1,171 research outputs found
Modulation of the GABAergic pathway for the treatment of fragile X syndrome.
Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS
The Scholarship of Critique and Power
Critique can be defined as disciplinary feedback, analysis, or assessment provided to an individual or within a group, be it a classroom or a team. At a fundamental level, it is an exchange of ideas, impressions, evaluations, opinions, reflections, judgments, speculations, or suggestions to oneself or between two or more participants in a defined context. Scholars describe critique as a signature pedagogy in many disciplines, a cornerstone of the educational experience. There has been scant critical analysis of how critique also represents a performance of power with roots in positions of authority, expertise, or assigned roles. Such power dynamics have been explored in some areas within SoTL, for example in scholarship on assessment, epistemic disobedience, social justice, feminist pedagogies, and critical race theory. However, this has generally not been the case within the scholarship on critique. To better understand the dimensions of power in the context of critique we developed a conceptual framework that can be applied at the individual level (teacher to student, student to student) as well as the systemic level (critique as a construct of cultural hegemony in a specific episteme). Drawing from theoretical and pedagogical literature in areas such as cultural studies, whiteness studies, design education, and assessment, the conceptual framework defines power in three main expressions: power as inequity, power as authority, and power as cultural hegemony. The framework can be used to identify and define power within the critique context and to also inform reflection and shift perspectives at various academic levels
Developmental profiles of infants with an FMR1 premutation
Abstract Background Emerging evidence suggests that a subset of FMR1 premutation carriers is at an increased risk for cognitive, emotional, and medical conditions. However, because the premutation is rarely diagnosed at birth, the early developmental trajectories of children with a premutation are not known. Methods This exploratory study examined the cognitive, communication, and social-behavioral profiles of 26 infants with a premutation who were identified through participation in a newborn screening for fragile X syndrome pilot study. In this study, families whose newborn screened positive for an FMR1 premutation were invited to participate in a longitudinal study of early development. Twenty-six infants with the premutation and 21 matched, screen-negative comparison babies were assessed using validated standardized measures at 6-month intervals starting as young as 3 months of age. The babies were assessed up to seven times over a 4-year period. Results The premutation group was not statistically different from the comparison group on measures of cognitive development, adaptive behavior, temperament, or overall communication. However, the babies with the premutation had a significantly different developmental trajectory on measures of nonverbal communication and hyperresponsivity to sensory experiences. They also were significantly more hyporesponsive at all ages than the comparison group. Cytosine-guanine-guanine repeat length was linearly associated with overall cognitive development. Conclusions These results suggest that infants with a premutation may present with subtle developmental differences as young as 12 months of age that may be early markers of later anxiety, social deficits, or other challenges thought to be experienced by a subset of carriers
Changes in cocoa properties induced by the alkalization process: A review
[EN] Alkalization, also known as "Dutching," is an optional, but very useful, step taken in the production chain of cocoa to darken its color, modify its taste, and increase natural cocoa solubility. Over the years, various attempts have been made to design new and more effective alkalization methods. Moreover, different authors have attempted to elucidate the impact of alkalization on the physicochemical, nutritional, functional, microbiological, and sensory characteristics of alkalized cocoa. The aim of this review is to provide a clear guide about not only the conditions that can be applied to alkalize cocoa, but also the reported effects of alkalization on the nutritional, functional, microbiological, and sensory characteristics of cocoa. The first part of this review describes different cocoa alkalization systems and how they can be tuned to induce specific changes in cocoa properties. 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A Randomized Controlled Trial of Sertraline in Young Children With Autism Spectrum Disorder.
Objective: Selective serotonin reuptake inhibitors like sertraline have been shown in observational studies and anecdotal reports to improve language development in young children with fragile X syndrome (FXS). A previous controlled trial of sertraline in young children with FXS found significant improvement in expressive language development as measured by the Mullen Scales of Early Learning (MSEL) among those with comorbid autism spectrum disorder (ASD) in post hoc analysis, prompting the authors to probe whether sertraline is also indicated in nonsyndromic ASD. Methods: The authors evaluated the efficacy of 6 months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 58 children with ASD aged 24 to 72 months. Results: 179 subjects were screened for eligibility, and 58 were randomized to sertraline (32) or placebo (26). Eight subjects from the sertraline arm and five from the placebo arm discontinued. Intent-to-treat analysis showed no significant difference from placebo on the primary outcomes (MSEL expressive language raw score and age equivalent combined score) or secondary outcomes. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events possibly related to study treatment occurred. Conclusion: This randomized controlled trial of sertraline treatment showed no benefit with respect to primary or secondary outcome measures. For the 6-month period, treatment in young children with ASD appears safe, although the long-term side effects of low-dose sertraline in early childhood are unknown. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02385799
Fragile X Newborn Screening: Lessons Learned From a Multisite Screening Study
BACKGROUND: Delays in the diagnosis of children with fragile X syndrome (FXS) suggest the possibility of newborn screening as a way to identify children earlier. However, FXS does not have a proven treatment that must be provided early, and ethical concerns have been raised about the detection of infants who are carriers. This article summarizes major findings from a multisite, prospective, longitudinal pilot screening study.
METHODS: Investigators in North Carolina, California, and Illinois collaborated on a study in which voluntary screening for FXS was offered to parents in 3 birthing hospitals. FXS newborn screening was offered to >28 000 families to assess public acceptance and determine whether identification of babies resulted in any measurable harms or adverse events. Secondary goals were to determine the prevalence of FMR1 carrier gene expansions, study the consent process, and describe early development and behavior of identified children.
RESULTS: A number of publications have resulted from the project. This article summarizes 10 "lessons learned" about the consent process, reasons for accepting and declining screening, development and evaluation of a decision aid, prevalence of carriers, father participation in consent, family follow-up, and maternal reactions to screening.
CONCLUSIONS: The project documented public acceptance of screening as well as the challenges inherent in obtaining consent in the hospital shortly after birth. Collectively, the study provides answers to a number of questions that now set the stage for a next generation of research to determine the benefits of earlier identification for children and families
The challenges of clinical trials in fragile X syndrome
RATIONALE: Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement.
OBJECTIVES: We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders.
RESULTS: Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains.
CONCLUSION: Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders
A Comparison of Univariate and Multivariate Forecasting Models Predicting Emergency Department Patient Arrivals during the COVID-19 Pandemic
The COVID-19 pandemic has heightened the existing concern about the uncertainty surrounding patient arrival and the overutilization of resources in emergency departments (EDs). The prediction of variations in patient arrivals is vital for managing limited healthcare resources and facilitating data-driven resource planning. The objective of this study was to forecast ED patient arrivals during a pandemic over different time horizons. A secondary objective was to compare the performance of different forecasting models in predicting ED patient arrivals. We included all ED patient encounters at an urban teaching hospital between January 2019 and December 2020. We divided the data into training and testing datasets and applied univariate and multivariable forecasting models to predict daily ED visits. The influence of COVID-19 lockdown and climatic factors were included in the multivariable models. The model evaluation consisted of the root mean square error (RMSE) and mean absolute error (MAE) over different forecasting horizons. Our exploratory analysis illustrated that monthly and weekly patterns impact daily demand for care. The Holt–Winters approach outperformed all other univariate and multivariable forecasting models for short-term predictions, while the Long Short-Term Memory approach performed best in extended predictions. The developed forecasting models are able to accurately predict ED patient arrivals and peaks during a surge when tested on two years of data from a high-volume urban ED. These short-and long-term prediction models can potentially enhance ED and hospital resource planning
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