1. Aguiar D, Halldorsson BV, Morrow EM, Istrail S. {{DELISHUS: an efficient and exact algorithm for genome-wide detection of deletion polymorphism in autism}}. {Bioinformatics};2012 (Jun 15);28(12):i154-i162.
MOTIVATION: The understanding of the genetic determinants of complex disease is undergoing a paradigm shift. Genetic heterogeneity of rare mutations with deleterious effects is more commonly being viewed as a major component of disease. Autism is an excellent example where research is active in identifying matches between the phenotypic and genomic heterogeneities. A considerable portion of autism appears to be correlated with copy number variation, which is not directly probed by single nucleotide polymorphism (SNP) array or sequencing technologies. Identifying the genetic heterogeneity of small deletions remains a major unresolved computational problem partly due to the inability of algorithms to detect them. RESULTS: In this article, we present an algorithmic framework, which we term DELISHUS, that implements three exact algorithms for inferring regions of hemizygosity containing genomic deletions of all sizes and frequencies in SNP genotype data. We implement an efficient backtracking algorithm-that processes a 1 billion entry genome-wide association study SNP matrix in a few minutes-to compute all inherited deletions in a dataset. We further extend our model to give an efficient algorithm for detecting de novo deletions. Finally, given a set of called deletions, we also give a polynomial time algorithm for computing the critical regions of recurrent deletions. DELISHUS achieves significantly lower false-positive rates and higher power than previously published algorithms partly because it considers all individuals in the sample simultaneously. DELISHUS may be applied to SNP array or sequencing data to identify the deletion spectrum for family-based association studies. AVAILABILITY: DELISHUS is available at http://www.brown.edu/Research/Istrail_Lab/. CONTACT: Eric_Morrow@brown.edu and Sorin_Istrail@brown.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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2. Cook J, Barbalat G, Blakemore SJ. {{Top-down modulation of the perception of other people in schizophrenia and autism}}. {Front Hum Neurosci};2012;6:175.
Accurately and efficiently perceiving social cues such as body movements and facial expressions is important in social interaction. Accurate social perception of this kind does not solely rely on « bottom-up » visual processing but is also subject to modulation by « top-down » signals. For example, if instructed to look for signs of happiness rather than fear, participants are more likely to categorize facial expressions as happy-this prior expectation biases subsequent perception. Top-down modulation is also important in our reactions to others. For example, top-down control over imitation plays an important role in the development of smooth and harmonious social interactions. This paper highlights the importance of top-down modulation in our perception of, and reactions to, others. We discuss evidence that top-down modulation of social perception and imitation is atypical in Autism Spectrum Conditions and in schizophrenia, and we consider the effect this may have on the development of social interactions for individuals with these developmental disorders.
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3. De Filippis B, Ricceri L, Fuso A, Laviola G. {{Neonatal exposure to low dose corticosterone persistently modulates hippocampal mineralocorticoid receptor expression and improves locomotor/exploratory behavior in a mouse model of Rett syndrome}}. {Neuropharmacology};2012 (Jun 15)
Rett syndrome (RTT) is a pervasive neurodevelopmental disorder, primarily affecting girls. RTT causes a wide variety of debilitating symptoms and no cure currently exists. Mouse models bearing mutations in the Mecp2 gene recapitulate most physiological and behavioural RTT-related abnormalities. Stimulating neonatal environments (e.g. brief maternal separations or maternal low-dose corticosterone supplementation) reduces stress and fear responses at adulthood. The present study investigated whether impacting early in development the hypothalamic-pituitary-adrenal axis, by exposing Mecp2-308 mutant pups to a low dose of corticosterone (50 mg/ml, during the 1(st) week of life) may contrast RTT-related abnormalities in neuroendocrine regulation and behavioural adaptation at adulthood. In line with previous reports, when fully symptomatic, MeCP2-308 mice showed a reduction in the regular nocturnal hyperactivity in the home-cage and increased anxiety-like behaviours and plasma corticosterone (CORT) levels in response to restraint stress. An abnormal elevation in mRNA levels of mineralocorticoid receptors (MR) and BDNF gene was also evident in the hippocampus of fully symptomatic mutant mice. Neonatal CORT modulated MR gene expression and behavioral reactivity towards a novel object, also restoring wt-like levels of locomotor/exploratory behavior in mutant mice. Enhanced sensitivity to the neonatal treatment (in terms of increase in GR and MR mRNA levels), was also evident in the hippocampus of MeCP2-308 mice compared to wt littermates. Present results corroborate the hypothesis that pharmacological interventions targeting the glucocorticoid system may prove valid in contrasting at least some of the RTT-related symptoms and provide evidence that pharmacological interventions during critical early time windows can persistently improve the behavioural phenotype of RTT mice. Current data also support the emerging role played by Mecp2 in mediating the epigenetic programming induced by early life events and indicate that, in the absence of functional MeCP2, programming of the central nervous system in response to early environmental stimuli is abnormally regulated.
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4. Dratsch T, Schwartz C, Yanev K, Schilbach L, Vogeley K, Bente G. {{Getting a Grip on Social Gaze: Control over Others’ Gaze Helps Gaze Detection in High-Functioning Autism}}. {J Autism Dev Disord};2012 (Jun 14)
We investigated the influence of control over a social stimulus on the ability to detect direct gaze in high-functioning autism (HFA). In a pilot study, 19 participants with and 19 without HFA were compared on a gaze detection and a gaze setting task. Participants with HFA were less accurate in detecting direct gaze in the detection task, but did not differ in their ability to establish direct gaze in the setting task. In the main experiment, the results of the pilot study were replicated with 37 participants with and 39 without HFA, suggesting that individuals with HFA have a specific deficit in the passive perception of social cues as opposed to the active control, which seems to be intact.
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5. Kheir NM, Ghoneim OM, Sandridge AL, Hayder SA, Al-Ismail MS, Al-Rawi F. {{Concerns and considerations among caregivers of a child with autism in Qatar}}. {BMC Res Notes};2012 (Jun 13);5(1):290.
ABSTRACT: BACKGROUND: Autism impacts the lives of the family looking after a child with the condition in different ways, and forces family members to modify their daily lives to suit their reality. To our knowledge, no previous research investigated concern and considerations of parents/caregivers of children with autism in Qatar or the Arabic speaking Middle Eastern region. METHODS: Caregivers of a child who was between the age of 3 to17 years old at the time of the study and who was diagnosed with ASD (Autistic Group or AG) were recruited from the two main developmental pediatric and children rehabilitation clinics in Qatar. The control group (non-autism group, or NAG) was represented by caregivers of a non-autistic child between the age of 3 to 17 years old at the time of the study and who were visiting a family clinic of a primary health care facility for routine medical check-up. Data collected from both groups included related to the child (e.g. the child’s date of birth, his/her relation to the caregiver, number of siblings, number of hours of sleep in a day, number of hours spent watching television or videos prior to age 3, time spent indoors prior to age 3, absenteeism from school, and use of a nanny to care for the child) and to the caregiver (education level, profession, level of consanguinity using the phylogram method). In addition to these questions, caregivers in the AG were asked specific questions around maternal concern and considerations in respect to the future of their children and the specialized services they receive. RESULTS: Children in the autism group spent more time indoors, watching television, or sleeping than children in the non-autism group. Only around 40% of caregivers in the autism group said they would encourage their child to get married and become a parent when s/he grows up. A number of caregivers of children with autism frequently utilize specialized rehabilitation services; others did express their needs for these services and made comments about having to wait a long time before they were provided with some of the services. Religious faith helped caregivers in accepting having a child with autism. General health-related quality of life did not differ significantly between the caregivers of the two groups, although mental health was consistently poorer in the autism group of caregivers. CONCLUSIONS: The study draws attention to the concerns of the families of children with autism and their expectations about the future of their children. The findings can be used by policy makers in planning services to support these families in Qatar.
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6. Liu J, Koscielska KA, Cao Z, Hulsizer S, Grace N, Mitchell G, Nacey C, Githinji J, McGee J, Garcia-Arocena D, Hagerman RJ, Nolta J, Pessah IN, Hagerman PJ. {{Signaling defects in iPSC-derived fragile X premutation neurons}}. {Hum Mol Genet};2012 (Jun 15)
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a leading monogenic neurodegenerative disorder affecting premutation carriers of the fragile X (FMR1) gene. To investigate the underlying cellular neuropathology, we produced induced pluripotent stem cell-derived neurons from isogenic subclones of primary fibroblasts of a female premutation carrier, with each subclone bearing exclusively either the normal or the expanded (premutation) form of the FMR1 gene as the active allele. We show that neurons harboring the stably-active, expanded allele (EX-Xa) have reduced postsynaptic density protein 95 protein expression, reduced synaptic puncta density and reduced neurite length. Importantly, such neurons are also functionally abnormal, with calcium transients of higher amplitude and increased frequency than for neurons harboring the normal-active allele. Moreover, a sustained calcium elevation was found in the EX-Xa neurons after glutamate application. By excluding the individual genetic background variation, we have demonstrated neuronal phenotypes directly linked to the FMR1 premutation. Our approach represents a unique isogenic, X-chromosomal epigenetic model to aid the development of targeted therapeutics for FXTAS, and more broadly as a model for the study of common neurodevelopmental (e.g. autism) and neurodegenerative (e.g. Parkinsonism, dementias) disorders.
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7. Miller JS, Bilder D, Farley M, Coon H, Pinborough-Zimmerman J, Jenson W, Rice CE, Fombonne E, Pingree CB, Ritvo E, Ritvo RA, McMahon WM. {{Autism Spectrum Disorder Reclassified: A Second Look at the 1980s Utah/UCLA Autism Epidemiologic Study}}. {J Autism Dev Disord};2012 (Jun 13)
The purpose of the present study was to re-examine diagnostic data from a state-wide autism prevalence study (n = 489) conducted in the 1980s to investigate the impact of broader diagnostic criteria on autism spectrum disorder (ASD) case status. Sixty-four (59 %) of the 108 originally « Diagnosed Not Autistic » met the current ASD case definition. The average IQ estimate in the newly identified group (IQ = 35.58; SD = 23.01) was significantly lower than in the original group (IQ = 56.19 SD = 21.21; t = 5.75; p < .0001). Today’s diagnostic criteria applied to participants ascertained in the 1980s identified more cases of autism with intellectual disability. The current analysis puts this historic work into context and highlights differences in ascertainment between epidemiological studies performed decades ago and those of today.
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8. Mohanty PH, Gabel M. {{Agitation and decreased oral intake in an adolescent with autism}}. {Pediatr Ann};2012 (Jun 1);41(6):1-3.
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9. Rossignol DA, Bradstreet JJ, Van Dyke K, Schneider C, Freedenfeld SH, O’Hara N, Cave S, Buckley JA, Mumper EA, Frye RE. {{Hyperbaric oxygen treatment in autism spectrum disorders}}. {Med Gas Res};2012 (Jun 15);2(1):16.
ABSTRACT: Traditionally, hyperbaric oxygen treatment (HBOT) is indicated in several clinical disorders include decompression sickness, healing of problem wounds and arterial gas embolism. However, some investigators have used HBOT to treat individuals with autism spectrum disorders (ASD). A number of individuals with ASD possess certain physiological abnormalities that HBOT might ameliorate, including cerebral hypoperfusion, inflammation, mitochondrial dysfunction and oxidative stress. Studies of children with ASD have found positive changes in physiology and/or behavior from HBOT. For example, several studies have reported that HBOT improved cerebral perfusion, decreased markers of inflammation and did not worsen oxidative stress markers in children with ASD. Most studies of HBOT in children with ASD examined changes in behaviors and reported improvements in several behavioral domains although many of these studies were not controlled. Although the two trials employing a control group reported conflicting results, a recent systematic review noted several important distinctions between these trials. In the reviewed studies, HBOT had minimal adverse effects and was well tolerated. Studies which used a higher frequency of HBOT sessions (e.g., 10 sessions per week as opposed to 5 sessions per week) generally reported more significant improvements. Many of the studies had limitations which may have contributed to inconsistent findings across studies, including the use of many different standardized and non-standardized instruments, making it difficult to directly compare the results of studies or to know if there are specific areas of behavior in which HBOT is most effective. The variability in results between studies could also have been due to certain subgroups of children with ASD responding differently to HBOT. Most of the reviewed studies relied on changes in behavioral measurements, which may lag behind physiological changes. Additional studies enrolling children with ASD who have certain physiological abnormalities (such as inflammation, cerebral hypoperfusion, and mitochondrial dysfunction) and which measure changes in these physiological parameters would be helpful in further defining the effects of HBOT in ASD.
