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Objective: Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination. Methods: A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8-9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD. Results: Perinatal inflammation (ß [SE], 0.263 [0.017]; P < 0.001), ADHD-PRS (ß [SE], 0.116[0.042]; P = 0.006), and an interaction between the two (ß [SE], 0.031[0.011]; P = 0.010) were associated with ADHD symptoms. The association between perinatal inflammation and ADHD symptoms measured by ADHD-PRS was evident only in the two higher genetic risk groups (ß [SE], 0.623[0.122]; P < 0.001 for the medium-high risk group; ß [SE], 0.664[0.152]; P < 0.001 for the high-risk group). Conclusion: Inflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8-9 with genetically higher risk for ADHD.
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Little is known about the trajectory patterns and sex differences in adaptive behaviors in the general population. We examined the trajectory classes of adaptive behaviors using a representative sample and examined whether the class structure and trajectory patterns differed between females and males. We further explored sex differences in neurodevelopmental traits in each latent class. Participants (n = 994) were children in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study)-a prospective birth cohort study. Adaptive behaviors in each domain of communication, daily living skills, and socialization were evaluated at five time points when participants were 2.7, 3.5, 4.5, 6, and 9 years old using the Vineland Adaptive Behavior Scales-Second Edition. Parallel process multigroup latent class growth analysis extracted sex-specific trajectory classes. Neurodevelopmental traits of children at age 9, autistic traits, attention deficit hyperactivity disorder (ADHD) traits, and cognitive ability were examined for females and males in each identified class. A 4-class model demonstrated the best fit. Moreover, a 4-class model that allowed for differences in class probabilities and means of growth parameters between females and males provided a better fit than a model assuming no sex differences. In the communication domain, females scored higher than their male counterparts in all four classes. In the daily living skills and socialization domains, the two higher adaptive classes (Class 1: females, 18.6%; males, 17.8%; Class 2: females, 48.8%; males, 49.8%) had similar trajectories for males and females, whereas in the two lower adaptive behavior classes (Class 3: females, 27.5%; males, 29.4%; Class 4: females, 5.1%; males, 3.0%), females had higher adaptive scores than their male counterparts. In Class 4, females were more likely to have autistic and ADHD traits exceeding the cutoffs, while males were more likely to have below-average IQ. Different trajectories in females and males suggest that adaptive skills may require adjustment based on the sex of the child, when standardizing scores, in order to achieve better early detection of skill impairment.
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Introduction: Obesity is highly heritable, and recent evidence demonstrates that obesity is associated with cognitive deficits, specifically working memory. However, the relationship between genetic risks for obesity and working memory is not clear. In addition, whether the effect of these genetic risks on working memory in children is mediated by increased body mass index (BMI) has not been elucidated. Methods: In order to test whether the polygenic risk score (PRS) for obesity in adulthood (adulthood-BMI-PRS) is associated with working memory at 8 years of age, and whether the effect is mediated by childhood BMI, in children from the general population, participants in the Hamamatsu Birth Cohort for Mothers and Children (HBC) study in Hamamatsu, Japan, underwent testing for association of adulthood-BMI-PRS with working memory. HBC data collection began in December 2007 and is ongoing. Adulthood-BMI-PRS values were generated using summary data from the recent genome-wide association study (GWAS) undertaken in Japan, and the significance of thresholds was calculated for each outcome. Outcomes measured included the working memory index (WMI) of Weschler Intelligence Scale-4 (WISC-IV) scores and the BMI at 8 years of age. Gene-set enrichment analysis was conducted to clarify the molecular basis common to adulthood-BMI and childhood-WMI. Mediation analysis was performed to assess whether childhood-BMI of children mediated the association between adulthood-BMI-PRS and working memory. Results: A total of 734 participants (377 males, 357 females) were analyzed. Adulthood-BMI-PRS was associated with lower childhood-WMI (ß[SE], -1.807 [0.668]; p = 0.010, corrected) of WISC-IV. Gene-set enrichment analyses found that regulation of neurotrophin Trk receptor signaling (ß[SE], -2.020 [6.39]; p = 0.002, corrected), negative regulation of GTPase activity (ß[SE], 2.001 [0.630]; p = 0.002, corrected), and regulation of gene expression epigenetic (ß[SE], -2.119 [0.664]; p = 0.002, corrected) were enriched in BMI in adulthood and WMI in childhood. Mediation analysis showed that there is no mediation effect of childhood-BMI between the adulthood-BMI-PRS and working memory deficits in children. Conclusion: Adulthood-BMI-PRS was associated with working memory among children in the general population. These genetic risks were not mediated by the childhood-BMI itself and were directly associated with working memory deficits.
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INTRODUCTION: Accumulating evidence has shown that maternal metabolic conditions, such as pre-pregnancy overweight, diabetes mellitus, and hypertensive disorders of pregnancy (HDP) are potential risk factors of autism spectrum disorder (ASD). However, it remains unclear how these maternal conditions lead to neurodevelopmental outcomes in the offspring, including autistic symptoms. Leptin, an adipokine that has pro-inflammatory effects and affects fetal neurodevelopment, is a candidate mediator of the association between maternal metabolic factors and an increased risk of ASD. However, whether prenatal exposure to leptin mediates the association between maternal metabolic conditions and autistic symptoms in children has not been investigated yet. METHODS: This study investigated the associations between mothers' metabolic conditions (pre-pregnancy overweight, diabetes mellitus during or before pregnancy, and HDP), leptin concentrations in umbilical cord serum, and autistic symptoms among 762 children from an ongoing cohort study, using generalized structural equation modeling. We used the Social Responsive Scale, Second Edition (SRS-2) at 8-9 years old to calculate total T-scores. Additionally, we used the T-scores for two subdomains: Social Communication and Interaction (SCI) and Restricted Interests and Repetitive Behavior (RRB). RESULTS: Umbilical cord leptin levels were associated with pre-pregnancy overweight [coefficient = 1.297, 95% confidence interval (CI) 1.081-1.556, p = 0.005] and diabetes mellitus (coefficient = 1.574, 95% CI 1.206-2.055, p = 0.001). Furthermore, leptin levels were significantly associated with SRS-2 total T-scores (coefficient = 1.002, 95% CI 1.000-1.004, p = 0.023), SCI scores (coefficient = 1.002, 95% CI 1.000-1.004, p = 0.020), and RRB scores (coefficient = 1.001, 95% CI 1.000-1.003, p = 0.044) in children. Associations between maternal metabolic factors and autistic symptoms were not significant. DISCUSSION: The present study uncovered an association between cord leptin levels and autistic symptoms in children, while maternal metabolic conditions did not have an evident direct influence on the outcome. These results imply that prenatal pro-inflammatory environments affected by maternal metabolic conditions may contribute to the development of autistic symptoms in children. The findings warrant further investigation into the role of leptin in the development of autistic symptoms.
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Autism spectrum disorder is a neurodevelopmental disorder characterized by difficulties in social communication and interaction, as well as repetitive and characteristic patterns of behaviour. Although the pathogenesis of autism spectrum disorder is unknown, being overweight or obesity during infancy and low weight at birth are known as risks, suggesting a metabolic aspect. In this study, we investigated adipose tissue development as a pathophysiological factor of autism spectrum disorder by examining the serum levels of adipokines and other metabolic markers in autism spectrum disorder children (n = 123) and typically developing children (n = 92) at 4-12 years of age. Among multiple measures exhibiting age-dependent trajectories, the leptin levels displayed different trajectory patterns between autism spectrum disorder and typically developing children, supporting an adipose tissue-dependent mechanism of autism spectrum disorder. Of particular interest, the levels of fatty acid binding protein 4 (FABP4) were significantly lower in autism spectrum disorder children than in typically developing subjects, at preschool age (4-6 years old: n = 21 for autism spectrum disorder and n = 26 for typically developing). The receiver operating characteristic curve analysis discriminated autism spectrum disorder children from typically developing children with a sensitivity of 94.4% and a specificity of 75.0%. We re-sequenced the exons of the FABP4 gene in a Japanese cohort comprising 659 autism spectrum disorder and 1000 control samples, and identified two rare functional variants in the autism spectrum disorder group. The Trp98Stop, one of the two variants, was transmitted to the proband from his mother with a history of depression. The disruption of the Fabp4 gene in mice evoked autism spectrum disorder-like behavioural phenotypes and increased spine density on apical dendrites of pyramidal neurons, which has been observed in the postmortem brains of autism spectrum disorder subjects. The Fabp4 knockout mice had an altered fatty acid composition in the cortex. Collectively, these results suggest that an 'adipo-brain axis' may underlie the pathophysiology of autism spectrum disorder, with FABP4 as a potential molecule for use as a biomarker.
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This case-control study aimed to assess oxidative stress alterations in autism spectrum disorder (ASD). We used the MULTIS method, an electron spin resonance-based technique measuring multiple free radical scavenging activities simultaneously, in combination with conventional oxidative stress markers to investigate the ability of this MULTIS approach as a non-behavioural diagnostic tool for children with ASD. Serum samples of 39 children with ASD and 58 age-matched children with typical development were analysed. The ASD group showed decreased hydroxyl radical (·OH) and singlet oxygen scavenging activity with increased serum coenzyme Q10 oxidation rate, indicating a prooxidative tendency in ASD. By contrast, scavenging activities against superoxide (O2·-) and alkoxyl radical (RO·) were increased in the ASD group suggesting antioxidative shifts. In the subgroup analysis of 6-year-olds or younger, the combination of ·OH, O2·-, and RO· scavenging activities predicted ASD with high odds ratio (50.4), positive likelihood (12.6), and percentage of correct classification (87.0%). Our results indicate that oxidative stress in children with ASD is not simply elevated but rather shows a compensatory shift. MULTIS measurements may serve as a very powerful non-behavioural tool for the diagnosis of ASD in children.
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Trastorno del Espectro Autista/diagnóstico , Estrés Oxidativo , Trastorno del Espectro Autista/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Masculino , Especies Reactivas de Oxígeno/sangre , Ubiquinona/análogos & derivados , Ubiquinona/sangreRESUMEN
Attention deficit hyperactive disorder (ADHD) is a highly heritable neurodevelopmental disorder, and excessive daytime sleepiness is frequently observed in ADHD patients. Excessive daytime sleepiness is also a core symptom of narcolepsy and essential hypersomnia (EHS), which are also heritable conditions. Psychostimulants are effective for the symptomatic control of ADHD (primary recommended intervention) and the two sleep disorders (frequent off-label use). However, the common biological mechanism for these disorders has not been well understood. Using a previously collected genome-wide association study of narcolepsy and EHS, we calculated polygenic risk scores (PRS) for each individual. We investigated a possible genetic association between ADHD and narcolepsy traits in the Hamamatsu Birth Cohort for mothers and children (HBC study) (n = 876). Gene-set enrichment analyses were used to identify common pathways underlying these disorders. Narcolepsy PRS were significantly associated with ADHD traits both in the hyperactivity domain (e.g., P-value threshold < 0.05, ß [SE], 5.815 [1.774]; P = 0.002) and inattention domain (e.g., P-value threshold < 0.05, ß [SE], 5.734 [1.761]; P = 0.004). However, EHS PRS was not significantly associated with either domain of ADHD traits. Gene-set enrichment analyses revealed that pathways related to dopaminergic signaling, immune systems, iron metabolism, and glial cell function involved in both ADHD and narcolepsy. Findings indicate that ADHD and narcolepsy are genetically related, and there are possible common underlying biological mechanisms for this relationship. Future studies replicating these findings would be warranted to elucidate the genetic vulnerability for daytime sleepiness in individuals with ADHD.
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Trastorno por Déficit de Atención con Hiperactividad , Narcolepsia , Trastorno por Déficit de Atención con Hiperactividad/genética , Niño , Antecedentes Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Narcolepsia/genética , Factores de RiesgoRESUMEN
BACKGROUND: Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation. METHODS: An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses. FINDINGS: Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children. INTERPRETATION: Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology. FUNDING: This study was supported mainly by MEXT, Japan.
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Trastorno del Espectro Autista/psicología , Dislipidemias/sangre , Ácidos Grasos/sangre , Lipidómica/métodos , Lipoproteínas VLDL/sangre , Adolescente , Apolipoproteína B-100/sangre , Trastorno del Espectro Autista/sangre , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Japón , Modelos Logísticos , Masculino , Metabolómica , Estrés Oxidativo , Interacción SocialRESUMEN
Importance: Autism spectrum disorder (ASD) is highly heritable, and modest contributions of common genetic variants to ASD have been reported. However, the association of genetic risks derived from common risk variants with ASD traits in children from the general population is not clear, and the association of these genetic risks with neurodevelopment in infants has not been well understood. Objective: To test whether a polygenic risk score (PRS) for ASD is associated with neurodevelopmental progress at age 18 months and ASD traits at age 6 years among children from the general population. Design, Setting, and Participants: In this cohort study, 876 children in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan, underwent testing for the association of an ASD PRS with neurodevelopmental progress and ASD traits. Data collection began in December 2007 and is ongoing. Data analysis was conducted from April to December 2019. Main Outcomes and Measures: Summary data from the largest genome-wide association study were used to generate ASD PRSs, and significance of thresholds was calculated for each outcome. The Autism Diagnostic Observation Schedule 2 was used to measure ASD traits at age 6 years, and the Mullen Scales of Early Learning was used to measure neurodevelopmental progress at age 18 months. Results: Of 876 participants (mean [SD] gestational age at birth, 38.9 [1.6] weeks; 438 [50.0%] boys; 868 [99.1%] Japanese), 734 were analyzed. The ASD PRS was associated with ASD traits (R2 = 0.024; ß, 0.71; SE, 0.24; P = .03). The association of ASD PRS with infant neurodevelopment was most pronounced in gross motor (R2 = 0.015; ß, -1.25; SE, 0.39; P = .01) and receptive language (R2 = 0.014; ß, -1.19; SE, 0.39; P = .02) scores on the Mullen Scales of Early Learning. Gene set enrichment analyses found that several pathways, such as cell maturation (R2 = 0.057; ß, -5.28; SE, 1.40; P < .001) and adenylyl cyclase activity and cyclic adenosine monophosphate concentration (R2 = 0.064; ß, -5.30; SE 1.30; P < .001), were associated with ASD traits. Gene sets associated with inflammation were commonly enriched with ASD traits and gross motor skills (eg, chemokine motif ligand 2 production: R2 = 0.051; ß, -6.04; SE, 1.75; P = .001; regulation of monocyte differentiation: R2 = 0.052; ß, -6.63; SE, 1.90; P = .001; and B-cell differentiation: R2 = 0.051; ß, 7.37; SE, 2.15; P = .001); glutamatergic signaling-associated gene sets were commonly enriched with ASD traits and receptive language skills (eg, regulation of glutamate secretion: R2 = 0.052; ß, -5.82; SE, 1.68; P = .001; ionotropic glutamate receptor signaling pathway: R2 = 0.047; ß, 3.54; SE, 1.09; P = .001; and negative regulation of glutamate secretion: R2 = 0.045; ß, -5.38; SE, 1.74; P = .002). Conclusions and Relevance: In this study, the ASD PRS was associated with ASD traits among children from the general population. Genetic risks for ASD might be associated with delays in some neurodevelopmental domains, such as gross motor and receptive language skills.
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Trastorno del Espectro Autista , Discapacidades del Desarrollo , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/genética , Niño , Estudios de Cohortes , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/genética , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Masculino , Polimorfismo de Nucleótido Simple/genética , Medición de RiesgoRESUMEN
BACKGROUND: Sensory processing difficulties, which commonly occur in autism spectrum disorder (ASD), are expected to have negative effects on the primary caregiver's mental health. The aim of this study was to examine the association between sensory processing difficulties in children with ASD and the mental health of primary caregivers. METHODS: A total of 707 primary caregivers (mothers in the present study) and their children with ASD (4-18â¯years of age) participated in this study. Sensory processing difficulties were indexed using the Short Sensory Profile (SSP). The mental health of primary caregivers was indexed using the General Health Questionnaire (GHQ12). RESULTS: Higher scores on Auditory Filtering as measured with the SSP were associated with poorer mental health of primary caregivers, even after an adjustment for ASD symptom severity. Analyses of two age sub-groups, a young (4-10â¯years) and an old age group (11-18â¯years), revealed that higher scores on Tactile Sensitivity and Auditory Filtering were associated with poorer mental health of primary caregivers in younger children, whereas only higher scores on Auditory Filtering were associated with poorer mental health of primary caregivers in older children. CONCLUSIONS: Our findings suggest that practitioners who support primary caregivers of children with ASD need to focus not only on the social and communication-related symptoms of the child but also on their specific sensory processing difficulties.
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Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/fisiopatología , Cuidadores/psicología , Adolescente , Adulto , Niño , Preescolar , Cognición/fisiología , Femenino , Humanos , Masculino , Salud Mental , Madres/psicología , Desempeño Psicomotor/fisiología , Sensación/fisiologíaRESUMEN
Involvement of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia pathogenesis through disrupted neurodevelopment has been highlighted in numerous studies. However, the function of common genetic variants of this system in determining schizophrenia risk is unknown. We therefore tested the association of 375 tagged SNPs in genes derived from the GABAergic system, such as GABAA receptor subunit genes, and GABA related genes (glutamate decarboxylase genes, GABAergic-marker gene, genes involved in GABA receptor trafficking and scaffolding) in Japanese schizophrenia case-control samples (n=2926; 1415 cases and 1511 controls). We observed nominal association of SNPs in nine GABAA receptor subunit genes and the GPHN gene with schizophrenia, although none survived correction for study-wide multiple testing. Two SNPs located in the GABRA1 gene, rs4263535 (Pallele=0.002; uncorrected) and rs1157122 (Pallele=0.006; uncorrected) showed top hits, followed by rs723432 (Pallele=0.007; uncorrected) in the GPHN gene. All three were significantly associated with schizophrenia and survived gene-wide multiple testing. Haplotypes containing associated variants in GABRA1 but not GPHN were significantly associated with schizophrenia. To conclude, we provided substantiating genetic evidence for the involvement of the GABAergic system in schizophrenia susceptibility. These results warrant further investigations to replicate the association of GABRA1 and GPHN with schizophrenia and to discern the precise mechanisms of disease pathophysiology.
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Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genética , Transducción de Señal/genética , Adulto , Anciano , Pueblo Asiatico , Femenino , Frecuencia de los Genes , Pruebas Genéticas , Glutamato Descarboxilasa/genética , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Receptores de GABA/genética , Esquizofrenia/metabolismo , Ácido gamma-Aminobutírico/genética , Ácido gamma-Aminobutírico/metabolismoRESUMEN
We investigated the potential relationship between maternal depressive symptoms during the postpartum period and non-verbal communication skills of infants at 14 months of age in a birth cohort study of 951 infants and assessed what factors may influence this association. Maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale, and non-verbal communication skills were measured using the MacArthur-Bates Communicative Development Inventories, which include Early Gestures and Later Gestures domains. Infants whose mothers had a high level of depressive symptoms (13+ points) during both the first month postpartum and at 10 weeks were approximately 0.5 standard deviations below normal in Early Gestures scores and 0.5-0.7 standard deviations below normal in Later Gestures scores. These associations were independent of potential explanations, such as maternal depression/anxiety prior to birth, breastfeeding practices, and recent depressive symptoms among mothers. These findings indicate that infants whose mothers have postpartum depressive symptoms may be at increased risk of experiencing delay in non-verbal development.
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Desarrollo Infantil , Depresión Posparto/psicología , Gestos , Relaciones Madre-Hijo/psicología , Madres/psicología , Comunicación no Verbal/psicología , Adolescente , Adulto , Lactancia Materna/psicología , Desarrollo Infantil/fisiología , Estudios de Cohortes , Depresión Posparto/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Comunicación no Verbal/fisiología , Periodo Posparto/psicología , Valor Predictivo de las Pruebas , Adulto JovenRESUMEN
BACKGROUND: Previous research has demonstrated that the season of birth may predict development of emotional and behavioral regulation during childhood or adolescence. This study examined whether the season of birth predicts effortful control (i.e., the ability to voluntarily choose course of actions during conflict and to plan for the future) and aggression (i.e., the use of physical force and expression of anger toward others) in 18-month-old infants. METHODS: Participants included 885 infants who were enrolled in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan. Seasons of birth were categorized into winter (December, January, and February), spring (March, April, and May), summer (June, July, and August), and autumn (September, October, and November). At 18 months of age, effortful control was assessed using the Early Childhood Behavior Questionnaire, and aggression was measured using the Cardiff Infant Contentiousness Scale. Structural equation modeling analysis with measurement and structural equations was conducted to test our prediction. RESULTS: Effortful control was higher in infants born in spring [B = 0.095, 95% CI (0.014 to 0.175), p = 0.021, ß = 0.146] and summer [B = 0.078, 95% CI (0.001 to 0.156), p = 0.049, ß = 0.118] than in those born in winter. In addition, aggression was lower in those born in spring [B = -0.286, 95% CI (-0.551 to -0.021), p = 0.035, ß = -0.135] than those born in winter, even after controlling for seven covariates. CONCLUSION: The findings suggest that season of birth may determine development of emotional and behavioral regulation skills during early infancy. Future research should pay more attention to the underlying mechanisms of the effects of birth season on development of emotional and behavioral regulation during infancy.
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OBJECTIVE: Neuroimaging studies of depression considered as a stress-related disorder have shown uncoupling in regional cerebral blood flow (rCBF) and regional cerebral metabolic rate for glucose (rCMRglc). We hypothesised that the mismatch change of rCBF and rCMRglc could be a stress-related phenomenon. METHODS: We exposed male rats to 15-min period of forced swim (FS), followed by the measurement of rCBF using N-isopropyl-4-[123I] iodoamphetamine (123I-IMP) and rCMRglc using 2-deoxy-2-[18F] fluoro-D-glucose (18F-FDG). RESULTS: The uptake rate of 18F-FDG in the FS group showed a significant decrease in the prefrontal cortex (0.86±0.20%ID/g, p<0.01) and thalamus (0.77±0.17%ID/g, p<0.05) and tended to be lower in the hippocampus (0.58±0.13%ID/g) and cerebellum (0.59±0.13%ID/g) without overt alteration in the uptake rate of 123I-IMP. CONCLUSIONS: The FS stress can cause mismatch change of rCBF and rCMRglc, which reflect a stress-related phenomenon.
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Encéfalo/metabolismo , Circulación Cerebrovascular , Glucosa/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Animales , Encéfalo/irrigación sanguínea , Masculino , Ratas , Ratas Sprague-Dawley , NataciónAsunto(s)
Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/psicología , Relaciones Madre-Hijo , Mujeres Embarazadas/psicología , Adulto , Desarrollo Infantil , Preescolar , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Japón , Masculino , Escalas de Valoración Psiquiátrica , Proyectos de Investigación , Factores de TiempoRESUMEN
The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology.
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Trastorno del Espectro Autista/genética , Proteínas de Transporte de Ácidos Grasos/genética , Ácidos Grasos/metabolismo , Estudios de Asociación Genética , Secuencia de Aminoácidos/genética , Animales , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/patología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Proteínas de Transporte de Ácidos Grasos/biosíntesis , Ácidos Grasos/genética , Femenino , Humanos , Masculino , Ratones , Mutación , Células-Madre Neurales/metabolismo , Conformación Proteica , Análisis de Secuencia de ADNAsunto(s)
Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Trastorno Bipolar/complicaciones , Resistencia a Medicamentos/efectos de los fármacos , Trastornos del Movimiento/tratamiento farmacológico , Piperazinas/uso terapéutico , Quinolonas/uso terapéutico , Adulto , Aripiprazol , Trastorno Bipolar/tratamiento farmacológico , Humanos , Masculino , Trastornos del Movimiento/complicacionesRESUMEN
BACKGROUND: Accumulating evidence suggests that dysregulation of the immune system is involved in the pathophysiology of autism spectrum disorders (ASD). The aim of the study was to explore immunological markers in peripheral plasma samples from non-medicated subjects with high-functioning ASD. METHODOLOGY/PRINCIPAL FINDINGS: A multiplex assay for cytokines and chemokines was applied to plasma samples from male subjects with high-functioning ASD (nâ=â28) and matched controls (nâ=â28). Among a total of 48 analytes examined, the plasma concentrations of IL-1ß, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17 and GRO-α were significantly higher in subjects with ASD compared with the corresponding values of matched controls after correction for multiple comparisons. CONCLUSION/SIGNIFICANCE: The results suggest that abnormal immune responses as assessed by multiplex analysis of cytokines may serve as one of the biological trait markers for ASD.