34 research outputs found

    A pilot open label, single dose trial of fenobam in adults with fragile X syndrome

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    ObjectiveA pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS).MethodsTwelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition.ResultsThere were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects.ConclusionsClinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS

    PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

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    Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS

    Open-label add-on treatment trial of minocycline in fragile X syndrome

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    <p>Abstract</p> <p>Background</p> <p>Fragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in <it>fmr1 </it>knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS.</p> <p>Methods</p> <p>Twenty individuals with FXS, ages 13-32, were randomly assigned to receive 100 mg or 200 mg of minocycline daily. Behavioural evaluations were made prior to treatment (baseline) and again 8 weeks after daily minocycline treatment. The primary outcome measure was the Aberrant Behaviour Checklist-Community Edition (ABC-C) Irritability Subscale, and the secondary outcome measures were the other ABC-C subscales, clinical global improvement scale (CGI), and the visual analog scale for behaviour (VAS). Side effects were assessed using an adverse events checklist, a complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA), done at baseline and at 8 weeks.</p> <p>Results</p> <p>The ABC-C Irritability Subscale scores showed significant improvement (p < 0.001), as did the VAS (p = 0.003) and the CGI (p < 0.001). The only significant treatment-related side effects were minor diarrhea (n = 3) and seroconversion to a positive ANA (n = 2).</p> <p>Conclusions</p> <p>Results from this study demonstrate that minocycline provides significant functional benefits to FXS patients and that it is well-tolerated. These findings are consistent with the <it>fmr1 </it>knockout mouse model results, suggesting that minocycline modifies underlying neural defects that account for behavioural abnormalities. A placebo-controlled trial of minocycline in FXS is warranted.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Open-Label Trial NCT00858689.</p

    Prevalence of interstitial pneumonia suggestive of COVID-19 at 18F-FDG PET/CT in oncological asymptomatic patients in a high prevalence country during pandemic period: a national multi-centric retrospective study

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    Purpose: To assess the presence and pattern of incidental interstitial lung alterations suspicious of COVID-19 on fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) ([18F]FDG PET/CT) in asymptomatic oncological patients during the period of active COVID-19 in a country with high prevalence of the virus. Methods: This is a multi-center retrospective observational study involving 59 Italian centers. We retrospectively reviewed the prevalence of interstitial pneumonia detected during the COVID period (between March 16 and 27, 2020) and compared to a pre-COVID period (January\u2013February 2020) and a control time (in 2019). The diagnosis of interstitial pneumonia was done considering lung alterations of CT of PET. Results: Overall, [18F]FDG PET/CT was performed on 4008 patients in the COVID period, 19,267 in the pre-COVID period, and 5513 in the control period. The rate of interstitial pneumonia suspicious for COVID-19 was significantly higher during the COVID period (7.1%) compared with that found in the pre-COVID (5.35%) and control periods (5.15%) (p&nbsp;&lt; 0.001). Instead, no significant difference among pre-COVID and control periods was present. The prevalence of interstitial pneumonia detected at PET/CT was directly associated with geographic virus diffusion, with the higher rate in Northern Italy. Among 284 interstitial pneumonia detected during COVID period, 169 (59%) were FDG-avid (average SUVmax of 4.1). Conclusions: A significant increase of interstitial pneumonia incidentally detected with [18F]FDG PET/CT has been demonstrated during the COVID-19 pandemic. A majority of interstitial pneumonia were FDG-avid. Our results underlined the importance of paying attention to incidental CT findings of pneumonia detected at PET/CT, and these reports might help to recognize early COVID-19 cases guiding the subsequent management

    “Fitness and Fatness” in Children and Adolescents: An Italian Cross-Sectional Study

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    Children with obesity tend to have lower level of physical activity compared to non-obese peers. In fact, sedentary behaviors are prevalent in obese children causing difficulties to perform motor tasks and engaging in sport activities. This, in turn, has direct repercussions on adiposity and related comorbidities. The aim of the study was to investigate several components of fitness and their relationship with the degree of fatness in children. We considered 485 Italian schoolchildren (9.5 ± 1.12 years). BMI and prediction modelling outputs of fat mass were employed as markers of body fatness. Physical fitness (PF) was assessed by the 9-item test battery (explosive power, leg muscle power, arm muscle power, upper body power, coordination, agility, speed and endurance). Differences between groups in the PF tests (p < 0.05) were noted. A similar pattern was reflected in both genders. The relationship between anthropometrics’ characteristics and PF tests showed that weight and fat mass had a high level of correlation with different PF tests. Our findings highlight the importance of investigating the degree of fatness in relation with different components of fitness, in children and adolescents. This combination of proxies may cover an unexpectedly helpful screening of the youth population, for both health and performance

    Gait patterns in Parkinsonian patients with or without mild cognitive impairment.

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    Background: Although in recent years the relationship between cognition and gait in Parkinson’s disease (PD) has received increasing attention, the specific connections between gait patterns and cognitive features are not fully understood. Objective: To describe the gait patterns in patients affected by Parkinson’s disease (PD) with or without mild cognitive impairment (MCI+, MCI-). We also sought to find an association between gait patterns and specific cognitive profiles. Methods: Using a gait analysis system, we compared the gait patterns among MCI+ (n=19), MCI- (n=24) and age- and gender-matched healthy subjects (HS; n=20) in the following conditions: 1) normal gait; 2) motor dual task; 3) cognitive dual task. In PD patients, gait parameters were evaluated in both off and on state. Memory, executive and visuospatial domains were assessed with an extensive neuropsychological battery. Results: Compared with MCI- and HS, MCI+ PD patients displayed reduced step length and swing time, and impairment of measures of dynamic stability; these dysfunctions were only partially reverted by levodopa. We also found that dual task conditions affected several walking parameters in MCI+PD at off and on state with respect to MCI- and HS. Factor analysis revealed two independent factors, namely pace and stability. The latter was strongly and directly correlated with the visuospatial domain. Conclusions: Dysfunctions on specific gait parameters, which were poorly responsive to levodopa and highly sensitive to dual task conditions, were associated with MCI in PD patients. Importantly, visuospatial impairment was strongly associated with the development of instability and more generally with the progression of PD
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