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Prevalence of FMR1 repeat expansions in movement disorders /Hall, Deborah A., January 2008 (has links)
Thesis (Ph.D. in Clinical Science) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 59-67). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;
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Les facteurs de transcription impliqués dans la régulation de l'expression du gène du retard mental lié à l'X fragile-1 et du gène du récepteur B1 des bradykininesAngers, Martin. January 1900 (has links) (PDF)
Thèse (Ph.D.)--Université Laval, 2004. / Titre de l'écran-titre (visionné le 29 novembre 2004). Bibliogr.
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Baseline characteristics influencing placebo response in clinical trials of treatments for fragile X syndromePenz, Craig Christopher 12 March 2016 (has links)
Fragile X Syndrome (FXS) is a disorder caused by a congenital mutation of the FMR1 gene on the X chromosome. FXS is associated with moderate to severe intellectual disability and is one known cause of autism spectrum disorders. There are no approved medications to treat FXS symptoms. In 2013, Seaside Therapeutics completed two Phase 3 studies of an investigational medication, STX209, for treatment of social withdrawal in FXS. Efficacy results for these studies were not positive.
Clinical trials of psychoactive drugs often fail to show a statistical difference from placebo controls and a robust response to placebo is often cited as a reason for the failure. Retrospective studies of baseline variables in clinical trials have identified characteristics that were associated with an increased likelihood of responding to placebo. Such information is valuable for the design of future clinical trials and no such studies have been conducted in FXS. This study was a post-hoc analysis of data from Seaside Therapeutics' Phase 3 clinical trials in FXS. Baseline variables for subjects receiving placebo were pooled for analysis. To determine if a subject responded to placebo, the parent-rated ABC-SA and the ABC-IR were used. Clinician-rated assessments, including the CGI-S and CGI-I, were examined as well. Two-sample t-testing, one-way ANOVA testing, and correlation coefficients were calculated to compare the responses of subjects with different baseline characteristics. General linear regression modeling was used to determine if there were multiple baseline variables that could predict placebo response. Logistic regression modeling was used to determine if the baseline variables could predict whether a subject had a higher chance of being a treatment responder.
A total of 287 subjects were randomized and completed the Phase 3 studies. Analyses for this study were conducted in a subgroup containing 106 subjects who received placebo. 76% improved during the study on the ABC-SA, indicating that there was a strong placebo effect on the study. None of the dichotomous baseline variables were associated with statistically significant differences in ABC-SA, ABC-IR, CGI-S, or CGI-I scores. Placebo-treated subjects in the 209FX302 study who were taking antipsychotics improved less on the CGI-S than those not on those medications. A similar pattern was observed on the ABC-IR and ABC-SA. Other categorical baseline variables were tested and there was no difference in the mean changes. The CGI-S score at baseline appeared to predict a statistically significant difference in the ABC-IR as more severe subjects were more likely to show a larger change in the ABC-IR. Similar, although not statistically significant results were seen with ABC-SA, CGI-I, and CGI-S changes, in that more severe subjects had greater responses to placebo.
ABC-IR score changes were correlated independently with each of the ABC-C subscales but also with parental distress, CGI-S, and VAS-Anxiety. Only one variable, the ABC-IR at baseline, was significantly correlated with the ABC-SA score change, the rest of the variables were not significant. A multiple linear regression model predicting placebo response for the ABC-SA included only the baseline ABC-SA score. When the studies were modeled separately, the 209FX302 model contained additional variables including gender, antipsychotic use, and ABC-stereotypy scores. For the ABC-IR change model, the highest correlation coefficient was found in the 209FX301 study with ABC-IR, gender, Vineland-communication, maternal FMR1 status, and ABC-SL included in the model. 70% of the placebo treated subjects improved on the ABC-SA by at least 25%. Placebo responders were less frequently observed in clinician-rated assessments such as the CGI-I and CGI-S. In logistic regression models, for the ABC-IR response, a higher score on the hyperactivity subscale of the ABC-C was predictive of a lower placebo response. The CGI-S model was statistically significant and included the subject's age, race and ABC-IS score. The ABC-SA response could be modeled only in the 209FX302 study with gender and ADHD medication use remaining in the model. Also in the 209FX302 study, subjects were far less likely to be a responder on the ABC-IR or a total responder, if they were taking antipsychotic medications.
Results of this study indicate that the ABC-SA is not recommended in future trials in the FXS patient population. Future trials should also allow ADHD and antipsychotic medication use as they were associated with a lower placebo response in some analyses. In addition, due to their inclusion in regression models, future studies should consider baseline variables such as parental stress and Vineland scores, and when designing study eligibility criteria or stratification variables.
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Avaliação do emprego de um novo método de triagem molecular da síndrome do cromossomo X frágil em indivíduos brasileiros /Curtis, Karen Maria de Carvalho. January 2010 (has links)
Resumo: A síndrome do cromossomo X frágil (SXF) é a forma mais comum de deficiência mental herdada. A doença ocorre pela expansão das repetições de trinucleotídeos na região 5' não traduzida do gene FMR1 no cromossomo X. Dependendo do número de repetições CGG originam-se 4 tipos de alelos: normal (NL), pré-mutado (PM), gray zone (GZ) e mutação completa (FM). A instabilidade e expansão das repetições, aliado à metilação do DNA, causam a diminuição ou ausência na produção da proteína FMRP, a qual é essencial para a função cerebral. O diagnóstico da SXF tem sido realizado principalmente por análise molecular Southern blot. Porém, este método é trabalhoso, demorado e de custo elevado. Recentemente foi desenvolvido um novo método molecular para triagem da SXF por PCR, que segundo os autores, é rápido, de baixo custo, e eficiente na detecção das repetições CGG em homens e mulheres. No entanto, notou-se a ausência de informações importantes para reprodução do método. Os objetivos deste estudo foram: (i) padronizar a técnica de PCR proposta por Tassone et al., (2008), adaptando-a, devido a carência de informações metodológicas; (ii) comprovar a exatidão (acurácia), sensibilidade e especificidade do método, comparando-a ao Southern blot; (iii) avaliar a aplicação da técnica utilizando DNA extraído de diferentes materiais biológicos/métodos de extração; (iv) estimar o custo e o tempo de execução do método no mercado nacional. Os materiais biológicos utilizados foram: sangue coletado por sistema à vácuo e células da mucosa oral, que foram extraídos por solventes orgânicos e sangue coletado em cartões FTA, purificado pelo kit Whatman. Obtevese sucesso na reprodução do método da PCR em 75 indivíduos utilizando a enzima Expand Long Template PCR System (Roche Diagnostics). A exatidão (acurácia), sensibilidade e especificidade foram... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Fragile X Syndrome (FXS) is the most common form of inherited mental retardation. The disease occurs by the expansion of triplet nucleotide repeats in the 5' untranslated of the FMR1 gene on chromosome X. Depending on the number of CGG repeats four types of alleles originate from it: normal (NL), pre-mutated (PM), gray zone (GZ) and full mutation (FM). The instability and expansion of these repetitions, together with the methylation of DNA, cause a decrease or absence in the production of the protein FMRP, which is essential for the brain function. The diagnosis of FXS has been done mainly by molecular analysis Southern blot. However, this method is laborious, time consuming and expensive. Recently we have developed a new molecular method for FXS screening by PCR, which according to the authors, is rapid, inexpensive, and efficient in the detection of CGG repeats in male and female. However, we noted the absence of important information for breeding method. The objectives of this study were: (i) to standardize the PCR technique proposed by Tassone et al. (2008), adapting it, due to the lack of methodological information, (ii) verify the accuracy, sensitivity and specificity of the method, comparing it to the Southern blot, and (iii) to evaluate the technique using DNA extracted from different biological materials / extraction methods, and (iv) estimate the cost and time of the method execution in the domestic market. The biological materials used were: blood collected by vacuum system and oral mucosal cells, which were extracted by organic solvents and blood collected on FTA cards, purified by Whatman kit. Success was achieved in the reproduction of the PCR method in 75 individuals using the enzyme Expand Long Template PCR System (Roche Diagnostics). The accuracy, sensitivity and specificity were 100% when analyzing the total sample, indicating that the technique can detect the presence... (Complete abstract click electronic access below) / Orientador: Regina Maria Barretto Cicarelli / Coorientador: Raquel Mantuaneli Scarel Caminaga / Banca: Robson Francisco Carvalho / Banca: Débora Aparecida Rodrigueiro / Mestre
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Convergence of synaptic pathophysiology in the hippocampus of Fmr1-/y and Syngap1+/- miceBarnes, Stephanie A. January 2015 (has links)
The genetic causes of intellectual disability (ID) and autism spectrum disorder (ASD) are frequently associated with mutations in genes that encode synaptic proteins. A recent screen of ID patients has revealed that approximately 4% of individuals carry spontaneous autosomal-dominant de novo mutations in the SYNGAP1 gene. This gene encodes the synaptic GTPase activating protein (SYNGAP) a known regulator of Ras signalling. Investigations into the pathological consequences of Syngap1 haploinsufficiency (Syngap+/−) in mice have reported abnormalities in behaviour, synaptic plasticity and dendritic spine development. These are analogous to findings from the mouse model of fragile X syndrome (FXS; Fmr1-/y), the most common inherited form of ID. One of the prominent phenotypes reported in the mouse model of FXS is that a form of hippocampal long-term depression (LTD) mediated by the activation of Group 1 (Gp1) metabotropic glutamate (mGlu) receptors is enhanced and independent of new protein synthesis (Huber et al. 2002; Nosyreva et al. 2006). The cause of these synaptic plasticity deficits together with other cognitive abnormalities observed in FXS are thought to arise, in part, from excessive protein synthesis, the consequence of altered mGlu5 receptor signalling via the Ras-ERK1/2 signalling pathway. Enhanced protein synthesis rates in Fmr1-/y mice can be corrected by either inhibiting mGlu5 receptors or reducing Ras and subsequent ERK1/2 activity (Osterweil et al. 2013). In this thesis mGluR-dependent LTD was examined at Schaffer collateral/commissural inputs to CA1 pyramidal neurones in hippocampal slices obtained from Fmr1-/y, Syngap+/− and Fmr1-/ySyngap+/− double mutant mice. Extracellular field recordings reveal that acute application of the Gp1 mGluR agonist dihydroxyphenylglycine (DHPG) induces a form of mGluR-dependent LTD that is enhanced and independent of new protein synthesis in CA1 of Fmr1-/y mice. In Syngap+/− mice, the magnitude of mGluR-dependent LTD is also significantly increased relative to WT littermates and insensitive to protein synthesis inhibitors. Furthermore, in the Fmr1-/ySyngap+/− double mutant, Syngap haploinsufficiency occludes the increase in mGluR-dependent LTD caused by the loss of FMRP. In addition, metabolic labelling studies reveal basal protein synthesis rates to be modestly enhanced in the hippocampus of Fmr1-/y mice compared to WT mice. Importantly this phenotype translates to the rat model of FXS. In Syngap+/- hippocampal slices, basal protein synthesis rates are also significantly elevated compared to WT counterparts. Interestingly, elevated basal protein synthesis rates in Syngap+/- mice could be corrected in the hippocampus by similarly pharmacological strategies employed in Fmr1-/y mice. The comparable neuropathophysiology we observe between Syngap+/− and Fmr1-/y mice suggests that SYNGAP and fragile X mental retardation protein (FMRP) may converge on similar biochemical pathways raising the intriguing possibility that therapeutic strategies used in the treatment of FXS may also be of benefit in treating individuals with ID caused by mutations in SYNGAP1.
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La prévention de la dépendance : facteurs associés à l'observance d'une intervention multidomaine / Prevention of dependency : associated factors of multidomaine interventionDupuy, Charlotte 20 October 2015 (has links)
Entre 2000 et 2040, la population âgée fragile sera multipliée par 2,5 et touchera 10 millions de sujets âgés de 65 ans et plus. Les études épidémiologiques récentes ont illustré que la dépendance est fréquente et multidimensionnelle (impliquant des déficits fonctionnels, cognitifs et sensoriels). Récemment, des éléments tels que l'effet protecteur de l'activité physique ou encore de la nutrition (en action isolée) sur le déclin cognitif et fonctionnel sont bien connus cependant peu d'études se sont intéressées à l'impact d'une intervention multidomaine. L'efficacité de ces interventions est actuellement en cours d'étude dans des études randomisées et contrôlées (MAPT, Do-health, Mid-frail, Finger, preVida). Ainsi, il semble important d'étudier l'observance et les facteurs prédicteurs (la motivation et les obstacles pour ces personnes âgées fragiles) de la participation à un programme de prévention à long terme. Pour déterminer la population cible à risque de perte d'autonomie chez les personnes âgées, l'étude de la définition la plus pertinente de la sarcopénie est nécessaire. La conception des essais liés à des facteurs nutritionnels pertinents (la vitamine D et les compléments nutritionnels oraux(CNO)) est également discutée actuellement. / Between 2000 and 2040, the elderly frail population will be multiplied by 2,5 to affect 10 million people aged 65 years and over. Previous epidemiologic studies have highlighted that functional limitations are frequent and multidimensional (associated with functional, cognitive and sensorial decline). Currently, the evidence for the protective role of physical activity or nutrition (action isolated) on cognitive and functional decline are well known but few studies have examined the impact of multidomain interventions. The effectiveness of such interventions must be demonstrated in the current randomized trials. It seems important to study rates of adherence and attrition factors (motivation and barriers for these frail elderly) to participate in a prevention program of long-term. To determine the target population to prevent disability in elderly, consideration of the most relevant definition of sarcopenia is necessary. The design of trials related to the relevant nutritional factors (vitamin D and the Oral Nutritional Supplement (ONS)) is also currently discussed.
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Ultrastructure and morphometric analysis of hippocampal synapses in the Fmr1-/y mouse model of fragile X syndromeWeiser Novak, Samuel 29 April 2015 (has links)
Fragile X Syndrome (FXS) is a prevalent monogenic disease, often presenting with cognitive and neurological disorders including autism and epilepsy. The Fmr1 gene - transcriptionally silenced in FXS - normally encodes the Fragile X Mental Retardation Protein (FMRP), which acts as an activity dependent translational regulator at the base of dendritic spines. In an attempt to understand its role, dendritic spines in the dentate gyrus (DG) and cornu ammonis 1 (CA1) hippocampal regions of three-week old Fmr1- mice were analyzed and compared to wildtype (WT) littermate controls using electron microscopy. Dendritic spines with a continuous profile of the parent dendrite, spine neck, and spine head complete with synaptic components (presynaptic vesicles and postsynaptic densities) were included in our morphological analyses. We observed no changes in postsynaptic density length (DG: 5.69±0.30/6.18±0.85; SR: 7.55±0.87/6,96±0.33 µm/100 µm2; p=0.627/0.620), synapse density (DG: 32.3±3.8/30.3±1.9; SR: 34.4±1.8/30.7±0.5 synapses/100 µm2; p=0.655/0.270), spine head diameters (DG: 0.524±0.016/0.529±0.014; SR: 0.524±0.014/0.515±0.014 µm; p=0.098/0.20) or spine neck lengths (DG: 0.457±0.016/0.485±0.019; SR: 0.421 ± 0.015/0.425±0.017 µm; p=0.14/0.26), but found that in the DG spine necks were significantly narrower in the Fmr1- mice (0.193±0.0062/0.167±0.0064 µm; p=0.0002), whereas there were no changes in CA1 spine neck widths (0.162±0.0049/0.161±0.0061 µm; p=0.073). Estimated resistance calculated from spine necks morphologies revealed a ~1.7 fold increase in the Fmr1- DG compared to WT DG. These findings support that FMRP plays a role in granule cell spine neck structure and may influence synaptic signal compartmentalization and propagation in a regionally dependent manner. / Graduate
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Hippocampal Synaptic Plasticity in a Murine Knock-Out Model of Fragile X SyndromeGandhi, Reno January 2014 (has links)
The dissertation is divided into two separate experiments that explore the effects of visual-spatial learning on PSD-95 dorsal hippocampal expression. Specifically, the aim of these studies was to explore the effect of learning an assay, the Hebb-Williams mazes, on the protein expression of PSD-95 in Fmr1 KO mice. PSD-95 is an important scaffolding protein hypothesized to be involved in learning and memory. In cellular models of Fragile X Syndrome it has been shown to be dysregulated but it has never been measured following behavioural learning. Establishment of a deficit using an ecologically valid behavioural assay could lead to the development of novel interventions. Study one employed a subset of the Hebb-Williams mazes of various levels of difficulty to evaluate PSD-95 protein expression in Fmrp intact and Fmr1 KO mice following learning. The results revealed significant increases in PSD-95 protein expression in control runners when compared to Fmr1 KO mice. There was a negative correlation between PSD-95 protein levels and mean total errors on the mazes meaning that as expression was increased, errors were decreased. The goals of study two were to reverse the molecular and behavioural deficits using pharmacological antagonist treatment shown to be effective in cellular models of Fragile X Syndrome. Fmr1 KO mice were treated with either saline or 20 mg/kg of a metabotropic glutamate receptor antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP). Relative to saline treated controls, drug treated Fmr1 KO mice made fewer errors on the same subset of Hebb-Williams mazes used in study one. Latency to complete these mazes did not differ between groups, indicating that MPEP treatment does not adversely affect motor functioning. Protein assessment revealed that PSD-95 was selectively rescued in MPEP treated mice and not saline controls. Similar to study one, a negative correlation between PSD-95 protein levels and mean total errors was observed. When taken together, these studies indicate that protein deficits are associated with a deficit of learning that can be reversed with a selective glutamate receptor antagonist. One of the strengths of the Hebb-Williams mazes is that performance is measurable without floor or ceiling effects, which plague other common behavioural assays. These data further suggest that pharmacological antagonist treatments may be promising in correcting the learning deficits in human Fragile X Syndrome patients.
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Private rituals, public selves : reclaiming urban public space through celebrating the ritual of washingSteynberg, Kristen Fay January 2014 (has links)
The thesis explores the existing urban landscape of Jeppestown, specifically with
regard to the consequences of the hijacking of inner-city buildings for residential
purposes. The aim is to reclaim public space from the post-industrial landscape and
reconfigure the existing fabric, by means of a fragile intervention so as to connect the
social realm with the built fabric. The project accepts the hijacked typology of urban
living as part of the context. It is viewed as an existing and ongoing condition, which
far exceeds the current capacity of state-funded housing. From this stance, the project
aims to provide public services that celebrate the rituals of washing in a meaningful
and accessible way. The project endeavours to utilise theories related to African space
to address local contemporary urban issues contextually. It uses the rituals of the
everyday as a muse for creating eventful public space, an amenity which is becoming
increasingly important with the growing densities of South Africa’s cities. / Dissertation (MArch(Prof))--University of Pretoria, 2014. / Architecture / MArch(Prof) / Unrestricted
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Food Insecurity and Housing Instability for Fragile FathersResor, Jessica 04 April 2020 (has links)
While reducing food insecurity is a major health initiative, most studies and programs focus only on health-related outcomes and not on other types of hardships. This secondary data analysis of the Fragile Families and Child Wellbeing Study examined the relationship between food insecurity and housing instability with social support, parental depression, and material hardship in vulnerable fathers. Using structural equation modeling on Wave 3 data, the final resulting model was X2 (4, N= 4898) = 3.72 at p = .444. For fathers, material hardship, depression, social support impact the relationship between food insecurity and housing instability. This research has implications for programs and services that may serve low income, single, or minority fathers and families to provide supports to improve food and house instabilities. Agencies and organizations should examine material hardship, not just health-related outcomes. They should provide services for mental health concerns as well as facilitate greater social support.
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