Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Radiolyse du polyacrylate et du polyméthacrylate de méthyle

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Gait alterations of diabetic patients while walking on different surfaces

Patients with diabetes have been shown to suffer from increased fall risk. However, authors disagree as to whether only diabetic patients with neuropathy, or also those without neuropathy, present gait alterations. Existing studies evaluate gait indoors, i.e. in specialized gait laboratories. This study evaluates gait parameters in diabetic patients under various real life conditions and compares them to those recorded for healthy controls. METHODS: We conducted a clinical observation study. Forty-five subjects' gait was assessed on three different surfaces (tar, grass and stones) with a Physilog system (BioAGM, CH), consisting of accelerometers and gyroscopes. Temporal and spatial gait parameters as well as stride-to-stride variability of 30 patients with type 2 diabetes, 15 with and 15 without neuropathy were compared to 15 healthy controls. The three groups were comparable for age, height and body weight (p>0.05). RESULTS: Diabetic patients' gait parameters differed significantly from those of healthy controls. Post hoc analysis revealed a significant difference between healthy individuals and patients with neuropathy, and between healthy individuals and patients without neuropathy. No difference was observed between patients with and without neuropathy. The highest surface effect was found in patients with diabetic neuropathy, followed by patients without neuropathy and healthy controls. CONCLUSIONS: Walking in real life conditions revealed gait difficulties in patients with type 2 diabetes before neuropathy was clinically detectable. Clinicians should be aware that diabetic individuals' gait capacity decreases and fall risk increases at an early stage of the disease

Barriers and enablers to physical activity in patients during hospital stay: a scoping review

Background: Low levels of physical activity are common during the hospital stay and have been associated with negative health outcomes. Understanding barriers and enablers to physical activity during a hospital stay can improve the development and implementation of tailored interventions aimed at improving physical activity. Previous studies have identified many barriers and enablers, but a comprehensive overview is lacking. This study aimed to identify and categorize all published patient- and healthcare professional-reported barriers and enablers to physical activity during a hospital stay for acute care, using the Theoretical Domains Framework (TDF). Methods: We conducted a scoping review of Dutch and English articles using MEDLINE, CINAHL Plus, EMBASE, PsycINFO, and Cochrane Library (inception to September 2020), which included quantitative, qualitative, and mixed-methods studies reporting barriers and enablers to physical activity during a hospital stay for acute care, as perceived by patients or healthcare professionals. Two reviewers systematically extracted, coded, and categorized all barriers and enablers into TDF domains. Results: Fifty-six articles were included in this review (32 qualitative, 7 quantitative, and 17 mixed-methods). In total, 264 barriers and 228 enablers were reported by patients, and 415 barriers and 409 enablers by healthcare professionals. Patient-reported barriers were most frequently assigned to the TDF domains Environmental Context & Resources (ECR, n = 148), Social Influences (n = 32), and Beliefs about Consequences (n = 25), while most enablers were assigned to ECR (n = 67), Social Influences (n = 54), and Goals (n = 32). Barriers reported by healthcare professionals were most frequently assigned to ECR (n = 210), Memory, Attention and Decision Process (n = 45), and Social/Professional Role & Identity (n = 31), while most healthcare professional-reported enablers were assigned to the TDF domains ECR (n = 143), Social Influences (n = 76), and Behavioural Regulation (n = 54). Conclusions: Our scoping review presents a comprehensive overview of all barriers and enablers to physical activity during a hospital stay and highlights the prominent role of the TDF domains ECR and Social Influences in hospitalized patients’ physical activity behavior. This TDF-based overview provides a theoretical foundation to guide clinicians and researchers in future intervention development and implementation. Scoping review registration: No protocol was registered for this review

Barriers and enablers to physical activity in patients during hospital stay: a scoping review

BACKGROUND: Low levels of physical activity are common during the hospital stay and have been associated with negative health outcomes. Understanding barriers and enablers to physical activity during a hospital stay can improve the development and implementation of tailored interventions aimed at improving physical activity. Previous studies have identified many barriers and enablers, but a comprehensive overview is lacking. This study aimed to identify and categorize all published patient- and healthcare professional-reported barriers and enablers to physical activity during a hospital stay for acute care, using the Theoretical Domains Framework (TDF). METHODS: We conducted a scoping review of Dutch and English articles using MEDLINE, CINAHL Plus, EMBASE, PsycINFO, and Cochrane Library (inception to September 2020), which included quantitative, qualitative, and mixed-methods studies reporting barriers and enablers to physical activity during a hospital stay for acute care, as perceived by patients or healthcare professionals. Two reviewers systematically extracted, coded, and categorized all barriers and enablers into TDF domains. RESULTS: Fifty-six articles were included in this review (32 qualitative, 7 quantitative, and 17 mixed-methods). In total, 264 barriers and 228 enablers were reported by patients, and 415 barriers and 409 enablers by healthcare professionals. Patient-reported barriers were most frequently assigned to the TDF domains Environmental Context & Resources (ECR, n = 148), Social Influences (n = 32), and Beliefs about Consequences (n = 25), while most enablers were assigned to ECR (n = 67), Social Influences (n = 54), and Goals (n = 32). Barriers reported by healthcare professionals were most frequently assigned to ECR (n = 210), Memory, Attention and Decision Process (n = 45), and Social/Professional Role & Identity (n = 31), while most healthcare professional-reported enablers were assigned to the TDF domains ECR (n = 143), Social Influences (n = 76), and Behavioural Regulation (n = 54). CONCLUSIONS: Our scoping review presents a comprehensive overview of all barriers and enablers to physical activity during a hospital stay and highlights the prominent role of the TDF domains ECR and Social Influences in hospitalized patients' physical activity behavior. This TDF-based overview provides a theoretical foundation to guide clinicians and researchers in future intervention development and implementation. SCOPING REVIEW REGISTRATION: No protocol was registered for this review

Optimization and testing of dried antibody tube: The EuroFlow LST and PIDOT tubes as examples

Within EuroFlow, we recently developed screening tubes for hematological malignancies and immune deficiencies. Pipetting of antibodies for such 8-color 12-marker tubes however is time-consuming and prone to operational mistakes. We therefore evaluated dried formats of the lymphocytosis screening tube (LST) and of the primary immune deficiency orientation tube (PIDOT). Both tubes were evaluated on normal and/or on patient samples, comparing the mean fluorescence intensity of specific lymphocyte populations. Our data show that the dried tubes and liquid counterparts give highly comparable staining results, particularly when analyzed in multidimensional plots. In addition, the use of dried tubes may result in a reduced staining variability between different samples and thereby contributes to the generation of more robust data. Therefore, by using ready-to-use reagents in a dried single test tube format, the laboratory efficiency and quality will be improved

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

International audienceAutosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression

Trial of Deferiprone in Parkinson's Disease

Background Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. Methods We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. Results A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. Conclusions In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks