WD-repeat instability and diversification of the Podospora anserina hnwd non-self recognition gene family

<p>Abstract</p> <p>Background</p> <p>Genes involved in non-self recognition and host defence are typically capable of rapid diversification and exploit specialized genetic mechanism to that end. Fungi display a non-self recognition phenomenon termed heterokaryon incompatibility that operates when cells of unlike genotype fuse and leads to the cell death of the fusion cell. In the fungus <it>Podospora anserina</it>, three genes controlling this allorecognition process <it>het-d, het-e </it>and <it>het-r </it>are paralogs belonging to the same <it>hnwd </it>gene family. HNWD proteins are STAND proteins (signal transduction NTPase with multiple domains) that display a WD-repeat domain controlling recognition specificity. Based on genomic sequence analysis of different <it>P. anserina </it>isolates, it was established that repeat regions of all members of the gene family are extremely polymorphic and undergoing concerted evolution arguing for frequent recombination within and between family members.</p> <p>Results</p> <p>Herein, we directly analyzed the genetic instability and diversification of this allorecognition gene family. We have constituted a collection of 143 spontaneous mutants of the <it>het-R </it>(<it>HNWD2</it>) and <it>het-E </it>(<it>hnwd5</it>) genes with altered recognition specificities. The vast majority of the mutants present rearrangements in the repeat arrays with deletions, duplications and other modifications as well as creation of novel repeat unit variants.</p> <p>Conclusions</p> <p>We investigate the extreme genetic instability of these genes and provide a direct illustration of the diversification strategy of this eukaryotic allorecognition gene family.</p

Dedicated mobile application for drug adverse reaction reporting by patients with relapsing remitting multiple sclerosis (Vigip-SEP study): study protocol for a randomized controlled trial

BackgroundThe reporting of adverse drug reactions (ADR) by patients represents an interesting challenge in the field of pharmacovigilance, but the reporting system is not adequately implemented in France. In 2015, only 20 MS patients in France reported ADR due to first-line disease-modifying drugs (DMD), while more than 3000 patients were initiated on DMD.The aim of this study is to validate a proof-of-concept as to whether the use of a mobile application (App) increases ADR reporting among patients with relapsing-remitting multiple sclerosis (RR-MS) receiving DMD.Methods/designWe designed a multi-centric, open cluster-randomized controlled trial, called the Vigip-SEP study (NCT03029897), using the App My eReport France® to report ADR to the appropriate authorities in E2B language, in accordance with European regulations. RR-MS patients who were initiated on, or switched, first-line DMD will be included. In the experimental arm, a neurologist will introduce the patient to the App to report ADR to the appropriate French authorities. In the control arm, the patient will be informed of the existence of the App but will not be introduced to its use and will then report ADR according to the usual reporting procedures. Primary assessment criteria are defined as the average number of ADR per patient and per center. We assume that the App will increase patient reporting by 10-fold. Therefore, we will require 24 centers (12 per arm: 6 MS academic expert centers, 3 general hospitals, 3 private practice neurologists), allowing for an expected enrollment of 180 patients (alpha risk 5%, power 90% and standard deviation 4%).DiscussionIncreasing patient reporting of ADR in a real-life setting is extremely important for therapeutic management of RR-MS, particularly for monitoring newly approved DMD to gain better knowledge of their safety profiles. To increase patient involvement, teaching patients to use tools, such as mobile applications, should be encouraged, and these tools should be tested rigorously

Instabilité génétique au locus het-r membre d'une famille de gènes d'incompatibilité

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Additional file 1: of Dedicated mobile application for drug adverse reaction reporting by patients with relapsing remitting multiple sclerosis (Vigip-SEP study): study protocol for a randomized controlled trial

SPIRIT 2013 Checklist: recommended items to address in a clinical trial protocol and related documents*. (DOCX 49 kb

Adverse Drug Reaction Reporting Using a Mobile Device Application by Persons with Multiple Sclerosis: A Cluster Randomized Controlled Trial

International audienceIntroduction: Patient reporting adds value to pharmacovigilance. Encouraging it to be done through a mobile device application (App) is a method that should be evaluated.Objective: This study aimed to determine whether the use of an App, compared to traditional use through e-mail, telephone, or the national website, increased suspected adverse drug reaction (ADR) reporting by persons with multiple sclerosis receiving a first-line disease-modifying drug.Methods: An open multi-centric, cluster-randomized controlled trial was conducted (VigipSEP study). Clusters were centers allocated (1:1) to the use of the My eReport France® App (experimental arm), and traditional reporting (control arm). Persons with multiple sclerosis initiating or switching to a first-line disease-modifying drug between April 2017 and April 2019 were included. The primary outcome was the mean number of ADR reports per patient for the center-level analysis, and the number of ADR reports per patient for the individual-level analysis using the hierarchical Poisson regression model.Results: Twenty-four centers (12 per arm: six public neurologists from the multiple sclerosis academic expert centers, three public neurologists from general hospitals, and three private practice neurologists) were randomized, including 159 patients. The mean number of ADR reports per patient was significantly higher in centers that used the App: 0.47 vs 0.03 in control centers (p = 0.002). At an individual-level analysis, the experimental arm was significantly associated with a relative risk of ADR reports at 18.6 (95% confidence interval 4.1-84.2; p < 0.001), compared to the control arm, adjusted for sex and type of disease-modifying drug.Conclusions: The use of a mobile App increased the ADR reporting by persons with multiple sclerosis receiving a first-line disease-modifying drug. CLINICALTRIALS

Amantadine use in the French prospective NS-Park cohort

International audienceObjective: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD).Background: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres.Methods: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis).Results: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users.Conclusions: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs