Age-related macular degeneration (AMD) is one of the leading causes of blindness in adults over the age of 60. Currently, at least 11 million patients in the United States have some form of macular degeneration and this number is projected to grow as the population ages. The more severe form of the disease – neovascular (wet) AMD, is characterized by intraocular neovascularization, inflammation, and retinal damage; however, the disease progression can be deterred through intraocular injections of anti-angiogenic agents. The complications and burden that arise from repetitive injections as well as the difficulty posed by targeting the posterior segment of the eye make this an interesting territory for the development of novel drug delivery systems. New methods for drug delivery are being investigated exploring the use of nanoparticles and other polymeric materials. The goal of this project is to study the potential use of poly(lactide-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles in thermoreversible gels as localized sustained intraocular drug delivery. We prepared stable and reproducible corticosteroid-encapsulated nanoparticles in thermoreversible gels to inhibit vascular endothelial growth factor (VEGF) overexpression characteristic of neovascular AMD. We characterized the drug delivery system by obtaining size, shape, and drug encapsulation data. We also demonstrated that the polymer could be injected into the vitreous as a solution and transition to a gel phase based on the temperature difference between regular indoor environment and the vitreous body. The drug delivery system was tested on human retinal pigment epithelial cells (ARPE-19), for cytotoxicity, uptake and VEGF expression. We also examined the drug delivery system's ability to mitigate the disease progression in a mouse model of choroidal neovascularization (CNV). The effect on blood vessel area was shown and the changes in the mRNA expression of angiogenesis mediators were analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR). These results indicate that the proposed drug delivery systems has the promise to be developed for retinal diseases, involving CNV, including neovascular AMD. Further studies are warranted in developing this promising intraocular drug delivery system for wet AMD and similar ophthalmic diseases. / Ph. D.

Yes / PURPOSE. To compare microperimetric sensitivity around the monocular preferred retinal locus (mPRL) in age-related macular degeneration (AMD) to normative data, and to describe the characteristics of visual field defects around the mPRL in AMD. METHODS. Participants with AMD (total n ¼ 185) were either prospectively recruited (n ¼ 135) or retrospectively reviewed from an existing database (n ¼ 50). Participants underwent microperimetry using a test pattern (37 point, 58 radius) centered on their mPRL. Sensitivities were compared to normative data by spatial interpolation, and conventional perimetric indices were calculated. The location of the mPRL relative to the fovea and to visual field defects was also investigated. RESULTS. Location of mPRL varied approximately 158 horizontally and vertically. Visual field loss within 58 of the mPRL was considerable in the majority of participants (median mean deviation 14.7 dB, interquartile range [IQR] 19.6 to 9.6 dB, median pattern standard deviation 7.1 dB [IQR 4.8–9.0 dB]). Over 95% of participants had mean total deviation worse than 2 dB across all tested locations and similarly within 18 of their mPRL. A common pattern of placing the mPRL just foveal to a region of normal pattern deviation was found in 78% of participants. Total deviation was outside normal limits in this region in 68%. CONCLUSIONS. Despite altering fixation to improve vision, people with AMD exhibit considerable visual field loss at and around their mPRL. The location of the mPRL was typically just foveal to, but not within, a region of relatively normal sensitivity for the individual, suggesting that a combination of factors drives mPRL selection. / This report presents independent research funded by the NIHR

Yes / Objective: Many patients with acromegaly, a hormonal disorder with excessive growth hormone (GH) production, report pain in joints. We undertook this study to characterize the joint pathology of mice with overexpression of bovine GH (bGH) or a GH receptor antagonist (GHa) and to investigate the effect of GH on regulation of chondrocyte cellular metabolism. Methods: Knee joints from mice overexpressing bGH or GHa and wild-type (WT) control mice were examined using histology and micro–computed tomography for osteoarthritic (OA) pathologies. Additionally, cartilage from bGH mice was used for metabolomics analysis. Mouse primary chondrocytes from bGH and WT mice, with or without pegvisomant treatment, were used for quantitative polymerase chain reaction and Seahorse respirometry analyses. Results: Both male and female bGH mice at ~13 months of age had increased knee joint degeneration, which was characterized by loss of cartilage structure, expansion of hypertrophic chondrocytes, synovitis, and subchondral plate thinning. The joint pathologies were also demonstrated by significantly higher Osteoarthritis Research Society International and Mankin scores in bGH mice compared to WT control mice. Metabolomics analysis revealed changes in a wide range of metabolic pathways in bGH mice, including beta-alanine metabolism, tryptophan metabolism, lysine degradation, and ascorbate and aldarate metabolism. Also, bGH chondrocytes up-regulated fatty acid oxidation and increased expression of Col10a. Joints of GHa mice were remarkably protected from developing age-associated joint degeneration, with smooth articular joint surface. Conclusion: This study showed that an excessive amount of GH promotes joint degeneration in mice, which was associated with chondrocyte metabolic dysfunction and hypertrophic changes, whereas antagonizing GH action through a GHa protects mice from OA development. / Dr. Zhu's work was supported by Ohio University, the Arthritis National Research Foundation (grant 833836), a FIRST award from the American Society for Bone and Mineral Research, the NIH (grant R15-AR-080813), and a Hevolution Foundation AGE grant (AGE-008). Dr. Davis’ work was supported by a medical student seed grant from Ohio University. Dr. Lotz's work was supported by the NIH (grant R37-AG-059418). Dr. Berryman was supported by the NIH (grant R01-AG-059779). Dr. Kopchick was supported by the State of Ohio's Eminent Scholar Program that includes a gift from Milton and Lawrence Goll and the AMVETS, and by the NIH (grant R01-AG-059779).

Yes / Purpose: Frequency-of-seeing (FoS) curves (psychometric functions) for perimetric stimuli have been widely used in computer simulations of new visual field test procedures. FoS curves for age-related macular degeneration (AMD) are not available in the literature and are needed for the development of improved microperimetry test procedures, which are of particular interest for use as clinical trial endpoints. Methods: Data were refitted from a previous study to generate FoS curves for 20 participants with AMD, each tested at nine locations within the central 10°. Stimulus parameters, background luminance and dB scale were matched to the MAIA-2 microperimeter, and stimuli were presented in a method of constant stimuli to build up FoS curves over multiple runs. FoS curves were fitted with a modified cumulative Gaussian function. The relationship between sensitivity and slope of fitted FoS curves was modelled by robust linear regression, producing models both with and without an eccentricity parameter. Results: FoS curves were satisfactorily fitted to data from 174 visual field locations in 20 participants (age 65–83 years, 11 female). Each curve was made up of a median of 243 (range 177–297) stimulus presentations over a median of 12 (range 9–32) levels. Median sensitivity was 25.5dB (range 3.8–31.4dB). The median slope (SD of fitted function) was 1.6dB (range 0.5–8.5dB). As in previous studies of other conditions, the slope of fitted FoS curves increased as sensitivity decreased (p<0.001). Conclusions: FoS are provided for participants with AMD, as well as models of the relationship between sensitivity and slope. These fitted models and data may be useful for computer simulation studies of microperimetry procedures. Full details of the fitted curves are provided as supporting information.

Yes / We investigated whether perceptual learning could be used to improve peripheral word identification speed. The relationship between the magnitude of learning and age was established in normal participants to determine whether perceptual learning effects are age invariant. We then investigated whether training could lead to improvements in patients with age-related macular degeneration (AMD). Twenty-eight participants with normal vision and five participants with AMD trained on a word identification task. They were required to identify three-letter words, presented 10° from fixation. To standardize crowding across each of the letters that made up the word, words were flanked laterally by randomly chosen letters. Word identification performance was measured psychophysically using a staircase procedure. Significant improvements in peripheral word identification speed were demonstrated following training (71% ± 18%). Initial task performance was correlated with age, with older participants having poorer performance. However, older adults learned more rapidly such that, following training, they reached the same level of performance as their younger counterparts. As a function of number of trials completed, patients with AMD learned at an equivalent rate as age-matched participants with normal vision. Improvements in word identification speed were maintained at least 6 months after training. We have demonstrated that temporal aspects of word recognition can be improved in peripheral vision with training across a range of ages and these learned improvements are relatively enduring. However, training targeted at other bottlenecks to peripheral reading ability, such as visual crowding, may need to be incorporated to optimize this approach. / This work was supported by a National Institute of Health Research (NIHR) Post Doctoral Fellowship awarded to ATA, an Age UK Studentship awarded to AJB, and a Wellcome Trust Career Development Fellowship awarded to BSW. This article presents independent research funded by the NIHR.

Denna uppsats undersöker dekadensens betydelse för Klas Östergrens generationsroman Gentlemen (1980). Syftet är dels att uppmärksamma ett hittills förbisett författarskap, dels att applicera en teori som kan belysa Gentlemen. Frågeställningen utgår därmed ifrån hur dekadensen återspeglas i romanens huvudkaraktärsskildringar, samhällsstämningar och form. Uppsatsens dekadensdefinition grundar sig i Paul Bourgets Théorie de la decadence (1883), där han skildrar samhällets, individens och språkets förfall. Utifrån dessa tankar antar jag en bred dekadensdefinition som fokuserar människans ambivalens inför att leva i en värdemässigt förfallen värld. Dekadensteorin är därmed utgångspunkten för analysen där jag genom närläsning urskiljer framträdande dekadenta drag. Framförallt betydande är den s.k. Makten, och dess förväntningar på lojalitet, som orsak till undergångsstämningar. För att hantera samtidens mörker blir konsten en utväg likt, dekadensens artificiella paradis. Henry gör likt dandyn konst av sig själv och sina trygghetsskapande vardagsritualer, Leo försöker sin illojalitet trogen avslöja sanningen om Maktens lögner i sin poesi, och berättaren Klas berättar sanningen om Henry och Leo genom att skriva Gentlemen. Genom en homodiegetiskt berättare upplöses karaktärerna till deras handlingar, och intrigen till detaljerna. Därmed återfinns dekadensen både i bokens tematik och estetik. / This essay examines the importance of decadence in the generational novel Gentlemen (1980) by Klas Östergren. The aim is partly to draw attention to a neglected authorship, partly to apply a theory that can illuminate Gentlemen. That is why I ask how decadence is reflected in the novel's main characters, community atmosphere and form. My definition of decadence is based on Paul Bourget's Theorie de la decadence (1883), in which he portrays society, individuals and the language's decline. With these thoughts in mind, I assume a broad definition of decadence that focuses on man's ambivalence towards life in a world that is fallen in sense of values. The theory of decadence is thus the starting point of this analysis through close reading, where I discern prominent aspects of decadence. Especially significant is the so-called Makten (The Force), and its claims for loyalty, as a cause of apocalyptic atmosphere. In order to deal with this dark, contemporary period, art becomes a refuge in similar ways as the artificial paradises of the Decadent era. Henry, like a dandy turns himself and his comforting everyday rituals into art; Leo, faithful to his disloyalty, tries to uncover the truth about the lies of Makten in his poetry; and Klas the narrator tells the truth about Henry and Leo by writing Gentlemen. By a homodiegetic narrator the characters are dissolved into their actions and the plot into details. Thus, both the book's aesthetics and themes can be traced to decadence.

The extent to which cortical maps may reorganize in adult humans is a significant and topical debate in visual neuroscience. Though there are conflicting findings, evidence from humans and animals indicates that the topography of the visual cortex may change after retinal deafferentation. Remarkably, this reorganization seems to be possible in adults, whose brains are less amenable to plastic change. If adult visual reorganization is legitimate, an understanding of its causes and consequences could be profound considering the millions suffering from age-related visual disorders. This dissertation explores whether visual training may yield a reorganization of sensory maps in the adult visual cortex. It describes research in which patients, diagnosed with age-related macular degeneration (AMD), underwent visual rehabilitation therapy. Functional brain scans and behavioral tests were conducted pre and post training. These interventions generated valuable knowledge regarding whether "reorganized" activity is a true rewiring of feed forward cortical processes or an artifact of attentional feedback. The rehabilitation training produced demonstrable differences in activation patterns along the primary visual cortex (V1), but sparse improvement in the behavioral tests. In contrast, there was significant improvement in fixation tests which assessed oculomotor control. These results suggest that the nature of reorganized activity has more to do with attentional mechanisms than feed forward reorganization. Future investigations could benefit from examining the brain sites that govern visual attention in the frontal and parietal cortices. These areas may have more to do with visual adaptation in AMD patients than V1.

MRI can provide anatomical, functional, and physiological images at relatively high spatial resolution and is non-invasive and does not have depth limitation. However, the application of MRI to study the retina is difficult due to the very small size of the retina. This thesis details the development of MRI methods to image blood flow (BF), anatomy, and function of the retina and choroid, and their application to two diseases of the retina: diabetic retinopathy and retinal degeneration. A unique continuous arterial spin labeling technique was developed to image BF in mice and tested by imaging cerebral BF. This method was then applied to image layer-specific BF of the retina and choroid in mice, and to acquire BF functional MRI of the retina and choroid in response to hypoxic challenge. Additionally blood oxygen level dependent functional MRI of the mouse retina and choroid in response to hypoxic challenge was obtained using a balanced steady state free precession sequence which provides fast acquisition, has high signal to noise ratio, and does not have geometric distortion or signal dropout artifacts. In a mouse model of diabetic retinopathy, MRI detected reduced retinal BF in diabetic animals. Visual function in the diabetic mice, as determined by psychophysical tests, was also reduced. Finally, in a mouse model of retinal degeneration, BF and anatomical MRI detected reductions of retinal BF and the thickness of the retina. The studies detailed in this thesis demonstrate the feasibility of layer-specific MRI to study BF, anatomy, and function, in the mouse retina. Further, these methods were shown to provide a novel means of studying animal models of retinal disease in vivo.

<p>Denna uppsats undersöker dekadensens betydelse för Klas Östergrens generationsroman <em>Gentlemen </em>(1980). Syftet är dels att uppmärksamma ett hittills förbisett författarskap, dels att applicera en teori som kan belysa <em>Gentlemen</em>. Frågeställningen utgår därmed ifrån hur dekadensen återspeglas i romanens huvudkaraktärsskildringar, samhällsstämningar och form.</p><p>Uppsatsens dekadensdefinition grundar sig i Paul Bourgets <em>Théorie de la decadence </em>(1883), där han skildrar samhällets, individens och språkets förfall. Utifrån dessa tankar antar jag en bred dekadensdefinition som fokuserar människans ambivalens inför att leva i en värdemässigt förfallen värld. Dekadensteorin är därmed utgångspunkten för analysen där jag genom närläsning urskiljer framträdande dekadenta drag.</p><p>Framförallt betydande är den s.k. Makten, och dess förväntningar på lojalitet, som orsak till undergångsstämningar. För att hantera samtidens mörker blir konsten en utväg likt, dekadensens artificiella paradis. Henry gör likt dandyn konst av sig själv och sina trygghetsskapande vardagsritualer, Leo försöker sin illojalitet trogen avslöja sanningen om Maktens lögner i sin poesi, och berättaren Klas berättar sanningen om Henry och Leo genom att skriva <em>Gentlemen</em>. Genom en homodiegetiskt berättare upplöses karaktärerna till deras handlingar, och intrigen till detaljerna. Därmed återfinns dekadensen både i bokens tematik och estetik.</p> / <p>This essay examines the importance of decadence in the generational novel <em>Gentlemen </em>(1980) by Klas Östergren. The aim is partly to draw attention to a neglected authorship, partly to apply a theory that can illuminate <em>Gentlemen.</em> That is why I ask how decadence is reflected in the novel's main characters, community atmosphere and form.</p><p>My definition of decadence is based on Paul Bourget's <em>Theorie de la decadence</em> (1883), in which he portrays society, individuals and the language's decline. With these thoughts in mind, I assume a broad definition of decadence that focuses on man's ambivalence towards life in a world that is fallen in sense of values. The theory of decadence is thus the starting point of this analysis through close reading, where I discern prominent aspects of decadence.</p><p>Especially significant is the so-called Makten (The Force), and its claims for loyalty, as a cause of apocalyptic atmosphere. In order to deal with this dark, contemporary period, art becomes a refuge in similar ways as the artificial paradises of the Decadent era. Henry, like a dandy turns himself and his comforting everyday rituals into art; Leo, faithful to his disloyalty, tries to uncover the truth about the lies of Makten in his poetry; and Klas the narrator tells the truth about Henry and Leo by writing <em>Gentlemen</em>. By a homodiegetic narrator the characters are dissolved into their actions and the plot into details. Thus, both the book's aesthetics and themes can be traced to decadence.</p>

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