Ubiquitination of IgG1 cytoplasmic tail modulates B-cell signalling and activation.

Upon antigen stimulation, IgG+ B cells rapidly proliferate and differentiate into plasma cells, which has been attributed to the characteristics of membrane-bound IgG (mIgG), but the underlying molecular mechanisms remain elusive. We have found that a part of mouse mIgG1 is ubiquitinated through the two responsible lysine residues (K378 and K386) in its cytoplasmic tail and this ubiquitination is augmented upon antigen stimulation. The ubiquitination of mIgG1 involves its immunoglobulin tail tyrosine (ITT) motif, Syk/Src-family kinases and Cbl proteins. Analysis of a ubiquitination-defective mutant of mIgG1 revealed that ubiquitination of mIgG1 facilitates its ligand-induced endocytosis and intracellular trafficking from early endosome to late endosome, and also prohibits the recycling pathway, thus attenuating the surface expression level of mIgG1. Accordingly, ligation-induced activation of B-cell receptor (BCR) signalling molecules is attenuated by the mIgG1 ubiquitination, except MAP kinase p38 whose activation is up-regulated due to the ubiquitination-mediated prohibition of mIgG1 recycling. Adaptive transfer experiments demonstrated that ubiquitination of mIgG1 facilitates expansion of germinal centre B cells. These results indicate that mIgG1-mediated signalling and cell activation is regulated by ubiquitination of mIgG1, and such regulation may play a role in expansion of germinal centre B cells.

Atypical Sensory Processing Profiles and Their Associations With Motor Problems In Preschoolers With Developmental Coordination Disorder.

The aims of this study were to identify sensory processing profiles specific to preschoolers with DCD in a community sample and examine the association of sensory processing problems with motor coordination difficulties in these children. Sixty-three 5-year-old children with DCD and without other neurodevelopmental disorders and 106 age-matched typically developing children participated in this study. Sensory processing problems were assessed using the Sensory Profile. Our results demonstrated problems in wide sensory processing patterns (low registration, sensitivity and avoiding) and areas (auditory, vestibular, touch and oral) in children with DCD compared with typically developing children. Additionally, the association of problems in sensory processing patterns (sensitivity and avoiding) and areas (touch and auditory) with motor coordination difficulties were identified in children with DCD alone. Our findings indicate that sensory processing abnormalities may contribute to the pathophysiology of DCD, suggesting the importance of assessing sensory processing functions in children with DCD.

[Increase in Alkaline Phosphatase Activity after High-Fat Meal Ingestion is Correlated to the Amount of ABH Substances in Saliva].

Intestinal alkaline phosphatase (IAP) appears in the circulation more frequently in blood group B or O secretors than in blood group A or AB secretors and non-secretors, and serum IAP activity rises following the ingestion of a high-fat meal. In a previous study, the occurrence of two IAP isoforms, with high (HIAP) and normal molecular mass (NIAP), in healthy sera was demonstrated by 6.0% polyacrylamide gel electrophoresis in the presence of 1% Triton X-100. NIAP was present in the fasting serum of only healthy blood group B or O secretors, but was present in all subjects following ingestion of a high-fat meal. We classified 56 healthy subjects into 3 blood groups: B (n = 19), O (n = 17), and A (n = 20), and measured their serum ALP activity in a fasting state and 6 h after a high-fat meal. The amount of ABH substances in the saliva of each subject was determined by the hemagglutination inhibition test. Correlation coefficients between the change in ALP activity after high-fat meal ingestion and the hemagglutination inhibition values in saliva were 0.925 in blood group B, 0.879 in blood group O, and 0.906 in blood group A. These results suggest that increases in ALP activity in the circulation following the ingestion of a high-fat meal are closely related to the amount of ABH substances in saliva.

Prevalence and factors of sleep problems among Japanese children: a population-based study.

Background: High prevalence of sleep problems in not only children with neurodevelopmental disorders (NDS) but also non NDS has been established. However, there are few studies that have looked into population-based and age-specific prevalence of sleep problems of children. Moreover, there are even fewer studies that have investigated the correlation of demographic and lifestyle-related factors affecting sleep problems in children. Considering these, the purpose of this study is to assess the correlation of the prevalence of sleep problems and selected socio-demographic and lifestyle-related factors in 5-year-old Japanese children in population-based study. Methods: Study children (SC) were recruited from two cohorts of the Hirosaki City 5-Year-Old Child Developmental Health Checkup Study. The first cohort consisted of 281 (162 males, 119 females) children recruited from 2014 to 2015, and the second cohort consisted of 2055 (1,068 males, 987 females) children from 2018 to 2019. In total there were 2,336 SC participants (1,230 males and 1,106 females). To determine the prevalence of sleep problems the Japanese Sleep Questionnaire for Preschoolers (JSQ-P) was utilized, and sleep problems are defined by a total score of ≥86. To determine socio-demographic and lifestyle-related factors affecting sleep, 10 factors (NDS diagnosis, birth month, childcare place, income, number of siblings, bedtime, waking time, sleeping hours, sleep onset delay, and screen time) were selected. Finally, to determine the correlation between prevalence of sleep problems and the selected demographic and lifestyle-related factors, data was analyzed using chi-square test. Results: The prevalence rate of sleep problems in 5-year-olds was 18% (369/2,055). Further, the prevalence of sleep problems was high in participants with ASD (50.4%), ADHD (39.8%), <2 million yen of income (30.5%), no siblings (24.2%), >22:00 of bedtime (30.7%), >7:30 of waking time (30.7%), <9 h of sleeping hours (25.3%), >30 min of sleep onset delay (35.3%), and ≥2 h of screen time (21.1%). Conclusion: The findings report 18% prevalence rate of sleep problems in 5-year-old children. Further, the findings establish a significant correlation of sleep problems and NDS, specific socio-demographic, and lifestyle-related factors. In considering the identified modifiable lifestyle-related factors contributing to sleep problems among the participants (i.e., bed/waking times and screen times), sleep programs to address these concerns are suggested.

Two Patients with Schizophrenia Treated with Clozapine Developed Neutropenia After Receiving a COVID-19 Vaccine.

BACKGROUND: We observed two cases of patients with schizophrenia who were treated with clozapine (250mg/day and 275mg/day, respectively) and showed neutropenia after receiving a COVID-19 vaccine (BNT162b2). CASE PRESENTATION: Case 1 is a twenty-two year old woman with a diagnosis of schizophrenia. She enrolled in Clozaril® Patient Monitoring Service in 2017 and had been taking clozapine for 4 years. She received two doses of a COVID-19 vaccine and developed neutropenia (1850/mm3 (37.9% of white blood cell 4880/mm3)) 6 days after the second vaccination, but her neutropenia self-resolved naturally. Case 2 is a twenty year old woman with a diagnosis of schizophrenia. She enrolled in Clozaril® Patient Monitoring Service in 2020 and had been taking clozapine for 10 months. She received two doses of a COVID-19 vaccine and white blood cell and neutrocyte counts were below (3730/mm3 and 1440/mm3 (38.6%), respectively) the lower limits 3 days after the second vaccination. She had to discontinue clozapine according to the withdrawal definition (her neutrocyte count was <1500/mm3), and her neutropenia self-resolved naturally. CONCLUSION: Physicians need to have a strict follow-up protocol in place for patients after vaccination for COVID-19.

Neurodevelopmental Traits and Longitudinal Transition Patterns in Internet Addiction: A 2-year Prospective Study.

Despite increasing attention to internet addiction (IA) in both clinical practice and research, our understanding of longitudinal changes of IA status is limited. In the present study, we employed latent transition analysis to investigate patterns of transitions and the stability of IA status among 5483 students (aged 9-12 years) over the two-year study periods. Additionally, we examined whether neurodevelopmental traits predicted certain transition patterns. The stability rate of IA class membership and the conversion rate from non-IA to IA status across the 2 years were 47% and 11%, respectively. The regression model revealed that autistic traits predicted the persisting IA pattern and that inattention traits predicted both the persisting and converting (from non-IA to IA status) patterns.

Determining Factors for Independent Walking in Patients Undergoing Cardiovascular Surgery: Differences between Coronary Artery Bypass Grafting, Heart Valve Surgery, and Aortic Surgery.

Physical deconditioning often occurs during the acute phase after cardiovascular surgery, and unassisted walking is required to achieve independence, to manage cardiac diseases, and to prevent recurrences. This study aims to investigate the characteristics of independent walking after cardiovascular surgery. We conducted a retrospective cohort study in patients who underwent cardiovascular surgeries (total of 567 patients): 153 in the coronary artery bypass grafting (CABG) group, 312 in the heart valve surgery group, and 102 in the aortic surgery group. We evaluated the effect of each surgery group on the cardiac rehabilitation (CR) progression. The factors associated with independent walking were age, renal diseases, intensive care unit (ICU) length of stay, and post-operative respiratory complications in the CABG group. In the heart valve surgery group, the factors were New York Heart Association functional classification, renal and respiratory diseases, ICU length of stay, duration of mechanical ventilatory support, and post-operative cardiovascular and respiratory complications. In the aortic surgery group, these were ICU length of stay and acute kidney injury. The CR progression in patients who underwent aortic surgery was significantly longer than those who underwent CABG and heart valve surgery (p < 0.001). New intervention strategies are needed for patients with prolonged ICU stays.

Copy number variations in Japanese children with autism spectrum disorder.

OBJECTIVE: Although autism spectrum disorder (ASD) occurs worldwide, most genomic studies on ASD were performed on those of Western ancestry. We hypothesized ASD-related copy number variations (CNVs) of Japanese individuals might be different from those of Western individuals. METHODS: Subjects were recruited from the Hirosaki 5-year-old children's developmental health check-up (HFC) between 2013 and 2016 (ASD group; n = 68, control group; n = 124). This study conducted CNV analysis using genomic DNA from peripheral blood of 5-year-old Japanese children. Fisher's exact test was applied for profiling subjects and CNV loci. RESULTS: Four ASD-related CNVs: deletion at 12p11.1, duplications at 4q13.2, 8p23.1 and 18q12.3 were detected (P = 0.015, 0.024, 0.009, 0.004, respectively). Specifically, the odds ratio of duplication at 18q12.3 was highest among the 4 CNVs (odds ratio, 8.13). CONCLUSIONS: Four CNVs: microdeletion at 12p11.1, microduplications at 4q13.2, 8p23.1 and 18q12.3 were detected as ASD-related CNVs in Japanese children in this study. Although these CNVs were consistent with several reports by Western countries at cytoband levels, these did not consistent at detailed genomic positions and sizes. Our data indicate the possibility that these CNVs are characteristic of Japanese children with ASD. We conclude that Japanese individuals with ASD may harbor CNVs different from those of Western individuals with ASD.

Prevalence and cumulative incidence of autism spectrum disorders and the patterns of co-occurring neurodevelopmental disorders in a total population sample of 5-year-old children.

BACKGROUNDS: Whether there is a true increase in autism spectrum disorder (ASD) frequency or not remains unclear. Additionally, the rates of co-existing neurodevelopmental disorders (NDD) in a total population sample has not been fully examined before. Therefore, using a total population sample in Japan, we aimed to estimate the prevalence and cumulative incidence of autism spectrum disorder (ASD) annually, to determine whether there is a true increase in ASD prevalence by estimating the cumulative incidence of ASD annually, and to examine the rates of co-existing neurodevelopmental disorders (NDD). METHOD: In this cross-sectional sequential design study, all 5-year-old children in the catchment area underwent the screening annually from the year 2013-2016. Screen-positive children were invited to participate in a comprehensive assessment, including child and parent interview, behavioral observation, and cognitive and motor function testing. All cases were reviewed by a multidisciplinary research team. RESULTS: Caregivers of 3954 children returned the screening, among which 559 children underwent the assessment with 87 children receiving an ASD diagnosis. Adjusted ASD prevalence was 3.22% (95% confidence interval (CI) 2.66-3.76%). The male to female ratio of the crude prevalence was 2.2:1. The cumulative incidence of ASD up to 5 years of age for the total study years was 1.31% (95% CI 1.00-1.62%). A generalized linear model revealed no significant linear trends in 5-year cumulative incidence over the study years. Only 11.5% of children had ASD alone; the remaining 88.5% were found to have at least one co-existing NDD. LIMITATIONS: Modest sample size for a total population study. CONCLUSIONS: Our findings demonstrate the stability of the 5-year cumulative incidence of ASD, implying no true rise in ASD incident cases over the 4-year study period in the study catchment area. High rates of co-existing NDDs reflect the importance of investigating broad developmental challenges in children with ASD.

Lipopolysaccharide induces mouse translocator protein (18 kDa) expression via the AP-1 complex in the microglial cell line, BV-2.

It has been reported that neuroinflammation occurs in the central nervous system (CNS) in patients with neuropathic pain, Alzheimer's disease and autism spectrum disorder. The 18-kDa translocator protein TSPO is used as an imaging target in positron emission tomography to detect neuroinflammation, and its expression is correlated with microglial activation. However, the mechanism underlying the transcriptional regulation of Tspo induced by inflammation is not clear. Here, we revealed that lipopolysaccharide (LPS) -induced Tspo expression was activated by the AP-1 complex in a mouse microglial cell line, BV-2. Knockdown of c-Fos and c-Jun, the components of AP-1, reduced LPS-induced Tspo expression. Furthermore, the enrichment of Sp1 in the proximal promoter region of Tspo was increased in the presence of LPS. In addition, the binding of histone deacetylase 1 (HDAC1) to the enhancer region, which contains the AP-1 site, was decreased by LPS treatment, but there were no significant differences in HDAC1 binding to the proximal promoter region with or without LPS. These results indicated that HDAC1 is involved not in the proximal promoter region but in the enhancer region. Our study revealed that inflammatory signals induce the recruitment of AP-1 to the enhancer region and Sp1 to the proximal promoter region of the Tspo gene and that Sp1 may regulate the basal expression of Tspo.