1. Berry-Kravis EM, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, Mu Y, Nguyen DV, Gonzalez-Heydrich J, Wang PP, Carpenter RL, Bear MF, Hagerman RJ. {{Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial}}. {Science translational medicine}. 2012 Sep 19;4(152):152ra27.
Research on animal models of fragile X syndrome suggests that STX209, a gamma-aminobutyric acid type B (GABA(B)) agonist, might improve neurobehavioral function in affected patients. We evaluated whether STX209 improves behavioral symptoms of fragile X syndrome in a randomized, double-blind, placebo-controlled crossover study in 63 subjects (55 male), ages 6 to 39 years, with a full mutation in the FMR1 gene (>200 CGG triplet repeats). We found no difference from placebo on the primary endpoint, the Aberrant Behavior Checklist-Irritability (ABC-I) subscale. In the other analyses specified in the protocol, improvement was seen on the visual analog scale ratings of parent-nominated problem behaviors, with positive trends on multiple global measures. Post hoc analysis with the ABC-Social Avoidance scale, a newly validated scale for the assessment of fragile X syndrome, showed a significant beneficial treatment effect in the full study population. A post hoc subgroup of 27 subjects with more severe social impairment showed improvements on the Vineland II-Socialization raw score, on the ABC-Social Avoidance scale, and on all global measures. STX209 was well tolerated, with 8% incidences of sedation and of headache as the most frequent side effects. In this exploratory study, STX209 did not show a benefit on irritability in fragile X syndrome. Nonetheless, our results suggest that GABA(B) agonists have potential to improve social function and behavior in patients with fragile X syndrome.
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2. Chang L, Chui CS, Ding HJ, Hwang IM, Ho SY. {{Calibration of EBT2 film by the PDD method with scanner non-uniformity correction}}. {Physics in medicine and biology}. 2012 Sep 21;57(18):5875-87.
The EBT2 film together with a flatbed scanner is a convenient dosimetry QA tool for verification of clinical radiotherapy treatments. However, it suffers from a relatively high degree of uncertainty and a tedious film calibration process for every new lot of films, including cutting the films into several small pieces, exposing with different doses, restoring them back and selecting the proper region of interest (ROI) for each piece for curve fitting. In this work, we present a percentage depth dose (PDD) method that can accurately calibrate the EBT2 film together with the scanner non-uniformity correction and provide an easy way to perform film dosimetry. All films were scanned before and after the irradiation in one of the two homemade 2 mm thick acrylic frames (one portrait and the other landscape), which was located at a fixed position on the scan bed of an Epson 10 000XL scanner. After the pre-irradiated scan, the film was placed parallel to the beam central axis and sandwiched between six polystyrene plates (5 cm thick each), followed by irradiation of a 20 x 20 cm(2) 6 MV photon beam. Two different beams on times were used on two different films to deliver a dose to the film ranging from 32 to 320 cGy. After the post-irradiated scan, the net optical densities for a total of 235 points on the beam central axis on the films were auto-extracted and compared with the corresponding depth doses that were calculated through the measurement of a 0.6 cc farmer chamber and the related PDD table to perform the curve fitting. The portrait film location was selected for routine calibration, since the central beam axis on the film is parallel to the scanning direction, where non-uniformity correction is not needed (Ferreira et al 2009 Phys. Med. Biol. 54 1073-85). To perform the scanner non-uniformity calibration, the cross-beam profiles of the film were analysed by referencing the measured profiles from a Profiler. Finally, to verify our method, the films were exposed to 60 degrees physical wedge fields and the compositive fields, and their relative dose profiles were compared with those from the water phantom measurement. The fitting uncertainty was less than 0.5% due to the many calibration points, and the overall calibration uncertainty was within 3% for doses above 50 cGy, when the average of four films were used for the calibration. According to our study, the non-uniformity calibration factor was found to be independent of the given dose for the EBT2 film and the relative dose differences between the profiles measured by the film and the Profiler were within 1.5% after applying the non-uniformity correction. For the verification tests, the relative dose differences between the measurements by films and in the water phantom, when the average of three films were used, were generally within 3% for the 60 degrees wedge fields and compositive fields, respectively. In conclusion, our method is convenient, time-saving and cost-effective, since no film cutting is needed and only two films with two exposures are needed.
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3. Henderson C, Wijetunge L, Kinoshita MN, Shumway M, Hammond RS, Postma FR, Brynczka C, Rush R, Thomas A, Paylor R, Warren ST, Vanderklish PW, Kind PC, Carpenter RL, Bear MF, Healy AM. {{Reversal of Disease-Related Pathologies in the Fragile X Mouse Model by Selective Activation of GABAB Receptors with Arbaclofen}}. {Science translational medicine}. 2012 Sep 19;4(152):152ra28.
Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, results from the transcriptional silencing of FMR1 and loss of the mRNA translational repressor protein fragile X mental retardation protein (FMRP). Patients with FXS exhibit changes in neuronal dendritic spine morphology, a pathology associated with altered synaptic function. Studies in the mouse model of fragile X have shown that loss of FMRP causes excessive synaptic protein synthesis, which results in synaptic dysfunction and altered spine morphology. We tested whether the pharmacologic activation of the gamma-aminobutyric acid type B (GABA(B)) receptor could correct or reverse these phenotypes in Fmr1-knockout mice. Basal protein synthesis, which is elevated in the hippocampus of Fmr1-knockout mice, was corrected by the in vitro application of the selective GABA(B) receptor agonist STX209 (arbaclofen, R-baclofen). STX209 also reduced to wild-type values the elevated AMPA receptor internalization in Fmr1-knockout cultured neurons, a known functional consequence of increased protein synthesis. Acute administration of STX209 in vivo, at doses that modify behavior, decreased mRNA translation in the cortex of Fmr1-knockout mice. Finally, the chronic administration of STX209 in juvenile mice corrected the increased spine density in Fmr1-knockout mice without affecting spine density in wild-type mice. Thus, activation of the GABA(B) receptor with STX209 corrected synaptic abnormalities considered central to fragile X pathophysiology, a finding that suggests that STX209 may be a potentially effective therapy to treat the core symptoms of FXS.
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4. Kanellopoulos AK, Semelidou O, Kotini AG, Anezaki M, Skoulakis EM. {{Learning and memory deficits consequent to reduction of the fragile x mental retardation protein result from metabotropic glutamate receptor-mediated inhibition of cAMP signaling in Drosophila}}. {The Journal of neuroscience : the official journal of the Society for Neuroscience}. 2012 Sep 19;32(38):13111-24.
Loss of the RNA-binding fragile X protein [fragile X mental retardation protein (FMRP)] results in a spectrum of cognitive deficits, the fragile X syndrome (FXS), while aging individuals with decreased protein levels present with a subset of these symptoms and tremor. The broad range of behavioral deficits likely reflects the ubiquitous distribution and multiple functions of the protein. FMRP loss is expected to affect multiple neuronal proteins and intracellular signaling pathways, whose identity and interactions are essential in understanding and ameliorating FXS symptoms. We used heterozygous mutants and targeted RNA interference-mediated abrogation in Drosophila to uncover molecular pathways affected by FMRP reduction. We present evidence that FMRP loss results in excess metabotropic glutamate receptor (mGluR) activity, attributable at least in part to elevation of the protein in affected neurons. Using high-resolution behavioral, genetic, and biochemical analyses, we present evidence that excess mGluR upon FMRP attenuation is linked to the cAMP decrement reported in patients and models, and underlies olfactory associative learning and memory deficits. Furthermore, our data indicate positive transcriptional regulation of the fly fmr1 gene by cAMP, via protein kinase A, likely through the transcription factor CREB. Because the human Fmr1 gene also contains CREB binding sites, the interaction of mGluR excess and cAMP signaling defects we present suggests novel combinatorial pharmaceutical approaches to symptom amelioration upon FMRP attenuation.
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5. Lim F, Downs J, Li J, Bao XH, Leonard H. {{Caring for a child with severe intellectual disability in China: The example of Rett syndrome}}. {Disability and rehabilitation}. 2012 Sep 20.
Purpose: Rett syndrome is one of several genetic disorders known to cause severe intellectual and physical disability, mostly in girls. Girls affected by Rett syndrome appear to develop normally in the first 6 months of life, after which the usual clinical presentation comprises regression of communication and hand skills, the appearance of hand stereotypies and impaired gait. Intellectual disability affects more than 1.5% of the population of children in developing countries yet we know little about the daily lives and support services available for them and their caregivers. Method: This qualitative study explored the daily experiences of 14 mothers and one grandmother caring for a child with Rett syndrome in China via telephone interviews. Results: Participants reported a lack of education, rehabilitation and support services available to them. Limited access to information reduced families’ capacity to adequately meet the needs of their child. These gaps were further exacerbated by discrimination and perceived stigma from some members of the community. Conclusions: Additional support services and educational programs at the governmental level can improve the quality of life of persons with an intellectual disability and their families and programs involving community participation in the care of people with disabilities may help to address discrimination. [Box: see text].
