Depressive symptoms in the elderly : an early symptom of dementia? A systematic review

Background Depression and dementia are common incapacitating diseases in old age. The exact nature of the relationship between these conditions remains unclear, and multiple explanations have been suggested: depressive symptoms may be a risk factor for, a prodromal symptom of, or a coincidental finding in dementia. They may even be unrelated or only connected through common risk factors. Multiple studies so far have provided conflicting results. Objectives To determine whether a systematic literature review can clarify the nature of the relation between depressive symptoms and dementia. Methods Using the Patient/Problem/Population, Intervention, Comparator, Outcome or PICO paradigm, a known framework for framing healthcare and evidence questions, we formulated the question "whether depressive symptoms in cognitively intact older adults are associated with a diagnosis of dementia later in life." We performed a systematic literature review of MEDLINE and PsycINFO in November 2018, looking for prospective cohort studies examining the aforementioned question. Results We critically analyzed and listed 31 relevant papers out of 1,656 and grouped them according to the main hypothesis they support: depressive symptoms as a risk factor, not a risk factor, a prodromal symptom, both, or some specific other hypothesis. All but three studies used clinical diagnostic criteria for dementia alone (i.e., no biomarkers or autopsy confirmation). Several studies contain solid arguments for the hypotheses they support, yet they do not formally contradict other findings or suggested explanations and are heterogeneous. Conclusions The exact nature of the relationship between depressive symptoms and dementia in the elderly remains inconclusive, with multiple studies supporting both the risk factor and prodromal hypotheses. Some provide arguments for common risk factors. It seems unlikely that there is no connection at all. We conclude that at least in a significant part of the patients, depressive symptoms and dementia are related. This may be due to common risk factors and/or depressive symptoms being a prodromal symptom of dementia and/or depression being a risk factor for dementia. These causal associations possibly overlap in some patients. Further research is warranted to develop predictive biomarkers and to develop interventions that may attenuate the risk of "conversion" from depressive symptoms to dementia in the elderly

Experiences in using model checking to verify real time properties of a landing gear control system

International audienceThis paper presents experiences in using several model checking tools to verify properties of a critical real time embedded system. The tools we tested are Lesar, SMV, Prover Plug In for SCADE and Uppaal. The application is the landing gear control system of a military aircraft, developed by Dassault Aviation. The property to be verified states that the gear must be down in at most 14 seconds. Results (success and verification time) depend a lot on the way time is handled by the verification tools

Guidance for Using Formal Methods in a Certification Context

This paper discusses some of the challenges to using formal methods in a certification context and describes the effort by the Formal Methods Subgroup of RTCA SC-205/EUROCAE WG-71 to propose guidance to make the use of formal methods a recognized approach. This guidance, expected to take the form of a Formal Methods Technical Supplement to DO-178C/ED-12C, is described, including the activities that are needed when using formal methods, new or modified objectives with respect to the core DO-178C/ED-12C document, and evidence needed for meeting those objectives

Differential role of FL-BID and t-BID during verotoxin-1-induced apoptosis in Burkitt's lymphoma cells

Funding Information: Acknowledgements We thank Yann Lécluse (Imaging and Cytometry Platform, Institut Gustave Roussy) for expert technical assistance in performing flow cytometry analyses. We are very grateful to Hana Raslova and Julie Rivière (INSERM UMR 1170, Institut Gustave-Roussy) for their help in producing lentivirus and to Evelyne May and Martine Raphaël (UMR 8126 CNRS) for helpful discussions and suggestions. This work was supported by grants from the Fondation de France 2014 00047509 (JW), the Ligue National Contre le Cancer (doctoral fellowship to JD) and the Fondation ARC (doctoral fellowship to EH).Peer reviewe

Etude des mécanismes de résistance à l'apoptose induits par le virus d'Epstein-Barr et mise en place de nouvelles stratégies thérapeutiques pour le traitement des lymphomes B

Résumé en français : Notre équipe étudie les mécanismes de l apoptose induite par la nutline-3, une molécule capable de se fixer sur MDM2 et d activer la p53, dans différents types de lymphomes associés au virus d Epstein-Barr (EBV) comme le lymphome de Burkitt (LB) ou syndromes lymphoprolifératifs post-transplantation (PTLD). Nos résultats montrent que la nutline-3 induit l apoptose des cellules de LB EBV (-) alors que les cellules EBV (+) en latence de type III sont résistantes. Mon travail de thèse a consisté à étudier les mécanismes impliqués dans ce phénomène de résistance afin de mettre en place des stratégies pour les contourner. Une première étude initiée par les résultats d une analyse transcriptomique, effectuée après traitement avec la nutline-3 de deux lignées qui ne diffèrent que par leur statut EBV, nous a permis de montrer que : 1) l autophagie est induite en réponse au traitement dans les cellules EBV (+) en latence de type III ; 2) ces cellules expriment fortement Bécline-1 et présentent une activation constitutive de l autophagie ; 3) l autophagie contribue à la résistance de ces cellules à l apoptose. Par ailleurs, nos résultats indiquent que la protéine anti-apoptotique Bcl-2 est également impliquée dans la résistance de ces cellules et que l utilisation d ABT-737, un inhibiteur de Bcl-2, restaure leur sensibilité à la nutline-3. L efficacité de ce composé a donc été évaluée in vivo, seul ou en combinaison avec des traitements conventionnels (Cyclophosphamide pour le LB et Rituximab pour les PTLD). Les résultats obtenus lors de ces études pré-cliniques montrent que : 1) ABT-737 réduit considérablement la croissance tumorale et augmente la survie de souris xénogreffées avec des cellules d une lignée lymphoblastoïde (LCL, utilisées comme modèle pour les PTLD) alors qu il n a pas d effets chez les souris xénogreffées avec une lignée de LB ; 2) la combinaison BT-737/Cyclophosphamide permet de limiter la croissance tumorale durant le traitement mais n améliore pas la survie des souris xénogreffées avec une lignée de LB ; 3) l association ABT-737/Rituximab est très efficace et induit une rémission complète chez 70% des souris xénogreffées avec la lignée de LCL- Résumé en anglais : Our team is working on the mechanisms of apoptosis induced by nutlin-3, a small molecule which binds to MDM2 and activates p53, in different lymphomas associated with Epstein-Barr virus such as Burkitt lymphoma (BL) or Post-transplant lymphoproliferative disorder (PTLD). Our results show that nutlin-3 strongly induce apoptosis in EBV (-) cells whereas EBV (+) latency III cells are much more resistant. The aim of my PhD project was to study the mechanisms involved in the resistance of EBV (+) latency III cells to apoptosis and to develop new therapeutic strategies to bypass these mechanisms. A transcriptomic analysis was realized after treatment with nutlin-3 of two cell lines which only differs by their EBV status. Based on the results obtained, a study was performed which allow us to show that: 1) autophagy is induced after nutlin-3 treatment in EBV (+) latency III cells; 2) these cells strongly expressed beclin-1 and present a constitutively high level of autophagy; 3) autophagy is involved in the resistance of apoptosis observed in these cells. Furthermore, our results demonstrate that Bcl-2 also contributes to the resistance of EBV (+) latency III cells and that treatment with ABT-737, a Bcl-2 inhibitor, restores their susceptibility to nutlin-3 treatment. We thus assessed the efficiency of this compound in vivo, in monotherapy or associated with conventional treatments (Cyclophosphamide for BL and Rituximab for PTLD). Results obtained during these pre-clinical studies show that: 1) ABT-737 reduces tumor growth and increase the overall survival of mice xenografted with a lymphoblastoïd cell line (LCL, used as a model for PTLD studies) but has no effects on mice xenografed with BL cell lines; 2) the association ABT-737/Cyclophosphamide reduces tumor growth during treatment but doesn t improve the overall survival of mice xenografed with BL cell lines; 3) the association ABT-737/Rituximab is very efficient and induces 70% of complete remission in mice xenografted with LCL.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Statistical Automaton for Verifying Temporal Properties and Computing Information on Traces

Verification is decisive for embedded software. The goal of this work is to verify temporal properties on industrial applications, with the help of formal dynamic analysis. The approach presented in this paper is composed of three steps: formalization of temporal properties using an adequate language, generation of execution traces from a given property and verification of this property on execution traces. This paper focuses on the verification step. Use of a new kind of Büchi automaton has been proposed to provide an efficient verification taking into account the industrial needs and constraints. A prototype has been developed and used to carry out experiments on different anonymous real industrial applications

Statistical Automaton for Verifying Temporal Properties and Computing Information on Traces

Verification is decisive for embedded software. The goal of this work is to verify temporal properties on industrial applications, with the help of formal dynamic analysis. The approach presented in this paper is composed of three steps: formalization of temporal properties using an adequate language, generation of execution traces from a given property and verification of this property on execution traces. This paper focuses on the verification step. Use of a new kind of Büchi automaton has been proposed to provide an efficient verification taking into account the industrial needs and constraints. A prototype has been developed and used to carry out experiments on different anonymous real industrial applications