1. Fong BM, Tam S, Leung KS. {{Determination of plasma cholesterol sulfate by LC-APCI-MS/MS in the context of pediatric autism}}. {Talanta}. 2013; 116: 115-21.
Cholesterol sulfate (CS) has various biological functions. Previously, plasma CS was measured primarily as a means to diagnose X-linked ichthyosis; however, a recent hypothesis suggests that CS deficiency might be related to autism. As such, an assay capable of measuring both very high (in the case of X-linked ichthyosis) and very low (in the case of autism) plasma CS levels is required. Here we describe a novel LC-APCI-MS/MS method for the determination of CS in human plasma, and we propose normal CS ranges for children, based on studies of a local population of normal Chinese children between the ages of 2 and 10. In addition, we have used this method to measure plasma CS in autistic children. CS was isolated by solid-phase extraction, and quantified by isotope-dilution LC-APCI-MS/MS in negative ion mode monitoring 465.3>97.1m/z (CS) and 472.3>97.1m/z (CS-d7). Mean recovery of the assay ranged from 88.1 to 112.7%; within- and between-run imprecisions have CVs less than 7.2 and 8.1%, respectively. The assay was linear up to at least 100micromolL(-1). The reference interval of plasma CS in males (range: 1.16-4.23micromolL(-1)) was found to be higher than in females (range: 0.86-3.20micromolL(-1)). Comparison of normal and autistic children showed no statistically significant difference in the plasma CS level. In conclusion, a robust LC-APCI-MS/MS method for plasma CS was developed, and a pediatric reference interval was derived from applying the method to normal and autistic children.
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2. Janusz A, Milek J, Perycz M, Pacini L, Bagni C, Kaczmarek L, Dziembowska M. {{The fragile x mental retardation protein regulates matrix metalloproteinase 9 mRNA at synapses}}. {J Neurosci}. 2013; 33(46): 18234-41.
Activity-dependent protein synthesis at synapses is dysregulated in the Fragile X syndrome (FXS). This process contributes to dendritic spine dysmorphogenesis and synaptic dysfunction in FXS. Matrix Metalloproteinase 9 (MMP-9) is an enzyme involved in activity-dependent reorganization of dendritic spine architecture and was shown to regulate spine morphology in a mouse model of FXS, the Fmr1 knock-out mice. Here we show that MMP-9 mRNA is part of the FMRP complex and colocalizes in dendrites. In the absence of FMRP MMP-9 mRNA translation is increased at synapses, suggesting that this mechanism contributes to the increased metalloproteinase level at synapses of Fmr1 knock-out mice. We propose that such a local effect can contribute to the aberrant dendritic spine morphology observed in the Fmr1 knock-out mice and in patients with FXS.
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3. Jing W, Fang J. {{Brief Report: Do Children with Autism Gather Information from Social Contexts to Aid Their Word Learning?}}. {J Autism Dev Disord}. 2013.
Typically developing (TD) infants could capitalize on social eye gaze and social contexts to aid word learning. Although children with autism disorder (AD) are known to exhibit atypicality in word learning via social eye gaze, their ability to utilize social contexts for word learning is not well understood. We investigated whether verbal AD children exhibit word learning ability via social contextual cues by late childhood. We found that AD children, unlike TD controls, failed to infer the speaker’s referential intention through information gathered from the social context. This suggests that TD children can learn words in diverse social pragmatic contexts in as early as toddlerhood whereas AD children are still unable to do so by late childhood.
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4. Li YW, Ma L, Sui B, Cao CH, Liu XD. {{Etomidate with or without flumazenil anesthesia for stem cell transplantation in autistic children}}. {Drug Metabol Drug Interact}. 2013: 1-5.
Abstract Background: The aim of this study was to investigate etomidate administration with or without flumazenil in autistic children who underwent intrathecal transplantation of stem cells by lumbar puncture. Methods: Forty autistic children aged 2-12, who were scheduled for stem cell transplantation via lumbar puncture under anesthesia, were randomized for a double-blind study. The children were randomly assigned to two groups: the flumazenil group (group F, n=20) and the etomidate group (group E, n=20). All children received 0.2 mg/kg of etomidate. In the case of inadequate anesthesia, patients received repeated doses of 0.1 mg/kg of etomidate until reaching deep sedation. After operation, children in group F were given flumazenil (0.01 mg/kg) and children in group E received placebo. Heart rate (HR), mean arterial pressure, oxygen saturation, respiratory rate, the Ramsay sedation score (RSS), and recovery time of all children were continuously monitored and recorded during the entire procedure. Results: After anesthesia, blood pressure and HR measurements were not significantly changed in both groups compared with the baseline. There were no respiratory depression, bradycardia, hypotension, nausea, and vomiting. Five patients complained of pain on the site of injection. Myoclonus occurred in seven patients. Recovery time in group F was significantly shorter than in group E (p<0.001), and after the injection of flumazenil, RSS in group F significantly decreased than in group E. There were no significant differences in operation time. Physician satisfaction in both groups was similar. Conclusions: Etomidate resulted in stable hemodynamic responses and relatively less adverse effects, and flumazenil antagonized the anesthetic effect of etomidate; thus, etomidate with flumazenil is suitable for performing stem cell transplantation in autistic children.
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5. Pop AS, Gomez-Mancilla B, Neri G, Willemsen R, Gasparini F. {{Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development}}. {Psychopharmacology (Berl)}. 2013.
RATIONALE: Fragile X syndrome (FXS) is considered the leading inherited cause of intellectual disability and autism. In FXS, the fragile X mental retardation 1 (FMR1) gene is silenced and the fragile X mental retardation protein (FMRP) is not expressed, resulting in the characteristic features of the syndrome. Despite recent advances in understanding the pathophysiology of FXS, there is still no cure for this condition; current treatment is symptomatic. Preclinical research is essential in the development of potential therapeutic agents. OBJECTIVES: This review provides an overview of the preclinical evidence supporting metabotropic glutamate receptor 5 (mGluR5) antagonists as therapeutic agents for FXS. RESULTS: According to the mGluR theory of FXS, the absence of FMRP leads to enhanced glutamatergic signaling via mGluR5, which leads to increased protein synthesis and defects in synaptic plasticity including enhanced long-term depression. As such, efforts to develop agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. Animal models, particularly the Fmr1 knockout mouse model, have become invaluable in exploring therapeutic approaches on an electrophysiological, behavioral, biochemical, and neuroanatomical level. Two direct approaches are currently being investigated for FXS treatment: reactivating the FMR1 gene and compensating for the lack of FMRP. The latter approach has yielded promising results, with mGluR5 antagonists showing efficacy in clinical trials. CONCLUSIONS: Targeting mGluR5 is a valid approach for the development of therapeutic agents that target the underlying pathophysiology of FXS. Several compounds are currently in development, with encouraging results.
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6. Stockbridge MD, Happe FG, White SJ. {{Impaired Comprehension of Alternating Syntactic Constructions in Autism}}. {Autism Res}. 2013.
Individuals on the higher-functioning end of the autism spectrum have significant impairments in communication. Language delay can occur, particularly in syntactic or structural linguistic knowledge. However, classically observed semantic deficits generally overshadow these structural deficits. This research examined the potential effects on comprehension of dative expressions that exhibited syntactic alternation versus those that were restricted, whether in syntactic construction or through marked semantic differences in construction. Children with autism and matched neurotypical control participants were presented with a sentence battery of dative statements representing these variations in construction and were asked to display basic comprehension of the sentence meaning by identifying the recipient, or indirect object, of the dative verb. Construction, restriction, and semantic differentiation variables were analyzed for potential effects on the rate of accurate comprehension. Both groups performed with greater accuracy when dative expressions used a prepositional phrase than when the dative action was expressed in the syntax. The autism group performed more poorly when the dative expression could syntactically alternate than when it was restricted. These effects improve our knowledge of how children with autism understand alternating grammatical constructions. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
