1. {{Correction to Supporting Information for Gadad et al., Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology}}. {Proc Natl Acad Sci U S A};2015 (Dec 8);112(49):E6827.
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2. Bhattacharyya A, Zhao X. {{Human pluripotent stem cell models of Fragile X syndrome}}. {Mol Cell Neurosci};2015 (Nov 27)
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. The causal mutation in FXS is a trinucleotide CGG repeat expansion in the FMR1 gene that leads to human specific epigenetic silencing and loss of Fragile X Mental Retardation Protein (FMRP) expression. Human pluripotent stem cells (PSCs), including human embryonic stem cells (ESCs) and particularly induced PSCs (iPSCs), offer a model system to reveal cellular and molecular events underlying human neuronal development and function in FXS. Human FXS PSCs have been established and have provided insight into the epigenetic silencing of the FMR1 gene as well as aspects of neuronal development.
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3. Brown K, Selfridge J, Lagger S, Connelly J, De Sousa D, Kerr A, Webb S, Guy J, Merusi C, Koerner MV, Bird A. {{The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome}}. {Hum Mol Genet};2015 (Dec 8)
Rett syndrome is caused by mutations in the X-linked MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Mouse models mirror the human disorder and therefore allow investigation of phenotypes at a molecular level. We describe an Mecp2 allelic series representing the three most common missense RTT mutations, including first reports of Mecp2[R133C] and Mecp2[T158M] knock-in mice, in addition to Mecp2[R306C] mutant mice. Together these three alleles comprise approximately 25% of all RTT mutations in humans, but they vary significantly in average severity. This spectrum is mimicked in the mouse models; R133C being least severe, T158M most severe and R306C of intermediate severity. Both R133C and T158M mutations cause compound phenotypes at the molecular level, combining compromised DNA binding with reduced stability, the destabilising effect of T158M being more severe. Our findings contradict the hypothesis that the R133C mutation exclusively abolishes binding to hydroxymethylated DNA, as interactions with DNA containing methyl-CG, methyl-CA and hydroxymethyl-CA are all reduced in vivo. We find that MeCP2[T158M] is significantly less stable than MeCP2[R133C], which may account the divergent clinical impact of the mutations. Overall this allelic series recapitulates human RTT severity, reveals compound molecular aetiologies, and provides a valuable resource in the search for personalised therapeutic interventions.
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4. Calman N, Little V, Garozzo S. {{Electronic Health Records: Optimizing Communication to Support the Nonverbal Medical Patient With Developmental Disabilities}}. {Prog Community Health Partnersh};2015;9(4):591-594.
BACKGROUND: A comprehensive look at health status in developmentally disabled populations shows poorer physical, oral, and vision health, and higher rates of heart disease and obesity. Generally, individuals with developmental disabilities have difficulty locating able providers, and face significant barriers in accessing health services. The health care system’s failure to achieve effective collaboration between medical, mental health, and residential providers too often results in substandard care and poor outcomes for these populations. METHODS: A creative partnership between two organizations in rural upstate New York, Ulster Green ARC and the Institute for Family Health, has made substantial inroads toward addressing this problem. The organizations have transformed a relationship borne of a financially failing health care model into a successful, comprehensive care network for a severely developmentally disabled population-based in a Federally Qualified Health Center. CONCLUSIONS: The success of this effort is largely owing to an innovative use of health information technology to share information.
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5. Cheng XP, Zhao J, Chen Y, Meng FK, Xu B, Yu HW, Meng QH, Liu YM, Zhang SB, Meng S, Zhang JY, Duan ZP, Zheng SJ. {{Comparison of the ability of the PDD-ICG clearance test, CTP, MELD, and MELD-Na to predict short-term and medium-term mortality in patients with decompensated hepatitis B cirrhosis}}. {Eur J Gastroenterol Hepatol};2015 (Dec 8)
OBJECTIVE: Various methods, including the indocyanine green (ICG) clearance test, the Child-Turcotte-Pugh score (CTP), model for end-stage liver disease (MELD), and MELD combined with serum sodium concentration (MELD-Na), have been used widely in liver function evaluation in patients with end-stage liver disease. In this study, we compared the ability of these methods to predict mortality in patients with decompensated hepatitis B cirrhosis. METHODS: A total of 98 patients with decompensated hepatitis B cirrhosis were included in this study and followed up for 12 months. The ICG-derived measurements (ICG-PDR, ICG-R15, EHBF), CTP, MELD, and MELD-Na were obtained within 2 days after patients’ admission and patients’ survival at 1, 3, 6, and 12 months was recorded. Receiver operating curve was used to evaluate the ability of these methods to predict mortality in these patients with decompensated hepatitis B cirrhosis. RESULTS: At 1 month, 3 months, 6 months and 12 months, the cumulative number of deaths and liver transplant recipients was 12 (12.2%), 17 (17.3%), 21 (21.4%) and 25 (25.5%), respectively. The ICG-derived measurements, CTP, MELD, and MELD-Na of nonsurvivors were significantly different compared with that in survivors. All methods yielded viable values in predicting short-term and medium-term prognosis for patients with decompensated hepatitis B cirrhosis, with most area under the curve exceeding 0.8. Moreover, the ICG-derived measurements showed a significant correlation with that of CTP, MELD, and MELD-Na. CONCLUSION: All four methods, ICG clearance test, CTP, MELD, and MELD-Na, provided reliable prediction of mortality in patients with decompensated hepatitis B cirrhosis for both short-term and medium-term prognosis.
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6. D’Gama AM, Pochareddy S, Li M, Jamuar SS, Reiff RE, Lam AT, Sestan N, Walsh CA. {{Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms}}. {Neuron};2015 (Dec 2);88(5):910-917.
Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss-of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis.
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7. Gao J, Wang X, Sun H, Cao Y, Liang S, Wang H, Wang Y, Yang F, Zhang F, Wu L. {{Neuroprotective effects of docosahexaenoic acid on hippocampal cell death and learning and memory impairments in a valproic acid-induced rat autism model}}. {Int J Dev Neurosci};2015 (Nov 27)
Prenatal exposure to valproic acid (VPA) in rat offspring is capable of inducing experimental autism with neurobehavioral aberrations. This study investigated the effect of docosahexaenoic acid (DHA) on hippocampal cell death, learning and memory alteration in an experimental rat autism model. We found that DHA supplementation (75, 150 or 300mg/kg/day, 21 days) rescued the VPA (600mg/kg) induced DHA reduction in plasma and hippocampus in a dose-dependent manner, increased the levels of hippocampal p-CaMKII and p-CREB without affecting total protein level, and altered BDNF-AKT-Bcl-2 signaling pathway, as well as inhibited the activity of caspase-3. DHA also influenced the content of malondialdehyde (MDA) and the activities of antioxidant enzymes in the VPA-treated offspring. Consistent with the previous results, we also observed that 300mg/kg DHA supplementation markedly increased the cell survival, decreased the cell apoptosis, and increased mature neuronal cell in the hippocampus in VPA-treated offspring. Utilizing the Morris water maze test, we found that DHA prevented cognitive impairment in offspring of VPA-treated rats. The data suggested that DHA may play a neuroprotective role in hippocampal neuronal cell and ameliorates dysfunctions in learning and memory in this rat autism model. Thus, DHA could be used as treatment intervention for mitigating behavioral dysfunctions in autism spectrum disorder (ASD).
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8. Gevarter C, O’Reilly MF, Kuhn M, Mills K, Ferguson R, Watkins L, Sigafoos J, Lang R, Rojeski L, Lancioni GE. {{Increasing the vocalizations of individuals with autism during intervention with a speech-generating device}}. {J Appl Behav Anal};2015 (Dec 6)
This study aimed to teach individuals with autism spectrum disorder (ASD) and limited vocal speech to emit target vocalizations while using a speech-generating device (SGD). Of the 4 participants, 3 began emitting vocal word approximations with SGD responses after vocal instructional methods (delays, differential reinforcement, prompting) were introduced. Two participants met mastery criterion with a reinforcer delay and differential reinforcement, and 1 met criterion after fading an echoic model and prompt delay. For these participants, vocalizations initiated before speech outputs were shown to increase, and vocalizations generalized to a context in which the SGD was absent. The 4th participant showed high vocalization rates only when prompted. The results suggest that adding vocal instruction to an SGD-based intervention can increase vocalizations emitted along with SGD responses for some individuals with ASD.
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9. Gliga T, Smith TJ, Likely N, Charman T, Johnson MH. {{Early Visual Foraging in Relationship to Familial Risk for Autism and Hyperactivity/Inattention}}. {J Atten Disord};2015 (Dec 4)
OBJECTIVE: Information foraging is atypical in both autism spectrum disorders (ASDs) and ADHD; however, while ASD is associated with restricted exploration and preference for sameness, ADHD is characterized by hyperactivity and increased novelty seeking. Here, we ask whether similar biases are present in visual foraging in younger siblings of children with a diagnosis of ASD with or without additional high levels of hyperactivity and inattention. METHOD: Fifty-four low-risk controls (LR) and 50 high-risk siblings (HR) took part in an eye-tracking study at 8 and 14 months and at 3 years of age. RESULTS: At 8 months, siblings of children with ASD and low levels of hyperactivity/inattention (HR/ASD-HI) were more likely to return to previously visited areas in the visual scene than were LR and siblings of children with ASD and high levels of hyperactivity/inattention (HR/ASD+HI). CONCLUSION: We show that visual foraging is atypical in infants at-risk for ASD. We also reveal a paradoxical effect, in that additional family risk for ADHD core symptoms mitigates the effect of ASD risk on visual information foraging.
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10. Kitzerow J, Teufel K, Wilker C, Freitag CM. {{Using the brief observation of social communication change (BOSCC) to measure autism-specific development}}. {Autism Res};2015 (Dec 8)
To date no reliable and objective, change sensitive instrument for autistic symptoms is available. The brief observation of social communication change (BOSCC) was specifically developed to measure change of core autistic symptoms, for example, for use as outcome measure in early intervention trials. This study investigated quality criteria of a preliminary research version of the BOSCC in N = 21 children with autism spectrum disorder (ASD) who had participated for 1 year in the Frankfurt early intervention program (FFIP). BOSCC rating was done on play based ADOS video scenes. Inter-rater agreement on the BOSCC average total was very high. The BOSCC showed a significant decrease of autistic symptoms after 1 year with a medium effect size. Symptom specific improvements were captured by the social communication subscale and most single items. The BOSCC showed comparable change sensitivity to other autism specific instruments. Future studies should focus on the finalized BOSCC version, and replicate findings in a larger sample. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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11. Knutsen J, Mandell DS, Frye D. {{Children with autism are impaired in the understanding of teaching}}. {Dev Sci};2015 (Dec 8)
Children learn novel information using various methods, and one of the most common is human pedagogical communication or teaching – the purposeful imparting of information from one person to another. Neuro-typically developing (TD) children gain the ability to recognize and understand teaching as a core method for acquiring knowledge from others. However, it is not known when children with Autism Spectrum Disorder (ASD) acquire the ability to recognize and understand teaching. This study (total N = 70) examined whether children with ASD recognize the two central elements that define teaching: (1) that teaching is an intentional activity; and (2) that teaching requires a knowledge difference between teacher and learner. Theory of mind understanding was also tested. Compared to individually matched TD children, high cognitively functioning children with ASD were impaired in their comprehension of both components of teaching understanding, and their performance was correlated with theory of mind understanding. These findings could have broad implications for explaining learning in children with autism, and could help in designing more effective interventions, which could ultimately lead to improved learning outcomes for everyday life skills, school performance, health, and overall well-being.
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12. Kosidou K, Dalman C, Widman L, Arver S, Lee BK, Magnusson C, Gardner RM. {{Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden}}. {Mol Psychiatry};2015 (Dec 8)
Although many studies indicate the interplay of genetic and environmental factors in the etiology of autism spectrum disorder (ASD), our limited understanding of the underlying mechanisms hampers the development of effective ways of detecting and preventing the disorder. Recent studies support the hypothesis that prenatal androgen exposure contributes to the development of ASD. This would suggest that maternal polycystic ovary syndrome (PCOS), a condition associated with excess androgens, would increase the risk of ASD in the offspring. We conducted a matched case-control study nested within the total population of Sweden (children aged 4-17 who were born in Sweden from 1984 to 2007). The sample consisted of 23 748 ASD cases and 208 796 controls, matched by birth month and year, sex and region of birth. PCOS and ASD were defined from ICD codes through linkage to health-care registers. Maternal PCOS increased the odds of ASD in the offspring by 59%, after adjustment for confounders (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.34-1.88). The odds of offspring ASD were further increased among mothers with both PCOS and obesity, a condition common to PCOS that is related to more severe hyperandrogenemia (OR 2.13, 95% CI 1.46-3.10). Risk estimates did not differ between sexes. In conclusion, children of women with PCOS appear to have a higher risk of developing ASD. This finding awaits confirmation, and exploration of potentially underlying mechanisms, including the role of sex steroids in the etiology of ASD.Molecular Psychiatry advance online publication, 8 December 2015; doi:10.1038/mp.2015.183.
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13. Thomas S, Lycett K, Papadopoulos N, Sciberras E, Rinehart N. {{Exploring Behavioral Sleep Problems in Children With ADHD and Comorbid Autism Spectrum Disorder}}. {J Atten Disord};2015 (Dec 4)
OBJECTIVE: This study (a) compared behavioral sleep problems in children with comorbid ADHD and autism spectrum disorder (ASD) with those with ADHD and (b) examined child/family factors associated with sleep problems. METHOD: Cross-sectional study comparison of 392 children with a confirmed ADHD diagnosis (ADHD+ASD, n=93, ADHD, n=299) recruited from 21 peadiatric practises in Victoria, Australia. Data were collected from parents. Key measures included the Child Sleep Habits Questionnaire (CSHQ). RESULTS: Children with ADHD + ASD experienced similar levels and types of behavioral sleep problems compared with those with ADHD. In both groups, the presence of co-occurring internalizing and externalizing comorbidities was associated with sleep problems. Sleep problems were also associated with parent age in the ADHD + ASD group and poorer parent mental health in the ADHD group. CONCLUSION: Findings suggest comorbid ASD is not associated with increased behavioral sleep problems in children with ADHD and that co-occurring internalizing and externalizing comorbidities may flag children in these groups with sleep problems.
