1. Abraham SS, Taragin B, Djukic A. {{Co-occurrence of Dystonic and Dyskinetic Tongue Movements with Oral Apraxia in Post-regression Dysphagia in Classical Rett Syndrome Years of Life 1 Through 5}}. {Dysphagia}. 2014.
We do not know the natural history of dysphagia in classical Rett syndrome (RTT) by stage or age. This study investigated swallowing physiology in 23 females ages 1:7 to 5:8 (years, months) with classical Rett syndrome to determine common and distinguishing features of dysphagia in post-regression early Pseudostationary Stage III. In-depth analysis of videofluoroscopic swallowing studies (VFSS) found dysmotility of oral stage events across subjects implicating oral apraxia. Impaired motility was further compromised by recurrent dystonic and dyskinetic movements that co-occurred with oral apraxia during oral ingestion in 78 % (n = 18) of the subjects with RTT. Of this group, 44 % displayed rocking and/or rolling lingual pattern, 56 % had recurrent oral tongue retroflexions, and/or elevated posturing of the tongue tip, and, 72 % displayed multi-wave oropharyngeal transfer pattern. The proportion of subjects whose swallowing motility was disrupted by aberrant involuntary tongue movements did not differ significantly between bolus types (liquid, puree, and solid) trialed. Liquid ingestion was significantly more efficient in subjects using bottles with nipples than their counterparts who used spouted or straw cups. Dystonic and dyskinetic tongue movements disrupted liquid ingestion in subjects using cups with spouts or straws significantly more than those using bottles. Analysis of food ingestion revealed that significantly more subjects were able to orally form, transport, and transfer a puree bolus into the pharynx than they were a solid bolus. A significantly larger number of subjects aspirated and penetrated liquid than they did puree or solid. No significant relationship was found between subjects with airway contamination and those with dystonic and dyskinetic tongue movements. Subjects’ rocking and rolling lingual patterns were consistent with those evidenced in adults with Parkinson’s disease. Subjects’ tongue retroflexions were classified as provisionally unique to RTT. VFSS pre-planning, fluoroscopic procedures, and therapeutic strategies specific to this specialty population were derived.
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2. Blick MG, Puchalski BH, Bolanos VJ, Wolfe KM, Green MC, Ryan BC. {{NOVEL OBJECT EXPLORATION IN THE C58/J MOUSE MODEL OF AUTISTIC-LIKE BEHAVIOR}}. {Behav Brain Res}. 2014.
Mouse models of autistic like behaviors are a valuable tool to use when studying the causes, symptoms, and potential treatments for autism. The inbred C58/J strain is a strain of interest for this model and has previously been shown to possess face validity for some of the core traits of autism, including low social behavior and elevated motor stereotypies. Higher order repetitive behaviors have not been extensively studied in this strain, or in mice in general. In this study, we looked for evidence of higher-order repetitive behaviors in the C58/J strain using a novel object assay. This assay utilized a mouse’s natural exploratory behavior among unfamiliar objects to identify potential sequencing patterns in motor activity. The motor stereotypies displayed by the C58/J strain during testing were consistent with past studies. The C58/J strain also displayed a high preference for a single object in the round arena assays and the females demonstrating elevated sequencing patterns in the round arena. Although the C58/J strain did not show pervasive evidence of higher-order repetitive behaviors across all measures, there was evidence of higher order repetitive behaviors in certain situations. This study further demonstrates the potential of the C58/J mouse strains as a model for lower-order and potentially, higher-order repetitive behaviors. This study also demonstrates that the shape of the novel object arena can change the behavior displayed by the test animals. Further studies utilizing the C58/J strain and further validation of the novel object assay are warranted.
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3. Chantiluke K, Barrett N, Giampietro V, Santosh P, Brammer M, Simmons A, Murphy DG, Rubia K. {{Inverse fluoxetine effects on inhibitory brain activation in non-comorbid boys with ADHD and with ASD}}. {Psychopharmacology (Berl)}. 2014.
RATIONALE: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are often comorbid and have both performance and brain dysfunctions during motor response inhibition. Serotonin agonists modulate motor response inhibition and have shown positive behavioural effects in both disorders. AIMS: We therefore used functional magnetic resonance imaging (fMRI) to investigate the so far unknown shared and disorder-specific inhibitory brain dysfunctions in these two disorders, as well as the effects of a single dose of the selective serotonin reuptake inhibitor fluoxetine. METHODS: Age-matched boys with ADHD (18), ASD (19) and healthy controls (25) were compared with fMRI during a stop task measuring motor inhibition. Patients were scanned twice, under either an acute dose of fluoxetine or placebo in a double-blind, placebo-controlled randomised design. Repeated measures analyses within patients assessed drug effects. To test for potential normalisation effects of brain dysfunctions, patients under each drug condition were compared to controls. RESULTS: Under placebo, relative to controls, ASD boys showed overactivation in left and right inferior frontal cortex (IFC), while ADHD boys showed disorder-specific underactivation in orbitofrontal cortex (OFC) and basal ganglia. Under fluoxetine, the prefrontal dysfunctions were no longer observed, due to inverse effects of fluoxetine on these activations: fluoxetine downregulated IFC and OFC activation in ASD but upregulated them in ADHD. CONCLUSIONS: The findings show that fluoxetine normalises frontal lobe dysfunctions in both disorders via inverse effects, downregulating abnormally increased frontal activation in ASD and upregulating abnormally decreased frontal activation in ADHD, potentially reflecting inverse baseline serotonin levels in both disorders.
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4. Chaste P, Klei L, Sanders SJ, Hus V, Murtha MT, Lowe JK, Willsey AJ, Moreno-De-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Mane SM, Martin DM, Morrow EM, Walsh CA, Sutcliffe JS, Lese Martin C, Beaudet AL, Lord C, State MW, Cook EH, Jr., Devlin B. {{A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity?}}. {Biol Psychiatry}. 2014.
BACKGROUND: Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. METHODS: Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. RESULTS: Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. CONCLUSIONS: In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.
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5. Fairthorne J, Hammond G, Bourke J, Jacoby P, Leonard H. {{Early mortality and primary causes of death in mothers of children with intellectual disability or autism spectrum disorder: a retrospective cohort study}}. {PLoS One}. 2014; 9(12): e113430.
INTRODUCTION: Mothers of children with intellectual disability or autism spectrum disorder (ASD) have poorer health than other mothers. Yet no research has explored whether this poorer health is reflected in mortality rates or whether certain causes of death are more likely. We aimed to calculate the hazard ratios for death and for the primary causes of death in mothers of children with intellectual disability or ASD compared to other mothers. METHODS: The study population comprised all mothers of live-born children in Western Australia from 1983-2005. We accessed state-wide databases which enabled us to link socio-demographic details, birth dates, diagnoses of intellectual disability or ASD in the children and dates and causes of death for all mothers who had died prior to 2011. Using Cox Regression with death by any cause and death by each of the three primary causes as the event of interest, we calculated hazard ratios for death for mothers of children intellectual disability or ASD compared to other mothers. RESULTS AND DISCUSSION: During the study period, mothers of children with intellectual disability or ASD had more than twice the risk of death. Mothers of children with intellectual disability were 40% more likely to die of cancer; 150% more likely to die of cardiovascular disease and nearly 200% more likely to die from misadventure than other mothers. Due to small numbers, only hazard ratios for cancer were calculated for mothers of children with ASD. These mothers were about 50% more likely to die from cancer than other mothers. Possible causes and implications of our results are discussed. CONCLUSION: Similar studies, pooling data from registries elsewhere, would improve our understanding of factors increasing the mortality of mothers of children with intellectual disability or ASD. This would allow the implementation of informed services and interventions to improve these mothers’ longevity.
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6. Martinez-Cerdeno V, Camacho J, Fox E, Miller E, Ariza J, Kienzle D, Plank K, Noctor SC, Van de Water J. {{Prenatal Exposure to Autism-Specific Maternal Autoantibodies Alters Proliferation of Cortical Neural Precursor Cells, Enlarges Brain, and Increases Neuronal Size in Adult Animals}}. {Cereb Cortex}. 2014.
Autism spectrum disorders (ASDs) affect up to 1 in 68 children. Autism-specific autoantibodies directed against fetal brain proteins have been found exclusively in a subpopulation of mothers whose children were diagnosed with ASD or maternal autoantibody-related autism. We tested the impact of autoantibodies on brain development in mice by transferring human antigen-specific IgG directly into the cerebral ventricles of embryonic mice during cortical neurogenesis. We show that autoantibodies recognize radial glial cells during development. We also show that prenatal exposure to autism-specific maternal autoantibodies increased cellular proliferation in the subventricular zone (SVZ) of the embryonic neocortex, increased adult brain size also and weight, and increased the size of adult cortical neurons. We propose that prenatal exposure to autism-specific maternal autoantibodies directly affects radial glial cell development and presents a viable pathologic mechanism for the maternal autoantibody-related prenatal ASD risk factor.
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7. Segura M, Pedreno C, Obiols J, Taurines R, Pamias M, Grunblatt E, Gella A. {{Neurotrophin blood-based gene expression and social cognition analysis in patients with autism spectrum disorder}}. {Neurogenetics}. 2014.
Autism spectrum disorders (ASD) comprise neurodevelopmental disorders with clinical onset during the first years of life. The identification of peripheral biomarkers could significantly impact diagnosis and an individualized, early treatment. Although the aetiology of ASD remains poorly understood, there is increasing evidence that neurotrophins and their receptors represent a group of candidate genes for ASD pathophysiology and biomarker research. Total messenger RNA (mRNA) from whole blood was obtained from adolescents and adults diagnosed as ASD (n = 21) according to DSM-IV criteria and confirmed by the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R) algorithms, as well as healthy controls (n = 10). The mRNA expression of neurotrophins (BDNF, NT3 and NT4) and their receptors (TrkA, TrkB and p75 NTR ) was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, social cognition abilities of ASD patients and controls were determined according to three Theory of Mind (ToM) tests (Reading the Mind in the Eyes, Faux pas, and Happe stories). The NT3 and NT4 mRNA expression in the whole blood was significantly lower in ASD compared to healthy controls, while p75NTR was higher (P < 0.005). In addition, lower scores in three of the ToM tests were observed in ASD subjects compared to controls. A significant (P < 0.005) ToM impairment in Happe stories test was demonstrated in ASD. Nevertheless, no correlations were observed between neurotrophins and their receptors expressions and measures of ToM. Given their potential as peripheral blood-based biomarkers, NT3, NT4 and p75 NTR mRNA expression patterns may be useful tools for a more personalized diagnostics and therapy in ASD. Further investigations with larger numbers of samples are needed to verify these results.
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8. Tolakanahalli RP, Tewatia DK. {{Impact of energy variation on Cone Ratio, PDD10, TMR20/10 and IMRT doses for flattening filter free (FFF) beam of TomoTherapy Hi-Art(TM)machines}}. {J BUON}. 2014; 19(4): 1105-10.
PURPOSE: The beam energy (PDD10: Percent depth dose) of a Tomotherapy Hi-ArtTM machine was varied in a controlled experiment from -1.64 to +1.66%, while keeping the output at 100% and the effect of this on IMRT output, MU chamber ratio (MUR), cone ratio (CR) and Tissue Maximum Ratio (TMR20/10) was studied METHODS: In this study, Injector Current Voltage (VIC) and Pulse Forming Network Voltage (VPFN) were changed in steps such that the PDD10 was varied from golden beam value incrementally between -1.64 to +1.66%. The effect of this on other energy indicators was studied to verify the sensitivity of TMR20/10, MUR, and detector data-based-CR. To quantify the effect of energy variation on Intensity Modulated Radiation Therapy (IMRT) dose, multiple ion-chamber based dose measurements were recorded by irradiating a cylindrical phantom with standard IMRT plans. Dose variation across each commissioned Field width (FW) was tabulated against energy variation. RESULTS: Good agreement between PDD10 and TMR20/10, MUR, CR was observed. CR was more sensitive to energy change than PDD10. More variation was observed across standard IMRT plan with increasing energy. CONCLUSION: CR is more sensitive to energy changes compared to PDD10, and CR with MUR can definitely be used as surrogates for checks on a daily/weekly basis. Variation in output across the 6 standard IMRT plans can vary up to 2.8% for a 1.6% increase in energy. Hence, it is of utmost importance to manage the PDD10 tightly around +0.5% in order to regulate standard IMRT QA agreement to within 1% and patient IMRT QA within +/-3%.
