 differentially expressed proteins in schizophrenia brains. The protein profile indicates attenuation of "GNA13-ERK signaling" in schizophrenia brain. In particular, EIF4G2 and CYFIP1, which are located downstream of the GNA13-ERK network, were decreased, suggesting that the attenuation of this signal network may cause impairment of axon formation and synapse plasticity in the brain of schizophrenia patients. Our results provide a novel insight into schizophrenia pathology, and could be helpful for drug development., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The etiology of schizophrenia includes phospholipid abnormalities. Phospholipids are bioactive substances essential for brain function. To analyze differences in the quantity and types of phospholipids present in the brain tissue of patients with schizophrenia, we performed a global analysis of phospholipids in multiple brain samples using liquid chromatography electrospray ionization mass/mass spectrometry (LC-ESI/MS/MS) and imaging mass spectrometry (IMS). We found significantly decreased 16:0/20:4-phosphatidylinositol (PI) levels in the prefrontal cortex (PFC) in the brains from patients with schizophrenia in the LC-ESI/MS/MS, and that the 16:0/20:4-PI in grey matter was most prominently diminished according to the IMS experiments. Previous reports investigating PI pathology of schizophrenia did not identify differences in the sn-1 and sn-2 fatty acyl chains. This study is the first to clear the fatty acid composition of PI in brains from patients with schizophrenia. Alteration in the characteristic fatty acid composition of PI may also affect neuronal function, and could play a role in the etiology of schizophrenia. Although further studies are necessary to understand the role of reduced 16:0/20:4-PI levels within the prefrontal cortex in the etiology of schizophrenia, our results provide insight into the development of a novel therapy for the clinical treatment of schizophrenia.

Aim: Psychiatric side-effects are the main reason for discontinuation of interferon (IFN)-based therapy. Recent developments in near-infrared spectroscopy (NIRS) have enabled non-invasive clarification of brain functions in psychiatric disorders. We prospectively evaluated brain activation in 20 chronic hepatitis C patients with or without IFN-based therapy by using NIRS during a verbal fluency task (VFT)., Methods: The relative concentrations of oxygenated hemoglobin were measured while patients completed a questionnaire survey at the start of treatment and at 4 and 12 weeks during treatment, using NIRS., Results: The VFT performance did not change among the two groups. Patients with IFN-based therapy showed significantly lower activation during VFT in frontal channels at 12 weeks than those at the start of treatment and control (P < 0.05). Their Center for Epidemiologic Studies Depression Scale scores were significantly higher at 12 weeks than those at the start of treatment, although major depressive symptoms were not found (8.3 ± 7.9 vs. 13.2 ± 6.0, P < 0.001)., Conclusion: The decrease in oxygenated hemoglobin concentrations of the frontal lobe detected using NIRS in this study reflects hypofunction of the frontal lobe. This functional decline that was caused by IFN-based therapy may be associated with the prodromal phase of depression., (© 2016 The Japan Society of Hepatology.)

The disaster at the Fukushima Daiichi Nuclear Power Plant after the Great East Japan Earthquake on March 11, 2011, might have affected the mental health status of children. To assess the mental health status, we measured the Strengths and Difficulties Questionnaire (SDQ) in 15 274 children (aged 4-15 years). The proportions of those who scored above the cutoff (≥16) of SDQ, reflecting the clinical range of the mental health status, were 25.0% (aged 4-6 years), 22.0% (aged 7-12 years, and 16.3% (aged 13-15 years), which were higher than that in the usual state (9.5%). We also explored the possibility that the distribution on the Fukushima prefectural map of the proportions of those who scored above the cutoff (≥16) of SDQ might correspond with the environmental radiation levels, but there was no significant correlation.

Mismatch negativity (MMN) is generated by a comparison between an incoming sound and the memory trace of preceding sounds stored in sensory memory without any attention to the sound. N100 (N1) is associated with the afferent response to sound onset and reflects early analysis of stimulus characteristics. MMN generators are present in the temporal and frontal lobe, and N1 generators are present in the temporal lobe. The parietal lobe is involved in MMN generation elicited by a change in duration. The anatomical network connecting these areas, lateralization, and the effect of the side of ear stimulation on MMN remain unknown. Thus, we studied the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) over the left parietal lobe on MMN and N1 in 10 healthy subjects. Low-frequency rTMS over the left parietal lobe decreased the amplitude of MMN following right ear sound stimulation, but the amplitude was unaffected with left ear sound stimulation. We observed no significant changes in the amplitude of N1 or the latency of MMN or N1. These results suggest that low-frequency rTMS over the left parietal lobe modulates the detection of early auditory changes in duration in healthy subjects. Stimulation that is contralateral to the side of the ear experiencing sound may affect the generation of duration MMN more than ipsilateral stimulation., (© EEG and Clinical Neuroscience Society (ECNS) 2016.)

Many neuroimaging studies have demonstrated structural changes in the superior temporal gyrus (STG) in patients with schizophrenia. Several postmortem studies have reported on the pathogenesis of schizophrenia, but few reports have investigated alterations in molecules in the STG. In addition, several studies have suggested that calcineurin (CaN) inadequacy may be a risk factor for schizophrenia, but no reports about CaN expression in the STG in schizophrenia have been published. We compared the density of CaN-immunoreactive (CaN-IR) neurons in the STG from 11 patients with schizophrenia with that of 11 sex- and age-matched controls. We used immunohistochemical analysis with rabbit polyclonal antibodies against human CaN. In the STG, the density of CaN-IR neurons in layers II - VI in the group with schizophrenia was significantly higher than that in the control group. Our results confirmed pathological changes in the STG in patients with schizophrenia, suggesting that alterations in the CaN pathway play a role in the pathogenesis of schizophrenia., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Colorectal cancer is a prevalent malignancy worldwide, and investigations are required to elucidate the underlying carcinogenic mechanisms. Amongst these mechanisms, de novo carcinogenesis and the adenoma to carcinoma sequence, are the most understood. Metastasis of colorectal cancer to the liver often results in fatality, therefore, it is important for any associated risk factors to be identified. Regarding the treatment of the disease, it is important to manage not only the primary colorectal tumor, but also the liver metastases. Previously, through gene variation analysis, chromosomal loss has been indicated to serve an important role in liver metastasis. Such analysis may aid in the prediction of liver metastasis risk, alongside individual responses to treatment, thus improving the management of colorectal cancer. In the present study, we aimed to clarify a cause of the liver metastasis of colorectal cancer using comparative genomic hybridization analysis. A total of 116 frozen samples were analyzed from patients with advanced colorectal cancer that underwent surgery from 2004 to 2011. The present study analyzed mutations within tumor suppressor genes non-metastatic gene 23 (NM23), deleted in colorectal carcinoma (DCC) and deleted in pancreatic carcinoma, locus 4 (DPC4), which are located on chromosomes 17 and 18 and have all been reported to affect liver metastasis of colorectal cancer. The association between chromosomal abnormalities (duplication and deletion) and liver metastasis of colorectal cancer was evaluated using comparative genomic hybridization. Cluster analysis indicated that the group of patients lacking the long arm of chromosome 17 demonstrated the highest rate of liver metastasis. No significant association was observed between the frequency of liver metastases for synchronous and heterochronous colorectal cancer cases and gene variation (P=0.206). However, when these liver metastasis cases were divided into the synchronous and heterochronous types, the ratio of each was significantly different between gene variation groups, classified by the existence of the 17q deletion (P=0.023). These results indicate that the deletion of 17q may act as a predictive marker of liver metastasis in postoperative states.

Background: After the 3.11 complex disaster, fear of radioactive contamination and forced evacuation influenced a number of residents to seek psychiatric care., Objectives: This study assessed the sequential changes in the number of new outpatients and patients with acute stress disorder (ASD), post-traumatic stress disorder (PTSD), adjustment disorder, and depression after the Fukushima disaster., Methods: We distributed questionnaires to 77 psychiatric institutions to determine the number of new outpatients between March and June in 2010, 2011, and 2012., Findings: There were 771, 1000, and 733 new patients in 2010, 2011, and 2012, respectively. We observed a statistically significant increase in new patients with ASD or PTSD and a significant decrease in patients with depression in 2011, which returned to predisaster levels in 2012., Conclusions: There were time- and disease-dependent changes in the numbers of psychiatric care-seeking individuals after the 3.11 complex disaster in Fukushima., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective and Design: Following a report that a well-known soccer player achieved a perfect score on the Block Design subtest of WAIS-R, WAIS-R was conducted on 31 skilled rugby players., Participants: Twenty-seven of the 31 players were recruited for further analyses., Results: In 14 of 27 players, Block Design scores were the highest of the 11 subtests. In addition to Block Design scores that exceeded the scores for the other subtests, the players' Block Design scores were also better than scores for the standard sample., Conclusions: The Block Design is related to spatial cognitive ability. These results showed that highly skilled players of field and ball games possess high spatial cognitive abilities.