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Reproducibility is one of the most important issues for generalizing the results of clinical research; however, low reproducibility in neuroimaging studies is well known. To overcome this problem, the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) consortium, an international neuroimaging consortium, established standard protocols for imaging analysis and employs either meta‐ and mega‐analyses of psychiatric disorders with large sample sizes. The Cognitive Genetics Collaborative Research Organization (COCORO) in Japan promotes neurobiological studies in psychiatry and has successfully replicated and extended works of ENIGMA especially for neuroimaging studies. For example, (a) the ENIGMA consortium showed subcortical regional volume alterations in patients with schizophrenia (n = 2,028) compared to controls (n = 2,540) across 15 cohorts using meta‐analysis. COCORO replicated the volumetric changes in patients with schizophrenia (n = 884) compared to controls (n = 1,680) using the ENIGMA imaging analysis protocol and mega‐analysis. Furthermore, a schizophrenia‐specific leftward asymmetry for the pallidum volume was demonstrated; and (b) the ENIGMA consortium identified white matter microstructural alterations in patients with schizophrenia (n = 1,963) compared to controls (n = 2,359) across 29 cohorts. Using the ENIGMA protocol, a study from COCORO showed similar results in patients with schizophrenia (n = 696) compared to controls (n = 1,506) from 12 sites using mega‐analysis. Moreover, the COCORO study found that schizophrenia, bipolar disorder (n = 211) and autism spectrum disorder (n = 126), but not major depressive disorder (n = 398), share similar white matter microstructural alterations, compared to controls. Further replication and harmonization of the ENIGMA consortium and COCORO will contribute to the generalization of their research findings., The Cognitive Genetics Collaborative Research Organization (COCORO), which is a Japanese consortium established to elucidate psychiatric disorders and brain functions, replicated the results of the ENIGMA consortium, such as subcortical volume abnormalities and white matter microstructural abnormalities in schizophrenia, using the mega‐analysis method. These replication studies strengthened the reliability and generalization of the results of the ENIGMA consortium based on common and different methods in both consortiums. Further replication and harmonization of large consortia will contribute to the generalization of their research findings.

Patients with adipsic hypernatremia present with chronic hypernatremia because of defects in thirst sensation and dysregulated salt appetite, without demonstrable hypothalamic structural lesions. The involvement of autoantibodies directed against the sodium channel, Na(x) in the subfornical organ (SFO) has recently been reported. However, the pathophysiology of water and electrolyte imbalance underlying the disease has yet to be elucidated. We describe the case of a 5-year-old boy who complained of headaches and vomiting that gradually worsened. Brain magnetic resonance imaging detected no abnormal lesions. Blood laboratory testing revealed a serum sodium (Na) concentration of 152 mmol/L and a serum osmolarity of 312 mOsm/L. His body weight had slightly decreased, and his thirst sensation was absent. His plasma vasopressin concentration was 0.9 pg/mL, despite the high serum osmolarity. He was encouraged to drink water, and oral 1-deamino-8-D-arginine-vasopressin was administered. When serum sodium concentrations were normalized, plasma vasopressin concentrations were apparently normal and ranged from 0.8 to 2.0 pg/mL. He did not present with polyuria at any time. Immunohistochemical study using mouse brain sections and the patient’s serum revealed the deposition of human immunoglobulin G (IgG) antibody in the mouse SFO. In conclusion, our observations suggested that water and electrolyte imbalance in adipsic hypernatremia is characterized by a certain amount of vasopressin release regardless of serum sodium concentrations with no response to hyperosmolarity.

Approximately 10 years have passed since the Peritoneal Dialysis Guidelines were formulated in 2009. Much evidence has been reported during the succeeding years, which were not taken into consideration in the previous guidelines, e.g., the next peritoneal dialysis PD trial of encapsulating peritoneal sclerosis (EPS) in Japan, the significance of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), the effects of icodextrin solution, new developments in peritoneal pathology, and a new international recommendation on a proposal for exit-site management. It is essential to incorporate these new developments into the new clinical practice guidelines. Meanwhile, the process of creating such guidelines has changed dramatically worldwide and differs from the process of creating what were “clinical practice guides.” For this revision, we not only conducted systematic reviews using global standard methods but also decided to adopt a two-part structure to create a reference tool, which could be used widely by the society’s members attending a variety of patients. Through a working group consensus, it was decided that Part 1 would present conventional descriptions and Part 2 would pose clinical questions (CQs) in a systematic review format. Thus, Part 1 vastly covers PD that would satisfy the requirements of the members of the Japanese Society for Dialysis Therapy (JSDT). This article is the duplicated publication from the Japanese version of the guidelines and has been reproduced with permission from the JSDT.

According to the annual survey of the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR) conducted at the end of 2018, there were a total of 339,841 patients receiving dialysis (hereinafter, dialysis patients) in Japan. The survey included questions regarding the presence/absence of dementia, the performance status (PS), and the exercise habits of individual patients. The survey revealed that 10.8% of all dialysis patients had dementia (1.8% in the age group of less than 65 years, 6.8% in the age group of 65–74 years, and 22.7% in the age group of 75 years or older). These prevalences of dementia were approximately equal to those estimated from the survey conducted in 2010. Regarding PS, the percentage of patients with lower activity levels tended to be relatively high among patients who were less than 15 years old and those who were 60 years old or older. Concerning the exercise habits of dialysis patients, the percentage of patients who were classified as “not at all or hardly” in response to the question about exercise habit was the highest (60–80%) of all the exercise habit classifications in each of the age groups analyzed.

Only a few studies have investigated epidemiological and clinicopathological information regarding pediatric and adolescent and young adult (AYA) patients with renal disease. The purpose of this study was to clarify the differences and relationship of clinicopathological findings between pediatric and AYA patients using the Japan Renal Biopsy Registry (J-RBR). This cross-sectional study analyzed data from patients registered in the J-RBR between 2007 and 2017. Clinicopathological findings at diagnosis were analyzed for 3,463 pediatric (age 5 years, nephrotic syndrome was the most frequent diagnosis at age

Background To implement clinical practice guidelines (CPGs), it is necessary for psychiatrists to deepen their understanding of the CPGs. The Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project is a nationwide dissemination and implementation study of two sets of CPGs for schizophrenia and major depressive disorder (MDD). Methods A total of 413 psychiatrists (n = 212 in 2016; n = 201 in 2017) learned the two CPGs in the education program of the EGUIDE project, and clinical knowledge of these CPGs was evaluated at baseline and after the programs. To improve the correct answer rate for clinical knowledge after the programs, we revised the lecture materials associated with items that had a low correct answer rate in 2016 and used the revised lecture materials with the CPGs in 2017. The rates of correct answers after the programs between the 2016 and 2017 groups were compared. Results The correct answer rate of one item on the schizophrenia CPG and one item on the MDD CPG tended to be improved (S‐D5 and D‐C6) and that of one on the MDD CPG was significantly improved (D‐D3, P = 0.0008) in the 2017 group compared to those in the 2016 group. Conclusions We reported improvements in clinical knowledge of CPGs after the EGUIDE program in the 2017 group following revision of the lecture materials based on results from the 2016 group. These attempts to improve the degree of understanding of CPGs may facilitate the successful dissemination and implementation of psychiatric guidelines in everyday practice., Effective implementation and dissemination of CPGs for psychiatry is necessary, as research has shown that CPGs have minimal effects on clinical practice in the context of mental health pharmacotherapy. The EGUIDE project is a nationwide dissemination and implementation study of CPGs for psychiatry. We revealed that the clinical knowledge of CPGs improved the EGUIDE program. We also provided evidence for the effectiveness of lecture revisions, which further improved the clinical knowledge of the CPGs. This attempt to improve the clinical knowledge of CPGs can facilitate the successful dissemination and implementation of psychiatric guidelines in everyday practice.

Abnormal eye movements are often associated with psychiatric disorders. Eye movements are sensorimotor functions of the brain, and aging and sex would affect their characteristics. A precise understanding of normal eye movements is required to distinguish disease‐related abnormalities from natural differences associated with aging or sex. To date, there is no multicohort study examining age‐related dependency and sex effects of eye movements in healthy, normal individuals using large samples to ensure the robustness and reproducibility of the results. In this study, we aimed to provide findings showing the impact of age and sex on eye movement measures. The present study used eye movement measures of more than seven hundred healthy individuals from three large independent cohorts. We herein evaluated eye movement measures quantified by using a set of standard eye movement tests that have been utilized for the examination of patients with schizophrenia. We assessed the statistical significance of the effects of age and sex and its reproducibility across cohorts. We found that 4‐18 out of 35 eye movement measures were significantly correlated with age, depending on the cohort, and that 10 of those, which are related to the fixation and motor control of smooth pursuit and saccades, showed high reproducibility. On the other hand, the effects of sex, if any, were less reproducible. The present results suggest that we should take age into account when we evaluate abnormalities in eye movements., In this study, we aimed to provide findings showing the impact of age and sex on eye movement measures. We found significant effects of age on the eye movement measures related to the fixation and motor control of smooth pursuit and saccades, with high reproducibility. Thus, we should take age into account when we evaluate abnormalities in eye movements.

There are two approaches for treating cytomegalovirus (CMV) infection occurring after kidney transplantation (KTx). One is preemptive therapy in which treatment is started after confirming positive CMV antigenemia using periodic antigenemia assay. The other approach is prophylactic therapy in which oral valganciclovir (VGCV) is started within 10 days after KTx and continued for 200 days. The Transplantation Society guidelines recommend prophylactic therapy for high-risk (donor’s CMV-IgG antibody positive and recipient’s negative) pediatric recipients. However, the adequate dose and side effects of VGCV are not clear in children, and there is no sufficient information about prophylaxis for Japanese pediatric recipients. A single-center retrospective analysis was conducted on case series of high-risk pediatric patients who underwent KTx and received oral VGCV prophylaxis at the Department of Pediatric Nephrology, Tokyo Women’s Medical University, between August 2018 and March 2019. Data were collected using medical records. The dose of administration was 450 mg in all the study patients (n = 5). Reduction or discontinuation was required in four of five patients due to adverse events, which included neutropenia in one patient, anemia in two patients, and neutropenia and digestive symptoms in one patient. Late-onset CMV disease occurred in all patients. No seroconversion was observed during prophylaxis. Our preliminary study suggests that the dosage endorsed by The Transplantation Society may be an overdose for Japanese pediatric recipients. Further studies are required to examine the safety and efficacy of VGCV prophylaxis in Japanese pediatric recipients.

We treated the case of a 22-year-old male patient with liver dysfunction. At 1 year of age, hepatic fibrosis was suspected. In addition, due to the presence of retinitis pigmentosa, renal failure, obesity, mental retardation, and hypogonadism, he was diagnosed with Bardet-Biedl syndrome (BBS). Skipping of exons 14 and 17 in the sodium channel and clathrin linker 1 (SCLT1) gene was observed. At 22 years of age, the liver enzyme levels were further elevated and a diagnosis of microvesicular steatohepatitis was made. Insulin resistance, a reduction of muscle mass, an impairment of the fatty acid metabolism, and hyperleptinemia in this syndrome may cause steatohepatitis.

Parvovirus B19 (PVB19) has been known to cause acute glomerulonephritis and nephrotic syndrome with various renal histologic patterns, such as endocapillary glomerulonephritis and collapsing glomerulopathy. Remission is achieved spontaneously or by treatment with steroid and/or immunosuppressants in most patients, except those with sickle cell anemia or two APOL1 risk alleles. In this study, we report the case of a previously healthy 5-year-old boy with infection-related glomerulonephritis (IRGN) associated with PVB19 that progressed to end-stage renal disease (ESRD). He presented with macrohematuria, nephrotic-range proteinuria, and progressive renal dysfunction despite treatment with methylprednisolone pulse therapy, plasmapheresis, and intravenous immunoglobulin. The kidney biopsy specimens exhibited endocapillary infiltration and mesangiolysis with cellular crescent formation. Immunofluorescence analysis revealed that IgA was dominantly positive in the glomeruli, with some co-localized with KM55, which is a specific monoclonal antibody for galactose-deficient IgA1 (Gd-IgA1). The intensity of the KM55 signal in the present patient was weaker than that in patients with IgA nephropathy. To our knowledge, this is the first report of IRGN associated with PVB19 that progressed to ESRD without any underlying diseases. Further investigations are needed to determine the significance of IgA and Gd-IgA1 deposition in IRGN associated with PVB19.

Mutations of OCRL cause Lowe syndrome, which is characterised by congenital cataracts, infantile hypotonia with mental retardation, and renal tubular dysfunction and Dent-2 disease, which only affects the kidney. While few patients with an intermediate phenotype between these diseases have been reported, the mechanism underlying variability in the phenotype is unclear. We identified an intronic mutation, c.2257-5G>A, in intron 20 of OCRL in an older brother with atypical Lowe syndrome without eye involvement and a younger brother with renal phenotype alone. This mutation created a splice acceptor motif that was accompanied by a cryptic premature termination codon at the junction of exons 20 and 21. The mutation caused incomplete alternative splicing, which created a small amount of wild-type transcript and a relatively large amount of alternatively spliced transcript with a premature termination codon. In the patients' cells, the alternatively spliced transcript was degraded by nonsense-mediated decay and the wild-type transcript was significantly decreased, but not completely depleted. These findings imply that an intronic mutation creating an incomplete alternative splicing acceptor site results in a relatively low level of wild-type OCRL mRNA expression, leading to partial phenotypes of Lowe syndrome.

Renal hypoplasia (RH) is the most common cause of chronic kidney disease in children. In cases of RH, proteinuria is often induced by glomerular hypertrophy and hyperfiltration that is commonly associated with focal segmental glomerulosclerosis. This study reports the first case series of a possible association between RH and membranous nephropathy (MN). Of the 168 children with RH who visited our department between 1999 and 2017, five with overt proteinuria (≥ 1 g/gCr) underwent renal biopsy. We retrospectively reviewed the medical charts and analyzed biopsy specimens using light microscopy (LM), immunofluorescence (IF), and electron microscopy. The five children (four boys and one girl) had a median age of 5.5 years at the time of renal biopsy. The median proteinuria was 4.23 g/gCr (range 1.46–14.25), median serum albumin, 2.9 g/dL (range 2.3–3.7), and median estimated glomerular filtration rate, 59.7 mL/min/1.73 m2 (range 36.7–103.6). LM showed segmental spike formation and mesangial hypercellularity and IF study showed segmental granular immunoglobulin G (IgG) staining (IgG1 and IgG3 dominant) along the capillary loops in all five patients. Electron-dense deposits were observed in the subepithelial and mesangial areas. Thus, the pathological studies showed MN-like lesions in all patients. Our study suggests that RH can be the cause of MN-like lesions.

Aim Previous studies have reported different brain morphologies in different cognitive subgroups of patients with schizophrenia. We aimed to examine the brain structures and functional connectivity in these cognitive subgroups of schizophrenia. Methods We compared brain structures among healthy controls and cognitively deteriorated and preserved subgroups of patients with schizophrenia according to the decline in IQ. Connectivity analyses between subcortical regions and other brain areas were performed using resting-state functional magnetic resonance imaging among the groups. Results Whole brain and total cortical gray matter, right fusiform gyrus, left pars orbitalis gyrus, right pars triangularis, left superior temporal gyrus and left insula volumes, and bilateral cortical thickness were decreased in the deteriorated group compared to the control and preserved groups. Both schizophrenia subgroups had increased left lateral ventricle, right putamen and left pallidum, and decreased bilateral hippocampus, left precentral gyrus, right rostral middle frontal gyrus, and bilateral superior frontal gyrus volumes compared with controls. Hyperconnectivity between the thalamus and a broad range of brain regions was observed in the deteriorated group compared to connectivity in the control group, and this hyperconnectivity was less evident in the preserved group. We also found hyperconnectivity between the accumbens and the superior and middle frontal gyri in the preserved group compared with connectivity in the deteriorated group. Conclusion These findings provide evidence of prominent structural and functional brain abnormalities in deteriorated patients with schizophrenia, suggesting that cognitive subgroups in schizophrenia might be useful biotypes to elucidate brain pathophysiology for new diagnostic and treatment strategies.

The precise mechanism of hyponatremia in Kawasaki disease (KD) remains elusive because assessment of volume status based on serial changes in body weight is lacking in previous reports.Seventeen patients who were diagnosed with KD and hyponatremia (serum sodium levels135 mmol/L) were analyzed. Volume status was assessed based on serial changes in body weight. Plasma arginine vasopressin (ADH), urine electrolytes, and serum cytokine levels were measured on diagnosis of hyponatremia. An increase in body weight by3% was defined as hypervolemia and a decrease in body weight by3% was defined as hypovolemia.The volume status was hypervolemic in three patients (18%), euvolemic in 14 (82%), and hypovolemic in none (0%). Five (29%) patients were diagnosed with "syndrome of inappropriate secretion of antidiuretic hormone" (SIADH) and no patients were diagnosed with hypotonic dehydration. The contribution of decreased total exchangeable cations (salt loss) to hyponatremia (5.9% [interquartile range, 4.3%, 6.7%]) was significantly larger than that of increased total body water (-0.7% [-1.8%, 3.1%]) (P = 0.004). Serum interleukin-6 levels were elevated in all of the nine patients who were evaluated. Among the 12 (71%) patients who did not meet the criteria of SIADH and hypotonic dehydration, plasma ADH levels were inappropriately high in ten patients. These patients were also characterized by euvolemic or hypervolemic hyponatremia and salt loss, which might be compatible with a diagnosis of SIADH.Our study shows that hyponatremia in KD is euvolemic or hypervolemic and is associated with nonosmotic secretion of ADH and salt loss in the majority of patients.

Glomerular IgG deposition is rarely observed in antibody-mediated rejection. Here, we report chronic active antibody-mediated rejection with linear IgG deposition on glomerular capillary walls in a pediatric kidney transplant recipient. A 6-year-old boy with bilateral renal hypoplasia underwent preemptive deceased-donor kidney transplantation. Five years after the transplantation, an allograft biopsy revealed chronic active antibody-mediated rejection with diffuse linear IgG deposition on glomerular capillaries. Anti-glomerular basement membrane antibody, donor-specific anti-human leukocyte antigen (HLA) antibodies, and anti-angiotensin II type 1 receptor antibody were negative. A multiplex antibody assay identified anti-major histocompatibility complex class I chain-related molecule A antibody. Additionally, a single-antigen bead assay identified autoantibodies to 12 non-HLA antigens, including vimentin and glutathione S-transferase theta-1. To investigate whether IgG autoantibodies in the patient’s serum bind to antigens on glomerular capillaries, we incubated the patient’s serum with 0-h biopsy specimens of tissue donated to the patient and a control subject, both obtained immediately after nephrectomy from respective donors. IgG signals were observed in neither patient nor control samples. Nevertheless, linear IgG deposition may be explained by the binding of autoantibodies to non-HLA antigens that are usually hidden and only exposed via severe endothelial cell injury. Further studies are needed to confirm the significance of non-HLA antibodies in glomerular IgG deposition.

Background Researchers have identified about 40 genes with mutations that result in the most common cause of CKD in children, congenital anomalies of the kidney and urinary tract (CAKUT), but approximately 85% of patients with CAKUT lack mutations in these genes. The anomalies that comprise CAKUT are clinically heterogenous, and thought to be caused by disturbances at different points in kidney development. However, identification of novel CAKUT-causing genes remains difficult because of their variable expressivity, incomplete penetrance, and heterogeneity. Methods We investigated two generations of a family that included two siblings with CAKUT. Although the parents and another child were healthy, the two affected siblings presented the same manifestations, unilateral renal agenesis and contralateral renal hypoplasia. To search for a novel causative gene of CAKUT, we performed whole-exome and whole-genome sequencing of DNA from the family members. We also generated two lines of genetically modified mice with a gene deletion present only in the affected siblings, and performed immunohistochemical and phenotypic analyses of these mice. Results We found that the affected siblings, but not healthy family members, had a homozygous deletion in the Cobalamin Synthetase W Domain-Containing Protein 1 (CBWD1) gene. Whole-genome sequencing uncovered genomic breakpoints, which involved exon 1 of CBWD1, harboring the initiating codon. Immunohistochemical analysis revealed high expression of Cbwd1 in the nuclei of the ureteric bud cells in the developing kidneys. Cbwd1-deficient mice showed CAKUT phenotypes, including hydronephrosis, hydroureters, and duplicated ureters. Conclusions The identification of a deletion in CBWD1 gene in two siblings with CAKUT implies a role for CBWD1 in the etiology of some cases of CAKUT.

BACKGROUND Hypotonic maintenance i.v. fluids (IVF) pose a higher risk of hyponatremia than isotonic maintenance IVF, but isotonic maintenance IVF can result in excess sodium (Na) load in children. This study analyzed the incidence and risk factors for hyponatremia in children given hypotonic fluids with different Na concentrations and different maintenance rates. METHODS We performed a retrospective analysis using medical charts of children aged 3 months-15 years. The children were normonatremic (Na ≥135 mmol/L and

Aim Eye movement abnormalities are often associated with psychiatric illness. Subjects with either schizophrenia or autism spectrum disorder (ASD) have been reported to show eye movement abnormalities. However, it is still unclear whether eye movement abnormalities in schizophrenia and in ASD have common features. This study aimed to understand the similarities/differences in eye movement abnormalities of subjects with schizophrenia and those with ASD. Methods We analyzed 75 eye movement characteristics of 83 subjects with schizophrenia, 17 subjects with ASD and 255 healthy controls that were collected during fixation, smooth pursuit and free viewing tasks using analysis of covariance with the covariates age and sex. Results We found significant effects across groups on 21 eye movement characteristics, of which 4 characteristics had large effect sizes. Post hoc multiple comparisons indicated significant differences between the subjects with schizophrenia and healthy controls across all 21 characteristics. On the other hand, no significant difference between the ASD group and healthy control group was found. Instead, the subjects with ASD showed significant differences from the subjects with schizophrenia in 5 eye movement characteristics during the free viewing and smooth pursuit eye movements. Conclusions The present results suggest that eye movement abnormalities in the subjects with ASD are different from those with schizophrenia and that the tasks in this study are suitable to detect eye movement abnormality in schizophrenia. Thus, the eye movement examinations used here may distinguish subjects with schizophrenia from those with ASD., This study aimed to understand the similarities/differences in eye movement abnormalities of subjects with schizophrenia and those with ASD. The subjects with ASD showed significant differences from the subjects with schizophrenia in five characteristics during the free viewing and smooth pursuit eye movements. The results suggest that eye movement abnormalities in the subjects with ASD are different from those with schizophrenia.

Cystinuria is an autosomal recessive disorder characterized by a decrease in the reabsorption of cystine and dibasic amino acids (lysine, ornithine, and arginine) in the renal proximal tubule. It presents with recurrent urolithiasis. Cystinuria accounts for 6-8% of all pediatric urolithiasis. The age of onset is typically 10-30 years. Here, we report a case of early-onset cystinuria. A 4-month-old girl presented with hematuria. We noticed multiple renal calculi in ultrasonography and abdominal computerized tomography scans. The diagnosis was cystinuria with urinary calculus analysis and urinary amino acid analysis. The patient was treated with urine alkalinization and cystine chelating drugs. Gene analysis showed a P482L heterozygous mutation from her mother, and an A70V heterozygous mutation from her father, in the SLC7A9 gene. This gene encodes a putative subunit of the neutral and basic amino acid transport protein, BAT1. Although cystinuria is an autosomal recessive disease, there have been previous reports of P482L heterozygous mutations greatly suppressing cystine reabsorption and causing cystinuria symptoms. Therefore, the highly influential P482L mutation of the SLC7A9 gene may have contributed to the onset of this autosomal recessive disease at an extremely young age.

The underlying pathologies of psychiatric disorders, which cause substantial personal and social losses, remain unknown, and their elucidation is an urgent issue. To clarify the core pathological mechanisms underlying psychiatric disorders, in addition to laboratory-based research that incorporates the latest findings, it is necessary to conduct large-sample-size research and verify reproducibility. For this purpose, it is critical to conduct multicenter collaborative research across various fields, such as psychiatry, neuroscience, molecular biology, genomics, neuroimaging, cognitive science, neurophysiology, psychology and pharmacology. Moreover, collaborative research plays an important role in the development of young researchers. In this respect, the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium and Cognitive Genetics Collaborative Research Organization (COCORO) have played important roles. In this review, we first overview the importance of multicenter collaborative research and our target psychiatric disorders. Then, we introduce research findings on the pathophysiology of psychiatric disorders from neurocognitive, neurophysiological, neuroimaging, genetic, and basic neuroscience perspectives, focusing mainly on the findings obtained by COCORO. It is our hope that multicenter collaborative research will contribute to the elucidation of the pathological basis of psychiatric disorders. This article is protected by copyright. All rights reserved.

Background Monopharmacy with antipsychotics and antidepressants is the first-line treatment for schizophrenia and major depressive disorder (MDD) in most clinical guidelines, while polypharmacy with psychotropic agents in the treatment of schizophrenia is common in clinical practice. There are no detailed data on the prescription patterns for inpatients with mental illness with reliable diagnoses made by treating psychiatrists. Methods We gathered prescription data at discharge from 2177 patients with schizophrenia and 1238 patients with MDD from October 2016 to March 2018. Results The patients with schizophrenia aged between 60 and 79 were prescribed lower doses of antipsychotics and hypnotics/anxiolytics than those aged between 40 and 59. There were significant differences between the prescription rate of antipsychotics in the patients with schizophrenia and that of antidepressants in the patients with MDD. The frequency of concomitant drugs such as anti-Parkinson drugs, anxiolytics/hypnotics and mood stabilizers in the subjects with schizophrenia prescribed antipsychotic polypharmacy was significantly higher than that with monotherapy. For the patients with schizophrenia, olanzapine, risperidone, aripiprazole, quetiapine, and blonanserin were the five most prescribed antipsychotics. For the patients with MDD, mirtazapine, duloxetine, escitalopram, trazodone and sertraline were the five most prescribed antidepressants. Conclusions Our results showed the use of high doses of antipsychotics, high percentages of antipsychotic polypharmacy and concurrent use of hypnotics/anxiolytics in patients with schizophrenia. Notably, these data were collected before intensive instruction regarding the guidelines; therefore, we need to assess the change in the prescription pattern post guideline instruction.

Background: Despite their high lifetime prevalence, major depressive disorder (MDD) is often difficult to diagnose, and there is a need for useful biomarkers for the diagnosis of MDD. Eye movements are considered a non-invasive potential biomarker for the diagnosis of psychiatric disorders such as schizophrenia. However, eye movement deficits in MDD remain unclear. Thus, we evaluated detailed eye movement measurements to validate its usefulness as a biomarker in MDD.Methods: Eye movements were recorded from 37 patients with MDD and 400 healthy controls (HCs) using the same system at five University hospitals. We administered free-viewing, fixation stability, and smooth pursuit tests, and obtained 35 eye movement measurements. We performed analyses of covariance with group as an independent variable and age as a covariate. In 4 out of 35 measurements with significant group-by-age interactions, we evaluated aging effects. Discriminant analysis and receiver operating characteristic (ROC) analysis were conducted.Results: In the free-viewing test, scanpath length was significantly shorter in MDD (p = 4.2 × 10−3). In the smooth pursuit test, duration of saccades was significantly shorter and peak saccade velocity was significantly lower in MDD (p = 3.7 × 10−3, p = 3.9 × 10−3, respectively). In the fixation stability test, there were no significant group differences. There were significant group differences in the older cohort, but not in the younger cohort, for the number of fixations, duration of fixation, number of saccades, and fixation density in the free-viewing test. A discriminant analysis using scanpath length in the free-viewing test and peak saccade velocity in the smooth pursuit showed MDD could be distinguished from HCs with 72.1% accuracy. In the ROC analysis, the area under the curve was 0.76 (standard error = 0.05, p = 1.2 × 10−7, 95% confidence interval = 0.67–0.85).Conclusion: These results suggest that detailed eye movement tests can assist in differentiating MDD from HCs, especially in older subjects.

[Study objectives] To investigate the proportion of inpatients with schizophrenia and major depressive disorder prescribed hypnotic medication, and the association between such medication and the use of other antipsychotic agents. [Methods] This was a nationwide cross-sectional study performed as part of the ‘Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment’ (EGUIDE) project. Data from 2146 inpatients with schizophrenia and 1031 inpatients with major depressive disorder were analyzed. All types and dosages of psychotropic drugs were recorded and the data at the time of discharge were analyzed. Associations between the use of hypnotic medication and other antipsychotic agents were evaluated using multivariate logistic regression analyses. [Results] The proportions of schizophrenia patients who were prescribed any and two or more hypnotic agents were 55.7% and 17.6%, respectively, and the corresponding proportions for patients with major depressive disorder were 63.6% and 22.6%, respectively. In schizophrenia patients, multivariate logistic regression analyses showed that two or more antipsychotics, anticholinergic drugs, anxiolytics, and mood stabilizers/antiepileptic drugs were positively associated with the use of any hypnotic agent. In patients with major depressive disorder, multivariate logistic regression analyses revealed that two or more antidepressants, two or more antipsychotics, anxiolytics, and mood stabilizers/antiepileptic drugs were positively associated with the use of any hypnotic agent. [Conclusions] Prescription of hypnotic agents was found to be highly frequent among inpatients with psychiatric disorders. Prescription of two or more main antipsychotic agents was commonly associated with the use of hypnotic medication for both schizophrenia and major depressive disorder.

Background Recurrence of SRNS is a major challenge in KT. Several clinical factors, including initial steroid sensitivity, have been associated with increased post-transplant SRNS recurrence risk. However, conflicting data have been reported, possibly due to the heterogeneous pathophysiology of SRNS and the lack of genetic testing of SRNS patients. Furthermore, the response to immunosuppressive therapies has not been evaluated. Methods Seventy patients aged 1-15 years at SRNS onset who underwent KT between 2002 and 2018 were enrolled. Patients with secondary, familial, syndromic, and genetic forms of SRNS and those who were not treated with steroid were excluded. This study aimed to assess the risk factors for post-transplant recurrence, including treatment responses to initial steroid therapy and additional therapies with immunosuppressive agents, rituximab, plasmapheresis, and/or LDL-A. Results Data from 36 kidney transplant recipients were analyzed. Twenty-two (61%) patients experienced post-transplant SRNS recurrence, while 14 patients did not. The proportion of patients who achieved complete or partial remission with initial steroid therapy and/or additional therapies with immunosuppressive agents, rituximab, plasmapheresis, and/or LDL-A was significantly higher in the SRNS recurrence group (19/22, 86%) than in the group without SRNS recurrence (6/14, 43%; p = .01). Conclusion This study suggests that the response to steroid treatment, other immunosuppressive agents, rituximab, plasmapheresis, and/or LDL-A may predict post-transplant SRNS recurrence.

The pursuit system has the ability to perform predictive control of eye movements. Even when the target motion is unpredictable due to velocity or direction changes, preceding changes in eye velocity are generated based on weighted averaging of past stimulus timing. However, it is still uncertain whether behavioral history influences the control of predictive pursuit. Thus, we attempted to clarify the influences of stimulus and behavioral histories on predictive pursuit to randomized target velocity. We used alternating-ramp stimuli, where the rightward velocity was fixed while the leftward velocity was either fixed (predictable) or randomized (unpredictable). Predictive eye deceleration was observed regardless of whether the target velocity was predictable or not. In particular, the predictable condition showed that the predictive pursuit responses corresponded to future target velocity. The linear mixed-effects model showed that both stimulus and behavioral histories of the previous two or three trials had influences on the predictive pursuit responses to the unpredictable target velocity. Our results suggest that the predictive pursuit system allows to track randomized target motion using the information from previous several trials, and the information of sensory input (stimulus) and motor output (behavior) in the past time sequences have partially different influences on predictive pursuit.

Determining the cause of focal segmental glomerulosclerosis (FSGS) has crucial implications for evaluating the risk of posttransplant recurrence. The degree of foot process effacement (FPE) on electron micrographs (EM) of native kidney biopsies can reportedly differentiate primary FSGS from secondary FSGS. However, no systematic evaluation of FPE in genetic FSGS has been performed. In this study, percentage of FPE and foot process width (FPW) in native kidney biopsies were analyzed in eight genetic FSGS patients and nine primary FSGS patients. All genetic FSGS patients showed segmental FPE up to 38% and FPW below 2000 nm, while all primary FSGS patients showed diffuse FPE above 88% and FPW above 3000 nm. We reviewed the literature which described the degree of FPE in genetic FSGS patients and identified 38 patients with a description of the degree of FPE. The degree of FPE in patients with mutations in the genes encoding proteins associated with slit diaphragm and cytoskeletal proteins was varied, while almost all patients with mutations in other FSGS genes showed segmental FPE. In conclusion, the present study suggests that the degree of FPE in native kidney biopsies may be useful for differentiating some genetic FSGS patients from primary FSGS patients.

Abstract According to the annual survey of the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR) conducted at the end of 2018, a total of 339,841 patients were receiving dialysis (hereinafter, dialysis patients) in Japan. This survey included an investigation of individual test results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody (HCV-Ab), HCV-RNA, and serum alanine aminotransferase (ALT) (glutamic pyruvic transaminase [GPT]). The survey revealed that among dialysis patients in Japan, the prevalence of HBsAg positivity was 1.38% and the prevalence of HCV-Ab positivity was 4.7% at the end of 2018, both of which were markedly lower than the corresponding rates documented in 2007 (9.8% and 4.7%, respectively). The proportion of HCV-RNA-positive patients among all HCV-Ab-positive patients was 37.5%, which was also markedly lower than the percentage recorded in 2007 (64.0%). The prevalence of HBsAg positivity tended to increase as the dialysis vintage increased. The prevalence of HCV-Ab positivity was also not correlated with the dialysis vintage during the first 30 years of dialysis; however, it tended to increase as the dialysis vintage increased beyond the 30th year. Trial registration University hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000018641. The JRDR was approved by the ethics committee of the JSDT (approval number 1-3) and was registered on August 8, 2015 (accessed June 2, 2020).

Introduction: Mutations in genes encoding nucleoporins (NUPs; components of nuclear pore complexes [NPCs]), such as NUP93, have been reported to cause steroid-resistant nephrotic syndrome (SRNS) or focal segmental glomerulosclerosis (FSGS), which often progresses to end-stage renal disease (ESRD) in childhood. The expression of NUP93 in renal or extrarenal tissues, and the mechanism by which NUP93 mutations cause this renal phenotype, remain unclear. Methods: The expression of NUP93 in normal control kidney and in a patient with FSGS carrying NUP93 mutations was examined by immunofluorescence analysis. The expression of NUP93 in blood cells was analyzed by Western blot analysis. Results: Immunofluorescence analysis detected NUP93 expression in nuclei of all glomerular and tubulointerstitial cells in human kidneys. Whole-exome sequencing identified a compound heterozygous NUP93 mutation comprising a novel missense mutation p.Arg525Trp, and a previously reported mutation, p.Tyr629Cys, in a patient with FSGS that developed ESRD at the age of 6 years. In the patient’s kidney, the intensity of NUP93 immunofluorescence was significantly decreased in the nuclei of both glomerular and extraglomerular cells. The expression of CD2-associated protein (CD2AP) and nephrin in the patient’s podocytes was relatively intact. The amount of NUP93 protein was not significantly altered in the peripheral blood mononuclear cells of the patient. Conclusion: NUP93 is expressed in the nuclei of all the cell types of the human kidney. Altered NUP93 expression in glomerular cells as well as extraglomerular cells by NUP93 mutations may underlie the pathogenic mechanism of SRNS or FSGS. Keywords: focal segmental glomerulosclerosis, nuclear pore complex, nucleoporin, NUP93, steroid-resistant nephrotic syndrome

Background Hepatocyte nuclear factor 1β(HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype–phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. Methods We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. Results Most cases had morphological abnormalities in the renal–urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091). Conclusion We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.

Background Eye movement abnormalities have been identified in schizophrenia; however, their relevance to cognition is still unknown. In this study, we explored the general relationship between eye movements and cognitive function. Methods The three eye movement measures (scanpath length, horizontal position gain, and duration of fixations) that were previously reported to be useful in distinguishing subjects with schizophrenia from healthy subjects, as well as Wechsler Adult Intelligence Scale-III (WAIS-III) scores, were collected and tested for association in 113 subjects with schizophrenia and 404 healthy subjects. Results Scanpath length was positively correlated with matrix reasoning and digit symbol coding in subjects with schizophrenia and correlated with vocabulary and symbol search in healthy subjects. Upon testing for interaction effects of diagnosis and scanpath length on correlated WAIS-III scores, a significant interaction effect was only observed for matrix reasoning. The positive correlation between scanpath length and matrix reasoning, which was specific to subjects with schizophrenia, remained significant after controlling for demographic confounders such as medication and negative symptoms. No correlation was observed between the two other eye movement measures and any of the WAIS-III scores. Conclusions Herein, we reveal novel findings on the association between eye-movement-based measures of visual exploration and cognitive scores requiring visual search in subjects with schizophrenia and in healthy subjects. The association between scanpath length and matrix reasoning, a measure of perceptual organization in subjects with schizophrenia, implies the existence of common cognitive processes, and subjects with longer scanpath length may be advantageous in performance of perceptual organization tasks.

Two successive image frames presented with a blank inter-stimulus interval (ISI) induce reversals of perceived motion in humans. This illusory effect is a manifestation of the temporal properties of image filters embedded in the visual processing pathway. In the present study, ISI experiments were performed to identify the temporal characteristics of vision underlying optokinetic responses (OKRs) in mice. These responses are thought to be mediated by subcortical visual processing. OKRs of C57BL/6 J mice, induced by a 1/4-wavelength shift of a square-wave grating presented with and without an ISI were recorded. When a 1/4-wavelength shift was presented without, or with shorter ISIs (≤106.7 ms), OKRs were induced in the direction of the shift, with progressively decreasing amplitude as the ISI increased. However, when ISIs were 213.3 ms or longer, OKR direction reversed. Similar dependence on ISIs was also obtained using a sinusoidal grating. We subsequently quantitatively estimated temporal filters based on the ISI effects. We found that filters with biphasic impulse response functions could reproduce the ISI and temporal frequency dependence of the mouse OKR. Comparison with human psychophysics and behaviors suggests that mouse vision has more sluggish response dynamics to light signals than that of humans.

Supplemental Digital Content is available in the text., Background. The cancer incidence, types, and risk factors after pediatric kidney transplantation (KT) have been reported in the United States, Canada, Europe, Australia, and New Zealand. However, no information is available about cancer in pediatric KT recipients in Asian countries. Methods. Children aged

Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation and is associated with poor graft survival. To date, few studies have investigated predictive factors for treatment responses in recurrent FSGS. We retrospectively analyzed 16 patients who were < 16 years at the age of onset and had post-transplant recurrence of FSGS from 1993 to 2018. Patients who achieved complete remission or partial remission after initiating therapy for recurrent FSGS were defined as responders. We compared several clinical characteristics between responders and non-responders. Time to remission was also analyzed. Ten patients were responders, and six patients were non-responders. Univariate analysis showed that responders had a significantly lower amount of maximum proteinuria at the time of recurrence (P = 0.015) and more highly selective proteinuria (P = 0.013) than non-responders. The time to remission from initiation of therapy was 2 months (interquartile range 0.2–4.4). In all responders, except for one patient, remission was achieved within 6 months. Therapeutic responses may be predicted by examining the amount and selectivity of proteinuria at the time of recurrence. Further studies with larger numbers of patients are clearly required to validate these findings.

The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) based on immunofluorescence findings in kidney biopsies has provided insights into these two distinct diseases. C3G is further classified into dense deposit disease and C3 glomerulonephritis (C3GN) based on electron micrographic findings. Although these diseases have poor outcomes, limited Japanese literature confined to small, single-center cohorts exist on these diseases. We retrospectively analyzed 81 patients with MPGN type I and III from 15 hospitals in the Japan Renal Biopsy Registry to compare demographic, clinical characteristics and treatment outcomes of patients with IC-MPGN to those with C3GN. Of the 81 patients reviewed by immunofluorescence findings in kidney biopsies, 67 patients had IC-MPGN and 14 patients had C3GN. Age at diagnosis and systolic and diastolic pressure were higher and proteinuria and impaired renal function were significantly more prevalent in patients with IC-MPGN than those with C3GN. About 80% of the patients in both groups were treated with immunosuppressive therapy. At last follow-up (median 4.8 years), complete remission rate of proteinuria was significantly higher in patients with C3GN (64.3%) than in those with IC-MPGN (29.9%; P = 0.015). The renal survival rate was lower in patients with IC-MPGN when compared to C3GN (73.1% vs. 100%; log-rank, P = 0.031). Systolic blood pressure and renal function at baseline were independent predictors of progression to end-stage kidney disease. The overall prognosis of patients with C3GN is more favorable than for patients with IC-MPGN.

BACKGROUND: The development of glomerulosclerosis in FSGS is associated with a reduction in podocyte number in the glomerular capillary tufts. Although it has been reported that the number of urinary podocytes in FSGS exceeds that of minimal-change nephrotic syndrome, the nature of events that promote podocyte detachment in FSGS remains elusive. METHODS: In this study, we provide detailed, morphologic analysis of the urinary podocytes found in FSGS by examining the size of the urinary podocytes from patients with FSGS, minimal-change nephrotic syndrome, and GN. In addition, in urinary podocytes from patients with FSGS and minimal-change nephrotic syndrome, we analyzed podocyte hypertrophy and mitotic catastrophe using immunostaining of p21 and phospho-ribosomal protein S6. RESULTS: The size of the urinary podocytes was strikingly larger in samples obtained from patients with FSGS compared with those with minimal-change nephrotic syndrome and GN (P=0.008). Urinary podocytes from patients with FSGS had a higher frequency of positive immunostaining for p21 (P

Human social activities are realized by a synergy of neuronal activity over various regions of the brain, which is supported by their connectivity. In the present study, we examined associations between social activities, represented by work hours, and brain connectivity as quantified using diffusion tensor imaging (DTI). In 483 healthy participants, DTI analysis was performed using 3 T magnetic resonance imaging, and work hours were calculated, considering hours of paid employment (the “Work for Pay” category), hours of housework (the “Work at Home” category), and hours of school-related study (the “Student” category). The correlations between each class of work time and DTI indices were analyzed. The mean diffusivity (MD) values of the anterior limb of the internal capsule (ALIC) and the superior fronto-occipital fasciculus (SFO) were negatively correlated with total work hours (ALIC: r = -0.192, p = 2.3 × 10−5; SFO: r = -0.161, p = 3.8 × 10-4). We also found that the MD values of the ALIC and the SFO were correlated with work hours in the Work for Pay category (ALIC: r = -0.211, p = 3.2 × 10-6; SFO: r = -0.163, p = 3.4 × 10-4) but not with those in the Work at Home category or the Student category. These results suggest that social activity is associated with the white matter microstructure of the ALIC and the SFO. The main difference between “Work for Pay” and the other two social activities appears to be the type of motivation—for example, external versus internal. Therefore, the white matter microstructure of the ALIC and SFO may be related to externally motivated social activities.