Enhancing multi-sectoral collaboration in health: the open arena for public health as a model for bridging the knowledge-translation gap

Effective public health interventions at local level must involve communities and stakeholders beyond the health services spectrum. A dedicated venue for structured discussion will ensure ongoing multi-sectoral collaboration more effectively than convening ad hoc meetings. Such a venue can be created using existing resources, at minimal extra cost. The University Hospital in Nice (France) has established an Open Arena for Public Health which can serve as a model for promoting collaborative partnerships at local level. The Arena has been successful in implementing sustainable interventions thanks to a set of principles, including: non-hierarchical governance and operating, fair representation of stakeholders, consensus as to best available evidence internationally and locally, policy dialogues: open, free-flowing discussions without preconceived solutions, and an experimental approach to interventions

LRP1 Has a Predominant Role in Production over Clearance of Aβ in a Mouse Model of Alzheimer's Disease.

The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-β (Aβ) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Aβ from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Aβ in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Aβ metabolism showed that, despite reduced Aβ clearance due to LRP1 inactivation in vivo, less Aβ was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Aβ-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Aβ and an increase of soluble APP-α (sAPP-α). This shift in APP processing resulted in overall lower Aβ levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Aβ generation overrules the simultaneous impaired Aβ clearance, resulting in less extracellular Aβ and reduced plaque deposition in a mouse model of AD

Impact of aging : sporadic, and genetic risk factors on vulnerability to apoptosis in Alzheimer's disease

The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4+ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4+ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4+ and CD8+ T cells

Neural Differentiation of Embryonic Stem Cells In Vitro: A Road Map to Neurogenesis in the Embryo

Background: The in vitro generation of neurons from embryonic stem (ES) cells is a promising approach to produce cells suitable for neural tissue repair and cell-based replacement therapies of the nervous system. Available methods to promote ES cell differentiation towards neural lineages attempt to replicate, in different ways, the multistep process of embryonic neural development. However, to achieve this aim in an efficient and reproducible way, a better knowledge of the cellular and molecular events that are involved in the process, from the initial specification of neuroepithelial progenitors to their terminal differentiation into neurons and glial cells, is required. Methodology/Principal Findings: In this work, we characterize the main stages and transitions that occur when ES cells are driven into a neural fate, using an adherent monolayer culture system. We established improved conditions to routinely produce highly homogeneous cultures of neuroepithelial progenitors, which organize into neural tube-like rosettes when they acquire competence for neuronal production. Within rosettes, neuroepithelial progenitors display morphological and functional characteristics of their embryonic counterparts, namely, apico-basal polarity, active Notch signalling, and proper timing of production of neurons and glia. In order to characterize the global gene activity correlated with each particular stage of neural development, the full transcriptome of different cell populations that arise during the in vitro differentiation protocol was determined by microarray analysis. By using embryo-oriented criteria to cluster the differentially expresse

Nationwide study in France investigating the impact of diabetes on mortality in patients undergoing abdominal aortic aneurysm repair.

The aim of this nationwide study was to analyze the impact of diabetes on post-operative mortality in patients undergoing AAA repair in France. This 10-year retrospective, multicenter study based on the French National electronic health data included patients undergoing AAA repair between 2010 and 2019. In-hospital post-operative mortality was analyzed using Kaplan-Meier curve survival and Log-Rank tests. A multivariate regression analysis was performed to calculate Hazard Ratios. Over 79,935 patients who underwent AAA repair, 61,146 patients (76.5%) had at least one hospital-readmission after the AAA repair, for a mean follow-up of 3.5 ± 2.5 years. Total in-hospital mortality over the 10-year study was 16,986 (21.3%) and 4581 deaths (5.8%) occurred during the first hospital stay for AAA repair. Age over 64 years old, the presence of AAA rupture and hospital readmission at 30-day were predictors of post-operative mortality (AdjHR = 1.59 CI 95% 1.51-1.67; AdjHR = 1.49 CI 95% 1.36-1.62 and AdjHR = 1.92, CI 95% 1.84-2.00). The prevalence of diabetes was significantly lower in ruptured AAA compared to unruptured AAA (14.8% vs 20.9%, P < 0.001 for type 2 diabetes and 2.5% vs 4.0%, P < 0.001 for type 1 diabetes). Type 1 diabetes was significantly associated with post-operative mortality (AdjHR = 1.30 CI 95% 1.20-1.40). For type 2 diabetes, the association was not statistically significant (Adj HR = 0.96, CI 95% 0.92-1.01). Older age, AAA rupture and hospital readmission were associated with deaths that occurred after discharge from the first AAA repair. Type 1 diabetes was identified as a risk factor of post-operative mortality. This study highlights the complex association between diabetes and AAA and should encourage institutions to report long-term follow-up after AAA repair to better understand its impact

Alzheimer's disease-associated R47H TREM2 increases, but wild-type TREM2 decreases, microglial phagocytosis of synaptosomes and neuronal loss

Triggering receptor on myeloid cells 2 (TREM2) is an innate immune receptor, upregulated on the surface of microglia associated with amyloid plaques in Alzheimer's disease (AD). Individuals heterozygous for the R47H variant of TREM2 have greatly increased risk of developing AD. We examined the effects of wild-type (WT), R47H and knock-out (KO) of human TREM2 expression in three microglial cell systems. Addition of mouse BV-2 microglia expressing R47H TREM2 to primary mouse neuronal cultures caused neuronal loss, not observed with WT TREM2. Neuronal loss was prevented by using annexin V to block exposed phosphatidylserine, an eat-me signal and ligand of TREM2, suggesting loss was mediated by microglial phagocytosis of neurons exposing phosphatidylserine. Addition of human CHME-3 microglia expressing R47H TREM2 to LUHMES neuronal-like cells also caused loss compared to WT TREM2. Expression of R47H TREM2 in BV-2 and CHME-3 microglia increased their uptake of phosphatidylserine-beads and synaptosomes versus WT TREM2. Human iPSC-derived microglia with heterozygous R47H TREM2 had increased phagocytosis of synaptosomes vs common-variant TREM2. Additionally, phosphatidylserine liposomes increased activation of human iPSC-derived microglia expressing homozygous R47H TREM2 versus common-variant TREM2. Finally, overexpression of TREM2 in CHME-3 microglia caused increased expression of cystatin F, a cysteine protease inhibitor, and knock-down of cystatin F increased CHME-3 uptake of phosphatidylserine-beads. Together, these data suggest that R47H TREM2 may increase AD risk by increasing phagocytosis of synapses and neurons via greater activation by phosphatidylserine and that WT TREM2 may decrease microglial phagocytosis of synapses and neurons via cystatin F

Novel potent liposome agonists of triggering receptor expressed on myeloid cells 2 phenocopy antibody treatment in cells

The receptor Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is associated with several neurodegenerative diseases including Alzheimer's Disease and TREM2 stimulation represents a novel therapeutic opportunity. TREM2 can be activated by antibodies targeting the stalk region, most likely through receptor dimerization. Endogenous ligands of TREM2 are suggested to be negatively charged apoptotic bodies, mimicked by phosphatidylserine incorporated in liposomes and other polyanionic molecules likely binding to TREM2 IgV fold. However, there has been much discrepancy in the literature on the nature of phospholipids (PLs) that can activate TREM2 and on the stability of the corresponding liposomes over time. We describe optimized liposomes as robust agonists selective for TREM2 over TREM1 in cellular system. The detailed structure/activity relationship studies of lipid polar heads indicate that negatively charged lipid heads are required for activity and we identified the shortest maximally active PL sidechain. Optimized liposomes are active on both TREM2 common variant and TREM2 R47H mutant. Activity and selectivity were further confirmed in different native TREM2 expressing cell types including on integrated cellular responses such as stimulation of phagocytic activity. Such tool agonists will be useful in further studies of TREM2 biology in cellular systems alongside antibodies, and in the design of small molecule synthetic TREM2 agonists

Is Impact of Statin Therapy on All-Cause Mortality Different in HIV-Infected Individuals Compared to General Population? Results from the FHDH-ANRS CO4 Cohort

French Hospital Database on HIVInternational audienceBackgroundThe effect of statins on all-cause mortality in the general population has been estimated as 0.86 (95%CI 0.79-0.94) for primary prevention. Reported values in HIV-infected individuals have been discordant. We assessed the impact of statin-based primary prevention on all-cause mortality among HIV-infected individuals.MethodsPatients were selected among controls from a multicentre nested case-control study on the risk of myocardial infarction. Patients with prior cardiovascular or cerebrovascular disorders were not eligible. Potential confounders, including variables that were associated either with statin use and/or death occurrence and statin use were evaluated within the last 3 months prior to inclusion in the case-control study. Using an intention to continue approach, multiple imputation of missing data, Cox’s proportional hazard models or propensity based weighting, the impact of statins on the 7-year all-cause mortality was evaluated.ResultsAmong 1,776 HIV-infected individuals, 138 (8%) were statins users. During a median follow-up of 53 months, 76 deaths occurred, including 6 in statin users. Statin users had more cardiovascular risk factors and a lower CD4 T cell nadir than statin non-users. In univariable analysis, the death rate was higher in statins users (11% vs 7%, HR 1.22, 95%CI 0.53-2.82). The confounders accounted for were age, HIV transmission group, current CD4 T cell count, haemoglobin level, body mass index, smoking status, anti-HCV antibodies positivity, HBs antigen positivity, diabetes and hypertension. In the Cox multivariable model the estimated hazard ratio of statin on all-cause mortality was estimated as 0.86 (95%CI 0.34-2.19) and it was 0.83 (95%CI 0.51-1.35) using inverse probability treatment weights.ConclusionThe impact of statin for primary prevention appears similar in HIV-infected individuals and in the general population

Compton Large Area Silicon Timing Tracker for Cosmic Vision M3

International audienceProposed in response to the ESA call for the third Medium size mission (M3), CAPSiTT is a small mission designed for a 3-year survey of the non-thermal high energy sky from an equatorial LEO orbit. With a large effective area and a very wide field of view, its single instrument, a silicon tracker, provides good imaging, spectroscopic and polarimetric capabilities with a sensitivity 10-100 times better than COMPTEL. Nucleosynthesis and particle acceleration mechanisms in various sites are the main scientific topics addressed by CAPSiTT