Idiopathic pulmonary fibrosis (IPF) is a disease of unknown aetiology, characterised by the progressive and irreversible scarring of parenchymal lung tissue that leads to respiratory failure and death. The disease is understood to be driven by an impaired and aberrant wound healing response, with an inappropriate reactivation of developmental signalling. The greatest risk factor for the disease is age, which is a process intimately associated with an increase in the burden of senescent cells. Such cells acquire a unique secretory phenotype and are known to have a significant impact on their local micro-environment. It was hypothesised that an alteration in epithelial-mesenchymal secretory communication, due to senescent-like changes in the fibroblast phenotype, may detrimentally contribute to lung homeostasis. An in vitro model of the lung airway was established in which primary human lung fibroblasts (HLFs) were co-cultured with human bronchial epithelial cells (HBECs). HBECs were cultured on a semi-permeable, transwell insert and co-cultured with either normal (NHLF), fibrotic (FHLF) or senescent fibroblasts. Over 72 hrs of co-culture, wound healing was assessed, via an epithelial scratch assay, and epithelial regeneration was measured, via trans-epithelial electrical resistance. Co-culture with NHLFs improves epithelial regeneration, however, FHLFs and senescent cells in co-culture show a diminished ability to promote epithelial regeneration and wound repair. The secretory repertoire of these cells contains elevated levels of IL-6, CXCL8, CXCL1 and GCSF (when assessed at both an RNA and protein level), factors strongly associated with the senescent phenotype. Targeting this secretome via treatment with the JAK 1/2 inhibitor Ruxolitinib attenuates these impairments and may point towards a new therapeutic strategy for the treatment of IPF.

No description available.

La dégénérescence maculaire liée à l’âge (DMLA) est la première cause de cécité chez les sujets âgés dans les pays industrialisés. Les questionnaires sur la qualité de vie suggèrent que les patients rencontrent des difficultés dans la recherche d’objets et dans leurs déplacements. En effet, les objets apparaissent rarement isolés dans leur environnement naturel. Ils apparaissent dans un contexte spatial qui peut les masquer en partie et le contraste d’une scène naturelle peut varier au cours de la journée. Nous étudions la capacité de reconnaissance des objets et des scènes naturelles chez les patients DMLA en utilisant des photographies de scènes naturelles. Nous nous sommes intéressés à la reconnaissance des scènes naturelles, puis à la capacité de discrimination figure/fond, à l’effet du contraste sur la reconnaissance des objets, et à la navigation spatiale dans un environnement virtuel. Nous avons comparé la performance de patients avec une DMLA à celle de sujets avec vision normale appariés en âge aux patients. Nos résultats montrent que les patients DMLA sont capables de catégoriser des scènes naturelle ou urbaine, et de discriminer une scène d’intérieur d’une scène extérieur avec un niveau de précision élevé, ce qui est en faveur des modèles centrés sur la scène. Ils détectent mieux un objet lorsque celui-ci était séparé du fond par un espace blanc et lorsque l’objet est présenté dans son contexte naturel que lorsqu’il est présenté sur un fond non structuré et non significatif ; ce qui indique que le fond est traité normalement en vision périphérique. Ils présentent plus de difficultés que les sujets avec vision normale pour détecter un objet dans une scène achromatique dont le contraste est réduit. Une étude sur la navigation spatiale met en évidence une compression de la représentation de l’espace: les sujets avec une DMLA sous-estiment plus la distance virtuelle que les sujets avec vision normale dans la tâche de navigation spatiale. Ces résultats peuvent avoir des applications pratiques dans la rééducation, dans la mise en page des textes et des magazines et dans l’agencement de l’environnement spatial des personnes âgés souffrant de DMLA afin d’améliorer la recherche d’objets, la mobilité et diminuer le risque de chute. / AMD (Age Related Macular Degeneration) is the leading cause of blindness in western countries. Quality of life Questionnaires indicate that people with AMD exhibit difficulties in finding objects and in mobility. In the natural environment, objects seldom appear in isolation. They appear in their natural setting in which they can be masked by other objects. The contrast of a scene may also change, as light varies as a function of the hour in the day and the light source. The objective of the study was to access objects and scene recognition impairments in people with AMD. We studied the perception of natural scenes, figure/ground discrimination, the effect of contrast on object recognition in achromatic scenes, and then navigation and spatial memory in a virtual environment. Performance was compared for people with AMD and age matched normally sighted controls. The results show that scene gist recognition can be accomplished with high accuracy with the low spatial resolution of peripheral vision, which supports the “scene centered approach” in scene recognition. Figure/ground discrimination is impaired in AMD. A white space surrounding the object is sufficient to improve its recognition and to facilitate figure/ground segregation. Performance is also improved when the object is displayed on its natural setting than when it appears on a non structured, non significant background. Sensitivity for the detection of a target object in achromatic scenes is impaired in AMD patients, who are more affected by contrast reductions than normally sighted people. A study on spatial nagigation showed a compression of space representation. People with AMD underestimate the virtual distance in a spatial navigation task. The results of our studies have implications for rehabilitation, for improving texts and magazines destined to people with low vision and for the improvement of the spatial environment of people suffering from AMD in order to facilitate mobility, object search and reduce the risk of falls.

People with presbyacusis commonly report difficulties in conversation in everyday settings. Although previous research has focused on self-report inventories concerning conversation difficulties in age related hearing difficulties, there is a lack of published work describing the interactions between people with presbyacusis and their conversational partners. The aim of this study is to describe conversational interactions between people with presbyacusis and their main everyday conversational partner and to determine whether there is evidence of change in interaction before and after the fitting of hearing aids. Ten participants recruited from a larger cohort were included in this study, consisting of 5 participants with diagnosed presbyacusis and 5 frequent conversation partners. A battery of audiological assessments was completed for each participant with presbyacusis. Each participant with presbyacusis was videotaped in conversation at home with their main everyday conversational partner: once before hearing aid fitting and once two months following hearing aid fitting. The conversational interactions before and after hearing aid fitting were analysed using Conversation Analysis. The results of the study revealed that both the people with presbyacusis and the conversation partners used patterns of interaction in instances of mishearings in conversation. The person with presbyacusis shifted gaze direction to show a need for repair. In addition, the conversation partner used physical prompting to gain gaze directed attention from the person with presbyacusis. The person with presbyacusis also made verbal requests for a repair as a result of mishearings. These patterns in interaction showed co-ordination and timing of the repair recognition, initiation and completion by both parties. The phenomena uncovered in this study indicate that the responsibility to monitor and maintain conversation was increasingly placed on the conversation partner of the person with presbyacusis. This could explain why people with presbyacusis and their conversation partners frequently complain of frustration in conversation activities. In the postamplification conversations, no mishearings occurred, suggesting a trend towards fewer mishearings on conversation as a result of amplification of hearing. The research findings contribute to the evidence base concerning the real benefit of digital hearing aids to these elderly clients. The findings of this study can be used to design assessment and intervention tools in the future. / Dissertation (M (Communication Pathology))--University of Pretoria, 2007. / Speech-Language Pathology and Audiology / M (Communication Pathology) / Unrestricted

PURPOSE. The mutation R345W in EFEMP1 (fibulin-3) causes macular degeneration. This study sought to determine whether proteoglycan content and diffusion across Bruch's membrane are altered in Efemp1(ki/ki) mice carrying this mutation or in Efemp1(-/-) mice. METHODS. Proteoglycans in mouse Bruch's membranes were stained with Cupromeronic Blue (CB). Heparan sulfated proteoglycan (HSPG) and chondroitin/dermatan sulfate proteoglycan (C/DSPG) distributions were visualized following treatments with chondroitinase ABC (C-ABC) or nitrous acid. Total sulfated glycosaminoglycans (sGAGs) in Bruch's membrane/choroid (BrM/Ch) were measured with dimethylmethylene blue (DMMB). Matrix metalloprotease (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-3 were examined by immunofluorescence and quantified using Image J. Molecules with different Stokes radius (R-s) were allowed simultaneously to diffuse through mouse BrM/Ch mounted in a modified Ussing chamber. Samples were quantified using gel exclusion chromatography. RESULTS. HSPGs and C/DSPGs were markedly increased in Efemp1(ki/ki) Bruch's membrane, and MMP-2 and MMP-9 were decreased, but TIMP-3 was increased. Diffusion across Efemp1(ki/ki) Bruch's membrane was impaired. In contrast, the proteoglycan amount in Efemp1(-/-) Bruch's membrane was not significantly different, but the size of proteoglycans was much larger. MMP-2, MMP-3, and TIMP-3 levels were similar to that of Efemp1(+/+) mice, but they were localized diffusely in retinal pigment epithelium (RPE) cells instead of Bruch's membrane. Diffusion across Efemp1(-/-) Bruch's membrane was enhanced. CONCLUSIONS. Mutant fibulin-3 causes proteoglycan accumulation, reduction of MMP-2 and MMP-9, but increase of TIMP-3, and impairs diffusion across Bruch's membrane. Fibulin-3 ablation results in altered sizes of proteoglycans, altered distributions of MMP-2, MMP-9, and TIMP-3, and enhances diffusion across Bruch's membrane.

Cette thèse avait pour principal objectif d’étudier la dissociation du système magnocellulaire et parvocellulaire en testant l’évolution de ces systèmes dans le vieillissement normal et la réhabilitation à l’aide de lunettes à filtre jaune. Pour cela deux paradigmes expérimentaux dont les caractéristiques des stimuli permettaient de biaiser le traitement visuel vers l’un ou l’autre des deux systèmes et dont les tâches impliquaient un niveau de traitement cognitif plus ou moins élaboré ont été utilisés. A l’aide d’une tâche de discrimination de luminance, les travaux ont mis en évidence l’apparition d’un déficit parvocellulaire massif dans le vieillissement ainsi qu’un déficit magnocellulaire de moindre ampleur au début du vieillissement mais qui s’accentuait rapidement au-delà de 75 ans. Dans une tâche de catégorisation d’objets, la présence du déficit magnocellulaire avec l’âge et le grand âge a été corroborée mais aucune répercussion du déficit parvocellulaire mis en évidence à un niveau de traitement plus précoce n’a été observée dans cette tâche. Concernant la réhabilitation, seul le groupe de participants très âgé (>75 ans) a vu ses performances améliorées par le filtre jaune dans la condition impliquant spécifiquement le système magnocellulaire à l’épreuve de discrimination de luminance. Dans l’épreuve de catégorisation, les deux groupes de participants âgés et très âgés ont montré une diminution significative de leur temps de réponse avec le filtre jaune accompagnée d’une amélioration de la précision de catégorisation pour le groupe très âgé, spécifiquement dans la condition mettant en jeu le système magnocellulaire.L’ensemble des résultats confirment donc la dissociation neuropsychologique entre système magnocellulaire et parvocellulaire : ils peuvent être sollicités de façon privilégiée chez l’adulte jeune en faisant varier à la fois plusieurs caractéristiques de la stimulation et la tâche ; ils ne vieillissent pas au même rythme et l’un d’entre eux peut être spécifiquement réhabilité / The thesis aimed at studying the dissociation between the magnocellular and the parvocellular system by testing their evolution in normal aging and their rehabilitation with yellow filter glasses. Two experimental paradigms whose specific stimuli characteristics and task allow to bias visual processing toward one or the other system and which involved a low or an elaborated cognitive processing were used.In a luminance discrimination task, the results showed a massive parvocellular and a lower magnocellular deficit at the beginning of aging, but the magnocellular deficit increased rapidly beyond 75 years old. In an object categorization task, the presence of magnocellular deficit with age and very old age was corroborated but there was no parvocellular deficit suggesting that the parvocellular deficit found at earlier stage of processing had no consequence for higher-level processes.Regarding rehabilitation, yellow filter improved sensitivity in the discrimination of luminance specifically in the condition involving the magnocellular system and for the very old group of participants (> 75 years old) only. In the categorization task, yellow filter significantly decreased response time specifically in the condition isolating the magnocellular system for both old groups and increased the accuracy for the very-old group.Taken together, the results confirm the dissociation between the magnocellular and parvocellular systems. Magnocellular system undergoes age-related changes at later stage of ageing than parvocellular system and it could be rehabilitated with yellow filter

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23087号 / 医博第4714号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 木村 剛, 教授 YOUSSEFIAN Shohab, 教授 大森 孝一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

In the epoch of advanced mHealth (mobile health) use in ophthalmology, there is a scientific call for regulating the validity and reliability of eye-related apps. For a positive health outcome that works towards enhancing mobile-application guided diagnosis in joint decision-making between eye specialists and individuals, the aging population should be provided with a reliable and valid tool for assessment of their eye status outside the physician office. This interdisciplinary study aims to determine through hypothesis testing validity and reliability of a limited set of five mHealth apps (mHAs ) and through binary logistic regression the prediction possibilities of investigated apps to exclude the four major eye diseases in the particular demographic population. The study showed that 189 aging adults (45- 86 years old) who did complete the mHAs’ tests were able to produce reliable results of selected eye function tests through four out of five mHAs measuring visual acuity, contrast sensitivity, red desaturation, visual field and Amsler grid in comparison with a “gold standard” - comprehensive eye examination. Also, part of the participants was surveyed for assessing the Quality of Experience on mobile apps. Understanding of current reliability of existing eye-related mHAs will lead to the creation of ideal mobile application’ self-assessment protocol predicting the timely need for clinical assessment and treatment of age-related macular degeneration, diabetic retinopathy, glaucoma and cataract. Detecting the level of eye function impairments by mHAs is cost-effective and can contribute to research methodology in eye diseases’ prediction by expanding the system of clear criteria specially created for mobile applications and provide returning significant value in preventive ophthalmology.

No description available.

Eine lokale Aktivierung des Komplementsystems im RPE ist ein pathogener Faktor der AMD. Neben der Wirkung von angiogenen Faktoren wie VEGF könnte eine Aktivierung des Blutgerinnungssystems im RPE dazu beitragen, dass sich aus einer trockenen eine feuchte AMD entwickelt. Dies könnte auf mehreren Ebenen geschehen: Gerinnungsfaktoren könnten die Expression der Komplementfaktoren und der angiogenen Faktoren regulieren sowie Wirkungen auf die Proliferation und Migration der RPE-Zellen besitzen. Eine Stimulierung der Proliferation und Migration der RPE-Zellen trägt zur Ausbildung von CNV-Membranen bei. Es ist aber bis jetzt nichts darüber bekannt, ob RPE-Zellen Faktoren des Blutgerinnungssystems exprimieren und ob z.B. Thrombin (als zentrale Protease des Blutgerinnungssystems) die Genexpression von Komplementfaktoren und von VEGF im RPE beeinflusst. Die Ziele der vorliegenden Dissertation waren daher: ● Nachweis der mRNA-Expression von Blutgerinnungs- und Komplementfaktoren im RPE; ● Nachweis der Wirkung von Thrombin auf die Expression von VEGF und von Komplementfaktoren, sowie auf die Proliferation und Migration der RPE-Zellen; und ● Nachweis der Wirkung der Komplementfaktoren C5a und C9 auf die Sekretion von VEGF und die Proliferation und Migration der RPE-Zellen.