Pluripotent Stem Cell-Based Approaches to Explore and Treat Optic Neuropathies

Sight is a major sense for human and visual impairment profoundly affects quality of life, especially retinal degenerative diseases which are the leading cause of irreversible blindness worldwide. As for other neurodegenerative disorders, almost all retinal dystrophies are characterized by the specific loss of one or two cell types, such as retinal ganglion cells, photoreceptor cells, or retinal pigmented epithelial cells. This feature is a critical point when dealing with cell replacement strategies considering that the preservation of other cell types and retinal circuitry is a prerequisite. Retinal ganglion cells are particularly vulnerable to degenerative process and glaucoma, the most common optic neuropathy, is a frequent retinal dystrophy. Cell replacement has been proposed as a potential approach to take on the challenge of visual restoration, but its application to optic neuropathies is particularly challenging. Many obstacles need to be overcome before any clinical application. Beyond their survival and differentiation, engrafted cells have to reconnect with both upstream synaptic retinal cell partners and specific targets in the brain. To date, reconnection of retinal ganglion cells with distal central targets appears unrealistic since central nervous system is refractory to regenerative processes. Significant progress on the understanding of molecular mechanisms that prevent central nervous system regeneration offer hope to overcome this obstacle in the future. At the same time, emergence of reprogramming of human somatic cells into pluripotent stem cells has facilitated both the generation of new source of cells with therapeutic potential and the development of innovative methods for the generation of transplantable cells. In this review, we discuss the feasibility of stem cell-based strategies applied to retinal ganglion cells and optic nerve impairment. We present the different strategies for the generation, characterization and the delivery of transplantable retinal ganglion cells derived from pluripotent stem cells. The relevance of pluripotent stem cell-derived retinal organoid and retinal ganglion cells for disease modeling or drug screening will be also introduced in the context of optic neuropathies

Hospitalizations in neonatal intensive care unit at Mahajanga: impacts on parents

Background: Experiencing a birth with a pathology imposes on parents a lot of frustration. Objectives of this study were to describe the general profiles of newborns and to describe the hospitalization’s psychosomatic impact on parents; in intensive care unit of the neonatalogy ward at the mother-child complex at the university Hospital Androva Mahajanga Madagascar.Methods: It was prospective descriptive study, by a survey of parents, among 3 months, from 01st May to 31th July.Results: Were included 102 newborns. Mains reasons of admission are low birth weigth (51.9%), prematurity (42.1%) and perinatal asphyxia (23.5%). One hundred mothers and 90 fathers had answered our survey. Sleep distturance (all parents), negative feelings (70% of fathers and 75% of mothers), depressed mood (52.2% of fathers and 78% of mothers) and guilt (25.5% of fathers and 58% of mothers) were the most prominent psycological manifestations among parents; then somatic manifestations as digestive, cardiovascular type; weight loss was objectified on 33% of fathers.Conclusions: Newborns’s hospitalization is a difficult situation for parents. Caregivers have an important role in enabling the family to build up

A mixed-methods study on evaluating an updated, francophone version of ETAT+ training in Madagascar

Background: Madagascar needs major efforts to achieve the UN Sustainable Development Goals, despite the considerable reduction of child mortality during past years. In this context, implementation of emergency triage assessment and treatment (ETAT) plays an important role. In recent years, ETAT training activities rarely took place in Madagascar. To strengthen ETAT in Madagascar, a pilot training course was conducted in December 2019 at the University Hospital Mahajanga. Objective: This study aims to evaluate if the ETAT+ pilot training content matches clinical needs in Madagascar and whether participants achieved their learning objectives. Methods: In this cross-sectional mixed-methods study, a 41-item questionnaire was used at the end of the ETAT+ training to evaluate their learning experience from the 12 participants (paediatricians, physicians, nurses and midwives). Six weeks after the training, guided interviews were conducted among five participants to describe how training content could be transferred into clinical practice in five health facilities. Results: Results suggest that this pilot project designed to contribute to the re-establishment of ETAT in Madagascar meets participants’ needs and is adapted to clinical realities in terms of transmitted knowledge, skills and competencies. However, results also show that considerable multidisciplinary efforts are needed to advance ETAT+ implementation in Madagascar. Conclusions: Implementation processes of ETAT training programmes need re-evaluation to assure their validity to contribute to quality of care improvements efficiently. Further operational research is required to evaluate sustainable, innovative implementation strategies adapted to contexts in Madagascar

Aberrant Receptor-Mediated Endocytosis of Schistosoma mansoni Glycoproteins on Host Lipoproteins

BACKGROUND: Bilharzia is one of the major parasitic infections affecting the public health and socioeconomic circumstances in (sub) tropical areas. Its causative agents are schistosomes. Since these worms remain in their host for decades, they have developed mechanisms to evade or resist the immune system. Like several other parasites, their surface membranes are coated with a protective layer of glycoproteins that are anchored by a lipid modification. METHODS AND FINDINGS: We studied the release of glycosyl-phosphatidylinositol (GPI)-anchored proteins of S. mansoni and found them in the circulation associated with host lipoprotein particles. Host cells endocytosed schistosomal GPI-anchored proteins via their lipoprotein receptor pathway, resulting in disturbed lysosome morphology. In patients suffering from chronic schistosomiasis, antibodies attacked the parasite GPI-anchored glycoproteins that were associated with the patients' own lipoprotein particles. These immunocomplexes were endocytosed by cells carrying an immunoglobulin-Fc receptor, leading to clearance of lipoproteins by the immune system. As a consequence, neutral lipids accumulated in neutrophils of infected hamsters and in human neutrophils incubated with patient serum, and this accumulation was associated with apoptosis and reduced neutrophil viability. Also, Trypanosoma brucei, the parasite that causes sleeping sickness, released its major GPI-anchored glycoprotein VSG221 on lipoprotein particles, demonstrating that this process is generalizable to other pathogens/parasites. CONCLUSIONS: Transfer of parasite antigens to host cells via host lipoproteins disrupts lipid homeostasis in immune cells, promotes neutrophil apoptosis, may result in aberrant antigen presentation in host cells, and thus cause an inefficient immune response against the pathogen

Navigating spaces between conservation research and practice: are we making progress?

1. Despite aspirations for conservation impact, mismatches between research and implementation have limited progress towards this goal. There is, therefore, an urgent need to identify how we can more effectively navigate the spaces between research and practice. 2. In 2014, we ran a workshop with conservation researchers and practitioners to identify mismatches between research and implementation that needed to be overcome to deliver evidence‐informed conservation action. Five mismatches were highlighted: spatial, temporal, priority, communication, and institutional. 3. Since 2014, thinking around the ‘research–implementation gap’ has progressed. The term ‘gap’ has been replaced by language around the dynamic ‘spaces’ between research and action, representing a shift in thinking around what it takes to better align research and practice. 4. In 2019, we ran a follow‐up workshop reflecting on this shift, whether the five mismatches identified in the 2014 workshop were still present in conservation, and whether progress had been made to overcome these mismatches during the past 5 years. We found that while there has been progress, we still have some way to go across all dimensions. 5. Here, we report on the outcomes of the 2019 workshop, reflect on what has changed over the past 5 years, and offer 10 recommendations for strengthening the alignment of conservation research and practice

Patterns of Loss and Regeneration of Tropical Dry Forest in Madagascar: The Social Institutional Context

Loss of tropical forests and changes in land-use/land-cover are of growing concern worldwide. Although knowledge exists about the institutional context in which tropical forest loss is embedded, little is known about the role of social institutions in influencing regeneration of tropical forests. In the present study we used Landsat images from southern Madagascar from three different years (1984, 1993 and 2000) and covering 5500 km(2), and made a time-series analysis of three distinct large-scale patterns: 1) loss of forest cover, 2) increased forest cover, and 3) stable forest cover. Institutional characteristics underlying these three patterns were analyzed, testing the hypothesis that forest cover change is a function of strength and enforcement of local social institutions. The results showed a minor decrease of 7% total forest cover in the study area during the whole period 1984–2000, but an overall net increase of 4% during the period 1993–2000. The highest loss of forest cover occurred in a low human population density area with long distances to markets, while a stable forest cover occurred in the area with highest population density and good market access. Analyses of institutions revealed that loss of forest cover occurred mainly in areas characterized by insecure property rights, while areas with well-defined property rights showed either regenerating or stable forest cover. The results thus corroborate our hypothesis. The large-scale spontaneous regeneration dominated by native endemic species appears to be a result of a combination of changes in precipitation, migration and decreased human population and livestock grazing pressure, but under conditions of maintained and well-defined property rights. Our study emphasizes the large capacity of a semi-arid system to spontaneously regenerate, triggered by decreased pressures, but where existing social institutions mitigate other drivers of deforestation and alternative land-use

Human induced pluripotent stem cell-derived retinal ganglion cells : from characterization to transplantation

Parmi les stratégies en développement de nouveaux traitements pour les neuropathies optiques, la thérapie cellulaire par transplantation de cellules ganglionnaires rétiniennes (CGRs) dérivées de cellules pluripotentes humaines est l’un des axes de recherche les plus prometteurs. Au cours de la réalisation du projet présenté dans ce document, nous avons validé la production optimisée de CGRs, à partir de quatre lignées de cellules souches pluripotentes induites (iPS) humaines, par une double sélection selon les conditions de culture in vitro et un protocole de tri magnétique basé sur l’expression de l’antigène de surface CD90/THY1. Nous avons caractérisé les CGRs enrichies par ce double protocole de sélection selon leurs propriétés morphologiques, moléculaires et fonctionnelles. Ces résultats furent validés pour un total de quatre lignées cellulaires iPS, dont une lignée rapportrice fluorescente ubiquitaire, générée par stratégie Crispr-Cas9. La transplantation par injection intravitréenne des CGRs dérivées de cette lignée rapportrice, sur un modèle murin ayant subi un écrasement du nerf optique, a permis d’observer une intégration partielle des cellules survivantes dans la rétine hôte permettant d’établir la preuve de concept quant à la possibilité de réaliser ce type de transplantation. Ce travail devra être poursuivi afin d’étudier la capacité de ces cellules à établir des contacts fonctionnels avec les partenaires rétiniens et cérébraux.Among the different treatments for optic neuropathies, cell therapy using transplantation of retinal ganglion cells (RGCs) derived from human induced pluripotent stem cells (hiPSC) is one of the most promising strategy. In this project, we validated the optimized production of RGCs from retinal organoids derived from four different hiPSC lines. Our methodology included a double selection process, comprising the culture of retinal dissociated cell in adherent conditions and a magnetic sorting protocol, based on the expression of surface antigen CD90/THY1. We identified enriched RGCs resulting from this double protocol, according morphological, molecular and functional properties. These results were validated for all four hiPSC lines, including a ubiquitous fluorescent reporter cell line, using Crispr/Cas9 strategy. Intravitreal injection of reporter hiPSC line-derived RGCs into an optic nerve crush mouse model led to a partial integration of surviving cells into the host retina establishing the possibility to performed RGC transplantation. This work will be continued in order to explore the capacity of hiPSC-derived RGCs to reconnect with both retinal partners and with the different targets in the brain

Dépenses de santé et productivité du travail dans une économie vieillissante

La population française vieillit et continuera de vieillir dans l'avenir. Les conséquences négatives de cette mutation démographique sur l'économie sont bien connues. Cependant, l'ampleur de ces conséquences dépendra entre autre de l'évolution de la productivité du travail. Afin d'analyser l'évolution future de la productivité du travail en France, cette thèse s'est focalisée sur le rôle des dépenses de santé dans l'économie. En effet, d'un côté, les dépenses de santé, en améliorant la santé de la population, accroissent la productivité du travail. D'un autre côté, elles favorisent le vieillissement de la population en allongeant son espérance de vie. Ainsi, cette thèse vise à vérifier si les gains de productivité générés par les dépenses de santé sont suffisants pour annihiler les effets négatifs du vieillissement de la population. Nous démontrons théoriquement que les dépenses de santé privées génèrent une externalité positive améliorant l'efficacité du travail et par voie de conséquence la productivité du travail (Chapitre I). Cependant, nos résultats empiriques soulignent que cet effet positif n'est pas significatif dès lors que nous considérons les dépenses de santé qui restent à la charge des patients (Chapitre II). Les gains de productivité permis par l'amélioration future de la santé des français sont ensuite mesurés grâce à un modèle de comptabilité générationnelle. Les gains de productivité apparaissent non négligeables mais insuffisants pour annihiler les effets négatifs du vieillissement démographique (Chapitre III). Ce constat est confirmé par les résultats fournis par notre modèle d'équilibre général (Chapitre IV).French population is aging and this demographic mutation should also occur in the coming decades. The negative economic effects of population aging are well-known but the magnitude of these effects depends partially on the evolution of labor productivity. To determine the evolution of labor productivity in France, this dissertation focuses on the economic effects of health spending. Indeed, on one side, health spending, by improving population’s health status, affect positively labor productivity. On the other side, these health expenditures foster the aging process by extending population longevity. This dissertation aims then to check if productivity gains from health spending are enough to annihilate the negative economic effects of population aging. We demonstrate theoretically that private health spending generate a positive externality affecting positively labor productivity (Chapter I). However, our empirical results underline that this positive effect is limited when we consider the out-of-pocket expenditure on health (Chapter II). Thereafter, we assess the productivity gains resulting from the health status enhancement of French population by using a generational accounting model. It appears that the productivity gains should be significant but not enough to annihilate the negative economic effects of population aging (Chapter III). The simulation outcomes provided by our applied general equilibrium model confirm this result (Chapter IV)