Using Hebb’s (1961) paradigm, it has been shown that older adults (OAs) fail to learn recurrent visuospatial supra-span sequence information (Turcotte, Gagnon, & Poirier, 2005); a deficit which has not been demonstrated on verbal versions of the same task or in younger adults (YAs). Since the Hebb paradigm is thought to rely on working memory and thus attention (Conway & Engle, 1996), one interpretation concerns an OA’s capacity to allocate the necessary attentional resources to carry out the various components of the task. Five studies investigated this proposal. The first three (Article 1) examined attention in a general manner by reducing the amount of attentional resources that a YA could devote to carrying out the visuospatial Hebb supra-span sequence learning task through the implementation of a verbal dual task (DT) procedure. The fourth (Article 2) further investigated the role of attention by using a DT induced at retrieval that overlapped extensively with the requirements (spatial and response features) of the visuospatial Hebb task. The final study (Article 3) aimed to use our previous findings to demonstrate learning among OAs in a visuospatial Hebb learning paradigm in which the motor response was replaced by a verbal response. Our findings confirm that attentional resources employed at the retrieval phase of the task appear to be particularly important for the demonstration of visuospatial sequence learning. The inclusion of a spatial and motor based DT at recall eliminated learning of the repeated sequence in YAs. Interestingly, the learning deficit of OAs was partially eliminated when the motor and spatial requirements at retrieval were reduced. Our findings offer strong support to the contention that supra-span learning of the Hebb type is not altered by the effect of age. However, learning deficits can be observed among OAs when the retrieval component of the task overly taxes attention-related processes. In the case of the visuospatial sequences, the basis of the deficit likely concerns an individual’s capacity to discriminate between responses made to previously presented sequences versus those that need to be made in reaction to the just seen sequence.

Patients with macular degeneration (MD) often fixate with a preferred retinal locus (PRL). Eye movements made while fixating with the PRL (in MD patients) has been observed to be maladaptive compared to those made while fixating with the fovea (normal sighted individuals). For example, in MD patients, PRL eye movements negatively affect fixation stability and re-fixation precision; consequently creating difficulty in reading and limits to their execution of other everyday activities. Abnormal eye movements from the PRL affect research on the physiological adaptations to MD. Specifically, previous research on cortical reorganization using functional magnetic resonance imaging (fMRI), indicates a critical need to accurately determine a MD patient's point of gaze in order to better infer existence of cortical reorganization. Unfortunately, standard MR compatible hardware eye-tracking systems do not work well with these patients. Their reduction in fixation stability often overwhelms the tracking algorithms used by these systems. This research investigates the use of an existing magnetic resonance imaging (MRI) based technique called Predictive Eye Estimation Regression (PEER) to determine the point of gaze of MD patients and thus control for fixation instability. PEER makes use of the fluctuations in the MR signal caused by eye movements to identify position of gaze. Engineering adaptations such as temporal resolution and brain coverage were applied to tailor PEER to MD patients. Also participants were evaluated on different fixation protocols and the results compared to that of the micro-perimeter MP-1 to test the efficacy of PEER. The fixation stability results obtained from PEER were similar to that obtained from the eye tracking results of the micro-perimeter MP-1. However, PEER's point of gaze estimations was different from the MP-1's in the fixation tests. The difference in this result cannot be concluded to be specific to PEER. In order to resolve this issue, advancements to PEER by the inclusion of an eye tracker in the scanner to run concurrently with PEER could provide more evidence of PEER's reliability. In addition, increasing the diversity of AMD patients in terms of the different scotoma types will help provide a better estimate of PEER flexibility and robustness.

Doctor of Philosophy (PhD) / BACKGROUND: The accumulation of abnormal extracellular deposits beneath the retinal pigment epithelium characterises the pathology of early age-related macular degeneration. However, the histopathological threshold at which age-related changes become early AMD is not defined, and the effect of each of the deposits (basal laminar deposit and membranous debris) on disease progression is poorly understood. Evidence suggests that macrophages play a key role in the development of AMD lesions, but the influence of basal laminar deposit (BLamD) and membranous debris on the recruitment and programming of local macrophages has not been explored. Although evidence also suggests that inflammation and innate immunity are involved in AMD, the significance of anti-retinal autoantibodies to disesase pathogenesis is not known. AIMS: (i) To determine the histopathological threshold that distinguishes normal ageing from early AMD; (ii) to determine the influence of BLamD and membranous debris on disease progression; (iii) to examine whether distinct early AMD phenotypes exist based on clinicopathological evidence; (iv) to determine the histopathological context in which Bruch’s membrane macrophages first found; (v) to examine the relationship between Bruch’s membrane macrophages and subclinical neovascularisation; (vi) to determine if the progressive accumulation of BLamD and membranous debris alters the immunophenotype of Bruch’s membrane macrophages and/or resident choroidal macrophages; (vii) to determine if the anti-retinal autoantibody profile differs significantly between normal individuals and those with early AMD, neovascular AMD or geographic atrophy; (viii) to examine whether baseline anti-retinal autoantibodies can predict progression to advanced AMD in individuals with early AMD; and (ix) to examine whether baseline anti-retinal autoantibodies can predict vision loss in individuals with neovascular AMD. METHODS:Clinicopathological studies were performed to correlate progressive accumulation of BLamD and membranous debris to fundus characteristics and visual acuity, as well as to sub-macular Bruch’s membrane macrophage count. Immunohistochemical studies were perfomed to determine whether the presence of BLamD and membranous debris altered the programming of Bruch’s membrane or resident choroidal macrophages. The presence of serum anti-retinal autoantibodies was determined by western blotting, and the association with disease progression examined in early and neovascular AMD. RESULTS: The presence of both basal linear deposit (BLinD) and a continuous layer of BLamD represents threshold early AMD histopathologically, which was seen clinically as a normal fundus in the majority of cases. Membranous debris accumulation appeared to influence the pathway of progression from early AMD to advanced AMD. Bruch’s membrane macrophages were first noted when a continuous layer of BLamD and clinical evidence of early AMD were present, and increased with the amount of membranous debris in eyes with thin BLamD. Eyes with subclinical CNV had high macrophage counts and there was some evidence of altered resident choroidal macrophage programming in the presence of BLamD and membranous debris. Serum anti-retinal autoantibodies were found in a higher proportion of early AMD participants compared with both controls and participants with neovascular AMD, and in a higher proportion of individuals with atrophic AMD compared to those with neovascular AMD. The presence of baseline anti-retinal autoantibodies in participants with early AMD was not associated with progression to advanced AMD. Participants with neovascular AMD lost more vision over 24 months if they had IgG autoantibodies at baseline compared to autoantibody negative participants. CONCLUSIONS: The finding that eyes with threshold early AMD appear clinically normal underscores the need to utilise more sophisticated tests to enable earlier disease detection. Clinicopathological evidence suggests two distinct early AMD phenotypes, which follow two pathways of AMD progression. Macrophage recruitment and programming may be altered by the presence of BLamD and membranous debris, highlighting the need to further characterise the biology of human resident choroidal macropahges. Anti-retinal autoantibodies can be found in both control and AMD sera, and future approaches that allow the examination of subtle changes in complex repertoires will determine whether they are involved in AMD disease pathogenesis.

Made available in DSpace on 2015-07-22T20:49:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-04-28 / O objetivo deste trabalho é avaliar as anormalidades da esclera, coroide e retina de coelhos induzidas pela dieta hipercolesterolêmica, além da possibilidade de prevenção dessas anormalidades com administração sistêmica de rosiglitazona. Para isto, 54 coelhos new zealand foram distribuídos em quatro grupos: grupo-controle (GC) recebeu dieta normal; grupo 1 recebeu dieta hipercolesterolêmica; grupo 2 recebeu dieta hipercolesterolêmica associada à administração diária de 3 mg de rosiglitazona a partir do 14º dia do início do experimento; e grupo 3 recebeu dieta hipercolesterolêmica associada à administração diária de 3 mg de rosiglitazona desde o início do experimento. Os coelhos foram pesados e submetidos à dosagem sérica de colesterol total, triglicerídeos, high density lipoprotein (HDL) colesterol e glicemia de jejum no início do experimento, no 14º dia e no momento da eutanásia (42º dia). A esclera e coroide foram submetidas à análise histológica e histomorfométrica. A retina foi submetida à análise imuno-histoquímica com o anticorpo monoclonal anticalretinina (CR) e anticorpo anti-glial fibrillary acidic protein (GFAP). Quando positivo para o marcador anticalretinina, duas análises quantitativas foram realizadas. Na primeira, foram contadas todas as células ganglionares imunorreativas. Na segunda, todas as células e elementos celulares imunorreativos foram avaliados pelo exame de morfometria de cores. Os dados foram analisados pelo teste nãoparamétrico de Kruskal-Wallis e teste de Shapiro-Wilks-Testand. Valores abaixo de 0,05 foram considerados estatisticamente significantes. Os resultados referentes ao peso demonstraram significativo aumento nos grupos 1 e 3 em relação ao GC no 14º dia (p<0,009), enquanto no 42º dia os grupos 1, 2 e 3 apresentaram representativamente mais peso que o GC (p<0,023). Quanto às variáveis laboratoriais, destacaram-se o aumento significativo da glicose e colesterol total de G1 em relação ao controle (p<0,001), assim como o acentuado aumento da HDL no G3 em relação aos demais grupos (p<0,001), no 14º dia. A HDL manteve-se expressivamente elevada no G3 em relação aos demais grupos no momento da eutanásia (p<0,001). À análise histomorfométrica da esclera e coroide obteve-se normalidade do GC. Por outro lado, o G1 mostrou marcante aumento da espessura da esclera e coroide em relação ao GC (p=0,008), enquanto que no G3 houve espessamento de esclera e coroide menor que no G1 (p=0,048). Elevado número de histiócitos foi observado na parede escleral do grupo submetido à dieta hipercolesterolêmica (G1), seguido de forma decrescente por G2, G3 e GC. A análise imuno-histoquímica da retina com o anticorpo monoclonal anticalretinina ressaltou número mais alto de células ganglionares imunorreativas no G1 que no G3 (p=0,002). O exame de morfometria de cores revelou significativa imunorreatividade das células e elementos celulares do G1 em relação aos outros grupos (p<0,001). Nesta análise evidenciou-se também acentuada imunorreatividade das células e elementos celulares de G2 e G3 em relação ao GC (p≤0,002). GFAP foi negativo em todos os grupos. Neste modelo, os achados permitem concluir que a hipercolesterolemia provoca anormalidades precoces histomorfométricas e imuno-histoquímicas do complexo esclerocoriorretiniano; e a ativação dos receptores do PPAR gama-ocular, a partir da dieta oral de rosiglitazona, foi efetiva em atenuar tais anormalidades nessas estruturas. / The purpose of this study is to evaluate scleral, choroid and retinal abnormalities in rabbits induced by a hypercholesterolemic diet and the prevention of these abnormalities after oral administration of rosiglitazone in rabbits. Fifty-four new zealand rabbits were divided into four groups: the control group (CG) was fed a normal diet; group 1 G1), a hypercholesterolemic diet; group 2 (G2) a hypercholesterolemic diet associated with daily administration of 3 mg of rosiglitazone from day 14 after the beginning of the diet; and group 3 G3), a hypercholesterolemic diet associated with daily administration of 3 mg of rosiglitazone since the beginning of the experiment. The rabbits were weighed and underwent the following examinations: seric dosages of total cholesterol, triglycerides, cholesterol HDL, and fasting glycemia at the beginning of the experiment, on the 14th day and on the 42nd, the euthanasia day. The sclera and choroid underwent histologic and histomorphometric analyses and the retina underwent immunohistochemical analysis with anti-calretinin (CR) and anti-glial fibrillary acidic protein (GFAP) antibody. When positive for the anti-calretinin marker, two quantitative analyses were performed. In the first analysis, all immunoreactive ganglion cells were counted. In the second analysis, all immunoreactive cells and cell elements were studied with the color morphometry method. The data were evaluated using the nonparametric Kruskal-Wallis and the Shapiro – Wilk tests. Values of p<0.05 were considered statistically significant. The results obtained showed a significant weight increase in Groups 1 and 3 in relation to CG on Day 14 (p<0.009). Additionally, a significant weight increase was observed in G1, G2 and G3 in relation to CG on Day 42 (p<0.023). The lab results showed a significant increase in glucose and total cholesterol in G1 in relation to CG (p<0.001) on Day 14, as well as a significant HDL increase in G3, when compared with the other groups (p<0.001) on Day 14. HDL in G3 was significantly high when compared to the other groups, on the euthanasia day (p<0.001). The results obtained regarding weight showed a significant increase in Groups 1, 2 and 3 in relation to CG on Day 14 (p<0.01) and Day 42 (p<0.02). The lab results showed a significant increase in glucose and total cholesterol in Groups 1, 2 and 3 in relation to CG (p<0.01) on Day 14, as well as a significant increase in HDL in G3 when compared with the other groups, on euthanasia day (p<0.01). The histomorphometric analysis of CG sclera and choroid presented normal results. Conversely, G1 showed a significant increase in sclera and choroid thickness in relation to CG (p= 0,008), whereas G3 showed thickness lower than in G1 (p=0,048). A larger number of histiocytes were observed on the scleral wall of the group that was fed the hypercholesterolemic diet (G1), followed, in a descending order, by groups 2 and 3, and the control group. The immunohistochemical analysis of the retina with the anti-calretinin monoclonal antibody showed that G1 presented a larger number of immunoreactive ganglion cells than G3 (p = 0.002). The color morphometry showed significant immunoreactivity of G1 cells and cell elements when compared with the other groups (p<0.001). A significant immunoreactivity of G2 and G3 cells and cell elements in relation to CG was also observed (p<0.002). GFAP results were negative in all groups. The findings of this proposed study model suggest that hypercholesterolemia induces early histomorphometric and immunohistochemical abnormalities in the sclerochorioretinal complex and that the activation of PPAR gamma in ocular cells attenuated these abnormalities with the administration of the oral rosiglitazone diet. / TEDE / BV UNIFESP: Teses e dissertações

The aim of the thesis is the most faithful interpretation of a senior´s image presented by media taking into consideration possible culture, political, social, alternatively other contexts jointly forming and affecting this image. During the data collection and their evaluation following research questions were taken into account: Do media information concerning seniors come under a typification and/or stereo-typification? Do the media correctly use terms "a senior" or "a pensioner"? Is it possible to discover an age-related discrimination in the media? To achieve this objective there was used a methodical support in a form of a content analysis of the most popular Czech dailies (Blesk, MF Dnes, Právo, Aha!) in the period from January 1st, 2010 to June 30th, 2012. The content analysis was followed by an interpretative part of the research based on the Glaser-Strauss´ grounded theory method. It was followed by a comparison and evaluation of the above stated methods using a categorization and a description of each of those categories arising from the research results.

La rétinopathie diabétique est la cause principale de cécité dans la population en âge de travailler. Une détection précoce et un traitement adapté permettent de réduire considérablement le risque de perte de vue. Les autorités médicales recommandent un examen annuel pour les patients diabétiques. Plusieurs programmes de dépistage de la rétinopathie diabétique ont été déployés pour appliquer cette recommandation. L'objectif du projet TeleOphta était de détecter automatiquement des examens normaux dans un système de dépistage du diabète, afin de réduire le fardeau des lecteurs, et donc servir plus de patients. Cette thèse propose plusieurs méthodes pour extraire des informations liées à des lésions provoquées par la rétinopathie diabétique dans des images en couleurs du fond d'œil.La détection des exsudats, microanévrismes et hémorragies est discutée en détail. L'un des principaux défis de ce travail est de traiter des images cliniques, acquises avec différents types de caméras de fond d'œil, par des personnes différentes. Par conséquent, l'hétérogénéité de la base de données est élevé. Des nouvelles méthodes de pré-traitement, qui effectuent non seulement des tâches de normalisation et de débruitage, mais aussi de détection de réflexions et d'artefacts optiques, sont proposées. Des méthodes de segmentation des candidats basées sur la morphologie mathématique, et de nouveaux descripteurs de texture et de contexte sont proposées pour la caractérisation des lésions. Un algorithme de forêts aléatoires est utilisé pour choisir les lésions parmi les candidats. Les méthodes proposées utilisent largement des nouvelles méthodes d'analyse des résidus.En outre, trois nouvelles bases de données publiques d'images de la rétine, e-ophtha EX, e-ophtha MA et e-ophtha HM, respectivement conçues pour développer et évaluer les méthodes de détection d' exsudats,de microanévrismes et d'hémorragies, sont proposées dans ce travail. Les images ont été extraites du réseau de télémédecine OPHDIAT pour le dépistage de la rétinopathie diabétique. Des annotations manuelles détaillées des lésions sont fournies avec ces bases de données. Les algorithmes proposés sont évalués sur ces bases.Les méthodes proposées ont été intégrées dans le système TeleOphta , qui est présentée et évaluée sur deux grandes bases de données. Chaque dossier du patient est classé en deux catégories: “Pour avis” ou “Normal". La classification est basée non seulement sur les résultats des méthodes présentées, mais aussi sur les signatures d'image fournies par d'autres partenaires, ainsi que sur l'information médicale du patient, et les données liées à l'acquisition. L'évaluation montre que le système TeleOphta permet de traiter deux fois plus de patients dans un réseau de dépistage, à moyens constants. / Diabetic retinopathy is the main cause of blindness among the middle-aged population. An early detection and adapted treatment considerably reduce the risk of sight loss. Medical authorities recommend an annual examination to diabetic patients. Several diabetic retinopathy screening programs have been deployed to enforce this recommendation. The aim of the TeleOphta project was to automatically detect normal examinations in a diabetic screening system, in order to reduce the burden on readers, and therefore serve more patients. This thesis proposes several methods to extract information linked to diabetic retinopathy lesions from color eye fundus images.The detection of exudates, microaneurysms and hemorrhages is discussed in detail. One of the main challenges of this work is to deal with clinical images, acquired by different types of eye fundus cameras, by different persons. Therefore the data base heterogeneity is high. New pre-processing methods, which perform not only normalization and denoising tasks, but also detect reflections and artifacts in the images, are proposed. Novel candidate segmentation methods based on mathematical morphology, and new textural and contextual features for lesion characterization, are proposed. A random forest algorithm is used to detect lesions among the candidates. The proposed methods make extensive use of new residue analysis methods.Moreover, three new publicly available retinal image databases, e-ophtha EX, e-ophtha MA and e-ophtha HM, respectively designed to develop and evaluate exudate, microaneurysms and hemorrhages detections methods, are proposed in this work. The images are extracted from the OPHDIAT telemedicine network for diabetic retinopathy screening. Manual annotations of the lesions are given in detail in these databases. The proposed algorithms are evaluated on these databases.The proposed methods have been integrated within the TeleOphta system, which is presented and evaluated on two large databases. Each patient record is classified into two categories: “To be referred” or “Normal”. The classification is based not only on the results of the presented methods, but also on image signatures provided by other partners, as well as on medical and acquisition-related information. The evaluation shows that the TeleOphta system can make about 2 times more patients benefit from the diagnosis service.

Le glaucome est une maladie neurodégénérative qui se définit par une perte progressive en fibres nerveuses rétiniennes et un rétrécissement du champ visuel. Il s’agit de la première cause de cécité irréversible dans le monde et le principal facteur de risque est la pression intraoculaire (PIO). L’étude ALIENOR (Antioxydants, Lipides Essentiels, Nutrition et maladies OculaiRes) est une étude épidémiologique qui a pour but de déterminer l’incidence des différentes pathologies oculaires liées à l’âge avec les facteurs nutritionnels, démographiques ou environnementaux dans une population représentative de la région de Bordeaux. En 2009-2010, 624 sujets âgés de plus de 74 ans ont bénéficié d’un examen ophtalmologique complet incluant un examen du nerf optique en rétinophotographie et en tomographie à cohérence optique spectral-domain (SD-OCT), d’une mesure la PIO au tonomètre à air et d’une évaluation des propriétés biomécaniques de la cornée. Une mesure de l’accumulation cutanée de produits de glycation avancée a été réalisée par autofluorescence. Le diagnostic de glaucome a été réalisé en utilisant les critères de la classification ISGEO (International Society for Epidemiologic and Geographical Ophthalmology). Les paramètres biomécaniques de la cornée étaient modifiés avec l’âge et chez les sujets ayant une histoire résidentielle à des latitudes plus exposées aux ultraviolets ambiants. L’épaisseur de cornée était plus élevée chez les sujets anciennement fumeurs. L’autofluorescence cutanée ≥ 2.7 UA (Unité Arbitraire) était indépendamment associée au glaucome. Les paramètres d’épaisseur en fibres nerveuses rétiniennes du SD-OCT présentaient de bonnes performances diagnostiques pour discriminer les sujets glaucomateux des témoins et la base normative présentait de bonnes performances discriminatives lorsqu’au moins un des paramètres était considéré comme anormal. Notre étude apporte des résultats originaux en termes de facteurs de risque de glaucome ou de déterminants des facteurs de risque de glaucome. De plus les performances diagnostiques du SD-OCT pourraient fournir des informations utiles pour optimiser les stratégies de dépistage du glaucome dans une population générale âgée. / Glaucoma is a neurodegenerative disease defined by a progressive loss of optic nerve axons and retinal ganglion cells resulting in a characteristic enlargement of the optic nerve head cup and associated visual field defects. It remains the first cause of irreversible blindness worldwide and intraocular pressure (IOP) is the main risk factor. The ALIENOR (Antioxydants, Lipides Essentiels, Nutrition et maladies OculaiRes) study is a population-based study. It aims to assess the associations of age-related eye diseases with nutritional, demographic and environmental factors in a representative population of the Bordeaux area. In 2009-2010, 624 subjects, aged 74 years or more, underwent a complete eye examination, including an optic nerve head evaluation using retinophotography and a spectral-domain optical coherence tomography (SD-OCT), an IOP measurement using air-puff tonometry and an evaluation of biomechanical properties of the cornea. A measurement of skin accumulation of advanced glycation end-products was performed using an autofluorescence reader. Glaucoma diagnosis was made using ISGEO (International Society for Epidemiologic and Geographical Ophthalmology) criteria. Biomechanical properties of the cornea were modified by increasing age and in subjects having a higher lifetime ambient ultraviolet exposure. Central corneal thickness was thicker in former smokers. Skin autofluorescence values ≥ 2.7 AU (Arbitrary Unit) were independently associated with glaucoma. SD-OCT retinal nerve fiber layer thickness parameters had good diagnostic performances for discriminating glaucoma and control subjects and the normative database had good diagnostic performances if at least one parameter was considered abnormal by the machine. Our study provides new insights on glaucoma risk factors and determinants of glaucoma risk factors. Furthermore diagnostic performances of SD-OCT may provide valuable information in a screening strategy to optimize glaucoma detection in a general population of elderly people.

Les rétinopathies ischémiques et la forme humide de la dégénérescence maculaire liée à l’âge (DMLA) sont la principale cause de malvoyance respectivement chez les personnes en âge de travailler et les personnes agées. Les néovascularisations choroïdiennes (NVC) et rétiniennes et l’œdème maculaire associés à ces pathologies sont traités à l’aide de biomolécules qui ciblent uniquement la voie de signalisation des VEGF. Le développement de thérapies indépendantes de cette voie permettrait d’offrir aux patients résistants aux anti-VEGF une alternative thérapeutique pour préserver leur vision. Les intégrines αvβ3 et αvβ5, impliquées dans la néovascularisation oculaire, apparaissent ainsi comme une cible alternative intéressante. La Lébécetine (LCT), une lectine de type-C, de 30 kDa et de structure hétérodimèrique issue de venin de serpent Macrovipera lebetina interagit spécifiquement avec les intégrines α5β1 et αvβ3, αvβ5. La LCT a une activité anti-angiogénique in vitro sur des cellules endothéliales microvasculaire du cerveau humain (HBMEC) et in vivo sur le modèle de la membrane chorioallantoïde du poulet (CAM). Afin d’étudier son effet sur la néovascularisation oculaire, nous avons eu recours aux modèles d’angiogenèse ex vivo utilisant des explants aortique ou choroïdien cultivés en présence de LCT, puis son effet a été évalué in vivo dans un modèle de NVC chez la souris et également sur la néovascularisation rétinienne dans le modèle de rétinopathie induite par l’oxygène (RIO). Nos données démontrent qu’une injection unique de LCT est capable de réduire la NVC et rétinienne dans ces modèles sans affecter les vaisseaux quiescents matures indiquant un bon profil d’innocuité. / Ischemic retinopathies and the wet form of age-related macular degeneration (AMD) are characterized by devastating angiogenesis responsible for the majority of irreversible blindness. Current therapies include use of anti-VEGF agents to reduce choroidal neovascularization and edema. These treatments are effective in most cases, but spontaneous or acquired resistance to anti-VEGF highlight a need for additional alternative therapies. In recent years, pharmacological inhibition of αvβ3 and αvβ5, which regulate endothelial cell proliferation and stabilization, have emerged as new therapeutic tools for the treatment of these diseases. Lebecetin (LCT), a 30-kDa heterodimeric C-type lectin that is isolated from Macrovipera lebetina venom, interacts with α5β1 and αv-containing integrins (αvβ3, αvβ5). We previously showed that LCT has an anti-angiogenic effect in vitro on human brain microvascular endothelial cells (HBMEC) and in vivo in a chick chorioallontoic membrane assay (CAM). To evaluate the inhibitory effect of LCT on ocular angiogenesis, we cultured aortic and choroidal explants in the presence of LCT and analyzed the effect of LCT on choroidal neovascularization in the mouse CNV model and on retinal neovascularization in the oxygen induced retinopathy (OIR) model. Our data demonstrated that a single injection of LCT efficiently reduced choroidal and retinal neovascularization in these models with no significant effect on mature blood vessels predicting a good safety profile.

Ansamling av amyloid beta (Aβ) i de extracellulära miljöerna är associerad till många svåra sjukdomar som Alzheimers och ålders-relaterad makuladegeneration (AMD). Amyloider karaktäriseras av att de är olösliga, toxiska mot neuron och orsakar därför svår skada. AMD är den ledande orsaken till blindhet och irreversibelt förlorande av skarp syn då Aβ manifesterar i makula. I AMD orsakar Aβ inflammatorisk aktivitet där det retinala pigmentepitelet bryts ned och ljuskänsliga fotoreceptorer dör genom apoptos. Idag lever ca 150 miljoner människor med AMD där mänga har svårt att utföra vardagliga uppgifter till följd av förlust av skarp syn. Idag är Kongo röd en av de vanligaste metoderna för att visualisera amyloider in vitro. Den patogenes som orsakas av amyloider kan analyseras med immunofluorescens och immunohistokemi. Syftet med studien var att undersöka förekomst av amyloider i samband med celldöd i näthinna från gris, undersöka den patogenes som amyloider orsakar med immunofluorescens och immunohistokemi, samt undersöka om det finns korrelation mellan amyloider och celldöd. Resultatet visade att amyloider var förekommande i näthinnan och hade orsakat celldöd och ansamling av aggresomer. Amyloider och den patologi som orsakats kunde visualiseras i det yttre lagret av näthinnan. / Deposition of amyloid beta (Aβ) in the extracellular environment are associated to some severe diseases, like Alzheimer’s disease and age-related macular degeneration (AMD). Amyloids are characterized by insolubility, toxicity towards neuron and are there-for damaging to tissues. AMD is the primary cause of blindness and irreversible loss of central vision through manifestation of Aβ in the macula. In AMD, Aβ drives an inflammatory action that degenerates the retinal pigment epithelium and cause atrophy of photoreceptors. Today ~150 million people live with AMD where many find difficulties performing everyday tasks due to loss of sharp vision. Congo red is a gold standard for visualizing amyloids in vitro and the pathogenesis caused by amyloids can be analyzed by immunofluorescence and immunohistochemistry. The purpose of this study was to show the presence of amyloids relating to cell death in pig retina, show the pathogenesis caused by amyloids by using immunofluorescence and immunohistochemistry, and investigate whether there is correlation between amyloids and cell death. The result showed that amyloids were present in the retina and caused cell death and gathering of aggresomes. Amyloids and the caused pathology could be visualized in the outer layer of the retina.

Le vieillissement des populations dans les économies développées apparaît comme un enjeu majeur dans lequel l’emploi est au centre de toutes les préoccupations. Il influence, également, l’équilibre de leur système de protection sociale. Cette thèse s’intéresse à la faiblesse du taux d’emploi des séniors français, représentés par les plus de 50 ans, comparativement à celui des autres pays européens. L’inflexion des politiques publiques à l’égard des séniors, d’une logique d’exclusion à une logique d’inclusion du marché du travail, dans les années 2000, ne permet qu’une amélioration lente et limitée de leur taux d’emploi. Alors que les autres pays européens ont aussi été concernés par le changement de politiques, il est légitime de s’interroger sur les raisons de leur impact modéré en France.Cette thèse s’organise autour de deux parties complémentaires. La première partie fait état du constat de la faiblesse du taux d’emploi des séniors, en France comparativement à ses voisins européens (chapitre un). Cette faiblesse se traduit par une ségrégation professionnelle augmentant avec l’âge qui aboutit à une difficulté d’orientation des hommes âgés, dans certains secteurs et certaines professions au sein de ces secteurs. D’autres pistes de réflexion sur les raisons supposées de cette faiblesse des taux d’emploi des séniors sont également envisagées dans une revue de littérature (chapitre deux). Ces raisons proviennent de plusieurs champs : du champ structurel et des caractéristiques de l’offre et de la demande de travail, ce qui illustre la complexité de la problématique pour les pouvoirs publics. La deuxième partie s’attache à mesurer un facteur de sous-emploi des séniors persistant alors même qu’on neutralise toutes les raisons objectives pour lesquelles les préférences des recruteurs, à l’embauche, se portent moins sur les séniors : la discrimination à l’embauche liée à l’âge (et au sexe pour quelques cas particuliers). Deux types de méthodes et de données sont utilisés pour mesurer la partie résiduelle des écarts de probabilité d’être en emploi ou d’accès à l’emploi (dont la discrimination est un des composants) : les méthodes de décomposition sur des données d’enquête, donnant une mesure qualifiée d’objective (chapitre trois) avec une extension analysant le lien entre cette partie résiduelle et la conjoncture économique et la méthodologie des tests de correspondance, ou testing, sur des données expérimentales collectées sur une sélection de professions en tension (chapitre quatre). La première méthode démontre une partie résiduelle de l’écart de probabilité importante, laissant présager des risques élevés de discrimination liée à l’âge et au genre. La comparaison des taux d’accès à l’emploi de la deuxième méthode conduite sur près de 6 000 candidatures illustrent ces risques selon lesquels les séniors ont moins de chances d’accéder à un entretien d’embauche comparativement aux plus jeunes à caractéristiques semblables. Nous verrons les différentes hypothèses explicatives du sous-emploi des séniors, documentées par la littérature, comme la distance courte à la retraite, l’obsolescence des compétences en situation de chocs technologiques, les normes sociales de sexe (par la reconversion professionnelle) et d’âge (par les préférences exogènes des recruteurs).L’un des fils directeurs de la thèse est de distinguer la situation des hommes et des femmes séniors en matière d’emploi. On observe des différences manifestes sur l’ensemble de cette thèse avec une situation des hommes plus problématique que celle de leurs homologues féminines en termes d’écart de taux d’emploi, de ségrégation professionnelle et de discrimination à l’embauche. / The ageing of populations in developed economies appears as a major issue in which employment is at the centre of all concerns. It also influences the balance of their social protection system. This thesis is interested in the weakness employment rate of French older workers, considered as the population over 50 years old, compared to other European countries. The inflection of public policies for them, from logic of exclusion to logic of inclusion in the labour market, in the 2000s, allows only slow and limited improvements in the employment rate. While other European countries have also been affected by the policy change, it is legitimate to wonder about the reasons for their moderate impact on France.This thesis is organized into two complementary parts. The first part reports the finding of the low employment rate of older workers, in France compared to its European neighbours (chapter one) This weakness is reflected in occupational segregation increases with age, resulting in difficulties in terms of orientation of men, with age in some sectors and occupations within these sectors. Other subjects of reflection on why this supposed weakness of older workers employment rates are also considered in a literature review (chapter two). Those reasons come from many fields: both the structural field and the characteristics of labour supply and labour demand, which illustrates the complexity of the issue for the government. The second part attempts to measure a factor of persistent underemployment of older workers even as we neutralize all objective reasons why the hiring preferences of recruiters, move on less to seniors: the hiring age-related discrimination (and gender for some particular cases). Two types of methods and data are used to measure the residual part of the probability gaps of being in employment and access to employment (including discrimination is a component): decomposition methods on data of survey, giving a measure qualified objective (chapter three) with an extension analysing the link between this residual part and business cycle, and methodology of correspondence tests or testing on experimental data collected on a selection of occupations in tension (chapter four). The first method finds a significant residual part of the probability gap, suggesting high risk of related-age and gender discrimination. The comparison of access to employment rates of the second method made on around 6,000 applications illustrates these risks according to which the senior applicant have less chances to get a job interview, compared with younger having similar characteristics. We shall see the different explanatory assumptions of underemployment of older workers supported by the literature as the short distance from retirement, the obsolescence of skills in situation of technological shocks, the social norms of gender (by the vocational training) and of age (by exogenous preferences of employers).One of the recurring threads in the thesis is to distinguish the situation of older men of the senior women in employment. There are clear differences in this whole thesis with a situation more problematic men than their female counterparts in terms of employment rates gap, occupational segregation and employment discrimination.