1. Ben-David E, Shohat S, Shifman S. {{Allelic expression analysis in the brain suggests a role for heterogeneous insults affecting epigenetic processes in autism spectrum disorders}}. {Hum Mol Genet}. 2014.
Monoallelic expression, including genomic imprinting, X-chromosome inactivation and random monoallelic expression of autosomal genes are epigenetic phenomena. Genes that are expressed in a monoallelic way may be more vulnerable to genetic or epigenetic mutations. Thus, comprehensive exploration of monoallelic expression in human brains may shed light on complex brain disorders. Autism-related disorders are known to be associated with imprinted genes on chromosome 15. However, it is not clear if other imprinted regions or other types of monoallelic expression are associated with autism spectrum disorder (ASD). Here, we performed a genome-wide survey of allele expression imbalance (AEI) in the human brain using single nucleotide polymorphisms (SNPs), in 18 individuals with ASD and 15 controls. Individuals with ASD had the most extreme number of monoallelic expressed SNPs in both the autosomes and the X chromosome. In two cases that were studied in detail the monoallelic expression was confined to specific brain region or cell type. Using these data we were also able to define the allelic expression status of known imprinted genes in the human brain, and to identify abnormal imprinting in an individual with ASD. Lastly, we developed an analysis of individual level expression, focusing on the difference of each individual from the mean. We found that individuals with ASD had more genes that were up or down-regulated in an individual-specific manner. We also identified pathways perturbed in specific individuals. These results underline the heterogeneity in gene regulation in ASD, at the level of both allelic and total expression.
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2. Chen J, Alberts I, Li X. {{Dysregulation of the IGF-I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders}}. {Int J Dev Neurosci}. 2014.
The IGF-I/PI3K/AKT/mTOR signaling pathway plays an important role in the regulation of cell growth, proliferation, differentiation, motility, survival, metabolism and protein synthesis. Insulin-like growth factor-I (IGF-I) is synthesized in the liver and fibroblasts, and its biological actions are mediated by the IGF-I receptor (IGF-IR). The binding of IGF-I to IGF-IR leads to the activation of phosphatidylinositol 3-kinase (PI3K). Activated PI3K stimulates the production of phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] and phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3]. The PH domain of AKT (protein kinase B, PKB) (v-AKT murine thymoma viral oncogene homolog) binds to PI(4,5)P2 and PI(3,4,5)P3, followed by phosphorylation of the Thr308 and Ser473 regulatory sites. Tuberous sclerosis complex 1 (TSC1) and TSC2 are upstream regulators of mammalian target of rapamycin (mTOR) and downstream effectors of the PI3K/AKT signaling pathway. The activation of AKT suppresses the TSC1/TSC2 heterodimer, which is an upstream regulator of mTOR. Dysregulated IGF-I/PI3K/AKT/mTOR signaling has been shown to be associated with autism spectrum disorders (ASDs). In this review, we discuss the emerging evidence for a functional relationship between the IGF-I/PI3K/AKT/mTOR pathway and ASDs, as well as a possible role of this signaling pathway in the diagnosis and treatment of ASDs.
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3. Davignon MN, Friedlaender E, Cronholm PF, Paciotti B, Levy SE. {{Parent and Provider Perspectives on Procedural Care for Children with Autism Spectrum Disorders}}. {J Dev Behav Pediatr}. 2014.
OBJECTIVE:: Children with autism spectrum disorders (CWASDs) have more difficulty tolerating hospital procedures than many other children. The aim of this study was to identify parent and provider perspectives on barriers and facilitators to procedural care for CWASDs. METHODS:: Semistructured interviews were conducted with medical staff and parents of CWASDs. Those parents whose child with autism required a procedure in a tertiary care sedation unit and those whose child was enrolled in autismMatch (a research registry for individuals with autism) were recruited. Staff providing direct patient care in the tertiary care sedation unit were recruited. Participants were asked open-ended questions about factors contributing to or interfering with successful completion of medical procedures for CWASDs. Interviews were audio-recorded, transcribed verbatim, coded, and analyzed using modified grounded theory techniques. RESULTS:: Twenty mothers and 20 medical staff members were interviewed. Participants described 2 domains essential to care of CWASDs but in which barriers existed: (1) productive interactions between providers and families, largely dependent on advanced preparation and (2) modifications to healthcare organization and delivery in the areas of patient flow and clinical environment. Individualized care is essential to quality care in both domains. CONCLUSIONS:: Children with autism spectrum disorders require individualized interventions to maximize the quality of procedural care. However, many hospitals and providers are not sufficiently equipped to accommodate these children’s needs. This study suggests that targeted improvements in preparation and communication between providers and families as well as modifications in patient flow and clinical environments have the potential to improve the quality and successful completion of procedures.
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4. Fletcher-Watson S, McConnell F, Manola E, McConachie H. {{Interventions based on the Theory of Mind cognitive model for autism spectrum disorder (ASD)}}. {Cochrane Database Syst Rev}. 2014; 3: CD008785.
BACKGROUND: The ‘Theory of Mind’ (ToM) model suggests that people with autism spectrum disorder (ASD) have a profound difficulty understanding the minds of other people – their emotions, feelings, beliefs, and thoughts. As an explanation for some of the characteristic social and communication behaviours of people with ASD, this model has had a significant influence on research and practice. It implies that successful interventions to teach ToM could, in turn, have far-reaching effects on behaviours and outcome. OBJECTIVES: To review the efficacy of interventions based on the ToM model for individuals with ASD. SEARCH METHODS: In August 2013 we searched CENTRAL, Ovid MEDLINE, Embase, CINAHL, PsycINFO, ERIC, Social Services Abstracts, AutismData, and two trials registers. We also searched the reference lists of relevant papers, contacted authors who work in this field, and handsearched a number of journals. SELECTION CRITERIA: Review studies were selected on the basis that they reported on an applicable intervention (linked to ToM in one of four clearly-defined ways), presented new randomised controlled trial data, and participants had a confirmed diagnosis of an autism spectrum disorder. Studies were selected by two review authors independently and a third author arbitrated when necessary. DATA COLLECTION AND ANALYSIS: Risk of bias was evaluated and data were extracted by two review authors independently; a third author arbitrated when necessary. Most studies were not eligible for meta-analysis, the principal reason being mis-matching methodologies and outcome measures. Three small meta-analyses were carried out. MAIN RESULTS: Twenty-two randomised trials were included in the review (N = 695). Studies were highly variable in their country of origin, sample size, participant age, intervention delivery type, and outcome measures. Risk of bias was variable across categories. There were very few studies for which there was adequate blinding of participants and personnel, and some were also judged at high risk of bias in blinding of outcome assessors. There was also evidence of some bias in sequence generation and allocation concealment. Not all studies reported data that fell within the pre-defined primary outcome categories for the review, instead many studies reported measures which were intervention-specific (e.g. emotion recognition). The wide range of measures used within each outcome category and the mixed results from these measures introduced further complexity when interpreting results.Studies were grouped into four main categories according to intervention target/primary outcome measure. These were: emotion recognition studies, joint attention and social communication studies, imitation studies, and studies teaching ToM itself. Within the first two of these categories, a sub-set of studies were deemed suitable for meta-analysis for a limited number of key outcomes.There was very low quality evidence of a positive effect on measures of communication based on individual results from three studies. There was low quality evidence from 11 studies reporting mixed results of interventions on measures of social interaction, very low quality evidence from four studies reporting mixed results on measures of general communication, and very low quality evidence from four studies reporting mixed results on measures of ToM ability. The meta-analysis results we were able to generate showed that interventions targeting emotion recognition across age groups and working with people within the average range of intellectual ability had a positive effect on the target skill, measured by a test using photographs of faces (mean increase of 0.75 points, 95% confidence interval (CI) 0.22 to 1.29 points, Z = 2.75, P < 0.006, four studies, N = 105). Therapist-led joint attention interventions can promote production of more joint attention behaviours within adult-child interaction (mean increase of 0.55 points, 95% CI 0.11 to 0.99 points, Z = 2.45, P value = 0.01, two studies, N = 88). Further analysis undermines this conclusion somewhat by demonstrating that there was no clear evidence that intervention can have an effect on joint attention initiations as measured using a standardised assessment tool (mean increase of 0.23 points, 95% CI -0.48 to 0.94 points, Z = 0.63, P value = 0.53, three studies, N = 92). No adverse effects were apparent. AUTHORS’ CONCLUSIONS: While there is some evidence that ToM, or a precursor skill, can be taught to people with ASD, there is little evidence of maintenance of that skill, generalisation to other settings, or developmental effects on related skills. Furthermore, inconsistency in findings and measurement means that evidence has been graded of ‘very low’ or ‘low’ quality and we cannot be confident that suggestions of positive effects will be sustained as high-quality evidence accumulates. Further longitudinal designs and larger samples are needed to help elucidate both the efficacy of ToM-linked interventions and the explanatory value of the ToM model itself. It is possible that the continuing refinement of the ToM model will lead to better interventions which have a greater impact on development than those investigated to date.
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5. Lerna A, Esposito D, Conson M, Massagli A. {{Long-term effects of PECS on social-communicative skills of children with autism spectrum disorders: a follow-up study}}. {Int J Lang Commun Disord}. 2014.
BACKGROUND: The Picture Exchange Communication System (PECS) is a popular augmentative communication system frequently used with ‘nonverbal’ children with autism. Several studies suggested that PECS could represent an effective tool for promoting improvement of several social-communicative skills. Only sparse evidence is instead available on the long-term effectiveness of this treatment system. AIMS: To test the long-term effects of PECS, for which a follow-up study was conducted by assessing social-communicative skills in nonverbal preschool children with autism after 12 months from treatment completion. METHODS & PROCEDURES: Two groups of children (N = 14) were assessed; one group had completed the PECS training and the other conventional language therapy (CLT). At follow-up all children received the same pre- and post-treatment assessment. Outcome measures were the following: Communication and Social domains of Autism Diagnostic Observation Schedule (ADOS); Language and Personal-Social subscales of the Griffiths’ Mental Developmental Scales (GMDS); Communication and Social Abilities domains of the Vineland Adaptive Behavior Scales (VABS); and several social-communicative variables coded in an unstructured setting. OUTCOMES & RESULTS: The PECS group showed significant improvements compared with the CLT group on ADOS severity scores (Communication, Social and Total), on GMDS Social domain and on VABS Communication and Social domains. PECS-related gains on the VABS Social domain and on specific social-communicative measures coded during free-play, i.e. frequency of joint attention and initiation, and duration of cooperative play, were stable after 1-year follow-up. Cooperative play continued to improve on follow-up with respect to both post- and pre-treatment assessment. CONCLUSIONS & IMPLICATIONS: These findings demonstrated that PECS training can promote long-term enhancement of specific socio-communicative skills in children with autism.
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6. Olli J, Vehkakoski T, Salantera S. {{The habilitation nursing of children with developmental disabilities-Beyond traditional nursing practices and principles?}}. {Int J Qual Stud Health Well-being}. 2014; 9: 23106.
Research-based descriptions of the contents of the habilitation nursing of children with developmental disabilities are lacking. The objective of this qualitative study was to describe the habilitation nursing of children with developmental disabilities in a Finnish children’s neurological ward. In addition, the purpose was to outline the principles that directed the nursing functions (which consisted of various nursing interventions). The data collection included observation, a retrospective think-aloud method with video-taped nursing situations, the nursing records, and an open-ended questionnaire. The data were analysed with a qualitative content analysis of the manifest and latent content. The findings show that habilitation nursing in a children’s neurological ward consists of assessing the child’s skills, supporting the child’s development, and collaborating with the child’s immediate adults. When implementing those functions with nursing interventions, the nurses demonstrated four principles: client-originated and professional-originated principles, and individual-centred and community-centred principles. Becoming conscious of these principles and the theoretical frameworks behind them enables the development of a nursing science-based model for habilitation nursing.
7. Sun MK, Hongpaisan J, Lim C, Alkon DL. {{Bryostatin-1 restores hippocampal synapses and spatial learning and memory in adult fragile X mice}}. {J Pharmacol Exp Ther}. 2014.
Fragile X syndrome (FXS) is caused by transcriptional silencing in neurons of the FMR1 gene product, fragile X mental retardation protein (FMRP), a repressor of dendritic mRNA translation. The lack of FMRP leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, a disorder which currently has no effective therapeutics. Fragile X mice were treated with chronic bryostatin-1, a relatively selective PKCepsilon activator with pharmacological profiles of a rapid mGluR desensitization, synaptogenesis, and synaptic maturation/repairing. Differences in the major FXS phenotypes, synapses, and cognitive functions were evaluated and compared among the age-matched groups. Chronic treatment with bryostatin-1 rescues adult fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in hippocampal brain-derived neurotrophic factor (BDNF) expression and secretion, PSD-95 levels, GSK-3beta phosphorylation, transformation of immature dendritic spines to mature synapses, densities of the presynaptic and postsynaptic membranes, and spatial learning and memory. Our results show that synaptic and cognitive function of adult FXS mice can be normalized through pharmacological treatment and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation even after postpartum brain development has largely completed.
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8. Taha MS, Nouri K, Milroy LG, Moll JM, Herrmann C, Brunsveld L, Piekorz RP, Ahmadian MR. {{Subcellular Fractionation and Localization Studies Reveal a Direct Interaction of the Fragile X Mental Retardation Protein (FMRP) with Nucleolin}}. {PLoS One}. 2014; 9(3): e91465.
Fragile X mental Retardation Protein (FMRP) is a well-known regulator of local translation of its mRNA targets in neurons. However, despite its ubiquitous expression, the role of FMRP remains ill-defined in other cell types. In this study we investigated the subcellular distribution of FMRP and its protein complexes in HeLa cells using confocal imaging as well as detergent-free fractionation and size exclusion protocols. We found FMRP localized exclusively to solid compartments, including cytosolic heavy and light membranes, mitochondria, nuclear membrane and nucleoli. Interestingly, FMRP was associated with nucleolin in both a high molecular weight ribosomal and translation-associated complex (>/=6 MDa) in the cytosol, and a low molecular weight complex ( approximately 200 kDa) in the nucleoli. Consistently, we identified two functional nucleolar localization signals (NoLSs) in FMRP that are responsible for a strong nucleolar colocalization of the C-terminus of FMRP with nucleolin, and a direct interaction of the N-terminus of FMRP with the arginine-glycine-glycine (RGG) domain of nucleolin. Taken together, we propose a novel mechanism by which a transient nucleolar localization of FMRP underlies a strong nucleocytoplasmic translocation, most likely in a complex with nucleolin and possibly ribosomes, in order to regulate translation of its target mRNAs.
