Age-related macular degeneration (AMD) is one of the leading causes of blindness in the United States in people who are 50 and older. The safety and efficacy of aflibercept for the treatment of late stage neovascular AMD (NAMD) has been demonstrated by clinical trials among several populations; however, it is unclear whether all NAMD patients respond in the same manner as was studied in the clinical trials. The purpose of this study was to examine if populations of patients treated with aflibercept for the treatment of NAMD were significantly different from one another in terms of health characteristics, treatment regimens, and treatment outcomes. The burden of treatment theory was used to guide this study. Data collected from electronic medical records were used to investigate NAMD characteristics 199 patients from 3 private, retinal practices in the United States. Data were analyzed using one-way ANOVA, 2, Spearman's correlation, and point-biserial correlation tests. The results of this study showed the specific retinal practice populations of NAMD patients treated with aflibercept were generally similar with respect to selected health characteristics, treatment regimens, and treatment outcomes. By using the information reported from this research, public health initiatives can be developed that focus on the need for early detection of AMD to capture changes that represent NAMD and move to early treatment for better outcomes. The positive social change that could result from this research is that retinal specialists may gain insight into the use and outcomes of aflibercept treatment.

La Dégénérescence Maculaire Liée à l’Age (DMLA) est la première cause de cécité légale dans les pays industrialisés chez les personnes âgées. L’atrophie géographique – l’une des formes tardives de la DMLA - est caractérisée par la perte de l’épithélium pigmentaire et la dégénérescence des photorécepteurs. Nous groupe a montré précédemment que dans l’atrophie géographique, les phagocytes mononucléés (PMs) s’accumulent dans l’espace sous-rétinien, et induisent la dégénérescence rétinienne via la production d’IL-1β. Dans un premier temps, nous montrons que la présence de PMs sous-rétiniens est associée à la perte des bâtonnets et la dégénérescence des segments de cônes dans la zone de transition de patients atrophiques. Nous montrons ensuite dans différents modèles in vivo et ex vivo que les macrophages récapitulent ces effets, et qu’IL-1β est nécessaire à la perte des segments externes des cônes induite par les PMs. Dans un deuxième temps, nos résultats montrent qu’IL-1β induit indirectement la mort des bâtonnets, en perturbant l’homéostasie rétinienne du glutamate. L’inhibition des récepteurs glutamatergiques pour prévenir l’excitotoxicité du glutamate, ou la supplémentation en cystine favorisant la restauration de la machinerie neuronale antioxydante, permettent de protéger les bâtonnets de la toxicité induite par IL-1β. L’ensemble de nos résultats démontre le rôle joué par IL-1β dans la dégénérescence des segments de cônes et la perte des bâtonnets dans l’inflammation sous-rétinienne. Cette étude permettra la mise au point de thérapies innovantes, afin de lutter contre la forme atrophique de la DMLA, pour laquelle il n’existe actuellement aucun traitement. / In geographic atrophy (GA), one of the late forms of Age-related Macular Degeneration (AMD), an extending atrophic zone forms, characterized by the loss of retinal pigment epithelium and photoreceptor degeneration. Subretinal mononuclear phagocytes (MPs) accumulate in GA, and are associated with IL-1β-dependent retinal degeneration. First, we confirmed that subretinal accumulation of MPs is associated with rod degeneration and cone segment loss in the transitional zone in GA human samples. Using ex vivo and in vivo models, we then demonstrated that MPs-derived IL-1β leads to severe cone segment degeneration. Therefore, inhibiting subretinal MP accumulation or IL-1β might protect the cone segment, and help preserve high acuity daytime vision in conditions characterized by subretinal inflammation. Second, we showed that IL-1β effect on rod degeneration is indirect, and mediated by glutamate. Our results indicate that IL-1β impairs Müller glial cells glutamate recycling, and subsequently leads to the extracellular increase in glutamate content. Inhibiting glutamate receptors to prevent excitotoxicity, or exogenous cystine supplementation to supply antioxidant metabolism, are sufficient to protect rods from IL-1β-induced neurotoxicity. Our results provide new perspectives to treat pathologies associated with subretinal inflammation such as late AMD. Our results collectively demonstrated that MP-derived IL-1β induces cone segment loss, and glutamate homeostasis disruption associated with rod degeneration. This study will help with the development of new therapeutic strategies in dealing with inflammatory retinal pathologies as geographic atrophy.

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.

Background: Diabetes mellitus and vascular diseases have a significant impact on the eye. / Aim: To determine the prevalence, risk factors, and racial/ethnic differences of major eye conditions, particularly retinal conditions, associated with diabetes and vascular diseases. / Scope: To date, the majority of studies have examined the association of retinal vascular calibre and diabetes in predominantly white Caucasian populations. Further elucidation of ethnic differences in effects of hyperglycaemia on early microvascular disease is relevant, particularly amongst Asians where diabetes is likely to see the largest increase in prevalence over the next decade. We therefore examined these findings from three Asian population-based studies, the Singapore Malay Eye Study (n=3280), Singapore Prospective Cohort Study and Singapore Cardiovascular Cohort Study 2 (n=3748). / Results: The prevalence of diabetic retinopathy in the Singapore Malay Eye Study was 35%, and associated with longer duration of diabetes, poorer glycemic and blood pressure control. More importantly, 9.0% had vision-threatening retinopathy, and retinopathy was found in 6.0% of people without diabetes. Retinal vascular calibre changes were incriminated in diseases such as diabetes and hypertension, independent of traditional cardiovascular risk factors. Wider venular calibre was independently associated with early age-related macular degeneration. We also found a novel association between peripheral artery disease and glaucoma, stronger in persons with diabetes, independent of vascular risk factors, supporting the vascular theory of glaucoma. / Implications: Subtle changes in retina, including retinal vascular calibre may be early markers of widespread microvascular changes in diabetes, resulting from chronic hyperglycaemia and other pathogenic processes. These results will have broad implications for understanding the impact of both microvascular and macrovascular complications of diabetes in the Asia Pacific region and targeting relevant therapeutic interventions.

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.

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.

Few would disagree that the media landscape has undergone significant changes the last decade. From bulky computers and plain mobile phones to portable High-Definition computers and multi-functional smartphones. Other media, such as newspapers and music, have evolved and prospered in a digitalized environment. The constant urge to digitalize aspects and functions of our daily lives seems almost instinctive. Television has taken further steps into this environment as it is now accepted and featured via the Internet. This essay investigates in the ways the new platforms of television will affect the traditional one. More specifically, whether the Internet Streaming Media functions as an extension or as a replacement to the current form of television.  Furthermore, this essay explores age- and gender-related content-preferences in Streaming, as well as speculating on the subject of the consequences of Streaming consumption.  The method in acquiring the empirical data is through a quantitative one, in a survey.  The conclusions made are that the survey respondents, at this current time, are using Streaming as an extension to traditional TV, that there are, in some genres, significant gender-related content preferences when watching TV over the Internet (these include: Drama, reality and sports) and that there are age-related content preference when using Streaming; as the younger age-groups watch “entertainment-shows” more than the older age-groups but neither of the groups do so exclusively. When it then comes to the discussion concerning increased individualization it is, at this point in time, too early to speculate since the respondents mostly use Streaming as an extension to the traditional television.

In this thesis we look at one of the aging mechanisms that may have affected current aged Nuclear Power Plants (NPPs). Irradiation as an age-related degradation mechanism is studied for Reinforced Concrete (RC) in NPPs. This problem can be important for aged reactor buildings, radwaste buildings, spent nuclear fuel, research reactors, or accelerators that experience high levels of radiation close to existing thresholds. Mechanical properties of concrete are the most important parameters affected by radiation in NPPs. Compressive strength of concrete is reduced between 80 and 35 \% for radiation fluences between $2\times 10^{19}$ and $2\times 10^{21} n/cm^2$. Tensile strength reduction is more significant than compressive strength. It is reduced between 20 and 80 \% for a radiation fluence equal to $5\times 10^{19}$. We chose three radiation levels $2\times 10^{19}$, $2\times 10^{20}$, $2\times 10^{20}$ based on experimental results as the critical levels of radiation that RC structures in NPPs may be exposed to. Structures susceptible to the problem are mostly RC walls; so the RC panel is chosen as an appropriate representative scale element for the analysis. The effect of radiation on mechanical properties of concrete is considered to analyze degraded scale elements. Material properties, geometry, and loading scenarios of scale elements are selected to be close to actual quantities in existing nuclear power plant. Elements are analyzed under six types of loading combination of shear and axial loading conditions. A nonlinear finite element program, Membrane-2000, based on the Modified Compression Field Theory (MCFT) is used to solve scale elements numerically. Element behaviors are studied considering the factors influence ultimate strength capacity, failure mode, and structural ductility index of members. The results show that ultimate shear capacity of the elements subjected to combinations of shear and tension loading are reduced significantly for highly reinforced elements ($1.35<\rho<1.88$) in $2\times 10^{21} n/cm^2$ radiation. RC panels under shear-biaxial and uniaxial compression also show significant strength capacity reduction in radiation levels $2\times 10^{20} n/cm^2$ and $2\times 10^{21} n/cm^2$, respectively. Failure modes of the elements change from yielding of steel to shear failure by increasing level of degradation for the elements with reinforcement ratio between 0.9 and 1.88. Ductility of the RC panels is reduced significantly in the critical levels of radiation. Ductility of the elements became less than the allowable ductility value by increasing level of radiation.

Auditorische Synaptopathien verursachen sensorineurale Schwerhörigkeit unterschiedlicher Ausprägung. Dabei sind sowohl erworbene, als auch angeborene Formen bekannt. Eine häufige Form ist die rezessive, nichtsyndromale Taubheitsform DFNB9, die auf einer Mutation des für Otoferlin kodierenden Gens beruht. Otoferlin ist ein Transmembranprotein, das essentiell für die stimulusabhängige Transmitterausschüttung an der Bändersynapse der Haarzellen ist . Um die Prognose von Patienten mit auditorischen Synaptopathien einschätzen zu können, ist es wichtig, den zeitlichen Verlauf der neuronalen Degeneration zu kennen. Aufgrund des Fehlens von protektiven Mittelohr und olivocochleären Reflexen könnte zusätzlich eine erhöhte Lärmempfindlichkeit bestehen, die einen frühen Verlust der Funktion der äußeren Haarzellen begünstigen wurde. Wir haben Otoferlin-Knockout-Mäuse im Alter von 6 Tagen bis 12 Monaten untersucht und die Funktion des Corti-Organs mittels Hirnstammaudiometrie und Messung der otoakustischen Emissionen getestet. In immunhistochemischen Färbungen von Corti-Organ Präparaten wurde die Degeneration von inneren und äußeren Haarzellen, Bändersynapsen und Spiralganglienneuronen beobachtet. Weiterhin wurden bei 2 Monate alten Otoferlin-Knockout-Mäusen die Auswirkungen eines leichten oder schweren Lärmtraumas quantifiziert. Wir beobachteten bei den Mutanten eine frühere und schnellere Degeneration der inneren und äußeren Haarzellen, insbesondere in der basalen Windung der Kochlea. Die Lärmtraumaversuche zeigten keinen Unterschied in der Empfindlichkeit von Otoferlin-Knockout-Mäusen und Wildtyp-Kontrollen, so dass die Ursache des Haarzellverlustes ungeklärt bleibt. Die Zahl der Bändersynapsen war ab Beginn des Hörens auf die Hälfte reduziert und blieb dann konstant, dennoch waren Spiralganglienneurone auch bei 12 Monate alten Tieren kaum reduziert. Das lässt auf einen relativ langen Erhalt des Hörnerven schließen Wir beschrieben hier zum ersten Mal die Degeneration des Corti-Organs in Otoferlin-Knockout-Mäusen. Gleichzeitig erfolgte die systematische Quantifizierung der synaptischen Degeneration von C57BL/6-Mäusen im Zusammenhang mit deren Altersschwerhörigkeit.

Objective: The aim of the present study was to investigate the mechanics with which older adults activate and access different subdomains of their mental lexicons during word retrieval for picture naming. Method: Data were analyzed for 12 aging, native English speakers who performed a picture-word priming task. The auditory probe words were presented in the following conditions in relation to the picture stimuli: Identically related, strongly semantically related, weakly semantically related, strongly phonologically related, weakly phonologically related, semantically related to the strong phonological relative of the target picture label, or phonologically-related to the strong semantic relative of the target picture label. Event related potentials were used to measure picture-word priming effects. Results: Three main results were observed. First, our healthy aging adult participants evidenced strong activation of whole-word phonological representations as well as rhyme representations of target picture labels, but weakened activation of initial phoneme information. Second, they processed semantic information robustly. Finally, our participants appeared to experience phonological competition when accessing target picture labels. Conclusion: Results from this study suggest that healthy aging adults maintain efficient access to whole-word phonological representations, rhyme representations, and conceptual-semantic representations of target picture labels. However, in line with previously-reported findings, they do seem to evidence limited activation of initial phonological information on the path to picture naming.