Pubmed du 15/10/14

Pubmed du jour

2014-10-15 12:03:50

1. Bowton E, Saunders C, Reddy IA, Campbell NG, Hamilton PJ, Henry LK, Coon H, Sakrikar D, Veenstra-VanderWeele JM, Blakely RD, Sutcliffe J, Matthies HJ, Erreger K, Galli A. {{SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking}}. {Transl Psychiatry};2014;4:e464.

Emerging evidence associates dysfunction in the dopamine (DA) transporter (DAT) with the pathophysiology of autism spectrum disorder (ASD). The human DAT (hDAT; SLC6A3) rare variant with an Ala to Val substitution at amino acid 559 (hDAT A559V) was previously reported in individuals with bipolar disorder or attention-deficit hyperactivity disorder (ADHD). We have demonstrated that this variant is hyper-phosphorylated at the amino (N)-terminal serine (Ser) residues and promotes an anomalous DA efflux phenotype. Here, we report the novel identification of hDAT A559V in two unrelated ASD subjects and provide the first mechanistic description of its impaired trafficking phenotype. DAT surface expression is dynamically regulated by DAT substrates including the psychostimulant amphetamine (AMPH), which causes hDAT trafficking away from the plasma membrane. The integrity of DAT trafficking directly impacts DA transport capacity and therefore dopaminergic neurotransmission. Here, we show that hDAT A559V is resistant to AMPH-induced cell surface redistribution. This unique trafficking phenotype is conferred by altered protein kinase C beta (PKCbeta) activity. Cells expressing hDAT A559V exhibit constitutively elevated PKCbeta activity, inhibition of which restores the AMPH-induced hDAT A559V membrane redistribution. Mechanistically, we link the inability of hDAT A559V to traffic in response to AMPH to the phosphorylation of the five most distal DAT N-terminal Ser. Mutation of these N-terminal Ser to Ala restores AMPH-induced trafficking. Furthermore, hDAT A559V has a diminished ability to transport AMPH, and therefore lacks AMPH-induced DA efflux. Pharmacological inhibition of PKCbeta or Ser to Ala substitution in the hDAT A559V background restores AMPH-induced DA efflux while promoting intracellular AMPH accumulation. Although hDAT A559V is a rare variant, it has been found in multiple probands with neuropsychiatric disorders associated with imbalances in DA neurotransmission, including ADHD, bipolar disorder, and now ASD. These findings provide valuable insight into a new cellular phenotype (altered hDAT trafficking) supporting dysregulated DA function in these disorders. They also provide a novel potential target (PKCbeta) for therapeutic interventions in individuals with ASD.

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2. Ditzian K, Wilder DA, King A, Tanz J. {{An evaluation of the performance diagnostic checklist-human services to assess an employee performance problem in a center-based autism treatment facility}}. {J Appl Behav Anal};2014 (Oct 14)
The Performance Diagnostic Checklist-Human Services (PDC-HS) is an informant-based tool designed to assess the environmental variables that contribute to poor employee performance in human services settings. We administered the PDC-HS to 3 supervisors to assess the variables that contributed to poor performance by 4 staff members when securing clients in therapy rooms at a treatment center for children with autism. The PDC-HS identified a lack of appropriate consequences as contributing to poor staff performance. We then evaluated a PDC-HS-indicated intervention as well as an intervention not suggested by PDC-HS results. The PDC-HS-indicated intervention (graphed feedback) was effective to increase performance; the non-PDC-HS-based intervention was ineffective.

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3. Fisher WW, Pawich TL, Dickes N, Paden AR, Toussaint K. {{Increasing the saliency of behavior-consequence relations for children with autism who exhibit persistent errors}}. {J Appl Behav Anal};2014 (Oct 14)
Some children with autism spectrum disorders (ASD) display persistent errors that are not responsive to commonly used prompting or error-correction strategies; one possible reason for this is that the behavior-consequence relations are not readily discriminable (Davison & Nevin, 1999). In this study, we increased the discriminability of the behavior-consequence relations in conditional-discrimination acquisition tasks for 3 children with ASD using schedule manipulations in concert with a unique visual display designed to increase the saliency of the differences between consequences in effect for correct responding and for errors. A multiple baseline design across participants was used to show that correct responding increased for all participants, and, after 1 or more exposures to the intervention, correct responding persisted to varying degrees across participants when the differential reinforcement baseline was reintroduced to assess maintenance. These findings suggest that increasing the saliency of behavior-consequence relations may help to increase correct responding in children with ASD who exhibit persistent errors.

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4. Goldman S, DeNigris D. {{Parents’ Strategies to Elicit Autobiographical Memories in Autism Spectrum Disorders, Developmental Language Disorders and Typically Developing Children}}. {J Autism Dev Disord};2014 (Oct 14)
Conversations about the past support the development of autobiographical memory. Parents’ strategies to elicit child’s participation and recall during past event conversations were compared across three school-age diagnostic groups: autism spectrum disorder (ASD, n = 11), developmental language disorders (n = 11) and typically developing (TD, n = 11). We focused on the prevalence of directives versus enrichment of events. Groups did not differ in number of events, length, and total turns. However, parents of children with ASD produced more direct questions, corrections, and unrelated turns than parents of TD children. Results highlight how parents adjusted their conversational style to their child’s communication difficulties to maximize interactions and how these strategies may affect the development of personal conversations.

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5. Gunby KV, Rapp JT. {{The use of behavioral skills training and in situ feedback to protect children with autism from abduction lures}}. {J Appl Behav Anal};2014 (Oct 13)
We examined the effects of behavioral skills training with in situ feedback on safe responding by children with autism to abduction lures that were presented after a high-probability (high-p) request sequence. This sequence was intended to simulate a grooming or recruitment process. Results show that all 3 participants ultimately acquired the safety response to abduction lures presented after a high-p sequence and maintained the safety response at a 1-month follow-up.

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6. Irwin J, Preston J, Brancazio L, D’Angelo M, Turcios J. {{Development of an audiovisual speech perception app for children with autism spectrum disorders}}. {Clin Linguist Phon};2014 (Oct 14):1-8.

Abstract Perception of spoken language requires attention to acoustic as well as visible phonetic information. This article reviews the known differences in audiovisual speech perception in children with autism spectrum disorders (ASD) and specifies the need for interventions that address this construct. Elements of an audiovisual training program are described. This researcher-developed program delivered via an iPad app presents natural speech in the context of increasing noise, but supported with a speaking face. Children are cued to attend to visible articulatory information to assist in perception of the spoken words. Data from four children with ASD ages 8-10 are presented showing that the children improved their performance on an untrained auditory speech-in-noise task.

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7. Kao YC, Kramer JM, Liljenquist K, Coster WJ. {{Association between impairment, function, and daily life task management in children and adolescents with autism}}. {Dev Med Child Neurol};2014 (Oct 14)
AIM: This cross-sectional study examined whether impairments or functional skills are associated with the level of responsibility for life tasks for children and adolescents with autism spectrum disorders (ASDs). METHOD: Parents of 263 children and adolescents with ASDs (215 males; 48 females; mean age 12y 6mo [SD 4y 6mo], range 3-21y) completed an online survey that included the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test – Autism Spectrum Disorders (PEDI-CAT-ASD) Daily Activities, Social/Cognitive, and Responsibility domains, a demographic questionnaire, and the Social Communication Questionnaire (SCQ) Current. The International Classification of Functioning, Disability and Health Framework guided the selection of model variables. We used hierarchical multiple regression to examine the relationship between impairment and functional skill predictor variables and the outcome variable, Responsibility. Age was entered in step 1 to control for the impact of development. SCQ Current, IQ, and remaining PEDI-CAT-ASD domains were then entered in step 2. RESULTS: After controlling for age, the model showed that step 2 predictor variables representing both impairments and functional skill improved the model (p<0.001). All variables except the SCQ score were significant predictors of Responsibility. The variance explained by the Daily Activities (2.7%) and Social/Cognitive (4.8%) domain scores was greater than IQ (0.3%). INTERPRETATION: The functional skills of Daily Activities and Social/Cognitive domains were more strongly associated with the management of life tasks than impairments after controlling for age.

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8. Lawson RA, Papadakis AA, Higginson CI, Barnett JE, Wills MC, Strang JF, Wallace GL, Kenworthy L. {{Everyday Executive Function Impairments Predict Comorbid Psychopathology in Autism Spectrum and Attention Deficit Hyperactivity Disorders}}. {Neuropsychology};2014 (Oct 13)
Objective: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) both have psychiatric comorbidities and distinctive profiles of executive dysfunction. Although there is evidence that executive function (EF) plays a role in the expression of specific behaviors and psychiatric symptoms, it is not known whether specific EF deficits in ASD and ADHD may be pathways to comorbidities in the disorders. This study examines whether parent reported problems with flexibility in ASD and inhibition in ADHD mediate the disorders’ associations with anxiety/depression and oppositional/aggressive behavior, respectively. Method: Parent report data from the Behavior Rating Inventory of Executive Function (BRIEF) and the Child Behavior Checklist (CBCL) were obtained for 125 children (70 ASD, 55 ADHD Hyperactive/Impulsive or Combined type) as part of a neuropsychological assessment. Diagnostic status, BRIEF Shift (shifting/flexibility) and Inhibit (behavioral inhibition) scale scores, and CBCL Anxious/Depressed (anxiety/depression) and Aggressive Behavior (oppositionality/aggression) scale scores were analyzed with a path analysis to investigate the relation of flexibility and inhibition to comorbid symptoms in children with ASD and ADHD. Results: In a path model with good fit ASD predicted greater inflexibility which predicted greater anxiety/depression, while ADHD predicted greater disinhibition that predicted greater aggression, consistent with our mediational hypotheses. Unexpectedly, the greater inflexibility associated with ASD also predicted greater aggression. Conclusions: Findings support the importance of everyday EF problems in ASD and ADHD as predictors of comorbid psychopathology and as crucial intervention targets for potential prevention and mitigation of comorbid symptoms. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

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9. Miller M, Young GS, Hutman T, Johnson S, Schwichtenberg AJ, Ozonoff S. {{Early pragmatic language difficulties in siblings of children with autism: implications for DSM-5 social communication disorder?}}. {J Child Psychol Psychiatry};2014 (Oct 15)
BACKGROUND: We evaluated early pragmatic language skills in preschool-age siblings of children with autism spectrum disorder (ASD), and examined correspondence between pragmatic language impairments and general language difficulties, autism symptomatology, and clinical outcomes. METHODS: Participants were younger siblings of children with ASD (high-risk, n = 188) or typical development (low-risk, n = 119) who were part of a prospective study of infants at risk for ASD; siblings without ASD outcomes were included in analyses. Pragmatic language skills were measured via the Language Use Inventory (LUI). RESULTS: At 36 months, the high-risk group had significantly lower parent-rated pragmatic language scores than the low-risk group. When defining pragmatic language impairment (PLI) as scores below the 10th percentile on the LUI, 35% of the high-risk group was identified with PLI versus 10% of the low-risk group. Children with PLI had higher rates of general language impairment (16%), defined as scores below the 10th percentile on the Receptive or Expressive Language subscales of the Mullen Scales of Early Learning, relative to those without PLI (3%), but most did not evidence general language impairments. Children with PLI had significantly higher ADOS scores than those without PLI and had higher rates of clinician-rated atypical clinical best estimate outcomes (49%) relative to those without PLI (15%). CONCLUSIONS: Pragmatic language problems are present in some siblings of children with ASD as early as 36 months of age. As the new DSM-5 diagnosis of Social (Pragmatic) Communication Disorder (SCD) is thought to occur more frequently in family members of individuals with ASD, it is possible that some of these siblings will meet criteria for SCD as they get older. Close monitoring of early pragmatic language development in young children at familial risk for ASD is warranted.

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10. Singh K, Connors SL, Macklin EA, Smith KD, Fahey JW, Talalay P, Zimmerman AW. {{Sulforaphane treatment of autism spectrum disorder (ASD)}}. {Proc Natl Acad Sci U S A};2014 (Oct 13)
Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13-27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)-derived from broccoli sprout extracts-or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50-150 micromol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015-0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.

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11. Tsilioni I, Dodman N, Petra AI, Taliou A, Francis K, Moon-Fanelli A, Shuster L, Theoharides TC. {{Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism}}. {Transl Psychiatry};2014;4:e466.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by defects in communication and social interactions, as well as stereotypic behaviors. Symptoms typically worsen with anxiety and stress. ASD occur in early childhood, often present with regression and have a prevalence of 1 out of 68 children. The lack of distinct pathogenesis or any objective biomarkers or reliable animal models hampers our understanding and treatment of ASD. Neurotensin (NT) and corticotropin-releasing hormone (CRH) are secreted under stress in various tissues, and have proinflammatory actions. We had previously shown that NT augments the ability of CRH to increase mast cell (MC)-dependent skin vascular permeability in rodents. CRH also induced NT receptor gene and protein expression in MCs, which have been implicated in ASD. Here we report that serum of ASD children (4-10 years old) has significantly higher NT and CRH levels as compared with normotypic controls. Moreover, there is a statistically significant correlation between the number of children with gastrointestinal symptoms and high serum NT levels. In Bull Terriers that exhibit a behavioral phenotype similar to the clinical presentation of ASD, NT and CRH levels are also significantly elevated, as compared with unaffected dogs of the same breed. Further investigation of serum NT and CRH, as well as characterization of this putative canine breed could provide useful insights into the pathogenesis, diagnosis and treatment of ASD.

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12. Tudor ME, Lerner MD. {{Intervention and Support for Siblings of Youth with Developmental Disabilities: A Systematic Review}}. {Clin Child Fam Psychol Rev};2014 (Oct 15)
Both the population of siblings of youth with developmental disabilities (DDs) and the popularity of clinical services designed for these youth are on the rise. However, the research base for such services has yet to be evaluated. A systematic review of studies on intervention and support for siblings of youth with DDs was conducted in order to evaluate the current state of the literature and provide recommendations for research and practice. Sixteen articles were selected and reviewed in terms of their experimental design, participant characteristics, measurement, intervention or support group protocol, outcomes, and dissemination of findings. Results indicate substantial variability in both methodology and outcomes across sibling-focused intervention and support group studies, which put the overall effects and utility of these services into question. Recommendations for future research are outlined, with a focus on advancing a more systematic and careful approach to asking and effectively answering questions about siblings, their families, and meaningful services for both.

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13. Whiteley P. {{Nutritional management of (some) autism: a case for gluten- and casein-free diets?}}. {Proc Nutr Soc};2014 (Oct 14):1-6.

Autism spectrum disorders represent a diverse and heterogeneous array of conditions unified by the variable presence of specific behaviours impacting social and communicative functions (social affect) alongside other presentation. Common overt characteristics may come about as a consequence of several different genetic and biological processes differentially manifesting across different people or groups. The concept of plural ‘autisms’ is evolving, strengthened by an increasingly important evidence base detailing different developmental trajectories across the autism spectrum and the appearance of comorbidity variably interacting with core symptoms and onwards influencing quality of life. Reports that dietary intervention, specifically the removal of foods containing gluten and/or casein from the diet, may impact on the presentation of autism for some, complement this plural view of autism. Evidence suggestive of differing responses to the use of a gluten- and casein-free diet, defined as best- and non-response, has combined with some progress on determining the underlying genetic and biological correlates potentially related to such dietary elements. The preliminary suggestion of a possible diet-related autism phenotype is the result. This review will highlight several pertinent aspects onwards to an effect of food in some cases of autism including research on the pharmacological activity of food metabolites, immune response, issues with gut barrier function and some contribution from the gut microbiota. These represent promising areas in need of far greater research inspection in order to potentially define such a diet-related subgroup on the autism spectrum.

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14. Wong JD, Mailick MR, Greenberg JS, Hong J, Coe CL. {{Daily Work Stress and Awakening Cortisol in Mothers of Individuals with Autism Spectrum Disorders or Fragile X Syndrome}}. {Fam Relat};2014 (Feb);63(1):135-147.

The effect of daily work stress on the next morning’s awakening cortisol level was determined in a sample of 124 mothers (M age = 49.89, SD= 6.33) of adolescents and adults with developmental disabilities and compared to 115 mothers (M age = 46.19, SD = 7.08) of individuals without disabilities. Mothers participated in 8 days of diary telephone interviews and provided saliva samples. Multilevel models revealed that mothers of individuals with developmental disabilities had lower awakening cortisol levels than comparison mothers. Work stress interacted with parental status to predict the awakening cortisol level on the following morning. When mothers of individuals with developmental disabilities experienced a work stressor, their awakening cortisol level was significantly higher on the subsequent morning, but for comparison mothers, work stressors were not significantly associated with cortisol level. Findings extend understanding of the differential impacts of specific types of stressors on physiological functioning of mothers of individuals with and without developmental disabilities.

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15. Woods AG, Wormwood KL, Wetie AG, Aslebagh R, Crimmins BS, Holsen TM, Darie CC. {{Autism spectrum disorder: An omics perspective}}. {Proteomics Clin Appl};2014 (Oct 14)
Current directions in autism spectrum disorder (ASD) research may require moving beyond genetic analysis alone, based on the complexity of the disorder, heterogeneity and convergence of genetic alterations at the cellular/functional level. Mass spectrometry (MS) has been increasingly used to study central nervous system (CNS) disorders, including ASDs. Proteomic research using MS is directed at understanding endogenous protein changes that occur in ASD. This review focuses on how MS has been used to study ASDs, with particular focus on proteomic analysis. Other neurodevelopmental disorders have been investigated using MS, including fragile X syndrome (FXS) and Smith-Lemli-Opitz Syndrome (SLOS), genetic syndromes highly associated with ASD comorbidity. This article is protected by copyright. All rights reserved.

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16. Yasui DH, Gonzales ML, Aflatooni JO, Crary FK, Hu DJ, Gavino BJ, Golub MS, Vincent JB, Schanen NC, Olson CO, Rastegar M, Lasalle JM. {{Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome}}. {Hum Mol Genet};2014 (Oct 13)

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17. Zwaigenbaum L. {{Congenital anomalies and etiological diversity in autism}}. {Dev Med Child Neurol};2014 (Oct 14)

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