Developmental changes in prefrontal cortex activation in children with or without autism spectrum traits on near-infrared spectroscopy.

BACKGROUND: Autism spectrum disorder (ASD) ranges from mild to severe symptoms, with autistic traits possibly distributed throughout the population. However, the precise neurodevelopmental differences in children with autistic traits remain unknown. SUBJECTS AND METHODS: Fifty-three healthy volunteers (32 male and 21 female, mean [standard deviation] age: 12.9 [2.5] years) having a normal intelligence quotient and without social impairment were divided into two groups according to scores of the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS). Subjects with or without autistic traits were placed into the high-PARS (n = 14) or low-PARS (n = 39) group, respectively. Activation of the prefrontal cortex was estimated using change in hemoglobin oxygenation concentration (Δ[oxy-Hb]) on near-infrared spectroscopy (NIRS) during a verbal fluency test. Age-related changes in prefrontal cortex activation were first assessed for each group. Then, the effects of age (elementary school age or junior/senior high school age) and PARS score on Δ[oxy-Hb] in the task were analyzed by two-way analysis of variance. RESULTS: We observed significant positive correlations between mean Δ[oxy-Hb] and age in the prefrontal cortex region in the low-PARS group. Mean Δ[oxy-Hb] in the low-PARS group was significantly higher than in the high-PARS group. Task performance results were comparable between the groups. CONCLUSION: In PARS-determined typically developed children, prefrontal cortex activation on NIRS correlated positively with age. In healthy volunteers without ASD but harboring autistic traits, prefrontal cortex activation was markedly lower than in normal counterparts. Our results provide biological evidence that ASD may be a pervasively distributed disorder.

Awareness of children's developmental problems and sharing of concerns with parents by preschool teachers and childcare workers: The Japanese context.

BACKGROUND: This study aims to determine the extent to which preschool teachers and childcare workers are aware of the presence of developmental problems among children and to what extent they share information with parents about their concerns regarding a child's development or diagnosis of neurodevelopmental disorders (NDDs). METHODS: We wrote to all 924 preschools and childcare centres in Japan's Nagano and Yamanashi prefectures to request participants. We then sent survey forms to the preschools and childcare centres that agreed to cooperate for three grades comprising 3-, 4- and 5-year-olds in the school year 2020. We asked the staff member in charge of each child to complete the survey. The survey included questions about the teacher's concerns regarding the possibility of an NDD and whether the matter had been shared with the children's parents. RESULTS: We obtained data for 10 354 children from 206 preschools and childcare centres (response rate = 22.3%). Among these children, 457 (4.4%) had an NDD diagnosis that their parents shared with the teachers. However, the teachers of 1274 children (12.3%) had concerns regarding their development but were not informed by the parents about the diagnosis, if any. These 1274 children included 775 (60.8%) cases where the teachers failed to share their concerns with parents because (1) the teachers could not communicate with parents (n = 119), (2) the teachers were not sure if there was a neurodevelopmental problem (n = 360) and (3) the parents were not aware of the problem (n = 296). CONCLUSIONS: Preschool teachers and childcare workers had concerns about the development of a substantial proportion of children in their charge. However, teachers and childcare workers did not share their concerns regarding many children's developmental problems with their parents. The findings suggest that there are challenges in information-sharing between teachers/childcare workers and parents.

Trends in Diagnosed Attention-Deficit/Hyperactivity Disorder Among Children, Adolescents, and Adults in Japan From April 2010 to March 2020.

This cohort study assesses trends in incidence of attention-deficit/hyperactivity disorder (ADHD) among children, adolescents, and adults in Japan from 2010 to 2019.

Twenty-year longitudinal birth cohort study of individuals diagnosed with autism spectrum disorder before seven years of age.

BACKGROUND: Previous longitudinal studies have demonstrated that psychosocial outcomes for autistic adults are very limited. However, most studies are clinic-based and liable to selection bias and major methodological problems. METHODS: We conducted a long-term follow-up study with 278 autistic individuals from our previous birth cohort study comprising 31,426 individuals. All participants were born in northern Yokohama between 1988 and 1996, diagnosed with autism spectrum disorder (ASD) by age seven, and followed up over 20 years. A total of 170 consented to participate in the study. Outcome measures included overall social functioning based on work, independent living, and friendships. Moreover, the time-use data concerning social participation and activities of daily living were compared with the general population. RESULTS: Psychosocial outcomes in adulthood (average age 25) were very good in 13.7%, good in 25.0%, fair in 31.0%, poor in 25.6%, and very poor in 4.8% of the participants. The majority participated in major life areas of and work and education (96.4%), sports (82.1%), and recreational activities and/or hobbies (98.8%). The proportion of participants who engaged in housework and self-care was comparable to that of the general population. Participants with IQ < 50 at age five had significantly worse outcomes than those with higher IQ; however, for those with IQ ≥ 50, outcomes were not significantly associated with IQ levels. CONCLUSIONS: Although complete independence was difficult to accomplish, many autistic adults engaged in organized community activities and housework and self-care. Time-use survey could offer a variety of data in investigating psychosocial outcomes of ASD cross-culturally.

Hyperactive/impulsive symptoms and autistic trait in institutionalized children with maltreatment experience.

The present study examined how maltreatment experience was associated with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) symptoms in children under institutional care. The key caregivers of children and adolescents aged 6 to 18 years who were under institutional care in Nagano prefecture, Japan were asked to answer the background questionnaire, ADHD-Rating Scale, and the Japanese children's version of the Autism-Spectrum Quotient. A total of 378 valid responses were obtained, of which 222 reported maltreatment experience prior to institutionalization. Both hyperactive/impulsive and inattentive scores were significantly higher in the maltreated group. Maltreatment experience was significantly associated with the presence of hyperactive/impulsive symptoms (p = 0.003) and inattentive symptoms (p = 0.027). Particularly, those who had experienced physical abuse were significantly more likely to have hyperactive/impulsive symptoms (p = 0.012) and autistic trait (p = 0.002). Thorough assessment of neurodevelopmental symptoms should be performed when placing children with maltreatment experience into institutional care.

Prevalence of clinical-level emotional/behavioral problems in schoolchildren during the coronavirus disease 2019 pandemic in Japan: A prospective cohort study.

BACKGROUND: Several empirical studies have investigated negative mental health outcomes related to the spread of infectious diseases, including coronavirus disease 2019 (COVID-19). However, little is known about children's emotional/behavioral problems, especially externalizing problems, during such situations. This prospective cohort study aimed to investigate pandemic-related emotional/behavioral problems and their risk factors among schoolchildren in Japan. METHODS: A total of 4800 parents with children in grades 1-12 participated in a two-wave longitudinal survey. Wave 1 and Wave 2 were conducted on March 4-8 and May 15-18, 2020, respectively. Survey items included demographic information, parental depression, children's diagnoses of neurodevelopmental disorders, the total length of school closure, and emotional/behavioral problems. Children's emotional/behavioral problems were assessed using the Strengths and Difficulties Questionnaire (SDQ), which has cutoff points to differentiate clinical-level problems, which were the primary focus of this study. RESULTS: The proportions of clinical-level problems were higher at Wave 2 (emotional symptoms = 24.8%, conduct problems = 22.7%, hyperactivity/inattention = 36.8%, peer relationship problems = 36.2%, and lack of prosocial behavior = 23.5%) compared to Wave 1. Lower grade-level and lower annual family income predicted the increased proportions of children's clinical-level emotional symptoms, hyperactivity/inattention, and prosocial behavior at Wave 2. The total length of school closure was not a significant predictor of subsequent emotional/behavioral problems. The highest proportion of clinical-level problems at Wave 2 for the four SDQ subscales was observed in children with neurodevelopmental disorders. CONCLUSIONS: The number of schoolchildren with severe emotional/behavioral problems increased during the COVID-19 pandemic. Appropriate prevention and early intervention programs should be provided, especially for children who are in lower grade levels, have low family incomes, or have neurodevelopmental disorders.

Possible utilization of salivary IFN-γ/IL-4 ratio as a marker of chronic stress in healthy individuals.

INTRODUCTION: Several studies show that psychological stress reduces Th1/Th2 ratio in blood samples. However, evidence is scarce regarding the cytokine alterations during stress in saliva. We investigated the influence of chronic stress on Th1/Th2 ratio and cytokine profiles in the saliva of healthy individuals. Further, we examined the associations of the salivary cytokine levels with sleep and attention problems, which are closely related with psychological stress. METHODS: Salivary levels of 27 cytokines were measured by multiplex bead array assays in 31 healthy young individuals (health science students and hospital staff consisting of 11 men and 20 women, mean age [standard deviation] =21.5 [0.8] years). The Kessler Psychological Distress scale (K10) and Athens Insomnia Scale (AIS) were administered to assess subjective chronic psychological stress and sleep problems. Further, participants were asked to wear Actigraph GT3X accelerometers for 3 days to assess the total sleep time. Attention problems were assessed by administering the Integrated Visual and Auditory Continuous Performance Test (IVA-CPT). RESULTS: Thirteen cytokines with >80% detectable results were included in the main analyses. The IFN-γ/IL-4 ratio, which is a commonly used index for Th1/Th2 ratio, showed significant negative correlations with the K10 and AIS scores. None of the cytokines were significantly associated with sex, body mass index, sleep index measured by Actigraph, or IVA-CPT scores. CONCLUSION: Chronic stress may be associated with alterations of the Th1/Th2 balance in salivary cytokine production. IFN-γ/IL-4 ratio in saliva may serve as a potential biomarker of chronic stress in healthy individuals.

Brief Report: Cumulative Incidence of Autism Spectrum Disorder Before School Entry in a Thoroughly Screened Population.

The present study aimed to identify the cumulative incidence of autism spectrum disorder (ASD) in a thoroughly screened population and to examine the behavioral and motor characteristics observed in children with ASD at the age of 18 months. Subjects were 1067 children who underwent a screening assessment for ASD at the routine 18-months health checkup. By the age of 6 years, 3.1% (4.3% of boys and 2.0% of girls) were diagnosed as having ASD by their attending pediatricians. Higher rate of difficulties in motor skills and social and communication skills had been reported in children with ASD at 18 months of age. This study showed that careful community-based screening system may be helpful in detecting ASD at early age.

Negative Correlation between Serum Cytokine Levels and Cognitive Abilities in Children with Autism Spectrum Disorder.

Evidence suggests that cytokines may be one of the major factors influencing cognitive development in those with autism spectrum disorder (ASD). To shed light on the neural and cognitive mechanisms of ASD, we investigated the association between peripheral cytokine levels and cognitive profiles in children with ASD. The serum levels of 10 cytokines (granulocyte macrophage colony-stimulating factor, interferon (IFN)-γ, interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor-α) were examined in 14 children with ASD using the Human Ultrasensitive Cytokine Magnetic 10-Plex Panel for the Luminex platform. The Wechsler Intelligence Scale for Children (WISC) was administered to each subject, and the relationships between WISC scores and serum levels of the cytokines were examined. The full-scale intelligence quotient (IQ) was significantly negatively correlated with the levels of IL-6 (Spearman's rank, p < 0.0001, false discovery rate q < 0.01). The levels of IL-6 and IFN-γ showed significant negative correlations with the verbal comprehension index (p < 0.001, q < 0.01) and working memory index (p < 0.01, q < 0.05), respectively. No other cytokines were significantly correlated with full-scale IQ or with any of the subscale scores of the WISC. The present results suggest negative correlations of IL-6 and IFN-γ levels with cognitive development of children with ASD. Our preliminary findings add to the evidence that cytokines may play a role in the neural development in ASD.

[Developmental disorders in adulthood: concept, differential diagnosis, and treatment].

The number of cases diagnosed with developmental disorders is rapidly increasing among those consulting psychiatry clinics for the first time in their adulthood. The author presents the concept of developmental disorders, discusses how they can be differentiated from other psychiatric disorders, and proposes some treatments. From now on, all psychiatrists should know the difference between developmental disorders and other psychiatric disorders, and diagnose them multi-axially, including the dimension of development. They should always keep in mind how developmental disorders lead to difficulties in everyday life, and treat developmental disorders in conjunction with adequate environmental modifications along with the treatment of other comorbid psychiatric disorders.

[Effect of developmental disorders on personality and personality disorders].

Developmental disorders (DD) are now so common that it is even more necessary to investigate the relationship between DD and personality disorders (PD). Despite the lack of studies, DD and PD have much in common. For research on personality and its disorders, direct, real-time observation by researchers themselves on the "black box" of temperament and its interaction with the environment is needed. For research on DD, especially in those with mild DD symptoms, how developmental characteristics and their interaction with the environment affect the personality in adulthood should be investigated.

How can epidemiological studies contribute to understanding autism spectrum disorders?

More and more studies on the frequency of autism spectrum disorders (ASD) have been published recently, most of which show the increase in prevalence data. In this review, the author pointed out factors and parameters to be considered in analyzing frequency data, i.e., the enlargement of the concept of autism, prevalence and incidence, accuracy and precision in the initial screening, and the effect of the "vaccine debate". The proportion of high-functioning ASD has been growing higher and higher due to better recognition in the last few years, and the apparent increase might still be the tip of an iceberg. Future epidemiological studies should include themes on diversity of the longitudinal course and re-conceptualization of ASD by dimensional diagnosis.

Novel monoclonal antibodies recognizing the active conformation of epidermal growth factor receptor.

The precise regulation of epidermal growth factor receptor (EGFR) is crucial for its function in cellular growth control. Although many antibodies against EGFR have been developed and used to analyze its regulation and function, it is not yet easy to analyze activated EGFR specifically. Activated EGFR has been mainly detected by its phosphorylation state using anti-phospho-EGFR and anti-phosphotyrosine antibodies. In the present study, we have established novel monoclonal antibodies which recognize the activated EGFR independently of its phosphorylation. Our antibodies detected active state of EGFR in immunoprecipitation and immunofluorescence, by recognizing the epitopes which are exposed through the conformational change induced by ligand-binding. Furthermore, we found that our antibodies preferentially detected the conformation of constitutively active EGFR mutants found in lung cancer cell lines. These results indicate that our antibodies may become novel research and diagnostic tools for detecting and analyzing the conformation of active EGFR in various cells and tissues.

Extraction and Refinement Strategy for detection of autism in 18-month-olds: a guarantee of higher sensitivity and specificity in the process of mass screening.

BACKGROUND: For early detection of autism, it is difficult to maintain an efficient level of sensitivity and specificity based on observational data from a single screening. The Extraction and Refinement (E&R) Strategy utilizes a public children's health surveillance program to produce maximum efficacy in early detection of autism. In the extraction stage, all cases at risk of childhood problems, including developmental abnormality, are identified; in the refinement stage, cases without problems are excluded, leaving only cases with conclusive diagnoses. METHODS: The city of Yokohama, Japan, conducts a routine child health surveillance program for children at 18 months in which specialized public health nurses administer YACHT-18 (Young Autism and other developmental disorders CHeckup Tool), a screening instrument to identify children at risk for developmental disorders. Children who screen positive undergo further observation, and those without disorders are subsequently excluded. To study the efficacy of early detection procedures for developmental disorders, including autism, 2,814 children born in 1988, examined at 18 months of age, and not already receiving treatment for diseases or disorders were selected. RESULTS: In the extraction stage, 402 (14.3%) children were identified for follow-up. In the refinement stage, 19 (.7%) of these were referred to the Yokohama Rehabilitation Center and diagnosed with developmental disorders. The extraction stage produced four false negatives, bringing total diagnoses of developmental disorders to 23 (.8%) - including 5 with autistic disorder and 9 with pervasive developmental disorder - not otherwise specified (PDDNOS). Sensitivity was 60% for autistic disorder and 82.6% for developmental disorders. Specificity for developmental disorders rose to 100% with the E&R Strategy. Picture cards used in YACHT-18 provided a finer screen that excluded some false positive cases. CONCLUSIONS: An extraction and refinement methodology utilizing child health surveillance programs achieve high efficacy for early detection of autism.

Insect muscarinic acetylcholine receptor: pharmacological and toxicological profiles of antagonists and agonists.

The insect muscarinic acetylcholine receptor (mAChR) is evaluated as a potential target for insecticide action. The mammalian M2/M4-selective antagonist radioligand [3H]AF-DX 384 (a pirenzepine analogue) binds to Drosophila mAChR at a single high-affinity site identical to that for the nonselective antagonist [3H]quinuclidinyl benzilate (QNB) and with a pharmacological profile distinct from that of all mammalian mAChR subtypes. Three nonselective antagonists (QNB, scopolamine, and atropine) show the highest affinity (Ki=0.5-2.4 nM) at the Drosophila target, and AF-DX 384 and M3-selective 4-DAMP (dimethyl-4-(diphenylacetoxy)piperidinium iodide) rank next in potency (Ki=5-18 nM). Eleven muscarinic antagonists generally exhibit higher affinity than eight agonists. On injection into houseflies, the antagonists 4-DAMP and (S)-(+)-dimethindene produce suppressed movement, the agonist (methyloxadiazolyl)quinuclidine causes knockdown and tremors, and all of them inhibit [3H]QNB binding ex vivo, indicating possible mAChR-mediated intoxication. The insect mAChR warrants continuing study in lead generation to discover novel insecticides.

Comparison of endothelial function in the carotid artery between normal and short-term hypercholesterolemic rabbits.

The present study was undertaken to investigate and compare the vascular function in carotid arteries isolated from normal short-term hypercholesterolemic rabbits. Rabbits were fed normal or 0.5% cholesterol chow for 5 weeks. The tension of isolated carotid artery rings was measured isometrically. Serum lipid levels were measured and morphometric analysis was performed. And content of nitrate/nitrite in the carotid artery was also determined. In the carotid artery precontracted by phenylephrine, the cholesterol chow diet administered for 5 weeks decreased acetylcholine-induced relaxation at only middle concentrations, though it significantly increased the content of nitrate/nitrite, the sum of stable nitric oxide metabolites, in the carotid artery. Cholesterol chow for 5 weeks had no influence on sodium nitroprusside-induced relaxation in the carotid artery. The N(G)-nitro-L-arginine- and indomethacin-resistant endothelium-dependent relaxation induced by acetylcholine was significantly decreased in rabbits receiving the cholesterol chow as compared to rabbits receiving the control diet. The resistant part of acetylcholine-induced relaxation was significantly inhibited when the carotid artery was treated with glibenclamide, a selective inhibitor of ATP-sensitive K(+) channels, 4-aminopyridine, an inhibitor of voltage-dependent K(+) channels, or charybdotoxin, an inhibitor of large and intermediate conductance Ca(2+)-activated K(+) channels, and it was significantly inhibited by tetraethylammonium, a non-selective inhibitor of Ca(2+)-activated K(+) channels and N,N-di-ethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525a), a nonselective cytochrome P-450 monooxygenase (CYP) inhibitor, or ketoconazole, a selective CYP3A inhibitor in only normal rabbits. These results suggest that short-term hypercholesterolemia decreased EDHF-induced relaxation mediated through K(+) channels in rabbit carotid artery and that it may be due partially to the inhibition of CYP3A system in the carotid artery at an early stage of hypercholesterolemia.