1. Ariza J, Rogers H, Hashemi E, Noctor SC, Martinez-Cerdeno V. {{The Number of Chandelier and Basket Cells Are Differentially Decreased in Prefrontal Cortex in Autism}}. {Cereb Cortex};2016 (Nov 24)
An interneuron alteration has been proposed as a source for the modified balance of excitation / inhibition in the cerebral cortex in autism. We previously demonstrated a decreased number of parvalbumin (PV)-expressing interneurons in prefrontal cortex in autism. PV-expressing interneurons include chandelier (Ch) and basket (Bsk) cells. We asked whether the decreased PV+ interneurons affected both Ch cells and Bsk cells in autism. The lack of single markers to specifically label Ch cells or Bsk cells presented an obstacle for addressing this question. We devised a method to discern between PV-Ch and PV-Bsk cells based on the differential expression of Vicia villosa lectin (VVA). VVA binds to N-acetylgalactosamine, that is present in the perineuronal net surrounding some cell types where it plays a role in intercellular communication. N-acetylgalactosamine is present in the perineuronal net surrounding Bsk but not Ch cells. We found that the number of Ch cells is consistently decreased in the prefrontal cortex of autistic (n = 10) when compared with control (n = 10) cases, while the number of Bsk cells is not as severely affected. This finding expand our understanding of GABAergic system functioning in the human cerebral cortex in autism, which will impact translational research directed towards providing better treatment paradigms for individuals with autism.
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2. de Hemptinne Q, Horlick EM, Osten MD, Millan X, Tadros VX, Pighi M, Gonzalez Barlatey F, Alnasser SM, Miro J, Asgar AW, Ibrahim R. {{Initial clinical experience with the GORE(R) CARDIOFORM ASD occluder for transcatheter atrial septal defect closure}}. {Catheter Cardiovasc Interv};2017 (Jan 27)
OBJECTIVES: To report the initial clinical experience with a novel atrial septal defect (ASD) closure device, the GORE(R) CARDIOFORM ASD Occluder (GCO). BACKGROUND: Transcatheter closure has become the treatment of choice for secundum ASD. A wide range of occluder devices are available, but concern has been raised about the risk of cardiac erosion associated with rigid devices and future access to the left atrium METHODS: Retrospective chart review of patients treated with the GCO at three Canadian centers. Primary outcomes were procedural success and residual shunting at follow-up, as well as 30-day major adverse events. Secondary outcomes included new onset atrial arrhythmias, wire frame fractures (WFF), and all cause mortality. Clinical, echocardiographic, procedural data, and follow-up outcome variables were collected in each participating hospital. RESULTS: Between February and December 2015, 26 patients (5 children and 21 adults) underwent transcatheter ASD closure with the GCO and were included in the study cohort. Procedural success was achieved in 22 of 26 patients (85%) and no major procedural complications were observed. Two patients (8%) presented new onset atrial tachyarrhythmia during early follow-up (0-30 days). Follow-up echocardiography (median of 119 days [IQR: 92-146]) demonstrated no residual shunt in all implanted patients. After a median clinical follow-up of 174 days (IQR: 135-239), one patient died of an unrelated cause, there were no documented major adverse cardiovascular events. Fluoroscopic imaging of the device was performed in 20 patients (91%), and WFF was noted in five cases. No clinical consequence or device dysfunction was observed in these patients. CONCLUSIONS: In this first-in-man multicenter study, the GCO was safe and effective for ASD closure, with no major adverse events or residual shunt at follow-up. (c) 2017 Wiley Periodicals, Inc.
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3. Dixon MR, Peach J, Daar JH, Penrod C. {{Teaching complex verbal operants to children with autism and establishing generalization using the peak curriculum}}. {J Appl Behav Anal};2017 (Jan 27)
The present study evaluated the feasibility of the PEAK Relational Training System’s Generalization Module (Dixon, 2014b) to teach and establish generalization of autoclitic mands, distorted tacts, and creative path finding in three children diagnosed with autism spectrum disorder. Using a multiple-baseline design across behaviors, each participant was provided with differential reinforcement and a least-to-most prompting hierarchy for correct responses to a subset of stimuli, and responses to other similar stimulus sets were probed for emergent generalization. Following training, each participant successfully acquired the directly trained behaviors and demonstrated generalization to the nonreinforced test exemplars. These data support the utility of Skinner’s (1957) analysis to teach complex forms of verbal operants, and suggest that a manualized curriculum such as PEAK may have utility for promoting skill development and generalization for front line staff and caregivers of children with autism.
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4. Hwang YT, Dudding T, Aliaga SM, Arpone M, Francis D, Li X, Slater HR, Rogers C, Bretherton L, du Sart D, Heard R, Godler DE. {{Erratum: Hwang Y.T. et al. Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia. Genes 2016, 7, 68}}. {Genes (Basel)};2017 (Jan 24);8(2)
n/a.
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5. Kang DW, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, Khoruts A, Geis E, Maldonado J, McDonough-Means S, Pollard EL, Roux S, Sadowsky MJ, Lipson KS, Sullivan MB, Caporaso JG, Krajmalnik-Brown R. {{Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study}}. {Microbiome};2017 (Jan 23);5(1):10.
BACKGROUND: Autism spectrum disorders (ASD) are complex neurobiological disorders that impair social interactions and communication and lead to restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. The causes of these disorders remain poorly understood, but gut microbiota, the 1013 bacteria in the human intestines, have been implicated because children with ASD often suffer gastrointestinal (GI) problems that correlate with ASD severity. Several previous studies have reported abnormal gut bacteria in children with ASD. The gut microbiome-ASD connection has been tested in a mouse model of ASD, where the microbiome was mechanistically linked to abnormal metabolites and behavior. Similarly, a study of children with ASD found that oral non-absorbable antibiotic treatment improved GI and ASD symptoms, albeit temporarily. Here, a small open-label clinical trial evaluated the impact of Microbiota Transfer Therapy (MTT) on gut microbiota composition and GI and ASD symptoms of 18 ASD-diagnosed children. RESULTS: MTT involved a 2-week antibiotic treatment, a bowel cleanse, and then an extended fecal microbiota transplant (FMT) using a high initial dose followed by daily and lower maintenance doses for 7-8 weeks. The Gastrointestinal Symptom Rating Scale revealed an approximately 80% reduction of GI symptoms at the end of treatment, including significant improvements in symptoms of constipation, diarrhea, indigestion, and abdominal pain. Improvements persisted 8 weeks after treatment. Similarly, clinical assessments showed that behavioral ASD symptoms improved significantly and remained improved 8 weeks after treatment ended. Bacterial and phagedeep sequencing analyses revealed successful partial engraftment of donor microbiota and beneficial changes in the gut environment. Specifically, overall bacterial diversity and the abundance of Bifidobacterium, Prevotella, and Desulfovibrio among other taxa increased following MTT, and these changes persisted after treatment stopped (followed for 8 weeks). CONCLUSIONS: This exploratory, extended-duration treatment protocol thus appears to be a promising approach to alter the gut microbiome and virome and improve GI and behavioral symptoms of ASD. Improvements in GI symptoms, ASD symptoms, and the microbiome all persisted for at least 8 weeks after treatment ended, suggesting a long-term impact. TRIAL REGISTRATION: This trial was registered on the ClinicalTrials.gov, with the registration number NCT02504554.
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6. Lv MN, Zhang H, Shu Y, Chen S, Hu YY, Zhou M. {{The neonatal levels of TSB, NSE and CK-BB in autism spectrum disorder from Southern China}}. {Transl Neurosci};2016;7(1):6-11.
Background » Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder that impairs a child’s ability to communicate with others. It also includes restricted repetitive behaviors, interests and activities. Symptoms manifest before the age of 3. In the previous studies, we found structural abnormalities of the temporal lobe cortex. High spine densities were most commonly found in ASD subjects with lower levels of cognitive functioning. In the present study, we retrospectively analyzed medical records in relation to the neonatal levels of total serum bilirubin (TSB), neuron-specific enolase (NSE), creatine kinase brain band isoenzyme (CK-BB), and neonatal behavior in ASD patients from Southern China. METHODS: A total of 80 patients with ASD (ASD group) were screened for this retrospective study. Among them, 34 were low-functioning ASD (L-ASD group) and 46 were high-functioning ASD (H-ASD group). Identification of the ASD cases was confirmed with a Revised Autism Diagnostic Inventory. For comparison with ASD cases, 80 normal neonates (control group) were selected from the same period. Biochemical parameters, including TSB, NSE and CK-BB in the neonatal period and medical records on neonatal behavior were collected. RESULTS: The levels of serum TSB, NSE and CK-BB in the ASD group were significantly higher when compared with those from the control group (P < 0.01, or P < 0.05). The amounts of serum TSB, NSE and CK-BB in the L-ASD group were significantly higher when compared with those in the H-ASD group (P < 0.01, or P < 0.05). The Neonatal Behavioral Assessment Scale (NBAS) scores in the ASD group were significantly lower than that in the control group (P < 0.05). Likewise, the NBAS scores in the L-ASD group were significantly lower than that in the H-ASD group (P < 0.05). There was no association between serum TSB, NSE, CK-BB and NBAS scores (P > 0.05) in the ASD group. CONCLUSIONS: The neonatal levels of TSB, NSE and CK-BB in ASD from Southern China were significantly higher than those of healthy controls. These findings need to be investigated thoroughly by future studies with large sample.
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7. Ozyilmaz B, Kirbiyik O, Koc A, Ozdemir TR, Ozer Kaya O, Saka Guvenc M, Erdogan KM, Kutbay YB. {{Experiences in Microarray-based Evaluation of Developmental Disabilities and Congenital Anomalies}}. {Clin Genet};2017 (Jan 27)
Chromosomal microarray analysis is the as first-tier test for the evaluation of developmental disabilities and congenital anomalies. In this report, we present CMA results of 971 patient and 301 parent samples. Among 971 patient samples, 133 (13,6%) had pathogenic variants. While analyzing, an « in-house » variant database was also used besides other databases. Owing to this, we have found chance to report the most frequent benign variants in Turkish population. With the additional data we acqured in this study, we also emphasized the high potential of CMA in revealing single gene disorders and novel gene-phenotype associations as well as copy number variations.
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8. Stephenson JR, Wang X, Perfitt TL, Parrish WP, Shonesy BC, Marks CR, Mortlock DP, Nakagawa T, Sutcliffe JS, Colbran RJ. {{A novel human CAMK2A mutation disrupts dendritic morphology and synaptic transmission, and causes ASD-related behaviors}}. {J Neurosci};2017 (Jan 27)
Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a de novo Glu183 to Val (E183V) mutation in the CaMKIIalpha catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIalpha substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIalpha-WT autophosphorylation. The E183V mutation also reduces CaMKIIalpha binding to established ASD-linked proteins, such as Shank3 and subunits of L-type calcium channels and NMDA receptors, and increases CaMKIIalpha turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIalpha targeting to dendritic spines. Moreover, neuronal expression of CaMKIIalpha-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIalpha-E183V mutation have lower total forebrain CaMKIIalpha levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIalpha-E183V mice also display aberrant behavioral phenotypes including hyperactivity, social interaction deficits and increased repetitive behaviors. Taken together, these data suggest that CaMKIIalpha plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes. SIGNIFICANCE STATEMENT: Many ASD-linked mutations disrupt the function of synaptic proteins, but no single gene accounts for >1% of total ASD cases. The molecular networks and mechanisms that couple the primary deficits caused by these individual mutations to core behavioral symptoms of ASD remain poorly understood. Here, we provide the first characterization of a mutation in the gene encoding CaMKIIalpha linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked de novo CAMK2A mutation disrupts multiple CaMKII functions, induces synaptic deficits and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD.
