La rétine est constituée de plusieurs types de neurones incluant les cellules amacrines, ganglionnaires, bipolaires et les photorécepteurs. Les photorécepteurs, qui englobent les cônes et les bâtonnets, sont des neurones sensoriels hautement spécialisés qui permettent la conversion de la lumière en signaux électriques par le mécanisme de phototransduction. Les mécanismes moléculaires par lesquels les progéniteurs rétiniens (RPCs) se différencient en différents neurones spécialisés comme les photorécepteurs sont encore peu connus. Le gène Polycomb Bmi1 appartient à la famille des gènes Polycomb qui forment des complexes multimériques impliqués dans la répression de l’expression génique via le remodelage de la chromatine. Au niveau biologique, le gène Bmi1 régule, entre autre, le contrôle de la prolifération cellulaire, le métabolisme des radicaux libres, et la réparation de l’ADN. Récemment, il a été démontré que Bmi1 joue un rôle critique dans la prolifération et l’auto-renouvellement d’un groupe de RPCs immatures. De plus, Bmi1 est essentiel au développement post-natal de la rétine. L'objectif de cette étude est d'analyser le rôle de Bmi1 dans le développement et la survie des photorécepteurs chez la souris. Nos résultats révèlent un phénotype de dégénérescence des photorécepteurs de types cônes chez notre modèle de souris déficiente pour Bmi1. Les bâtonnets sont insensibles à la mutation. De plus, Bmi1 est exprimé de façon prédominante dans les cônes. Nos expériences de culture de cellules rétiniennes suggèrent que le phénotype est cellule-autonome. Par ailleurs, la co-délétion du gène Chk2, membre de la réponse aux dommages à l'ADN, permet de ralentir la progression du phénotype. Les rétines Bmi1-/- et Bmi1-/-Chk2-/- présentent une augmentation importante des dommages oxydatifs à l'ADN. Ces résultats suggèrent que le stress oxydatif pourrait jouer un rôle important dans la survie des cônes. L'étude du rôle du gène Polycomb Bmi1 dans les photorécepteurs est importante pour une meilleure compréhension des mécanismes contribuant à la survie des cônes et pourrait mener à la découverte de nouveaux traitements des maladies dégénératives des cônes. / The retina is composed of several types of neurons such as amacrin, ganglion, bipolar and photoreceptor cells. Photoreceptors, which include cones and rods, are highly specialized neurons that convert light into electrical signals by phototransduction. The molecular mechanisms involved in differentiation of retinal progenitors (RPCs) into specialized neurons such as photoreceptors are poorly understood. The polycomb gene Bmi1 is a member of the Polycomb gene family that forms multimeric complexes involved in chromatin remodeling leading to gene repression. Biological functions of Bmi1 include regulation of cell proliferation, free radical metabolism, and DNA repair. Recently, it was shown that Bmi1 plays a critical role in the proliferation and self-renewal of a specific immature RPC group. Moreover Bmi1 is essential for post-natal retinal development. The objective of the current study is to analyze Bmi1 function in photoreceptor development and survival. Our results show that Bmi1 deficiency in mice causes degeneration of cone photoreceptors, but not of rods. Furthermore, Bmi1 is predominantly expressed in cones. Experiments using primary retinal cell cultures suggest a cell-autonomous phenotype. In addition, codeletion of Bmi1 and the critical DNA damage response protein Chk2 resulted in partial rescue and slow-down of cone degeneration. Bmi1-/- and Bmi1-/-Chk2-/- retinas also exhibit an important increase in oxidative DNA damage, suggesting that cellular redox state could play an important role in cone survival. Our studies on the role of Bmi1 in photoreceptors elucidate the mechanisms contributing to cone survival, and could lead to the development of new treatments for cone degenerative diseases.

No description available.

Purpose: The main objective of the present study was the investigation of possible influence of lens opacification on macular pigment optical density (MPOD) measurements. Methods: 86 eyes of 64 patients (mean age 73.4(±8.3)years) were included in the study. MPOD was prospectively measured using one-wavelength reflection method (Visucam500, Carl Zeiss Meditec AG) before and after cataract extraction with implantation of a blue-light filtering intraocular lens (AlconSN60WF). The median of the maximum optical density (MaxOD) and the median of the mean optical density (MeanOD) measurements of macular pigment across the subject group were evaluated. Results: Statistically significant differences were noticed between pre-operative and post-operative measurements, the absolute values were generally lower after cataract extraction. The following median(lower/upper quartile) differences across the group were determined: MaxOD -33.8%(-46.2%/-19.1%), MeanOD -44.0%(-54.6%/-26.6%). Larger changes were observed in elderly patients (<70years of age: (n=25eyes) MaxOD -13.4%(-20.5%/3.6%), MeanOD -23.6%(-30.5%/-15.3%) versus patients ≥70years: (n=61eyes) MaxOD -40.5%(-53.2%/-30.1%), MeanOD -47.2%(-57.8%/-40.1%)) and in patients with progressed stage of cataract. MaxOD for lens opacification grade 1:(n=9eyes) -27.4%(-42.1%/-19.6%), 2:(n=26eyes) -35.0%(-44.2%/-25.3%), 3:(n=21eyes) -34.4%(-45.4%/-11.4%), 4:(n=25eyes) -32.6%(-53.2%/-6.4%) and 5:(n=5eyes) -53.5%(-61.7%/-38.7%) and MeanOD for cataract stage 1:(n=9eyes) -42.6%(-46.0%/-26.0%), 2:(n=26eyes) -44.1%(-51.8%/26.2%), 3:(n=21eyes) -45.7%(-54.7%/-24.7%), 4:(n=25eyes) -39.5%(-59.4%/-26.1%), 5:(n=5eyes) -57.0%(-66.1%/-51.4%). Conclusions: As established by comparison of pre- to post-operative measurements, cataract presented a strong effect on MPOD measured by one-wavelength reflection method. Particular care should therefore be taken when evaluating MPOD using this method in elderly patients with progressed stage of cataract. Future optimization of correcting parameters of scattered light and consideration of cataract influence may allow more precise evaluation of MPOD.

Sammanfattning   Syfte och frågeställningar Syftet med denna studie var att sammanställa kvalitet på och resultat av studier som undersökt om långdistanslöpning ger artros i höft-, knä- eller fotleder. Finns det vetenskaplig evidens för att långdistanslöpning ger artros i höft-, knä- eller fotleder? Vilka styrkor och svagheter har de studier som försökt utröna om samband finns mellan långdistanslöpning och artros i höft-, knä- eller fotleder?   Metod Sökning av litteratur utfördes i PubMed, CINAHL, Cochrane Library och PEDro. Detta resulterade i att tio artiklar inkluderades för närmare granskning och sammanställning. Utifrån artiklarnas sammantagna bevisvärde poängsattes och graderades artiklarna efter evidensnivå enligt Statens Beredning för medicinsk Utvärderings (SBU) granskningsmallar för kohortstudier med kontrollgrupper.   Resultat Endast en av tio studier visar ett positivt samband mellan långdistanslöpning och artros i höft-, knä- eller fotleder, i detta fall höftledsartros. Studierna har ingen tydlig och gemensam definition över vad långdistanslöpning är. De granskade studierna använder sig av olika mätmetoder för att bedöma leddegenerationen, både av självrapportering och av olika diagnostiska kriterier för artros. Alla studier har inslag av selektionsbias.   Slutsats En indikation på att det inte finns ett vetenskapligt stöd för att långdistanslöpning ger höft-, knä- eller fotledsartros hos människor. Studierna har brister i hantering av confounders och selektionsbias och bedöms vara av låg eller medelhög kvalitet. / Abstract   Aim The purpose of this study was to compile the quality and results of studies that examined if long-distance running gives osteoarthritis of the hip, knee or ankle joints. Is there scientific evidence that long-distance running gives osteoarthritis of the hip, knee or ankle? What strengths and weaknesses of the studies attempted to determine if the link between long-distance running and osteoarthritis of the hip, knee or ankle joints.   Method Search of the literature was performed in PubMed, CINAHL, Cochrane Library, and PEDro. This resulted in ten articles that were included for further review and compilation. Based on the articles combined probative value was scored and graded articles for level of evidence according to the National Council on Technology Evaluation (SBU) examination templates for cohort studies with control groups.   Results Only one of the ten studies showed a positive association between long distance running and osteoarthritis of the hip, knee or ankle joints, in this case hip joint. The studies have not a clear and common definition of what long-distance running is. The studies reviewed use different metrics to assess joint degeneration, both by self-report and of different diagnostic criteria for osteoarthritis. All studies have an element of selection bias.   Conclusion An indication that there is no scientific evidence that long-distance running gives hip, knee or ankle osteoarthritis in humans. The studies were inadequate handling of confounders and selection bias and judged to be of low or medium quality.

Osteoarthritis (OA) is the leading cause of disability in North American and has major economic consequences for society. People with knee OA experience the worst quality of life, among musculoskeletal conditions, with function and mobility being influenced by symptoms such as pain and stiffness. However, the impact of OA symptoms varies due to intrinsic and extrinsic factors, leading many researchers to employ biopsychosocial and other population health frameworks to study the disease. These population health approaches have not been adopted when studying knee OA outcomes in bioarchaeology, where a limited biological lens prevails due to the sole reliance on skeletal remains. The purpose of this research was to explore methods for identifying the impairment potential of knee OA in archaeological populations using a clinical sample and population health approaches. Clinical studies have the advantage of assessing not only the biological implications of knee OA but also the functional outcomes. By creating a knee OA grading system applicable for both MRI and dry bone femora samples (Clinical Archaeological Osteoarthritis Score) a link between clinical and archaeological populations was proposed. Using this link to infer functional deficits onto archaeological populations using population health frameworks, a theoretical analysis was performed with two populations; the 17th century Huron and the 19th century Inuit from the Igloolik region of Nunavut. The results demonstrated the increased impairment potential of knee OA in the Inuit population versus the Huron population, produced by contrasting factors captured by the determinants of health, including social and physical environments.

No description available.

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.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Oklahoma. / Includes bibliographical references.