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Sample records for abca4-associated retinal degenerations

  1. Macular Pigment and Lutein Supplementation in ABCA4-associated Retinal Degenerations

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    Aleman, Tomas S.; Cideciyan, Artur V.; Windsor, Elizabeth A. M.; Schwartz, Sharon B.; Swider, Malgorzata; Chico, John D.; Sumaroka, Alexander; Pantelyat, Alexander Y.; Duncan, Keith G.; Gardner, Leigh M.; Emmons, Jessica M.; Steinberg, Janet D.; Stone, Edwin M.; Jacobson, Samuel G.

    2008-01-01

    PURPOSE To determine macular pigment (MP) optical density (OD) in patients with ABCA4-associated retinal degenerations (ABCA4-RD) and the response of MP and vision to supplementation with lutein. METHODS Stargardt disease or cone-rod dystrophy patients with foveal fixation and with known or suspected disease-causing mutations in the ABCA4 gene were included. MPOD profiles were measured with heterochromatic flicker photometry. Serum carotenoids, visual acuity, foveal sensitivity and retinal thickness were quantified. Changes in MPOD and central vision were determined in a subset of patients receiving oral supplementation with lutein for 6 months. RESULTS MPOD in patients ranged from normal to markedly abnormal. As a group, ABCA4-RD patients had reduced foveal MPOD and there was strong correlation with retinal thickness. Average foveal tissue concentration of MP, estimated by dividing MPOD by retinal thickness, was normal in patients whereas serum concentration of lutein and zeaxanthin was significantly lower than normal. After oral lutein supplementation for 6 months, 91% of the patients showed significant increases in serum lutein and 63% of the patient eyes showed a significant augmentation in MPOD. The retinal responders tended to be female, and have lower serum lutein and zeaxanthin, lower MPOD and greater retinal thickness at baseline. Responding eyes had significantly lower baseline MP concentration compared to non-responding eyes. Central vision was unchanged after the period of supplementation. CONCLUSIONS MP is strongly affected by the stage of ABCA4 disease leading to abnormal foveal architecture. MP could be augmented by supplemental lutein in some patients. There was no change in central vision after 6 months of lutein supplementation. Long-term influences on the natural history of this supplement on macular degenerations require further study. PMID:17325179

  2. Retinal Cell Degeneration in Animal Models

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    Masayuki Niwa; Hitomi Aoki; Akihiro Hirata; Hiroyuki Tomita; Green, Paul G.; Akira Hara

    2016-01-01

    The aim of this review is to provide an overview of various retinal cell degeneration models in animal induced by chemicals (N-methyl-d-aspartate- and CoCl2-induced), autoimmune (experimental autoimmune encephalomyelitis), mechanical stress (optic nerve crush-induced, light-induced) and ischemia (transient retinal ischemia-induced). The target regions, pathology and proposed mechanism of each model are described in a comparative fashion. Animal models of retinal cell degeneration provide insi...

  3. The cell stress machinery and retinal degeneration.

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    Athanasiou, Dimitra; Aguilà, Monica; Bevilacqua, Dalila; Novoselov, Sergey S; Parfitt, David A; Cheetham, Michael E

    2013-06-27

    Retinal degenerations are a group of clinically and genetically heterogeneous disorders characterised by progressive loss of vision due to neurodegeneration. The retina is a highly specialised tissue with a unique architecture and maintaining homeostasis in all the different retinal cell types is crucial for healthy vision. The retina can be exposed to a variety of environmental insults and stress, including light-induced damage, oxidative stress and inherited mutations that can lead to protein misfolding. Within retinal cells there are different mechanisms to cope with disturbances in proteostasis, such as the heat shock response, the unfolded protein response and autophagy. In this review, we discuss the multiple responses of the retina to different types of stress involved in retinal degenerations, such as retinitis pigmentosa, age-related macular degeneration and glaucoma. Understanding the mechanisms that maintain and re-establish proteostasis in the retina is important for developing new therapeutic approaches to fight blindness.

  4. [New drug therapy for retinal degeneration].

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    Ohguro, Hiroshi

    2008-01-01

    Retinitis pigmentosa (RP) is an inherited retinal degeneration characterized by nyctalopia, ring scotoma, and bone-spicule pigmentation of the retina. So far, no effective therapy has been found for RP. As a possible molecular etiology of RP, retina-specific gene deficits are most likely involved, but little has been identified in terms of intracellular mechanisms leading to retinal photoreceptor cell death at post-translational levels. In order to find an effective therapy for RP, we must look for underlying common mechanisms that are responsible for the development of RP, instead of designing a specific therapy for each of the RP types with different causes. Therefore, in the present study, several animal models with different causes of RP were studied, including (1)Royal College of Surgeons (RCS) rats with a deficit of retinal pigment epithelium (RPE) function caused by rhodopsin mutation; (2) P23H rats, (3) S334ter rats, (4) photo stress rats, (5) retinal degeneration (rd) mice with a deficit of phosphodiesterase(PDE) function; and (6) cancer-associated retinopathy (CAR) model rats with a deficit of recoverin-dependent photoreceptor adaptation function. In each of these models, the following assessments were made in order to elucidate common pathological mechanisms among the models: (1) retinal function assessed by electroretinogram (ERG), (2) retinal morphology, (3) retinoid analysis, (4) rhodopsin regeneration, (5) rhodopsin phosphorylation and dephosphorylation, and (6) cytosolic cGMP levels. We found that unregulated photoreceptor adaptation processes caused by an imbalance of rhodopsin phosphorylation and dephosphorylation caused retinal dysfunction leading to photoreceptor cell death. As possible candidate drugs for normalizing these retinal dysfunctions and stopping further retinal degeneration, nilvadipine, a Ca channel blocker, retinoid derivatives, and anthocyanine were chosen and tested to determine their effect on the above animal models with

  5. Prospectives for gene therapy of retinal degenerations.

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    Thumann, Gabriele

    2012-08-01

    Retinal degenerations encompass a large number of diseases in which the retina and associated retinal pigment epithelial (RPE) cells progressively degenerate leading to severe visual disorders or blindness. Retinal degenerations can be divided into two groups, a group in which the defect has been linked to a specific gene and a second group that has a complex etiology that includes environmental and genetic influences. The first group encompasses a number of relatively rare diseases with the most prevalent being Retinitis pigmentosa that affects approximately 1 million individuals worldwide. Attempts have been made to correct the defective gene by transfecting the appropriate cells with the wild-type gene and while these attempts have been successful in animal models, human gene therapy for these inherited retinal degenerations has only begun recently and the results are promising. To the second group belong glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). These retinal degenerations have a genetic component since they occur more often in families with affected probands but they are also linked to environmental factors, specifically elevated intraocular pressure, age and high blood sugar levels respectively. The economic and medical impact of these three diseases can be assessed by the number of individuals affected; AMD affects over 30 million, DR over 40 million and glaucoma over 65 million individuals worldwide. The basic defect in these diseases appears to be the relative lack of a neurogenic environment; the neovascularization that often accompanies these diseases has suggested that a decrease in pigment epithelium-derived factor (PEDF), at least in part, may be responsible for the neurodegeneration since PEDF is not only an effective neurogenic and neuroprotective agent but also a potent inhibitor of neovascularization. In the last few years inhibitors of vascularization, especially antibodies against vascular endothelial cell

  6. [Pharmacological concepts to treat hereditary retinal degenerations].

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    Poloschek, C M; Jägle, H

    2012-02-01

    This article reviews the current pharmacological strategies to treat inherited retinal degeneration. To date there is no causal therapy despite growing knowledge of the particular pathomechanisms. However, treatment is available for complications, such as cystic macular changes and cystoid macular edema. To reduce retinal thickness systemic or topical carboanhydrase inhibitors can be applied and in rare cases combined with steroids when indicated, however reduction of retinal thickness is not always accompanied by improvement of visual acuity. Regular follow-up with optical coherence tomography is required. In some cases, potentially neuroprotective agents (valproic acid, ciliary neurotrophic factor and Ca(2+ ) channel inhibitors) or food supplementation (vitamin A, lutein, synthetic retinoids and decosahexaenoic acid) may have a positive impact on disease progression (e.g. reduction in progression of visual field loss or individual electrophysiological parameters). However, beneficial effects and side effects, e.g. of vitamin A substitution, depend not only on the disease phenotype (such as retinitis pigmentosa) but also on the actual genotype. Furthermore, no data are available regarding the application of pharmaceuticals in the pediatric population.

  7. CERKL knockdown causes retinal degeneration in zebrafish.

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    Marina Riera

    Full Text Available The human CERKL gene is responsible for common and severe forms of retinal dystrophies. Despite intense in vitro studies at the molecular and cellular level and in vivo analyses of the retina of murine knockout models, CERKL function remains unknown. In this study, we aimed to approach the developmental and functional features of cerkl in Danio rerio within an Evo-Devo framework. We show that gene expression increases from early developmental stages until the formation of the retina in the optic cup. Unlike the high mRNA-CERKL isoform multiplicity shown in mammals, the moderate transcriptional complexity in fish facilitates phenotypic studies derived from gene silencing. Moreover, of relevance to pathogenicity, teleost CERKL shares the two main human protein isoforms. Morpholino injection has been used to generate a cerkl knockdown zebrafish model. The morphant phenotype results in abnormal eye development with lamination defects, failure to develop photoreceptor outer segments, increased apoptosis of retinal cells and small eyes. Our data support that zebrafish Cerkl does not interfere with proliferation and neural differentiation during early developmental stages but is relevant for survival and protection of the retinal tissue. Overall, we propose that this zebrafish model is a powerful tool to unveil CERKL contribution to human retinal degeneration.

  8. Taurine Provides Neuroprotection against Retinal Ganglion Cell Degeneration

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    Nicolas Froger; Lucia Cadetti; Henri Lorach; Joao Martins; Alexis-Pierre Bemelmans; Elisabeth Dubus; Julie Degardin; Dorothée Pain; Valérie Forster; Laurent Chicaud; Ivana Ivkovic; Manuel Simonutti; Stéphane Fouquet; Firas Jammoul; Thierry Léveillard

    2012-01-01

    Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was inc...

  9. Rapid glutamate receptor 2 trafficking during retinal degeneration

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    Lin Yanhua

    2012-02-01

    Full Text Available Abstract Background Retinal degenerations, such as age-related macular degeneration (AMD and retinitis pigmentosa (RP, are characterized by photoreceptor loss and anomalous remodeling of the surviving retina that corrupts visual processing and poses a barrier to late-stage therapeutic interventions in particular. However, the molecular events associated with retinal remodeling remain largely unknown. Given our prior evidence of ionotropic glutamate receptor (iGluR reprogramming in retinal degenerations, we hypothesized that the edited glutamate receptor 2 (GluR2 subunit and its trafficking may be modulated in retinal degenerations. Results Adult albino Balb/C mice were exposed to intense light for 24 h to induce light-induced retinal degeneration (LIRD. We found that prior to the onset of photoreceptor loss, protein levels of GluR2 and related trafficking proteins, including glutamate receptor-interacting protein 1 (GRIP1 and postsynaptic density protein 95 (PSD-95, were rapidly increased. LIRD triggered neuritogenesis in photoreceptor survival regions, where GluR2 and its trafficking proteins were expressed in the anomalous dendrites. Immunoprecipitation analysis showed interaction between KIF3A and GRIP1 as well as PSD-95, suggesting that KIF3A may mediate transport of GluR2 and its trafficking proteins to the novel dendrites. However, in areas of photoreceptor loss, GluR2 along with its trafficking proteins nearly vanished in retracted retinal neurites. Conclusions All together, LIRD rapidly triggers GluR2 plasticity, which is a potential mechanism behind functionally phenotypic revisions of retinal neurons and neuritogenesis during retinal degenerations.

  10. Tyro3 Modulates Mertk-Associated Retinal Degeneration.

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    Vollrath, Douglas; Yasumura, Douglas; Benchorin, Gillie; Matthes, Michael T; Feng, Wei; Nguyen, Natalie M; Sedano, Cecilia D; Calton, Melissa A; LaVail, Matthew M

    2015-12-01

    Inherited photoreceptor degenerations (IPDs) are the most genetically heterogeneous of Mendelian diseases. Many IPDs exhibit substantial phenotypic variability, but the basis is usually unknown. Mutations in MERTK cause recessive IPD phenotypes associated with the RP38 locus. We have identified a murine genetic modifier of Mertk-associated photoreceptor degeneration, the C57BL/6 (B6) allele of which acts as a suppressor. Photoreceptors degenerate rapidly in Mertk-deficient animals homozygous for the 129P2/Ola (129) modifier allele, whereas animals heterozygous for B6 and 129 modifier alleles exhibit an unusual intermixing of degenerating and preserved retinal regions, with females more severely affected than males. Mertk-deficient mice homozygous for the B6 modifier allele display degeneration only in the far periphery, even at 8 months of age, and have improved retinal function compared to animals homozygous for the 129 allele. We genetically mapped the modifier to an approximately 2-megabase critical interval that includes Tyro3, a paralog of Mertk. Tyro3 expression in the outer retina varies with modifier genotype in a manner characteristic of a cis-acting expression quantitative trait locus (eQTL), with the B6 allele conferring an approximately three-fold higher expression level. Loss of Tyro3 function accelerates the pace of photoreceptor degeneration in Mertk knockout mice, and TYRO3 protein is more abundant in the retinal pigment epithelium (RPE) adjacent to preserved central retinal regions of Mertk knockout mice homozygous for the B6 modifier allele. Endogenous human TYRO3 protein co-localizes with nascent photoreceptor outer segment (POS) phagosomes in a primary RPE cell culture assay, and expression of murine Tyro3 in cultured cells stimulates phagocytic ingestion of POS. Our findings demonstrate that Tyro3 gene dosage modulates Mertk-associated retinal degeneration, provide strong evidence for a direct role for TYRO3 in RPE phagocytosis, and suggest

  11. Tyro3 Modulates Mertk-Associated Retinal Degeneration.

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    Douglas Vollrath

    2015-12-01

    Full Text Available Inherited photoreceptor degenerations (IPDs are the most genetically heterogeneous of Mendelian diseases. Many IPDs exhibit substantial phenotypic variability, but the basis is usually unknown. Mutations in MERTK cause recessive IPD phenotypes associated with the RP38 locus. We have identified a murine genetic modifier of Mertk-associated photoreceptor degeneration, the C57BL/6 (B6 allele of which acts as a suppressor. Photoreceptors degenerate rapidly in Mertk-deficient animals homozygous for the 129P2/Ola (129 modifier allele, whereas animals heterozygous for B6 and 129 modifier alleles exhibit an unusual intermixing of degenerating and preserved retinal regions, with females more severely affected than males. Mertk-deficient mice homozygous for the B6 modifier allele display degeneration only in the far periphery, even at 8 months of age, and have improved retinal function compared to animals homozygous for the 129 allele. We genetically mapped the modifier to an approximately 2-megabase critical interval that includes Tyro3, a paralog of Mertk. Tyro3 expression in the outer retina varies with modifier genotype in a manner characteristic of a cis-acting expression quantitative trait locus (eQTL, with the B6 allele conferring an approximately three-fold higher expression level. Loss of Tyro3 function accelerates the pace of photoreceptor degeneration in Mertk knockout mice, and TYRO3 protein is more abundant in the retinal pigment epithelium (RPE adjacent to preserved central retinal regions of Mertk knockout mice homozygous for the B6 modifier allele. Endogenous human TYRO3 protein co-localizes with nascent photoreceptor outer segment (POS phagosomes in a primary RPE cell culture assay, and expression of murine Tyro3 in cultured cells stimulates phagocytic ingestion of POS. Our findings demonstrate that Tyro3 gene dosage modulates Mertk-associated retinal degeneration, provide strong evidence for a direct role for TYRO3 in RPE phagocytosis

  12. Retinal changes in an ATP-induced model of retinal degeneration

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    Felix Peter Aplin

    2016-04-01

    Full Text Available In rodents and felines, intravitreal administration of adenosine triphosphate (ATP has been shown to induce photoreceptor death providing a tractable model of retinal degeneration in these species. This study investigated the long term effects of photoreceptor loss in an ATP induced feline model of retinal degeneration. Six normal sighted felines were unilaterally blinded using intravitreal ATP injections and assessed using electroretinography (ERG and optical coherence tomography (OCT. At 30 hours (n = 3 or 12 weeks (n = 3 post-injection, the animals were euthanized and the eyes enucleated. Retinae were sectioned and labelled using immunohistochemistry for markers of cell death, neural remodeling and gliosis. Ongoing cell death and retinal degeneration was observed in the outer retina at both 30 hours and 12 weeks following unilateral ATP injection. Markers of mid to late-stage retinal remodeling such as cell displacement and aberrant neurite growth were observed in the inner retina at 12 weeks post-injection. Ganglion cells appeared to remain intact in ATP injected eyes. Müller cell gliosis was observed throughout the inner and outer retina, in some parts completely enveloping and/or displacing the surviving neural tissue. Our data suggests that the ATP injected feline retina continues to undergo progressive retinal degeneration and exhibits abnormalities consistent with a description of retinal remodeling commonly seen in other models of retinal degeneration. These findings validate the use of intravitreal ATP injection in feline as a large animal model of retinal degeneration which may aid in development of therapies aiming to restore visual function after photoreceptor degeneration.

  13. Lack of Acid Sphingomyelinase Induces Age-Related Retinal Degeneration.

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    Bill X Wu

    Full Text Available Mutations of acid sphingomyelinase (ASMase cause Niemann-Pick diseases type A and B, which are fatal inherited lipid lysosomal storage diseases, characterized with visceral organ abnormalities and neurodegeneration. However, the effects of suppressing retinal ASMase expression are not understood. The goal of this study was to determine if the disruption of ASMase expression impacts the retinal structure and function in the mouse, and begin to investigate the mechanisms underlying these abnormalities.Acid sphingomyelinase knockout (ASMase KO mice were utilized to study the roles of this sphingolipid metabolizing enzyme in the retina. Electroretinogram and morphometric analysis were used to assess the retinal function and structure at various ages. Sphingolipid profile was determined by liquid chromatography-mass spectrometry. Western blots evaluated the level of the autophagy marker LC3-II.When compared to control animals, ASMase KO mice exhibited significant age-dependent reduction in ERG a- and b-wave amplitudes. Associated with these functional deficits, morphometric analysis revealed progressive thinning of retinal layers; however, the most prominent degeneration was observed in the photoreceptor and outer nuclear layer. Additional analyses of ASMase KO mice revealed early reduction in ERG c-wave amplitudes and increased lipofuscin accumulation in the retinal pigment epithelium (RPE. Sphingolipid analyses showed abnormal accumulation of sphingomyelin and sphingosine in ASMase KO retinas. Western blot analyses showed a higher level of the autophagosome marker LC3-II.These studies demonstrate that ASMase is necessary for the maintenance of normal retinal structure and function. The early outer retinal dysfunction, outer segment degeneration, accumulation of lipofuscin and autophagosome markers provide evidence that disruption of lysosomal function contributes to the age-dependent retinal degeneration exhibited by ASMase KO mice.

  14. Taurine Provides Neuroprotection against Retinal Ganglion Cell Degeneration

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    Froger, Nicolas; Cadetti, Lucia; Lorach, Henri; Martins, Joao; Bemelmans, Alexis-Pierre; Dubus, Elisabeth; Degardin, Julie; Pain, Dorothée; Forster, Valérie; Chicaud, Laurent; Ivkovic, Ivana; Simonutti, Manuel; Fouquet, Stéphane; Jammoul, Firas; Léveillard, Thierry; Benosman, Ryad; Sahel, José-Alain; Picaud, Serge

    2012-01-01

    Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats). After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%), whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM) partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases. PMID:23115615

  15. Taurine provides neuroprotection against retinal ganglion cell degeneration.

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    Nicolas Froger

    Full Text Available Retinal ganglion cell (RGC degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats. After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%, whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases.

  16. Taurine provides neuroprotection against retinal ganglion cell degeneration.

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    Froger, Nicolas; Cadetti, Lucia; Lorach, Henri; Martins, Joao; Bemelmans, Alexis-Pierre; Dubus, Elisabeth; Degardin, Julie; Pain, Dorothée; Forster, Valérie; Chicaud, Laurent; Ivkovic, Ivana; Simonutti, Manuel; Fouquet, Stéphane; Jammoul, Firas; Léveillard, Thierry; Benosman, Ryad; Sahel, José-Alain; Picaud, Serge

    2012-01-01

    Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats). After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%), whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM) partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases.

  17. Ccdc66 null mutation causes retinal degeneration and dysfunction.

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    Gerding, Wanda M; Schreiber, Sabrina; Schulte-Middelmann, Tobias; de Castro Marques, Andreia; Atorf, Jenny; Akkad, Denis A; Dekomien, Gabriele; Kremers, Jan; Dermietzel, Rolf; Gal, Andreas; Rülicke, Thomas; Ibrahim, Saleh; Epplen, Jörg T; Petrasch-Parwez, Elisabeth

    2011-09-15

    Retinitis pigmentosa (RP) is a group of human retinal disorders, with more than 100 genes involved in retinal degeneration. Canine and murine models are useful for investigating human RP based on known, naturally occurring mutations. In Schapendoes dogs, for example, a mutation in the CCDC66 gene has been shown to cause autosomal recessively inherited, generalized progressive retinal atrophy (gPRA), the canine counterpart to RP. Here, a novel mouse model with a disrupted Ccdc66 gene was investigated to reveal the function of protein CCDC66 and the pathogenesis of this form of gPRA. Homozygous Ccdc66 mutant mice lack retinal Ccdc66 RNA and protein expression. Light and electron microscopy reveal an initial degeneration of photoreceptors already at 13 days of age, followed by a slow, progressive retinal degeneration over months. Retinal dysfunction causes reduced scotopic a-wave amplitudes, declining from 1 to 7 months of age as well as an early reduction of the photopic b-wave at 1 month, improving slightly at 7 months, as evidenced by electroretinography. In the retina of the wild-type (WT) mouse, protein CCDC66 is present at highest levels after birth, followed by a decline until adulthood, suggesting a crucial role in early development. Protein CCDC66 is expressed predominantly in the developing rod outer segments as confirmed by subcellular analyses. These findings illustrate that the lack of protein CCDC66 causes early, slow progressive rod-cone dysplasia in the novel Ccdc66 mutant mouse model, thus providing a sound foundation for the development of therapeutic strategies.

  18. [Optogenetics and prosthetic treatment of retinal degeneration].

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    Kirpichnikov, M P; Ostrovskiy, M A

    2015-01-01

    This is a review of the current state of optogenetics-based research in the field of ophthalmology and physiology of vision. Optogenetics employs an interdisciplinary approach that amalgamates gene engineering, optics, and physiology. It involves exogenous expression of a light-activated protein in a very particular retinal cell enabling regulation (stimulation vs. inhibition) of its physiological activity. The experience with gene therapy came in very useful for optogenetics. However, unlike gene therapy, which is aimed at repairing damaged genes or replacing them with healthy ones, optogenetics is focused on protein genes delivery for further molecular control of the cell. In retina, the loss of photoreceptors is not necessarily followed by neuronal loss (at least ganglion cells remain intact), which determines the practicability of prosthetic treatment. Clinical trials can now be considered, owing to the first successful conversion of ganglion cells of mouse degenerative retinas into artificial photoreceptive cells with ON and OFF receptive fields, which is crucial for spatial vision. The following issues are reviewed here in detail: 1. Choice of cell targets within the degenerative retina. 2. Strategy of utilizing the existing light-sensitive agents and development of new optogenetic tools. 3. Gene delivery and expression in retinal cells. 4. Methods of evaluating the treatment success. 5. Selection criteria for optogenetic prosthetics. The conclusion discusses currently unsolved problems and prospects for optogenetic approaches to retinal prosthetics.

  19. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement.

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    Cideciyan, Artur V; Jacobson, Samuel G; Beltran, William A; Sumaroka, Alexander; Swider, Malgorzata; Iwabe, Simone; Roman, Alejandro J; Olivares, Melani B; Schwartz, Sharon B; Komáromy, András M; Hauswirth, William W; Aguirre, Gustavo D

    2013-02-05

    Leber congenital amaurosis (LCA) associated with retinal pigment epithelium-specific protein 65 kDa (RPE65) mutations is a severe hereditary blindness resulting from both dysfunction and degeneration of photoreceptors. Clinical trials with gene augmentation therapy have shown partial reversal of the dysfunction, but the effects on the degeneration are not known. We evaluated the consequences of gene therapy on retinal degeneration in patients with RPE65-LCA and its canine model. In untreated RPE65-LCA patients, there was dysfunction and degeneration of photoreceptors, even at the earliest ages. Examined serially over years, the outer photoreceptor nuclear layer showed progressive thinning. Treated RPE65-LCA showed substantial visual improvement in the short term and no detectable decline from this new level over the long term. However, retinal degeneration continued to progress unabated. In RPE65-mutant dogs, the first one-quarter of their lifespan showed only dysfunction, and there was normal outer photoreceptor nuclear layer thickness retina-wide. Dogs treated during the earlier dysfunction-only stage showed improved visual function and dramatic protection of treated photoreceptors from degeneration when measured 5-11 y later. Dogs treated later during the combined dysfunction and degeneration stage also showed visual function improvement, but photoreceptor loss continued unabated, the same as in human RPE65-LCA. The results suggest that, in RPE65 disease treatment, protection from visual function deterioration cannot be assumed to imply protection from degeneration. The effects of gene augmentation therapy are complex and suggest a need for a combinatorial strategy in RPE65-LCA to not only improve function in the short term but also slow retinal degeneration in the long term.

  20. Gene therapy for inherited retinal degenerations.

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    Dalkara, Deniz; Sahel, José-Alain

    2014-03-01

    Gene therapy is quickly becoming a reality applicable in the clinic for inherited retinal diseases. Progress over the past decade has moved proof-of-concept gene therapies from bench to bedside. The remarkable success in safety and efficacy, in the phase I/II clinical trials for the form of the severe childhood-onset blindness, Leber's Congenital Amaurosis (LCA) type II (due to mutations in the RPE65 gene) generated significant interest and opened up possibilities for a new era of retinal gene therapies. Success in these clinical trials was due to combining the favorable features of both the retina as a target organ and adeno-associated virus (AAV) as a vector. The retina offers several advantages for gene therapy approaches. It is an anatomically defined structure that is readily accessible for therapy and has some degree of immune privilege, making it suitable for application of viral vectors. AAV, on the other hand, is a non-pathogenic helper dependent virus that has little immunogenicity. This viral vector transduces quiescent cells efficiently and thanks to its small size diffuses well in the interneural matrix, making it suitable for applications in neural tissue. Building on this initial clinical success with LCA II, we have now many opportunities to extend this proof-of-concept to other retinal diseases. This article will discuss what are some of the most imminent targets for such therapies and what are the challenges that we face in moving these therapies to the clinic. Copyright © 2014 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  1. Degeneration modulates retinal response to transient exogenous oxidative injury.

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    Michal Lederman

    Full Text Available PURPOSE: Oxidative injury is involved in retinal and macular degeneration. We aim to assess if retinal degeneration associated with genetic defect modulates the retinal threshold for encountering additional oxidative challenges. METHODS: Retinal oxidative injury was induced in degenerating retinas (rd10 and in control mice (WT by intravitreal injections of paraquat (PQ. Retinal function and structure was evaluated by electroretinogram (ERG and histology, respectively. Oxidative injury was assessed by immunohistochemistry for 4-Hydroxy-2-nonenal (HNE, and by Thiobarbituric Acid Reactive Substances (TBARS and protein carbonyl content (PCC assays. Anti-oxidant mechanism was assessed by quantitative real time PCR (QPCR for mRNA of antioxidant genes and genes related to iron metabolism, and by catalase activity assay. RESULTS: Three days following PQ injections (1 µl of 0.25, 0.75, and 2 mM the average ERG amplitudes decreased more in the WT mice compared with the rd10 mice. For example, following 2 mM PQ injection, ERG amplitudes reduced 1.84-fold more in WT compared with rd10 mice (p = 0.02. Injection of 4 mM PQ resulted in retinal destruction. Altered retina morphology associated with PQ was substantially more severe in WT eyes compared with rd10 eyes. Oxidative injury according to HNE staining and TBARS assay increased 1.3-fold and 2.1-fold more, respectively, in WT compared with rd10 mice. At baseline, prior to PQ injection, mRNA levels of antioxidant genes (Superoxide Dismutase1, Glutathione Peroxidase1, Catalase and of Transferrin measured by quantitative PCR were 2.1-7.8-fold higher in rd10 compared with WT mice (p<0.01 each, and catalase activity was 1.7-fold higher in rd10 (p = 0.0006. CONCLUSIONS: This data suggests that degenerating rd10 retinas encounter a relatively lower degree of damage in response to oxidative injury compared with normal retinas. Constitutive up-regulation of the oxidative defense mechanism in degenerating retinas

  2. Conservation of retinal circadian rhythms during cavefish eye degeneration.

    Science.gov (United States)

    Espinasa, Luis; Jeffery, William R

    2006-01-01

    Regressive evolution of morphological features is a common evolutionary event. However, the relationship between structural degeneration and loss of physiological function is often unclear because the ancestral and derived states of a character are usually not available for comparison. Here, we report studies on retinomotor rhythms during development of the blind cavefish Astyanax mexicanus, a single teleost species consisting of a sighted surface-dwelling form (surface fish) and several blind cave-dwelling (cavefish) forms. The eyed and blind forms of Astyanax diverged from a common sighted ancestor within the past million years. Despite the absence of functional eyes in cavefish adults, optic primordia are formed in embryos, but then gradually arrest in development, degenerate, and sink into the orbits. Although a layered retina is formed in cavefish embryos, it is deficient in photoreceptor cells, and in some cases the retinal pigment epithelium has lost its pigmentation. We show that the capacity to exhibit light-entrained retinomotor rhythms has been conserved in the degenerating embryonic eyes of two different Astyanax cavefish populations. The results indicate that loss of circadian retinal function does not precede and is therefore not required for eye degeneration in the blind cavefish.

  3. Inner retinal change in a novel rd1-FTL mouse model of retinal degeneration

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    Ursula eGreferath

    2015-07-01

    Full Text Available While photoreceptor loss is the most devastating result of inherited retinal degenerations such as retinitis pigmentosa, inner retinal neurons also undergo significant alteration. Detailing these changes has become important as many vision restorative therapies target the remaining neurons. In this study, the rd1-Fos-Tau-LacZ (rd1-FTL mouse model was used to explore inner retinal change at a late stage of retinal degeneration, after the loss of photoreceptor nuclei. The rd1-FTL model carries a mutation in the phosphodiesterase gene, Pde6b, and an axonally targeted transgenic beta galactosidase reporter system under the control of the c-fos promoter. Retinae of transgenic rd1-FTL mice and control FTL animals aged 2 to 12 months were processed for indirect fluorescence immunocytochemistry. At 2 months of age, a time when the majority of photoreceptor nuclei are lost, there was negligible c-fos reporter (FTL expression, however, from 4 months, reporter expression was observed to increase within subpopulations of amacrine and ganglion cells within the central retina. These areas of inner retinal FTL expression coincided with regions that contained aberrant Müller cells. Specifically, these cells exhibited reduced glutamine synthetase and Kir4.1 immunolabelling, whilst showing evidence of proliferative gliosis (increased cyclinD1 and GFAP expression. These changes were limited to distinct regions where cone photoreceptor terminals were absent. Overall, these results highlight that distinct areas of the rd1-FTL central retina undergo significant glial alterations after cone photoreceptor loss. These areas coincide with up-regulation of the c-fos reporter in the inner retina, which may represent a change in neuronal function/plasticity. The rd1-FTL mouse is a useful model system to probe changes that occur in the inner retina at later stages of retinal degeneration.

  4. Clinical characteristics and current therapies for inherited retinal degenerations.

    Science.gov (United States)

    Sahel, José-Alain; Marazova, Katia; Audo, Isabelle

    2014-10-16

    Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances.

  5. Transsynaptic retinal degeneration in optic neuropathies: optical coherence tomography study.

    Science.gov (United States)

    Sriram, Prema; Graham, Stuart L; Wang, Chenyu; Yiannikas, Con; Garrick, Raymond; Klistorner, Alexander

    2012-03-09

    Recently demonstrated neuronal loss in the inner nuclear layer of the retina in multiple sclerosis (MS) and glaucoma raises the question of a primary (possibly immune-mediated) or secondary (transsynaptic) mechanism of retinal damage in these diseases. In the present study we used optical coherence tomography to investigate retrograde retinal transsynaptic degeneration in patients with long-standing and severe loss of ganglion cells due to optic neuropathy. Fifteen eyes of glaucoma patients with visual field defect limited to upper hemifield and 15 eyes of MS patients with previous episode of optic neuritis (ON) and extensive loss of ganglion cells were imaged using spectral-domain optical coherence tomography and compared with two groups of age-matched controls. Combined retinal ganglion cell layer/inner plexiform layer (GCL/IPL) thickness and inner nuclear layer (INL) thickness were analyzed. In the glaucoma group there was a significant (P = 0.0005) reduction of GCL/IPL thickness in the lower (affected) retina compared with normal controls; however INL thickness was not statistically reduced (P = 0.49). In the MS group reduction of GCL/IPL thickness in both hemifields of ON eyes was also significant (P = 0.0001 and P < 0.0001 for inferior and superior retina respectively). However, similar to the glaucomatous eyes, there was no significant reduction of INL thickness in both hemifields (P = 0.25 and P = 0.45). This study demonstrates no significant loss of INL thickness in parts of the retina with long-standing and severe loss of retinal ganglion cells.

  6. Decreased fixation stability of the preferred retinal location in juvenile macular degeneration

    NARCIS (Netherlands)

    Bethlehem, Richard A I; Dumoulin, Serge O.; Dalmaijer, Edwin S.; Smit, Miranda; Berendschot, Tos T J M; Nijboer, Tanja C W; Van Der Stigchel, Stefan

    2014-01-01

    Macular degeneration is the main cause for diminished visual acuity in the elderly. The juvenile form of macular degeneration has equally detrimental consequences on foveal vision. To compensate for loss of foveal vision most patients with macular degeneration adopt an eccentric preferred retinal lo

  7. Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or retinitis pigmentosa.

    NARCIS (Netherlands)

    Klevering, B.J.; Maugeri, A.; Wagner, A.; Go, S.L.; Vink, C.W.; Cremers, F.P.M.; Hoyng, C.B.

    2004-01-01

    OBJECTIVE: To investigate the clinical spectrum and molecular causes of retinal dystrophies in 3 families. DESIGN: Family molecular genetics study. PARTICIPANTS: Sixteen patients and 15 relatives in 3 families. METHODS: Members of 3 families with multiple ABCA4-associated retinal disorders were clin

  8. Changes in ganglion cell physiology during retinal degeneration influence excitability by prosthetic electrodes

    Science.gov (United States)

    Cho, Alice; Ratliff, Charles; Sampath, Alapakkam; Weiland, James

    2016-01-01

    Objective Here we investigate ganglion cell physiology in healthy and degenerating retina to test its influence on threshold to electrical stimulation. Approach Age-related Macular Degeneration and Retinitis Pigmentosa cause blindness via outer retinal degeneration. Inner retinal pathways that transmit visual information to the central brain remain intact, so direct electrical stimulation from prosthetic devices offers the possibility for visual restoration. Since inner retinal physiology changes during degeneration, we characterize physiological properties and responses to electrical stimulation in retinal ganglion cells of both wild type mice and the rd10 mouse model of retinal degeneration. Main results Our aggregate results support previous observations that elevated thresholds characterize diseased retinas. However, a physiology-driven classification scheme reveals distinct sub-populations of ganglion cells with thresholds either normal or strongly elevated compared to wild-type. When these populations are combined, only a weakly elevated threshold with large variance is observed. The cells with normal threshold are more depolarized at rest and exhibit periodic oscillations. Significance During degeneration, physiological changes in retinal ganglion cells affect the threshold stimulation currents required to evoke action potentials. PMID:26905177

  9. Repeatability of Cone Spacing Measures in Eyes With Inherited Retinal Degenerations

    National Research Council Canada - National Science Library

    Zayit-Soudry, Shiri; Sippl-Swezey, Nicolas; Porco, Travis C; Lynch, Stephanie K; Syed, Reema; Ratnam, Kavitha; Menghini, Moreno; Roorda, Austin J; Duncan, Jacque L

    2015-01-01

    ...)-derived cone spacing measures in eyes with inherited retinal degenerations (IRD) and in normal eyes. Twenty IRD patients and 10 visually normal subjects underwent AOSLO imaging at two visits separated by no more than 1 month...

  10. Safranal, a saffron constituent, attenuates retinal degeneration in P23H rats.

    Science.gov (United States)

    Fernández-Sánchez, Laura; Lax, Pedro; Esquiva, Gema; Martín-Nieto, José; Pinilla, Isabel; Cuenca, Nicolás

    2012-01-01

    Saffron, an extract from Crocus sativus, has been largely used in traditional medicine for its antiapoptotic and anticarcinogenic properties. In this work, we investigate the effects of safranal, a component of saffron stigmas, in attenuating retinal degeneration in the P23H rat model of autosomal dominant retinitis pigmentosa. We demonstrate that administration of safranal to homozygous P23H line-3 rats preserves both photoreceptor morphology and number. Electroretinographic recordings showed higher a- and b-wave amplitudes under both photopic and scotopic conditions in safranal-treated versus non-treated animals. Furthermore, the capillary network in safranal-treated animals was preserved, unlike that found in untreated animals. Our findings indicate that dietary supplementation with safranal slows photoreceptor cell degeneration and ameliorates the loss of retinal function and vascular network disruption in P23H rats. This work also suggests that safranal could be potentially useful to retard retinal degeneration in patients with retinitis pigmentosa.

  11. Safranal, a saffron constituent, attenuates retinal degeneration in P23H rats.

    Directory of Open Access Journals (Sweden)

    Laura Fernández-Sánchez

    Full Text Available Saffron, an extract from Crocus sativus, has been largely used in traditional medicine for its antiapoptotic and anticarcinogenic properties. In this work, we investigate the effects of safranal, a component of saffron stigmas, in attenuating retinal degeneration in the P23H rat model of autosomal dominant retinitis pigmentosa. We demonstrate that administration of safranal to homozygous P23H line-3 rats preserves both photoreceptor morphology and number. Electroretinographic recordings showed higher a- and b-wave amplitudes under both photopic and scotopic conditions in safranal-treated versus non-treated animals. Furthermore, the capillary network in safranal-treated animals was preserved, unlike that found in untreated animals. Our findings indicate that dietary supplementation with safranal slows photoreceptor cell degeneration and ameliorates the loss of retinal function and vascular network disruption in P23H rats. This work also suggests that safranal could be potentially useful to retard retinal degeneration in patients with retinitis pigmentosa.

  12. 670-nm light treatment reduces complement propagation following retinal degeneration

    Directory of Open Access Journals (Sweden)

    Rutar Matt

    2012-11-01

    Full Text Available Abstract Aim Complement activation is associated with the pathogenesis of age-related macular degeneration (AMD. We aimed to investigate whether 670-nm light treatment reduces the propagation of complement in a light-induced model of atrophic AMD. Methods Sprague–Dawley (SD rats were pretreated with 9 J/cm2 670-nm light for 3 minutes daily over 5 days; other animals were sham treated. Animals were exposed to white light (1,000 lux for 24 h, after which animals were kept in dim light (5 lux for 7 days. Expression of complement genes was assessed by quantitative polymerase chain reaction (qPCR, and immunohistochemistry. Counts were made of C3-expressing monocytes/microglia using in situ hybridization. Photoreceptor death was also assessed using outer nuclear layer (ONL thickness measurements, and oxidative stress using immunohistochemistry for 4-hydroxynonenal (4-HNE. Results Following light damage, retinas pretreated with 670-nm light had reduced immunoreactivity for the oxidative damage maker 4-HNE in the ONL and outer segments, compared to controls. In conjunction, there was significant reduction in retinal expression of complement genes C1s, C2, C3, C4b, C3aR1, and C5r1 following 670 nm treatment. In situ hybridization, coupled with immunoreactivity for the marker ionized calcium binding adaptor molecule 1 (IBA1, revealed that C3 is expressed by infiltrating microglia/monocytes in subretinal space following light damage, which were significantly reduced in number after 670 nm treatment. Additionally, immunohistochemistry for C3 revealed a decrease in C3 deposition in the ONL following 670 nm treatment. Conclusions Our data indicate that 670-nm light pretreatment reduces lipid peroxidation and complement propagation in the degenerating retina. These findings have relevance to the cellular events of complement activation underling the pathogenesis of AMD, and highlight the potential of 670-nm light as a non-invasive anti-inflammatory therapy.

  13. XLPRA: A canine retinal degeneration inherited as an X-linked trait

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    Acland, G.M.; Blanton, S.H.; Hershfield, B.; Aguirre, G.D.

    1994-08-01

    Breeding studies are reported of a previously undescribed hereditary retinal degeneration identified in the Siberian Husky breed of dog. This disorder clinically resembles the previously reported autosomal recessive canine hereditary retinal degenerations collectively termed progressive retinal atrophy (PRA). However, the pedigree of the propositus, a male Siberian Husky, exhibited an X-linked pattern of transmission. This dog was outcrossed to three phenotypically normal female laboratory Beagles and two of their F1 daughters were bred to a phenotypically normal male Beagle, producing affected males in the F2 generation. Subsequent inbreedings produced further affected males and affected females as well. X-linked transmission was established by exclusion of alternative modes of inheritance and, consequently, the disease has been termed X-linked progressive retinal atrophy (XLPRA). This is the first reported X-linked retinal degeneration in an animal. Because of the many similarities of PRA in dogs to retinitis pigmentosa (RP) in humans, this new disease may not only represent the first animal model of X-linked RP (XLRP) but may well be a true homolog of one of the XLRP loci (RP2, RP3, RP6). It is the first retinal degeneration in dogs that can be assigned to an identified canine chromosome, and the first for which linkage mapping offers a realistic approach to proceed by positional cloning towards identifying the responsible gene. 58 refs., 1 fig., 3 tabs.

  14. Spontaneous oscillatory rhythms in the degenerating mouse retina modulate retinal ganglion cell responses to electrical stimulation

    Directory of Open Access Journals (Sweden)

    Yong Sook eGoo

    2016-01-01

    Full Text Available Characterization of the electrical activity of the retina in the animal models of retinal degeneration has been carried out in part to understand the progression of retinal degenerative diseases like age-related macular degeneration (AMD and retinitis pigmentosa (RP, but also to determine optimum stimulus paradigms for use with retinal prosthetic devices. The models most studied in this regard have been the two lines of mice deficient in the β-subunit of phosphodiesterase (rd1 and rd10 mice, where the degenerating retinas exhibit characteristic spontaneous hyperactivity and oscillatory local field potentials (LFPs. Additionally, there is a robust ~10 Hz rhythmic burst of retinal ganglion cell (RGC spikes on the trough of the oscillatory LFP. In rd1 mice, the rhythmic burst of RGC spikes is always phase-locked with the oscillatory LFP and this phase-locking property is preserved regardless of postnatal ages. However, in rd10 mice, the frequency of the oscillatory rhythm changes according to postnatal age, suggesting that this rhythm might be a marker of the stage of degeneration. Furthermore when a biphasic current stimulus is applied to rd10 mice degenerate retina, distinct RGC response patterns that correlate with the stage of degeneration emerge. This review also considers the significance of these response properties.

  15. Age-Dependent Retinal Iron Accumulation and Degeneration in Hepcidin Knockout Mice

    Science.gov (United States)

    Hadziahmetovic, Majda; Song, Ying; Ponnuru, Padmavathi; Iacovelli, Jared; Hunter, Allan; Haddad, Nadine; Beard, John; Connor, James R.; Vaulont, Sophie

    2011-01-01

    Purpose. Iron dysregulation can cause retinal disease, yet retinal iron regulatory mechanisms are incompletely understood. The peptide hormone hepcidin (Hepc) limits iron uptake from the intestine by triggering degradation of the iron transporter ferroportin (Fpn). Given that Hepc is expressed in the retina and Fpn is expressed in cells constituting the blood-retinal barrier, the authors tested whether the retina may produce Hepc to limit retinal iron import. Methods. Retinas of Hepc−/− mice were analyzed by histology, autofluorescence spectral analysis, atomic absorption spectrophotometry, Perls' iron stain, and immunofluorescence to assess iron-handling proteins. Retinal Hepc mRNA was evaluated through qPCR after intravitreal iron injection. Mechanisms of retinal Hepc upregulation were tested by Western blot analysis. A retinal capillary endothelial cell culture system was used to assess the effect of exogenous Hepc on Fpn. Results. Hepc−/− mice experienced age-dependent increases in retinal iron followed by retinal degeneration with autofluorescent RPE, photoreceptor death, and subretinal neovascularization. Hepc−/− mice had increased Fpn immunoreactivity in vascular endothelial cells. Conversely, in cultured retinal capillary endothelial cells, exogenous Hepc decreased both Fpn levels and iron transport. The retina can sense increased iron levels, upregulating Hepc after phosphorylation of extracellular signal regulated kinases. Conclusions. These findings indicate that Hepc is essential for retinal iron regulation. In the absence of Hepc, retinal degeneration occurs. Increases in Hepc mRNA levels after intravitreal iron injection combined with Hepc-mediated decreases in iron export from cultured retinal capillary endothelial cells suggest that the retina may use Hepc for its tissue-specific iron regulation. PMID:20811044

  16. Astrocytes and Müller cells changes during retinal degeneration in a transgenic rat model of retinitis pigmentosa.

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    Laura eFernández-Sánchez

    2015-12-01

    Full Text Available Purpose: Retinitis pigmentosa includes a group of progressive retinal degenerative diseases that affect the structure and function of photoreceptors. Secondarily to the loss of photoreceptors, there is a reduction in retinal vascularization, which seems to influence the cellular degenerative process. Retinal macroglial cells, astrocytes and Müller cells provide support for retinal neurons and are fundamental for maintaining normal retinal function. The aim of this study was to investigate the evolution of macroglial changes during retinal degeneration in P23H rats. Methods: Homozygous P23H line-3 rats aged from P18 to 18 months were used to study the evolution of the disease, and SD rats were used as controls. Immunolabeling with antibodies against GFAP, vimentin, and transducin were used to visualize macroglial cells and cone photoreceptors. Results: In P23H rats, increased GFAP labeling in Müller cells was observed as an early indicator of retinal gliosis. At 4 and 12 months of age, the apical processes of Müller cells in P23H rats clustered in firework-like structures, which were associated with ring-like shaped areas of cone degeneration in the outer nuclear layer. These structures were not observed at 16 months of age. The number of astrocytes was higher in P23H rats than in the SD matched controls at 4 and 12 months of age, supporting the idea of astrocyte proliferation. As the disease progressed, astrocytes exhibited a deteriorated morphology and marked hypertrophy. The increase in the complexity of the astrocytic processes correlated with greater connexin 43 expression and higher density of connexin 43 immunoreactive puncta within the ganglion cell layer of P23H versus SD rat retinas. Conclusions: In the P23H rat model of retinitis pigmentosa, the loss of photoreceptors triggers major changes in the number and morphology of glial cells affecting the inner retina.

  17. Characterization of an Early-Onset, Autosomal Recessive, Progressive Retinal Degeneration in Bengal Cats

    Science.gov (United States)

    Ofri, Ron; Reilly, Christopher M.; Maggs, David J.; Fitzgerald, Paul G.; Shilo-Benjamini, Yael; Good, Kathryn L.; Grahn, Robert A.; Splawski, Danielle D.; Lyons, Leslie A.

    2015-01-01

    Purpose A form of retinal degeneration suspected to be hereditary was discovered in a family of Bengal cats. A breeding colony was established to characterize disease progression clinically, electrophysiologically, and morphologically, and to investigate the mode of inheritance. Methods Affected and related cats were donated by owners for breeding trials and pedigree analysis. Kittens from test and complementation breedings underwent ophthalmic and neuro-ophthalmic examinations and ERG, and globes were evaluated using light microscopy. Results Pedigree analysis, along with test and complementation breedings, indicated autosomal recessive inheritance and suggested that this disease is nonallelic to a retinal degeneration found in Persian cats. Mutation analysis confirmed the disease is not caused by CEP290 or CRX variants found predominantly in Abyssinian and Siamese cats. Ophthalmoscopic signs of retinal degeneration were noted at 9 weeks of age and became more noticeable over the next 4 months. Visual deficits were behaviorally evident by 1 year of age. Electroretinogram demonstrated reduced rod and cone function at 7 and 9 weeks of age, respectively. Rod responses were mostly extinguished at 14 weeks of age; cone responses were minimal by 26 weeks. Histologic degeneration was first observed at 8 weeks, evidenced by reduced photoreceptor numbers, then rapid deterioration of the photoreceptor layer and, subsequently, severe outer retinal degeneration. Conclusions A recessively inherited primary photoreceptor degeneration was characterized in the Bengal cat. The disease is characterized by early onset, with histologic, ophthalmoscopic, and electrophysiological signs evident by 2 months of age, and rapid progression to blindness. PMID:26258614

  18. Progress on retinal image analysis for age related macular degeneration.

    Science.gov (United States)

    Kanagasingam, Yogesan; Bhuiyan, Alauddin; Abràmoff, Michael D; Smith, R Theodore; Goldschmidt, Leonard; Wong, Tien Y

    2014-01-01

    Age-related macular degeneration (AMD) is the leading cause of vision loss in those over the age of 50 years in the developed countries. The number is expected to increase by ∼1.5 fold over the next ten years due to an increase in aging population. One of the main measures of AMD severity is the analysis of drusen, pigmentary abnormalities, geographic atrophy (GA) and choroidal neovascularization (CNV) from imaging based on color fundus photograph, optical coherence tomography (OCT) and other imaging modalities. Each of these imaging modalities has strengths and weaknesses for extracting individual AMD pathology and different imaging techniques are used in combination for capturing and/or quantification of different pathologies. Current dry AMD treatments cannot cure or reverse vision loss. However, the Age-Related Eye Disease Study (AREDS) showed that specific anti-oxidant vitamin supplementation reduces the risk of progression from intermediate stages (defined as the presence of either many medium-sized drusen or one or more large drusen) to late AMD which allows for preventative strategies in properly identified patients. Thus identification of people with early stage AMD is important to design and implement preventative strategies for late AMD, and determine their cost-effectiveness. A mass screening facility with teleophthalmology or telemedicine in combination with computer-aided analysis for large rural-based communities may identify more individuals suitable for early stage AMD prevention. In this review, we discuss different imaging modalities that are currently being considered or used for screening AMD. In addition, we look into various automated and semi-automated computer-aided grading systems and related retinal image analysis techniques for drusen, geographic atrophy and choroidal neovascularization detection and/or quantification for measurement of AMD severity using these imaging modalities. We also review the existing telemedicine studies which

  19. Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice.

    Science.gov (United States)

    Yu, Wenhan; Mookherjee, Suddhasil; Chaitankar, Vijender; Hiriyanna, Suja; Kim, Jung-Woong; Brooks, Matthew; Ataeijannati, Yasaman; Sun, Xun; Dong, Lijin; Li, Tiansen; Swaroop, Anand; Wu, Zhijian

    2017-03-14

    In retinitis pigmentosa, loss of cone photoreceptors leads to blindness, and preservation of cone function is a major therapeutic goal. However, cone loss is thought to occur as a secondary event resulting from degeneration of rod photoreceptors. Here we report a genome editing approach in which adeno-associated virus (AAV)-mediated CRISPR/Cas9 delivery to postmitotic photoreceptors is used to target the Nrl gene, encoding for Neural retina-specific leucine zipper protein, a rod fate determinant during photoreceptor development. Following Nrl disruption, rods gain partial features of cones and present with improved survival in the presence of mutations in rod-specific genes, consequently preventing secondary cone degeneration. In three different mouse models of retinal degeneration, the treatment substantially improves rod survival and preserves cone function. Our data suggest that CRISPR/Cas9-mediated NRL disruption in rods may be a promising treatment option for patients with retinitis pigmentosa.

  20. [Retinal and trabecular degeneration in glaucoma: new insights into pathogenesis and treatment].

    Science.gov (United States)

    Denoyer, A; Roubeix, C; Sapienza, A; Réaux-Le Goazigo, A; Mélik-Parsadaniantz, S; Baudouin, C

    2015-04-01

    Academic and industrial research has brought new insights into the pathogenesis of glaucoma, aiming at identifying and targeting specific mechanisms to improve our current therapeutic strategy. Retinal neurodegeneration is still the main focus, whether in terms of extrinsic factors such as neurotrophin deprivation, glutamate toxicity, vascular deficiency and neuro-inflammation from glial cells, or in terms of retinal ganglion cell intrinsic sensibility to proapoptotic signals. However, glaucoma is not solely a retinal disease but also involves retinal and trabecular meshwork degeneration, extending into and/or even originating from the brain. The present review summarizes our current knowledge of key mechanisms involved in glaucoma degeneration, focusing on the direction of current research towards the future of glaucoma therapy.

  1. Quantitative genetic analysis of retinal degeneration in the blind cavefish Astyanax mexicanus.

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    Kelly E O'Quin

    Full Text Available The retina is the light-sensitive tissue of the eye that facilitates vision. Mutations within genes affecting eye development and retinal function cause a host of degenerative visual diseases, including retinitis pigmentosa and anophthalmia/microphthalmia. The characin fish Astyanax mexicanus includes both eyed (surface fish and eyeless (cavefish morphs that initially develop eyes with normal retina; however, early in development, the eyes of cavefish degenerate. Since both surface and cave morphs are members of the same species, they serve as excellent evolutionary mutant models with which to identify genes causing retinal degeneration. In this study, we crossed the eyed and eyeless forms of A. mexicanus and quantified the thickness of individual retinal layers among 115 F(2 hybrid progeny. We used next generation sequencing (RAD-seq and microsatellite mapping to construct a dense genetic map of the Astyanax genome, scan for quantitative trait loci (QTL affecting retinal thickness, and identify candidate genes within these QTL regions. The map we constructed for Astyanax includes nearly 700 markers assembled into 25 linkage groups. Based on our scans with this map, we identified four QTL, one each associated with the thickness of the ganglion, inner nuclear, outer plexiform, and outer nuclear layers of the retina. For all but one QTL, cavefish alleles resulted in a clear reduction in the thickness of the affected layer. Comparative mapping of genetic markers within each QTL revealed that each QTL corresponds to an approximately 35 Mb region of the zebrafish genome. Within each region, we identified several candidate genes associated with the function of each affected retinal layer. Our study is the first to examine Astyanax retinal degeneration in the context of QTL mapping. The regions we identify serve as a starting point for future studies on the genetics of retinal degeneration and eye disease using the evolutionary mutant model Astyanax.

  2. Differential modulation of retinal degeneration by Ccl2 and Cx3cr1 chemokine signalling.

    Science.gov (United States)

    Luhmann, Ulrich F O; Lange, Clemens A; Robbie, Scott; Munro, Peter M G; Cowing, Jill A; Armer, Hannah E J; Luong, Vy; Carvalho, Livia S; MacLaren, Robert E; Fitzke, Frederick W; Bainbridge, James W B; Ali, Robin R

    2012-01-01

    Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-)/Crb1(Rd8/RD8), Cx3cr1(-/-)/Crb1(Rd8/RD8) and CCl2(-/-)/Cx3cr1(-/-)/Crb1(Rd8/RD8) mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These findings

  3. CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration.

    Directory of Open Access Journals (Sweden)

    Yiwen Li

    Full Text Available BACKGROUND: Cone photoreceptors are responsible for color and central vision. In the late stage of retinitis pigmentosa and in geographic atrophy associated with age-related macular degeneration, cone degeneration eventually causes loss of central vision. In the present work, we investigated cone degeneration secondary to rod loss in the S334ter-3 transgenic rats carrying the rhodopsin mutation S334ter. METHODOLOGY/PRINCIPAL FINDINGS: Recombinant human ciliary neurotrophic factor (CNTF was delivered by intravitreal injection to the left eye of an animal, and vehicle to the right eye. Eyes were harvested 10 days after injection. Cone outer segments (COS, and cell bodies were identified by staining with peanut agglutinin and cone arrestin antibodies in whole-mount retinas. For long-term treatment with CNTF, CNTF secreting microdevices were implanted into the left eyes at postnatal day (PD 20 and control devices into the right eyes. Cone ERG was recorded at PD 160 from implanted animals. Our results demonstrate that an early sign of cone degeneration is the loss of COS, which concentrated in many small areas throughout the retina and is progressive with age. Treatment with CNTF induces regeneration of COS and thus reverses the degeneration process in early stages of cone degeneration. Sustained delivery of CNTF prevents cones from degeneration and helps them to maintain COS and light-sensing function. CONCLUSIONS/SIGNIFICANCE: Loss of COS is an early sign of secondary cone degeneration whereas cell death occurs much later. At early stages, degenerating cones are capable of regenerating outer segments, indicating the reversal of the degenerative process. Sustained delivery of CNTF preserves cone cells and their function. Long-term treatment with CNTF starting at early stages of degeneration could be a viable strategy for preservation of central vision for patients with retinal degenerations.

  4. Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice.

    Science.gov (United States)

    Hafler, Brian P; Klein, Zoe A; Jimmy Zhou, Z; Strittmatter, Stephen M

    2014-11-07

    Prior investigations have shown that patients with neuronal ceroid lipofuscinosis (NCL) develop neurodegeneration characterized by vision loss, motor dysfunction, seizures, and often early death. Neuropathological analysis of patients with NCL shows accumulation of intracellular autofluorescent storage material, lipopigment, throughout neurons in the central nervous system including in the retina. A recent study of a sibling pair with adult onset NCL and retinal degeneration showed linkage to the region of the progranulin (GRN) locus and a homozygous mutation was demonstrated in GRN. In particular, the sibling pair with a mutation in GRN developed retinal degeneration and optic atrophy. This locus for this form of adult onset neuronal ceroid lipofuscinosis was designated neuronal ceroid lipofuscinosis-11 (CLN11). Based on these clinical observations, we wished to determine whether Grn-null mice develop accumulation of autofluorescent particles and retinal degeneration. Retinas of both wild-type and Progranulin deficient mice were examined by immunostaining and autofluorescence. Accumulation of autofluorescent material was present in Progranulin deficient mice at 12 months. Degeneration of multiple classes of neurons including photoreceptors and retinal ganglion cells was noted in mice at 12 and 18 months. Our data shows that Grn(-/-) mice develop degenerative pathology similar to features of human CLN11.

  5. Morphological and physiological retinal degeneration induced by intravenous delivery of vitamin A dimers in rabbits

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    Jackie Penn

    2015-02-01

    Full Text Available The eye uses vitamin A as a cofactor to sense light and, during this process, some vitamin A molecules dimerize, forming vitamin A dimers. A striking chemical signature of retinas undergoing degeneration in major eye diseases such as age-related macular degeneration (AMD and Stargardt disease is the accumulation of these dimers in the retinal pigment epithelium (RPE and Bruch’s membrane (BM. However, it is not known whether dimers of vitamin A are secondary symptoms or primary insults that drive degeneration. Here, we present a chromatography-free method to prepare gram quantities of the vitamin A dimer, A2E, and show that intravenous administration of A2E to the rabbit results in retinal degeneration. A2E-damaged photoreceptors and RPE cells triggered inflammation, induced remolding of the choroidal vasculature and triggered a decline in the retina’s response to light. Data suggest that vitamin A dimers are not bystanders, but can be primary drivers of retinal degeneration. Thus, preventing dimer formation could be a preemptive strategy to address serious forms of blindness.

  6. Effect of a complex lutein formula in an animal model for light-induced retinal degeneration.

    Science.gov (United States)

    Cheng, Yin-Pin; Ke, Chia-Ying; Kuo, Chih-Chieh; Lee, Yih-Jing

    2016-08-31

    Several retinal degenerative diseases cause vision loss and retinal cell death. Currently, people face prolonged exposure to digital screens, rendering vision protection from light exposure a critical topic. In this study, we designed a complex lutein formula (CLF) by combining several natural compounds: Calendula officinalis, Lycium barbarum, Vaccinium myrtillus, Cassia obtusifolia, and Rhodiola rosea. In addition, we evaluated the protective effects of the formula on retinal functions in an animal model for light-induced retinal degeneration. We employed electroretinography to analyse retinal function, and conducted a histological examination of the morphological changes in the retina treated under various conditions. We revealed that the retinal function in animals exposed to light for 7 days decreased significantly; however, the retinal function of animals that had received the CLF exhibited superior performance, despite light exposure. In addition, a greater portion of the outer nuclear layer (ONL) (i.e. the nuclei of photoreceptors) in these animals was preserved compared with the animals that had not received the formula after 7 days of light exposure. These results revealed that our dietary CLF supplement attenuated retinal function loss resulting from long-term light exposure.

  7. Effect of eye NGF administration on two animal models of retinal ganglion cells degeneration

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    Valeria Colafrancesco

    2011-01-01

    Full Text Available The aim of this study was to investigate the effect of nerve growth factor (NGF administration on retinal ganglion cells (RGCs in experimentally induced glaucoma (GL and diabetic retinopathy (DR. GL was induced in adult rats by injection of hypertonic saline into the episcleral vein of the eye and diabetes (DT was induced by administration of streptozoticin. Control and experimental rats were treated daily with either ocular application of NGF or vehicle solution. We found that both animal models present a progressive degeneration of RGCs and changing NGF and VEGF levels in the retina and optic nerve. We then proved that NGF eye drop administration exerts a protective effect on these models of retinal degeneration. In brief, our findings indicate that NGF can play a protective role against RGC degeneration occurring in GL and DR and suggest that ocular NGF administration might be an effective pharmacological approach.

  8. Primary visual cortical remapping in patients with inherited peripheral retinal degeneration.

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    Ferreira, Sónia; Pereira, Andreia Carvalho; Quendera, Bruno; Reis, Aldina; Silva, Eduardo Duarte; Castelo-Branco, Miguel

    2017-01-01

    Human studies addressing the long-term effects of peripheral retinal degeneration on visual cortical function and structure are scarce. Here we investigated this question in patients with Retinitis Pigmentosa (RP), a genetic condition leading to peripheral visual degeneration. We acquired functional and anatomical magnetic resonance data from thirteen patients with different levels of visual loss and twenty-two healthy participants to study primary (V1) visual cortical retinotopic remapping and cortical thickness. We identified systematic visual field remapping in the absence of structural changes in the primary visual cortex of RP patients. Remapping consisted in a retinotopic eccentricity shift of central retinal inputs to more peripheral locations in V1. Importantly, this was associated with changes in visual experience, as assessed by the extent of the visual loss, with more constricted visual fields resulting in larger remapping. This pattern of remapping is consistent with expansion or shifting of neuronal receptive fields into the cortical regions with reduced retinal input. These data provide evidence for functional changes in V1 that are dependent on the magnitude of peripheral visual loss in RP, which may be explained by rapid cortical adaptation mechanisms or long-term cortical reorganization. This study highlights the importance of analyzing the retinal determinants of brain functional and structural alterations for future visual restoration approaches.

  9. Deletion of myosin VI causes slow retinal optic neuropathy and age-related macular degeneration (AMD)-relevant retinal phenotype.

    Science.gov (United States)

    Schubert, Timm; Gleiser, Corinna; Heiduschka, Peter; Franz, Christoph; Nagel-Wolfrum, Kerstin; Sahaboglu, Ayse; Weisschuh, Nicole; Eske, Gordon; Rohbock, Karin; Rieger, Norman; Paquet-Durand, François; Wissinger, Bernd; Wolfrum, Uwe; Hirt, Bernhard; Singer, Wibke; Rüttiger, Lukas; Zimmermann, Ulrike; Knipper, Marlies

    2015-10-01

    The unconventional myosin VI, a member of the actin-based motor protein family of myosins, is expressed in the retina. Its deletion was previously shown to reduce amplitudes of the a- and b-waves of the electroretinogram. Analyzing wild-type and myosin VI-deficient Snell's Waltzer mice in more detail, the expression pattern of myosin VI in retinal pigment epithelium, outer limiting membrane, and outer plexiform layer could be linked with differential progressing ocular deficits. These encompassed reduced a-waves and b-waves and disturbed oscillatory potentials in the electroretinogram, photoreceptor cell death, retinal microglia infiltration, and formation of basal laminar deposits. A phenotype comprising features of glaucoma (neurodegeneration) and age-related macular degeneration could thus be uncovered that suggests dysfunction of myosin VI and its variable cargo adaptor proteins for membrane sorting and autophagy, as possible candidate mediators for both disease forms.

  10. Retrograde degeneration of retinal ganglion cells in homonymous hemianopsia

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    Herro AM

    2015-06-01

    Full Text Available Angela M Herro, Byron L Lam Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA Background: The aim of this study was to demonstrate the relationship between topographic reduction in macular ganglion cell complex (GCC thickness as detected with spectral-domain optical coherence tomography and visual field defects caused by ischemic occipital cortical injury.Methods: This study was a retrospective review of all patients who presented to our eye institution between January 2012 and July 2014 with visual field defects secondary to ischemic cortical injury. The visual field defect pattern and mean deviation were analyzed. Retinal nerve fiber layer (RNFL and macular GCC were both assessed with spectral-domain optical coherence tomography. Patients with any ocular pathology that could affect these measurements were excluded. The topographic relationship of visual field defect to reduction in GCC was specifically analyzed. Results: Nine patients met the inclusion criteria. Their average age was 65 (57–73 years; eight were men and six had right hemianopsias. The laterality of the visual field defect was used to assign an affected and unaffected side of analysis for RNFL and GCC layer thickness. A right hemianopsia meant that the nasal fibers of the right eye and temporal fibers of the left eye were assigned as the “affected side”, and the temporal fibers of the right eye and nasal fibers of the left eye were assigned as “unaffected”. There was no statistically significant difference between affected and unaffected RNFL. However, there was a significant difference in GCC layer reduction between the affected and unaffected sides (P=0.029.Conclusion: There is evidence of retrograde trans-synaptic retinal ganglion cell loss in patients with homonymous hemianopsias from cortical visual impairment. This relationship is reflected in thinning of the GCC and maintains the topographic

  11. Decreased fixation stability of the preferred retinal location in juvenile macular degeneration.

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    Richard A I Bethlehem

    Full Text Available Macular degeneration is the main cause for diminished visual acuity in the elderly. The juvenile form of macular degeneration has equally detrimental consequences on foveal vision. To compensate for loss of foveal vision most patients with macular degeneration adopt an eccentric preferred retinal location that takes over tasks normally performed by the healthy fovea. It is unclear however, whether the preferred retinal locus also develops properties typical for foveal vision. Here, we investigated whether the fixation characteristics of the preferred retinal locus resemble those of the healthy fovea. For this purpose, we used the fixation-offset paradigm and tracked eye-position using a high spatial and temporal resolution infrared eye-tracker. The fixation-offset paradigm measures release from fixation under different fixation conditions and has been shown useful to distinguish between foveal and non-foveal fixation. We measured eye-movements in nine healthy age-matched controls and five patients with juvenile macular degeneration. In addition, we performed a simulation with the same task in a group of five healthy controls. Our results show that the preferred retinal locus does not adopt a foveal type of fixation but instead drifts further away from its original fixation and has overall increased fixation instability. Furthermore, the fixation instability is most pronounced in low frequency eye-movements representing a slow drift from fixation. We argue that the increased fixation instability cannot be attributed to fixation under an unnatural angle. Instead, diminished visual acuity in the periphery causes reduced oculomotor control and results in increased fixation instability.

  12. Progressive Retinal Degeneration and Accumulation of Autofluorescent Lipopigments in Progranulin Deficient Mice

    OpenAIRE

    Hafler, Brian P.; Klein, Zoe A.; Zhou, Z. Jimmy; Strittmatter, Stephen M.

    2014-01-01

    Prior investigations have shown that patients with neuronal ceroid lipofuscinosis (NCL) develop neurodegeneration characterized by vision loss, motor dysfunction, seizures, and often early death. Neuropathological analysis of patients with NCL shows accumulation of intracellular autofluorescent storage material, lipopigment, throughout neurons in the central nervous system including in the retina. A recent study of a sibling pair with adult onset NCL and retinal degeneration showed linkage to...

  13. Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

    OpenAIRE

    Ueda, Keiko; Zhao, Jin; Kim, Hye Jin; Sparrow, Janet R.

    2016-01-01

    Visual cycle adducts having bisretinoid structures accumulate in retinal pigment epithelial cells as lipofuscin. These light-sensitive compounds are implicated in disease mechanisms leading to visual impairment in some inherited and age-related forms of macular degeneration. The means by which these diretinal adducts impart chronic damage is not fully understood. By studying mice raised under varying levels of intraocular light and by analyzing mice treated with vitamin E, we provide evidence...

  14. Myelin vacuolation, optic neuropathy and retinal degeneration after closantel overdosage in sheep and in a goat.

    Science.gov (United States)

    van der Lugt, J J; Venter, I

    2007-01-01

    Toxicity of closantel, a halogenated salicylanilide anthelmintic, is described in 11 sheep and a goat, humanely killed 4-70 days after accidental overdosage. Status spongiosis of the cerebrum and cerebellum was present, its severity decreasing with time after treatment. Ultrastructurally, vacuoles in the cerebral white matter were seen to be intramyelinic due to splitting of myelin lamellae at the intraperiod lines, indicating myelin oedema. In the optic nerves, Wallerian degeneration and eventual fibrosis and atrophy of the nerves followed myelin vacuolation. Lesions in the optic nerves were particularly advanced in the intracanalicular portion, indicating a compressive neuropathy within the optic canal. Acute retinal lesions consisted of papilloedema, necrosis of the outer retinal layers (especially the photoreceptor layer), and retinal separation in tapetal and non-tapetal areas. In more chronic cases, the outer nuclear layer was diffusely attenuated and generally reduced to a single row of cells.

  15. Neuroprotective effects of the cannabinoid agonist HU210 on retinal degeneration.

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    Lax, Pedro; Esquiva, Gema; Altavilla, Cesare; Cuenca, Nicolás

    2014-03-01

    Cannabinoids have been demonstrated to exert neuroprotective effects on different types of neuronal insults. Here we have addressed the therapeutic potential of the synthetic cannabinoid HU210 on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model for autosomal dominant retinitis pigmentosa (RP). In P23H rats administered with HU210 (100 μg/kg, i.p.) from P24 to P90, ERG recordings showed an amelioration of vision loss, as compared to vehicle-administered animals. Under scotopic conditions, the maximum a-wave amplitudes recorded at P60 and P90 were higher in HU210-treated animals, as compared to the values obtained in untreated animals. The scotopic b-waves were significantly higher in treated animals than in untreated rats at P30, P60 and P90. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. HU210-treated animals had 40% more photoreceptors than untreated animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were also preserved in HU210-treated P23H rats. These results indicate that HU210 preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in P23H rats. These data suggest that cannabinoids are potentially useful to delay retinal degeneration in RP patients.

  16. AAV-mediated Gene Therapy Halts Retinal Degeneration in PDE6β-deficient Dogs.

    Science.gov (United States)

    Pichard, Virginie; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Hulin, Philippe; Tshilenge, Kizito-Tshitoko; Biget, Marine; Ameline, Baptiste; Deschamps, Jack-Yves; Weber, Michel; Le Meur, Guylène; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

    2016-05-01

    We previously reported that subretinal injection of AAV2/5 RK.cpde6β allowed long-term preservation of photoreceptor function and vision in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency. The present study builds on these earlier findings to provide a detailed assessment of the long-term effects of gene therapy on the spatiotemporal pattern of retinal degeneration in rcd1 dogs treated at 20 days of age. We analyzed the density distribution of the retinal layers and of particular photoreceptor cells in 3.5-year-old treated and untreated rcd1 dogs. Whereas no rods were observed outside the bleb or in untreated eyes, gene transfer halted rod degeneration in all vector-exposed regions. Moreover, while gene therapy resulted in the preservation of cones, glial cells and both the inner nuclear and ganglion cell layers, no cells remained in vector-unexposed retinas, except in the visual streak. Finally, the retinal structure of treated 3.5-year-old rcd1 dogs was identical to that of unaffected 4-month-old rcd1 dogs, indicating near complete preservation. Our findings indicate that gene therapy arrests the degenerative process even if intervention is initiated after the onset of photoreceptor degeneration, and point to significant potential of this therapeutic approach in future clinical trials.

  17. The relevance of chemokine signalling in modulating inherited and age-related retinal degenerations.

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    Luhmann, Ulrich Fo; Robbie, Scott J; Bainbridge, James Wb; Ali, Robin R

    2014-01-01

    Systemic monocytes, tissue resident macrophages, dendritic cells and microglia have specific roles in immune surveillance and maintenance of tissue homeostasis and are key regulator and effector cells of the local immune response to acute and chronic tissue injury.Two major signalling pathways that differentially define trafficking behaviour and activation of systemic and local myeloid cell populations in response to exogenous and endogenous inflammatory stimuli are the Ccl2-Ccr2 and the Cx3cl1-Cx3cr1 chemokine pathways.Alterations in these pathways have been implicated in controlling myeloid cell activation during normal ageing and in age-related retinal degenerations, including age-related macular degeneration (AMD).We review the evidence for how altered chemokine signalling in acute and chronic inflammatory conditions regulate local and systemic myeloid cell responses in the retina and how this may contribute to or attenuate pathology in inherited and age-related retinal diseases. We discuss the role of environmental factors (e.g. light exposure) and the influence of genetic factors on the manifestation of pathology in experimental models and in human patients and how we envisage harnessing this knowledge for the development of targeted, more broadly applicable anti-inflammatory treatment strategies for a wide range of retinal degenerations.

  18. Potential role of retinal pigment epithelial lipofuscin accumulation in age-related macular degeneration.

    Science.gov (United States)

    Katz, Martin L

    2002-01-01

    Age-related macular degeneration (AMD) is a leading cause of severe visual impairment in developed countries. The vision loss associated with AMD is the result of degenerative changes in the central region of the retina called the macula. Maintenance of normal structure and function of the macular retina, and of the remainder of the retina as well, is critically dependent on the supporting role of the adjacent retinal pigment epithelium (RPE). Impairment of normal RPE functions is known to result in retinal degeneration and loss of visual function. Thus, it has been hypothesized that the retinal degeneration that characterizes AMD is secondary to age-related deterioration in RPE support functions. Like many other postmitotic cell types, the RPE accumulates autofluorescent lysosomal storage bodies (lipofuscin) during senescence. In human eyes, lipofuscin comes to occupy a substantial fraction of the RPE cytoplasmic volume in the elderly. Does this lipofuscin accumulation contribute to the development of AMD? This question is a specific case of the broader question of whether lipofuscin accumulation in general is detrimental to cells. Unfortunately, definitive data do not exist to allow these questions to be answered. Although a correlation between RPE lipofuscin content and AMD has been reported, a cause-and-effect relationship between RPE lipofuscin accumulation and the development of this disease has not been established. It has been reported that a mutation in a gene encoding a photoreceptor-specific protein results in massive RPE lipofuscin accumulation and early-onset macular degeneration. However, again the accelerated RPE lipofuscin accumulation has not been shown to be the cause of the accompanying macular degeneration. The lack of a definitive link between RPE lipofuscin accumulation and AMD illustrates one of the biggest challenges remaining in lipofuscin research-determining whether lipofuscin accumulation per se has an impact on cell function.

  19. Loss of Ikbkap Causes Slow, Progressive Retinal Degeneration in a Mouse Model of Familial Dysautonomia

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    Ramirez, Grisela

    2016-01-01

    Abstract Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that is caused by a mutation in the gene for inhibitor of kappa B kinase complex-associated protein (IKBKAP). Although FD patients suffer from multiple neuropathies, a major debilitation that affects their quality of life is progressive blindness. To determine the requirement for Ikbkap in the developing and adult retina, we generated Ikbkap conditional knockout (CKO) mice using a TUBA1a promoter-Cre (Tα1-Cre). In the retina, Tα1-Cre expression is detected predominantly in retinal ganglion cells (RGCs). At 6 months, significant loss of RGCs had occurred in the CKO retinas, with the greatest loss in the temporal retina, which is the same spatial phenotype observed in FD, Leber hereditary optic neuropathy, and dominant optic atrophy. Interestingly, the melanopsin-positive RGCs were resistant to degeneration. By 9 months, signs of photoreceptor degeneration were observed, which later progressed to panretinal degeneration, including RGC and photoreceptor loss, optic nerve thinning, Müller glial activation, and disruption of layers. Taking these results together, we conclude that although Ikbkap is not required for normal development of RGCs, its loss causes a slow, progressive RGC degeneration most severely in the temporal retina, which is later followed by indirect photoreceptor loss and complete retinal disorganization. This mouse model of FD is not only useful for identifying the mechanisms mediating retinal degeneration, but also provides a model system in which to attempt to test therapeutics that may mitigate the loss of vision in FD patients. PMID:27699209

  20. Retinal Degeneration Triggers the Activation of YAP/TEAD in Reactive Müller Cells.

    Science.gov (United States)

    Hamon, Annaïg; Masson, Christel; Bitard, Juliette; Gieser, Linn; Roger, Jérôme E; Perron, Muriel

    2017-04-01

    During retinal degeneration, Müller glia cells respond to photoreceptor loss by undergoing reactive gliosis, with both detrimental and beneficial effects. Increasing our knowledge of the complex molecular response of Müller cells to retinal degeneration is thus essential for the development of new therapeutic strategies. The purpose of this work was to identify new factors involved in Müller cell response to photoreceptor cell death. Whole transcriptome sequencing was performed from wild-type and degenerating rd10 mouse retinas at P30. The changes in mRNA abundance for several differentially expressed genes were assessed by quantitative RT-PCR (RT-qPCR). Protein expression level and retinal cellular localization were determined by western blot and immunohistochemistry, respectively. Pathway-level analysis from whole transcriptomic data revealed the Hippo/YAP pathway as one of the main signaling pathways altered in response to photoreceptor degeneration in rd10 retinas. We found that downstream effectors of this pathway, YAP and TEAD1, are specifically expressed in Müller cells and that their expression, at both the mRNA and protein levels, is increased in rd10 reactive Müller glia after the onset of photoreceptor degeneration. The expression of Ctgf and Cyr61, two target genes of the transcriptional YAP/TEAD complex, is also upregulated following photoreceptor loss. This work reveals for the first time that YAP and TEAD1, key downstream effectors of the Hippo pathway, are specifically expressed in Müller cells. We also uncovered a deregulation of the expression and activity of Hippo/YAP pathway components in reactive Müller cells under pathologic conditions.

  1. Neuroprotective Effect of Tauroursodeoxycholic Acid on N-Methyl-D-Aspartate-Induced Retinal Ganglion Cell Degeneration.

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    Violeta Gómez-Vicente

    Full Text Available Retinal ganglion cell degeneration underlies the pathophysiology of diseases affecting the retina and optic nerve. Several studies have previously evidenced the anti-apoptotic properties of the bile constituent, tauroursodeoxycholic acid, in diverse models of photoreceptor degeneration. The aim of this study was to investigate the effects of systemic administration of tauroursodeoxycholic acid on N-methyl-D-aspartate (NMDA-induced damage in the rat retina using a functional and morphological approach. Tauroursodeoxycholic acid was administered intraperitoneally before and after intravitreal injection of NMDA. Three days after insult, full-field electroretinograms showed reductions in the amplitudes of the positive and negative-scotopic threshold responses, scotopic a- and b-waves and oscillatory potentials. Quantitative morphological evaluation of whole-mount retinas demonstrated a reduction in the density of retinal ganglion cells. Systemic administration of tauroursodeoxycholic acid attenuated the functional impairment induced by NMDA, which correlated with a higher retinal ganglion cell density. Our findings sustain the efficacy of tauroursodeoxycholic acid administration in vivo, suggesting it would be a good candidate for the pharmacological treatment of degenerative diseases coursing with retinal ganglion cell loss.

  2. Retinal degeneration progression changes lentiviral vector cell targeting in the retina.

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    Maritza Calame

    Full Text Available In normal mice, the lentiviral vector (LV is very efficient to target the RPE cells, but transduces retinal neurons well only during development. In the present study, the tropism of LV has been investigated in the degenerating retina of mice, knowing that the retina structure changes during degeneration. We postulated that the viral transduction would be increased by the alteration of the outer limiting membrane (OLM. Two different LV pseudotypes were tested using the VSVG and the Mokola envelopes, as well as two animal models of retinal degeneration: light-damaged Balb-C and Rhodopsin knockout (Rho-/- mice. After light damage, the OLM is altered and no significant increase of the number of transduced photoreceptors can be obtained with a LV-VSVG-Rhop-GFP vector. In the Rho-/- mice, an alteration of the OLM was also observed, but the possibility of transducing photoreceptors was decreased, probably by ongoing gliosis. The use of a ubiquitous promoter allows better photoreceptor transduction, suggesting that photoreceptor-specific promoter activity changes during late stages of photoreceptor degeneration. However, the number of targeted photoreceptors remains low. In contrast, LV pseudotyped with the Mokola envelope allows a wide dispersion of the vector into the retina (corresponding to the injection bleb with preferential targeting of Müller cells, a situation which does not occur in the wild-type retina. Mokola-pseudotyped lentiviral vectors may serve to engineer these glial cells to deliver secreted therapeutic factors to a diseased area of the retina.

  3. Human organotypic retinal cultures (HORCs) as a chronic experimental model for investigation of retinal ganglion cell degeneration.

    Science.gov (United States)

    Osborne, Andrew; Hopes, Marina; Wright, Phillip; Broadway, David C; Sanderson, Julie

    2016-02-01

    There is a growing need for models of human diseases that utilise native, donated human tissue in order to model disease processes and develop novel therapeutic strategies. In this paper we assessed the suitability of adult human retinal explants as a potential model of chronic retinal ganglion cell (RGC) degeneration. Our results confirmed that RGC markers commonly used in rodent studies (NeuN, βIII Tubulin and Thy-1) were appropriate for labelling human RGCs and followed the expected differential expression patterns across, as well as throughout, the macular and para-macular regions of the retina. Furthermore, we showed that neither donor age nor post-mortem time (within 24 h) significantly affected the initial expression levels of RGC markers. In addition, the feasibility of using human post mortem donor tissue as a long-term model of RGC degeneration was determined with RGC protein being detectable up to 4 weeks in culture with an associated decline in RGC mRNA and significant, progressive, apoptotic labelling of NeuN(+) cells. Differences in RGC apoptosis might have been influenced by medium compositions indicating that media constituents could play a role in supporting axotomised RGCs. We propose that using ex vivo human explants may prove to be a useful model for testing the effectiveness of neuroprotective strategies.

  4. Rescuing axons from degeneration does not affect retinal ganglion cell death

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    S. de Lima

    2016-01-01

    Full Text Available After a traumatic injury to the central nervous system, the distal stumps of axons undergo Wallerian degeneration (WD, an event that comprises cytoskeleton and myelin breakdown, astrocytic gliosis, and overexpression of proteins that inhibit axonal regrowth. By contrast, injured neuronal cell bodies show features characteristic of attempts to initiate the regenerative process of elongating their axons. The main molecular event that leads to WD is an increase in the intracellular calcium concentration, which activates calpains, calcium-dependent proteases that degrade cytoskeleton proteins. The aim of our study was to investigate whether preventing axonal degeneration would impact the survival of retinal ganglion cells (RGCs after crushing the optic nerve. We observed that male Wistar rats (weighing 200-400 g; n=18 treated with an exogenous calpain inhibitor (20 mM administered via direct application of the inhibitor embedded within the copolymer resin Evlax immediately following optic nerve crush showed a delay in the onset of WD. This delayed onset was characterized by a decrease in the number of degenerated fibers (P<0.05 and an increase in the number of preserved fibers (P<0.05 4 days after injury. Additionally, most preserved fibers showed a normal G-ratio. These results indicated that calpain inhibition prevented the degeneration of optic nerve fibers, rescuing axons from the process of axonal degeneration. However, analysis of retinal ganglion cell survival demonstrated no difference between the calpain inhibitor- and vehicle-treated groups, suggesting that although the calpain inhibitor prevented axonal degeneration, it had no effect on RGC survival after optic nerve damage.

  5. Persistent inflammatory state after photoreceptor loss in an animal model of retinal degeneration.

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    Noailles, Agustina; Maneu, Victoria; Campello, Laura; Gómez-Vicente, Violeta; Lax, Pedro; Cuenca, Nicolás

    2016-09-14

    Microglia act as the resident immune cells of the central nervous system, including the retina. In response to damaging stimuli microglia adopt an activated state, which can progress into a phagocytic phenotype and play a potentially harmful role by eliciting the expression and release of pro-inflammatory cytokines. The aim of the present study was to assess longitudinal changes in microglia during retinal degeneration in the homozygous P23H rat, a model of dominant retinitis pigmentosa. Microglial phenotypes, morphology and density were analyzed by immunohistochemistry, flow cytometry, and cytokine antibody array. In addition, we performed electroretinograms to evaluate the retinal response. In the P23H retina, sclera, choroid and ciliary body, inflammatory cells increased in number compared with the control at all ages analyzed. As the rats became older, a higher number of amoeboid MHC-II(+) cells were observed in the P23H retina, which correlated with an increase in the expression of pro-inflammatory cytokines. These findings suggest that, in the P23H model, retinal neuroinflammation persists throughout the rat's life span even after photoreceptor depletion. Therefore, the inclusion of anti-inflammatory drugs at advanced stages of the neurodegenerative process may provide better retinal fitness so the remaining cells could still be used as targets of cellular or gene therapies.

  6. Dietary supplement enriched in antioxidants and omega-3 protects from progressive light-induced retinal degeneration.

    Directory of Open Access Journals (Sweden)

    Khaoula Ramchani-Ben Othman

    Full Text Available In the present study, we have evaluated one of the dietary supplements enriched with antioxidants and fish oil used in clinical care for patient with age-related macular degeneration. Rats were orally fed by a gastric canula daily with 0.2 ml of water or dietary supplement until they were sacrificed. After one week of treatment, animals were either sacrificed for lipid analysis in plasma and retina, or used for evaluation of rod-response recovery by electroretinography (ERG followed by their sacrifice to measure rhodopsin content, or used for progressive light-induced retinal degeneration (PLIRD. For PLIRD, animals were transferred to bright cyclic light for one week. Retinal damage was quantified by ERG, histology and detection of apoptotic nuclei. Animals kept in dim-cyclic-light were processed in parallel. PLIRD induced a thinning of the outer nuclear layer and a reduction of the b-wave amplitude of the ERG in the water group. Retinal structure and function were preserved in supplemented animals. Supplement induced a significant increase in omega-3 fatty acids in plasma by 168% for eicosapentaenoic acid (EPA, 142% for docosapentaenoic acid (DPA and 19% for docosahexaenoic acid (DHA and a decrease in the omega-6 fatty acids, DPA by 28%. In the retina, supplement induced significant reduction of linolenic acid by 67% and an increase in EPA and DPA by 80% and 72%, respectively, associated with significant decrease in omega-6 DPA by 42%. Supplement did not affect rhodopsin content or rod-response recovery. The present data indicate that supplement rapidly modified the fatty acid content and induced an accumulation of EPA in the retina without affecting rhodopsin content or recovery. In addition, it protected the retina from oxidative stress induced by light. Therefore, this supplement might be beneficial to slow down progression of certain retinal degeneration.

  7. Dietary Supplement Enriched in Antioxidants and Omega-3 Protects from Progressive Light-Induced Retinal Degeneration

    Science.gov (United States)

    Ramchani-Ben Othman, Khaoula; Cercy, Christine; Amri, Mohamed; Doly, Michel; Ranchon-Cole, Isabelle

    2015-01-01

    In the present study, we have evaluated one of the dietary supplements enriched with antioxidants and fish oil used in clinical care for patient with age-related macular degeneration. Rats were orally fed by a gastric canula daily with 0.2 ml of water or dietary supplement until they were sacrificed. After one week of treatment, animals were either sacrificed for lipid analysis in plasma and retina, or used for evaluation of rod-response recovery by electroretinography (ERG) followed by their sacrifice to measure rhodopsin content, or used for progressive light-induced retinal degeneration (PLIRD). For PLIRD, animals were transferred to bright cyclic light for one week. Retinal damage was quantified by ERG, histology and detection of apoptotic nuclei. Animals kept in dim-cyclic-light were processed in parallel. PLIRD induced a thinning of the outer nuclear layer and a reduction of the b-wave amplitude of the ERG in the water group. Retinal structure and function were preserved in supplemented animals. Supplement induced a significant increase in omega-3 fatty acids in plasma by 168% for eicosapentaenoic acid (EPA), 142% for docosapentaenoic acid (DPA) and 19% for docosahexaenoic acid (DHA) and a decrease in the omega-6 fatty acids, DPA by 28%. In the retina, supplement induced significant reduction of linolenic acid by 67% and an increase in EPA and DPA by 80% and 72%, respectively, associated with significant decrease in omega-6 DPA by 42%. Supplement did not affect rhodopsin content or rod-response recovery. The present data indicate that supplement rapidly modified the fatty acid content and induced an accumulation of EPA in the retina without affecting rhodopsin content or recovery. In addition, it protected the retina from oxidative stress induced by light. Therefore, this supplement might be beneficial to slow down progression of certain retinal degeneration. PMID:26042773

  8. Improvement in vision: a new goal for treatment of hereditary retinal degenerations.

    Science.gov (United States)

    Jacobson, Samuel G; Cideciyan, Artur V; Aguirre, Gustavo D; Roman, Alejandro J; Sumaroka, Alexander; Hauswirth, William W; Palczewski, Krzysztof

    2015-05-04

    Introduction: Inherited retinal degenerations (IRDs) have long been considered untreatable and incurable. Recently, one form of early-onset autosomal recessive IRD, Leber congenital amaurosis (LCA) caused by mutations in RPE65 (retinal pigment epithelium-specific protein 65 kDa) gene, has responded with some improvement of vision to gene augmentation therapy and oral retinoid administration. This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances. Areas covered: Progress toward human therapy for RPE65-LCA is detailed from the understanding of molecular mechanisms to preclinical proof-of-concept research to clinical trials. Unexpected positive and complicating results in the patients receiving treatment are explained. Logical next steps to advance the clinical value of the therapeutics are suggested. Expert opinion: The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space. Yet, there are features of the gene augmentation therapeutic response, such as slowed kinetics of night vision, lack of foveal cone function improvement and relentlessly progressive retinal degeneration despite therapy, that still require research attention.

  9. Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration.

    Directory of Open Access Journals (Sweden)

    Glenn P Lobo

    Full Text Available Inherited retinal disorders (IRDs result in severe visual impairments in children and adults. A challenge in the field of retinal degenerations is identifying mechanisms of photoreceptor cell death related to specific genetic mutations. Mutations in the gene TULP1 have been associated with two forms of IRDs, early-onset retinitis pigmentosa (RP and Leber congenital amaurosis (LCA. TULP1 is a cytoplasmic, membrane-associated protein shown to be involved in transportation of newly synthesized proteins destined for the outer segment compartment of photoreceptor cells; however, how mutant TULP1 causes cell death is not understood. In this study, we provide evidence that common missense mutations in TULP1 express as misfolded protein products that accumulate within the endoplasmic reticulum (ER causing prolonged ER stress. In an effort to maintain protein homeostasis, photoreceptor cells then activate the unfolded protein response (UPR complex. Our results indicate that the two major apoptotic arms of the UPR pathway, PERK and IRE1, are activated. Additionally, we show that retinas expressing mutant TULP1 significantly upregulate the expression of CHOP, a UPR signaling protein promoting apoptosis, and undergo photoreceptor cell death. Our study demonstrates that the ER-UPR, a known mechanism of apoptosis secondary to an overwhelming accumulation of misfolded protein, is involved in photoreceptor degeneration caused by missense mutations in TULP1. These observations suggest that modulating the UPR pathways might be a strategy for therapeutic intervention.

  10. X-82 to Treat Age-related Macular Degeneration

    Science.gov (United States)

    2017-01-12

    Age-Related Macular Degeneration (AMD); Macular Degeneration; Exudative Age-related Macular Degeneration; AMD; Macular Degeneration, Age-related, 10; Eye Diseases; Retinal Degeneration; Retinal Diseases

  11. Interactions of Prosthetic and Natural Vision in Animals With Local Retinal Degeneration

    Science.gov (United States)

    Lorach, Henri; Lei, Xin; Galambos, Ludwig; Kamins, Theodore; Mathieson, Keith; Dalal, Roopa; Huie, Philip; Harris, James; Palanker, Daniel

    2015-01-01

    Purpose Prosthetic restoration of partial sensory loss leads to interactions between artificial and natural inputs. Ideally, the rehabilitation should allow perceptual fusion of the two modalities. Here we studied the interactions between normal and prosthetic vision in a rodent model of local retinal degeneration. Methods Implantation of a photovoltaic array in the subretinal space of normally sighted rats induced local degeneration of the photoreceptors above the chip, and the inner retinal neurons in this area were electrically stimulated by the photovoltaic implant powered by near-infrared (NIR) light. We studied prosthetic and natural visually evoked potentials (VEP) in response to simultaneous stimulation by NIR and visible light patterns. Results We demonstrate that electrical and natural VEPs summed linearly in the visual cortex, and both responses decreased under brighter ambient light. Responses to visible light flashes increased over 3 orders of magnitude of contrast (flash/background), while for electrical stimulation the contrast range was limited to 1 order of magnitude. The maximum amplitude of the prosthetic VEP was three times lower than the maximum response to a visible flash over the same area on the retina. Conclusions Ambient light affects prosthetic responses, albeit much less than responses to visible stimuli. Prosthetic representation of contrast in the visual scene can be encoded, to a limited extent, by the appropriately calibrated stimulus intensity, which also depends on the ambient light conditions. Such calibration will be important for patients combining central prosthetic vision with natural peripheral sight, such as in age-related macular degeneration. PMID:26618643

  12. Reorganization of visual processing in macular degeneration is not specific to the "preferred retinal locus".

    Science.gov (United States)

    Dilks, Daniel D; Baker, Chris I; Peli, Eli; Kanwisher, Nancy

    2009-03-04

    Recent work has shown that foveal cortex, deprived of its normal bottom-up input as a result of macular degeneration (MD), begins responding to stimuli presented to a peripheral retinal location. However, these studies have only presented stimuli to the "preferred retinal location," or PRL, a spared part of the peripheral retina used by individuals with MD for fixating, face recognition, reading, and other visual tasks. Thus, previous research has not yet answered a question critical for understanding the mechanisms underlying this reorganization: Does formerly foveal cortex respond only to stimuli presented at the PRL, or does it also respond to other peripheral locations of similar eccentricity? If foveal cortex responds to stimuli at PRL because it is the long-term habitual use of this region as a functional fovea that drives the formerly foveal cortex to respond to stimuli presented at the PRL (the "use-dependent reorganization" hypothesis), then foveal cortex will not respond to stimuli presented at other locations. Alternatively, it may be that foveal cortex responds to any peripheral retinal input, independent of whether input at that retinal location has been chronically attended for months or years (the "use-independent reorganization" hypothesis). Using fMRI, we found clear activation of formerly foveal cortex to stimuli presented at either the PRL or an isoeccentric non-PRL location in two individuals with MD, supporting the use-independent reorganization hypothesis. This finding suggests that reorganization is driven by passive, not use-dependent mechanisms.

  13. Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration

    Science.gov (United States)

    Kimura, Atsuko; Namekata, Kazuhiko; Guo, Xiaoli; Harada, Chikako; Harada, Takayuki

    2016-01-01

    Neurotrophic factors play key roles in the development and survival of neurons. The potent neuroprotective effects of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF), suggest that they are good therapeutic candidates for neurodegenerative diseases. Glaucoma is a neurodegenerative disease of the eye that causes irreversible blindness. It is characterized by damage to the optic nerve, usually due to high intraocular pressure (IOP), and progressive degeneration of retinal neurons called retinal ganglion cells (RGCs). Current therapy for glaucoma focuses on reduction of IOP, but neuroprotection may also be beneficial. BDNF is a powerful neuroprotective agent especially for RGCs. Exogenous application of BDNF to the retina and increased BDNF expression in retinal neurons using viral vector systems are both effective in protecting RGCs from damage. Furthermore, induction of BDNF expression by agents such as valproic acid has also been beneficial in promoting RGC survival. In this review, we discuss the therapeutic potential of neurotrophic factors in retinal diseases and focus on the differential roles of glial and neuronal TrkB in neuroprotection. We also discuss the role of neurotrophic factors in neuroregeneration. PMID:27657046

  14. Investigating the Molecular Basis of Retinal Degeneration in a Familial Cohort of Pakistani Decent by Exome Sequencing.

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    Bruno Maranhao

    Full Text Available To define the molecular basis of retinal degeneration in consanguineous Pakistani pedigrees with early onset retinal degeneration.A cohort of 277 individuals representing 26 pedigrees from the Punjab province of Pakistan was analyzed. Exomes were captured with commercial kits and sequenced on an Illumina HiSeq 2500. Candidate variants were identified using standard tools and analyzed using exomeSuite to detect all potentially pathogenic changes in genes implicated in retinal degeneration. Segregation analysis was performed by dideoxy sequencing and novel variants were additionally investigated for their presence in ethnicity-matched controls.We identified a total of nine causal mutations, including six novel variants in RPE65, LCA5, USH2A, CNGB1, FAM161A, CERKL and GUCY2D as the underlying cause of inherited retinal degenerations in 13 of 26 pedigrees. In addition to the causal variants, a total of 200 variants each observed in five or more unrelated pedigrees investigated in this study that were absent from the dbSNP, HapMap, 1000 Genomes, NHLBI ESP6500, and ExAC databases were identified, suggesting that they are common in, and unique to the Pakistani population.We identified causal mutations associated with retinal degeneration in nearly half of the pedigrees investigated in this study through next generation whole exome sequencing. All novel variants detected in this study through exome sequencing have been cataloged providing a reference database of variants common in, and unique to the Pakistani population.

  15. Effects of combined ketamine/xylazine anesthesia on light induced retinal degeneration in rats.

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    Blanca Arango-Gonzalez

    Full Text Available OBJECTIVES: To explore the effect of ketamine-xylazine anesthesia on light-induced retinal degeneration in rats. METHODS: Rats were anesthetized with ketamine and xylazine (100 and 5 mg, respectively for 1 h, followed by a recovery phase of 2 h before exposure to 16,000 lux of environmental illumination for 2 h. Functional assessment by electroretinography (ERG and morphological assessment by in vivo imaging (optical coherence tomography, histology (hematoxylin/eosin staining, TUNEL assay and immunohistochemistry (GFAP and rhodopsin staining were performed at baseline (ERG, 36 h, 7 d and 14 d post-treatment. Non-anesthetized animals treated with light damage served as controls. RESULTS: Ketamine-xylazine pre-treatment preserved retinal function and protected against light-induced retinal degeneration. In vivo retinal imaging demonstrated a significant increase of outer nuclear layer (ONL thickness in the non-anesthetized group at 36 h (p0.05, indicating a stabilizing and/or protective effect with regard to phototoxicity. Histology confirmed light-induced photoreceptor cell death and Müller cells gliosis in non-anesthetized rats, especially in the superior hemiretina, while ketamine-xylazine treated rats showed reduced photoreceptor cell death (TUNEL staining: p<0.001 after 7 d, thicker ONL and longer IS/OS. Fourteen days after light damage, a reduction of standard flash induced a-wave amplitudes and a-wave slopes (p = 0.01 and significant alterations in parameters of the scotopic sensitivity function (e.g. Vmax of the Naka Rushton fit p = 0.03 were observed in non-treated vs. ketamine-xylazine treated animals. CONCLUSIONS: Our results suggest that pre-treatment with ketamine-xylazine anesthesia protects retinas against light damage, reducing photoreceptor cell death. These data support the notion that anesthesia with ketamine-xylazine provides neuroprotective effects in light-induced cell damage.

  16. Effects of Combined Ketamine/Xylazine Anesthesia on Light Induced Retinal Degeneration in Rats

    Science.gov (United States)

    Bolz, Sylvia; Eslava-Schmalbach, Javier; Willmann, Gabriel; Zhour, Ahmad; Zrenner, Eberhart; Fischer, M. Dominik; Gekeler, Florian

    2012-01-01

    Objectives To explore the effect of ketamine-xylazine anesthesia on light-induced retinal degeneration in rats. Methods Rats were anesthetized with ketamine and xylazine (100 and 5 mg, respectively) for 1 h, followed by a recovery phase of 2 h before exposure to 16,000 lux of environmental illumination for 2 h. Functional assessment by electroretinography (ERG) and morphological assessment by in vivo imaging (optical coherence tomography), histology (hematoxylin/eosin staining, TUNEL assay) and immunohistochemistry (GFAP and rhodopsin staining) were performed at baseline (ERG), 36 h, 7 d and 14 d post-treatment. Non-anesthetized animals treated with light damage served as controls. Results Ketamine-xylazine pre-treatment preserved retinal function and protected against light-induced retinal degeneration. In vivo retinal imaging demonstrated a significant increase of outer nuclear layer (ONL) thickness in the non-anesthetized group at 36 h (p0.05), indicating a stabilizing and/or protective effect with regard to phototoxicity. Histology confirmed light-induced photoreceptor cell death and Müller cells gliosis in non-anesthetized rats, especially in the superior hemiretina, while ketamine-xylazine treated rats showed reduced photoreceptor cell death (TUNEL staining: p<0.001 after 7 d), thicker ONL and longer IS/OS. Fourteen days after light damage, a reduction of standard flash induced a-wave amplitudes and a-wave slopes (p = 0.01) and significant alterations in parameters of the scotopic sensitivity function (e.g. Vmax of the Naka Rushton fit p = 0.03) were observed in non-treated vs. ketamine-xylazine treated animals. Conclusions Our results suggest that pre-treatment with ketamine-xylazine anesthesia protects retinas against light damage, reducing photoreceptor cell death. These data support the notion that anesthesia with ketamine-xylazine provides neuroprotective effects in light-induced cell damage. PMID:22558200

  17. Neuroprotective effects of the cannabinoid agonist HU210 on retinal degeneration

    OpenAIRE

    Lax Zapata, Pedro; Esquiva Sobrino, Gema; Altavilla, Cesare; Cuenca Navarro, Nicolás

    2014-01-01

    Cannabinoids have been demonstrated to exert neuroprotective effects on different types of neuronal insults. Here we have addressed the therapeutic potential of the synthetic cannabinoid HU210 on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model for autosomal dominant retinitis pigmentosa (RP). In P23H rats administered with HU210 (100 μg/kg, i.p.) from P24 to P90, ERG recordings showed an amelioration of vision...

  18. Acute and Protracted Cell Death in Light-Induced Retinal Degeneration in the Canine Model of Rhodopsin Autosomal Dominant Retinitis Pigmentosa.

    Science.gov (United States)

    Sudharsan, Raghavi; Simone, Kristina M; Anderson, Nathan P; Aguirre, Gustavo D; Beltran, William A

    2017-01-01

    To characterize a light damage paradigm and establish structural and immunocytochemical measures of acute and protracted light-induced retinal degeneration in the rhodopsin (RHO) T4R dog model of RHO-autosomal dominant retinitis pigmentosa (ADRP). Retinal light damage was induced in mutant dogs with a 1-minute exposure to various light intensities (0.1-1.0 mW/cm2) delivered with a Ganzfeld stimulator, or by fundus photography. Photoreceptor cell death was assessed by TUNEL assay, and alterations in retinal layers were examined by histology and immunohistochemistry 24 hours and 2 weeks after light exposure. Detailed topographic maps were made to document changes in the outer retinal layers of all four retinal quadrants 2 weeks post exposure. Twenty-four hours post light exposure, the severity of photoreceptor cell death was dose dependent. Immunohistochemical analysis revealed disruption of rod outer segments, focal loss of the RPE integrity, and an increase in expression of endothelin receptor B in Müller cells with the two highest doses of light and fundus photography. Two weeks after light exposure, persistence of photoreceptor death, thinning of the outer nuclear layer, and induction of Müller cell gliosis occurred with the highest doses of light. We have characterized outcome measures of acute and continuing retinal degeneration in the RHO T4R dog following light exposure. These will be used to assess the molecular mechanisms of light-induced damage and rescue strategies in this large animal model of RHO-ADRP.

  19. Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium.

    Science.gov (United States)

    Yao, Jingyu; Jia, Lin; Khan, Naheed; Lin, Chengmao; Mitter, Sayak K; Boulton, Michael E; Dunaief, Joshua L; Klionsky, Daniel J; Guan, Jun-Lin; Thompson, Debra A; Zacks, David N

    2015-01-01

    Autophagy regulates cellular homeostasis and response to environmental stress. Within the retinal pigment epithelium (RPE) of the eye, the level of autophagy can change with both age and disease. The purpose of this study is to determine the relationship between reduced autophagy and age-related degeneration of the RPE. The gene encoding RB1CC1/FIP200 (RB1-inducible coiled-coil 1), a protein essential for induction of autophagy, was selectively knocked out in the RPE by crossing Best1-Cre mice with mice in which the Rb1cc1 gene was flanked with Lox-P sites (Rb1cc1(flox/flox)). Ex vivo and in vivo analyses, including western blot, immunohistochemistry, transmission electron microscopy, fundus photography, optical coherence tomography, fluorescein angiography, and electroretinography were performed to assess the structure and function of the retina as a function of age. Deletion of Rb1cc1 resulted in multiple autophagy defects within the RPE including decreased conversion of LC3-I to LC3-II, accumulation of autophagy-targeted precursors, and increased numbers of mitochondria. Age-dependent degeneration of the RPE occurred, with formation of atrophic patches, subretinal migration of activated microglial cells, subRPE deposition of inflammatory and oxidatively damaged proteins, subretinal drusenoid deposits, and occasional foci of choroidal neovascularization. There was secondary loss of photoreceptors overlying the degenerated RPE and reduction in the electroretinogram. These observations are consistent with a critical role of autophagy in the maintenance of normal homeostasis in the aging RPE, and indicate that disruption of autophagy leads to retinal phenotypes associated with age-related degeneration.

  20. Epiretinal transplantation of human bone marrow mesenchymal stem cells rescues retinal and vision function in a rat model of retinal degeneration

    Directory of Open Access Journals (Sweden)

    Adi Tzameret

    2015-09-01

    Our findings suggest that transplantation of hBM-MSCs as a thin epiretinal layer is effective for treatment of retinal degeneration in RCS rats, and that transplanting the cells in close proximity to the retina enhances hBM-MSC therapeutic effect compared with intravitreal injection.

  1. Altered glial gene expression, density, and architecture in the visual cortex upon retinal degeneration.

    Science.gov (United States)

    Cornett, Ashley; Sucic, Joseph F; Hillsburg, Dylan; Cyr, Lindsay; Johnson, Catherine; Polanco, Anthony; Figuereo, Joe; Cabine, Kenneth; Russo, Nickole; Sturtevant, Ann; Jarvinen, Michael K

    2011-11-08

    Genes encoding the proteins of cytoskeletal intermediate filaments (IF) are tightly regulated, and they are important for establishing neural connections. However, it remains uncertain to what extent neurological disease alters IF gene expression or impacts cells that express IFs. In this study, we determined the onset of visual deficits in a mouse model of progressive retinal degeneration (Pde6b(-) mice; Pde6b(+) mice have normal vision) by observing murine responses to a visual task throughout development, from postnatal day (PND) 21 to adult (N=174 reliable observations). Using Q-PCR, we evaluated whether expression of the genes encoding two Type III IF proteins, glial fibrillary acidic protein (GFAP) and vimentin was altered in the visual cortex before, during, and after the onset of visual deficits. Using immunohistochemical techniques, we investigated the impact of vision loss on the density and morphology of astrocytes that expressed GFAP and vimentin in the visual cortex. We found that Pde6b(-) mice displayed 1) evidence of blindness at PND 49, with visual deficits detected at PND 35, 2) reduced GFAP mRNA expression in the visual cortex between PND 28 and PND 49, and 3) an increased ratio of vimentin:GFAP-labeled astrocytes at PND 49 with reduced GFAP cell body area. Together, these findings demonstrate that retinal degeneration modifies cellular and molecular indices of glial plasticity in a visual system with drastically reduced visual input. The functional consequences of these structural changes remain uncertain.

  2. Combining neuroprotectants in a model of retinal degeneration: no additive benefit.

    Directory of Open Access Journals (Sweden)

    Fabiana Di Marco

    Full Text Available The central nervous system undergoing degeneration can be stabilized, and in some models can be restored to function, by neuroprotective treatments. Photobiomodulation (PBM and dietary saffron are distinctive as neuroprotectants in that they upregulate protective mechanisms, without causing measurable tissue damage. This study reports a first attempt to combine the actions of PBM and saffron. Our working hypothesis was that the actions of PBM and saffron in protecting retinal photoreceptors, in a rat light damage model, would be additive. Results confirmed the neuroprotective potential of each used separately, but gave no evidence that their effects are additive. Detailed analysis suggests that there is actually a negative interaction between PBM and saffron when given simultaneously, with a consequent reduction of the neuroprotection. Specific testing will be required to understand the mechanisms involved and to establish whether there is clinical potential in combining neuroprotectants, to improve the quality of life of people affected by retinal pathology, such as age-related macular degeneration, the major cause of blindness and visual impairment in older adults.

  3. Complement System in Pathogenesis of AMD: Dual Player in Degeneration and Protection of Retinal Tissue

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    Milosz P. Kawa

    2014-01-01

    Full Text Available Age-related macular degeneration (AMD is the most common cause of blindness among the elderly, especially in Western countries. Although the prevalence, risk factors, and clinical course of the disease are well described, its pathogenesis is not entirely elucidated. AMD is associated with a variety of biochemical abnormalities, including complement components deposition in the retinal pigment epithelium-Bruch’s membrane-choriocapillaris complex. Although the complement system (CS is increasingly recognized as mediating important roles in retinal biology, its particular role in AMD pathogenesis has not been precisely defined. Unrestricted activation of the CS following injury may directly damage retinal tissue and recruit immune cells to the vicinity of active complement cascades, therefore detrimentally causing bystander damage to surrounding cells and tissues. On the other hand, recent evidence supports the notion that an active complement pathway is a necessity for the normal maintenance of the neurosensory retina. In this scenario, complement activation appears to have beneficial effect as it promotes cell survival and tissue remodeling by facilitating the rapid removal of dying cells and resulting cellular debris, thus demonstrating anti-inflammatory and neuroprotective activities. In this review, we discuss both the beneficial and detrimental roles of CS in degenerative retina, focusing on the diverse aspects of CS functions that may promote or inhibit macular disease.

  4. Complement system in pathogenesis of AMD: dual player in degeneration and protection of retinal tissue.

    Science.gov (United States)

    Kawa, Milosz P; Machalinska, Anna; Roginska, Dorota; Machalinski, Boguslaw

    2014-01-01

    Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly, especially in Western countries. Although the prevalence, risk factors, and clinical course of the disease are well described, its pathogenesis is not entirely elucidated. AMD is associated with a variety of biochemical abnormalities, including complement components deposition in the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex. Although the complement system (CS) is increasingly recognized as mediating important roles in retinal biology, its particular role in AMD pathogenesis has not been precisely defined. Unrestricted activation of the CS following injury may directly damage retinal tissue and recruit immune cells to the vicinity of active complement cascades, therefore detrimentally causing bystander damage to surrounding cells and tissues. On the other hand, recent evidence supports the notion that an active complement pathway is a necessity for the normal maintenance of the neurosensory retina. In this scenario, complement activation appears to have beneficial effect as it promotes cell survival and tissue remodeling by facilitating the rapid removal of dying cells and resulting cellular debris, thus demonstrating anti-inflammatory and neuroprotective activities. In this review, we discuss both the beneficial and detrimental roles of CS in degenerative retina, focusing on the diverse aspects of CS functions that may promote or inhibit macular disease.

  5. Electrophysiological assessment of retinal function during 6 months of bevacizumab treatment in neovascular age-related macular degeneration

    DEFF Research Database (Denmark)

    Pedersen, Karen Bjerg; Møller, Flemming; Sjølie, Anne Katrin;

    2010-01-01

    PURPOSE: The purpose of this study was to assess the alteration of retinal function by multifocal electroretinography and full-field electroretinography in patients with age-related macular degeneration treated with bevacizumab. METHODS: We performed a prospective pilot study of 26 eyes of 26...

  6. Repeatability of swept-source optical coherence tomography retinal and choroidal thickness measurements in neovascular age-related macular degeneration

    DEFF Research Database (Denmark)

    Hanumunthadu, Daren; Ilginis, Tomas; Restori, Marie

    2017-01-01

    BACKGROUND: The aim was to determine the intrasession repeatability of swept-source optical coherence tomography (SS-OCT)-derived retinal and choroidal thickness measurements in eyes with neovascular age-related macular degeneration (nAMD). METHODS: A prospective study consisting of patients with...

  7. Analysis of the RPE sheet in the rd10 retinal degeneration model

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Yi [Los Alamos National Laboratory

    2011-01-04

    The normal RPE sheet in the C57Bl/6J mouse is subclassified into two major tiling patterns: A regular generally hexagonal array covering most of the surface and a 'soft network' near the ciliary body made of irregularly shaped cells. Physics models predict these two patterns based on contractility and elasticity of the RPE cell, and strength of cellular adhesion between cells. We hypothesized and identified major changes in RPE regular hexagonal tiling pattern in rdl0 compared to C57BL/6J mice. RPE sheet damage was extensive but occurred in rd10 later than expected, after most retinal degeneration. RPE sheet changes occur in zones with a bullseye pattern. In the posterior zone around the optic nerve RPE cells take on larger irregular and varied shapes to form an intact monolayer. In mid periphery, there is a higher than normal density of cells that progress into involuted layers of RPE under the retina. The periphery remains mostly normal until late stages of degeneration. The number of neighboring cells varies widely depending on zone and progression. RPE morphology continues to deteriorate long after the photoreceptors have degenerated. The RPE cells are bystanders to the rd10 degeneration within photo receptors, and the collateral damage to the RPE sheet resembles stimulation of migration or chemotaxis. Quantitative measures of the tiling patterns and histopathology detected here, scripted in a pipeline written in Perl and Cell Profiler (an open source Matlab plugin), are directly applicable to RPE sheet images from noninvasive fundus autofluorescence (FAF), adaptive optics confocal scanning laser ophthalmoscope (AO-cSLO), and spectral domain optical coherence tomography (SD-OCT) of patients with early stage AMD or RP.

  8. Protective Effect of Proanthocyanidins from Sea Buckthorn (Hippophae Rhamnoides L.) Seed against Visible Light-Induced Retinal Degeneration in Vivo.

    Science.gov (United States)

    Wang, Yong; Zhao, Liang; Huo, Yazhen; Zhou, Feng; Wu, Wei; Lu, Feng; Yang, Xue; Guo, Xiaoxuan; Chen, Peng; Deng, Qianchun; Ji, Baoping

    2016-05-02

    Dietary proanthocyanidins (PACs) as health-protective agents have become an important area of human nutrition research because of their potent bioactivities. We investigated the retinoprotective effects of PACs from sea buckthorn (Hippophae rhamnoides L.) seed against visible light-induced retinal degeneration in vivo. Pigmented rabbits were orally administered sea buckthorn seed PACs (50 and 100 mg/kg/day) for 14 consecutive days of pre-illumination and seven consecutive days of post-illumination. Retinal function was quantified via electroretinography 7 days after light exposure. Retinal damage was evaluated by measuring the thickness of the full-thickness retina and outer nuclear layer 7 days after light exposure. Sea buckthorn seed PACs significantly attenuated the destruction of electroretinograms and maintained the retinal structure. Increased retinal photooxidative damage was expressed by the depletion of glutathione peroxidase and catalase activities, the decrease of total antioxidant capacity level and the increase of malondialdehyde level. Light exposure induced a significant increase of inflammatory cytokines (IL-1β, TNF-α and IL-6) and angiogenesis (VEGF) levels in retina. Light exposure upregulated the expression of pro-apoptotic proteins Bax and caspase-3 and downregulated the expression of anti-apoptotic protein Bcl-2. However, sea buckthorn seed PACs ameliorated these changes induced by light exposure. Sea buckthorn seed PACs mediated the protective effect against light-induced retinal degeneration via antioxidant, anti-inflammatory and antiapoptotic mechanisms.

  9. Protective Effect of Proanthocyanidins from Sea Buckthorn (Hippophae Rhamnoides L. Seed against Visible Light-Induced Retinal Degeneration in Vivo

    Directory of Open Access Journals (Sweden)

    Yong Wang

    2016-05-01

    Full Text Available Dietary proanthocyanidins (PACs as health-protective agents have become an important area of human nutrition research because of their potent bioactivities. We investigated the retinoprotective effects of PACs from sea buckthorn (Hippophae rhamnoides L. seed against visible light-induced retinal degeneration in vivo. Pigmented rabbits were orally administered sea buckthorn seed PACs (50 and 100 mg/kg/day for 14 consecutive days of pre-illumination and seven consecutive days of post-illumination. Retinal function was quantified via electroretinography 7 days after light exposure. Retinal damage was evaluated by measuring the thickness of the full-thickness retina and outer nuclear layer 7 days after light exposure. Sea buckthorn seed PACs significantly attenuated the destruction of electroretinograms and maintained the retinal structure. Increased retinal photooxidative damage was expressed by the depletion of glutathione peroxidase and catalase activities, the decrease of total antioxidant capacity level and the increase of malondialdehyde level. Light exposure induced a significant increase of inflammatory cytokines (IL-1β, TNF-α and IL-6 and angiogenesis (VEGF levels in retina. Light exposure upregulated the expression of pro-apoptotic proteins Bax and caspase-3 and downregulated the expression of anti-apoptotic protein Bcl-2. However, sea buckthorn seed PACs ameliorated these changes induced by light exposure. Sea buckthorn seed PACs mediated the protective effect against light-induced retinal degeneration via antioxidant, anti-inflammatory and antiapoptotic mechanisms.

  10. Optical coherence tomography (OCT) in hereditary retinal degenerations: Layer-by-layer analyses in normal and diseased retinas

    Science.gov (United States)

    Huang, Yijun

    OCT is a new technique for non-invasive, non-contact, cross-sectional imaging of biological tissues with micrometer longitudinal resolution. As it applies to the field of ophthalmology, OCT can delineate retinal sublayers based on their backscattering characteristics, and permit quantitative measurement of the structure of retina in vivo. This dissertation intended to clarify the basis of the OCT signals and whether this procedure has potential for diagnosis and monitoring of human retinal degenerative diseases. Key to this goal are quantitation of OCT signal features and accurate, layer-by-layer correlation of these features with underlying retinal microanatomy. In normal and degenerate avian and swine retinas, OCT signal features were quantified using custom computer programs, and were correlated with cryosections of unfixed retinas obtained at the same retinal location. The results suggested a definable and quantifiable relationship between OCT signal components and retinal microanatomy. The correlation in the outer retina indicated that the OCT posterior highly reflective band, or the outer- retina-choroid complex (ORCC), is attributable to the photoreceptor layer, RPE, and anterior choroid. Further evidence of OCT signal origin was provided by the rd chicken and the rhodopsin P347L mutant transgenic swine. In these animals where photoreceptors had degenerated, OCT abnormalities were observed at the level of and vitreal to the ORCC, consistent with the hypothesis that photoreceptors contribute to the ORCC. Studies of quantitative OCT analysis in man were also performed. In selected hereditary retinal degenerative diseases in which there was regional difference in retinal function, frequently observed OCT abnormalities that were associated with visual dysfunction were reduced OCT thickness, reduced ORCC thickness, increased reflectivity posterior to ORCC, and abnormal OCT signal lamination. These preliminary results suggested that OCT abnormalities at the level

  11. The Protective Role of PAC1-Receptor Agonist Maxadilan in BCCAO-Induced Retinal Degeneration.

    Science.gov (United States)

    Vaczy, A; Reglodi, D; Somoskeoy, T; Kovacs, K; Lokos, E; Szabo, E; Tamas, A; Atlasz, T

    2016-10-01

    A number of studies have proven that pituitary adenylate cyclase activating polypeptide (PACAP) is protective in neurodegenerative diseases. Permanent bilateral common carotid artery occlusion (BCCAO) causes severe degeneration in the rat retina. In our previous studies, protective effects were observed with PACAP1-38, PACAP1-27, and VIP but not with their related peptides, glucagon, or secretin in BCCAO. All three PACAP receptors (PAC1, VPAC1, VPAC2) appear in the retina. Molecular and immunohistochemical analysis demonstrated that the retinoprotective effects are most probably mainly mediated by the PAC1 receptor. The aim of the present study was to investigate the retinoprotective effects of a selective PAC1-receptor agonist maxadilan in BCCAO-induced retinopathy. Wistar rats were used in the experiment. After performing BCCAO, the right eye was treated with intravitreal maxadilan (0.1 or 1 μM), while the left eye was injected with vehicle. Sham-operated rats received the same treatment. Two weeks after the operation, retinas were processed for standard morphometric and molecular analysis. Intravitreal injection of 0.1 or 1 μM maxadilan caused significant protection in the thickness of most retinal layers and the number of cells in the GCL compared to the BCCAO-operated eyes. In addition, 1 μM maxadilan application was more effective than 0.1 μM maxadilan treatment in the ONL, INL, IPL, and the entire retina (OLM-ILM). Maxadilan treatment significantly decreased cytokine expression (CINC-1, IL-1α, and L-selectin) in ischemia. In summary, our histological and molecular analysis showed that maxadilan, a selective PAC1 receptor agonist, has a protective role in BCCAO-induced retinal degeneration, further supporting the role of PAC1 receptor conveying the retinoprotective effects of PACAP.

  12. A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration.

    Directory of Open Access Journals (Sweden)

    Liyun Zhang

    Full Text Available Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB, an active component isolated from the five-flavor fruit (Fructus Schisandrae that is postulated in traditional Chinese medicines to exert prophylactic visual benefit. This SchB benefit was investigated in this study in pde6cw59, a zebrafish retinal-degeneration model. In this model, the pde6c gene (phosphodiesterase 6C, cGMP-specific, cone, alpha prime carried a mutation which caused cone degeneration. This altered the local environment and caused the bystander rods to degenerate too. To test SchB on the pde6cw59 mutants, a treatment concentration was first determined that would not cause morphological defects, and would initiate known physiological response. Then, the mutants were treated with the optimized SchB concentration before the appearance of retinal degeneration at 3 days postfertilization (dpf. The light sensation of animals was evaluated at 6 dpf by the visual motor response (VMR, a visual startle that could be initiated by drastic light onset and offset. The results show that the VMR of pde6cw59 mutants towards light onset was enhanced by the SchB treatment, and that the initial phase of the enhancement was primarily mediated through the mutants' eyes. Further immunostaining analysis indicates that the treatment specifically reduced the size of the abnormally large rods. These observations implicate an interesting hypothesis: that the morphologically-improved rods drive the observed VMR enhancement. Together, these investigations have identified a possible visual benefit of SchB on retinal degeneration, a benefit that can potentially be further developed to

  13. A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration.

    Science.gov (United States)

    Zhang, Liyun; Xiang, Lue; Liu, Yiwen; Venkatraman, Prahatha; Chong, Leelyn; Cho, Jin; Bonilla, Sylvia; Jin, Zi-Bing; Pang, Chi Pui; Ko, Kam Ming; Ma, Ping; Zhang, Mingzhi; Leung, Yuk Fai

    2016-01-01

    Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB), an active component isolated from the five-flavor fruit (Fructus Schisandrae) that is postulated in traditional Chinese medicines to exert prophylactic visual benefit. This SchB benefit was investigated in this study in pde6cw59, a zebrafish retinal-degeneration model. In this model, the pde6c gene (phosphodiesterase 6C, cGMP-specific, cone, alpha prime) carried a mutation which caused cone degeneration. This altered the local environment and caused the bystander rods to degenerate too. To test SchB on the pde6cw59 mutants, a treatment concentration was first determined that would not cause morphological defects, and would initiate known physiological response. Then, the mutants were treated with the optimized SchB concentration before the appearance of retinal degeneration at 3 days postfertilization (dpf). The light sensation of animals was evaluated at 6 dpf by the visual motor response (VMR), a visual startle that could be initiated by drastic light onset and offset. The results show that the VMR of pde6cw59 mutants towards light onset was enhanced by the SchB treatment, and that the initial phase of the enhancement was primarily mediated through the mutants' eyes. Further immunostaining analysis indicates that the treatment specifically reduced the size of the abnormally large rods. These observations implicate an interesting hypothesis: that the morphologically-improved rods drive the observed VMR enhancement. Together, these investigations have identified a possible visual benefit of SchB on retinal degeneration, a benefit that can potentially be further developed to extend

  14. Nimodipine rescues N-methyl-N-nitrosourea-induced retinal degeneration in rats

    Directory of Open Access Journals (Sweden)

    Dan Wang

    2013-01-01

    Full Text Available Background: That nimodipine (NMD is potentially useful for ophthalmic treatment. However, the effect of NMD is unknown on retinal degenerative diseases. Objective: The purpose of the present study was to investigate the effect of NMD on N-methyl-N-nitrosourea (MNU-induced retinal degeneration (RD and elucidate its possible mechanisms. Materials and Methods: Morphological observation of NMD on MNU-induced RD was evaluated by light microscopy and electron microscopy. Nonenzymatic antioxidant glutathione (GSH was measured by a colorimetric method. Transforming growth factor-beta (TGF-β was measured by enzyme-linked immunosorbent assay (ELISA. Telomerase was detected by reverse transcriptase polymerase chain reaction (RT-PCR. Results: The significantly protective effect of NMD on MNU-induced RD was demonstrated morphologically. NMD increased the content of GSH and decreased the level of TGF-β in rat retina. RT-PCR analysis demonstrated that NMD treatment significantly decreased mRNA level of telomerase. Conclusion: These data suggest that NMD inhibit MNU-induced RD in rats. The expressions of TGF-β, telomerase and GSH contents might partially contribute to its protective effects on MNU-induced RD.

  15. Use of Hydrogen as a Novel Therapeutic Strategy Against Photoreceptor Degeneration in Retinitis Pigmentosa Patients.

    Science.gov (United States)

    Tao, Ye; Geng, Lei; Wang, Liqiang; Xu, Weiwei; Qin, Limin; Peng, Guanghua; Huang, Yi Fei; Yang, Ji xue

    2016-03-08

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterized by progressive photoreceptor apoptosis. Reactive oxygen species (ROS) have been recognized as critical initiators of the photoreceptor apoptosis in RP. Photoreceptor survival in RP mutants will not only require the inhibition of effectors of apoptotic machinery, but also the elimination of the initiating upstream signals, such as ROS. These cytotoxic ROS should be neutralized by the antioxidant defense system, otherwise they would interact with the macromolecules essential for photoreceptor survival. Hydrogen is a promising gaseous agent that has come to the forefront of therapeutic research over the last few years. It has been verified that hydrogen is capable of neutralizing the cytotoxic ROS selectively, rectifying abnormities in the apoptotic cascades, and attenuating the related inflammatory response. Hydrogen is so mild that it does not disturb the metabolic oxidation-reduction reactions or disrupt the physiologic ROS involved in cell signaling. Based on these findings, we hypothesize that hydrogen might be an effective therapeutic agent to slow or prevent photoreceptor degeneration in RP retinas. It is a logical step to test hydrogen for therapeutic use in multiple RP animal models, and ultimately in human RP patients.

  16. Relationship between Retinal Layer Thickness and the Visual Field in Early Age-Related Macular Degeneration

    Science.gov (United States)

    Acton, Jennifer H.; Smith, R. Theodore; Hood, Donald C.; Greenstein, Vivienne C.

    2012-01-01

    Purpose. To quantify and compare the structural and functional changes in subjects with early age-related macular degeneration (AMD), using spectral-domain optical coherence tomography (SD-OCT) and microperimetry. Methods. Twenty-one eyes of 21 subjects with early AMD were examined. MP-1 10-2 visual fields (VFs) and SD-OCT line and detail volume scans were acquired. The thicknesses of the outer segment (OS; distance between inner segment ellipsoid band and upper retinal pigment epithelium [RPE] border) and RPE layers and elevation of the RPE from Bruch's membrane were measured using a computer-aided manual segmentation technique. Thickness values were compared with those for 15 controls, and values at locations with VF total deviation defects were compared with values at nondefect locations at equivalent eccentricities. Results. Sixteen of 21 eyes with AMD had VF defects. Compared with controls, line scans showed significant thinning of the OS layer (P = 0.006) and thickening and elevation of the RPE (P = 0.037, P = 0.002). The OS layer was significantly thinner in locations with VF defects compared with locations without defects (P = 0.003). There was a negligible difference between the retinal layer thickness values of the 5 eyes without VF defects and the values of normal controls. Conclusions. In early AMD, when VF defects were present, there was significant thinning of the OS layer and thickening and elevation of the RPE. OS layer thinning was significantly associated with decreased visual sensitivity, consistent with known photoreceptor loss in early AMD. For AMD subjects without VF defects, thickness values were normal. The results highlight the clinical utility of both SD-OCT retinal layer quantification and VF testing in early AMD. PMID:23074210

  17. Segmentation and quantification of retinal lesions in age-related macular degeneration using polarization-sensitive optical coherence tomography.

    Science.gov (United States)

    Baumann, Bernhard; Gotzinger, Erich; Pircher, Michael; Sattmann, Harald; Schuutze, Christopher; Schlanitz, Ferdinand; Ahlers, Christian; Schmidt-Erfurth, Ursula; Hitzenberger, Christoph K

    2010-01-01

    We present polarization-sensitive optical coherence tomography (PS-OCT) for quantitative assessment of retinal pathologies in age-related macular degeneration (AMD). On the basis of the polarization scrambling characteristics of the retinal pigment epithelium, novel segmentation algorithms were developed that allow one to segment pathologic features such as drusen and atrophic zones in dry AMD as well as to determine their dimensions. Results from measurements in the eyes of AMD patients prove the ability of PS-OCT for quantitative imaging based on the retinal features polarizing properties. Repeatability measurements were performed in retinas diagnosed with drusen and geographic atrophy in order to evaluate the performance of the described methods. PS-OCT appears as a promising imaging modality for three-dimensional retinal imaging and ranging with additional contrast based on the structures' tissue-inherent polarization properties.

  18. Segmentation and quantification of retinal lesions in age-related macular degeneration using polarization-sensitive optical coherence tomography

    Science.gov (United States)

    Baumann, Bernhard; Götzinger, Erich; Pircher, Michael; Sattmann, Harald; Schütze, Christopher; Schlanitz, Ferdinand; Ahlers, Christian; Schmidt-Erfurth, Ursula; Hitzenberger, Christoph K.

    2010-11-01

    We present polarization-sensitive optical coherence tomography (PS-OCT) for quantitative assessment of retinal pathologies in age-related macular degeneration (AMD). On the basis of the polarization scrambling characteristics of the retinal pigment epithelium, novel segmentation algorithms were developed that allow one to segment pathologic features such as drusen and atrophic zones in dry AMD as well as to determine their dimensions. Results from measurements in the eyes of AMD patients prove the ability of PS-OCT for quantitative imaging based on the retinal features polarizing properties. Repeatability measurements were performed in retinas diagnosed with drusen and geographic atrophy in order to evaluate the performance of the described methods. PS-OCT appears as a promising imaging modality for three-dimensional retinal imaging and ranging with additional contrast based on the structures' tissue-inherent polarization properties.

  19. Hyperhomocysteinemia disrupts retinal pigment epithelial structure and function with features of age-related macular degeneration.

    Science.gov (United States)

    Ibrahim, Ahmed S; Mander, Suchreet; Hussein, Khaled A; Elsherbiny, Nehal M; Smith, Sylvia B; Al-Shabrawey, Mohamed; Tawfik, Amany

    2016-02-23

    The disruption of retinal pigment epithelial (RPE) function and the degeneration of photoreceptors are cardinal features of age related macular degeneration (AMD); however there are still gaps in our understanding of underlying biological processes. Excess homocysteine (Hcy) has been reported to be elevated in plasma of patients with AMD. This study aimed to evaluate the direct effect of hyperhomocysteinemia (HHcy) on structure and function of RPE. Initial studies in a mouse model of HHcy, in which cystathionine-β-synthase (cbs) was deficient, revealed abnormal RPE cell morphology with features similar to that of AMD upon optical coherence tomography (OCT), fluorescein angiography (FA), histological, and electron microscopic examinations. These features include atrophy, vacuolization, hypopigmentation, thickened basal laminar membrane, hyporeflective lucency, choroidal neovascularization (CNV), and disturbed RPE-photoreceptor relationship. Furthermore, intravitreal injection of Hcy per se in normal wild type (WT) mice resulted in diffuse hyper-fluorescence, albumin leakage, and CNV in the area of RPE. In vitro experiments on ARPE-19 showed that Hcy dose-dependently reduced tight junction protein expression, increased FITC dextran leakage, decreased transcellular electrical resistance, and impaired phagocytic activity. Collectively, our results demonstrated unreported effects of excess Hcy levels on RPE structure and function that lead to the development of AMD-like features.

  20. Retinal homeobox genes and the role of cell proliferation in cavefish eye degeneration.

    Science.gov (United States)

    Strickler, Allen G; Famuditimi, Kuburat; Jeffery, William R

    2002-05-01

    The teleost Astyanax mexicanus exhibits eyed surface dwelling (surface fish) and blind cave dwelling (cavefish) forms. Despite lacking functional eyes as adults, cavefish embryos form eye primordia, which later arrest in development, degenerate and sink into the orbit. We are comparing the expression patterns of various eye regulatory genes during surfacefish and cavefish development to determine the cause of eye degeneration. Here we examine Rx and Chx/Vsx family homeobox genes, which have a major role in cell proliferation in the vertebrate retina. We isolated and sequenced a full-length RxcDNA clone (As-Rx1) and part of a Chx/Vsx(As-Vsx2) gene, which appear to be most closely related to the zebrafish Rx1 and Alx/Vsx2 genes respectively. In situ hybridization shows that these genes have similar but non-identical expression patterns during Astyanax eye development. Expression is first detected in the optic vesicle, then throughout the presumptive retina of the optic cup, and finally in the ciliary marginal zone (CMZ), the region of the growing retina where most new retinoblasts are formed. In addition, As-Rx1 is expressed in the outer nuclear layer (ONL) of the retina, which contains the photoreceptor cells, and As-Vsx2 is expressed in the inner nuclear layer, probably in the bipolar cells. With the exception of reduced As-Rx-1 expression in the ONL, the As-Rx1 and As-Vsx2 expression patterns were unchanged in the developing retina of two different cavefish populations, suggesting that cell proliferation is not inhibited. These results were confirmed by using PCNA and BrdU markers for retinal cell division. We conclude that the CMZ is active in cell proliferation long after eye growth is diminished and is therefore not the major cause of eye degeneration.

  1. Spatiotemporal Cadence of Macrophage Polarisation in a Model of Light-Induced Retinal Degeneration.

    Directory of Open Access Journals (Sweden)

    Haihan Jiao

    Full Text Available The recruitment of macrophages accompanies almost every pathogenic state of the retina, and their excessive activation in the subretinal space is thought to contribute to the progression of diseases including age-related macular degeneration. Previously, we have shown that macrophages aggregate in the outer retina following damage elicited by photo-oxidative stress, and that inhibition of their recruitment reduces photoreceptor death. Here, we look for functional insight into macrophage activity in this model through the spatiotemporal interplay of macrophage polarisation over the course of degeneration.Rats were exposed to 1000 lux light damage (LD for 24 hrs, with some left to recover for 3 and 7 days post-exposure. Expression and localisation of M1- and M2- macrophage markers was investigated in light-damaged retinas using qPCR, ELISA, flow cytometry, and immunohistochemistry.Expression of M1- (Ccl3, Il-6, Il-12, Il-1β, TNFα and M2- (CD206, Arg1, Igf1, Lyve1, Clec7a related markers followed discrete profiles following light damage; up-regulation of M1 genes peaked at the early phase of cell death, while M2 genes generally exhibited more prolonged increases during the chronic phase. Moreover, Il-1β and CD206 labelled accumulations of microglia/macrophages which differed in their morphological, temporal, and spatial characteristics following light damage.The data illustrate a dynamic shift in macrophage polarisation following light damage through a broad swathe of M1 and M2 markers. Pro-inflammatory M1 activation appears to dominate the early phase of degeneration while M2 responses appear to more heavily mark the chronic post-exposure period. While M1/M2 polarisation represents two extremes amongst a spectrum of macrophage activity, knowledge of their predominance offers insight into functional consequences of macrophage activity over the course of damage, which may inform the spatiotemporal employment of therapeutics in retinal disease.

  2. Epiretinal transplantation of human bone marrow mesenchymal stem cells rescues retinal and vision function in a rat model of retinal degeneration.

    Science.gov (United States)

    Tzameret, Adi; Sher, Ifat; Belkin, Michael; Treves, Avraham J; Meir, Amilia; Nagler, Arnon; Levkovitch-Verbin, Hani; Rotenstreich, Ygal; Solomon, Arieh S

    2015-09-01

    Vision incapacitation and blindness associated with incurable retinal degeneration affect millions of people worldwide. In this study, 0.25×10(6) human bone marrow stem cells (hBM-MSCs) were transplanted epiretinally in the right eye of Royal College Surgeons (RCS) rats at the age of 28 days. Epiretinally transplanted cells were identified as a thin layer of cells along vitreous cavity, in close proximity to the retina or attached to the lens capsule, up to 6 weeks following transplantation. Epiretinal transplantation delayed photoreceptor degeneration and rescued retinal function up to 20 weeks following cell transplantation. Visual functions remained close to normal levels in epiretinal transplantation rats. No inflammation or any other adverse effects were observed in transplanted eyes. Our findings suggest that transplantation of hBM-MSCs as a thin epiretinal layer is effective for treatment of retinal degeneration in RCS rats, and that transplanting the cells in close proximity to the retina enhances hBM-MSC therapeutic effect compared with intravitreal injection.

  3. Animals deficient in C2Orf71, an autosomal recessive retinitis pigmentosa-associated locus, develop severe early-onset retinal degeneration.

    Science.gov (United States)

    Kevany, Brian M; Zhang, Ning; Jastrzebska, Beata; Palczewski, Krzysztof

    2015-05-01

    Genetic mapping was recently used to identify the underlying cause for a previously uncharacterized cohort of autosomal recessive retinitis pigmentosa cases. Genetic mapping of affected individuals resulted in the identification of an uncharacterized gene, C2Orf71, as the causative locus. However, initial homology searches failed to reveal similarities to any previously characterized protein or domain. To address this issue, we characterized the mouse homolog, BC027072. Immunohistochemistry with a custom polyclonal antibody showed staining localized to the inner segments (IS) of photoreceptor cells, as well as the outer segments (OS) of cone cells. A knockout mouse line (BC(-/-)) was generated and demonstrated that loss of this gene results in a severe, early-onset retinal degeneration. Histology and electron microscopy (EM) revealed disorganized OS as early as 3 weeks with complete loss by 24 weeks of age. EM micrographs displayed packets of cellular material containing OS discs or IS organelles in the OS region and abnormal retinal pigmented epithelium cells. Analyses of retinoids and rhodopsin levels showed retinal degenerations. Although its function remains unknown, this protein appears essential for normal OS development/maintenance and vision in humans and mice. RNAseq data are available in the GEO database under accession: GSE63810.

  4. Long-term Characterization of Retinal Degeneration in Royal College of Surgeons Rats Using Spectral-Domain Optical Coherence Tomography

    Science.gov (United States)

    Ryals, Renee C.; Andrews, Michael D.; Datta, Shreya; Coyner, Aaron S.; Fischer, Cody M.; Wen, Yuquan; Pennesi, Mark E.; McGill, Trevor J.

    2017-01-01

    Purpose Prospective treatments for age-related macular degeneration and inherited retinal degenerations are commonly evaluated in the Royal College of Surgeons (RCS) rat before translation into clinical application. Historically, retinal thickness obtained through postmortem anatomic assessments has been a key outcome measure; however, utility of this measurement is limited because it precludes the ability to perform longitudinal studies. To overcome this limitation, the present study was designed to provide a baseline longitudinal quantification of retinal thickness in the RCS rat by using spectral-domain optical coherence tomography (SD-OCT). Methods Horizontal and vertical linear SD-OCT scans centered on the optic nerve were captured from Long-Evans control rats at P30, P60, P90 and from RCS rats between P17 and P90. Total retina (TR), outer nuclear layer+ (ONL+), inner nuclear layer (INL), and retinal pigment epithelium (RPE) thicknesses were quantified. Histologic sections of RCS retina obtained from P21 to P60 were compared to SD-OCT images. Results In RCS rats, TR and ONL+ thickness decreased significantly as compared to Long-Evans controls. Changes in INL and RPE thickness were not significantly different between control and RCS retinas. From P30 to P90 a subretinal hyperreflective layer (HRL) was observed and quantified in RCS rats. After correlation with histology, the HRL was identified as disorganized outer segments and the location of accumulated debris. Conclusions Retinal layer thickness can be quantified longitudinally throughout the course of retinal degeneration in the RCS rat by using SD-OCT. Thickness measurements obtained with SD-OCT were consistent with previous anatomic thickness assessments. This study provides baseline data for future longitudinal assessment of therapeutic agents in the RCS rat. PMID:28253400

  5. Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection

    Science.gov (United States)

    Munemasa, Yasunari; Kitaoka, Yasushi

    2013-01-01

    Glaucoma, which affects more than 70 million people worldwide, is a heterogeneous group of disorders with a resultant common denominator; optic neuropathy, eventually leading to irreversible blindness. The clinical manifestations of primary open-angle glaucoma (POAG), the most common subtype of glaucoma, include excavation of the optic disc and progressive loss of visual field. Axonal degeneration of retinal ganglion cells (RGCs) and apoptotic death of their cell bodies are observed in glaucoma, in which the reduction of intraocular pressure (IOP) is known to slow progression of the disease. A pattern of localized retinal nerve fiber layer (RNFL) defects in glaucoma patients indicates that axonal degeneration may precede RGC body death in this condition. The mechanisms of degeneration of neuronal cell bodies and their axons may differ. In this review, we addressed the molecular mechanisms of cell body death and axonal degeneration in glaucoma and proposed axonal protection in addition to cell body protection. The concept of axonal protection may become a new therapeutic strategy to prevent further axonal degeneration or revive dying axons in patients with preperimetric glaucoma. Further study will be needed to clarify whether the combination therapy of axonal protection and cell body protection will have greater protective effects in early or progressive glaucomatous optic neuropathy (GON). PMID:23316132

  6. Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection

    Directory of Open Access Journals (Sweden)

    Yasunari eMunemasa

    2013-01-01

    Full Text Available Glaucoma, which affects more than 70 million people worldwide, is a heterogeneous group of disorders with a resultant common denominator; optic neuropathy, eventually leading to irreversible blindness. The clinical manifestations of primary open-angle glaucoma (POAG, the most common subtype of glaucoma, include excavation of the optic disc and progressive loss of visual field. Axonal degeneration of retinal ganglion cells (RGCs and apoptotic death of their cell bodies are observed in glaucoma, in which the reduction of intraocular pressure is known to slow progression of the disease. A pattern of localized retinal nerve fiber layer defects in glaucoma patients indicates that axonal degeneration may precede RGC body death in this condition. The mechanisms of degeneration of neuronal cell bodies and their axons may differ. In this review, we addressed the molecular mechanisms of cell body death and axonal degeneration in glaucoma and proposed axonal protection in addition to cell body protection. The concept of axonal protection may become a new therapeutic strategy to prevent further axonal degeneration or revive dying axons in patients with preperimetric glaucoma. Further study will be needed to clarify whether the combination therapy of axonal protection and cell body protection will have greater protective effects in early or progressive glaucomatous optic neuropathy.

  7. RPGR-containing protein complexes in syndromic and non-syndromic retinal degeneration due to ciliary dysfunction

    Indian Academy of Sciences (India)

    Carlos A. Murga-Zamalloa; Anand Swaroop; Hemant Khanna

    2009-12-01

    Dysfunction of primary cilia due to mutations in cilia-centrosomal proteins is associated with pleiotropic disorders. The primary (or sensory) cilium of photoreceptors mediates polarized trafficking of proteins for efficient phototransduction. Retinitis pigmentosa GTPase regulator (RPGR) is a cilia-centrosomal protein mutated in >70% of X-linked RP cases and 10%–20% of simplex RP males. Accumulating evidence indicates that RPGR may facilitate the orchestration of multiple ciliary protein complexes. Disruption of these complexes due to mutations in component proteins is an underlying cause of associated photoreceptor degeneration. Here, we highlight the recent developments in understanding the mechanism of cilia-dependent photoreceptor degeneration due to mutations in RPGR and RPGR-interacting proteins in severe genetic diseases, including retinitis pigmentosa, Leber congenital amaurosis (LCA), Joubert syndrome, and Senior–Loken syndrome, and explore the physiological relevance of photoreceptor ciliary protein complexes.

  8. Acanthocytosis, retinitis pigmentosa, and pallidal degeneration: a report of three patients, including the second reported case with hypoprebetalipoproteinemia (HARP syndrome).

    Science.gov (United States)

    Orrell, R W; Amrolia, P J; Heald, A; Cleland, P G; Owen, J S; Morgan-Hughes, J A; Harding, A E; Marsden, C D

    1995-03-01

    We describe an example of a variant of Hallervorden-Spatz disease, characterized by hypoprebeta-lipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome), in an 18-year-old woman who presented with longstanding intellectual subnormality, night blindness, and a 2-year history of orobuccolingual dystonia causing dysarthria and dysphagia. Investigation showed acanthocytosis and hypoprebetalipoproteinemia, and electroretinograms were typical of tapetoretinal degeneration. T2-weighted MRI showed decreased signal intensity in the pallidal nuclei with central hyperintensity, constituting the "eye-of-the-tiger" sign. The patient's sister and mother have a similar lipid disorder but no retinal or neurologic disease. We also report two patients with clinical and radiologic features similar to those of the patient with HARP syndrome but who had normal lipid studies. These various combinations of components of HARP syndrome may be caused by several distinct genetic diseases or may represent variable manifestations of a contiguous gene defect.

  9. Small Molecules that Protect Mitochondrial Function from Metabolic Stress Decelerate Loss of Photoreceptor Cells in Murine Retinal Degeneration Models.

    Science.gov (United States)

    Beeson, Craig; Lindsey, Chris; Nasarre, Cecile; Bandyopadhyay, Mausumi; Perron, Nathan; Rohrer, Bärbel

    2016-01-01

    One feature common to many of the pathways implicated in retinal degeneration is increased metabolic stress leading to impaired mitochondrial function. We found that exposure of cells to calcium ionophores or oxidants as metabolic stressors diminish maximal mitochondrial capacity. A library of 50,000 structurally diverse "drug-like" molecules was screened for protection against loss of calcium-induced loss of mitochondrial capacity in 661W rod-derived cells and C6 glioblastomas. Initial protective hits were then tested for protection against IBMX-induced loss of mitochondrial capacity as measured via respirometry. Molecules that protected mitochondria were then evaluated for protection of rod photoreceptor cells in retinal explants from rd1 mice. Two of the molecules attenuated loss of photoreceptor cells in the rd1 model. In the 661W cells, exposure to calcium ionophore or tert-butylhydroperoxide caused mitochondrial fragmentation that was blocked with the both compounds. Our studies have identified molecules that protect mitochondria and attenuate loss of photoreceptors in models of retinal degeneration suggesting that they could be good leads for development of therapeutic drugs for treatment of a wide variety of retinal dystrophies.

  10. Recessive NRL mutations in patients with clumped pigmentary retinal degeneration and relative preservation of blue cone function.

    Science.gov (United States)

    Nishiguchi, Koji M; Friedman, James S; Sandberg, Michael A; Swaroop, Anand; Berson, Eliot L; Dryja, Thaddeus P

    2004-12-21

    Mice lacking the transcription factor Nrl have no rod photoreceptors and an increased number of short-wavelength-sensitive cones. Missense mutations in NRL are associated with autosomal dominant retinitis pigmentosa; however, the phenotype associated with the loss of NRL function in humans has not been reported. We identified two siblings who carried two allelic mutations: a predicted null allele (L75fs) and a missense mutation (L160P) altering a highly conserved residue in the domain involved in DNA-binding-site recognition. In vitro luciferase reporter assays demonstrated that the NRL-L160P mutant had severely reduced transcriptional activity compared with the WT NRL protein, consistent with a severe loss of function. The affected patients had night blindness since early childhood, consistent with a severe reduction in rod function. Color vision was normal, suggesting the presence of all cone color types; nevertheless, a comparison of central visual fields evaluated with white-on-white and blue-on-yellow light stimuli was consistent with a relatively enhanced function of short-wavelength-sensitive cones in the macula. The fundi had signs of retinal degeneration (such as vascular attenuation) and clusters of large, clumped, pigment deposits in the peripheral fundus at the level of the retinal pigment epithelium (clumped pigmentary retinal degeneration). Our report presents an unusual clinical phenotype in humans with loss-of-function mutations in NRL.

  11. Recent advances in early-onset severe retinal degeneration: more than just basic research?

    DEFF Research Database (Denmark)

    Preising, M. N.; Heegaard, S.

    2004-01-01

    ophthalmology, Leber's congenital amaurosis, phenotype, gene therapy, retina, degeneration, rewiew......ophthalmology, Leber's congenital amaurosis, phenotype, gene therapy, retina, degeneration, rewiew...

  12. In vivo imaging of retinal pigment epithelium cells in age related macular degeneration.

    Science.gov (United States)

    Rossi, Ethan A; Rangel-Fonseca, Piero; Parkins, Keith; Fischer, William; Latchney, Lisa R; Folwell, Margaret A; Williams, David R; Dubra, Alfredo; Chung, Mina M

    2013-01-01

    Morgan and colleagues demonstrated that the RPE cell mosaic can be resolved in the living human eye non-invasively by imaging the short-wavelength autofluorescence using an adaptive optics (AO) ophthalmoscope. This method, based on the assumption that all subjects have the same longitudinal chromatic aberration (LCA) correction, has proved difficult to use in diseased eyes, and in particular those affected by age-related macular degeneration (AMD). In this work, we improve Morgan's method by accounting for chromatic aberration variations by optimizing the confocal aperture axial and transverse placement through an automated iterative maximization of image intensity. The increase in image intensity after algorithmic aperture placement varied depending upon patient and aperture position prior to optimization but increases as large as a factor of 10 were observed. When using a confocal aperture of 3.4 Airy disks in diameter, images were obtained using retinal radiant exposures of less than 2.44 J/cm(2), which is ~22 times below the current ANSI maximum permissible exposure. RPE cell morphologies that were strikingly similar to those seen in postmortem histological studies were observed in AMD eyes, even in areas where the pattern of fluorescence appeared normal in commercial fundus autofluorescence (FAF) images. This new method can be used to study RPE morphology in AMD and other diseases, providing a powerful tool for understanding disease pathogenesis and progression, and offering a new means to assess the efficacy of treatments designed to restore RPE health.

  13. Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration.

    Science.gov (United States)

    Yang, Zhenglin; Alvarez, Bernardo V; Chakarova, Christina; Jiang, Li; Karan, Goutam; Frederick, Jeanne M; Zhao, Yu; Sauvé, Yves; Li, Xi; Zrenner, Eberhart; Wissinger, Bernd; Hollander, Anneke I Den; Katz, Bradley; Baehr, Wolfgang; Cremers, Frans P; Casey, Joseph R; Bhattacharya, Shomi S; Zhang, Kang

    2005-01-15

    Retina and retinal pigment epithelium (RPE) belong to the metabolically most active tissues in the human body. Efficient removal of acid load from retina and RPE is a critical function mediated by the choriocapillaris. However, the mechanism by which pH homeostasis is maintained is largely unknown. Here, we show that a functional complex of carbonic anhydrase 4 (CA4) and Na+/bicarbonate co-transporter 1 (NBC1) is specifically expressed in the choriocapillaris and that missense mutations in CA4 linked to autosomal dominant rod-cone dystrophy disrupt NBC1-mediated HCO3- transport. Our results identify a novel pathogenic pathway in which a defect in a functional complex involved in maintaining pH balances, but not expressed in retina or RPE, leads to photoreceptor degeneration. The importance of a functional CA4 for survival of photoreceptors implies that CA inhibitors, which are widely used as medications, particularly in the treatment of glaucoma, may have long-term adverse effects on vision.

  14. Modeling retinal degeneration using patient-specific induced pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Zi-Bing Jin

    Full Text Available Retinitis pigmentosa (RP is the most common inherited human eye disease resulting in night blindness and visual defects. It is well known that the disease is caused by rod photoreceptor degeneration; however, it remains incurable, due to the unavailability of disease-specific human photoreceptor cells for use in mechanistic studies and drug screening. We obtained fibroblast cells from five RP patients with distinct mutations in the RP1, RP9, PRPH2 or RHO gene, and generated patient-specific induced pluripotent stem (iPS cells by ectopic expression of four key reprogramming factors. We differentiated the iPS cells into rod photoreceptor cells, which had been lost in the patients, and found that they exhibited suitable immunocytochemical features and electrophysiological properties. Interestingly, the number of the patient-derived rod cells with distinct mutations decreased in vitro; cells derived from patients with a specific mutation expressed markers for oxidation or endoplasmic reticulum stress, and exhibited different responses to vitamin E than had been observed in clinical trials. Overall, patient-derived rod cells recapitulated the disease phenotype and expressed markers of cellular stresses. Our results demonstrate that the use of patient-derived iPS cells will help to elucidate the pathogenic mechanisms caused by genetic mutations in RP.

  15. A frameshift mutation in golden retriever dogs with progressive retinal atrophy endorses SLC4A3 as a candidate gene for human retinal degenerations.

    Directory of Open Access Journals (Sweden)

    Louise M Downs

    Full Text Available Progressive retinal atrophy (PRA in dogs, the canine equivalent of retinitis pigmentosa (RP in humans, is characterised by vision loss due to degeneration of the photoreceptor cells in the retina, eventually leading to complete blindness. It affects more than 100 dog breeds, and is caused by numerous mutations. RP affects 1 in 4000 people in the Western world and 70% of causal mutations remain unknown. Canine diseases are natural models for the study of human diseases and are becoming increasingly useful for the development of therapies in humans. One variant, prcd-PRA, only accounts for a small proportion of PRA cases in the Golden Retriever (GR breed. Using genome-wide association with 27 cases and 19 controls we identified a novel PRA locus on CFA37 (p(raw = 1.94×10(-10, p(genome = 1.0×10(-5, where a 644 kb region was homozygous within cases. A frameshift mutation was identified in a solute carrier anion exchanger gene (SLC4A3 located within this region. This variant was present in 56% of PRA cases and 87% of obligate carriers, and displayed a recessive mode of inheritance with full penetrance within those lineages in which it segregated. Allele frequencies are approximately 4% in the UK, 6% in Sweden and 2% in France, but the variant has not been found in GRs from the US. A large proportion of cases (approximately 44% remain unexplained, indicating that PRA in this breed is genetically heterogeneous and caused by at least three mutations. SLC4A3 is important for retinal function and has not previously been associated with spontaneously occurring retinal degenerations in any other species, including humans.

  16. Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations.

    Science.gov (United States)

    Sun, X; Pawlyk, B; Xu, X; Liu, X; Bulgakov, O V; Adamian, M; Sandberg, M A; Khani, S C; Tan, M-H; Smith, A J; Ali, R R; Li, T

    2010-01-01

    Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is required for the biosynthesis of photoreceptor phosphodiesterase (PDE). Gene defects in AIPL1 cause a heterogeneous set of conditions ranging from Leber's congenital amaurosis (LCA), the severest form of early-onset retinal degeneration, to milder forms such as retinitis pigmentosa (RP) and cone-rod dystrophy. In mice, null and hypomorphic alleles cause retinal degeneration similar to human LCA and RP, respectively. Thus these mouse models represent two ends of the disease spectrum associated with AIPL1 gene defects in humans. We evaluated whether adeno-associated virus (AAV)-mediated gene replacement therapy in these models could restore PDE biosynthesis in rods and cones and thereby improve photoreceptor survival. We validated the efficacy of human AIPL1 (isoform 1) replacement gene controlled by a promoter derived from the human rhodopsin kinase (RK) gene, which is active in both rods and cones. We found substantial and long-term rescue of the disease phenotype as a result of transgene expression. This is the first gene therapy study in which both rods and cones were targeted successfully with a single photoreceptor-specific promoter. We propose that the vector and construct design used in this study could serve as a prototype for a human clinical trial.

  17. Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration.

    Science.gov (United States)

    Wang, Jing; Saul, Alan; Roon, Penny; Smith, Sylvia B

    2016-06-28

    Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6β(rd10) (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R(-/-) mice administered (+)-PTZ exhibited no cone preservation. (+)-PTZ treatment was associated with several beneficial cellular phenomena including attenuated reactive gliosis, reduced microglial activation, and decreased oxidative stress in mutant retinas. To our knowledge, this is the first report that activation of Sig1R attenuates inherited PRC loss. The findings may have far-reaching therapeutic implications for retinal neurodegenerative diseases.

  18. Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice.

    Science.gov (United States)

    Parry, David A; Toomes, Carmel; Bida, Lina; Danciger, Michael; Towns, Katherine V; McKibbin, Martin; Jacobson, Samuel G; Logan, Clare V; Ali, Manir; Bond, Jacquelyn; Chance, Rebecca; Swendeman, Steven; Daniele, Lauren L; Springell, Kelly; Adams, Matthew; Johnson, Colin A; Booth, Adam P; Jafri, Hussain; Rashid, Yasmin; Banin, Eyal; Strom, Tim M; Farber, Debora B; Sharon, Dror; Blobel, Carl P; Pugh, Edward N; Pierce, Eric A; Inglehearn, Chris F

    2009-05-01

    Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By autozygosity mapping, we identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice. These findings therefore not only identify ADAM9 as a CRD gene but also identify a form of pathology wherein retinal disease first manifests at the POS-RPE junction.

  19. N-methyl-N-nitrosourea-induced neuronal cell death in a large animal model of retinal degeneration in vitro.

    Science.gov (United States)

    Taylor, Linnéa; Arnér, Karin; Ghosh, Fredrik

    2016-07-01

    N-methyl-N-nitrosourea (MNU) has been reported to induce photoreceptor-specific degeneration with minimal inner retinal impact in small animals in vivo. Pending its use within a retinal transplantation paradigm, we here explore the effects of MNU on outer and inner retinal neurons and glia in an in vitro large animal model of retinal degeneration. The previously described degenerative culture explant model of adult porcine retina was used and compared with explants receiving 10 or 100 μg/ml MNU (MNU10 and MNU100) supplementation. All explants were kept for 5 days in vitro, and examined for morphology as well as for glial and neuronal immunohistochemical markers. Rhodopsin-labeled photoreceptors were present in all explants. The number of cone photoreceptors (transducin), rod bipolar cells (PKC) and horizontal cells (calbindin) was significantly lower in MNU treated explants (p cell proteins was almost extinguished. We here show that MNU causes degeneration of outer and inner retinal neurons and glia in the adult porcine retina in vitro. MNU10 explants display attenuation of gliosis, despite decreased neuronal survival compared with untreated controls. Our results have impact on the use of MNU as a large animal photoreceptor degeneration model, on tissue engineering related to retinal transplantation, and on our understanding of gliosis related neuronal degenerative cell death. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. X-linked dominant cone-rod degeneration: Linkage mapping of a new locus for retinitis pigmentosa (RP15) to Xp22.13-p22.11

    Energy Technology Data Exchange (ETDEWEB)

    McGuire, R.E.; Sullivan, L.S.; Daiger, S.P. [Univ. of Texas-Houston Health Science Center, TX (United States)] [and others

    1995-07-01

    Retinitis pigmentosa is the name given to a heterogeneous group of hereditary retinal degenerations characterized by progressive visual field loss, pigmentary changes of the retina, abnormal electroretinograms, and, frequently, night blindness. In this study, we investigated a family with dominant cone-rod degeneration, a variant form of retinitis pigmentosa. We used microsatellite markers to test for linkage to the disease locus and exluded all mapped autosomal loci. However, a marker from the short arm of the X chromosome, DXS989, showed 0% recombination to the disease locus, with a maximum lod (log-odds) score of 3.3. On the basis of this marker, the odds favoring X-linked dominant versus autosomal dominant inheritance are > 10{sup 5}:1. Haplotype analysis using an additional nine microsatellite markers places the disease locus in the Xp22.13-p22.11 region and excludes other X-linked disease loci causing retinal degeneration. The clinical expression of the retinal degeneration is consistent with X-linked dominant inheritance with milder, variable effects of Lyonization affecting expression in females. On the basis of these data we propose that this family has a novel form of dominant, X-linked cone-rod degeneration with the gene symbol {open_quotes}RP15{close_quotes}. 17 refs., 2 figs., 4 tabs.

  1. Functional expression of SCL/TAL1 interrupting locus (Stil) protects retinal dopaminergic cells from neurotoxin-induced degeneration.

    Science.gov (United States)

    Li, Jingling; Li, Ping; Carr, Aprell; Wang, Xiaokai; DeLaPaz, April; Sun, Lei; Lee, Eric; Tomei, Erika; Li, Lei

    2013-01-11

    We previously isolated a dominant mutation, night blindness b (nbb), which causes a late onset of retinal dopaminergic cell degeneration in zebrafish. In this study, we cloned the zebrafish nbb locus. Sequencing results revealed that nbb is a homolog of the vertebrate SCL/TAL1 interrupting locus (Stil). The Stil gene has been shown to play important roles in the regulation of vertebrate embryonic neural development and human cancer cell proliferation. In this study, we demonstrate that functional expression of Stil is also required for neural survival. In zebrafish, decreased expression of Stil resulted in increased toxic susceptibility of retinal dopaminergic cells to 6-hydroxydopamine. Increases in Stil-mediated Shh signaling transduction (i.e. by knocking down the Shh repressor Sufu) prevented dopaminergic cell death induced by neurotoxic insult. The data suggest that the oncogene Stil also plays important roles in neural protection.

  2. [Radiation preconditioning of mouse retina results in tolerance to MNU-induced degeneration and stimulates retinal recovery].

    Science.gov (United States)

    Tronov, V A; Vinogradova, Yu V; Poplinskaya, V A; Nekrasova, E I; Ostrovsky, M A

    2015-01-01

    Emerging body of data indicate protecting effect of low level of stress (preconditioning) on retina. Our previous studies have revealed a non-linear dose-response relationship for cytotoxic effect of both ionizing radiation and N-methyl-N-nitrosourea (MNU) on mouse retina. Moreover, non-cytotoxic dose of MNU increased tolerance of retina to following challenge dose of MNU. This result displays protection of retina through mechanism of recovery. In the present study we used the mouse model for MNU-induced retinal degeneration to evaluate the adaptive response of the retina to proton irradiation and implication of glial Muller cells in this response. In this paper, we have shown that the recovery of the retina after exposure to genotoxic agents is associated with an increased efficiency of DNA damage repair and lowered death of retinal photoreceptors.

  3. A novel platform for minimally invasive delivery of cellular therapy as a thin layer across the subretina for treatment of retinal degeneration

    Science.gov (United States)

    Rotenstreich, Ygal; Tzameret, Adi; Kalish, Sapir E.; Belkin, Michael; Meir, Amilia; Treves, Avraham J.; Nagler, Arnon; Sher, Ifat

    2015-03-01

    Incurable retinal degenerations affect millions worldwide. Stem cell transplantation rescued visual functions in animal models of retinal degeneration. In those studies cells were transplanted in subretinal "blebs", limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection sites. We developed a minimally-invasive surgical platform for drug and cell delivery in a thin layer across the subretina and extravascular spaces of the choroid. The novel system is comprised of a syringe with a blunt-tipped needle and an adjustable separator. Human bone marrow mesenchymal stem cells (hBM-MSCs) were transplanted in eyes of RCS rats and NZW rabbits through a longitudinal triangular scleral incision. No immunosuppressants were used. Retinal function was determined by electroretinogram analysis and retinal structure was determined by histological analysis and OCT. Transplanted cells were identified as a thin layer across the subretina and extravascular spaces of the choroid. In RCS rats, cell transplantation delayed photoreceptor degeneration across the entire retina and significantly enhanced retinal functions. No retinal detachment or choroidal hemorrhages were observed in rabbits following transplantation. This novel platform opens a new avenue for drug and cell delivery, placing the transplanted cells in close proximity to the damaged RPE and retina as a thin layer, across the subretina and thereby slowing down cell death and photoreceptor degeneration, without retinal detachment or choroidal hemorrhage. This new transplantation system may increase the therapeutic effect of other cell-based therapies and therapeutic agents. This study is expected to directly lead to phase I/II clinical trials for autologous hBM-MSCs transplantation in retinal degeneration patients.

  4. Retinal pigment epithelium protein of 65 kDA gene-linked retinal degeneration is not modulated by chicken acidic leucine-rich epidermal growth factor-like domain containing brain protein/Neuroglycan C/ chondroitin sulfate proteoglycan 5.

    Science.gov (United States)

    Cottet, Sandra; Jüttner, René; Voirol, Nathalie; Chambon, Pierre; Rathjen, Fritz G; Schorderet, Daniel F; Escher, Pascal

    2013-01-01

    To analyze in vivo the function of chicken acidic leucine-rich epidermal growth factor-like domain containing brain protein/Neuroglycan C (gene symbol: Cspg5) during retinal degeneration in the Rpe65⁻/⁻ mouse model of Leber congenital amaurosis. We resorted to mice with targeted deletions in the Cspg5 and retinal pigment epithelium protein of 65 kDa (Rpe65) genes (Cspg5⁻/⁻/Rpe65⁻/⁻). Cone degeneration was assessed with cone-specific peanut agglutinin staining. Transcriptional expression of rhodopsin (Rho), S-opsin (Opn1sw), M-opsin (Opn1mw), rod transducin α subunit (Gnat1), and cone transducin α subunit (Gnat2) genes was assessed with quantitative PCR from 2 weeks to 12 months. The retinal pigment epithelium (RPE) was analyzed at P14 with immunodetection of the retinol-binding protein membrane receptor Stra6. No differences in the progression of retinal degeneration were observed between the Rpe65⁻/⁻ and Cspg5⁻/⁻/Rpe65⁻/⁻ mice. No retinal phenotype was detected in the late postnatal and adult Cspg5⁻/⁻ mice, when compared to the wild-type mice. Despite the previously reported upregulation of Cspg5 during retinal degeneration in Rpe65⁻/⁻ mice, no protective effect or any involvement of Cspg5 in disease progression was identified.

  5. Retinal degeneration 3 (RD3) protein inhibits catalytic activity of retinal membrane guanylyl cyclase (RetGC) and its stimulation by activating proteins.

    Science.gov (United States)

    Peshenko, Igor V; Olshevskaya, Elena V; Azadi, Seifollah; Molday, Laurie L; Molday, Robert S; Dizhoor, Alexander M

    2011-11-08

    Retinal membrane guanylyl cyclase (RetGC) in the outer segments of vertebrate photoreceptors is controlled by guanylyl cyclase activating proteins (GCAPs), responding to light-dependent changes of the intracellular Ca(2+) concentrations. We present evidence that a different RetGC binding protein, retinal degeneration 3 protein (RD3), is a high-affinity allosteric modulator of the cyclase which inhibits RetGC activity at submicromolar concentrations. It suppresses the basal activity of RetGC in the absence of GCAPs in a noncompetitive manner, and it inhibits the GCAP-stimulated RetGC at low intracellular Ca(2+) levels. RD3 opposes the allosteric activation of the cyclase by GCAP but does not significantly change Ca(2+) sensitivity of the GCAP-dependent regulation. We have tested a number of mutations in RD3 implicated in human retinal degenerative disorders and have found that several mutations prevent the stable expression of RD3 in HEK293 cells and decrease the affinity of RD3 for RetGC1. The RD3 mutant lacking the carboxy-terminal half of the protein and associated with Leber congenital amaurosis type 12 (LCA12) is unable to suppress the activity of the RetGC1/GCAP complex. Furthermore, the inhibitory activity of the G57V mutant implicated in cone-rod degeneration is strongly reduced. Our results suggest that inhibition of RetGC by RD3 may be utilized by photoreceptors to block RetGC activity during its maturation and/or incorporation into the photoreceptor outer segment rather than participate in dynamic regulation of the cyclase by Ca(2+) and GCAPs.

  6. Compound 49b Restores Retinal Thickness and Reduces Degenerate Capillaries in the Rat Retina following Ischemia/Reperfusion.

    Directory of Open Access Journals (Sweden)

    Li Liu

    Full Text Available We have recently reported that Compound 49b, a novel β-adrenergic receptor agonist, can significantly reduce VEGF levels in retinal endothelial cells (REC grown in diabetic-like conditions. In this study, we investigated whether Compound 49b could protect the retina under hypoxic conditions using the ischemia-reperfusion (I/R-induced model in rats, as well REC cultured in hypoxic conditions. Some rats received 1mM topical Compound 49b for the 2 (5 rats each group or 10 (4 rats in each group days post-I/R. Analyses for retinal thickness and cell loss in the ganglion cell layer was done at 2 days post-I/R, while numbers of degenerate capillaries and pericyte ghosts were measured at 10 days post-I/R. Additionally, REC were cultured in normal oxygen or hypoxia (5% O2 only or treated with 50 nM Compound 49b for 12 hours. Twelve hours after Compound 49b exposure, cells were collected and analyzed for protein levels of insulin-like growth factor binding protein 3 (IGFBP-3, vascular endothelial cell growth factor (VEGF and its receptor (KDR, angiopoietin 1 and its receptor Tie2 for Western blotting. Data indicate that exposure to I/R significantly decreased retinal thickness, with increasing numbers of degenerate capillaries and pericyte ghosts. Compound 49b treatment inhibited these retinal changes. In REC cultured in hypoxia, levels of IGFBP-3 were reduced, which were significantly increased by Compound 49b. Hypoxia significantly increased protein levels of VEGF, KDR, Angiopoiein 1, and Tie2, which were reduced following Compound 49b treatment. These data strongly suggested that Compound 49b protected the retina against I/R-induced injury. This provides additional support for a role of β-adrenergic receptor actions in the retina.

  7. A reduced zinc diet or zinc transporter 3 knockout attenuate light induced zinc accumulation and retinal degeneration.

    Science.gov (United States)

    Bai, Shi; Sheline, Carolyn R; Zhou, Yongdong; Sheline, Christian T

    2013-03-01

    Our previous study on retinal light exposure suggests the involvement of zinc (Zn(2+)) toxicity in the death of RPE and photoreceptors (LD) which could be attenuated by pyruvate and nicotinamide, perhaps through restoration of NAD(+) levels. In the present study, we examined Zn(2+) toxicity, and the effects of NAD(+) restoration in primary retinal cultures. We then reduced Zn(2+) levels in rodents by reducing Zn(2+) levels in the diet, or by genetics and measured LD. Sprague Dawley albino rats were fed 2, or 61 mg Zn(2+)/kg of diet for 3 weeks, and exposed to 18 kLux of white light for 4 h. We light exposed (70 kLux of white light for 50 h) Zn(2+) transporter 3 knockout (ZnT3-KO, no synaptic Zn(2+)), or RPE65 knockout mice (RPE65-KO, lack rhodopsin cycling), or C57/BI6/J controls and determined light damage and Zn(2+) staining. Retinal Zn(2+) staining was examined at 1 h and 4 h after light exposure. Retinas were examined after 7 d by optical coherence tomography and histology. After LD, rats fed the reduced Zn(2+) diet showed less photoreceptor Zn(2+) staining and degeneration compared to a normal Zn(2+) diet. Similarly, ZnT3-KO and RPE65-KO mice showed less Zn(2+) staining, NAD(+) loss, and RPE or photoreceptor death than C57/BI6/J control mice. Dietary or ZnT3-dependent Zn(2+) stores, and intracellular Zn(2+) release from rhodopsin recycling are suggested to be involved in light-induced retinal degeneration. These results implicate novel rhodopsin-mediated mechanisms and therapeutic targets for LD. Our companion manuscript demonstrates that pharmacologic, circadian, or genetic manipulations which maintain NAD(+) levels reduce LD.

  8. Chitosan oligosaccharides attenuates oxidative-stress related retinal degeneration in rats.

    Directory of Open Access Journals (Sweden)

    I-Mo Fang

    Full Text Available This study investigated the therapeutic potential and mechanisms of chitosan oligosaccharides (COS for oxidative stress-induced retinal diseases. Retinal oxidative damage was induced in Sprague-Dawley rats by intravitreal injection of paraquat (PQ. Low-dose (5 mg/kg or high-dose (10 mg/kg COS or PBS was intragastrically given for 14 days after PQ injection. Electroretinograms were performed to determine the functionality of the retinas. The surviving neurons in the retinal ganglion cell layer and retinal apoptosis were determined by counting Neu N-positive cells in whole-mounted retinas and TUNEL staining, respectively. The generation of reactive oxygen species (ROS was determined by lucigenin- and luminol-enhanced chemiluminescence. Retinal oxidative damages were assessed by staining with nitrotyrosine, acrolein, and 8-hydroxy-2'-deoxyguanosine (8-OHdG. Immunohistochemical studies were used to demonstrate the expression of nuclear factor-kappa B (NF-κB p65 in retinas. An in vitro study using RGC-5 cells was performed to verify the results. We demonstrated COS significantly enhanced the recovery of retinal function, preserved inner retinal thickness, and decreased retinal neurons loss in a dose-dependent manner. COS administration demonstrated anti-oxidative effects by reducing luminol- and lucigenin-dependent chemiluminenscense levels and activating superoxide dismutase and catalase, leading to decreased retinal apoptosis. COS markedly reduced retinal NF-κB p65. An in vitro study demonstrated COS increased IκB expression, attenuated the increase of p65 and thus decreased NF-κB/DNA binding activity in PQ-stimulated RGC-5 cells. In conclusion, COS attenuates oxidative stress-induced retinal damages, probably by decreasing free radicals, maintaining the activities of anti-oxidative enzymes, and inhibiting the activation of NF-κB.

  9. Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration

    NARCIS (Netherlands)

    Nishiguchi, K.M.; Avila-Fernandez, A.; Huet, R.A.C. van; Corton, M.; Perez-Carro, R.; Martin-Garrido, E.; Lopez-Molina, M.I.; Blanco-Kelly, F.; Hoefsloot, L.H.; Zelst-Stams, W.A.G. van; Garcia-Ruiz, P.J.; Val, J. Del; Gioia, S.A. Di; Klevering, B.J.; Warrenburg, B.P.C. van de; Vazquez, C.; Cremers, F.P.M.; Garcia-Sandoval, B.; Hoyng, C.B.; Collin, R.W.J.; Rivolta, C.; Ayuso, C.

    2014-01-01

    OBJECTIVE: To identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: Three hundred forty-seven unrelated families affected by arRP and 33 unrelated families affected by retinitis pigmentosa (

  10. Degenerações periféricas da retina do olho míope X LASIK Peripheral retinal degenerations in myopic eye X LASIK

    Directory of Open Access Journals (Sweden)

    João J. Nassaralla Jr.

    2004-04-01

    Full Text Available O objetivo deste artigo é apresentar as degenerações periféricas mais comuns na retina dos olhos míopes, discutindo aquelas que oferecem maiores riscos para o descolamento regmatogênico da retina, seu relacionamento com a cirurgia de LASIK e a indicação para o tratamento profilático.The purpose of this paper is to present the most frequent peripheral retinal degenerations in myopic eyes and discuss those degenerations which are a great risk for the retina and to point out the features associated with retinal detachment, its relation to LASIK and the indication for prophylactic treatment.

  11. Metabolic bone disease and central retinal degeneration in a kitten due to nutritional inadequacy of an all-meat raw diet

    Directory of Open Access Journals (Sweden)

    Catherine Lenox

    2015-05-01

    Full Text Available A 5-month-old castrated male Sphynx kitten presented with left hindlimb lameness shortly after adoption. Prior to adoption, the breeder had fed the kitten an exclusively raw chicken diet. Radiographs revealed generalized osteopenia and a left tibia–fibula fracture. Ophthalmic examination revealed corneal vascularization and opacity in the right eye, and lesions suggestive of feline central retinal degeneration in the left eye. The patient’s diagnoses included metabolic bone disease and feline central retinal degeneration, which can result from taurine deficiency. The kitten’s nutritional diseases were managed with a complete and balanced canned diet designed for kitten growth and with taurine supplementation.

  12. Metabolic bone disease and central retinal degeneration in a kitten due to nutritional inadequacy of an all-meat raw diet

    Directory of Open Access Journals (Sweden)

    Catherine Lenox

    2015-05-01

    Full Text Available A 5-month-old castrated male Sphynx kitten presented with left hindlimb lameness shortly after adoption. Prior to adoption, the breeder had fed the kitten an exclusively raw chicken diet. Radiographs revealed generalized osteopenia and a left tibia–fibula fracture. Ophthalmic examination revealed corneal vascularization and opacity in the right eye, and lesions suggestive of feline central retinal degeneration in the left eye. The patient’s diagnoses included metabolic bone disease and feline central retinal degeneration, which can result from taurine deficiency. The kitten’s nutritional diseases were managed with a complete and balanced canned diet designed for kitten growth and with taurine supplementation.

  13. Suppressed retinal degeneration in aged wild type and APPswe/PS1ΔE9 mice by bone marrow transplantation.

    Directory of Open Access Journals (Sweden)

    Yue Yang

    Full Text Available Alzheimer's disease (AD is an age-related condition characterized by accumulation of neurotoxic amyloid β peptides (Aβ in brain and retina. Because bone marrow transplantation (BMT results in decreased cerebral Aβ in experimental AD, we hypothesized that BMT would mitigate retinal neurotoxicity through decreased retinal Aβ. To test this, we performed BMT in APPswe/PS1ΔE9 double transgenic mice using green fluorescent protein expressing wild type (wt mice as marrow donors. We first examined retinas from control, non-transplanted, aged AD mice and found a two-fold increase in microglia compared with wt mice, prominent inner retinal Aβ and paired helical filament-tau, and decreased retinal ganglion cell layer neurons. BMT resulted in near complete replacement of host retinal microglia with BMT-derived cells and normalized total AD retinal microglia to non-transplanted wt levels. Aβ and paired helical filament-tau were reduced (61.0% and 44.1% respectively in BMT-recipient AD mice, which had 20.8% more retinal ganglion cell layer neurons than non-transplanted AD controls. Interestingly, aged wt BMT recipients also had significantly more neurons (25.4% compared with non-transplanted aged wt controls. Quantitation of retinal ganglion cell layer neurons in young mice confirmed age-related retinal degeneration was mitigated by BMT. We found increased MHC class II expression in BMT-derived microglia and decreased oxidative damage in retinal ganglion cell layer neurons. Thus, BMT is neuroprotective in age-related as well as AD-related retinal degeneration, and may be a result of alterations in innate immune function and oxidative stress in BMT recipient mice.

  14. Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR.

    Science.gov (United States)

    Rao, Kollu N; Zhang, Wei; Li, Linjing; Ronquillo, Cecinio; Baehr, Wolfgang; Khanna, Hemant

    2016-05-15

    Mutations in RPGR (retinitis pigmentosa GTPase regulator) are the most common cause of X-linked RP, a severe blindness disorder. RPGR mutations result in clinically variable disease with early- to late-onset phenotypic presentation. Molecular mechanisms underlying such heterogeneity are unclear. Here we show that phenotypic expression of Rpgr-loss in mice is influenced genetically by the loss of Cep290, a human ciliopathy gene. We found that Rpgr(ko/Y) mice with a heterozygous hypomorphic allele of Cep290 (Cep290(rd16/+)) but not of a heterozygous null allele of Cep290 (Cep290(null/+)) or of other ciliopathy genes, Rpgrip1, Nphp1, Nphp4 and Nphp5, exhibit relatively early onset (by 3 months of age) retinal degeneration and dysfunction when compared with the onset at ∼7 months of age in the Rpgr(ko/Y) mice. We also observed disorganized photoreceptor outer-segment morphology and defective trafficking of opsins in the Rpgr(ko/Y)::Cep290(rd16/+) mice. Together with a physical interaction between RPGR and the C-terminal domain of CEP290, our data suggest that RPGR and CEP290 genetically interact and highlight the involvement of hypomorphic alleles of genes as potential modifiers of heterogeneous retinal ciliopathies. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Loosely coupled level sets for retinal layers and drusen segmentation in subjects with dry age-related macular degeneration

    Science.gov (United States)

    Novosel, Jelena; Wang, Ziyuan; de Jong, Henk; Vermeer, Koenraad A.; van Vliet, Lucas J.

    2016-03-01

    Optical coherence tomography (OCT) is used to produce high-resolution three-dimensional images of the retina, which permit the investigation of retinal irregularities. In dry age-related macular degeneration (AMD), a chronic eye disease that causes central vision loss, disruptions such as drusen and changes in retinal layer thicknesses occur which could be used as biomarkers for disease monitoring and diagnosis. Due to the topology disrupting pathology, existing segmentation methods often fail. Here, we present a solution for the segmentation of retinal layers in dry AMD subjects by extending our previously presented loosely coupled level sets framework which operates on attenuation coefficients. In eyes affected by AMD, Bruch's membrane becomes visible only below the drusen and our segmentation framework is adapted to delineate such a partially discernible interface. Furthermore, the initialization stage, which tentatively segments five interfaces, is modified to accommodate the appearance of drusen. This stage is based on Dijkstra's algorithm and combines prior knowledge on the shape of the interface, gradient and attenuation coefficient in the newly proposed cost function. This prior knowledge is incorporated by varying the weights for horizontal, diagonal and vertical edges. Finally, quantitative evaluation of the accuracy shows a good agreement between manual and automated segmentation.

  16. An Unconventional Approach To Reducing Retinal Degeneration After Traumatic Ocular Injury

    Science.gov (United States)

    2016-07-01

    abnormal retinal pericyte vasospasms after ocular trauma in mice, and their relationship to: retinal macrophage activity, and oral administration of L...specifically for blast-type ocular injury. Our hypotheses are based upon evidence that the vascular effects contribute to neurodegeneration after...the effects of oral administration of L-Arginine—a nitric oxide (NO) precursor—on ameliorating these vascular contributions. Blood flow control has

  17. Novel localization of peripherin 2, the photoreceptor-specific retinal degeneration slow protein, in retinal pigment epithelium.

    Science.gov (United States)

    Uhl, Patrizia B; Amann, Barbara; Hauck, Stefanie M; Deeg, Cornelia A

    2015-01-26

    Retinal pigment epithelium (RPE) builds the outer blood-retinal barrier of the eye. Since one typical feature of the autoimmune disease, equine recurrent uveitis (ERU), is the breakdown of this barrier, we recently performed comparative analysis of healthy and uveitic RPE. We identified for the first time peripherin 2, which is responsible for visual perception and retina development, to be localized in RPE. The purpose of this study was therefore to validate our findings by characterizing the expression patterns of peripherin 2 in RPE and retina. We also investigated whether peripherin 2 expression changes in ERU and if it is expressed by the RPE itself. Via immunohistochemistry, significant downregulation of peripherin 2 in uveitic RPE compared to the control was detectable, but there was no difference in healthy and uveitic retina. A further interesting finding was the clear distinction between peripherin 2 and the phagocytosis marker, rhodopsin, in healthy RPE. In conclusion, changes in the expression pattern of peripherin 2 selectively affect RPE, but not retina, in ERU. Moreover, peripherin 2 is clearly detectable in healthy RPE due to both phagocytosis and the expression by the RPE cells themselves. Our novel findings are very promising for better understanding the molecular mechanisms taking place on RPE in uveitis.

  18. Novel Localization of Peripherin 2, the Photoreceptor-Specific Retinal Degeneration Slow Protein, in Retinal Pigment Epithelium

    Directory of Open Access Journals (Sweden)

    Patrizia B. Uhl

    2015-01-01

    Full Text Available Retinal pigment epithelium (RPE builds the outer blood-retinal barrier of the eye. Since one typical feature of the autoimmune disease, equine recurrent uveitis (ERU, is the breakdown of this barrier, we recently performed comparative analysis of healthy and uveitic RPE. We identified for the first time peripherin 2, which is responsible for visual perception and retina development, to be localized in RPE. The purpose of this study was therefore to validate our findings by characterizing the expression patterns of peripherin 2 in RPE and retina. We also investigated whether peripherin 2 expression changes in ERU and if it is expressed by the RPE itself. Via immunohistochemistry, significant downregulation of peripherin 2 in uveitic RPE compared to the control was detectable, but there was no difference in healthy and uveitic retina. A further interesting finding was the clear distinction between peripherin 2 and the phagocytosis marker, rhodopsin, in healthy RPE. In conclusion, changes in the expression pattern of peripherin 2 selectively affect RPE, but not retina, in ERU. Moreover, peripherin 2 is clearly detectable in healthy RPE due to both phagocytosis and the expression by the RPE cells themselves. Our novel findings are very promising for better understanding the molecular mechanisms taking place on RPE in uveitis.

  19. Selective degeneration of the parvocellular-projecting retinal ganglion cells in a New World monkey, Saimiri sciureus.

    Science.gov (United States)

    Lynch, J J; Eskin, T A; Merigan, W H

    1989-10-16

    Selective degeneration of retinal ganglion cells projecting to parvocellular layers of the dorsal lateral geniculate nucleus (LGN) was observed in squirrel monkeys (Saimiri sciureus) exposed to a range of doses of acrylamide monomer. Similar acrylamide-induced neuronal loss has previously been reported in parvocellular-projecting ganglion cells of macaques, but no such selective degeneration has been found in acrylamide-dosed rats, squirrels, rabbits or cats. The extent of ganglion cell loss observed in the present study suggests that in the squirrel monkey, as in the macaque, a majority of ganglion cells project to parvocellular layers of the LGN. The locus of optic tract degeneration suggests that the squirrel monkey parvocellular pathway passes in dorsolateral optic tract, as does that of the macaque. Patterns of decreases in cytochrome oxidase activity confirm that, in both of these primates, geniculocortical pathways driven by these vulnerable neurons project to cortical layers 4A and 4C beta. These results suggest close parallels in the neuroanatomical projections and toxic vulnerability of the parvocellular-projecting pathway in New and Old World monkeys. They indicate that acrylamide intoxication can be used to selectively damage this pathway in order to study the functional roles of parallel visual pathways in both New and Old World monkeys.

  20. Repeatability of swept-source optical coherence tomography retinal and choroidal thickness measurements in neovascular age-related macular degeneration.

    Science.gov (United States)

    Hanumunthadu, Daren; Ilginis, Tomas; Restori, Marie; Sagoo, Mandeep S; Tufail, Adnan; Balaggan, Kamaljit S; Patel, Praveen J

    2017-05-01

    The aim was to determine the intrasession repeatability of swept-source optical coherence tomography (SS-OCT)-derived retinal and choroidal thickness measurements in eyes with neovascular age-related macular degeneration (nAMD). A prospective study consisting of patients with active nAMD enrolled in the Distance of Choroid Study at Moorfields Eye Hospital, London. Patients underwent three 12×9 mm macular raster scans using the deep range imaging (DRI) OCT-1 SS-OCT (Topcon) device in a single imaging session. Retinal and choroidal thicknesses were calculated for the ETDRS macular subfields. Repeatability was calculated according to methods described by Bland and Altman. 39 eyes of 39 patients with nAMD were included with a mean (±SD) age of 73.9 (±7.2) years. The mean (±SD) retinal thickness of the central macular subfield was 225.7 μm (±12.4 μm). The repeatability this subfield, expressed as a percentage of the mean central macular subfield thickness, was 23.2%. The percentage repeatability of the other macular subfields ranged from 13.2% to 28.7%. The intrasession coefficient of repeatability of choroidal thickness of the central macular subfield was 57.2 μm with a mean choroidal thickness (±SD) of 181 μm (±15.8 μm). This study suggests that a change >23.2% of retinal thickness and 57.2 μm choroidal thickness in the central macular subfield is required to distinguish true clinical change from measurement variability when using the DRI OCT-1 device to manage patients with nAMD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  1. Retinal degeneration slow (rds) in mouse results from simple insertion of a t haplotype-specific element into protein-coding exon II

    Energy Technology Data Exchange (ETDEWEB)

    Ma, J.; Norton, J.C.; Allen, A.C.; Burns, J.L.; Travis, G.H. [Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)] [and others

    1995-07-20

    Retinal degeneration slow (rds) is a semidominant mutation of mice that causes dysplasia and degeneration of rod and cone photoreceptors. Mutations in RDS, the human ortholog of the rds gene, are responsible for several inherited retinal dystrophies including a subset of retinitis pigmentosa. The normal rds locus encodes rds/peripherin, an integral membrane glycoprotein present in outer segment discs. Genomic libraries form wildtype and rds/rds mice were screened with an rds cDNA, and phage {lambda} clones that span the normal and mutant loci were mapped. We show that in mice, rds is caused by the insertion into exon II of a 9.2-kb repetitive genomic element that is very similar to the t haplotype-specific element in the H-2 complex. The entire element is included in the RNA products of the mutant locus. We present evidence that rds in mice represents a null allele. 40 refs., 4 figs.

  2. A novel homozygous truncating GNAT1 mutation implicated in retinal degeneration.

    LENUS (Irish Health Repository)

    Carrigan, Matthew

    2016-04-01

    The GNAT1 gene encodes the α subunit of the rod transducin protein, a key element in the rod phototransduction cascade. Variants in GNAT1 have been implicated in stationary night-blindness in the past, but unlike other proteins in the same pathway, it has not previously been implicated in retinitis pigmentosa.

  3. Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration.

    NARCIS (Netherlands)

    Yang, Z.; Alvarez, B.V.; Chakarova, C.; Jiang, L.; Karan, G.; Frederick, J.M.; Zhao, Y.; Sauve, Y.; Li, X.; Zrenner, E.; Wissinger, B.; Hollander, A.I. den; Katz, B.; Baehr, W.; Cremers, F.P.M.; Casey, J.R.; Bhattacharya, S.S.; Zhang, K.

    2005-01-01

    Retina and retinal pigment epithelium (RPE) belong to the metabolically most active tissues in the human body. Efficient removal of acid load from retina and RPE is a critical function mediated by the choriocapillaris. However, the mechanism by which pH homeostasis is maintained is largely unknown.

  4. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.

    NARCIS (Netherlands)

    Khanna, H.; Davis, E.E.; Murga-Zamalloa, C.A.; Estrada-Cuzcano, A.; Lopez, I.; Hollander, A.I. den; Zonneveld-Vrieling, M.N.; Othman, M.I.; Waseem, N.; Chakarova, C.; Maubaret, C.; Diaz-Font, A.; Macdonald, I.; Muzny, D.M.; Wheeler, D.A.; Morgan, M.; Lewis, L.R.; Logan, C.V.; Tan, P.L.; Beer, M.A.; Inglehearn, C.F.; Lewis, R.A.; Jacobson, S.G.; Bergmann, C.; Beales, P.L.; Attie-Bitach, T.; Johnson, C.A.; Otto, E.A.; Bhattacharya, S.S.; Hildebrandt, F.; Gibbs, R.A.; Koenekoop, R.K.; Swaroop, A.; Katsanis, N.

    2009-01-01

    Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulat

  5. Retinal degeneration in progressive supranuclear palsy measured by optical coherence tomography and scanning laser polarimetry.

    Science.gov (United States)

    Stemplewitz, Birthe; Kromer, Robert; Vettorazzi, Eik; Hidding, Ute; Frings, Andreas; Buhmann, Carsten

    2017-07-13

    This cross-sectional study compared the retinal morphology between patients with progressive supranuclear palsy (PSP) and healthy controls. (The retinal nerve fiber layer (RNFL) around the optic disc and the retina in the macular area of 22 PSP patients and 151 controls were investigated by spectral domain optical coherence tomography (SD-OCT). Additionally, the RNFL and the nerve fiber index (NFI) were measured by scanning laser polarimetry (SLP). Results of RNFL measurements with SD-OCT and SLP were compared to assess diagnostic discriminatory power. Applying OCT, PSP patients showed a smaller RNFL thickness in the inferior nasal and inferior temporal areas. The macular volume and the thickness of the majority of macular sectors were reduced compared to controls. SLP data showed a thinner RNFL thickness and an increase in the NFI in PSP patients. Sensitivity and specificity to discriminate PSP patients from controls were higher applying SLP than SD-OCT. Retinal changes did not correlate with disease duration or severity in any OCT or SLP measurement. PSP seems to be associated with reduced thickness and volume of the macula and reduction of the RNFL, independent of disease duration or severity. Retinal imaging with SD-OCT and SLP might become an additional tool in PSP diagnosis.

  6. Natural Compounds from Saffron and Bear Bile Prevent Vision Loss and Retinal Degeneration

    Directory of Open Access Journals (Sweden)

    Laura Fernández-Sánchez

    2015-07-01

    Full Text Available All retinal disorders, regardless of their aetiology, involve the activation of oxidative stress and apoptosis pathways. The administration of neuroprotective factors is crucial in all phases of the pathology, even when vision has been completely lost. The retina is one of the most susceptible tissues to reactive oxygen species damage. On the other hand, proper development and functioning of the retina requires a precise balance between the processes of proliferation, differentiation and programmed cell death. The life-or-death decision seems to be the result of a complex balance between pro- and anti-apoptotic signals. It has been recently shown the efficacy of natural products to slow retinal degenerative process through different pathways. In this review, we assess the neuroprotective effect of two compounds used in the ancient pharmacopoeia. On one hand, it has been demonstrated that administration of the saffron constituent safranal to P23H rats, an animal model of retinitis pigmentosa, preserves photoreceptor morphology and number, the capillary network and the visual response. On the other hand, it has been shown that systemic administration of tauroursodeoxycholic acid (TUDCA, the major component of bear bile, to P23H rats preserves cone and rod structure and function, together with their contact with postsynaptic neurons. The neuroprotective effects of safranal and TUDCA make these compounds potentially useful for therapeutic applications in retinal degenerative diseases.

  7. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.

    NARCIS (Netherlands)

    Khanna, H.; Davis, E.E.; Murga-Zamalloa, C.A.; Estrada-Cuzcano, A.; Lopez, I.; Hollander, A.I. den; Zonneveld-Vrieling, M.N.; Othman, M.I.; Waseem, N.; Chakarova, C.; Maubaret, C.; Diaz-Font, A.; Macdonald, I.; Muzny, D.M.; Wheeler, D.A.; Morgan, M.; Lewis, L.R.; Logan, C.V.; Tan, P.L.; Beer, M.A.; Inglehearn, C.F.; Lewis, R.A.; Jacobson, S.G.; Bergmann, C.; Beales, P.L.; Attie-Bitach, T.; Johnson, C.A.; Otto, E.A.; Bhattacharya, S.S.; Hildebrandt, F.; Gibbs, R.A.; Koenekoop, R.K.; Swaroop, A.; Katsanis, N.

    2009-01-01

    Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase

  8. Safety and Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells Therapy for Retinal Degeneration.

    Directory of Open Access Journals (Sweden)

    S N Leow

    Full Text Available To investigate the safety and efficacy of subretinal injection of human Wharton's Jelly-derived mesenchymal stem cells (hWJ-MSCs on retinal structure and function in Royal College of Surgeons (RCS rats.RCS rats were divided into 2 groups: hWJ-MSCs treated group (n = 8 and placebo control group (n = 8. In the treatment group, hWJ-MSCs from healthy donors were injected into the subretinal space in one eye of each rat at day 21. Control group received saline injection of the same volume. Additional 3 animals were injected with nanogold-labelled stem cells for in vivo tracking of cells localisation using a micro-computed tomography (microCT. Retinal function was assessed by electroretinography (ERG 3 days before the injection and repeated at days 15, 30 and 70 after the injection. Eyes were collected at day 70 for histology, cellular and molecular studies.No retinal tumor formation was detected by histology during the study period. MicroCT scans showed that hWJ-MSCs stayed localised in the eye with no systemic migration. Transmission electron microscopy showed that nanogold-labelled cells were located within the subretinal space. Histology showed preservation of the outer nuclear layer (ONL in the treated group but not in the control group. However, there were no significant differences in the ERG responses between the groups. Confocal microscopy showed evidence of hWJ-MSCs expressing markers for photoreceptor, Müller cells and bipolar cells.Subretinal injection of hWJ-MSCs delay the loss of the ONL in RCS rats. hWJ-MSCs appears to be safe and has potential to differentiate into retinal-like cells. The potential of this cell-based therapy for the treatment of retinal dystrophies warrants further studies.

  9. Systemic Injection of RPE65-Programmed Bone Marrow-Derived Cells Prevents Progression of Chronic Retinal Degeneration.

    Science.gov (United States)

    Qi, Xiaoping; Pay, S Louise; Yan, Yuanqing; Thomas, James; Lewin, Alfred S; Chang, Lung-Ji; Grant, Maria B; Boulton, Michael E

    2017-04-05

    Bone marrow stem and progenitor cells can differentiate into a range of non-hematopoietic cell types, including retinal pigment epithelium (RPE)-like cells. In this study, we programmed bone marrow-derived cells (BMDCs) ex vivo by inserting a stable RPE65 transgene using a lentiviral vector. We tested the efficacy of systemically administered RPE65-programmed BMDCs to prevent visual loss in the superoxide dismutase 2 knockdown (Sod2 KD) mouse model of age-related macular degeneration. Here, we present evidence that these RPE65-programmed BMDCs are recruited to the subretinal space, where they repopulate the RPE layer, preserve the photoreceptor layer, retain the thickness of the neural retina, reduce lipofuscin granule formation, and suppress microgliosis. Importantly, electroretinography and optokinetic response tests confirmed that visual function was significantly improved. Mice treated with non-modified BMDCs or BMDCs pre-programmed with LacZ did not exhibit significant improvement in visual deficit. RPE65-BMDC administration was most effective in early disease, when visual function and retinal morphology returned to near normal, and less effective in late-stage disease. This experimental paradigm offers a minimally invasive cellular therapy that can be given systemically overcoming the need for invasive ocular surgery and offering the potential to arrest progression in early AMD and other RPE-based diseases.

  10. The heat-shock response co-inducer arimoclomol protects against retinal degeneration in rhodopsin retinitis pigmentosa

    Science.gov (United States)

    Parfitt, D A; Aguila, M; McCulley, C H; Bevilacqua, D; Mendes, H F; Athanasiou, D; Novoselov, S S; Kanuga, N; Munro, P M; Coffey, P J; Kalmar, B; Greensmith, L; Cheetham, M E

    2014-01-01

    Retinitis pigmentosa (RP) is a group of inherited diseases that cause blindness due to the progressive death of rod and cone photoreceptors in the retina. There are currently no effective treatments for RP. Inherited mutations in rhodopsin, the light-sensing protein of rod photoreceptor cells, are the most common cause of autosomal-dominant RP. The majority of mutations in rhodopsin, including the common P23H substitution, lead to protein misfolding, which is a feature in many neurodegenerative disorders. Previous studies have shown that upregulating molecular chaperone expression can delay disease progression in models of neurodegeneration. Here, we have explored the potential of the heat-shock protein co-inducer arimoclomol to ameliorate rhodopsin RP. In a cell model of P23H rod opsin RP, arimoclomol reduced P23H rod opsin aggregation and improved viability of mutant rhodopsin-expressing cells. In P23H rhodopsin transgenic rat models, pharmacological potentiation of the stress response with arimoclomol improved electroretinogram responses and prolonged photoreceptor survival, as assessed by measuring outer nuclear layer thickness in the retina. Furthermore, treated animal retinae showed improved photoreceptor outer segment structure and reduced rhodopsin aggregation compared with vehicle-treated controls. The heat-shock response (HSR) was activated in P23H retinae, and this was enhanced with arimoclomol treatment. Furthermore, the unfolded protein response (UPR), which is induced in P23H transgenic rats, was also enhanced in the retinae of arimoclomol-treated animals, suggesting that arimoclomol can potentiate the UPR as well as the HSR. These data suggest that pharmacological enhancement of cellular stress responses may be a potential treatment for rhodopsin RP and that arimoclomol could benefit diseases where ER stress is a factor. PMID:24853414

  11. Bacterial endotoxin activates retinal pigment epithelial cells and induces their degeneration through IL-6 and IL-8 autocrine signaling.

    Science.gov (United States)

    Leung, Kar Wah; Barnstable, Colin J; Tombran-Tink, Joyce

    2009-04-01

    Inflammation is a major contributing factor to many blinding disorders including uveitis, diabetic retinopathy, and age-related macular degeneration. Here we examined the response of the retinal pigment epithelium (RPE) to physiological levels of lipopolysaccharide (LPS) to understand the role of this epithelium in inflammatory retinal conditions. Expression of a group of inflammatory mediators was identified by gene array analysis and confirmed by PCR and immunocytochemistry in primary human RPE cultures and ARPE19. The effects of LPS on the expression of these cytokines and RPE survival were examined by PCR, Luminex bead, and MTT assays. RPE cells express many cytokine receptors including IL-1R, -4R, -6R, -8RA, IFNAR1, IFNGR1/2 and secrete a range of pro- and anti-inflammatory cytokines including IL-4, -6, -8, -10, -17, IFN-gamma, MCP-1, and VEGF. LPS increases IL-13RA1 and IFNAR1, and decreases IL-7R receptor expression. It also increases RPE secretion of IL-4, -6, -8, -10, IFN-gamma and MCP-1, and is toxic to RPE cells at LC(50)=17.7 microg/ml. LPS toxicity is mediated by IL-6 and IL-8 through an autocrine feedback loop. Silencing IL-6R and IL-8RA gene expression by siRNA blocks death by their respective ligands or LPS. These findings imply that RPE cells are acutely sensitive to inflammatory stress and that over secretion of IL-6 and IL-8 by this epithelium during inflammatory stimulus may be an underlying factor in the progression of some retinal pathologies.

  12. Genome-wide association study in RPGRIP1(-/-) dogs identifies a modifier locus that determines the onset of retinal degeneration.

    Science.gov (United States)

    Miyadera, Keiko; Kato, Kumiko; Boursnell, Mike; Mellersh, Cathryn S; Sargan, David R

    2012-02-01

    Cone-rod dystrophy (CRD) is a form of inherited retinal degeneration (RD) causing blindness in man as well as in several breeds of dog. Previously, a 44 bp insertion in RPGRIP1 (retinitis pigmentosa GTPase regulator interacting protein-1) was associated with a recessive early-onset CRD (cone-rod dystrophy 1, cord1) in a Miniature longhaired dachshund (MLHD) research colony. Yet in the MLHD pet population, extensive range of the onset age has been observed among RD cases, with some RPGRIP1(-/-) dogs lacking obvious clinical signs. Phenotypic variation has been known in human homologous diseases, including retinitis pigmentosa and Leber congenital amaurosis, indicating possible involvement of modifiers. To explore additional genetic loci associated with the phenotypic variation observed in MLHDs, a genome-wide association study was carried out using Canine SNP20 arrays in 83 RPGRIP1(-/-) MLHDs with variable ages of onset or no clinical abnormality. Using these samples, comparison of 31 early-onset RD cases against 49 controls (15 late-onset RD and 34 normal dogs combined) identified a strong association (P = 5.05 × 10(-13)) at a single locus on canine chromosome 15. At this locus, the majority of early-onset RD cases but few of the controls were homozygous for a 1.49 Mb interval containing ~11 genes. We conclude that homozygosity at both RPGRIP1 and the newly mapped second locus is necessary to develop early-onset RD, whereas RPGRIP1(-/-) alone leads to late-onset RD or no apparent clinical phenotype. This study establishes a unique model of canine RD requiring homozygous mutations at two distinct genetic loci for the manifestation of early-onset RD.

  13. [Laser photocoagulation and photodynamic therapy (PDT) with verteporfin for retinal angiomatous proliferation (RAP) in age-related macular degeneration (AMD)].

    Science.gov (United States)

    Stoffelns, B M; Kramann, C; Schoepfer, K

    2008-05-01

    Retinal angiomatous proliferation (RAP) is a subtype of neovascular age-related macular degeneration (AMD) with particularly bad prognosis. Diverse treatment modalities are performed. This is a retrospective review on the treatment results of 41 consecutive patients from 1/2003 to 12/2005 with RAP stage 1-3 (Yannuzzi classification), who were treated with laser photocoagulation, photodynamic therapy (PDT) and intravitreal injection of triamcinolone acetonide (IVT). Follow-up was 12 months minimally. In RAP stage I complete closure of the vascular lesion in 14 / 22 eyes was achieved by 1.2 +/- 0.5 sessions of laser photocoagulation (4 x combined with IVT) and in 3/14 eyes with photodynamic therapy (2 +/- 0.5 sessions). In RAP stage II closure of the lesion was achieved by 3.2 +/- 0.6 sessions of photodynamic therapy in 6/14 eyes (4 x combined with IVT). In RAP stage III closure of the lesion was achieved by 3.2 +/- 0.4 sessions of photodynamic therapy in 0 / 5 eyes (3 x combined with IVT). A rip of the retinal pigment epithelium was observed in 2/14 eyes of RAP stage II and 2/5 eyes of RAP stage III. Visual acuity improved in 9/17 eyes with occlusion of RAP stage I. Without closure of the vascular lesion all eyes got legally blind (visual acuity 1/50 or less). Early detection and subsequent direct treatment of RAP stage I in AMD is recommended. In advanced stages anatomical closure of the vascular complex is rarely achieved and the risk is improved for development of tears in the retinal pigment epithelium and getting legally blind.

  14. Inflammatory Cytokines Induce Expression of Chemokines by Human Retinal Cells: Role in Chemokine Receptor Mediated Age-related Macular Degeneration.

    Science.gov (United States)

    Nagineni, Chandrasekharam N; Kommineni, Vijay K; Ganjbaksh, Nader; Nagineni, Krishnasai K; Hooks, John J; Detrick, Barbara

    2015-11-01

    Chemokine reeptor-3 (CCR-3) was shown to be associated with choroidal neovascularization (CNV) in age-related macular degeneration (AMD). AMD is a vision threatening retinal disease that affects the aging population world-wide. Retinal pigment epithelium and choroid in the posterior part of the retina are the key tissues targeted in the pathogenesis of CNV in AMD. We used human retinal pigment epithelial (HRPE) and choroidal fibroblast (HCHF) cells, prepared from aged adult human donor eyes, to evaluate the expression of major CCR-3 ligands, CCL-5, CCL -7, CCL-11,CCL-24 and CCL-26. Microarray analysis of gene expression in HRPE cells treated with inflammatory cytokine mix (ICM= IFN-γ+TNF-α+IL-1β) revealed 75 and 23-fold increase in CCL-5 and CCL-7 respectively, but not CCL-11, CCL-24 and CCL-26. Chemokine secretion studies of the production of CCL5 and CCL7 by HRPE corroborated with the gene expression analysis data. When the HRPE cells were treated with either individual cytokines or the ICM, both CCL-5 and CCL-7 were produced in a dose dependent manner. Similar to the gene expression data, the ICM did not enhance HRPE production of CCL-11, CCL-24 and CCL-26. CCL-11 and CCL-26 were increased with IL-4 treatment and this HRPE production was augmented in the presence of TNF-α and IL1β. When HCHF cells were treated with either individual cytokines or the ICM, both CCL-5 and CCL-7 were produced in a dose dependent fashion. IL-4 induced low levels of CCL-11 and CCL-26 in HCHF and this production was significantly enhanced by TNF-α. Under these conditions, neither HRPE nor HCHF were demonstrated to produce CCL-24. These data demonstrate that chronic inflammation triggers CCL-5 and CCL-7 release by HRPE and HCHF and the subsequent interactions with CCR3 may participate in pathologic processes in AMD.

  15. Expression of wild-type Rp1 protein in Rp1 knock-in mice rescues the retinal degeneration phenotype.

    Directory of Open Access Journals (Sweden)

    Qin Liu

    Full Text Available Mutations in the retinitis pigmentosa 1 (RP1 gene are a common cause of autosomal dominant retinitis pigmentosa (adRP, and have also been found to cause autosomal recessive RP (arRP in a few families. The 33 dominant mutations and 6 recessive RP1 mutations identified to date are all nonsense or frameshift mutations, and almost exclusively (38 out of 39 are located in the 4(th and final exon of RP1. To better understand the underlying disease mechanisms of and help develop therapeutic strategies for RP1 disease, we performed a series of human genetic and animal studies using gene targeted and transgenic mice. Here we report that a frameshift mutation in the 3(rd exon of RP1 (c.686delC; p.P229QfsX35 found in a patient with recessive RP1 disease causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism for RP1 disease. We then generated Rp1 knock-in mice with a nonsense Q662X mutation in exon 4, as well as Rp1 transgenic mice carrying a wild-type BAC Rp1 transgene. The Rp1-Q662X allele produces a truncated Rp1 protein, and homozygous Rp1-Q662X mice experience a progressive photoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expression of a normal amount of Rp1 protein from the BAC transgene without removal of the mutant Rp1-Q662X protein. Over-expression of Rp1 protein in additional BAC Rp1 transgenic lines resulted in retinal degeneration. These findings suggest that the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. These results also imply that in principle gene augmentation therapy could be beneficial for both recessive and dominant RP1 patients, but the levels of RP1 protein delivered for therapy will have to be carefully controlled.

  16. Transplantation of human bone marrow mesenchymal stem cells as a thin subretinal layer ameliorates retinal degeneration in a rat model of retinal dystrophy.

    Science.gov (United States)

    Tzameret, Adi; Sher, Ifat; Belkin, Michael; Treves, Avraham J; Meir, Amilia; Nagler, Arnon; Levkovitch-Verbin, Hani; Barshack, Iris; Rosner, Mordechai; Rotenstreich, Ygal

    2014-01-01

    Vision incapacitation and blindness associated with retinal degeneration affect millions of people worldwide. Cell based therapy and specifically transplantation of human adult bone marrow-derived stem cells (hBM-MSCs) present possible treatment strategy. Subretinal transplantation of human or rat BM-MSCs was shown previously to improve retinal function in Royal College Surgeons (RCS) rats. In those studies cells were transplanted via a transscleral-transchoroidal approach, creating a localized subretinal bleb. Limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection site. Here we describe a new surgical method for subretinal transplantation that facilitates uniform distribution of transplanted cells as a thin layer along most of the subretinal space. We assessed the therapeutic effect of hBM-MSCs on RCS rats when transplanted either subretinally or intravitreally. We also examined whether a second transplantation can prolong the therapeutic effect. A cell suspension of 2.5 × 10(6) cells in 5 μl was injected subretinally or intravitreally in RCS rats at 28 days postnatal. In the subretinal group, hBM-MSCs were transplanted posterior to the limbus in the superotemporal part of the eye through a longitudinal triangular scleral tunnel reaching the choroid. In the intravitreal group, the cells were injected into the superotemporal part of the vitreous cavity. In cross sections of subretinally transplanted eyes, removed 2 h following transplantation, hBM-MSCs were distributed as a near-homogenous thin layer along most of the subretinal space. In some animals the cells were also detected in the choroid. In the intravitreal injection group, hBM-MSCs were clustered in the vitreous cavity. Transplanted cells could be detected up to 2 weeks after transplantation but not at later time points. Retinal function and structure were assessed by electroretinogram (ERG) and histology analysis, respectively. Six

  17. Q344ter mutation causes mislocalization of rhodopsin molecules that are catalytically active: a mouse model of Q344ter-induced retinal degeneration.

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    Francis Concepcion

    Full Text Available Q344ter is a naturally occurring rhodopsin mutation in humans that causes autosomal dominant retinal degeneration through mechanisms that are not fully understood, but are thought to involve an early termination that removed the trafficking signal, QVAPA, leading to its mislocalization in the rod photoreceptor cell. To better understand the disease mechanism(s, transgenic mice that express Q344ter were generated and crossed with rhodopsin knockout mice. Dark-reared Q344ter(rho+/- mice exhibited retinal degeneration, demonstrating that rhodopsin mislocalization caused photoreceptor cell death. This degeneration is exacerbated by light-exposure and is correlated with the activation of transducin as well as other G-protein signaling pathways. We observed numerous sub-micrometer sized vesicles in the inter-photoreceptor space of Q344ter(rho+/- and Q344ter(rho-/- retinas, similar to that seen in another rhodopsin mutant, P347S. Whereas light microscopy failed to reveal outer segment structures in Q344ter(rho-/- rods, shortened and disorganized rod outer segment structures were visible using electron microscopy. Thus, some Q344ter molecules trafficked to the outer segment and formed disc structures, albeit inefficiently, in the absence of full length wildtype rhodopsin. These findings helped to establish the in vivo role of the QVAPA domain as well as the pathways leading to Q344ter-induced retinal degeneration.

  18. Biochemical Measurements of Free Opsin in Macular Degeneration Eyes: Examining the 11-CIS Retinal Deficiency Hypothesis of Delayed Dark Adaptation (An American Ophthalmological Society Thesis).

    Science.gov (United States)

    Hanneken, Anne; Neikirk, Thomas; Johnson, Jennifer; Kono, Masahiro

    2017-08-01

    To test the hypothesis that delayed dark adaptation in patients with macular degeneration is due to an excess of free unliganded opsin (apo-opsin) and a deficiency of the visual chromophore, 11-cis retinal, in rod outer segments. A total of 50 human autopsy eyes were harvested from donors with and without macular degeneration within 2-24 hrs. postmortem. Protocols were developed which permitted dark adaptation of normal human eyes after death and enucleation. Biochemical methods of purifying rod outer segments were optimized and the concentration of rhodopsin and apo-opsin was measured with UV-visible scanning spectroscopy. The presence of apo-opsin was calculated by measuring the difference in the rhodopsin absorption spectra before and after the addition of 11-cis retinal. A total of 20 normal eyes and 16 eyes from donors with early, intermediate and advanced stages of macular degeneration were included in the final analysis. Dark adaptation was achieved by harvesting whole globes in low light, transferring into dark (light-proof) canisters and dissecting the globes using infrared light and image converters for visualization. Apo-opsin was readily detected in positive controls after the addition of 11-cis retinal. Normal autopsy eyes showed no evidence of apo-opsin. Eyes with macular degeneration also showed no evidence of apo-opsin, regardless of the severity of disease. Methods have been developed to study dark adaptation in human autopsy eyes. Eyes with age-related macular degeneration do not show a deficiency of 11-cis retinal or an excess of apo-opsin within rod outer segments.

  19. Ccl2, Cx3cr1 and Ccl2/Cx3cr1 chemokine deficiencies are not sufficient to cause age-related retinal degeneration.

    Science.gov (United States)

    Luhmann, Ulrich F O; Carvalho, Livia S; Robbie, Scott J; Cowing, Jill A; Duran, Yanai; Munro, Peter M G; Bainbridge, James W B; Ali, Robin R

    2013-02-01

    Monocytes, macrophages, dendritic cells and microglia play critical roles in the local immune response to acute and chronic tissue injury and have been implicated in the pathogenesis of age-related macular degeneration. Defects in Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling cause enhanced accumulation of bloated subretinal microglia/macrophages in senescent mice and this phenomenon is reported to result in the acceleration of age-related retinal degeneration. The purpose of this study was to determine whether defects in CCL2-CCR2 and CX3CL1-CX3CR1 signalling pathways, alone or in combination, cause age-dependent retinal degeneration. We tested whether three chemokine knockout mouse lines, Ccl2(-/-), Cx3cr1(-/-) and Ccl2(-/-)/Cx3cr1(-/-), in comparison to age-matched C57Bl/6 control mice show differences in subretinal macrophage accumulation and loss of adjacent photoreceptor cells at 12-14 months of age. All mouse lines are derived from common parental strains and do not carry the homozygous rd8 mutation in the Crb1 gene that has been a major confounding factor in previous reports. We quantified subretinal macrophages by counting autofluorescent lesions in fundus images obtained by scanning laser ophthalmoscopy (AF-SLO) and by immunohistochemistry for Iba1 positive cells. The accumulation of subretinal macrophages was enhanced in Ccl2(-/-), but not in Cx3cr1(-/-) or Ccl2(-/-)/Cx3cr1(-/-) mice. We identified no evidence of retinal degeneration in any of these mouse lines by TUNEL staining or semithin histology. In conclusion, CCL2-CCR2 and/or CX3CL1-CX3CR1 signalling defects may differentially affect the trafficking of microglia and macrophages in the retina during ageing, but do not appear to cause age-related retinal degeneration in mice.

  20. The generation of induced pluripotent stem cells for macular degeneration as a drug screening platform: identification of curcumin as a protective agent for retinal pigment epithelial cells against oxidative stress

    National Research Council Canada - National Science Library

    Chang, Yun-Ching; Chang, Wei-Chao; Hung, Kuo-Hsuan; Yang, Der-Ming; Cheng, Yung-Hsin; Liao, Yi-Wen; Woung, Lin-Chung; Tsai, Ching-Yao; Hsu, Chih-Chien; Lin, Tai-Chi; Liu, Jorn-Hon; Chiou, Shih-Hwa; Peng, Chi-Hsien; Chen, Shih-Jen

    2014-01-01

    .... Its pathogenesis remains unclear, but oxidative stress inducing retinal pigment epithelial (RPE) cells damage is perhaps responsible for the aging sequence of retina and may play an important role in macular degeneration...

  1. Mutations in the mitochondrial tRNA Ser(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy.

    Science.gov (United States)

    Tuppen, Helen A L; Naess, Karin; Kennaway, Nancy G; Al-Dosary, Mazhor; Lesko, Nicole; Yarham, John W; Bruhn, Helene; Wibom, Rolf; Nennesmo, Inger; Weleber, Richard G; Blakely, Emma L; Taylor, Robert W; McFarland, Robert

    2012-08-01

    Although over 200 pathogenic mitochondrial DNA (mtDNA) mutations have been reported to date, determining the genetic aetiology of many cases of mitochondrial disease is still not straightforward. Here, we describe the investigations undertaken to uncover the underlying molecular defect(s) in two unrelated Caucasian patients with suspected mtDNA disease, who presented with similar symptoms of myopathy, deafness, neurodevelopmental delay, epilepsy, marked fatigue and, in one case, retinal degeneration. Histochemical and biochemical evidence of mitochondrial respiratory chain deficiency was observed in the patient muscle biopsies and both patients were discovered to harbour a novel heteroplasmic mitochondrial tRNA (mt-tRNA)(Ser(AGY)) (MTTS2) mutation (m.12264C>T and m.12261T>C, respectively). Clear segregation of the m.12261T>C mutation with the biochemical defect, as demonstrated by single-fibre radioactive RFLP, confirmed the pathogenicity of this novel variant in patient 2. However, unusually high levels of m.12264C>T mutation within both COX-positive (98.4 ± 1.5%) and COX-deficient (98.2 ± 2.1%) fibres in patient 1 necessitated further functional investigations to prove its pathogenicity. Northern blot analysis demonstrated the detrimental effect of the m.12264C>T mutation on mt-tRNA(Ser(AGY)) stability, ultimately resulting in decreased steady-state levels of fully assembled complexes I and IV, as shown by blue-native polyacrylamide gel electrophoresis. Our findings expand the spectrum of pathogenic mutations associated with the MTTS2 gene and highlight MTTS2 mutations as an important cause of retinal and syndromic auditory impairment.

  2. Degeneration of retinal on bipolar cells induced by serum including autoantibody against TRPM1 in mouse model of paraneoplastic retinopathy.

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    Shinji Ueno

    Full Text Available The paraneoplastic retinopathies (PRs are a group of eye diseases characterized by a sudden and progressive dysfunction of the retina caused by an antibody against a protein in a neoplasm. Evidence has been obtained that the transient receptor potential melastatin 1 (TRPM1 protein was one of the antigens for the autoantibody against the ON bipolar cells in PR patients. However, it has not been determined how the autoantibody causes the dysfunction of the ON bipolar cells. We hypothesized that the antibody against TRPM1 in the serum of patients with PR causes a degeneration of retinal ON bipolar cells. To test this hypothesis, we injected the serum from the PR patient, previously shown to contain anti-TRPM1 antibodies by westerblot, intravitreally into mice and examined the effects on the retina. We found that the electroretinograms (ERGs of the mice were altered acutely after the injection, and the shape of the ERGs resembled that of the patient with PR. Immunohistochemical analysis of the eyes injected with the serum showed immunoreactivity against bipolar cells only in wild-type animals and not in TRPM1 knockout mice,consistent with the serum containing anti-TRPM1 antibodies. Histology also showed that some of the bipolar cells were apoptotic by 5 hours after the injection in wild type mice, but no bipolar cell death was found in TRPM1 knockout mice, . At 3 months, the inner nuclear layer was thinner and the amplitudes of the ERGs were still reduced. These results indicate that the serum of a patient with PR contained an antibody against TRPM1 caused an acute death of retinal ON bipolar cells of mice.

  3. Research resource: nuclear receptor atlas of human retinal pigment epithelial cells: potential relevance to age-related macular degeneration.

    Science.gov (United States)

    Dwyer, Mary A; Kazmin, Dmitri; Hu, Peng; McDonnell, Donald P; Malek, Goldis

    2011-02-01

    Retinal pigment epithelial (RPE) cells play a vital role in retinal physiology by forming the outer blood-retina barrier and supporting photoreceptor function. Retinopathies including age-related macular degeneration (AMD) involve physiological and pathological changes in the epithelium, severely impairing the retina and effecting vision. Nuclear receptors (NRs), including peroxisome proliferator-activated receptor and liver X receptor, have been identified as key regulators of physiological pathways such as lipid metabolic dysregulation and inflammation, pathways that may also be involved in development of AMD. However, the expression levels of NRs in RPE cells have yet to be systematically surveyed. Furthermore, cell culture lines are widely used to study the biology of RPE cells, without knowledge of the differences or similarities in NR expression and activity between these in vitro models and in vivo RPE. Using quantitative real-time PCR, we assessed the expression patterns of all 48 members of the NR family plus aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator in human RPE cells. We profiled freshly isolated cells from donor eyes (in vivo), a spontaneously arising human cell line (in vitro), and primary cell culture lines (in vitro) to determine the extent to which NR expression in the cultured cell lines reflects that of in vivo. To evaluate the validity of using cell culture models for investigating NR receptor biology, we determined transcriptional activity and target gene expression of several moderately and highly expressed NRs in vitro. Finally, we identified a subset of NRs that may play an important role in pathobiology of AMD.

  4. Ablation of C/EBP homologous protein does not protect T17M RHO mice from retinal degeneration.

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    Sonali Nashine

    Full Text Available Despite the proposed link between ablation of the CHOP protein and delay of the onset of ER stress-mediated disorders including diabetes, Alzheimer Disease, and cardiac hypertrophy, the role of CHOP protein in photoreceptor cell death associated with Autosomal Dominant Retinitis Pigmentosa (ADRP has not been investigated. T17M RHO transgenic mice carry a mutated human rhodopsin transgene, the expression of which in retina leads to protein misfolding, activation of UPR and progressive retinal degeneration. The purpose of this study is to investigate the role of CHOP protein in T17M RHO retina. Wild-type, CHOP-/-, T17M RHO and T17M RHO CHOP-/-mice were used in the study. Evaluation of the impact of CHOP ablation was performed using electroretinography (ERG, spectral-domain optical coherence tomography (SD-OCT, quantitative Real-Time PCR (qRT-PCR and western blot analysis. Dark-adapted ERG analysis demonstrated that by 1 month, the T17M RHO CHOP-/- mice had a 70% reduction of the a-wave amplitude compared to the T17M RHO mice. The loss of function in T17M RHO CHOP-/- photoreceptors was associated with a 22-24% decline in the thickness of the outer nuclear layer. These mice had significant reduction in the expression of transcription factors, Crx and Nrl, and also in mouse Rho, and human RHO. The reduction was associated with an 8-fold elevation of the UPR marker, p-eIf2α protein and 30% down-regulation of sXbp1 protein. In addition, the histone deacetylase 1 (Hdac1 protein was 2-fold elevated in the T17M RHO CHOP-/- retina. The ablation of CHOP led to a reduction in the expression of photoreceptor-specific transcriptional factors, and both endogenous and exogenous RHO mRNA. Thus, despite its role in promoting apoptosis, CHOP protects rod photoreceptors carrying an ADRP mutation.

  5. Complement system dysregulation and inflammation in the retinal pigment epithelium of a mouse model for Stargardt macular degeneration.

    Science.gov (United States)

    Radu, Roxana A; Hu, Jane; Yuan, Quan; Welch, Darcy L; Makshanoff, Jacob; Lloyd, Marcia; McMullen, Stephen; Travis, Gabriel H; Bok, Dean

    2011-05-27

    Accumulation of vitamin A-derived lipofuscin fluorophores in the retinal pigment epithelium (RPE) is a pathologic feature of recessive Stargardt macular dystrophy, a blinding disease caused by dysfunction or loss of the ABCA4 transporter in rods and cones. Age-related macular degeneration, a prevalent blinding disease of the elderly, is strongly associated with mutations in the genes for complement regulatory proteins (CRP), causing chronic inflammation of the RPE. Here we explore the possible relationship between lipofuscin accumulation and complement activation in vivo. Using the abca4(-/-) mouse model for recessive Stargardt, we investigated the role of lipofuscin fluorophores (A2E-lipofuscin) on oxidative stress and complement activation. We observed higher expression of oxidative-stress genes and elevated products of lipid peroxidation in eyes from abca4(-/-) versus wild-type mice. We also observed higher levels of complement-activation products in abca4(-/-) RPE cells. Unexpectedly, expression of multiple CRPs, which protect cells from attack by the complement system, were lower in abca4(-/-) versus wild-type RPE. To test whether acute exposure of healthy RPE cells to A2E-lipofuscin affects oxidative stress and expression of CRPs, we fed cultured fetal-derived human RPE cells with rod outer segments from wild-type or abca4(-/-) retinas. In contrast to RPE cells in abca4(-/-) mice, human RPE cells exposed to abca4(-/-) rod outer segments adaptively increased expression of both oxidative-stress and CRP genes. These results suggest that A2E accumulation causes oxidative stress, complement activation, and down-regulation of protective CRP in the Stargardt mouse model. Thus, Stargardt disease and age-related macular degeneration may both be caused by chronic inflammation of the RPE.

  6. ER stress in retinal degeneration in S334ter Rho rats.

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    Vishal M Shinde

    Full Text Available The S334ter rhodopsin (Rho rat (line 4 bears the rhodopsin gene with an early termination codon at residue 334 that is a model for several such mutations found in human patients with autosomal dominant retinitis pigmentosa (ADRP. The Unfolded Protein Response (UPR is implicated in the pathophysiology of several retinal disorders including ADRP in P23H Rho rats. The aim of this study was to examine the onset of UPR gene expression in S334ter Rho retinas to determine if UPR is activated in ADRP animal models and to investigate how the activation of UPR molecules leads to the final demise of S334ter Rho photoreceptors. RT-PCR was performed to evaluate the gene expression profiles for the P10, P12, P15, and P21 stages of the development and progression of ADRP in S334ter Rho photoreceptors. We determined that during the P12-P15 period, ER stress-related genes are strongly upregulated in transgenic retinas, resulting in the activation of the UPR that was confirmed using western blot analysis and RT-PCR. The activation of UPR was associated with the increased expression of JNK, Bik, Bim, Bid, Noxa, and Puma genes and cleavage of caspase-12 that together with activated calpains presumably compromise the integrity of the mitochondrial MPTP, leading to the release of pro-apoptotic AIF1 into the cytosol of S334ter Rho photoreceptor cells. Therefore, two major cross-talking pathways, the UPR and mitochondrial MPTP occur in S334ter-4 Rho retina concomitantly and eventually promote the death of the photoreceptor cells.

  7. Mice with early retinal degeneration show differences in neuropeptide expression in the suprachiasmatic nucleus

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    Brown R Lane

    2010-07-01

    Full Text Available Abstract Background In mammals, the brain clock responsible for generating circadian rhythms is located in the suprachiasmatic nucleus (SCN of the hypothalamus. Light entrainment of the clock occurs through intrinsically photosensitive retinal ganglion cells (ipRGCs whose axons project to the SCN via the retinohypothalamic tract. Although ipRGCs are sufficient for photoentrainment, rod and cone photoreceptors also contribute. Adult CBA/J mice, which exhibit loss of rod and cone photoreceptors during early postnatal development, have greater numbers of ipRGCs compared to CBA/N control mice. A greater number of photosensitive cells might argue for enhanced light responses, however, these mice exhibit attenuated phase shifting behaviors. To reconcile these findings, we looked for potential differences in SCN neurons of CBA/J mice that might underly the altered circadian behaviors. We hypothesized that CBA/J mice have differences in the expression of neuropeptides in the SCN, where ipRGCs synapse. The neuropeptides vasoactive intestinal peptide (VIP and vasopressin (VP are expressed by many SCN neurons and play an important role in the generation of circadian rhythms and photic entrainment. Methods Using immunohistochemistry, we looked for differences in the expression of VIP and VP in the SCN of CBA/J mice, and using a light-induced FOS assay, we also examined the degree of retinal innervation of the SCN by ipRGCs. Results Our data demonstrate greater numbers of VIP-and VP-positive cells in the SCN of CBA/J mice and a greater degree of light-induced FOS expression. Conclusions These results implicate changes in neuropeptide expression in the SCN which may underlie the altered circadian responses to light in these animals.

  8. Age-related retinal degeneration (arrd2) in a novel mouse model due to a nonsense mutation in the Mdm1 gene.

    Science.gov (United States)

    Chang, Bo; Mandal, Md Nawajes A; Chavali, Venkata R M; Hawes, Norman L; Khan, Naheed W; Hurd, Ronald E; Smith, Richard S; Davisson, Muriel L; Kopplin, Laura; Klein, Barbara E K; Klein, Ronald; Iyengar, Sudha K; Heckenlively, John R; Ayyagari, Radha

    2008-12-15

    We observed that a naturally occurring mouse strain developed age-related retinal degeneration (arrd2). These mice had normal fundi, electroretinograms (ERGs) and retinal histology at 6 months of age; vessel attenuation, RPE atrophy and pigmentary abnormalities at 14 months, which progressed to complete loss of photoreceptors and extinguished ERG by 22 months. Genetic analysis revealed that the retinal degeneration in arrd2 segregates in an autosomal recessive manner and the disease gene localizes to mouse chromosome 10. A positional candidate cloning approach detected a nonsense mutation in the mouse double minute-1 gene (Mdm1), which results in the truncation of the putative protein from 718 amino acids to 398. We have identified a novel transcript of the Mdm1 gene, which is the predominant transcript in the retina. The Mdm1 transcript is localized to the nuclear layers of neural retina. Expression of Mdm1 in the retina increases steadily from post-natal day 30 to 1 year, and a high level of Mdm1 are subsequently maintained. The Mdm1 transcript was found to be significantly depleted in the retina of arrd2 mice and the transcript was observed to degrade by nonsense-mediated decay. These results indicate that the depletion of the Mdm1 transcript may underlie the mechanism leading to late-onset progressive retinal degeneration in arrd2 mice. Analysis of a cohort of patients with age-related macular degeneration (AMD) wherein the susceptibility locus maps to chromosome 12q, a region bearing the human ortholog to MDM1, did not reveal association between human MDM1 and AMD.

  9. Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration.

    Science.gov (United States)

    Murakami, Y; Matsumoto, H; Roh, M; Giani, A; Kataoka, K; Morizane, Y; Kayama, M; Thanos, A; Nakatake, S; Notomi, S; Hisatomi, T; Ikeda, Y; Ishibashi, T; Connor, K M; Miller, J W; Vavvas, D G

    2014-02-01

    There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I : C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3(-/-) mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I : C)-induced retinal degeneration. Moreover, after poly(I : C) injection, Rip3(-/-) mice displayed decreased levels of pro-inflammatory cytokines (such as TNF-α and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I : C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF-α and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF-α and IL-6 production after poly(I : C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.

  10. Sudden acquired retinal degeneration syndrome (SARDS) - a review and proposed strategies toward a better understanding of pathogenesis, early diagnosis, and therapy

    OpenAIRE

    Komáromy, AM; Abrams, KL; Heckenlively, JR; Lundy, SK; Maggs, DJ; Leeth, CM; Mohankumar, PS; Petersen-Jones, SM; Serreze, DV; van der Woerdt, A

    2015-01-01

    © 2015 American College of Veterinary Ophthalmologists. Sudden acquired retinal degeneration syndrome (SARDS) is one of the leading causes of currently incurable canine vision loss diagnosed by veterinary ophthalmologists. The disease is characterized by acute onset of blindness due to loss of photoreceptor function, extinguished electroretinogram with an initially normal appearing ocular fundus, and mydriatic pupils which are slowly responsive to bright white light, unresponsive to red, but ...

  11. Time-Dependent Nerve Growth Factor Signaling Changes in the Rat Retina During Optic Nerve Crush-Induced Degeneration of Retinal Ganglion Cells

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    Louise A. Mesentier-Louro

    2017-01-01

    Full Text Available Nerve growth factor (NGF is suggested to be neuroprotective after nerve injury; however, retinal ganglion cells (RGC degenerate following optic-nerve crush (ONC, even in the presence of increased levels of endogenous NGF. To further investigate this apparently paradoxical condition, a time-course study was performed to evaluate the effects of unilateral ONC on NGF expression and signaling in the adult retina. Visually evoked potential and immunofluorescence staining were used to assess axonal damage and RGC loss. The levels of NGF, proNGF, p75NTR, TrkA and GFAP and the activation of several intracellular pathways were analyzed at 1, 3, 7 and 14 days after crush (dac by ELISA/Western Blot and PathScan intracellular signaling array. The progressive RGC loss and nerve impairment featured an early and sustained activation of apoptotic pathways; and GFAP and p75NTR enhancement. In contrast, ONC-induced reduction of TrkA, and increased proNGF were observed only at 7 and 14 dac. We propose that proNGF and p75NTR contribute to exacerbate retinal degeneration by further stimulating apoptosis during the second week after injury, and thus hamper the neuroprotective effect of the endogenous NGF. These findings might aid in identifying effective treatment windows for NGF-based strategies to counteract retinal and/or optic-nerve degeneration.

  12. Time-Dependent Nerve Growth Factor Signaling Changes in the Rat Retina During Optic Nerve Crush-Induced Degeneration of Retinal Ganglion Cells

    Science.gov (United States)

    Mesentier-Louro, Louise A.; De Nicolò, Sara; Rosso, Pamela; De Vitis, Luigi A.; Castoldi, Valerio; Leocani, Letizia; Mendez-Otero, Rosalia; Santiago, Marcelo F.; Tirassa, Paola; Rama, Paolo; Lambiase, Alessandro

    2017-01-01

    Nerve growth factor (NGF) is suggested to be neuroprotective after nerve injury; however, retinal ganglion cells (RGC) degenerate following optic-nerve crush (ONC), even in the presence of increased levels of endogenous NGF. To further investigate this apparently paradoxical condition, a time-course study was performed to evaluate the effects of unilateral ONC on NGF expression and signaling in the adult retina. Visually evoked potential and immunofluorescence staining were used to assess axonal damage and RGC loss. The levels of NGF, proNGF, p75NTR, TrkA and GFAP and the activation of several intracellular pathways were analyzed at 1, 3, 7 and 14 days after crush (dac) by ELISA/Western Blot and PathScan intracellular signaling array. The progressive RGC loss and nerve impairment featured an early and sustained activation of apoptotic pathways; and GFAP and p75NTR enhancement. In contrast, ONC-induced reduction of TrkA, and increased proNGF were observed only at 7 and 14 dac. We propose that proNGF and p75NTR contribute to exacerbate retinal degeneration by further stimulating apoptosis during the second week after injury, and thus hamper the neuroprotective effect of the endogenous NGF. These findings might aid in identifying effective treatment windows for NGF-based strategies to counteract retinal and/or optic-nerve degeneration. PMID:28067793

  13. Progressive retinal degeneration and glial activation in the CLN6 (nclf mouse model of neuronal ceroid lipofuscinosis: a beneficial effect of DHA and curcumin supplementation.

    Directory of Open Access Journals (Sweden)

    Myriam Mirza

    Full Text Available Neuronal ceroid lipofuscinosis (NCL is a group of neurodegenerative lysosomal storage disorders characterized by vision loss, mental and motor deficits, and spontaneous seizures. Neuropathological analyses of autopsy material from NCL patients and animal models revealed brain atrophy closely associated with glial activity. Earlier reports also noticed loss of retinal cells and reactive gliosis in some forms of NCL. To study this phenomenon in detail, we analyzed the ocular phenotype of CLN6 (nclf mice, an established mouse model for variant-late infantile NCL. Retinal morphometry, immunohistochemistry, optokinetic tracking, electroretinography, and mRNA expression were used to characterize retinal morphology and function as well as the responses of Müller cells and microglia. Our histological data showed a severe and progressive degeneration in the CLN6 (nclf retina co-inciding with reactive Müller glia. Furthermore, a prominent phenotypic transformation of ramified microglia to phagocytic, bloated, and mislocalized microglial cells was identified in CLN6 (nclf retinas. These events overlapped with a rapid loss of visual perception and retinal function. Based on the strong microglia reactivity we hypothesized that dietary supplementation with immuno-regulatory compounds, curcumin and docosahexaenoic acid (DHA, could ameliorate microgliosis and reduce retinal degeneration. Our analyses showed that treatment of three-week-old CLN6 (nclf mice with either 5% DHA or 0.6% curcumin for 30 weeks resulted in a reduced number of amoeboid reactive microglia and partially improved retinal function. DHA-treatment also improved the morphology of CLN6 (nclf retinas with a preserved thickness of the photoreceptor layer in most regions of the retina. Our results suggest that microglial reactivity closely accompanies disease progression in the CLN6 (nclf retina and both processes can be attenuated with dietary supplemented immuno-modulating compounds.

  14. Retinal pigment epithelium cell-derived exosomes: Possible relevance to CNV in wet-age related macular degeneration.

    Science.gov (United States)

    Tong, Yao; Zhou, Ya-Li; Wang, Yi-Xiao; Zhao, Pei-Quan; Wang, Zhao-Yang

    2016-12-01

    Exosomes are small vesicles that are released by almost every cell type and play a crucial role in many physiological and pathological processes associated with different diseases. Specifically, they promote angiogenesis in the pathogenesis of some diseases. According to previous research, the proteins of exosomes taken from the aqueous humor (AH) of patients with wet-age related macular degeneration (AMD) may function as a new diagnostic biomarker of AMD, suggesting that exosomes may play an important role in the occurrence and development of choroidal neovascularization (CNV). Moreover, additional research has revealed that the levels of some protein makers of exosomes are up-regulated in aged retinal pigment epithelium (RPE) and that drusen and oxidative stress may promote the secretion of exosomes derived from RPE cells. Consequently, we hypothesize that RPE cell-derived exosomes may be relevant to CNV in wet AMD. If this hypothesis is proven correct, future studies based on this link may also help to elucidate the molecular mechanisms of wet AMD and to find new therapeutic targets for the treatment of AMD.

  15. Plasma polymer coatings to aid retinal pigment epithelial growth for transplantation in the treatment of age related macular degeneration.

    Science.gov (United States)

    Kearns, Victoria; Mistry, Anita; Mason, Sharon; Krishna, Yamini; Sheridan, Carl; Short, Robert; Williams, Rachel L

    2012-08-01

    Subretinal transplantation of functioning retinal pigment epithelial (RPE) cells grown on a synthetic substrate is a potential treatment for age-related macular degeneration (AMD), a common cause of irreversible vision loss in developed countries. Plasma polymers give the opportunity to tailor the surface chemistry of the artificial substrate whilst maintaining the bulk properties. In this study, plasma polymers with different functionalities were investigated in terms of their effect on RPE attachment and growth. Plasma polymers of acrylic acid (AC), allyl amine (AM) and allyl alcohol (AL) were fabricated and characterised using X-ray photoelectron spectroscopy (XPS) and water contact angle measurements. Octadiene (OD) hydrocarbon films and tissue culture polystyrene were used as controls. Wettability varied from hydrophobic OD to relatively hydrophilic AC. XPS demonstrated four very different surfaces with the expected functionalities. Attachment, proliferation and morphological examination of an RPE cell line and primary RPE cells were investigated. Both cell types grew on all surfaces, with the exception of OD, although the proliferation rate of primary cells was low. Good epithelial morphology was also demonstrated. Plasma polymerised films show potential as cell carrier surfaces for RPE cells in the treatment of AMD.

  16. SNAREs Interact with Retinal Degeneration Slow and Rod Outer Segment Membrane Protein-1 during Conventional and Unconventional Outer Segment Targeting.

    Science.gov (United States)

    Zulliger, Rahel; Conley, Shannon M; Mwoyosvi, Maggie L; Stuck, Michael W; Azadi, Seifollah; Naash, Muna I

    2015-01-01

    Mutations in the photoreceptor protein peripherin-2 (also known as RDS) cause severe retinal degeneration. RDS and its homolog ROM-1 (rod outer segment protein 1) are synthesized in the inner segment and then trafficked into the outer segment where they function in tetramers and covalently linked larger complexes. Our goal is to identify binding partners of RDS and ROM-1 that may be involved in their biosynthetic pathway or in their function in the photoreceptor outer segment (OS). Here we utilize several methods including mass spectrometry after affinity purification, in vitro co-expression followed by pull-down, in vivo pull-down from mouse retinas, and proximity ligation assay to identify and confirm the SNARE proteins Syntaxin 3B and SNAP-25 as novel binding partners of RDS and ROM-1. We show that both covalently linked and non-covalently linked RDS complexes interact with Syntaxin 3B. RDS in the mouse is trafficked from the inner segment to the outer segment by both conventional (i.e., Golgi dependent) and unconventional secretory pathways, and RDS from both pathways interacts with Syntaxin3B. Syntaxin 3B and SNAP-25 are enriched in the inner segment (compared to the outer segment) suggesting that the interaction with RDS/ROM-1 occurs in the inner segment. Syntaxin 3B and SNAP-25 are involved in mediating fusion of vesicles carrying other outer segment proteins during outer segment targeting, so could be involved in the trafficking of RDS/ROM-1.

  17. Retinitis pigmentosa and macular degeneration in a patient with ataxia with isolated vitamin E deficiency with a novel c.717 del C mutation in the TTPA gene.

    Science.gov (United States)

    Iwasa, Kazuo; Shima, Keisuke; Komai, Kiyonobu; Nishida, Yoichiro; Yokota, Takanori; Yamada, Masahito

    2014-10-15

    Ataxia with isolated vitamin E deficiency (AVED) is a neurodegenerative disease caused by a mutation in the α-tocopherol transfer protein gene (TTPA). The clinical features of the disease resemble Friedreich's ataxia. However, AVED is associated with low plasma vitamin E levels, which results in compromised antioxidant function. Dysregulation of this lipid-soluble antioxidant vitamin plays a major role in the neurodegeneration observed in AVED. Some AVED patients experience decreased visual acuity. Retinitis pigmentosa is thought to be the main cause of this visual impairment. Although antioxidant levels are important for the prevention of macular degeneration, there have been no reports of macular degeneration in AVED. Here, we describe a patient with AVED with progressive macular degeneration, who carried a novel truncating mutation-c.717 del C (p.D239EfsX25)-in exon 5 of the TTPA gene. These findings suggest that this newly identified mutation results in severely low serum vitamin E levels, which may be associated with the development of retinitis pigmentosa and macular degeneration.

  18. Characterization of Phototransduction Gene Knockouts Revealed Important Signaling Networks in the Light-Induced Retinal Degeneration

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    Jayalakshmi Krishnan

    2008-01-01

    Full Text Available Understanding the molecular pathways mediating neuronal function in retinas can be greatly facilitated by the identification of genes regulated in the retinas of different mutants under various light conditions. We attempted to conduct a gene chip analysis study on the genes regulated during rhodopsin kinase (Rhok-/- and arrestin (Sag-/- knockout and double knockouts in mice retina. Hence, mice were exposed to constant illumination of 450 lux or 6,000 lux on dilated pupils for indicated periods. The retinas were removed after the exposure and processed for microarray analysis. Double knockout was associated with immense changes in gene expression regulating a number of apoptosis inducing transcription factors. Subsequently, network analysis revealed that during early exposure the transcription factors, p53, c-MYC, c-FOS, JUN, and, in late phase, NF-B, appeared to be essential for the initiation of light-induced retinal rod loss, and some other classical pro- and antipoptotic genes appeared to be significantly important as well.

  19. Involvement of Autophagic Pathway in the Progression of Retinal Degeneration in a Mouse Model of Diabetes.

    Science.gov (United States)

    Piano, Ilaria; Novelli, Elena; Della Santina, Luca; Strettoi, Enrica; Cervetto, Luigi; Gargini, Claudia

    2016-01-01

    The notion that diabetic retinopathy (DR) is essentially a micro-vascular disease has been recently challenged by studies reporting that vascular changes are preceded by signs of damage and loss of retinal neurons. As to the mode by which neuronal death occurs, the evidence that apoptosis is the main cause of neuronal loss is far from compelling. The objective of this study was to investigate these controversies in a mouse model of streptozotocin (STZ) induced diabetes. Starting from 8 weeks after diabetes induction there was loss of rod but not of cone photoreceptors, together with reduced thickness of the outer and inner synaptic layers. Correspondingly, rhodopsin expression was downregulated and the scotopic electroretinogram (ERG) is suppressed. In contrast, cone opsin expression and photopic ERG response were not affected. Suppression of the scotopic ERG preceded morphological changes as well as any detectable sign of vascular alteration. Only sparse apoptotic figures were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and glia was not activated. The physiological autophagy flow was altered instead, as seen by increased LC3 immunostaining at the level of outer plexiform layer (OPL) and upregulation of the autophagic proteins Beclin-1 and Atg5. Collectively, our results show that the streptozotocin induced DR in mouse initiates with a functional loss of the rod visual pathway. The pathogenic pathways leading to cell death develop with the initial dysregulation of autophagy well before the appearance of signs of vascular damage and without strong involvement of apoptosis.

  20. Dementia of the eye: the role of amyloid beta in retinal degeneration.

    Science.gov (United States)

    Ratnayaka, J A; Serpell, L C; Lotery, A J

    2015-08-01

    Age-related macular degeneration (AMD) is one of the most common causes of irreversible blindness affecting nearly 50 million individuals globally. The disease is characterised by progressive loss of central vision, which has significant implications for quality of life concerns in an increasingly ageing population. AMD pathology manifests in the macula, a specialised region of the retina, which is responsible for central vision and perception of fine details. The underlying pathology of this complex degenerative disease is incompletely understood but includes both genetic as well as epigenetic risk factors. The recent discovery that amyloid beta (Aβ), a highly toxic and aggregate-prone family of peptides, is elevated in the ageing retina and is associated with AMD has opened up new perspectives on the aetiology of this debilitating blinding disease. Multiple studies now link Aβ with key stages of AMD progression, which is both exciting and potentially insightful, as this identifies a well-established toxic agent that aggressively targets cells in degenerative brains. Here, we review the most recent findings supporting the hypothesis that Aβ may be a key factor in AMD pathology. We describe how multiple Aβ reservoirs, now reported in the ageing eye, may target the cellular physiology of the retina as well as associated layers, and propose a mechanistic pathway of Aβ-mediated degenerative change leading to AMD.

  1. Abnormal photoreceptor outer segment development and early retinal degeneration in kif3a mutant zebrafish.

    Science.gov (United States)

    Raghupathy, Rakesh K; Zhang, Xun; Alhasani, Reem H; Zhou, Xinzhi; Mullin, Margaret; Reilly, James; Li, Wenchang; Liu, Mugen; Shu, Xinhua

    2016-08-01

    Photoreceptors are highly specialized sensory neurons that possess a modified primary cilium called the outer segment. Photoreceptor outer segment formation and maintenance require highly active protein transport via a process known as intraflagellar transport. Anterograde transport in outer segments is powered by the heterotrimeric kinesin II and coordinated by intraflagellar transport proteins. Here, we describe a new zebrafish model carrying a nonsense mutation in the kinesin II family member 3A (kif3a) gene. Kif3a mutant zebrafish exhibited curved body axes and kidney cysts. Outer segments were not formed in most parts of the mutant retina, and rhodopsin was mislocalized, suggesting KIF3A has a role in rhodopsin trafficking. Both rod and cone photoreceptors degenerated rapidly between 4 and 9 days post fertilization, and electroretinography response was not detected in 7 days post fertilization mutant larvae. Loss of KIF3A in zebrafish also resulted in an intracellular transport defect affecting anterograde but not retrograde transport of organelles. Our results indicate KIF3A plays a conserved role in photoreceptor outer segment formation and intracellular transport.

  2. Choice of Cell Source in Cell-Based Therapies for Retinal Damage due to Age-Related Macular Degeneration: A Review

    Directory of Open Access Journals (Sweden)

    Sudhakar John

    2013-01-01

    Full Text Available Background. Age-related macular degeneration (AMD is a complex disorder that affects primarily the macula involving the retinal pigment epithelium (RPE but also to a certain extent the photoreceptor layer and the retinal neurons. Cell transplantation is a promising option for AMD and clinical trials are underway using different cell types. Methods. We hypothesize that instead of focusing on a particular cell source for concurrent regeneration of all the retinal layers and also to prevent exhaustive research on an array of cell sources for regeneration of each layer, the choice should depend on, precisely, which layer is damaged. Results. Thus, for a damage limited to the retinal pigment epithelial (RPE layer, the choice we suggest would be RPE cells. When the damage extends to rods and cones, the choice would be bone marrow stem cells and when retinal neurons are involved, relatively immature stem cell populations with an inherent capacity to yield neuronal lineage such as hematopoietic stem cells, embryonic stem cells, or induced pluripotent stem cells can be tried. Conclusion. This short review will prove to be a valuable guideline for those working on cell therapy for AMD to plan their future directions of research and therapy for this condition.

  3. Choice of Cell Source in Cell-Based Therapies for Retinal Damage due to Age-Related Macular Degeneration: A Review.

    Science.gov (United States)

    John, Sudhakar; Natarajan, Sundaram; Parikumar, Periyasamy; Shanmugam P, Mahesh; Senthilkumar, Rajappa; Green, David William; Abraham, Samuel J K

    2013-01-01

    Background. Age-related macular degeneration (AMD) is a complex disorder that affects primarily the macula involving the retinal pigment epithelium (RPE) but also to a certain extent the photoreceptor layer and the retinal neurons. Cell transplantation is a promising option for AMD and clinical trials are underway using different cell types. Methods. We hypothesize that instead of focusing on a particular cell source for concurrent regeneration of all the retinal layers and also to prevent exhaustive research on an array of cell sources for regeneration of each layer, the choice should depend on, precisely, which layer is damaged. Results. Thus, for a damage limited to the retinal pigment epithelial (RPE) layer, the choice we suggest would be RPE cells. When the damage extends to rods and cones, the choice would be bone marrow stem cells and when retinal neurons are involved, relatively immature stem cell populations with an inherent capacity to yield neuronal lineage such as hematopoietic stem cells, embryonic stem cells, or induced pluripotent stem cells can be tried. Conclusion. This short review will prove to be a valuable guideline for those working on cell therapy for AMD to plan their future directions of research and therapy for this condition.

  4. Hearing impairment in the P23H-1 retinal degeneration rat model

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    Jorge V. Sotoca

    2014-09-01

    Full Text Available The transgenic P23H line 1 (P23H-1 rat expresses a variant of rhodopsin with a mutation that leads to loss of visual function. This rat strain is an experimental model usually employed to study photoreceptor degeneration. Although the mutated protein should not interfere with other sensory functions, observing severe loss of auditory reflexes in response to natural sounds led us to study auditory brain response (ABR recording. Animals were separated into different hearing levels following the response to natural stimuli (hand clapping and kissing sounds. Of all the analyzed animals, 25.9% presented auditory loss before 50 days of age (P50 and 45% were totally deaf by P200. ABR recordings showed that all the rats had a higher hearing threshold than the control Sprague-Dawley (SD rats, which was also higher than any other rat strains. The integrity of the central and peripheral auditory pathway was analyzed by histology and immunocytochemistry. In the cochlear nucleus (CN, statistical differences were found between SD and P23H-1 rats in VGluT1 distribution, but none were found when labeling all the CN synapses with anti-Syntaxin. This finding suggests anatomical and/or molecular abnormalities in the auditory downstream pathway. The inner ear of the hypoacusic P23H-1 rats showed several anatomical defects, including loss and disruption of hair cells and spiral ganglion neurons. All these results can explain, at least in part, how hearing impairment can occur in a high percentage of P23H-1 rats. P23H-1 rats may be considered an experimental model with visual and auditory dysfunctions in future research.

  5. Pigment Epithelium-Derived Factor Reduces Apoptosis and Pro-Inflammatory Cytokine Gene Expression in a Murine Model of Focal Retinal Degeneration

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    Yujuan Wang

    2013-10-01

    Full Text Available AMD (age-related macular degeneration is a neurodegenerative disease causing irreversible central blindness in the elderly. Apoptosis and inflammation play important roles in AMD pathogenesis. PEDF (pigment epithelium-derived factor is a potent neurotrophic and anti-inflammatory glycoprotein that protects the retinal neurons and photoreceptors against cell death caused by pathological insults. We studied the effects of PEDF on focal retinal lesions in DKO rd8 (Ccl2 −/− /Cx3cr1 −/− on C57BL/6N [Crb1rd8 ] mice, a model for progressive, focal rd (retinal degeneration. First, we found a significant decrease in PEDF transcript expression in DKO rd8 mouse retina and RPE (retinal pigment epithelium than WT (wild-type, C57BL/6N. Next, cultured DKO rd8 RPE cells secreted lower levels of PEDF protein in the media than WT. Then the right eyes of DKO rd8 mice were injected intravitreously with recombinant human PEDF protein (1 μg, followed by a subconjunctival injection of PEDF (3 μg 4 weeks later. The untreated left eyes served as controls. The effect of PEDF was assessed by fundoscopy, ocular histopathology and A2E {[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl-1E,3E,5E,7E-octatetra-enyl]-1-(2-hydroxyethyl-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl 1E,3E,5E,7E-hexatrienyl]-pyridinium} levels, as well as apoptotic and inflammatory molecules. The PEDF-treated eyes showed slower progression or attenuation of the focal retinal lesions, fewer and/or smaller photoreceptor and RPE degeneration, and significantly lower A2E, relative to the untreated eyes. In addition, lower expression of apoptotic and inflammatory molecules were detected in the PEDF-treated than untreated eyes. Our results establish that PEDF potently stabilizes photoreceptor degeneration via suppression of both apoptotic and inflammatory pathways. The multiple beneficial effects of PEDF represent a novel approach for potential AMD treatment.

  6. Network oscillations drive correlated spiking of ON and OFF ganglion cells in the rd1 mouse model of retinal degeneration.

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    David J Margolis

    Full Text Available Following photoreceptor degeneration, ON and OFF retinal ganglion cells (RGCs in the rd-1/rd-1 mouse receive rhythmic synaptic input that elicits bursts of action potentials at ∼ 10 Hz. To characterize the properties of this activity, RGCs were targeted for paired recording and morphological classification as either ON alpha, OFF alpha or non-alpha RGCs using two-photon imaging. Identified cell types exhibited rhythmic spike activity. Cross-correlation of spike trains recorded simultaneously from pairs of RGCs revealed that activity was correlated more strongly between alpha RGCs than between alpha and non-alpha cell pairs. Bursts of action potentials in alpha RGC pairs of the same type, i.e. two ON or two OFF cells, were in phase, while bursts in dissimilar alpha cell types, i.e. an ON and an OFF RGC, were 180 degrees out of phase. This result is consistent with RGC activity being driven by an input that provides correlated excitation to ON cells and inhibition to OFF cells. A2 amacrine cells were investigated as a candidate cellular mechanism and found to display 10 Hz oscillations in membrane voltage and current that persisted in the presence of antagonists of fast synaptic transmission and were eliminated by tetrodotoxin. Results support the conclusion that the rhythmic RGC activity originates in a presynaptic network of electrically coupled cells including A2s via a Na(+-channel dependent mechanism. Network activity drives out of phase oscillations in ON and OFF cone bipolar cells, entraining similar frequency fluctuations in RGC spike activity over an area of retina that migrates with changes in the spatial locus of the cellular oscillator.

  7. Can Vitamin A be Improved to Prevent Blindness due to Age-Related Macular Degeneration, Stargardt Disease and Other Retinal Dystrophies?

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    Saad, Leonide; Washington, Ilyas

    2016-01-01

    We discuss how an imperfect visual cycle results in the formation of vitamin A dimers, thought to be involved in the pathogenesis of various retinal diseases, and summarize how slowing vitamin A dimerization has been a therapeutic target of interest to prevent blindness. To elucidate the molecular mechanism of vitamin A dimerization, an alternative form of vitamin A, one that forms dimers more slowly yet maneuvers effortlessly through the visual cycle, was developed. Such a vitamin A, reinforced with deuterium (C20-D3-vitamin A), can be used as a non-disruptive tool to understand the contribution of vitamin A dimers to vision loss. Eventually, C20-D3-vitamin A could become a disease-modifying therapy to slow or stop vision loss associated with dry age-related macular degeneration (AMD), Stargardt disease and retinal diseases marked by such vitamin A dimers. Human clinical trials of C20-D3-vitamin A (ALK-001) are underway.

  8. Characterisation of a C1qtnf5 Ser163Arg knock-in mouse model of late-onset retinal macular degeneration.

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    Xinhua Shu

    Full Text Available A single founder mutation resulting in a Ser163Arg substitution in the C1QTNF5 gene product causes autosomal dominant late-onset retinal macular degeneration (L-ORMD in humans, which has clinical and pathological features resembling age-related macular degeneration. We generated and characterised a mouse "knock-in" model carrying the Ser163Arg mutation in the orthologous murine C1qtnf5 gene by site-directed mutagenesis and homologous recombination into mouse embryonic stem cells. Biochemical, immunological, electron microscopic, fundus autofluorescence, electroretinography and laser photocoagulation analyses were used to characterise the mouse model. Heterozygous and homozygous knock-in mice showed no significant abnormality in any of the above measures at time points up to 2 years. This result contrasts with another C1qtnf5 Ser163Arg knock-in mouse which showed most of the features of L-ORMD but differed in genetic background and targeting construct.

  9. Molecular composition of drusen and possible involvement of anti-retinal autoimmunity in two different forms of macular degeneration in cynomolgus monkey (Macaca fascicularis).

    Science.gov (United States)

    Umeda, Shinsuke; Suzuki, Michihiro T; Okamoto, Haru; Ono, Fumiko; Mizota, Atsushi; Terao, Keiji; Yoshikawa, Yasuhiro; Tanaka, Yasuhiko; Iwata, Takeshi

    2005-10-01

    We have previously reported a cynomolgus monkey (Macaca fascicularis) pedigree with early onset macular degeneration that develops drusen at 2 yr after birth. In this study, the molecular composition of drusen in monkeys affected with late onset and early onset macular degeneration was both characterized. Involvement of anti-retinalautoimmunity in the deposition of drusen and the pathogenesis of the disease was also evaluated. Funduscopic and histological examinations were performed on 278 adult monkeys (mean age=16.94 yr) for late onset macular degeneration. The molecular composition of drusen was analyzed by immunohistochemistry and/or direct proteome analysis using liquid chromatography tandem mass spectroscopy (LC-MS/MS). Anti-retinal autoantibodies in sera were screened in 20 affected and 10 age-matched control monkeys by Western blot techniques. Immunogenic molecules were identified by 2D electrophoresis and LC-MS/MS. Relative antibody titer against each antigen was determined by ELISA in sera from 42 affected (late onset) and 41 normal monkeys. Yellowish-white spots in the macular region were observed in 90 (32%) of the late onset monkeys that were examined. Histological examination demonstrated that drusen or degenerative retinal pigment epithelium (RPE) cells were associated with the pigmentary abnormalities. Drusen in both late and early onset monkeys showed immunoreactivities for apolipoprotein E, amyloid P component, complement component C5, the terminal C5b-9 complement complex, vitronectin, and membrane cofactor protein. LC-MS/MS analyses identified 60 proteins as constituents of drusen, including a number of common components in drusen of human age-related macular degeneration (AMD), such as annexins, crystallins, immunoglobulins, and complement components. Half of the affected monkeys had single or multiple autoantibodies against 38, 40, 50, and 60 kDa retinal proteins. The reacting antigens of 38 and 40 kDa were identified as annexin II and mu

  10. A level-set method for pathology segmentation in fluorescein angiograms and en face retinal images of patients with age-related macular degeneration

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    Mohammad, Fatimah; Ansari, Rashid; Shahidi, Mahnaz

    2013-03-01

    The visibility and continuity of the inner segment outer segment (ISOS) junction layer of the photoreceptors on spectral domain optical coherence tomography images is known to be related to visual acuity in patients with age-related macular degeneration (AMD). Automatic detection and segmentation of lesions and pathologies in retinal images is crucial for the screening, diagnosis, and follow-up of patients with retinal diseases. One of the challenges of using the classical level-set algorithms for segmentation involves the placement of the initial contour. Manually defining the contour or randomly placing it in the image may lead to segmentation of erroneous structures. It is important to be able to automatically define the contour by using information provided by image features. We explored a level-set method which is based on the classical Chan-Vese model and which utilizes image feature information for automatic contour placement for the segmentation of pathologies in fluorescein angiograms and en face retinal images of the ISOS layer. This was accomplished by exploiting a priori knowledge of the shape and intensity distribution allowing the use of projection profiles to detect the presence of pathologies that are characterized by intensity differences with surrounding areas in retinal images. We first tested our method by applying it to fluorescein angiograms. We then applied our method to en face retinal images of patients with AMD. The experimental results included demonstrate that the proposed method provided a quick and improved outcome as compared to the classical Chan-Vese method in which the initial contour is randomly placed, thus indicating the potential to provide a more accurate and detailed view of changes in pathologies due to disease progression and treatment.

  11. Early Changes of Retinal Morphology in Therapy of Neovascular Age-Related Macular Degeneration with Three Commonly Used Anti-VEGF Agents.

    Science.gov (United States)

    Enders, Philip; Sitnilska, Vasilena; Altay, Lebriz; Fauser, Sascha

    2017-09-27

    To compare changes of retinal morphology in the first weeks following injection of anti-VEGF agents for neovascular age-related macular degeneration (nAMD). In a prospective study 50 patients with active choroidal neovascularization secondary to nAMD were monitored weekly by spectral-domain optical coherence tomography for 3 weeks after treatment. Twenty-two patients received bevacizumab, 15 ranibizumab, and 13 aflibercept. Morphological parameters of retinal compartments were compared. Mean central retinal thickness (391.22 ± 123.41 µm) was reduced by -26.15 µm (p < 0.001) after 1 week, by -12.54 µm (p < 0.001) after 2 weeks, and by -3.52 µm (p = 0.09) after 3 weeks. Mean intraretinal layer thickness changed only significantly between baseline and week 1 (p < 0.001). Mean subretinal thickness also decreased between weeks 1 and 2 (p = 0.01). Early morphological changes occur primarily in the first 14 days after treatment. This information could be clinically helpful to evaluate early non-response. © 2017 S. Karger AG, Basel.

  12. Semiautomated segmentation and analysis of retinal layers in three-dimensional spectral-domain optical coherence tomography images of patients with atrophic age-related macular degeneration.

    Science.gov (United States)

    Hu, Zhihong; Shi, Yue; Nandanan, Kiran; Sadda, Srinivas R

    2017-01-01

    Historically, regular drusen and geographic atrophy (GA) have been recognized as the hallmarks of nonneovascular age-related macular degeneration (AMD). Recent imaging developments have revealed another distinct nonneovascular AMD phenotype, reticular pseudodrusen (RPD). We develop an approach to semiautomatically quantify retinal surfaces associated with various AMD lesions (i.e., regular drusen, RPD, and GA) in spectral domain (SD) optical coherence tomography (OCT) images. More specifically, a graph-based algorithm was used to segment multiple retinal layers in SD-OCT volumes. Varying surface feasibility constraints based on the presegmentation were applied on the double-surface graph search to refine the surface segmentation. The thicknesses of these layers and their correlation with retinal functional measurements, including microperimetry (MP) sensitivity and visual acuity (VA), were investigated. The photoreceptor outer segment layer demonstrated significant thinning with a reduction in MP sensitivity and VA score when atrophic AMD lesions were present. Regular drusen and RPD were separately segmented on SD-OCT images to allow their characteristics and distribution to be studied separately. The mean thickness of regular drusen was found to significantly correlate with the VA score. RPD appeared to be distributed evenly throughout the macula and regular drusen appeared to be more concentrated centrally.

  13. Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle.

    NARCIS (Netherlands)

    Thompson, D.A.; Janecke, A.R.; Lange, J. de; Feathers, K.L.; Hubner, C.; McHenry, C.; Stockton, D.W.; Rammesmayer, G.; Lupski, J.R.; Antinolo, G.; Ayuso, C.; Baiget, M.; Gouras, P.; Heckenlively, J.R.; Hollander, A.I. den; Jacobson, S.G.; Lewis, R.A.; Sieving, P.A.; Wissinger, B.; IJzer, S.; Zrenner, E.; Utermann, G.; Gal, A.

    2005-01-01

    Retinoid dehydrogenases/reductases catalyze key oxidation-reduction reactions in the visual cycle that converts vitamin A to 11-cis retinal, the chromophore of the rod and cone photoreceptors. It has recently been shown that mutations in RDH12, encoding a retinol dehydrogenase, result in severe and

  14. Protective Effects of Human iPS-Derived Retinal Pigmented Epithelial Cells in Comparison with Human Mesenchymal Stromal Cells and Human Neural Stem Cells on the Degenerating Retina in rd1 mice.

    Science.gov (United States)

    Sun, Jianan; Mandai, Michiko; Kamao, Hiroyuki; Hashiguchi, Tomoyo; Shikamura, Masayuki; Kawamata, Shin; Sugita, Sunao; Takahashi, Masayo

    2015-05-01

    Retinitis pigmentosa (RP) is a group of visual impairments characterized by progressive rod photoreceptor cell loss due to a genetic background. Pigment epithelium-derived factor (PEDF) predominantly secreted by the retinal pigmented epithelium (RPE) has been reported to protect photoreceptors in retinal degeneration models, including rd1. In addition, clinical trials are currently underway outside Japan using human mesenchymal stromal cells and human neural stem cells to protect photoreceptors in RP and dry age-related macular degeneration, respectively. Thus, this study aimed to investigate the rescue effects of induced pluripotent stem (iPS)-RPE cells in comparison with those types of cells used in clinical trials on photoreceptor degeneration in rd1 mice. Cells were injected into the subretinal space of immune-suppressed 2-week-old rd1 mice. The results demonstrated that human iPS-RPE cells significantly attenuated photoreceptor degeneration on postoperative days (PODs) 14 and 21 and survived longer up to at least 12 weeks after operation than the other two types of graft cells with less immune responses and apoptosis. The mean PEDF concentration in the intraocular fluid in RPE-transplanted eyes was more than 1 µg/ml at PODs 14 and 21, and this may have contributed to the protective effect of RPE transplantation. Our findings suggest that iPS-RPE cells serve as a competent source to delay photoreceptor degeneration through stable survival in degenerating ocular environment and by releasing neuroprotective factors such as PEDF.

  15. Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

    Science.gov (United States)

    Bax, Nathalie M.; Fakin, Ana; Groenewoud, Joannes M. M.; Klevering, B. Jeroen; Moore, Anthony T.; Michaelides, Michel; Webster, Andrew R.; van der Wilt, Gert Jan; Hoyng, Carel B.

    2017-01-01

    Background Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. Methods and findings We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. Conclusions These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a

  16. Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle.

    Science.gov (United States)

    Thompson, Debra A; Janecke, Andreas R; Lange, Jessica; Feathers, Kecia L; Hübner, Christian A; McHenry, Christina L; Stockton, David W; Rammesmayer, Gabriele; Lupski, James R; Antinolo, Guillermo; Ayuso, Carmen; Baiget, Montserrat; Gouras, Peter; Heckenlively, John R; den Hollander, Anneke; Jacobson, Samuel G; Lewis, Richard A; Sieving, Paul A; Wissinger, Bernd; Yzer, Suzanne; Zrenner, Eberhart; Utermann, Gerd; Gal, Andreas

    2005-12-15

    Retinoid dehydrogenases/reductases catalyze key oxidation-reduction reactions in the visual cycle that converts vitamin A to 11-cis retinal, the chromophore of the rod and cone photoreceptors. It has recently been shown that mutations in RDH12, encoding a retinol dehydrogenase, result in severe and early-onset autosomal recessive retinal dystrophy (arRD). In a cohort of 1011 individuals diagnosed with arRD, we have now identified 20 different disease-associated RDH12 mutations, of which 16 are novel, in a total of 22 individuals (2.2%). Haplotype analysis suggested a founder mutation for each of the three common mutations: p.L99I, p.T155I and c.806_810delCCCTG. Patients typically presented with early disease that affected the function of both rods and cones and progressed to legal blindness in early adulthood. Eleven of the missense variants identified in our study exhibited profound loss of catalytic activity when expressed in transiently transfected COS-7 cells and assayed for ability to convert all-trans retinal to all-trans retinol. Loss-of-function appeared to result from decreased protein stability, as expression levels were significantly reduced. For the p.T49M variant, differing activity profiles were associated with each of the alleles of the common p.R161Q RDH12 polymorphism, suggesting that genetic background may act as a modifier of mutation effect. A locus (LCA3) for Leber congenital amaurosis, a severe, early-onset form of arRD, maps close to RDH12 on chromosome 14q24. Haplotype analysis in the family in which LCA3 was mapped excluded RDH12 as the LCA3 gene and thus suggests the presence of a novel arRD gene in this region.

  17. A Longitudinal Follow-Up Study of Saffron Supplementation in Early Age-Related Macular Degeneration: Sustained Benefits to Central Retinal Function

    Science.gov (United States)

    Piccardi, M.; Marangoni, D.; Minnella, A. M.; Savastano, M. C.; Valentini, P.; Ambrosio, L.; Capoluongo, E.; Maccarone, R.; Bisti, S.; Falsini, B.

    2012-01-01

    Objectives. In a previous randomized clinical trial (Falsini et al. (2010)), it was shown that short-term Saffron supplementation improves retinal flicker sensitivity in early age-related macular degeneration (AMD). The aim of this study was to evaluate whether the observed functional benefits from Saffron supplementation may extend over a longer follow-up duration. Design. Longitudinal, interventional open-label study. Setting. Outpatient ophthalmology setting. Participants. Twenty-nine early AMD patients (age range: 55–85 years) with a baseline visual acuity >0.3. Intervention. Saffron oral supplementation (20 mg/day) over an average period of treatment of 14 (±2) months. Measurements. Clinical examination and focal-electroretinogram-(fERG-) derived macular (18°) flicker sensitivity estimate (Falsini et al. (2010)) every three months over a followup of 14 (±2) months. Retinal sensitivity, the reciprocal value of the estimated fERG amplitude threshold, was the main outcome measure. Results. After three months of supplementation, mean fERG sensitivity improved by 0.3 log units compared to baseline values (P < 0.01), and mean visual acuity improved by two Snellen lines compared to baseline values (0.75 to 0.9, P < 0.01). These changes remained stable over the follow-up period. Conclusion. These results indicate that in early AMD Saffron supplementation induces macular function improvements from baseline that are extended over a long-term followup. PMID:22852021

  18. A Longitudinal Follow-Up Study of Saffron Supplementation in Early Age-Related Macular Degeneration: Sustained Benefits to Central Retinal Function

    Directory of Open Access Journals (Sweden)

    M. Piccardi

    2012-01-01

    Full Text Available Objectives. In a previous randomized clinical trial (Falsini et al. (2010, it was shown that short-term Saffron supplementation improves retinal flicker sensitivity in early age-related macular degeneration (AMD. The aim of this study was to evaluate whether the observed functional benefits from Saffron supplementation may extend over a longer follow-up duration. Design. Longitudinal, interventional open-label study. Setting. Outpatient ophthalmology setting. Participants. Twenty-nine early AMD patients (age range: 55–85 years with a baseline visual acuity >0.3. Intervention. Saffron oral supplementation (20 mg/day over an average period of treatment of 14 (±2 months. Measurements. Clinical examination and focal-electroretinogram-(fERG- derived macular (18° flicker sensitivity estimate (Falsini et al. (2010 every three months over a followup of 14 (±2 months. Retinal sensitivity, the reciprocal value of the estimated fERG amplitude threshold, was the main outcome measure. Results. After three months of supplementation, mean fERG sensitivity improved by 0.3 log units compared to baseline values (P<0.01, and mean visual acuity improved by two Snellen lines compared to baseline values (0.75 to 0.9, P<0.01. These changes remained stable over the follow-up period. Conclusion. These results indicate that in early AMD Saffron supplementation induces macular function improvements from baseline that are extended over a long-term followup.

  19. Investigation of retinal microstructure in healthy eyes and dry age-related macular degeneration using a combined AO-OCT-SLO system

    Science.gov (United States)

    Wells-Gray, Elaine M.; Choi, Stacey S.; Ohr, Matthew; Cebulla, Colleen M.; Doble, Nathan

    2017-02-01

    Combined adaptive optics (AO) optical coherence tomography (OCT) scanning laser ophthalmoscopy (SLO) imaging allows simultaneous en face and cross sectional views of the retina. We describe improvements to our AO-OCT-SLO system and highlight its resolution capability and clinical utility by presenting results from 3 control and 4 dry agerelated macular degeneration (AMD) subjects. From a group of subjects with healthy eyes, OCT A-scans were grouped as originating from cones or rods and were averaged. The resulting reflectance profiles were then used to identify the location of cone and rod segments. Results for rods and cones were compared, with the focus on inner segment (IS) and outer segment (OS) structures and where these cells embed into the retinal pigment epithelium (RPE). In the AMD patients, cone IS and OS lengths were measured over and around drusen for two retinal regions (fovea-2° and 2°-4°), and those results were correlated to drusen height. For the fovea-2° region, the drusen height that caused statistically significant shortening of cone ISL and OSL compared to the unaffected adjacent area were 40 μm and 50 μm respectively (p = 0.009, and p region, the equivalent drusen heights that caused significant shortening of segment length were 60 μm for IS (p = 0.017) and 80 μm for OS (p < 0.001)

  20. Review: Animal models of N-Methyl-N-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials.

    Science.gov (United States)

    Tsubura, Airo; Lai, Yen-Chang; Miki, Hisanori; Sasaki, Tomo; Uehara, Norihisa; Yuri, Takashi; Yoshizawa, Katsuhiko

    2011-01-01

    N-Methyl-N-nitrosourea (MNU) is a direct-acting alkylating agent that interacts with DNA. Accumulation of mutations may enhance cancer risk in target organs or cause cell death in susceptible tissues or cells when excessive DNA damage is not repaired. MNU targets various organs in a variety of animal species. MNU-induced carcinogenesis can be used as organ-specific animal models for human cancer, and MNU has been most extensively utilized for the induction of mammary cancer in rats. MNU-induced rat mammary tumors possess many similarities to those of human breast cancer, and the model is utilized for screening cancer modulators. MNU-induced cell disruption is also seen in several organs and tissues, especially when MNU is applied before maturity. However, photoreceptor cells in adults are highly sensitive to MNU, which causes cell death due to apoptosis. MNU-induced photoreceptor apoptosis mimics human retinitis pigmentosa and can be used for studies of therapeutic intervention. In this review, the targets of MNU in various animal species are described, and special emphasis is given to therapeutic trials against MNU-induced mammary cancer and retinal degeneration in animal models.

  1. Systemic administration of Abeta mAb reduces retinal deposition of Abeta and activated complement C3 in age-related macular degeneration mouse model.

    Directory of Open Access Journals (Sweden)

    Ian Catchpole

    Full Text Available Age-related macular degeneration (AMD is a leading cause of legal blindness in the Western world. There are effective treatments for the vascular complications of neo-vascular AMD, but no effective therapies are available for the dry/atrophic form of the disease. A previously described transgenic CFH-gene deficient mouse model, (cfh-/-, shows hallmarks of early AMD. The ocular phenotype has been further analysed to demonstrate amyloid beta (Aβ rich basement membrane deposits associated with activated complement C3. Cfh-/- mice were treated systemically in both prophylactic and therapeutic regimes with an anti-Aβ monoclonal antibody (mAb, 6F6, to determine the effect on the cfh-/- retinal phenotype. Prophylactic treatment with 6F6 demonstrated a dose dependent reduction in the accumulation of both Aβ and activated C3 deposition. A similar reduction in the retinal endpoints could be seen after therapeutic treatment. Serum Aβ levels after systemic administration of 6F6 show accumulation of Aβ in the periphery suggestive of a peripheral sink mechanism. In summary, anti-Aβ mAb treatment can partially prevent or reverse ocular phenotypes of the cfh-/- mouse. The data support this therapeutic approach in humans potentially modulating two key elements in the pathogenesis of AMD - Aβ and activated, complement C3.

  2. The Crumbs_C isoform of Drosophila shows tissue- and stage-specific expression and prevents light-dependent retinal degeneration

    Directory of Open Access Journals (Sweden)

    Stephanie Spannl

    2017-02-01

    Full Text Available Drosophila Crumbs (Crb is a key regulator of epithelial polarity and fulfils a plethora of other functions, such as growth regulation, morphogenesis of photoreceptor cells and prevention of retinal degeneration. This raises the question how a single gene regulates such diverse functions, which in mammals are controlled by three different paralogs. Here, we show that in Drosophila different Crb protein isoforms are differentially expressed as a result of alternative splicing. All isoforms are transmembrane proteins that differ by just one EGF-like repeat in their extracellular portion. Unlike Crb_A, which is expressed in most embryonic epithelia from early stages onward, Crb_C is expressed later and only in a subset of embryonic epithelia. Flies specifically lacking Crb_C are homozygous viable and fertile. Strikingly, these flies undergo light-dependent photoreceptor degeneration despite the fact that the other isoforms are expressed and properly localised at the stalk membrane. This allele now provides an ideal possibility to further unravel the molecular mechanisms by which Drosophila crb protects photoreceptor cells from the detrimental consequences of light-induced cell stress.

  3. Drosophila Lin-7 is a component of the Crumbs complex in epithelia and photoreceptor cells and prevents light-induced retinal degeneration.

    Science.gov (United States)

    Bachmann, André; Grawe, Ferdi; Johnson, Kevin; Knust, Elisabeth

    2008-03-01

    The Drosophila Crumbs protein complex is required to maintain epithelial cell polarity in the embryo, to ensure proper morphogenesis of photoreceptor cells and to prevent light-dependent retinal degeneration. In Drosophila, the core components of the complex are the transmembrane protein Crumbs, the membrane-associated guanylate kinase (MAGUK) Stardust and the scaffolding protein DPATJ. The composition of the complex and some of its functions are conserved in mammalian epithelial and photoreceptor cells. Here, we report that Drosophila Lin-7, a scaffolding protein with one Lin-2/Lin-7 (L27) domain and one PSD-95/Dlg/ZO-1 (PDZ) domain, is associated with the Crumbs complex in the subapical region of embryonic and follicle epithelia and at the stalk membrane of adult photoreceptor cells. DLin-7 loss-of-function mutants are viable and fertile. While DLin-7 localization depends on Crumbs, neither Crumbs, Stardust nor DPATJ require DLin-7 for proper accumulation in the subapical region. Unlike other components of the Crumbs complex, DLin-7 is also enriched in the first optic ganglion, the lamina, where it co-localizes with Discs large, another member of the MAGUK family. In contrast to crumbs mutant photoreceptor cells, those mutant for DLin-7 do not display any morphogenetic abnormalities. Similar to crumbs mutant eyes, however, DLin-7 mutant photoreceptors undergo progressive, light-dependent degeneration. These results support the previous conclusions that the function of the Crumbs complex in cell survival is independent from its function in photoreceptor morphogenesis.

  4. Autologous Translocation of the Retinal Pigment Epithelium and Choroid in the Treatment of Exudative Age-related Macular Degeneration

    NARCIS (Netherlands)

    K.J.M. Maaijwee (Kristel Johanna Maria)

    2008-01-01

    textabstractAge-related macular degeneration (AMD) is the most important cause of irreversible legal blindness in elderly persons in industrialized countries. AMD has two forms: atrophic (dry) and exudative (wet). In the wet form, abnormal blood vessels, arising from the choriocapillaris (choroidal

  5. Müller Glia Activation in Response to Inherited Retinal Degeneration Is Highly Varied and Disease-Specific

    OpenAIRE

    2015-01-01

    Despite different aetiologies, most inherited retinal disorders culminate in photoreceptor loss, which induces concomitant changes in the neural retina, one of the most striking being reactive gliosis by Müller cells. It is typically assumed that photoreceptor loss leads to an upregulation of glial fibrilliary acidic protein (Gfap) and other intermediate filament proteins, together with other gliosis-related changes, including loss of integrity of the outer limiting membrane (OLM) and deposit...

  6. Retinitis pigmentosa

    NARCIS (Netherlands)

    Hartong, Dyonne T.; Berson, Eliot L.; Dryja, Thaddeus P.

    2006-01-01

    Hereditary degenerations of the human retina are genetically heterogeneous, with well over 100 genes implicated so far. This Seminar focuses on the subset of diseases called retinitis pigmentosa, in which patients typically lose night vision in adolescence, side vision in young adulthood, and centra

  7. Amyloid beta deposition and phosphorylated tau accumulation are key features in aged choroidal vessels in the complement factor H knock out model of retinal degeneration.

    Science.gov (United States)

    Aboelnour, Asmaa; Kam, Jaimie Hoh; Elnasharty, M A; Sayed-Ahmed, Ahmed; Jeffery, Glen

    2016-06-01

    Extra-cellular deposition including amyloid beta (Aβ) is a feature of retinal ageing. It has been documented for Bruch's membrane (BM) where Aβ is elevated in complement factor H knockout mice (Cfh(-/-)) proposed as a model for age related macular degeneration. However, arterial deposition in choroidal vessels prior to perfusion across BM has not been examined. Aβ is associated with tau phosphorylation and these are linked in blood vessels in Alzheimers Disease where they can drive perivascular pathology. Here we ask if Aβ, tau and phosphorylated tau are features of ageing in choroidal vessels in 12 month C57 BL/6 and Cfh(-/-) mice, using immune staining and Western blot analysis. Greater levels of Aβ and phosphorylated tau are found in choroidal vessels in Cfh(-/-) mice. Western blot revealed a 40% increase in Aβ in Cfh(-/-) over C57 BL/6 mice. Aβ deposits coat around 55% of the luminal wall in Cfh(-/-) compared to only about 40% in C57 BL/6. Total tau was similar in both groups, but phosphorylated tau increased by >100% in Cfh(-/-) compared to C57 BL/6 and covered >75% of the luminal wall compared to 50% in C57 BL/6. Hence, phosphorylated tau is a marked choroidal feature in this mouse model. Aβ deposition was clumped in Cfh(-/-) mice and likely to influence blood flow dynamics. Disturbed flow is associated with atherogenesis and may be related to the accumulation of membrane attack complex recently identified between choroidal vessels in those at high risk of macular degeneration due to complement factor H polymorphisms.

  8. GARP2 accelerates retinal degeneration in rod cGMP-gated cation channel β-subunit knockout mice

    Science.gov (United States)

    DeRamus, Marci L.; Stacks, Delores A.; Zhang, Youwen; Huisingh, Carrie E.; McGwin, Gerald; Pittler, Steven J.

    2017-01-01

    The Cngb1 locus-encoded β-subunit of rod cGMP-gated cation channel and associated glutamic acid rich proteins (GARPs) are required for phototransduction, disk morphogenesis, and rod structural integrity. To probe individual protein structure/function of the GARPs, we have characterized several transgenic mouse lines selectively restoring GARPs on a Cngb1 knockout (X1−/−) mouse background. Optical coherence tomography (OCT), light and transmission electron microscopy (TEM), and electroretinography (ERG) were used to analyze 6 genotypes including WT at three and ten weeks postnatal. Comparison of aligned histology/OCT images demonstrated that GARP2 accelerates the rate of degeneration. ERG results are consistent with the structural analyses showing the greatest attenuation of function when GARP2 is present. Even 100-fold or more overexpression of GARP1 could not accelerate degeneration as rapidly as GARP2, and when co-expressed GARP1 attenuated the structural and functional deficits elicited by GARP2. These results indicate that the GARPs are not fully interchangeable and thus, likely have separate and distinct functions in the photoreceptor. We also present a uniform murine OCT layer naming nomenclature system that is consistent with human retina layer designations to standardize murine OCT, which will facilitate data evaluation across different laboratories. PMID:28198469

  9. Retinal Spectral Domain Optical Coherence Tomography in Early Atrophic Age-Related Macular Degeneration (AMD and a New Metric for Objective Evaluation of the Efficacy of Ocular Nutrition

    Directory of Open Access Journals (Sweden)

    Stuart Richer

    2012-11-01

    Full Text Available Purpose: A challenge in ocular preventive medicine is identification of patients with early pathological retinal damage that might benefit from nutritional intervention. The purpose of this study is to evaluate retinal thinning (RT in early atrophic age-related macular degeneration (AMD against visual function data from the Zeaxanthin and Visual Function (ZVF randomized double masked placebo controlled clinical trial (FDA IND #78973. Methods: Retrospective, observational case series of medical center veterans with minimal visible AMD retinopathy (AREDS Report #18 simplified grading 1.4/4.0 bilateral retinopathy. Foveal and extra-foveal four quadrant SDOCT RT measurements were evaluated in n = 54 clinical and ZVF AMD patients. RT by age was determined and compared to the OptoVue SD OCT normative database. RT by quadrant in a subset of n = 29 ZVF patients was correlated with contrast sensitivity and parafoveal blue cone increment thresholds. Results: Foveal RT in AMD patients and non-AMD patients was preserved with age. Extrafoveal regions, however, showed significant slope differences between AMD patients and non-AMD patients, with the superior and nasal quadrants most vulnerable to retinal thinning (sup quad: −5.5 μm/decade thinning vs. Non-AMD: −1.1 μm/decade, P < 0.02; nasal quad: −5.0 μm/decade thinning vs. Non-AMD: −1.0 μm/decade, P < 0.04. Two measures of extrafoveal visual deterioration were correlated: A significant inverse correlation between % RT and contrast sensitivity (r = −0.33, P = 0.01, 2 Tailed Paired T and an elevated extrafoveal increment blue cone threshold (r = +0.34, P = 0.01, 2 Tailed T. Additional SD OCT RT data for the non-AMD oldest age group (ages 82–91 is needed to fully substantiate the model. Conclusion: A simple new SD OCT clinical metric called “% extra-foveal RT” correlates well with functional visual loss in early AMD patients having minimal visible retinopathy. This metric can be used to

  10. Retinal Nerve Fiber Loss in Anti-VEGF Therapy for Age-Related Macular Degeneration Can Be Decreased by Anterior Chamber Paracentesis.

    Science.gov (United States)

    Enders, Philip; Sitnilska, Vasilena; Altay, Lebriz; Schaub, Friederike; Muether, Philipp S; Fauser, Sascha

    2017-01-01

    To analyze peripapillary retinal nerve fiber layer thickness (RNFLT) change after long-term intravitreal anti-VEGF therapy. Patients with regular anterior chamber paracentesis (ACP) prior to intravitreal injections (IVIs) were compared to those without ACP. Neovascular age-related macular degeneration (nAMD) was treated in a pro re nata regimen with a minimum of 9 IVIs. RNFLT change was determined in spectral domain optical coherence tomography. In 32 patients without ACP, mean RNFLT loss (-2.16 ± 3.60 µm) was significantly higher than in 44 patients with regular ACP (0.16 ± 3.60; p = 0.029). Both groups were comparable in age (75.0 vs. 76.8 years; p = 0.35), number of IVIs (16.2 vs. 16.6; p = 0.98), and observational time (30.0 vs. 32.3 months; p = 0.32). In patients without ACP, RNFLT loss was higher compared to IVI-naive fellow eyes (p = 0.005), whereas in ACP patients, no difference was detected (p = 0.5). A moderate RNFLT loss is found in nonglaucomatous patients after injection therapy for nAMD. As it is decreased with regular ACP, tight management of intraocular pressure seems advisable. © 2017 S. Karger AG, Basel.

  11. Comparison of Progression Rate of Retinal Pigment Epithelium Loss in Patients with Neovascular Age-Related Macular Degeneration Treated with Ranibizumab and Aflibercept

    Directory of Open Access Journals (Sweden)

    Juliana Wons

    2017-01-01

    Full Text Available Purpose. Retinal pigment epithelium (RPE loss in neovascular age-related macular degeneration (nAMD seem to have a linear progression but might be influenced by the treatment. The purpose of the study is the comparison of RPE loss over three years in patients treated with intravitreal ranibizumab to patients who were switched to aflibercept. Methods. A retrospective analysis with 96 eyes switched to aflibercept was conducted. The progression rate of RPE loss was evaluated in patients who showed atrophy one year prior to switch (n=17 or on switch date (n=19. The RPE loss was evaluated by spectral domain optical coherence tomography (SD-OCT. Further, 22 eyes from patients treated with ranibizumab were compared. Results. The median yearly progression of RPE loss after square root transformation showed no significant difference in the year prior to switch compared to the year after switch (p=0.854. In patients who received only ranibizumab, the median yearly progression of RPE loss was 0.15 mm/y, for aflibercept patients, 0.13 mm/y. This difference was not statistically significant (p=0.172. Conclusions. There seems to be a linear progression rate of RPE loss in patients treated with ranibizumab as well as in patients with aflibercept. No significant increase of progression rate was found after switch to aflibercept.

  12. Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: Implications for age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Sung Hwan Kim

    2016-12-01

    Full Text Available Clinical and experimental observations indicate a critical role for vascular endothelial growth factor (VEGF, secreted by the retinal pigment epithelium (RPE, in pathological angiogenesis and the development of choroidal neovascularization (CNV in age-related macular degeneration (AMD. RPE-mediated VEGF expression, leading to angiogenesis, is a major signaling mechanism underlying ocular neovascular disease. Inhibiting this signaling pathway with a therapeutic molecule is a promising anti-angiogenic strategy to treat this disease with potentially fewer side effects. Oxalomalate (OMA is a competitive inhibitor of NADP+-dependent isocitrate dehydrogenase (IDH, which plays an important role in cellular signaling pathways regulated by reactive oxygen species (ROS. Here, we have investigated the inhibitory effect of OMA on the expression of VEGF, and the associated underlying mechanism of action, using in vitro and in vivo RPE cell models of AMD. We found that OMA reduced the expression and secretion of VEGF in RPE cells, and consequently inhibited CNV formation. This function of OMA was linked to its capacity to activate the pVHL-mediated HIF-1α degradation in these cells, partly via a ROS-dependent ATM signaling axis, through inhibition of IDH enzymes. These findings reveal a novel role for OMA in inhibiting RPE-derived VEGF expression and angiogenesis, and suggest unique therapeutic strategies for treating pathological angiogenesis and AMD development.

  13. Changes in retinal pigment epithelium related to cigarette smoke: possible relevance to smoking as a risk factor for age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Ai Ling Wang

    Full Text Available Age-related Macular Degeneration (AMD is a major cause of central vision loss in the elderly and smoking is a primary risk factor associated with the prevalence and incidence of AMD. To better understand the cellular and molecular bases for the association between smoking and AMD, we determined the effects of Benzo(aPyrene (B(aP, a toxic element in cigarette smoke, on cultured retinal pigment epithelia (RPE and we examined the RPE/choroid from mice exposed to chronic cigarette smoke. We measured: mitochondrial DNA (mtDNA damage, phagocytic activity, lysosomal enzymes, exosome markers and selected complement pathway components. In the presence of a non-cytotoxic dose of B(aP, there was extensive mtDNA damage but no nuclear DNA damage. RPE phagocytic activity was not altered but there were increased lysosomal activity, exocytotic activity and complement pathway components. Retinas from mice exposed to cigarette smoke contained markers for mtDNA damage, exosomes and complement pathway components surrounding Bruch's membrane. Markers for these processes are found in drusen from AMD patients. Thus, smoking may cause damage to mtDNA and increased degradative processes in the RPE. These altered cell biological processes in the RPE may contribute to the formation of drusen in individuals who are cigarette smokers and underlie susceptibility to genetic mutations associated with AMD.

  14. Volumetric image classification using homogeneous decomposition and dictionary learning: A study using retinal optical coherence tomography for detecting age-related macular degeneration.

    Science.gov (United States)

    Albarrak, Abdulrahman; Coenen, Frans; Zheng, Yalin

    2017-01-01

    Three-dimensional (3D) (volumetric) diagnostic imaging techniques are indispensable with respect to the diagnosis and management of many medical conditions. However there is a lack of automated diagnosis techniques to facilitate such 3D image analysis (although some support tools do exist). This paper proposes a novel framework for volumetric medical image classification founded on homogeneous decomposition and dictionary learning. In the proposed framework each image (volume) is recursively decomposed until homogeneous regions are arrived at. Each region is represented using a Histogram of Oriented Gradients (HOG) which is transformed into a set of feature vectors. The Gaussian Mixture Model (GMM) is then used to generate a "dictionary" and the Improved Fisher Kernel (IFK) approach is used to encode feature vectors so as to generate a single feature vector for each volume, which can then be fed into a classifier generator. The principal advantage offered by the framework is that it does not require the detection (segmentation) of specific objects within the input data. The nature of the framework is fully described. A wide range of experiments was conducted with which to analyse the operation of the proposed framework and these are also reported fully in the paper. Although the proposed approach is generally applicable to 3D volumetric images, the focus for the work is 3D retinal Optical Coherence Tomography (OCT) images in the context of the diagnosis of Age-related Macular Degeneration (AMD). The results indicate that excellent diagnostic predictions can be produced using the proposed framework.

  15. Spectral-domain Optical Coherence Tomography Retinal and Choroidal Thickness Metric Repeatability in Age-related Macular Degeneration

    DEFF Research Database (Denmark)

    Hanumunthadu, Daren; Ilginis, Tomas; Restori, Marie

    2016-01-01

    ) macular subfields. Center point thickness and total macular volume were also included in the analysis. Manual subfoveal choroidal thickness measurements were made by a masked observer. RESULTS: A total of 40 eyes of 40 patients were included in this analysis (mean [± standard deviation] age: 74.1 [± 7...... for the center point was 47.5 μm (95% CI 46.2-48.7 μm). Images were also reviewed for the presence of segmentation error in the central macular subfield, and after exclusion of these eyes the revised CR for this subfield was 13.7 μm (95% CI 13.3-14.1 μm). The intrasession CR of subfoveal choroidal thickness...... was 34.7 μm (95% CI 33.7-35.7 μm). CONCLUSIONS: This study suggests that a change of greater than 31 μm in Spectralis SDOCT-derived retinal thickness measurement of the central macular subfield and 35 μm in subfoveal choroidal thickness is necessary to detect true clinical change associated with disease...

  16. Novel therapeutic approaches to correct retinal metabolic abnormalities in primary open-angle glaucoma and age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    K. A. Mirzabekova

    2014-01-01

    Full Text Available Common pathogenic aspects of age-related macular degeneration (AMD and primary open-angle glaucoma (POAG, i.e., the role of free radicals inducing oxidative damage of the retina and optic nerve, are discussed. Factors that activate free radical reactions as well as multilevel antioxidant protection system are reviewed. Data derived from studies on current antioxidants that are used to treat and prevent dry AMD and glaucomatous optic nerve damage are compared. Neuroprotection for glaucoma will be considered soon as a basis for its treatment. B vitamins are generally included into therapeutic algorithms for glaucomatous optic neuropathy. While being metabolic therapeutics, they stimulate adaptive compensatory mechanisms and reduce the severity of various pathological processes, e.g., hypoxia, lipid peroxidation etc. Neurotrophic, antioxidant, and regenerative effects of B vitamins as wells as their involvement in metabolism, myelinsynthesis and other processes are of special importance for ophthalmologists. Currently, several vitamin and mineral supplements that differ in composition, dosage, and schedule are approved in Russia. SuperOptic, a biologically activeadditive, contains more free lutein (10 mg and zeaxanthin (500 μg as well as potent antioxidants (vitamin E and vitamin C, microelements (zinc and copper, and balanced vitamin B complex. These components play an important role in ocular health. SuperOptic can be recommended for the prevention and treatment of AMD and glaucomatous optic nerve damage.

  17. Novel therapeutic approaches to correct retinal metabolic abnormalities in primary open-angle glaucoma and age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    K. A. Mirzabekova

    2015-01-01

    Full Text Available Common pathogenic aspects of age-related macular degeneration (AMD and primary open-angle glaucoma (POAG, i.e., the role of free radicals inducing oxidative damage of the retina and optic nerve, are discussed. Factors that activate free radical reactions as well as multilevel antioxidant protection system are reviewed. Data derived from studies on current antioxidants that are used to treat and prevent dry AMD and glaucomatous optic nerve damage are compared. Neuroprotection for glaucoma will be considered soon as a basis for its treatment. B vitamins are generally included into therapeutic algorithms for glaucomatous optic neuropathy. While being metabolic therapeutics, they stimulate adaptive compensatory mechanisms and reduce the severity of various pathological processes, e.g., hypoxia, lipid peroxidation etc. Neurotrophic, antioxidant, and regenerative effects of B vitamins as wells as their involvement in metabolism, myelinsynthesis and other processes are of special importance for ophthalmologists. Currently, several vitamin and mineral supplements that differ in composition, dosage, and schedule are approved in Russia. SuperOptic, a biologically activeadditive, contains more free lutein (10 mg and zeaxanthin (500 μg as well as potent antioxidants (vitamin E and vitamin C, microelements (zinc and copper, and balanced vitamin B complex. These components play an important role in ocular health. SuperOptic can be recommended for the prevention and treatment of AMD and glaucomatous optic nerve damage.

  18. In vivo and in vitro investigations of retinal fluorophores in age-related macular degeneration by fluorescence lifetime imaging

    Science.gov (United States)

    Hammer, M.; Quick, S.; Klemm, M.; Schenke, S.; Mata, N.; Eitner, A.; Schweitzer, D.

    2009-02-01

    Ocular fundus autofluorescence imaging has been introduced into clinical diagnostics recently for the observation of the age pigment lipofuscin, a precursor of age-related macular degeneration (AMD). However, a deeper understanding of the generation of single compounds contributing to the lipofuscin as well as of the role of other fluorophores such as FAD, glycated proteins, and collagen needs their discrimination by fluorescence lifetime imaging (FLIM). FLIM at the ocular fundus is performed using a scanning laser ophthalmoscope equipped with a picosecond laser source (448nm or 468nm respectively, 100ps, 80 MHz repetition rate) and dual wavelength (490-560nm and 560-7600nm) time-correlated single photon counting. A three-exponential fit of the fluorescence decay revealed associations of decay times to anatomical structures. Disease-related features are identified from alterations in decay times and-amplitudes. The in-vivo investigations in patients were paralleled by experiments in an organ culture of the porcine ocular fundus. Photo-oxidative stress was induced by exposure to blue light (467nm, 0.41 mW/mm2). Subsequent analysis (fluorescence microscopy, HPLC, LC-MS) indicated the accumulation of the pyridinium bis-retinoid A2E and its oxidation products as well as oxidized phospholipids. These compounds contribute to the tissue auto-fluorescence and may play a key role in the pathogenesis of AMD. Thus, FLIM observation at the ocular fundus in vivo enhances our knowledge on the etiology of AMD and may become a diagnostic tool.

  19. Protective effect of autophagy on human retinal pigment epithelial cells against lipofuscin fluorophore A2E: implications for age-related macular degeneration.

    Science.gov (United States)

    Zhang, J; Bai, Y; Huang, L; Qi, Y; Zhang, Q; Li, S; Wu, Y; Li, X

    2015-11-12

    Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. Degeneration of retinal pigment epithelial (RPE) cells is a crucial causative factor responsible for the onset and progression of AMD. A2E, a major component of toxic lipofuscin implicated in AMD, is deposited in RPE cells with age. However, the mechanism whereby A2E may contribute to the pathogenesis of AMD remains unclear. We demonstrated that A2E was a danger signal of RPE cells, which induced autophagy and decreased cell viability in a concentration- and time-dependent manner. Within 15 min after the treatment of RPE with 25 μM A2E, the induction of autophagosome was detected by transmission electron microscopy. After continuous incubating RPE cells with A2E, intense punctate staining of LC3 and increased expression of LC3-II and Beclin-1 were identified. Meanwhile, the levels of intercellular adhesion molecule (ICAM), interleukin (IL)1β, IL2, IL-6, IL-8, IL-17A, IL-22, macrophage cationic peptide (MCP)-1, stromal cell-derived factor (SDF)-1, and vascular endothelial growth factor A (VEGFA) were elevated. The autophagic inhibitor 3-methyladenine (3-MA) and activator rapamycin were also used to verify the effect of autophagy on RPE cells against A2E. Our results revealed that 3-MA decreased the autophagosomes and LC3 puncta induced by A2E, increased inflammation-associated protein expression including ICAM, IL1β, IL2, IL-6, IL-8, IL-17A, IL-22, and SDF-1, and upregulated VEGFA expression. Whereas rapamycin augmented the A2E-mediated autophagy, attenuated protein expression of inflammation-associated and angiogenic factors, and blocked the Akt/mTOR pathway. Taken together, A2E induces autophagy in RPE cells at the early stage of incubation, and this autophagic response can be inhibited by 3-MA or augmented by rapamycin via the mTOR pathway. The enhancement of autophagy has a protective role in RPE cells against the adverse effects of A2E by reducing the

  20. Change of retinal pigment epithelial atrophy after anti-vascular endothelial growth factor treatment in exudative age-related macular degeneration

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    Moosang Kim

    2016-01-01

    Full Text Available Purpose: The study aimed to investigate the quantitative changes of retinal pigment epithelial (RPE atrophy during a 24-month follow-up period of anti-vascular endothelial growth factor (VEGF for exudative age-related macular degeneration (AMD. Materials and Methods: This is a retrospective study. Sixty-five eyes of 62 consecutive patients with naοve exudative AMD who had received treatment with anti-VEGF therapy and followed for more 24 months were enrolled. All patients received three initial monthly injections of anti-VEGF (ranibizumab or bevacizumab, followed by pro re nata or treat-and-extend protocol. Color fundus image, optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy. Multiple regression analysis was performed to investigate the predictive factors found during univariate analysis to identify an association with increased RPE atrophic areas. Results: The mean number of anti-VEGF treatments was 9.18. RPE atrophic area was 1.293 ± 1.298 mm 2 at baseline and enlarged to 2.394 ± 1.940 mm 2 after 24 months, which differed significantly (P = 0.001. Multiple regression analysis revealed that larger areas of RPE atrophy at month 4 and larger numbers of anti-VEGF treatments were associated with increased RPE atrophic areas. Conclusions: RPE atrophy progresses in eyes with exudative AMD during anti-VEGF treatment. Larger areas of RPE atrophy at month 4 and larger numbers of anti-VEGF injections were associated with an increased risk of progression of RPE atrophy the following treatment. These findings may be useful to clinicians using intravitreal anti-VEGF for the treatment of exudative AMD, both for selecting an appropriate treatment plan and for predicting the progression of RPE atrophy.

  1. Transplante autólogo do epitélio pigmentado da retina na degeneração macular relacionada com a idade Autologous transplantation of retinal pigment epithelium in age related macular degeneration

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    Rubens Camargo Siqueira

    2009-02-01

    Full Text Available Acredita-se que a disfunção do epitélio pigmentado da retina é a principal causa de muitas doenças debilitantes da retina das quais a degeneração macular relacionada com a idade é a mais comum. Nesta doença a disfunção das células do epitélio pigmentado da retina leva a um comprometimento secundário dos fotorreceptores com perda visual grave. O epitélio pigmentado da retina e membrana de Bruch sofrem dano acumulativo com o tempo o qual induz à degeneração macular relacionada com a idade em indivíduos susceptíveis. Nos últimos 20 anos, uma grande quantidade de pesquisas tem sido conduzida na área de transplante do epitélio pigmentado da retina. A técnica tem como objetivo, restaurar a anatomia sub-retiniana e restabelecer a interação crítica entre o epitélio pigmentado da retina e o fotorreceptor, o qual é fundamental para a visão. O transplante autólogo do epitélio pigmentado da retina tem sido usado em alguns casos de degeneração macular relacionada com a idade através de duas técnicas: epitélio pigmentado da retina em suspensão e transplante de espessura total do epitélio pigmentado da retina-coróide. Apesar da viabilidade desta técnica, pesquisas buscando uma fonte de células para repor epitélio pigmentado da retina autólogo como células-tronco embrionárias, células-tronco derivadas da medula óssea e derivadas do cordão umbilical continuam em andamento. A combinação do transplante de células com outras modalidades de tratamento como transferência de genes permanecem como excitante perspectiva futura.Retinal pigment epithelial dysfunction is believed to be the main cause of many debilitating retinal diseases of which age-related macular degeneration is the most common. In this disease, the retinal pigment epithelial dysfunction leads to photoreceptors damage causing severe vision loss. The retinal pigment epithelium and Bruch's membrane suffer cumulative damage over lifetime, which is

  2. Tumorigenicity studies of induced pluripotent stem cell (iPSC-derived retinal pigment epithelium (RPE for the treatment of age-related macular degeneration.

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    Hoshimi Kanemura

    Full Text Available Basic studies of human pluripotential stem cells have advanced rapidly and stem cell products are now seeing therapeutic applications. However, questions remain regarding the tumorigenic potential of such cells. Here, we report the tumorigenic potential of induced pluripotent stem cell (iPSC-derived retinal pigment epithelium (RPE for the treatment of wet-type, age-related macular degeneration (AMD. First, immunodeficient mouse strains (nude, SCID, NOD-SCID and NOG were tested for HeLa cells' tumor-forming capacity by transplanting various cell doses subcutaneously with or without Matrigel. The 50% Tumor Producing Dose (TPD50 value is the minimal dose of transplanted cells that generated tumors in 50% of animals. For HeLa cells, the TPD50 was the lowest when cells were embedded in Matrigel and transplanted into NOG mice (TPD50 = 10(1.1, n = 75. The TPD50 for undifferentiated iPSCs transplanted subcutaneously to NOG mice in Matrigel was 10(2.12; (n = 30. Based on these experiments, 1×10(6 iPSC-derived RPE were transplanted subcutaneously with Matrigel, and no tumor was found during 15 months of monitoring (n = 65. Next, to model clinical application, we assessed the tumor-forming potential of HeLa cells and iPSC 201B7 cells following subretinal transplantation of nude rats. The TPD50 for iPSCs was 10(4.73 (n = 20 and for HeLa cells 10(1.32 (n = 37 respectively. Next, the tumorigenicity of iPSC-derived RPE was tested in the subretinal space of nude rats by transplanting 0.8-1.5×10(4 iPSC-derived RPE in a collagen-lined (1 mm×1 mm sheet. No tumor was found with iPSC-derived RPE sheets during 6-12 months of monitoring (n = 26. Considering the number of rodents used, the monitoring period, the sensitivity of detecting tumors via subcutaneous and subretinal administration routes and the incidence of tumor formation from the iPSC-derived RPE, we conclude that the tumorigenic potential of the iPSC-derived RPE was

  3. Selective impairment of a subset of Ran-GTP-binding domains of ran-binding protein 2 (Ranbp2) suffices to recapitulate the degeneration of the retinal pigment epithelium (RPE) triggered by Ranbp2 ablation.

    Science.gov (United States)

    Patil, Hemangi; Saha, Arjun; Senda, Eugene; Cho, Kyoung-in; Haque, MdEmdadul; Yu, Minzhong; Qiu, Sunny; Yoon, Dosuk; Hao, Ying; Peachey, Neal S; Ferreira, Paulo A

    2014-10-24

    Retinal pigment epithelium (RPE) degeneration underpins diseases triggered by disparate genetic lesions, noxious insults, or both. The pleiotropic Ranbp2 controls the expression of intrinsic and extrinsic pathological stressors impinging on cellular viability. However, the physiological targets and mechanisms controlled by Ranbp2 in tissue homeostasis, such as RPE, are ill defined. We show that mice, RPE-cre::Ranbp2(-/-), with selective Ranbp2 ablation in RPE develop pigmentary changes, syncytia, hypoplasia, age-dependent centrifugal and non-apoptotic degeneration of the RPE, and secondary leakage of choriocapillaris. These manifestations are accompanied by the development of F-actin clouds, metalloproteinase-11 activation, deregulation of expression or subcellular localization of critical RPE proteins, atrophic cell extrusions into the subretinal space, and compensatory proliferation of peripheral RPE. To gain mechanistic insights into what Ranbp2 activities are vital to the RPE, we performed genetic complementation analyses of transgenic lines of bacterial artificial chromosomes of Ranbp2 harboring loss of function of selective Ranbp2 domains expressed in a Ranbp2(-/-) background. Among the transgenic lines produced, only Tg(RBD2/3*-HA)::RPE-cre::Ranbp2(-/-)-expressing mutations, which selectively impair binding of RBD2/3 (Ran-binding domains 2 and 3) of Ranbp2 to Ran-GTP, recapitulate RPE degeneration, as observed with RPE-cre::Ranbp2(-/-). By contrast, Tg(RBD2/3*-HA) expression rescues the degeneration of cone photoreceptors lacking Ranbp2. The RPE of RPE-cre::Ranbp2(-/-) and Tg(RBD2/3*-HA)::RPE-cre::Ranbp2(-/-) share proteostatic deregulation of Ran GTPase, serotransferrin, and γ-tubulin and suppression of light-evoked electrophysiological responses. These studies unravel selective roles of Ranbp2 and its RBD2 and RBD3 in RPE survival and functions. We posit that the control of Ran GTPase by Ranbp2 emerges as a novel therapeutic target in diseases promoting

  4. The generation of induced pluripotent stem cells for macular degeneration as a drug screening platform: identification of curcumin as a protective agent for retinal pigment epithelial cells against oxidative stress

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    Yun-Ching eChang

    2014-08-01

    Full Text Available Age-related macular degeneration (AMD is one retinal aging process that may lead to irreversible vision loss in the elderly. Its pathogenesis remains unclear, but oxidative stress inducing retinal pigment epithelial (RPE cells damage is perhaps responsible for the aging sequence of retina and may play an important role in macular degeneration. In this study, we have reprogrammed T cells from patients with dry type AMD into induced pluripotent stem cells (iPSCs via integration-free episomal vectors and differentiated them into RPE cells that were used as an expandable platform for investigating pathogenesis of the AMD and in-vitro drug screening. These patient-derived RPEs with the AMD-associated background (AMD-RPEs exhibited reduced antioxidant ability, compared with normal RPE cells. Among several screened candidate drugs, curcumin caused most significant reduction of ROS in AMD-RPEs. Pre-treatment of curcumin protected these AMD-RPEs from H2O2-induced cell death and also increased the cytoprotective effect against the oxidative stress of H2O2 through the reduction of ROS levels. In addition, curcumin with its versatile activities modulated the expression of many oxidative stress-regulating genes such as PDGF, VEGF, IGFBP-2, HO1, SOD2 and GPX1. Our findings indicated that the RPE cells derived from AMD patients have decreased antioxidative defense, making RPE cells more susceptible to oxidative damage and thereby leading to AMD formation. Curcumin represented an ideal drug that can effectively restore the neuronal functions in AMD patient-derived RPE cells, rendering this drug an effective option for macular degeneration therapy and an agent against aging-associated oxidative stress.

  5. Retinal remodeling in human retinitis pigmentosa.

    Science.gov (United States)

    Jones, B W; Pfeiffer, R L; Ferrell, W D; Watt, C B; Marmor, M; Marc, R E

    2016-09-01

    Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies.

  6. Inherited Retinal Degenerative Disease Registry

    Science.gov (United States)

    2016-03-21

    Eye Diseases Hereditary; Retinal Disease; Achromatopsia; Bardet-Biedl Syndrome; Bassen-Kornzweig Syndrome; Batten Disease; Best Disease; Choroidal Dystrophy; Choroideremia; Cone Dystrophy; Cone-Rod Dystrophy; Congenital Stationary Night Blindness; Enhanced S-Cone Syndrome; Fundus Albipunctatus; Goldmann-Favre Syndrome; Gyrate Atrophy; Juvenile Macular Degeneration; Kearns-Sayre Syndrome; Leber Congenital Amaurosis; Refsum Syndrome; Retinitis Pigmentosa; Retinitis Punctata Albescens; Retinoschisis; Rod-Cone Dystrophy; Rod Dystrophy; Rod Monochromacy; Stargardt Disease; Usher Syndrome

  7. Human bZIP transcription factor gene NRL: structure, genomic sequence, and fine linkage mapping at 14q11.2 and negative mutation analysis in patients with retinal degeneration.

    Science.gov (United States)

    Farjo, Q; Jackson, A; Pieke-Dahl, S; Scott, K; Kimberling, W J; Sieving, P A; Richards, J E; Swaroop, A

    1997-10-15

    The NRL gene encodes an evolutionarily conserved basic motif-leucine zipper transcription factor that is implicated in regulating the expression of the photoreceptor-specific gene rhodopsin. NRL is expressed in postmitotic neuronal cells and in lens during embryonic development, but exhibits a retina-specific pattern of expression in the adult. To understand regulation of NRL expression and to investigate its possible involvement in retinopathies, we have determined the complete sequence of the human NRL gene, identified a polymorphic (CA)n repeat (identical to D14S64) within the NRL-containing cosmid, and refined its location by linkage analysis. Since a locus for autosomal recessive retinitis pigmentosa (arRP) has been linked to markers at 14q11 and since mutations in rhodopsin can lead to RP, we sequenced genomic PCR products of the NRL gene and of the rhodopsin-Nrl response element from a panel of patients representing independent families with inherited retinal degeneration. The analysis did not reveal any causative mutations in this group of patients. These investigations provide the basis for delineating the DNA sequence elements that regulate NRL expression in distinct neuronal cell types and should assist in the analysis of NRL as a candidate gene for inherited diseases/syndromes affecting visual function. Copyright 1997 Academic Press.

  8. Vitelliform macular degeneration associated with mitochondrial myopathy.

    OpenAIRE

    Modi, G; Heckman, J M; Saffer, D

    1992-01-01

    A patient with mitochondrial myopathy is described. Examination of his fundus revealed bilateral vitelliform degeneration of the maculae. This lesion is a focal abnormality of the retinal pigment epithelium and may be a manifestation of the underlying mitochondrial disease.

  9. The application of optogenetics in the treatment of retinal degeneration disease%光遗传学技术及其在视网膜变性性疾病治疗中的应用

    Institute of Scientific and Technical Information of China (English)

    沈雨濛; 邢怡桥; 沈吟

    2016-01-01

    Optogenetics is a novel technique which combines optics with genetics.Using genetic means,a selected opsin protein is ectopically expressed in target neurons,which are then stimulated by light to moderate the neuronal circuit,as a consequence to regulate the animal's behaviors.Retinal degeneration like retinitis pigmentosa and aged macular degeneration causes visual impairment and eventual blindness.Optogenetics techniques have opened the door to creating artificial photoreceptors in the remaining retinal circuits of retinal degeneration retinas via gene therapy.However,there are still limitations in optogenetics technique,for example,potential risk in virus infection,the choice of target cells and the low visual resolution of the experiment animal.It has been reported that vision was successfully restored to a certain extent in animal model using optogenetics technique.With higher photosensitivity of opsin protein,longer activation kinetics and higher transfection efficiency of virus vector,optogenetics techniques' application in ophthalmology will be improved.%光遗传学技术是一种将光学和遗传学技术相结合的新兴技术.其主要原理是应用遗传学方法将特异的视蛋白导入目标神经元,再用相应波长或频率的光刺激视蛋白,使神经元兴奋或抑制,进而控制特定神经环路的活动,最终起到调控实验动物生理活动和行为的作用.在视网膜色素变性、老年性黄斑变性等视网膜变性性疾病中,应用光遗传学技术玻璃体腔或视网膜下注射视蛋白基因,由外界给予相应的光照激活视蛋白,模拟并代替视网膜光感受器功能,可在一定程度上恢复患者视力.但其存在病毒转染有潜在风险、目标细胞的准确选择难以把握、治疗后视力分辨率能否恢复正常尚不确定等局限性.随着光敏感度更高、更易被激发的新型视蛋白和具有更高转染效率的病毒载体不断研发,相信光遗传学技术将会应用在更多眼科领域.

  10. Retinal locus for scanning text.

    Science.gov (United States)

    Timberlake, George T; Sharma, Manoj K; Grose, Susan A; Maino, Joseph H

    2006-01-01

    A method of mapping the retinal location of text during reading is described in which text position is plotted cumulatively on scanning laser ophthalmoscope retinal images. Retinal locations that contain text most often are the brightest in the cumulative plot, and locations that contain text least often are the darkest. In this way, the retinal area that most often contains text is determined. Text maps were plotted for eight control subjects without vision loss and eight subjects with central scotomas from macular degeneration. Control subjects' text maps showed that the fovea contained text most often. Text maps of five of the subjects with scotomas showed that they used the same peripheral retinal area to scan text and fixate. Text maps of the other three subjects with scotomas showed that they used separate areas to scan text and fixate. Retinal text maps may help evaluate rehabilitative strategies for training individuals with central scotomas to use a particular retinal area to scan text.

  11. Peripheral Retinal Changes Associated with Age-Related Macular Degeneration in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 12 by the Age-Related Eye Disease Study 2 Optos PEripheral RetinA (OPERA) Study Research Group.

    Science.gov (United States)

    Domalpally, Amitha; Clemons, Traci E; Danis, Ronald P; Sadda, SriniVas R; Cukras, Catherine A; Toth, Cynthia A; Friberg, Thomas R; Chew, Emily Y

    2017-04-01

    To compare rates of peripheral retinal changes in Age-Related Eye Disease Study 2 (AREDS2) participants with at least intermediate age-related macular degeneration (AMD) with control subjects without intermediate age-related changes (large drusen). Cross-sectional evaluation of clinic-based patients enrolled in AREDS2 and a prospective study. Participants from prospective studies. The 200° pseudocolor and fundus autofluorescence (FAF) images were captured on the Optos 200 Tx Ultrawide-field device (Optos, Dunfermline, Scotland) by centering on the fovea and then steering superiorly and inferiorly. The montaged images were graded at a reading center with the images divided into 3 zones (zone 1 [posterior pole], zone 2 [midperiphery], and zone 3 [far periphery]) to document the presence of peripheral lesions. Peripheral retinal lesions: drusen, hypopigmentary/hyperpigmentary changes, reticular pseudodrusen, senile reticular pigmentary changes, cobblestone degeneration, and FAF abnormalities. A total of 484 (951 eyes) AREDS2 participants with AMD (cases) and 89 (163 eyes) controls without AMD had gradable color and FAF images. In zones 2 and 3, neovascularization and geographic atrophy (GA) were present, ranging from 0.4% to 6% in eyes of cases, respectively, and GA was present in 1% of eyes of controls. Drusen were detected in 97%, 78%, and 64% of eyes of cases and 48%, 21%, and 9% of eyes of controls in zones 2 and 3 superior and 3 inferior, respectively (P < 0.001 for all). Peripheral reticular pseudodrusen were seen in 15%. Senile reticular pigmentary change was the predominant peripheral change seen in 48% of cases and 16% of controls in zone 2 (P < 0.001). Nonreticular pigment changes were less frequent in the periphery than in the posterior pole (46% vs. 76%) and negligible in controls. Peripheral retinal changes are more prevalent in eyes with AMD than in control eyes. Drusen are seen in a majority of eyes with AMD in both the mid and far periphery, whereas

  12. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex.

    Science.gov (United States)

    Bhutto, Imran; Lutty, Gerard

    2012-08-01

    There is a mutualistic symbiotic relationship between the components of the photoreceptor/retinal pigment epithelium (RPE)/Bruch's membrane (BrMb)/choriocapillaris (CC) complex that is lost in AMD. Which component in the photoreceptor/RPE/BrMb/CC complex is affected first appears to depend on the type of AMD. In atrophic AMD (~85-90% of cases), it appears that large confluent drusen formation and hyperpigmentation (presumably dysfunction in RPE) are the initial insult and the resorption of these drusen and loss of RPE (hypopigmentation) can be predictive for progression of geographic atrophy (GA). The death and dysfunction of photoreceptors and CC appear to be secondary events to loss in RPE. In neovascular AMD (~10-15% of cases), the loss of choroidal vasculature may be the initial insult to the complex. Loss of CC with an intact RPE monolayer in wet AMD has been observed. This may be due to reduction in blood supply because of large vessel stenosis. Furthermore, the environment of the CC, basement membrane and intercapillary septa, is a proinflammatory milieu with accumulation of complement components as well as proinflammatory molecules like CRP during AMD. In this toxic milieu, CC die or become dysfunction making adjacent RPE hypoxic. These hypoxic cells then produce angiogenic substances like VEGF that stimulate growth of new vessels from CC, resulting in choroidal neovascularization (CNV). The loss of CC might also be a stimulus for drusen formation since the disposal system for retinal debris and exocytosed material from RPE would be limited. Ultimately, the photoreceptors die of lack of nutrients, leakage of serum components from the neovascularization, and scar formation. Therefore, the mutualistic symbiotic relationship within the photoreceptor/RPE/BrMb/CC complex is lost in both forms of AMD. Loss of this functionally integrated relationship results in death and dysfunction of all of the components in the complex.

  13. Duration of rhegmatogenous retinal detachment predicts recovery of retinal sensitivity

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    Rose Rose

    2016-02-01

    Full Text Available The decision to treat a disease is often based on the presence or absence of symptoms, one prototype case being rhegmatogenous retinal detachment. Detachment of the neural retina from the pigment epithelium is a major cause of anatomical and functional dysfunction of the retina, where retinal recovery is inversely related to duration of detachment. The purpose of retinal reattachment is to effect recovery of the photoreceptors and pigment epithelium from degeneration. The aim of this study was to determine the critical duration of rhegmatogenous retinal detachment resulting in optimal retinal recovery after reattachment. A prospective study was conducted at a private hospital in Yogyakarta. Thirty five eyes were involved in this study. Three months after reattachment, central retinal recovery was measured by means of a Goldmann manual kinetic perimeter. The results showed that retinal recovery developed three months after surgery if the onset of rhegmatogenous retinal detachment was less than 28 days before surgery. The results were not significant if the onset of rhegmatogenous retinal detachment was more than 35 days. Although the Goldmann manual kinetic perimeter can efficiently detect central retinal sensitivity, it should be supported by more sensitive tools to evaluate the anatomy and function of the retina.

  14. Optic nerve compression and retinal degeneration in Tcirg1 mutant mice lacking the vacuolar-type H-ATPase a3 subunit.

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    Nobuyuki Kawamura

    Full Text Available BACKGROUND: Vacuolar-type proton transporting ATPase (V-ATPase is involved in the proper development of visual function. Mutations in the Tcirg1 (also known as Atp6V0a3 locus, which encodes the a3 subunit of V-ATPase, cause severe autosomal recessive osteopetrosis (ARO in humans. ARO is often associated with impaired vision most likely because of nerve compression at the optic canal. We examined the ocular phenotype of mice deficient in Tcirg1 function. METHODOLOGY/PRINCIPAL FINDINGS: X-ray microtomography showed narrowed foramina in the skull, suggesting that optic nerve compression occurred in the a3-deficient (Tcirg1-/- mice. The retina of the mutant mice had normal architecture, but the number of apoptotic cells was increased at 2-3 wks after birth. In the ocular system, the a3 subunit accumulated in the choriocapillary meshwork in uveal tissues. Two other subunit isoforms a1 and a2 accumulated in the retinal photoreceptor layer. We found that the a4 subunit, whose expression has previously been shown to be restricted to several transporting epithelia, was enriched in pigmented epithelial cells of the retina and ciliary bodies. The expression of a4 in the uveal tissue was below the level of detection in wild-type mice, but it was increased in the mutant choriocapillary meshwork, suggesting that compensation may have occurred among the a subunit isoforms in the mutant tissues. CONCLUSIONS: Our findings suggest that a similar etiology of visual impairment is involved in both humans and mice; thus, a3-deficient mice may provide a suitable model for clinical and diagnostic purposes in cases of ARO.

  15. Antisense Oligonucleotide-based Splice Correction for USH2A-associated Retinal Degeneration Caused by a Frequent Deep-intronic Mutation

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    Radulfus WN Slijkerman

    2016-01-01

    Full Text Available Usher syndrome (USH is the most common cause of combined deaf-blindness in man. The hearing loss can be partly compensated by providing patients with hearing aids or cochlear implants, but the loss of vision is currently untreatable. In general, mutations in the USH2A gene are the most frequent cause of USH explaining up to 50% of all patients worldwide. The first deep-intronic mutation in the USH2A gene (c.7595-2144A>G was reported in 2012, leading to the insertion of a pseudoexon (PE40 into the mature USH2A transcript. When translated, this PE40-containing transcript is predicted to result in a truncated non-functional USH2A protein. In this study, we explored the potential of antisense oligonucleotides (AONs to prevent aberrant splicing of USH2A pre-mRNA as a consequence of the c.7595-2144A>G mutation. Engineered 2'-O-methylphosphorothioate AONs targeting the PE40 splice acceptor site and/or exonic splice enhancer regions displayed significant splice correction potential in both patient derived fibroblasts and a minigene splice assay for USH2A c.7595-2144A>G, whereas a non-binding sense oligonucleotide had no effect on splicing. Altogether, AON-based splice correction could be a promising approach for the development of a future treatment for USH2A-associated retinitis pigmentosa caused by the deep-intronic c.7595-2144A>G mutation.

  16. Functional annotation of the human retinal pigment epithelium transcriptome

    NARCIS (Netherlands)

    J.C. Booij (Judith); S. van Soest (Simone); S.M.A. Swagemakers (Sigrid); A.H.W. Essing (Anke); J.H.M. Verkerk (Annemieke); P.J. van der Spek (Peter); T.G.M.F. Gorgels (Theo); A.A.B. Bergen (Arthur)

    2009-01-01

    textabstractBackground: To determine level, variability and functional annotation of gene expression of the human retinal pigment epithelium (RPE), the key tissue involved in retinal diseases like age-related macular degeneration and retinitis pigmentosa. Macular RPE cells from six selected healthy

  17. Functional annotation of the human retinal pigment epithelium transcriptome

    NARCIS (Netherlands)

    Booij, J.C.; van Soest, S.; Swagemakers, S.M.A.; Essing, A.H.W.; Verkerk, A.J.M.H.; van der Spek, P.J.; Gorgels, T.G.M.F.; Bergen, A.A.B.

    2009-01-01

    ABSTRACT: BACKGROUND: To determine level, variability and functional annotation of gene expression of the human retinal pigment epithelium (RPE), the key tissue involved in retinal diseases like age-related macular degeneration and retinitis pigmentosa. Macular RPE cells from six selected healthy hu

  18. Current Concepts in the Treatment of Retinitis Pigmentosa

    Directory of Open Access Journals (Sweden)

    Maria A. Musarella

    2011-01-01

    Full Text Available Inherited retinal degenerations, including retinitis pigmentosa (RP and Leber congenital amaurosis (LCA, affect 1 in 4000 individuals in the general population. A majority of the genes which are mutated in these conditions are expressed in either photoreceptors or the retinal pigment epithelium (RPE. There is considerable variation in the clinical severity of these conditions; the most severe being autosomal recessive LCA, a heterogeneous retinal degenerative disease and the commonest cause of congenital blindness in children. Here, we discuss all the potential treatments that are now available for retinal degeneration. A number of therapeutic avenues are being explored based on our knowledge of the pathophysiology of retinal degeneration derived from research on animal models, including: gene therapy, antiapoptosis agents, neurotrophic factors, and dietary supplementation. Technological advances in retinal implant devices continue to provide the promise of vision for patients with end-stage disease.

  19. Bioelectronic retinal prosthesis

    Science.gov (United States)

    Weiland, James D.

    2016-05-01

    Retinal prosthesis have been translated to clinical use over the past two decades. Currently, two devices have regulatory approval for the treatment of retinitis pigmentosa and one device is in clinical trials for treatment of age-related macular degeneration. These devices provide partial sight restoration and patients use this improved vision in their everyday lives to navigate and to detect large objects. However, significant vision restoration will require both better technology and improved understanding of the interaction between electrical stimulation and the retina. In particular, current retinal prostheses do not provide peripheral visions due to technical and surgical limitations, thus limiting the effectiveness of the treatment. This paper reviews recent results from human implant patients and presents technical approaches for peripheral vision.

  20. Spontaneous or secondary to intravitreal injections of anti-angiogenic agents retinal pigment epithelial tears in age-related macular degeneration

    Institute of Scientific and Technical Information of China (English)

    Pia; E.; Leon; Sandro; Saviano; Andrea; Zanei; Marco; R.; Pastore; Elvira; Guaglione; Alessandro; Mangogna; Daniele; Tognetto

    2014-01-01

    ·AIM:Toevaluatethevisualfunctionevolutionofretinal pigment epithelial(RPE) tears in patients with age-related macular degeneration(AMD) according to type of occurrence [spontaneous or secondary to anti-vascular endothelial growth factor(anti-VEGF) injection] and the topographic location of the tear after a two-year followup period.·METHODS: A total of 15 eyes of 14 patients with RPE tears in exudative AMD were analyzed retrospectively at the University Eye Clinic of Trieste. Inclusion criteria were: patient age of 50 or older with AMD and RPE tears both spontaneous occurring or post anti-VEGF treatment. Screening included: careful medical history,complete ophthalmological examination, fluorescein angiography(FA), indocyanine green angiography(ICG),autofluorescence and infrared imaging and optical coherence tomography(OCT). Patients were evaluated every month for visual acuity(VA), fundus examination and OCT. Other data reported were: presence of PED,number of injections before the tear, location of the lesion.·RESULTS:Meanfollow-up was24wk(SD±4wk). Atotal of 15 eyes were studied for RPE tear. In 6 cases(40%),the RPE tears occurred within two years of anti-VEGF injections the others occurred spontaneously. In 13cases(86.6%), the RPE tear was associated with pigment epithelial detachment(PED). In 7 cases(46.6%), the RPE tear occurred in the central area of the retina and involved the fovea. Two lesions were found in the parafoveal region, six in the extra-macular area. In all cases visual acuity decreased at the end of the follow-up period(P <0.01) independently of the type or the topographical location of the lesion.·CONCLUSION: RPE tear occurs in exudative AMD as a spontaneous complication or in relation to anti-VEGF injections. Visual acuity decreased significantly and gradually in the follow-up period in all cases. No correlation was found between visual loss and the type of onset or the topographic location of the tears.

  1. [Pathogenesis of age-related macular degeneration].

    Science.gov (United States)

    Kaarniranta, Kai; Seitsonen, Sanna; Paimela, Tuomas; Meri, Seppo; Immonen, Ilkka

    2009-01-01

    Age-related macular degeneration is a multiform disease of the macula, the region responsible for detailed central vision. In recent years, plenty of new knowledge of the pathogenesis of this disease has been obtained, and the treatment of exudative macular degeneration has greatly progressed. The number of patients with age-related macular degeneration will multiply in the following decades, because knowledge of mechanisms of development of macular degeneration that could be subject to therapeutic measures is insufficient. Central underlying factors are genetic inheritance, exposure of the retina to chronic oxidative stress and accumulation of inflammation-inducing harmful proteins into or outside of retinal cells.

  2. Optical coherent tomography in diagnoses of peripheral retinal degenarations

    Directory of Open Access Journals (Sweden)

    O. G. Pozdeyeva

    2013-01-01

    Full Text Available Purpose: Studying the capabilities of optical coherence tomography (RTVue-100, OPTOVUE, USA in evaluation of peripheral retinal degenerations, vitreoretinal adhesions, adjacent vitreous body as well as measurement of morphometric data.Methods: The study included 189 patients (239 eyes with peripheral retinal degeneration. 77 men and 112 women aged 18 to 84 underwent an ophthalmologic examination since November 2012 until October 2013. The peripheral retina was visualized with the help of optical coherence tomography («RTVue-100,» USA. The fundography was carried out using a Nikon NF505‑AF (Japan fundus camera. All patients were examined with a Goldmann lens.Results: Optical coherence tomography was used to evaluate different kinds of peripheral retinal degenerations, such as lattice and snail track degeneration, isolated retinal tears, cystoid retinal degeneration, pathological hyperpigmentation, retinoschisis and cobblestone degeneration. The following morphometric data were studied: dimensions of the lesion (average length, retinal thickness along the edge of the lesion, retinal thickness at the base of the lesion and the vitreoretinal interface.Conclusion: Optical coherence tomography is a promising in vivo visualization method which is useful in evaluation of peripheral retinal degenerations, vitreoretinal adhesions and tractions. It also provides a comprehensive protocolling system and monitoring. It will enable ophthalmologists to better define laser and surgical treatment indications and evaluate therapy effectiveness.

  3. Optical coherent tomography in diagnoses of peripheral retinal degenarations

    Directory of Open Access Journals (Sweden)

    O. G. Pozdeyeva

    2014-07-01

    Full Text Available Purpose: Studying the capabilities of optical coherence tomography (RTVue-100, OPTOVUE, USA in evaluation of peripheral retinal degenerations, vitreoretinal adhesions, adjacent vitreous body as well as measurement of morphometric data.Methods: The study included 189 patients (239 eyes with peripheral retinal degeneration. 77 men and 112 women aged 18 to 84 underwent an ophthalmologic examination since November 2012 until October 2013. The peripheral retina was visualized with the help of optical coherence tomography («RTVue-100,» USA. The fundography was carried out using a Nikon NF505‑AF (Japan fundus camera. All patients were examined with a Goldmann lens.Results: Optical coherence tomography was used to evaluate different kinds of peripheral retinal degenerations, such as lattice and snail track degeneration, isolated retinal tears, cystoid retinal degeneration, pathological hyperpigmentation, retinoschisis and cobblestone degeneration. The following morphometric data were studied: dimensions of the lesion (average length, retinal thickness along the edge of the lesion, retinal thickness at the base of the lesion and the vitreoretinal interface.Conclusion: Optical coherence tomography is a promising in vivo visualization method which is useful in evaluation of peripheral retinal degenerations, vitreoretinal adhesions and tractions. It also provides a comprehensive protocolling system and monitoring. It will enable ophthalmologists to better define laser and surgical treatment indications and evaluate therapy effectiveness.

  4. hEPO gene modified Müller cells protects against retinal degeneration of RCS rats%EPO修饰增强Müller细胞对RCS大鼠视网膜变性的干预效果

    Institute of Scientific and Technical Information of China (English)

    李宗义; 李鹏; 高芙蓉; 范氏雪幸; 张敬法; 王方; 吕立夏; 徐国彤

    2014-01-01

    目的:研究人源促红细胞生成素(hEPO)修饰的Müller(hEPO-Müller)细胞对视网膜退行性病变大鼠的干预作用。方法通过质粒转染法构建hEPO和GFP的Müller细胞稳转株(hEPO-Müller和GFP-Müller);以体外共培养和体内细胞移植为研究体系,利用RT-PCR和冰冻切片及免疫荧光染色的方法检测hEPO-Müller对RCS大鼠视网膜退行性病变的干预作用。内核层与外核层厚度比较采用t检验。结果本实验成功构建了hEPO-Müller和GFP-Müller细胞系。将RCS大鼠的视网膜组织剥离并在体外不同条件下培养两周后测定视网膜各核层厚度发现,与对照细胞裂解液共培养组的内核层(15.94±1.77)μm和外核层(24.81±3.03)μm的厚度相比较,两核层的厚度分别在hEPO组为(23.03±3.29)μm,(33.92±7.59)μm(P<0.05);Müller 组为(24.81±2.02)μm,(32.15±3.03)μm(P<0.05);hEPO-Müller组为(32.40±8.35)μm,(40.25±3.29)μm(n=3, P<0.01);以hEPO-Müller组厚度增加最为显著(P<0.05)。提示EPO和Müller细胞对视网膜变性都有干预作用且两者可以叠加。将hEPO-Müller和GFP-Müller分别移植到RCS大鼠的视网膜下腔,四周后取视网膜进行冰冻切片检测,染色结果显示,细胞移植后有更多的外核层细胞存活,且同样也是hEPO-Müller组的外核层细胞更多。此外,Müller移植并不会促进视网膜的胶质化。结论移植Müller细胞可以减缓RCS大鼠视网膜变性,而经hEPO修饰的Müller细胞对视网膜变性有更好的干预作用。因此,Müller细胞可以作为一种供体细胞兼携带hEPO等营养因子的载体用于视网膜变性的治疗。%Objective To study the effects of hEPO gene modified Müller cells (hEPO-Müller) in the rat model of retinal degeneration. Methods The hEPO-Müller and GFP modified Müller cells (GFP-Müller) were established by the transfection of M

  5. Morphologic characteristics of N-Nitroso-N-methylurea-induced retinal degeneration in mice%N-亚硝基-N-甲基脲诱导视网膜变性小鼠模型的特征

    Institute of Scientific and Technical Information of China (English)

    王晓琴; 陈媛媛; 邢怡桥

    2015-01-01

    Objective To explore the characteristics of N-Nitroso-N-methylurea (MNU) induced retinal degeneration in mice.Methods Experimental study.Thirty-two C57/BL mice (5 weeks) in total were randomly divided into two groups:a control group and a MNU group.Sixty mg·kg-1 of MNU was intraperitonealy injected in mice,leading to damage of retinal photoreceptors,while the control group was given physiological saline.The eyes of each group were enucleated at 3 d,7 d and 14 d after injection.The slides were stained by immunofluorescence labeling to observe the morphological changes to the photoreceptors in MNU-induced retinal damage.Retinal fiat-mount immunofluorescence was performed to observe the change in ganglion cells.The ultrastructures of the nucleus,mitochondria and synaptic ribbon were observed under transmission electron microscope.Ganzfeld electroretinogram ERG was used to test the electrophysiological changes.The data were analyzed using independent t test.Results After MNU administration,immunofluorescence labeling showed a gradual decrease in the thickness of the outer nuclear layer (ONL),the loss of photoreceptors labeled with anti-OPN1SW,reactive gliosis with anti-glial fibrillary acidic protein (GFAP) and oxidative damage in photoreceptors labeled with anti-nitrosylation.Brn-3a labeled ganglion cells did not appear to be lost two weeks after MNU administration.Electron microscopy showed concentrated coloring of the nucleus in the photoreceptor nucleus and the disappearance of mitochondria and metabolic synaptic ribbons after MNU administration.ERGs revealed that mice with MNU treatment showed a-waves and b-waves with reduced amplitudes.Conclusion MNU induced retinal apoptosis of ONL and outer piexiform layer.MNU administrated mice show similar electrophysiological results to retintis pigmentosa.%目的 探讨N-亚硝基-N-甲基脲(MNU)诱导的小鼠视网膜退行性病变的形态和电生理特征.方法 实验研究.32只5周龄的成年C57/BL小鼠随机

  6. The cost-effectiveness of the Argus II retinal prosthesis in Retinitis Pigmentosa patients

    OpenAIRE

    2014-01-01

    Background Retinitis Pigmentosa (RP) is a hereditary genetic disease causing bilateral retinal degeneration. RP is a leading cause of blindness resulting in incurable visual impairment and drastic reduction in the Quality of life of the patients. Second Sight Medical Products Inc. developed Argus II, a retinal prosthesis system for treating RP. Argus II is the world’s first ever-commercial implant intended to restore some vision in the blind patients. The objective of this study was to assess...

  7. Retinal prosthesis for the blind.

    Science.gov (United States)

    Margalit, Eyal; Maia, Mauricio; Weiland, James D; Greenberg, Robert J; Fujii, Gildo Y; Torres, Gustavo; Piyathaisere, Duke V; O'Hearn, Thomas M; Liu, Wentai; Lazzi, Gianluca; Dagnelie, Gislin; Scribner, Dean A; de Juan, Eugene; Humayun, Mark S

    2002-01-01

    Most of current concepts for a visual prosthesis are based on neuronal electrical stimulation at different locations along the visual pathways within the central nervous system. The different designs of visual prostheses are named according to their locations (i.e., cortical, optic nerve, subretinal, and epiretinal). Visual loss caused by outer retinal degeneration in diseases such as retinitis pigmentosa or age-related macular degeneration can be reversed by electrical stimulation of the retina or the optic nerve (retinal or optic nerve prostheses, respectively). On the other hand, visual loss caused by inner or whole thickness retinal diseases, eye loss, optic nerve diseases (tumors, ischemia, inflammatory processes etc.), or diseases of the central nervous system (not including diseases of the primary and secondary visual cortices) can be reversed by a cortical visual prosthesis. The intent of this article is to provide an overview of current and future concepts of retinal and optic nerve prostheses. This article will begin with general considerations that are related to all or most of visual prostheses and then concentrate on the retinal and optic nerve designs. The authors believe that the field has grown beyond the scope of a single article so cortical prostheses will be described only because of their direct effect on the concept and technical development of the other prostheses, and this will be done in a more general and historic perspective.

  8. Cell Therapy Applications for Retinal Vascular Diseases: Diabetic Retinopathy and Retinal Vein Occlusion.

    Science.gov (United States)

    Park, Susanna S

    2016-04-01

    Retinal vascular conditions, such as diabetic retinopathy and retinal vein occlusion, remain leading causes of vision loss. No therapy exists to restore vision loss resulting from retinal ischemia and associated retinal degeneration. Tissue regeneration is possible with cell therapy. The goal would be to restore or replace the damaged retinal vasculature and the retinal neurons that are damaged and/or degenerating from the hypoxic insult. Currently, various adult cell therapies have been explored as potential treatment. They include mesenchymal stem cells, vascular precursor cells (i.e., CD34+ cells, hematopoietic cells or endothelial progenitor cells), and adipose stromal cells. Preclinical studies show that all these cells have a paracrine trophic effect on damaged ischemic tissue, leading to tissue preservation. Endothelial progenitor cells and adipose stromal cells integrate into the damaged retinal vascular wall in preclinical models of diabetic retinopathy and ischemia-reperfusion injury. Mesenchymal stem cells do not integrate as readily but appear to have a primary paracrine trophic effect. Early phase clinical trials have been initiated and ongoing using mesenchymal stem cells or autologous bone marrow CD34+ cells injected intravitreally as potential therapy for diabetic retinopathy or retinal vein occlusion. Adipose stromal cells or pluripotent stem cells differentiated into endothelial colony-forming cells have been explored in preclinical studies and show promise as possible therapies for retinal vascular disorders. The relative safety or efficacy of these various cell therapies for treating retinal vascular disorders have yet to be determined.

  9. Retinal Vasculitis

    Science.gov (United States)

    Rosenbaum, James T.; Sibley, Cailin H.; Lin, Phoebe

    2016-01-01

    Purpose of review Ophthalmologists and rheumatologists frequently miscommunicate in consulting on patients with retinal vasculitis. This report seeks to establish a common understanding of the term, retinal vasculitis, and to review recent papers on this diagnosis. Recent findings 1) The genetic basis of some rare forms of retinal vascular disease have recently been described. Identified genes include CAPN5, TREX1, and TNFAIP3; 2) Behçet’s disease is a systemic illness that is very commonly associated with occlusive retinal vasculitis; 3) retinal imaging including fluorescein angiography and other newer imaging modalities has proven crucial to the identification and characterization of retinal vasculitis and its complications; 4) although monoclonal antibodies to IL-17A or IL-1 beta failed in trials for Behçet’s disease, antibodies to TNF alpha, either infliximab or adalimumab, have demonstrated consistent benefit in managing this disease. Interferon treatment and B cell depletion therapy via rituximab may be beneficial in certain types of retinal vasculitis. Summary Retinal vasculitis is an important entity for rheumatologists to understand. Retinal vasculitis associated with Behçet’s disease responds to monoclonal antibodies that neutralize TNF, but the many other forms of non-infectious retinal vasculitis may require alternate therapeutic management. PMID:26945335

  10. 干细胞移植治疗视网膜变性疾病面临的挑战和前景%Translation of stem-cell-based therapies for retinal degeneration

    Institute of Scientific and Technical Information of China (English)

    阴正勤

    2013-01-01

    Present therapies for retinal degenerative diseases are limited in their efficacy.Consequently,the development of novel neuroprotective and neuroregenerative treatments is a top priority.Stem cells hold great promise for regenerative medicine,and recently many efforts have been devoted to find suitable candidates for retinal transplants.A variety of stem-cell-based approaches are being advanced to replace impaired retinal cells and/or to slow the disease processes by providing neuroprotective factors,with the ultimate aim of longterm improvement in visual function.Furthermore,clinical trials are in the early stages,and data on safety and efficacy are widely anticipated.We discussed here the challenges and potential of stem-cell-based therapies in treatment of retinal blindness.

  11. [Study on preferred retinal locus].

    Science.gov (United States)

    Dai, Bing-Fa; Hu, Jian-Min; Xu, Duan-Lian

    2012-03-01

    Preferred retinal locus (PRL) is always found in the age-related macular degeneration and other macular damages in patients with low vision, and it is a very important anatomic position in patients with central vision impairment to achieve the rehabilitation. In recent years, the training of preferred retinal locus (PRL) has become a research hotspot of low vision rehabilitation, it can clearly improve functional vision and quality of life. The authors reviewed relevant literatures, and summarized the definition, position, characteristics, training and clinical implications of the PRL.

  12. Advances in bone marrow stem cell therapy for retinal dysfunction.

    OpenAIRE

    Park, SS; Moisseiev, E; Bauer, G.; Anderson, JD; Grant, MB; Zam, A; Zawadzki, RJ; Werner., JS; Nolta, JA

    2017-01-01

    The most common cause of untreatable vision loss is dysfunction of the retina. Conditions, such as age-related macular degeneration, diabetic retinopathy and glaucoma remain leading causes of untreatable blindness worldwide. Various stem cell approaches are being explored for treatment of retinal regeneration. The rationale for using bone marrow stem cells to treat retinal dysfunction is based on preclinical evidence showing that bone marrow stem cells can rescue degenerating and ischemic ret...

  13. Animal models for retinitis pigmentosa induced by MNU; disease progression, mechanisms and therapeutic trials.

    Science.gov (United States)

    Tsubura, A; Yoshizawa, K; Kuwata, M; Uehara, N

    2010-07-01

    Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases in humans characterized by loss of photoreceptor cells leading to visual disturbance and eventually to blindness. A single systemic administration of N-methyl-N-nitrosourea (MNU) causes retinal degeneration in various animal species. The retinal degeneration is highly reproducible, and the photoreceptor cell loss occurs within seven days after MNU administration via apoptosis resembling human RP. Here, we describe the disease progression, disease mechanisms, and therapeutic trials of MNU-induced retinal degeneration.

  14. Cellular Reparative Mechanisms of Mesenchymal Stem Cells for Retinal Diseases

    Directory of Open Access Journals (Sweden)

    Suet Lee Shirley Ding

    2017-07-01

    Full Text Available The use of multipotent mesenchymal stem cells (MSCs has been reported as promising for the treatment of numerous degenerative disorders including the eye. In retinal degenerative diseases, MSCs exhibit the potential to regenerate into retinal neurons and retinal pigmented epithelial cells in both in vitro and in vivo studies. Delivery of MSCs was found to improve retinal morphology and function and delay retinal degeneration. In this review, we revisit the therapeutic role of MSCs in the diseased eye. Furthermore, we reveal the possible cellular mechanisms and identify the associated signaling pathways of MSCs in reversing the pathological conditions of various ocular disorders such as age-related macular degeneration (AMD, retinitis pigmentosa, diabetic retinopathy, and glaucoma. Current stem cell treatment can be dispensed as an independent cell treatment format or with the combination of other approaches. Hence, the improvement of the treatment strategy is largely subjected by our understanding of MSCs mechanism of action.

  15. Retinal iron homeostasis in health and disease

    Directory of Open Access Journals (Sweden)

    Delu eSong

    2013-06-01

    Full Text Available Iron is essential for life, but excess iron can be toxic. As a potent free radical creator, iron generates hydroxyl radicals leading to significant oxidative stress. Since iron is not excreted from the body, it accumulates with age in tissues, including the retina, predisposing to age-related oxidative insult. Both hereditary and acquired retinal diseases are associated with increased iron levels. For example, retinal degenerations have been found in hereditary iron overload disorders, like aceruloplasminemia, Friedreich’s ataxia, and pantothenate kinase-associated neurodegeneration. Similarly, mice with targeted mutation of the iron exporter ceruloplasmin and its homolog hephaestin showed age-related retinal iron accumulation and retinal degeneration with features resembling human age-related macular degeneration (AMD. Post mortem AMD eyes have increased levels of iron in retina compared to age-matched healthy donors. Iron accumulation in AMD is likely to result, in part, from inflammation, hypoxia, and oxidative stress, all of which can cause iron dysregulation. Fortunately, it has been demonstrated by in vitro and in vivo studies that iron in the retinal pigment epithelium and retina is chelatable. Iron chelation protects photoreceptors and retinal pigment epithelial cells (RPE in a variety of mouse models. This has therapeutic potential for diminishing iron-induced oxidative damage to prevent or treat AMD.

  16. Non-syndromic retinal ciliopathies: translating gene discovery into therapy

    NARCIS (Netherlands)

    Estrada-Cuzcano, A.; Roepman, R.; Cremers, F.P.; Hollander, A.I. den; Mans, D.A.

    2012-01-01

    Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modifier alleles implicated in inherited retinal degeneration in humans. To date, 158 genes have been found to be mutated in individuals with retinal dystrophies. Approximately one-third of the gene defect

  17. Retinal Drug Delivery System, Phase I

    Science.gov (United States)

    1997-06-01

    macular degeneration (AMD) and diabetic retinopathy. Intraocular injection can place the drug directly into the vitreous cavity but is not recommended...drugs for treatment of other ocular diseases such as retinal tumors, diabetic retinopathy, age related macular degeneration and cytomegalovirus...with the changes in mobile phase as indicated in each section. Data was collected for 10 min and the peak area was analyzed using the standard

  18. Photostress Testing Device for Diagnosing Retinal Disease

    Directory of Open Access Journals (Sweden)

    Elizabeth Swan

    2014-08-01

    Full Text Available Retinal diseases such as Age-Related Macular Degeneration (ARMD affect nearly one in three elderly patients. ARMD damages the central vision photoreceptors in the fovea. The Photostress Test is a simple technique for testing for the early effects of ARMD. Here, the illumination sources in a novel self-administered Photostress Testing device were modeled for safety and distribution in illumination software. After satisfying the design constraints in the model, a prototype of the illumination system was fabricated and tested to confirm the modeling results. The resultant prototype can be used to aid in the diagnosis of retinal disease and is well within retinal safety levels.

  19. Retinal Macroglial Responses in Health and Disease

    Directory of Open Access Journals (Sweden)

    Rosa de Hoz

    2016-01-01

    Full Text Available Due to their permanent and close proximity to neurons, glial cells perform essential tasks for the normal physiology of the retina. Astrocytes and Müller cells (retinal macroglia provide physical support to neurons and supplement them with several metabolites and growth factors. Macroglia are involved in maintaining the homeostasis of extracellular ions and neurotransmitters, are essential for information processing in neural circuits, participate in retinal glucose metabolism and in removing metabolic waste products, regulate local blood flow, induce the blood-retinal barrier (BRB, play fundamental roles in local immune response, and protect neurons from oxidative damage. In response to polyetiological insults, glia cells react with a process called reactive gliosis, seeking to maintain retinal homeostasis. When malfunctioning, macroglial cells can become primary pathogenic elements. A reactive gliosis has been described in different retinal pathologies, including age-related macular degeneration (AMD, diabetes, glaucoma, retinal detachment, or retinitis pigmentosa. A better understanding of the dual, neuroprotective, or cytotoxic effect of macroglial involvement in retinal pathologies would help in treating the physiopathology of these diseases. The extensive participation of the macroglia in retinal diseases points to these cells as innovative targets for new drug therapies.

  20. Bucky Paper as a Support Membrane in Retinal Cell Transplantation

    Science.gov (United States)

    Loftus, David J. (Inventor); Leng, Theodore (Inventor); Huie, Philip (Inventor); Fishman, Harvey (Inventor)

    2006-01-01

    A method for repairing a retinal system of an eye, using bucky paper on which a plurality of retina pigment epithelial cells and/or iris pigment epithelial cells and/or stem cells is deposited, either randomly or in a selected cell pattern. The cell-covered bucky paper is positioned in a sub-retinal space to transfer cells to this space and thereby restore the retina to its normal functioning, where retinal damage or degeneration, such as macular degeneration, has occurred.

  1. Optic pathway degeneration in Japanese black cattle.

    Science.gov (United States)

    Chiba, Shiori; Funato, Shingo; Horiuchi, Noriyuki; Matsumoto, Kotaro; Inokuma, Hisashi; Furuoka, Hidefumi; Kobayashi, Yoshiyasu

    2015-02-01

    Degeneration of the optic pathway has been reported in various animal species including cattle. We experienced a case of bilateral optic tract degeneration characterized by severe gliosis in a Japanese black cattle without any obvious visual defects. To evaluate the significance, pathological nature and pathogenesis of the lesions, we examined the optic pathway in 60 cattle (41 Japanese black, 13 Holstein and 6 crossbreed) with or without ocular abnormalities. None of these animals had optic canal stenosis. Degenerative changes with severe gliosis in the optic pathway, which includes the optic nerve, optic chiasm and optic tract, were only observed in 8 Japanese black cattle with or without ocular abnormalities. Furthermore, strong immunoreactivity of glial fibrillary acidic protein was observed in the retinal stratum opticum and ganglion cell layer in all 5 cattle in which the optic pathway lesions could be examined. As etiological research, we also examined whether the concentrations of vitamin A and vitamin B12 or bovine viral diarrhea virus (BVDV) infection was associated with optic pathway degeneration. However, our results suggested that the observed optic pathway degeneration was probably not caused by these factors. These facts indicate the presence of optic pathway degeneration characterized by severe gliosis that has never been reported in cattle without bilateral compressive lesions in the optic pathway or bilateral severe retinal atrophy.

  2. Patterned electrical stimulation of primate retina for the development of retinal prostheses

    OpenAIRE

    2012-01-01

    Epiretinal prostheses are designed to restore vision to people blinded by retinal degenerations, using electrical stimulation with an array of electrodes implanted on the surface of the retina to convey artificial visual signals to the brain. Current clinical prostheses provide limited visual function, in part because the activity that they generate is different from natural retinal responses to visual stimuli. An ideal retinal prosthesis would stimulate the retinal ganglion cells (RGCs) in a...

  3. Prospects for retinal gene replacement therapy.

    Science.gov (United States)

    Smith, Alexander J; Bainbridge, James W; Ali, Robin R

    2009-04-01

    Inherited retinal degeneration, which includes conditions such as retinitis pigmentosa and Leber congenital amaurosis (LCA), affects approximately 1/3000 of the population in the Western world. It is characterized by loss of vision and results from mutations in any one of >100 different genes. There are currently no effective treatments, but many of the genes have now been identified and their functions elucidated, providing a major impetus to develop gene-based treatments. Preliminary results from three clinical trials indicate that the treatment of a form of LCA by gene therapy can be safe and effective. Here, we discuss the potential for treating other forms of retinal degeneration by gene therapy, focusing on the gene defects that are likely to be the most amenable to treatment.

  4. In vivo sectional imaging of the retinal periphery using conventional optical coherence tomography systems

    Directory of Open Access Journals (Sweden)

    Abhishek Kothari

    2012-01-01

    Full Text Available Optical coherence tomography (OCT has transformed macular disease practices. This report describes the use of conventional OCT systems for peripheral retinal imaging. Thirty-six eyes with peripheral retinal pathology underwent imaging with conventional OCT systems. In vivo sectional imaging of lattice degeneration, snail-track degeneration, and paving-stone degeneration was performed. Differences were noted between phenotypes of lattice degeneration. Several findings previously unreported in histopathology studies were encountered. Certain anatomic features were seen that could conceivably explain clinical and intraoperative behavior of peripheral lesions. Peripheral OCT imaging helped elucidate clinically ambiguous situations such as retinal breaks, subclinical retinal detachment, retinoschisis, choroidal nevus, and metastasis. Limitations of such scanning included end-gaze nystagmus and far peripheral lesions. This first of its kind study demonstrates the feasibility of peripheral retinal OCT imaging and expands the spectrum of indications for which OCT scanning may be clinically useful.

  5. Diagnostic imaging in patients with retinitis pigmentosa.

    Science.gov (United States)

    Mitamura, Yoshinori; Mitamura-Aizawa, Sayaka; Nagasawa, Toshihiko; Katome, Takashi; Eguchi, Hiroshi; Naito, Takeshi

    2012-01-01

    Retinitis pigmentosa (RP) is a progressive inherited retinal disease, and patients with RP have reduced visual function caused by a degeneration of the photoreceptors and retinal pigment epithelium (RPE). At the end stage of RP, the degeneration of the photoreceptors in the fovea reduces central vision, and RP is one of the main causes of acquired blindness in developed countries. Therefore, morphological and functional assessments of the photoreceptors in the macula area can be useful in estimating the residual retinal function in RP patients. Optical coherence tomography (OCT) is a well-established method of examining the retinal architecture in situ. The photoreceptor inner/outer segment (IS/OS) junction is observed as a distinct, highly reflective line by OCT. The presence of the IS/OS junction in the OCT images is essential for normal visual function. Fundus autofluorescence (FAF) results from the accumulation of lipofuscin in the RPE cells and has been used to investigate RPE and retinal function. More than one-half of RP patients have an abnormally high density parafoveal FAF ring (AF ring). The AF ring represents the border between functional and dysfunctional retina. In this review, we shall summarize recent progress on diagnostic imaging in eyes with RP.

  6. Vitreomacular traction and age-related macular degeneration.

    Science.gov (United States)

    Green-Simms, Amy E; Bakri, Sophie J

    2011-05-01

    The interaction between the vitreous and the internal limiting membrane of the retina is important in the pathoetiology of numerous ocular disease processes. Recent studies have focused on the vitreo-retinal interface in the context of age-related macular degeneration (AMD), linking vitreo-retinal adhesion to exudative AMD in particular. This review summarizes our knowledge of vitreous anatomy and recent investigations regarding vitreomacular adhesion and AMD.

  7. Regulatory and Economic Considerations of Retinal Drugs.

    Science.gov (United States)

    Shah, Ankoor R; Williams, George A

    2016-01-01

    The advent of anti-VEGF therapy for neovascular age-related macular degeneration and macular edema secondary to retinal vein occlusion and diabetes mellitus has prevented blindness in tens of thousands of people. However, the costs of these drugs are without precedent in ophthalmic drug therapeutics. An analysis of the financial implications of retinal drugs and the impact of the Food and Drug Administration on treatment of retinal disease must include not only an evaluation of the direct costs of the drugs and the costs associated with their administration, but also the cost savings which accrue from their clinical benefit. This chapter will discuss the financial and regulatory issues associated with retinal drugs.

  8. Methods for culturing retinal pigment epithelial cells: a review of current protocols and future recommendations

    Directory of Open Access Journals (Sweden)

    Aaron H Fronk

    2016-07-01

    Full Text Available The retinal pigment epithelium is an important part of the vertebrate eye, particularly in studying the causes and possible treatment of age-related macular degeneration. The retinal pigment epithelium is difficult to access in vivo due to its location at the back of the eye, making experimentation with age-related macular degeneration treatments problematic. An alternative to in vivo experimentation is cultivating the retinal pigment epithelium in vitro, a practice that has been going on since the 1970s, providing a wide range of retinal pigment epithelial culture protocols, each producing cells and tissue of varying degrees of similarity to natural retinal pigment epithelium. The purpose of this review is to provide researchers with a ready list of retinal pigment epithelial protocols, their effects on cultured tissue, and their specific possible applications. Protocols using human and animal retinal pigment epithelium cells, derived from tissue or cell lines, are discussed, and recommendations for future researchers included.

  9. Aquaporin-1 Expression in Retinal Pigment Epithelial Cells Overlying Retinal Drusen

    DEFF Research Database (Denmark)

    Tran, Thuy Linh; Bek, Toke; la Cour, Morten

    2016-01-01

    PURPOSE: In the outer retina, age-related macular degeneration (AMD) results in reduced hydraulic conductivity in Bruch's membrane, possibly leading to altered water transport in retinal pigment epithelial (RPE) cells. We hypothesize that RPE cells may express aquaporin-1 (AQP1) to compensate...

  10. Screening retinal transplants with Fourier-domain OCT

    Science.gov (United States)

    Rao, Bin

    2009-02-01

    Transplant technologies have been studied for the recovery of vision loss from retinitis pigmentosa (RP) and age-related macular degeneration (AMD). In several rodent retinal degeneration models and in patients, retinal progenitor cells transplanted as layers to the subretinal space have been shown to restore or preserve vision. The methods for evaluation of transplants are expensive considering the large amount of animals. Alternatively, time-domain Stratus OCT was previously shown to be able to image the morphological structure of transplants to some extent, but could not clearly identify laminated transplants. The efficacy of screening retinal transplants with Fourier-domain OCT was studied on 37 S334ter line 3 rats with retinal degeneration 6-67 days after transplant surgery. The transplants were morphologically categorized as no transplant, detachment, rosettes, small laminated area and larger laminated area with both Fourier-domain OCT and histology. The efficacy of Fourier-domain OCT in screening retinal transplants was evaluated by comparing the categorization results with OCT and histology. Additionally, 4 rats were randomly selected for multiple OCT examinations (1, 5, 9, 14 and 21days post surgery) in order to determine the earliest image time of OCT examination since the transplanted tissue may need some time to show its tendency of growing. Finally, we demonstrated the efficacy of Fourier-domain OCT in screening retinal transplants in early stages and determined the earliest imaging time for OCT. Fourier-domain OCT makes itself valuable in saving resource spent on animals with unsuccessful transplants.

  11. Non-syndromic retinal ciliopathies: translating gene discovery into therapy.

    Science.gov (United States)

    Estrada-Cuzcano, Alejandro; Roepman, Ronald; Cremers, Frans P M; den Hollander, Anneke I; Mans, Dorus A

    2012-10-15

    Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modifier alleles implicated in inherited retinal degeneration in humans. To date, 158 genes have been found to be mutated in individuals with retinal dystrophies. Approximately one-third of the gene defects underlying retinal degeneration affect the structure and/or function of the 'connecting cilium' in photoreceptors. This structure corresponds to the transition zone of a prototypic cilium, a region with increasing relevance for ciliary homeostasis. The connecting cilium connects the inner and outer segments of the photoreceptor, mediating bi-directional transport of phototransducing proteins required for vision. In fact, the outer segment, connecting cilium and associated basal body, forms a highly specialized sensory cilium, fully dedicated to photoreception and subsequent signal transduction to the brain. At least 21 genes that encode ciliary proteins are implicated in non-syndromic retinal dystrophies such as cone dystrophy, cone-rod dystrophy, Leber congenital amaurosis (LCA), macular degeneration or retinitis pigmentosa (RP). The generation and characterization of vertebrate retinal ciliopathy animal models have revealed insights into the molecular disease mechanism which are indispensable for the development and evaluation of therapeutic strategies. Gene augmentation therapy has proven to be safe and successful in restoring long-term sight in mice, dogs and humans suffering from LCA or RP. Here, we present a comprehensive overview of the genes, mutations and modifier alleles involved in non-syndromic retinal ciliopathies, review the progress in dissecting the associated retinal disease mechanisms and evaluate gene augmentation approaches to antagonize retinal degeneration in these ciliopathies.

  12. Optical coherence tomography angiography in retinal diseases

    Directory of Open Access Journals (Sweden)

    K V Chalam

    2016-01-01

    Full Text Available Optical coherence tomography angiography (OCTA is a new, non-invasive imaging system that generates volumetric data of retinal and choroidal layers. It has the ability to show both structural and blood flow information. Split-spectrum amplitude-decorrelation angiography (SSADA algorithm (a vital component of OCTA software helps to decrease the signal to noise ratio of flow detection thus enhancing visualization of retinal vasculature using motion contrast. Published studies describe potential efficacy for OCTA in the evaluation of common ophthalmologic diseases such as diabetic retinopathy, age related macular degeneration (AMD, retinal vascular occlusions and sickle cell disease. OCTA provides a detailed view of the retinal vasculature, which allows accurate delineation of microvascular abnormalities in diabetic eyes and vascular occlusions. It helps quantify vascular compromise depending upon the severity of diabetic retinopathy. OCTA can also elucidate the presence of choroidal neovascularization (CNV in wet AMD. In this paper, we review the knowledge, available in English language publications regarding OCTA, and compare it with the conventional angiographic standard, fluorescein angiography (FA. Finally, we summarize its potential applications to retinal vascular diseases. Its current limitations include a relatively small field of view, inability to show leakage, and tendency for image artifacts. Further larger studies will define OCTA's utility in clinical settings and establish if the technology may offer a non-invasive option of visualizing the retinal vasculature, enabling us to decrease morbidity through early detection and intervention in retinal diseases.

  13. Optical Coherence Tomography Angiography in Retinal Diseases.

    Science.gov (United States)

    Chalam, K V; Sambhav, Kumar

    2016-01-01

    Optical coherence tomography angiography (OCTA) is a new, non-invasive imaging system that generates volumetric data of retinal and choroidal layers. It has the ability to show both structural and blood flow information. Split-spectrum amplitude-decorrelation angiography (SSADA) algorithm (a vital component of OCTA software) helps to decrease the signal to noise ratio of flow detection thus enhancing visualization of retinal vasculature using motion contrast. Published studies describe potential efficacy for OCTA in the evaluation of common ophthalmologic diseases such as diabetic retinopathy, age related macular degeneration (AMD), retinal vascular occlusions and sickle cell disease. OCTA provides a detailed view of the retinal vasculature, which allows accurate delineation of microvascular abnormalities in diabetic eyes and vascular occlusions. It helps quantify vascular compromise depending upon the severity of diabetic retinopathy. OCTA can also elucidate the presence of choroidal neovascularization (CNV) in wet AMD. In this paper, we review the knowledge, available in English language publications regarding OCTA, and compare it with the conventional angiographic standard, fluorescein angiography (FA). Finally, we summarize its potential applications to retinal vascular diseases. Its current limitations include a relatively small field of view, inability to show leakage, and tendency for image artifacts. Further larger studies will define OCTA's utility in clinical settings and establish if the technology may offer a non-invasive option of visualizing the retinal vasculature, enabling us to decrease morbidity through early detection and intervention in retinal diseases.

  14. Fundus changes in central retinal vein occlusion.

    Science.gov (United States)

    Hayreh, Sohan Singh; Zimmerman, M Bridget

    2015-01-01

    To investigate systematically the retinal and optic disk changes in central retinal vein occlusion (CRVO) and their natural history. This study comprised 562 consecutive patients with CRVO (492 nonischemic [NI-CRVO] and 89 ischemic CRVO [I-CRVO] eyes) seen within 3 months of onset. Ophthalmic evaluation at initial and follow-up visits included recording visual acuity, visual fields, and detailed anterior segment and fundus examinations and fluorescein fundus angiography. Retinal and subinternal limiting membrane hemorrhages and optic disk edema in I-CRVO were initially more marked (P retinal epithelial pigment degeneration, serous macular detachment, and retinal perivenous sheathing developed at a higher rate in I-CRVO than that in NI-CRVO (P retinal venous engorgement than NI-CRVO (P = 0.003). Fluorescein fundus angiography showed significantly more fluorescein leakage, retinal capillary dilatation, capillary obliteration, and broken capillary foveal arcade (P < 0.0001) in I-CRVO than NI-CRVO. Resolution time of CRVO was longer for I-CRVO than NI-CRVO (P < 0.0001). Characteristics and natural history of fundus findings in the two types of CRVO are different.

  15. Adaptive optics technology for high-resolution retinal imaging.

    Science.gov (United States)

    Lombardo, Marco; Serrao, Sebastiano; Devaney, Nicholas; Parravano, Mariacristina; Lombardo, Giuseppe

    2012-12-27

    Adaptive optics (AO) is a technology used to improve the performance of optical systems by reducing the effects of optical aberrations. The direct visualization of the photoreceptor cells, capillaries and nerve fiber bundles represents the major benefit of adding AO to retinal imaging. Adaptive optics is opening a new frontier for clinical research in ophthalmology, providing new information on the early pathological changes of the retinal microstructures in various retinal diseases. We have reviewed AO technology for retinal imaging, providing information on the core components of an AO retinal camera. The most commonly used wavefront sensing and correcting elements are discussed. Furthermore, we discuss current applications of AO imaging to a population of healthy adults and to the most frequent causes of blindness, including diabetic retinopathy, age-related macular degeneration and glaucoma. We conclude our work with a discussion on future clinical prospects for AO retinal imaging.

  16. Adaptive Optics Technology for High-Resolution Retinal Imaging

    Directory of Open Access Journals (Sweden)

    Giuseppe Lombardo

    2012-12-01

    Full Text Available Adaptive optics (AO is a technology used to improve the performance of optical systems by reducing the effects of optical aberrations. The direct visualization of the photoreceptor cells, capillaries and nerve fiber bundles represents the major benefit of adding AO to retinal imaging. Adaptive optics is opening a new frontier for clinical research in ophthalmology, providing new information on the early pathological changes of the retinal microstructures in various retinal diseases. We have reviewed AO technology for retinal imaging, providing information on the core components of an AO retinal camera. The most commonly used wavefront sensing and correcting elements are discussed. Furthermore, we discuss current applications of AO imaging to a population of healthy adults and to the most frequent causes of blindness, including diabetic retinopathy, age-related macular degeneration and glaucoma. We conclude our work with a discussion on future clinical prospects for AO retinal imaging.

  17. Contribution of Microglia-Mediated Neuroinflammation to Retinal Degenerative Diseases

    Directory of Open Access Journals (Sweden)

    Maria H. Madeira

    2015-01-01

    Full Text Available Retinal degenerative diseases are major causes of vision loss and blindness worldwide and are characterized by chronic and progressive neuronal loss. One common feature of retinal degenerative diseases and brain neurodegenerative diseases is chronic neuroinflammation. There is growing evidence that retinal microglia, as in the brain, become activated in the course of retinal degenerative diseases, having a pivotal role in the initiation and propagation of the neurodegenerative process. A better understanding of the events elicited and mediated by retinal microglia will contribute to the clarification of disease etiology and might open new avenues for potential therapeutic interventions. This review aims at giving an overview of the roles of microglia-mediated neuroinflammation in major retinal degenerative diseases like glaucoma, age-related macular degeneration, and diabetic retinopathy.

  18. [Hepatolenticular degeneration].

    Science.gov (United States)

    Zudenigo, D; Relja, M

    1990-01-01

    Hepatolenticular degeneration (Wilson's disease) is a hereditary disease in which metabolic disorder of copper leads to its accumulation in the liver, brain, cornea and kidneys with consequent pathologic changes in those organs. Hereditary mechanism of the disease is autosomal recessive with prevalence of 30-100 per 1,000,000 inhabitants. Etiology of this disease is not yet explained. There are two hypotheses. The first one is that it is the disorder of ceruloplasmine metabolism caused by insufficient synthesis of normal ceruloplasmine, or synthesis of functionally abnormal ceruloplasmine. The second one is: the block of copper biliar excretion which is the consequence of the liver lysosomes functional defect. Pathogenetic mechanism of disease is firstly long-term accumulation of copper in the liver, and later, when the liver depo is full, its releasing in circulation and accumulation in the brain, cornea, kidneys and bones, which causes adequate pathologic changes. Toxic activity of copper is the consequence of its activity on enzymes, particularly on those with -SH group. There are two basic clinical forms of the disease: liver disease or neurologic disease. Before puberty the liver damage is more frequent, while in adolescents and young adults neurologic form of the disease is usual. The liver disease is nonspecific and characterized by symptoms of cirrhosis and chronic aggressive hepatitis. The only specificity is hemolytic anemia which, in combination with previous symptoms, is important for diagnosis of the disease. Neurologic symptoms are the most frequent consequence of pathologic changes in the basal ganglia. In our patients the most frequent symptoms were tremor (63%); dysarthria, choreoathetosis and rigor (38%); ataxia and mental disorders (31%); dysphagia and dystonia (12%), diplopia, hypersalivation, nystagmus and Babinski's sign (6%). Among pathologic changes in other tissues and organs the most important is the finding of Kayser-Fleischer ring in the

  19. Specific inhibition of TRPV4 enhances retinal ganglion cell survival in adult porcine retinal explants.

    Science.gov (United States)

    Taylor, Linnéa; Arnér, Karin; Ghosh, Fredrik

    2017-01-01

    Signaling through the polymodal cation channel Transient Receptor Potential Vanilloid 4 (TRPV4) has been implicated in retinal neuronal degeneration. To further outline the involvement of this channel in this process, we here explore modulation of Transient Receptor Potential Vanilloid 4 (TRPV4) activity on neuronal health and glial activation in an in vitro model of retinal degeneration. For this purpose, adult porcine retinal explants were cultured using a previously established standard protocol for up to 5 days with specific TRPV4 agonist GSK1016790A (GSK), or specific antagonist RN-1734, or culture medium only. Glial and neuronal cell health were evaluated by a battery of immunohistochemical markers, as well as morphological staining. Specific inhibition of TRPV4 by RN-1734 significantly enhanced ganglion cell survival, improved the maintenance of the retinal laminar architecture, reduced apoptotic cell death and attenuated the gliotic response as well as preserved the expression of TRPV4 in the plexiform layers and ganglion cells. In contrast, culture controls, as well as specimens treated with GSK, displayed rapid remodeling and neurodegeneration as well as a downregulation of TRPV4 and the Müller cell homeostatic mediator glutamine synthetase. Our results indicate that TRPV4 signaling is an important contributor to the retinal degeneration in this model, affecting neuronal cell health and glial homeostasis. The finding that pharmacological inhibition of the receptor significantly attenuates neuronal degeneration and gliosis in vitro, suggests that TRPV4 signaling may be an interesting pharmaceutical target to explore for treatment of retinal degenerative disease.

  20. Regenerative Therapy for Retinal Disorders

    Directory of Open Access Journals (Sweden)

    Narsis Daftarian

    2010-01-01

    Full Text Available Major advances in various disciplines of basic sciences including embryology, molecular and cell biology, genetics, and nanotechnology, as well as stem cell biology have opened new horizons for regenerative therapy. The unique characteristics of stem cells prompt a sound understanding for their use in modern regenerative therapies. This review article discusses stem cells, developmental stages of the eye field, eye field transcriptional factors, and endogenous and exogenous sources of stem cells. Recent studies and challenges in the application of stem cells for retinal pigment epithelial degeneration models will be summarized followed by obstacles facing regenerative therapy.

  1. Renal-Retinal Ciliopathy Gene Sdccag8 Regulates DNA Damage Response Signaling

    DEFF Research Database (Denmark)

    Airik, Rannar; Slaats, Gisela G; Guo, Zhi

    2014-01-01

    Nephronophthisis-related ciliopathies (NPHP-RCs) are developmental and degenerative kidney diseases that are frequently associated with extrarenal pathologies such as retinal degeneration, obesity, and intellectual disability. We recently identified mutations in a gene encoding the centrosomal pr...

  2. Retinitis pigmentosa

    Directory of Open Access Journals (Sweden)

    Hamel Christian

    2006-10-01

    Full Text Available Abstract Retinitis pigmentosa (RP is an inherited retinal dystrophy caused by the loss of photoreceptors and characterized by retinal pigment deposits visible on fundus examination. Prevalence of non syndromic RP is approximately 1/4,000. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. Some extreme cases may have a rapid evolution over two decades or a slow progression that never leads to blindness. In some cases, the clinical presentation is a cone-rod dystrophy, in which the decrease in visual acuity predominates over the visual field loss. RP is usually non syndromic but there are also many syndromic forms, the most frequent being Usher syndrome. To date, 45 causative genes/loci have been identified in non syndromic RP (for the autosomal dominant, autosomal recessive, X-linked, and digenic forms. Clinical diagnosis is based on the presence of night blindness and peripheral visual field defects, lesions in the fundus, hypovolted electroretinogram traces, and progressive worsening of these signs. Molecular diagnosis can be made for some genes, but is not usually performed due to the tremendous genetic heterogeneity of the disease. Genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, so the visual prognosis is poor. The therapeutic approach is restricted to slowing down the degenerative process by sunlight protection and vitaminotherapy, treating the complications (cataract and macular edema, and helping patients to cope with the social and psychological impact of blindness. However, new therapeutic strategies are emerging from intensive research (gene therapy, neuroprotection, retinal prosthesis.

  3. LONG-TERM OUTCOMES OF RETINAL DEGENERATIVE DISORDER TREATMENT WITH PEPTIDE BIOREGULATORS

    Directory of Open Access Journals (Sweden)

    M. I. Razumovskiy

    2015-01-01

    Full Text Available Aim. To analyze long-term outcomes and efficacy of retinal degeneration treatment with Retinalamin.Patients and methods. Group I included 20 patients (40 eyes with pigmentary retinal dystrophy (15 patients, 30 eyes and retinal abiotrophy (5 patients, 10 eyes who received treatment with Retinalamin for 5‑7 years. Group II included 11 patients (22 eyes with pigmentary retinal dystrophy (9 patients, 18 eyes and retinal abiotrophy (2 patients, 4 eyes who received treatment with Retinalamin for 23‑25 years. Group III (controls included 15 patients (30 eyes with pigmentary retinal dystrophy (11 patients, 22 eyes and retinal abiotrophy (4 patients, 8 eyes who received traditional treatment (vasodilators, angioprotectors, antisclerotic agents, vitamins for 25 years. Standard ophthalmological examination, i.e., visual acuity measurement, visual field test, refractometry, biomicroscopy, ophthalmoscopy, was performed.Results. First course of treatment with Retinalamin improved vision in 58.1 % of retinal degeneration patients. Visual fields improved in 64.5 % of cases. Repeated treatment courses (1‑2 times a year for 23‑25 years preserved residual vision in 55.6 % of patients and object vision in 11.1 % of cases. In retinal abiotrophy patients, residual vision preserved in 100 % of cases.Conclusions. In retinal degenerations, Retinalamin improves vision and visual fields and decreases total area of absolute scotomas even after the first treatment course as well as preserves vision in prolonged use. 

  4. PROPERTIES OF PROLIFERATION AND DIFFERENTIATION OF NEONATAL RAT RETINAL PROGENITOR CELLS IN VITRO

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Neural stem or progenitor cells are i mmature,multipotent cells that have the capacityto differenti-ate into the three CNSlineages(neurons,astrocytesand oligodendrocytes)[1].Neuronal degeneration isthe cause of visual i mpair ment associated with prev-alent ocular diseases such as retinitis pigmentosa,age-related macular degeneration,retinal detach-ment and glaucoma[2].Transplantation of culturedneural stemcells/progenitors may helprestore visionby repopulating the damaged retina and replacingthe degenerati...

  5. Advances in gene therapy technologies to treat retinitis pigmentosa

    OpenAIRE

    2013-01-01

    Hilda Petrs-Silva, Rafael LindenInstitute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilAbstract: Retinitis pigmentosa (RP) is a class of diseases that leads to progressive degeneration of the retina. Experimental approaches to gene therapy for the treatment of inherited retinal dystrophies have advanced in recent years, inclusive of the safe delivery of genes to the human retina. This review is focused on the development of gene therapy for RP using recombinant a...

  6. New approaches and potential treatments for dry age-related macular degeneration.

    Science.gov (United States)

    Damico, Francisco Max; Gasparin, Fabio; Scolari, Mariana Ramos; Pedral, Lycia Sampaio; Takahashi, Beatriz Sayuri

    2012-01-01

    Emerging treatments for dry age-related macular degeneration (AMD) and geographic atrophy focus on two strategies that target components involved in physiopathological pathways: prevention of photoreceptors and retinal pigment epithelium loss (neuroprotection induction, oxidative damage prevention, and visual cycle modification) and suppression of inflammation. Neuroprotective drugs, such as ciliary neurotrophic factor, brimonidine tartrate, tandospirone, and anti-amyloid β antibodies, aim to prevent apoptosis of retinal cells. Oxidative stress and depletion of essential micronutrients are targeted by the Age-Related Eye Disease Study (AREDS) formulation. Visual cycle modulators reduce the activity of the photoreceptors and retinal accumulation of toxic fluorophores and lipofuscin. Eyes with dry age-related macular degeneration present chronic inflammation and potential treatments include corticosteroid and complement inhibition. We review the current concepts and rationale of dry age-related macular degeneration treatment that will most likely include a combination of drugs targeting different pathways involved in the development and progression of age-related macular degeneration.

  7. Wet Macular Degeneration

    Science.gov (United States)

    ... macular degeneration Overview By Mayo Clinic Staff Wet macular degeneration is a chronic eye disease that causes blurred vision or a blind spot in your visual field. It's generally caused by abnormal blood vessels that leak fluid or blood into ... macular degeneration is one of two types of age-related ...

  8. Adaptation to Retinal Injury and Visual Loss

    Science.gov (United States)

    1994-06-20

    foveal visual loss is associated reading andincreasedeye fixation duration (Rayner with retinal diseases like macular degeneration or and Bertera, 1979...to visual loss. ൖ. SUBJECT TERMS 15. NUMBER OF PAGES Scotoma, Fovea, Vision, Rehabilitation , Laser, Human 16. PRICE CODE 17. 3ECLRITY...1990) further deter- might be used to explain the left right asymmetry, mined that macular disease scotomasof 5, 10,or2O such as, left-right biases from

  9. Photostress Testing Device for Diagnosing Retinal Disease

    OpenAIRE

    Elizabeth Swan; Jim Schwiegerling; Gholam Peyman; Eniko Enikov

    2014-01-01

    Retinal diseases such as Age-Related Macular Degeneration (ARMD) affect nearly one in three elderly patients. ARMD damages the central vision photoreceptors in the fovea. The Photostress Test is a simple technique for testing for the early effects of ARMD. Here, the illumination sources in a novel self-administered Photostress Testing device were modeled for safety and distribution in illumination software. After satisfying the design constraints in the model, a prototype of the illumination ...

  10. Loss of Responses to Visual But Not Electrical Stimulation in Ganglion Cells of Rats With Severe Photoreceptor Degeneration

    OpenAIRE

    2009-01-01

    Retinal implants are intended to help patients with degenerative conditions by electrically stimulating surviving cells to produce artificial vision. However, little is known about how individual retinal ganglion cells respond to direct electrical stimulation in degenerating retina. Here we used a transgenic rat model to characterize ganglion cell responses to light and electrical stimulation during photoreceptor degeneration. Retinas from pigmented P23H-1 rats were compared with wild-type re...

  11. Mitochondrial Protection by Exogenous Otx2 in Mouse Retinal Neurons

    Directory of Open Access Journals (Sweden)

    Hyoung-Tai Kim

    2015-11-01

    Full Text Available OTX2 (orthodenticle homeobox 2 haplodeficiency causes diverse defects in mammalian visual systems ranging from retinal dysfunction to anophthalmia. We find that the retinal dystrophy of Otx2+/GFP heterozygous knockin mice is mainly due to the loss of bipolar cells and consequent deficits in retinal activity. Among bipolar cell types, OFF-cone bipolar subsets, which lack autonomous Otx2 gene expression but receive Otx2 proteins from photoreceptors, degenerate most rapidly in Otx2+/GFP mouse retinas, suggesting a neuroprotective effect of the imported Otx2 protein. In support of this hypothesis, retinal dystrophy in Otx2+/GFP mice is prevented by intraocular injection of Otx2 protein, which localizes to the mitochondria of bipolar cells and facilitates ATP synthesis as a part of mitochondrial ATP synthase complex. Taken together, our findings demonstrate a mitochondrial function for Otx2 and suggest a potential therapeutic application of OTX2 protein delivery in human retinal dystrophy.

  12. Functional analysis of retinal microglia and their effects on progenitors.

    Science.gov (United States)

    Carter, Debra A; Balasubramaniam, Balini; Dick, Andrew D

    2013-01-01

    The identification of stem/progenitor cells within the retinal neural environment has opened up the possibility of therapy via cellular replacement and/or reprogramming of resident cell populations. Within the neuro-retinal niche, following injury or in disease states (including inflammation and degeneration), cellular responses affect tissue homeostasis, reduce cell density, disrupt tissue architecture, and produce scar formation. Microglia (resident retinal immune cell tissue macrophage) are key to the maintenance of retinal homeostasis and are implicated in responses that may influence the control and behavior of retinal progenitors. Factors to consider in the generation of a transplantable cell resource with good migratory and integrative capacity include their yield, purity, and functional viability. Utilizing human postmortem retina, we have created a research platform to isolate, culture, and characterize adult retinal microglia as well as analyze their effect on retinal progenitors. Here, we describe techniques using magnetic labeled bead cell separation to isolate pure populations of retinal CD133(+) precursor cells and CD11b(+) microglia from primary adult retinal cell suspensions (RCSs), enabling flow cytometric cell phenotypic and qPCR genotypic analysis, as well as functional analysis by real-time ratiometric calcium imaging.

  13. Changes in cortical grey matter density associated with long-standing retinal visual field defects

    NARCIS (Netherlands)

    Boucard, Christine C.; Hernowo, Aditya T.; Maguire, R. Paul; Jansonius, Nomdo M.; Roerdink, Jos B.T.M.; Hooymans, Johanna M.M.; Cornelissen, Frans W.

    2009-01-01

    Retinal lesions caused by eye diseases such as glaucoma and age-related macular degeneration can, over time, eliminate stimulation of parts of the visual cortex. This could lead to degeneration of inactive cortical neuronal tissue, but this has not been established in humans. Here, we used magnetic

  14. A method and technical equipment for an acute human trial to evaluate retinal implant technology

    Science.gov (United States)

    Hornig, Ralf; Laube, Thomas; Walter, Peter; Velikay-Parel, Michaela; Bornfeld, Norbert; Feucht, Matthias; Akguel, Harun; Rössler, Gernot; Alteheld, Nils; Lütke Notarp, Dietmar; Wyatt, John; Richard, Gisbert

    2005-03-01

    This paper reports on methods and technical equipment to investigate the epiretinal stimulation of the retina in blind human subjects in acute trials. Current is applied to the retina through a thin, flexible microcontact film (microelectrode array) with electrode diameters ranging from 50 to 360 µm. The film is mounted in a custom-designed surgical tool that is hand-held by the surgeon during stimulation. The eventual goal of the work is the development of a chronically implantable retinal prosthesis to restore a useful level of vision to patients who are blind with outer retinal degenerations, specifically retinitis pigmentosa and macular degeneration.

  15. Task-Dependent V1 Responses in Human Retinitis Pigmentosa

    OpenAIRE

    Masuda,Yoichiro; Horiguchi, Hiroshi; Dumoulin, Serge O.; Furuta, Ayumu; Miyauchi, Satoru; Nakadomari, Satoshi; Brian A Wandell

    2010-01-01

    The presence of large-scale reorganization in adult human V1 may have important implications for visual restoration therapy and rehabilitation. New measurements in patients with retinitis pigmentosa and prior data from patients with macular degeneration can be explained without assuming a large-scale reorganization that includes the development of new feed-forward connections.

  16. Neuroprotective Effects of Low-Dose Statins in the Retinal Ultrastructure of Hypercholesterolemic Rabbits.

    Science.gov (United States)

    Fernández-Navarro, Judith; Aldea, Pilar; de Hoz, Rosa; Salazar, Juan J; Ramírez, Ana I; Rojas, Blanca; Gallego, Beatriz I; Triviño, Alberto; Tejerina, Teresa; Ramírez, José M

    2016-01-01

    To evaluate the pleiotropic effects to statins, we analyze the qualitative and quantitative retinal changes in hypercholesterolemic rabbits after a low-dosage statin treatment. For this purpose, New Zealand rabbits were split into three groups: control (G0; n = 10), fed a standard diet; hypercholesterolemic (G1; n = 8), fed a 0.5% cholesterol-enriched diet for 8 months; and statins (G2; n = 8), fed a 0.5% cholesterol-enriched diet for 8 months, together with the administration of statin (pravastatin or fluvastatin sodium) at a dose of 2 mg / kg / day each diet. The retinas were analyzed by transmission electron microscopy and immunohistochemistry (glial fibrillary acidic protein). The retinal thickness of nuclear and plexiform layers were quantified in semi-thin sections. The results revealed that the low-statin-treated rabbits in comparison with the hypercholesterolemic group showed: i) a more preserved structure in all retinal layers; ii) a significant reduction in retinal thickness; iii) a decrease in cell death in the nuclear-and ganglion-cell layers; iv) a reduction of hydropic degeneration in the plexiform and nerve-fiber layers; v) a preservation of astrocytes and of the retinal area occupied by them; and vi) a better-preserved retinal vascular structure. Our findings indicate that low doses of statins can prevent retinal degeneration, acting on retinal macroglia, neurons and retinal vessels, despite that hypercholesterolemia remained unchanged. Thus, the pleiotropic effects of the statins may help safeguard the retinal ultrastructure.

  17. Stem Cell Therapies in Retinal Disorders

    Directory of Open Access Journals (Sweden)

    Aakriti Garg

    2017-02-01

    Full Text Available Stem cell therapy has long been considered a promising mode of treatment for retinal conditions. While human embryonic stem cells (ESCs have provided the precedent for regenerative medicine, the development of induced pluripotent stem cells (iPSCs revolutionized this field. iPSCs allow for the development of many types of retinal cells, including those of the retinal pigment epithelium, photoreceptors, and ganglion cells, and can model polygenic diseases such as age-related macular degeneration. Cellular programming and reprogramming technology is especially useful in retinal diseases, as it allows for the study of living cells that have genetic variants that are specific to patients’ diseases. Since iPSCs are a self-renewing resource, scientists can experiment with an unlimited number of pluripotent cells to perfect the process of targeted differentiation, transplantation, and more, for personalized medicine. Challenges in the use of stem cells are present from the scientific, ethical, and political realms. These include transplant complications leading to anatomically incorrect placement, concern for tumorigenesis, and incomplete targeting of differentiation leading to contamination by different types of cells. Despite these limitations, human ESCs and iPSCs specific to individual patients can revolutionize the study of retinal disease and may be effective therapies for conditions currently considered incurable.

  18. Retinal prosthetics, optogenetics, and chemical photoswitches.

    Science.gov (United States)

    Marc, Robert; Pfeiffer, Rebecca; Jones, Bryan

    2014-10-15

    Three technologies have emerged as therapies to restore light sensing to profoundly blind patients suffering from late-stage retinal degenerations: (1) retinal prosthetics, (2) optogenetics, and (3) chemical photoswitches. Prosthetics are the most mature and the only approach in clinical practice. Prosthetic implants require complex surgical intervention and provide only limited visual resolution but can potentially restore navigational ability to many blind patients. Optogenetics uses viral delivery of type 1 opsin genes from prokaryotes or eukaryote algae to restore light responses in survivor neurons. Targeting and expression remain major problems, but are potentially soluble. Importantly, optogenetics could provide the ultimate in high-resolution vision due to the long persistence of gene expression achieved in animal models. Nevertheless, optogenetics remains challenging to implement in human eyes with large volumes, complex disease progression, and physical barriers to viral penetration. Now, a new generation of photochromic ligands or chemical photoswitches (azobenzene-quaternary ammonium derivatives) can be injected into a degenerated mouse eye and, in minutes to hours, activate light responses in neurons. These photoswitches offer the potential for rapidly and reversibly screening the vision restoration expected in an individual patient. Chemical photoswitch variants that persist in the cell membrane could make them a simple therapy of choice, with resolution and sensitivity equivalent to optogenetics approaches. A major complexity in treating retinal degenerations is retinal remodeling: pathologic network rewiring, molecular reprogramming, and cell death that compromise signaling in the surviving retina. Remodeling forces a choice between upstream and downstream targeting, each engaging different benefits and defects. Prosthetics and optogenetics can be implemented in either mode, but the use of chemical photoswitches is currently limited to downstream

  19. Stem cells for investigation and treatment of inherited retinal disease.

    Science.gov (United States)

    Tucker, Budd A; Mullins, Robert F; Stone, Edwin M

    2014-09-15

    Vision is the most important human sense. It facilitates every major activity of daily living ranging from basic communication, mobility and independence to an appreciation of art and nature. Heritable diseases of the retina, such as age-related macular degeneration and retinitis pigmentosa, are the leading cause of blindness in the developed world, collectively affecting as many as one-third of all people over the age of 75, to some degree. For decades, scientists have dreamed of preventing vision loss or of restoring the vision of patients affected with retinal degeneration through some type of drug, gene or cell-based transplantation approach. In this review, we will discuss the current literature pertaining to retinal transplantation. We will focus on the use of induced pluripotent stem cells for interrogation of disease pathophysiology, analysis of drug and gene therapeutics and as a source of autologous cells for cell replacement.

  20. Effect of Purified Murine NGF on Isolated Photoreceptors of a Rodent Developing Retinitis Pigmentosa

    Science.gov (United States)

    Rocco, Maria Luisa; Balzamino, Bijorn Omar; Petrocchi Passeri, Pamela; Micera, Alessandra; Aloe, Luigi

    2015-01-01

    A number of different studies have shown that neurotrophins, including nerve growth factor (NGF) support the survival of retinal ganglion neurons during a variety if insults. Recently, we have reported that that eye NGF administration can protect also photoreceptor degeneration in a mice and rat with inherited retinitis pigmentosa. However, the evidence that NGF acts directly on photoreceptors and that other retinal cells mediate the NGF effect could not be excluded. In the present study we have isolated retinal cells from rats with inherited retinitis pigmentosa (RP) during the post-natal stage of photoreceptor degenerative. In presence of NGF, these cells are characterized by enhanced expression of NGF-receptors and rhodopsin, the specific marker of photoreceptor and better cell survival, as well as neuritis outgrowth. Together these observations support the hypothesis that NGF that NGF acts directly on photoreceptors survival and prevents photoreceptor degeneration as previously suggested by in vivo studies. PMID:25897972

  1. Retinal Remodeling: Concerns, Emerging Remedies, and Future Prospects

    Directory of Open Access Journals (Sweden)

    Vidhyasankar eKrishnamoorthy

    2016-02-01

    Full Text Available Deafferentation results not only in sensory loss, but also in a variety of alterations in the postsynaptic circuitry. These alterations may have detrimental impact on potential treatment strategies. Progressive loss of photoreceptors in retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration, leads to several changes in the remnant retinal circuitry. Müller glial cells undergo hypertrophy and form a glial seal. The second- and third-order retinal neurons undergo morphological, biochemical and physiological alterations. A result of these alterations is that retinal ganglion cells (RGCs, the output neurons of the retina, become hyperactive and exhibit spontaneous, oscillatory bursts of spikes. This aberrant electrical activity degrades the signal-to-noise ratio in RGC responses, and thus the quality of information they transmit to the brain. These changes in the remnant retina, collectively termed retinal remodeling, pose challenges for genetic, cellular and bionic approaches to restore vision. It is therefore crucial to understand the nature of retinal remodeling, how it affects the ability of remnant retina to respond to novel therapeutic strategies, and how to ameliorate its effects. In this article, we discuss these topics, and suggest that the pathological state of the retinal output following photoreceptor loss is reversible, and therefore, amenable to restorative strategies.

  2. Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

    Science.gov (United States)

    2016-01-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway.

  3. Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

    Directory of Open Access Journals (Sweden)

    Yasuhiro Nakagami

    2016-01-01

    Full Text Available Nuclear factor erythroid 2-related factor 2 (Nrf2 is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway.

  4. PHOTORECEPTOR DEGENERATION IN A MOUNTAIN LION CUB (PUMA CONCOLOR).

    Science.gov (United States)

    DiSalvo, Andrew R; Reilly, Christopher M; Wiggans, K Tomo; Woods, Leslie W; Wack, Ray F; Clifford, Deana L

    2016-12-01

    An orphaned 4-mo-old female mountain lion cub ( Puma concolor ) was captured along the coastline in Montaña de Oro State Park in Los Osos, California, USA. Following suspicion that the cub was visually impaired, ophthalmic examination revealed diffuse bilateral retinal atrophy. Due to a poor prognosis, humane euthanasia was elected. Necropsy and histopathological findings were consistent with photoreceptor degeneration. Based on the cub's signalment, history, and histopathology, a genetic or nutritional etiology was suspected, with the former etiology more strongly supported. To the authors' knowledge, this is the first report of photoreceptor degeneration in a wild felid and should be considered in cases of blindness.

  5. Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells.

    Science.gov (United States)

    Tochitsky, Ivan; Polosukhina, Aleksandra; Degtyar, Vadim E; Gallerani, Nicholas; Smith, Caleb M; Friedman, Aaron; Van Gelder, Russell N; Trauner, Dirk; Kaufer, Daniela; Kramer, Richard H

    2014-02-19

    Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. Here, we report a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight. A single intraocular injection of DENAQ photosensitizes the blind retina for days, restoring electrophysiological and behavioral responses with no toxicity. Experiments on mouse strains with functional, nonfunctional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated photoreceptors. DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing. The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Degenerate Euler zeta function

    OpenAIRE

    Kim, Taekyun

    2015-01-01

    Recently, T. Kim considered Euler zeta function which interpolates Euler polynomials at negative integer (see [3]). In this paper, we study degenerate Euler zeta function which is holomorphic function on complex s-plane associated with degenerate Euler polynomials at negative integers.

  7. An Immunologic Study on Age-related Macular Degeneration

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    Forty-one patients with age-related macular degeneration(AMD) were detected for serum autoantibodies against normal humanretinal protein by means of Western immunoblot analysis.Twenty-sevenout of the 41 patients showed positive response,with a rate of 66 percent.The positive rate of antiretinal antibody in the AMD patients wassignificantly higher than that in normal controls (18%) and in patients withother retinal diseases (24%) (p<0.0005).These antiretinal antibodies fromthe AMD patients partly reacted...

  8. Results of submacular surgery in age-related macula degeneration

    OpenAIRE

    Laue, Jessica

    2010-01-01

    Due to a disruption of barrier function of the membrane Bruch and a change of the phagocities retinal pigment epithelial (rpe), exists possibility for progress of pathologist invasion of new vessels from the choroidea under the retina. On the position of the macula it will cause quick loss of central visual acuity. The most frequent cause for a choroidal neovascular membrane (CNV) is age-related macula degeneration (AMD); further causes are based on idiopathic or postinflammable reasons. ...

  9. Gene Therapy Approaches For The Treatment Of Retinal Disorders

    Science.gov (United States)

    Petit, Lolita; Punzo, Claudio

    2016-01-01

    There is an impelling need to develop effective therapeutic strategies for patients with retinal disorders. Gleaning from the large quantity of information gathered over the past two decades on the mechanisms governing degeneration of the retina, it is now possible to devise innovative therapies based on retinal gene transfer. Different gene-based approaches are under active investigation. They include strategies to correct the specific genetic defect in inherited retinal diseases, strategies to delay the onset of blindness independently of the disease-causing mutations and strategies to reactivate residual cells at late stages of the diseases. In this review, we discuss the status of application of these technologies, outlining the future therapeutic potential for many forms of retinal blinding diseases. PMID:27875674

  10. Cell-Based Therapy for Degenerative Retinal Disease.

    Science.gov (United States)

    Zarbin, Marco

    2016-02-01

    Stem cell-derived retinal pigment epithelium (RPE) and photoreceptors (PRs) have restored vision in preclinical models of human retinal degenerative disease. This review discusses characteristics of stem cell therapy in the eye and the challenges to clinical implementation that are being confronted today. Based on encouraging results from Phase I/II trials, the first Phase II clinical trials of stem cell-derived RPE transplantation are underway. PR transplant experiments have demonstrated restoration of visual function in preclinical models of retinitis pigmentosa and macular degeneration, but also indicate that no single approach is likely to succeed in overcoming PR loss in all cases. A greater understanding of the mechanisms controlling synapse formation as well as the immunoreactivity of transplanted retinal cells is urgently needed.

  11. Retinal Prosthesis: A Potential Benefit for the Blind

    Institute of Scientific and Technical Information of China (English)

    YANG Xiao-jie

    2009-01-01

    Retinal degenerative diseases may induce the degeneration of outer retina and in turn, blindness. Nevertheless, due to the maintenance of inner retina, the coding and processing of visual neurons responses are still able to be executed naturally. Therefore,an effective retinal prosthesis device may be developed by mimicking the function of outer retina: transferring the visual light into artificial stimulus and delivering the stimulus to the retina aiming to evoke the neural responses. As two main developing directions for current retinal prosthesis,epiretinal (ER) and subretinal (SR) prosthesis are both undergoing experimental stage and possessing advantages and limitations. Further investigations in power supply, biocompatibility, etc.are still required. Additionally, suprachoroidal transretinal stimulation (STS) and neurotransmitter-induced stimulation as some other alternatives in retinal prosthesis are also considered as promising research directions, although they are not mature enough to be applied commercially, either.

  12. cGMP-Phosphodiesterase Inhibition Prevents Hypoxia-Induced Cell Death Activation in Porcine Retinal Explants

    Science.gov (United States)

    Olivares-González, Lorena; Martínez-Fernández de la Cámara, Cristina; Hervás, David; Marín, María Pilar; Lahoz, Agustin; Millán, José María

    2016-01-01

    Retinal hypoxia and oxidative stress are involved in several retinal degenerations including diabetic retinopathy, glaucoma, central retinal artery occlusion, or retinopathy of prematurity. The second messenger cyclic guanosine monophosphate (cGMP) has been reported to be protective for neuronal cells under several pathological conditions including ischemia/hypoxia. The purpose of this study was to evaluate whether the accumulation of cGMP through the pharmacological inhibition of phosphodiesterase (PDE) with Zaprinast prevented retinal degeneration induced by mild hypoxia in cultures of porcine retina. Exposure to mild hypoxia (5% O2) for 24h reduced cGMP content and induced retinal degeneration by caspase dependent and independent (PARP activation) mechanisms. Hypoxia also produced a redox imbalance reducing antioxidant response (superoxide dismutase and catalase activities) and increasing superoxide free radical release. Zaprinast reduced mild hypoxia-induced cell death through inhibition of caspase-3 or PARP activation depending on the cell layer. PDE inhibition also ameliorated the effects of mild hypoxia on antioxidant response and the release of superoxide radical in the photoreceptor layer. The use of a PKG inhibitor, KT5823, suggested that cGMP-PKG pathway is involved in cell survival and antioxidant response. The inhibition of PDE, therefore, could be useful for reducing retinal degeneration under hypoxic/ischemic conditions. PMID:27861632

  13. Increased vascular density and vitreo-retinal membranes accompany vascularization of the pigment epithelium in the dystrophic rat retina.

    Science.gov (United States)

    Caldwell, R B; Roque, R S; Solomon, S W

    1989-09-01

    Observations of vascularization of the retinal pigment epithelium (RPE) and formation of vitreo-retinal membranes (VRMs) in Royal College of Surgeons (RCS) rats with inherited retinal dystrophy suggest that vascular proliferation occurs in this model. To test this hypothesis, we studied the progression of vascular changes in RCS and age-matched control rats using quantitative light microscope morphometry and electron microscopy. At 2 weeks, prior to photoreceptor degeneration, the dystrophic retina is comparable with the control. By 2 months, extensive degeneration of photoreceptor cells results in significant thinning of the dystrophic retina as compared with the control. Signs of vascular degeneration are evident at the electron microscope level--"ghost" vessels consisting of acellular basal lamina surrounded by amorphous electron-dense material; degenerating endothelial cells and pericytes; and abnormal deposits of extracellular matrix (ECM) material around blood vessels. Vascular degeneration is accompanied by glial changes in the form of necrotic perivascular glial processes and abnormal ECM deposits among the altered Muller cell processes. At 2-4 months in the dystrophic retina, numbers of vessel profiles in dystrophic retinas are decreased as compared with controls. However, vascular degeneration is overshadowed by the formation of numerous capillary tufts within the RPE layer, which together with retinal thinning results in increased vessel density. Between 4-12 months, the retinal thickness diminishes further, vascularization of the RPE increases, vitreo-retinal membranes are formed, and vascular density increases. In summary, following an initial period of vascular degeneration, vascularization of the RPE is accompanied by an increase in retinal vessel density and by the formation of vitreo-retinal membranes.

  14. Reading visual braille with a retinal prosthesis.

    Science.gov (United States)

    Lauritzen, Thomas Z; Harris, Jordan; Mohand-Said, Saddek; Sahel, Jose A; Dorn, Jessy D; McClure, Kelly; Greenberg, Robert J

    2012-01-01

    Retinal prostheses, which restore partial vision to patients blinded by outer retinal degeneration, are currently in clinical trial. The Argus II retinal prosthesis system was recently awarded CE approval for commercial use in Europe. While retinal prosthesis users have achieved remarkable visual improvement to the point of reading letters and short sentences, the reading process is still fairly cumbersome. This study investigates the possibility of using an epiretinal prosthesis to stimulate visual braille as a sensory substitution for reading written letters and words. The Argus II retinal prosthesis system, used in this study, includes a 10 × 6 electrode array implanted epiretinally, a tiny video camera mounted on a pair of glasses, and a wearable computer that processes the video and determines the stimulation current of each electrode in real time. In the braille reading system, individual letters are created by a subset of dots from a 3 by 2 array of six dots. For the visual braille experiment, a grid of six electrodes was chosen out of the 10 × 6 Argus II array. Groups of these electrodes were then directly stimulated (bypassing the camera) to create visual percepts of individual braille letters. Experiments were performed in a single subject. Single letters were stimulated in an alternative forced choice (AFC) paradigm, and short 2-4-letter words were stimulated (one letter at a time) in an open-choice reading paradigm. The subject correctly identified 89% of single letters, 80% of 2-letter, 60% of 3-letter, and 70% of 4-letter words. This work suggests that text can successfully be stimulated and read as visual braille in retinal prosthesis patients.

  15. Reading visual Braille with a retinal prosthesis

    Directory of Open Access Journals (Sweden)

    Thomas Zaccarin Lauritzen

    2012-11-01

    Full Text Available Retinal prostheses, which restore partial vision to patients blinded by outer retinal degeneration, are currently in clinical trial. The Argus II retinal prosthesis system was recently awarded CE approval for commercial use in Europe. While retinal prosthesis users have achieved remarkable visual improvement to the point of reading letters and short sentences, the reading process is still fairly cumbersome. This study investigates the possibility of using an epiretinal prosthesis to stimulate visual Braille as a sensory substitution for reading written letters and words. The Argus II retinal prosthesis system, used in this study, includes a 10 x 6 electrode array implanted epiretinally, a tiny video camera mounted on a pair of glasses, and a wearable computer that processes the video and determines the stimulation current of each electrode in real time. In the Braille reading system, individual letters are created by a subset of dots from a 3 by 2 array of six dots. For the visual Braille experiment, a grid of six electrodes was chosen out of the 10 x 6 Argus II array. Groups of these electrodes were then directly stimulated (bypassing the camera to create visual percepts of individual Braille letters. Experiments were performed in a single subject. Single letters were stimulated in an alternative forced choice (AFC paradigm, and short 2-4-letter words were stimulated (one letter at a time in an open-choice reading paradigm. The subject correctly identified 89% of single letters, 80% of 2-letter, 60% of 3-letter, and 70% of 4-letter words. This work suggests that text can successfully be stimulated and read as visual Braille in retinal prosthesis patients.

  16. Retinal stem cells and potential cell transplantation treatments.

    Science.gov (United States)

    Lin, Tai-Chi; Hsu, Chih-Chien; Chien, Ke-Hung; Hung, Kuo-Hsuan; Peng, Chi-Hsien; Chen, Shih-Jen

    2014-11-01

    The retina, histologically composed of ten delicate layers, is responsible for light perception and relaying electrochemical signals to the secondary neurons and visual cortex. Retinal disease is one of the leading clinical causes of severe vision loss, including age-related macular degeneration, Stargardt's disease, and retinitis pigmentosa. As a result of the discovery of various somatic stem cells, advances in exploring the identities of embryonic stem cells, and the development of induced pluripotent stem cells, cell transplantation treatment for retinal diseases is currently attracting much attention. The sources of stem cells for retinal regeneration include endogenous retinal stem cells (e.g., neuronal stem cells, Müller cells, and retinal stem cells from the ciliary marginal zone) and exogenous stem cells (e.g., bone mesenchymal stem cells, adipose-derived stem cells, embryonic stem cells, and induced pluripotent stem cells). The success of cell transplantation treatment depends mainly on the cell source, the timing of cell harvesting, the protocol of cell induction/transplantation, and the microenvironment of the recipient's retina. This review summarizes the different sources of stem cells for regeneration treatment in retinal diseases and surveys the more recent achievements in animal studies and clinical trials. Future directions and challenges in stem cell transplantation are also discussed.

  17. Retinal and visual system: occupational and environmental toxicology.

    Science.gov (United States)

    Fox, Donald A

    2015-01-01

    Occupational chemical exposure often results in sensory systems alterations that occur without other clinical signs or symptoms. Approximately 3000 chemicals are toxic to the retina and central visual system. Their dysfunction can have immediate, long-term, and delayed effects on mental health, physical health, and performance and lead to increased occupational injuries. The aims of this chapter are fourfold. First, provide references on retinal/visual system structure, function, and assessment techniques. Second, discuss the retinal features that make it especially vulnerable to toxic chemicals. Third, review the clinical and corresponding experimental data regarding retinal/visual system deficits produced by occupational toxicants: organic solvents (carbon disulfide, trichloroethylene, tetrachloroethylene, styrene, toluene, and mixtures) and metals (inorganic lead, methyl mercury, and mercury vapor). Fourth, discuss occupational and environmental toxicants as risk factors for late-onset retinal diseases and degeneration. Overall, the toxicants altered color vision, rod- and/or cone-mediated electroretinograms, visual fields, spatial contrast sensitivity, and/or retinal thickness. The findings elucidate the importance of conducting multimodal noninvasive clinical, electrophysiologic, imaging and vision testing to monitor toxicant-exposed workers for possible retinal/visual system alterations. Finally, since the retina is a window into the brain, an increased awareness and understanding of retinal/visual system dysfunction should provide additional insight into acquired neurodegenerative disorders.

  18. Photovoltaic retinal prosthesis with high pixel density

    Science.gov (United States)

    Mathieson, Keith; Loudin, James; Goetz, Georges; Huie, Philip; Wang, Lele; Kamins, Theodore I.; Galambos, Ludwig; Smith, Richard; Harris, James S.; Sher, Alexander; Palanker, Daniel

    2012-06-01

    Retinal degenerative diseases lead to blindness due to loss of the `image capturing' photoreceptors, while neurons in the `image-processing' inner retinal layers are relatively well preserved. Electronic retinal prostheses seek to restore sight by electrically stimulating the surviving neurons. Most implants are powered through inductive coils, requiring complex surgical methods to implant the coil-decoder-cable-array systems that deliver energy to stimulating electrodes via intraocular cables. We present a photovoltaic subretinal prosthesis, in which silicon photodiodes in each pixel receive power and data directly through pulsed near-infrared illumination and electrically stimulate neurons. Stimulation is produced in normal and degenerate rat retinas, with pulse durations of 0.5-4 ms, and threshold peak irradiances of 0.2-10 mW mm-2, two orders of magnitude below the ocular safety limit. Neural responses were elicited by illuminating a single 70 µm bipolar pixel, demonstrating the possibility of a fully integrated photovoltaic retinal prosthesis with high pixel density.

  19. Connexin43 in retinal injury and disease.

    Science.gov (United States)

    Danesh-Meyer, Helen V; Zhang, Jie; Acosta, Monica L; Rupenthal, Ilva D; Green, Colin R

    2016-03-01

    Gap junctions are specialized cell-to-cell contacts that allow the direct transfer of small molecules between cells. A single gap junction channel consists of two hemichannels, or connexons, each of which is composed of six connexin protein subunits. Connexin43 is the most ubiquitously expressed isoform of the connexin family and in the retina it is prevalent in astrocytes, Müller cells, microglia, retinal pigment epithelium and endothelial cells. Prior to docking with a neighboring cell, Connexin43 hemichannels have a low open probability as open channels constitute a large, relatively non-specific membrane pore. However, with injury and disease Connexin43 upregulation and hemichannel opening has been implicated in all aspects of secondary damage, especially glial cell activation, edema and loss of vascular integrity, leading to neuronal death. We here review gap junctions and their roles in the retina, and then focus in on Connexin43 gap junction channels in injury and disease. In particular, the effect of pathological opening of gap junction hemichannels is described, and hemichannel mediated loss of vascular integrity explained. This latter phenomenon underlies retinal pigment epithelium loss and is a common feature in several retinal diseases. Finally, Connexin43 channel roles in a number of retinal diseases including macular degeneration, glaucoma and diabetic retinopathy are considered, along with results from related animal models. A final section describes gap junction channel modulation and the ocular delivery of potential therapeutic molecules. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Investigation of retinal morphology alterations using spectral domain optical coherence tomography in a mouse model of retinal branch and central retinal vein occlusion.

    Directory of Open Access Journals (Sweden)

    Andreas Ebneter

    Full Text Available Retinal vein occlusion is a leading cause of visual impairment. Experimental models of this condition based on laser photocoagulation of retinal veins have been described and extensively exploited in mammals and larger rodents such as the rat. However, few reports exist on the use of this paradigm in the mouse. The objective of this study was to investigate a model of branch and central retinal vein occlusion in the mouse and characterize in vivo longitudinal retinal morphology alterations using spectral domain optical coherence tomography. Retinal veins were experimentally occluded using laser photocoagulation after intravenous application of Rose Bengal, a photo-activator dye enhancing thrombus formation. Depending on the number of veins occluded, variable amounts of capillary dropout were seen on fluorescein angiography. Vascular endothelial growth factor levels were markedly elevated early and peaked at day one. Retinal thickness measurements with spectral domain optical coherence tomography showed significant swelling (p<0.001 compared to baseline, followed by gradual thinning plateauing two weeks after the experimental intervention (p<0.001. Histological findings at day seven correlated with spectral domain optical coherence tomography imaging. The inner layers were predominantly affected by degeneration with the outer nuclear layer and the photoreceptor outer segments largely preserved. The application of this retinal vein occlusion model in the mouse carries several advantages over its use in other larger species, such as access to a vast range of genetically modified animals. Retinal changes after experimental retinal vein occlusion in this mouse model can be non-invasively quantified by spectral domain optical coherence tomography, and may be used to monitor effects of potential therapeutic interventions.

  1. Novel Neuroprotective Strategies in Ischemic Retinal Lesions

    Science.gov (United States)

    Szabadfi, Krisztina; Mester, Laszlo; Reglodi, Dora; Kiss, Peter; Babai, Norbert; Racz, Boglarka; Kovacs, Krisztina; Szabo, Aliz; Tamas, Andrea; Gabriel, Robert; Atlasz, Tamas

    2010-01-01

    Retinal ischemia can be effectively modeled by permanent bilateral common carotid artery occlusion, which leads to chronic hypoperfusion-induced degeneration in the entire rat retina. The complex pathways leading to retinal cell death offer a complex approach of neuroprotective strategies. In the present review we summarize recent findings with different neuroprotective candidate molecules. We describe the protective effects of intravitreal treatment with: (i) urocortin 2; (ii) a mitochondrial ATP-sensitive K+ channel opener, diazoxide; (iii) a neurotrophic factor, pituitary adenylate cyclase activating polypeptide; and (iv) a novel poly(ADP-ribose) polymerase inhibitor (HO3089). The retinoprotective effects are demonstrated with morphological description and effects on apoptotic pathways using molecular biological techniques. PMID:20386654

  2. Retrograde degeneration of retinal ganglion cells in homonymous hemianopsia

    OpenAIRE

    Herro AM; Lam BL

    2015-01-01

    Angela M Herro, Byron L Lam Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA Background: The aim of this study was to demonstrate the relationship between topographic reduction in macular ganglion cell complex (GCC) thickness as detected with spectral-domain optical coherence tomography and visual field defects caused by ischemic occipital cortical injury.Methods: This study was a retrospective review of all pat...

  3. Retinal stimulation strategies to restore vision: Fundamentals and systems.

    Science.gov (United States)

    Yue, Lan; Weiland, James D; Roska, Botond; Humayun, Mark S

    2016-07-01

    Retinal degeneration, a leading cause of blindness worldwide, is primarily characterized by the dysfunctional/degenerated photoreceptors that impair the ability of the retina to detect light. Our group and others have shown that bioelectronic retinal implants restore useful visual input to those who have been blind for decades. This unprecedented approach of restoring sight demonstrates that patients can adapt to new visual input, and thereby opens up opportunities to not only improve this technology but also develop alternative retinal stimulation approaches. These future improvements or new technologies could have the potential of selectively stimulating specific cell classes in the inner retina, leading to improved visual resolution and color vision. In this review we will detail the progress of bioelectronic retinal implants and future devices in this genre as well as discuss other technologies such as optogenetics, chemical photoswitches, and ultrasound stimulation. We will discuss the principles, biological aspects, technology development, current status, clinical outcomes/prospects, and challenges for each approach. The review will cover functional imaging documented cortical responses to retinal stimulation in blind patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Recent Advances of Stem Cell Therapy for Retinitis Pigmentosa

    Directory of Open Access Journals (Sweden)

    Yuxi He

    2014-08-01

    Full Text Available Retinitis pigmentosa (RP is a group of inherited retinal disorders characterized by progressive loss of photoreceptors and eventually leads to retina degeneration and atrophy. Until now, the exact pathogenesis and etiology of this disease has not been clear, and many approaches for RP therapies have been carried out in animals and in clinical trials. In recent years, stem cell transplantation-based attempts made some progress, especially the transplantation of bone marrow-derived mesenchymal stem cells (BMSCs. This review will provide an overview of stem cell-based treatment of RP and its main problems, to provide evidence for the safety and feasibility for further clinical treatment.

  5. Canine retina has a primate fovea-like bouquet of cone photoreceptors which is affected by inherited macular degenerations.

    Directory of Open Access Journals (Sweden)

    William A Beltran

    Full Text Available Retinal areas of specialization confer vertebrates with the ability to scrutinize corresponding regions of their visual field with greater resolution. A highly specialized area found in haplorhine primates (including humans is the fovea centralis which is defined by a high density of cone photoreceptors connected individually to interneurons, and retinal ganglion cells (RGCs that are offset to form a pit lacking retinal capillaries and inner retinal neurons at its center. In dogs, a local increase in RGC density is found in a topographically comparable retinal area defined as the area centralis. While the canine retina is devoid of a foveal pit, no detailed examination of the photoreceptors within the area centralis has been reported. Using both in vivo and ex vivo imaging, we identified a retinal region with a primate fovea-like cone photoreceptor density but without the excavation of the inner retina. Similar anatomical structure observed in rare human subjects has been named fovea-plana. In addition, dogs with mutations in two different genes, that cause macular degeneration in humans, developed earliest disease at the newly-identified canine fovea-like area. Our results challenge the dogma that within the phylogenetic tree of mammals, haplorhine primates with a fovea are the sole lineage in which the retina has a central bouquet of cones. Furthermore, a predilection for naturally-occurring retinal degenerations to alter this cone-enriched area fills the void for a clinically-relevant animal model of human macular degenerations.

  6. Canine retina has a primate fovea-like bouquet of cone photoreceptors which is affected by inherited macular degenerations.

    Science.gov (United States)

    Beltran, William A; Cideciyan, Artur V; Guziewicz, Karina E; Iwabe, Simone; Swider, Malgorzata; Scott, Erin M; Savina, Svetlana V; Ruthel, Gordon; Stefano, Frank; Zhang, Lingli; Zorger, Richard; Sumaroka, Alexander; Jacobson, Samuel G; Aguirre, Gustavo D

    2014-01-01

    Retinal areas of specialization confer vertebrates with the ability to scrutinize corresponding regions of their visual field with greater resolution. A highly specialized area found in haplorhine primates (including humans) is the fovea centralis which is defined by a high density of cone photoreceptors connected individually to interneurons, and retinal ganglion cells (RGCs) that are offset to form a pit lacking retinal capillaries and inner retinal neurons at its center. In dogs, a local increase in RGC density is found in a topographically comparable retinal area defined as the area centralis. While the canine retina is devoid of a foveal pit, no detailed examination of the photoreceptors within the area centralis has been reported. Using both in vivo and ex vivo imaging, we identified a retinal region with a primate fovea-like cone photoreceptor density but without the excavation of the inner retina. Similar anatomical structure observed in rare human subjects has been named fovea-plana. In addition, dogs with mutations in two different genes, that cause macular degeneration in humans, developed earliest disease at the newly-identified canine fovea-like area. Our results challenge the dogma that within the phylogenetic tree of mammals, haplorhine primates with a fovea are the sole lineage in which the retina has a central bouquet of cones. Furthermore, a predilection for naturally-occurring retinal degenerations to alter this cone-enriched area fills the void for a clinically-relevant animal model of human macular degenerations.

  7. Culturing of retinal pigment epithelium cells.

    Science.gov (United States)

    Valtink, Monika; Engelmann, Katrin

    2009-01-01

    The retinal pigment epithelium (RPE) is a monolayer of cells adjacent to the photoreceptors of the retina. It plays a crucial role in maintaining photoreceptor health and survival. Degeneration or dysfunction of the RPE can lead to photoreceptor degeneration and as a consequence to visual impairment. The most common diseased state of the RPE becomes manifest in age-related macular degeneration, an increasing cause of blindness in the elderly. RPE cells are therefore of great interest to researchers working in the field of tissue engineering and cell transplantation. In fact, studies in animal models have proven that the transplantation of RPE cells can delay the course of photoreceptor degenerative diseases. Although first attempts to transplant RPE cells into the subretinal space in human individuals suffering from age-related macular degeneration were less successful, RPE cell transplantation is still favored as a future therapeutic option, and much work is done to develop and design cell transplants. Cell banking is a prerequisite to have well-differentiated and characterized cells at hand when needed for research purposes, but also for therapeutic approaches. In this chapter the authors will describe methods to isolate, culture and preserve adult human RPE cells for the purpose of RPE cell banking. Copyright 2009 S. Karger AG, Basel.

  8. Retinal Remodeling And Metabolic Alterations in Human AMD

    Directory of Open Access Journals (Sweden)

    Bryan William Jones

    2016-04-01

    Full Text Available Age-related macular degeneration (AMD is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression.The pathways and mechanisms through which genetic and non-genetic risk factors modulate development of AMD pathogenesis remain largely unexplored. Moreover, current treatment for AMD is palliative and limited to wet/exudative forms. Retina is a complex, heterocellular tissue and most retinal cell classes are impacted or altered in AMD. Defining disease and stage-specific cytoarchitectural and metabolic responses in AMD is critical for highlighting targets for intervention. The goal of this paper is to illustrate cell types impacted in AMD and demonstrate the implications of those changes, likely beginning in the retinal pigment epithelium (RPE, for remodeling of the the neural retina.Tracking heterocellular responses in disease progression is best achieved with computational molecular phenotyping (CMP, a tool that enables acquisition of a small molecule fingerprint for every cell in the retina. CMP uncovered critical cellular and molecular pathologies (remodeling and reprogramming in progressive retinal degenerations such as retinitis pigmentosa (RP. We now applied these approaches to normal human and AMD tissues mapping progression of cellular and molecular changes in AMD retinas, including late-stage forms of the disease.Major findings: 1 Evidence of metabolic instability in RPE in dry-AMD.2 Photoreceptors show clear indications of stress prior to cell death.3 Cone opsin processing by the RPE in AMD retinas may be differentially compromised vs. rod opsin.4 Müller cells in AMD exhibit

  9. Retinal stem cells and regeneration of vision system.

    Science.gov (United States)

    Yip, Henry K

    2014-01-01

    The vertebrate retina is a well-characterized model for studying neurogenesis. Retinal neurons and glia are generated in a conserved order from a pool of mutlipotent progenitor cells. During retinal development, retinal stem/progenitor cells (RPC) change their competency over time under the influence of intrinsic (such as transcriptional factors) and extrinsic factors (such as growth factors). In this review, we summarize the roles of these factors, together with the understanding of the signaling pathways that regulate eye development. The information about the interactions between intrinsic and extrinsic factors for retinal cell fate specification is useful to regenerate specific retinal neurons from RPCs. Recent studies have identified RPCs in the retina, which may have important implications in health and disease. Despite the recent advances in stem cell biology, our understanding of many aspects of RPCs in the eye remains limited. PRCs are present in the developing eye of all vertebrates and remain active in lower vertebrates throughout life. In mammals, however, PRCs are quiescent and exhibit very little activity and thus have low capacity for retinal regeneration. A number of different cellular sources of RPCs have been identified in the vertebrate retina. These include PRCs at the retinal margin, pigmented cells in the ciliary body, iris, and retinal pigment epithelium, and Müller cells within the retina. Because PRCs can be isolated and expanded from immature and mature eyes, it is possible now to study these cells in culture and after transplantation in the degenerated retinal tissue. We also examine current knowledge of intrinsic RPCs, and human embryonic stems and induced pluripotent stem cells as potential sources for cell transplant therapy to regenerate the diseased retina.

  10. A2E accumulation influences retinal microglial activation and complement regulation

    OpenAIRE

    2012-01-01

    Age-related macular degeneration (AMD) is an outer retinal disease that involves aging and immune dysfunction. In the aging retina, microglia aggregate in the outer retina and acquire intracellular autofluorescent lipofuscin deposits. In this study, we investigated whether accumulation of A2E, a key bisretinoid constituent of ocular lipofuscin, alters the physiology of retinal microglia in pathologically relevant ways. Our findings show that sublethal accumulations of intracellular A2E in cul...

  11. New approaches and potential treatments for dry age-related macular degeneration

    OpenAIRE

    Francisco Max Damico; Fabio Gasparin; Mariana Ramos Scolari; Lycia Sampaio Pedral; Beatriz Sayuri Takahashi

    2012-01-01

    Emerging treatments for dry age-related macular degeneration (AMD) and geographi c atrophy focus on two strategies that target components involved in physiopathological pathways: prevention of photoreceptors and retinal pigment epithelium loss (neuroprotection induction, oxidative damage prevention, and visual cycle modification) and suppression of inflammation. Neuroprotective drugs, such as ciliary neurotrophic factor, brimonidine tartrate, tandospirone, and anti-amyloid β antibodies, ...

  12. Degenerate Density Perturbation Theory

    CERN Document Server

    Palenik, Mark C

    2016-01-01

    Fractional occupation numbers can be used in density functional theory to create a symmetric Kohn-Sham potential, resulting in orbitals with degenerate eigenvalues. We develop the corresponding perturbation theory and apply it to a system of $N_d$ degenerate electrons in a harmonic oscillator potential. The order-by-order expansions of both the fractional occupation numbers and unitary transformations within the degenerate subspace are determined by the requirement that a differentiable map exists connecting the initial and perturbed states. Using the X$\\alpha$ exchange-correlation (XC) functional, we find an analytic solution for the first-order density and first through third-order energies as a function of $\\alpha$, with and without a self-interaction correction. The fact that the XC Hessian is not positive definite plays an important role in the behavior of the occupation numbers.

  13. Degenerate density perturbation theory

    Science.gov (United States)

    Palenik, Mark C.; Dunlap, Brett I.

    2016-09-01

    Fractional occupation numbers can be used in density functional theory to create a symmetric Kohn-Sham potential, resulting in orbitals with degenerate eigenvalues. We develop the corresponding perturbation theory and apply it to a system of Nd degenerate electrons in a harmonic oscillator potential. The order-by-order expansions of both the fractional occupation numbers and unitary transformations within the degenerate subspace are determined by the requirement that a differentiable map exists connecting the initial and perturbed states. Using the X α exchange-correlation (XC) functional, we find an analytic solution for the first-order density and first- through third-order energies as a function of α , with and without a self-interaction correction. The fact that the XC Hessian is not positive definite plays an important role in the behavior of the occupation numbers.

  14. Vortices as degenerate metrics

    CERN Document Server

    Baptista, J M

    2012-01-01

    We note that the Bogomolny equation for abelian vortices is precisely the condition for invariance of the Hermitian-Einstein equation under a degenerate conformal transformation. This leads to a natural interpretation of vortices as degenerate hermitian metrics that satisfy a certain curvature equation. Using this viewpoint, we rephrase standard results about vortices and make some new observations. We note the existence of a conceptually simple, non-linear rule for superposing vortex solutions, and we describe the natural behaviour of the L^2-metric on the moduli space upon certain restrictions.

  15. Dorzolamide increases retinal oxygen tension after branch retinal vein occlusion

    DEFF Research Database (Denmark)

    Noergaard, Michael Hove; Bach-Holm, Daniella; Scherfig, Erik;

    2008-01-01

    To study the effect of dorzolamide on the preretinal oxygen tension (RPO(2)) in retinal areas affected by experimental branch retinal vein occlusion (BRVO) in pigs.......To study the effect of dorzolamide on the preretinal oxygen tension (RPO(2)) in retinal areas affected by experimental branch retinal vein occlusion (BRVO) in pigs....

  16. Kraepelin and degeneration theory.

    Science.gov (United States)

    Hoff, Paul

    2008-06-01

    Emil Kraepelin's contribution to the clinical and scientific field of psychiatry is recognized world-wide. In recent years, however, there have been a number of critical remarks on his acceptance of degeneration theory in particular and on his political opinion in general, which was said to have carried "overtones of proto-fascism" by Michael Shepherd [28]. The present paper discusses the theoretical cornerstones of Kraepelinian psychiatry with regard to their relevance for Kraepelin's attitude towards degeneration theory. This theory had gained wide influence not only in scientific, but also in philosophical and political circles in the last decades of the nineteenth century. There is no doubt that Kraepelin, on the one hand, accepted and implemented degeneration theory into the debate on etiology and pathogenesis of mental disorders. On the other hand, it is not appropriate to draw a simple and direct line from early versions of degeneration theory to the crimes of psychiatrists and politicians during the rule of national socialism. What we need, is a differentiated view, since this will be the only scientific one. Much research needs to be done here in the future, and such research will surely have a significant impact not only on the historical field, but also on the continuous debate about psychiatry, neuroscience and neurophilosophy.

  17. Drusen-like beneath retinal deposits in type II mesangiocapillary glomerulonephritis: a review

    Directory of Open Access Journals (Sweden)

    Miguel Hage Amaro

    2015-02-01

    Full Text Available The aim of this paper is to do a review of Drusen-like beneath retinal deposits in type II mesangiocapillary glomerulonephritis. Drusenlike beneath retinal deposits in type II mesangiocapillary glomerulonephritis appear to develop at an early age, often second decade of life different of drusen from age-related macular degeneration (AMD.Long term follow-up of the cases in this disease shows in the most of them, no progression of the of drusen-like beneath retinal deposits in type II mesangiocapillary glomerulonefritis, the most of subjects retain good visual acuity and no specific treatment is indicated.

  18. Observation and management of retinal changes related to diving in professional divers

    Institute of Scientific and Technical Information of China (English)

    Zhou Dan; Wei Wenbin; Tian Bei; Wang Cong; Shi Xuehui; Jiao Xuan

    2014-01-01

    Background It is very common for professional divers to have damage on the retinas.Severe retinal lesions can profoundly affect athletes' training efficacy and their daily lives.At present,it is not clear if there is effective preventive action.Thus,in our study,we continuously tracked the ocular changes in athletes and closely monitored the risk factors associated with retinal detachment.Also,we analyzed possible interventions,their associated factors,and efficacies for timely preventions to protect the retina from damage in professional divers.Methods Between 2009 and 2012,a total of 39 professional divers enrolled in follow-up management.The conducted examinations included ocular examination,record screening on retinal lesion,monitoring best-corrected visual acuity,and checking intraocular pressure (lOP) and the scope of retinal lesion.The management included optimizing training methods,taking customized follow-up based on different retinal lesions,laser treatments for definite cases of retinal tear,retinal degeneration caused by retinal layer thinning or vitreous traction,and observing the changes in the scope of retinopathy.Results Every year,the percentage of divers who have various degrees of retinal lesions is between 43.3% and 56.2%.During the 4 years,there were no statistically significant differences in divers' best-corrected visual acuity and retinal lesions.There were also no statistically significant differences between male and female athletes.However,there were statistically significant differences in lOP during these years.Moreover there were statistically significant differences in IOP and the scope of retinal lesions between platform divers and springboard divers.Conclusions Our management of retinal lesions could be effective to prevent severe retinopathy in professional divers.At the same time,platform divers are more likely to have retinal lesions than springboard divers.

  19. Progress and perspectives on the role of RPE cell inflammatory responses in the development of age-related macular degeneration

    OpenAIRE

    Suofu Qin; Gerard A Rodrigues

    2008-01-01

    Suofu Qin, Gerard A RodriguesRetinal Disease Research, Department of Biological Sciences, Allergan, Inc., Irvine, CA, USAAbstract: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The etiology of AMD remains poorly understood and no treatment is currently available for the atrophic form of AMD. Atrophic AMD has been proposed to involve abnormalities of the retinal pigment epithelium (RPE), which lies beneath the photoreceptor cells and normally ...

  20. [Treatment of serous macular retinal detachment with antihistamines].

    Science.gov (United States)

    Kirschfeld, K

    2015-01-01

    The etiology of retinal detachment in central serous retinopathy (CSR) is unknown; however, three facts are generally accepted: (1) the serous exudate which raises the layers of the receptors/pigment epithelium is formed due to hyperpermeability in the choriocapillaries, (2) patients frequently suffer from headaches and (3) stress promotes the incidence of CSR. A high blood plasma histamine concentration can cause the abovementioned symptoms which suggests that histamine might provoke CSR. Within 1 week after administration of the antihistamine loratadin a considerable reduction in the retinal exudate and restoration of vision were observed. This supports the hypothesis that histamine could be involved in the process of retinal detachment. Further investigations and large scale clinical trials should clarify if this hypothesis can be proved or disproved and whether antihistamines can be used for age-related macular degeneration (AMD).

  1. Advances in gene therapy technologies to treat retinitis pigmentosa.

    Science.gov (United States)

    Petrs-Silva, Hilda; Linden, Rafael

    2014-01-01

    Retinitis pigmentosa (RP) is a class of diseases that leads to progressive degeneration of the retina. Experimental approaches to gene therapy for the treatment of inherited retinal dystrophies have advanced in recent years, inclusive of the safe delivery of genes to the human retina. This review is focused on the development of gene therapy for RP using recombinant adenoassociated viral vectors, which show a positive safety record and have so far been successful in several clinical trials for congenital retinal disease. Gene therapy for RP is under development in a variety of animal models, and the results raise expectations of future clinical application. Nonetheless, the translation of such strategies to the bedside requires further understanding of the mutations and mechanisms that cause visual defects, as well as thorough examination of potential adverse effects.

  2. Local signaling from a retinal prosthetic in a rodent retinitis pigmentosa model in vivo

    Science.gov (United States)

    Fransen, James W.; Pangeni, Gobinda; Pardue, Machelle T.; McCall, Maureen A.

    2014-08-01

    Objective. In clinical trials, retinitis pigmentosa patients implanted with a retinal prosthetic device show enhanced spatial vision, including the ability to read large text and navigate. New prosthetics aim to increase spatial resolution by decreasing pixel/electrode size and limiting current spread. To examine spatial resolution of a new prosthetic design, we characterized and compared two photovoltaic array (PVA) designs and their interaction with the retina after subretinal implantation in transgenic S334ter line 3 rats (Tg S334ter-3). Approach. PVAs were implanted subretinally at two stages of degeneration and assessed in vivo using extracellular recordings in the superior colliculus (SC). Several aspects of this interaction were evaluated by varying duration, irradiance and position of a near infrared laser focused on the PVA. These characteristics included: activation threshold, response linearity, SC signal topography and spatial localization. The major design difference between the two PVA designs is the inclusion of local current returns in the newer design. Main results. When tested in vivo, PVA-evoked response thresholds were independent of pixel/electrode size, but differ between the new and old PVA designs. Response thresholds were independent of implantation age and duration (⩽7.5 months). For both prosthesis designs, threshold intensities were within established safety limits. PVA-evoked responses require inner retina synaptic transmission and do not directly activate retinal ganglion cells. The new PVA design evokes local retinal activation, which is not found with the older PVA design that lacks local current returns. Significance. Our study provides in vivo evidence that prosthetics make functional contacts with the inner nuclear layer at several stages of degeneration. The new PVA design enhances local activation within the retina and SC. Together these results predict that the new design can potentially harness the inherent processing within

  3. Preservation of cone photoreceptors after a rapid yet transient degeneration and remodeling in cone-only Nrl-/- mouse retina.

    Science.gov (United States)

    Roger, Jerome E; Ranganath, Keerthi; Zhao, Lian; Cojocaru, Radu I; Brooks, Matthew; Gotoh, Norimoto; Veleri, Shobi; Hiriyanna, Avinash; Rachel, Rivka A; Campos, Maria Mercedes; Fariss, Robert N; Wong, Wai T; Swaroop, Anand

    2012-01-11

    Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss in many retinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor neural retina leucine zipper (NRL). The loss of Nrl (Nrl(-/-)) in mice results in a retina with predominantly S-opsin-containing cones that exhibit molecular and functional characteristics of wild-type cones. Here, we report that Nrl(-/-) retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by 4 months of age, resulting in a thinner but intact outer nuclear layer with residual cones expressing S- and M-opsins and a preserved photopic electroretinogram. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of genes related to stress response and inflammation, implying their involvement in cone death. The Nrl(-/-) mouse illustrates the long-term viability of cones in the absence of rods and retinal pigment epithelium defects in a rodless retina. We propose that Nrl(-/-) retina may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone-dominant human macula.

  4. Dark rearing maintains tyrosine hydroxylase expression in retinal amacrine cells following optic nerve transection

    Institute of Scientific and Technical Information of China (English)

    Wei Wan; Zhenghai Liu; Xiaosheng Wang; Xuegang Luo

    2012-01-01

    The present study examined changes in retinal tyrosine hydroxylase (TH) expression in rats having undergone optic nerve transection and housed under a normal day/night cycle or in the dark. The aim was to investigate the effects of amacrine cells on axonal regeneration in retinal ganglion cells and on the synapses that transmit visual signals. The results revealed that retinal TH expression gradually decreased following optic nerve transection in rats housed under a normal day/night cycle, reaching a minimum at 5 days. In contrast, retinal TH expression decreased to a minimum at 1 day following optic nerve transection in dark reared rats, gradually increasing afterward and reaching a normal level at 5-7 days. The number of TH-positive synaptic particles correlated with the TH levels, indicating that dark rearing can help maintain TH expression during the synaptic degeneration stage (5-7 days after optic nerve injury) in retinal amacrine cells.

  5. Zebrafish model for the genetic basis of X-linked retinitis pigmentosa.

    Science.gov (United States)

    Raghupathy, Rakesh Kotapati; McCulloch, Daphne L; Akhtar, Saeed; Al-mubrad, Turki M; Shu, Xinhua

    2013-03-01

    Retinitis pigmentosa (RP) affects 1/4000 individuals in most populations, and X-linked RP (XLRP) is one of the most severe forms of human retinal degeneration. Mutations in both the retinitis pigmentosa GTPase regulator (RPGR) gene and retinitis pigmentosa 2 (RP2) gene account for almost all cases of XLRP. The functional roles of both RPGR and RP2 in the pathogenesis of XLRP are unclear. Due to the surprisingly high degree of functional conservation between human genes and their zebrafish orthologues, the zebrafish has become an important model for human retinal disorders. In this brief review, we summarize the functional characterization of XLRP-causing genes, RPGR and RP2, in zebrafish, and highlight recent studies that provide insight into the cellular functions of both genes. This will not only shed light on disease mechanisms in XLRP but will also provide a solid platform to test RP-causing mutants before proposing XLRP gene therapy trials.

  6. RAGE and its ligands in retinal disease.

    Science.gov (United States)

    Barile, Gaetano R; Schmidt, Ann M

    2007-12-01

    RAGE, the receptor for advanced glycation endproducts (AGEs), is a multiligand signal transduction receptor of the immunoglobulin superfamily of cell surface molecules that has been implicated in the pathogenesis of diabetic complications, neurodegenerative diseases, inflammatory disorders, and cancer. These diverse biologic disorders reflect the multiplicity of ligands capable of cellular interaction via RAGE that include, in addition to AGEs, amyloid-beta (Abeta) peptide, the S100/calgranulin family of proinflammatory cytokines, and amphoterin, a member of the High Mobility Group Box (HMGB) DNA-binding proteins. In the retina, RAGE expression is present in neural cells, the vasculature, and RPE cells, and it has also been detected in pathologic cellular retinal responses including epiretinal and neovascular membrane formation. Ligands for RAGE, in particular AGEs, have emerged as relevant to the pathogenesis of diabetic retinopathy and age-related macular disease. While the understanding of RAGE and its role in retinal dysfunction with aging, diabetes mellitus, and/or activation of pro-inflammatory pathways is less complete compared to other organ systems, increasing evidence indicates that RAGE can initiate and sustain significant cellular perturbations in the inner and outer retina. For these reasons, antagonism of RAGE interactions with its ligands may be a worthwhile therapeutic target in such seemingly disparate, visually threatening retinal diseases as diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinopathy.

  7. On Degenerate Partial Differential Equations

    OpenAIRE

    Chen, Gui-Qiang G.

    2010-01-01

    Some of recent developments, including recent results, ideas, techniques, and approaches, in the study of degenerate partial differential equations are surveyed and analyzed. Several examples of nonlinear degenerate, even mixed, partial differential equations, are presented, which arise naturally in some longstanding, fundamental problems in fluid mechanics and differential geometry. The solution to these fundamental problems greatly requires a deep understanding of nonlinear degenerate parti...

  8. Molecular pathogenesis of retinal and choroidal vascular diseases.

    Science.gov (United States)

    Campochiaro, Peter A

    2015-11-01

    There are two major types of ocular neovascularization that affect the retina, retinal neovascularization (NV) and subretinal or choroidal NV. Retinal NV occurs in a group of diseases referred to as ischemic retinopathies in which damage to retinal vessels results in retinal ischemia. Most prevalent of these are diabetic retinopathy and retinal vein occlusions. Subretinal and choroidal NV occur in diseases of the outer retina and Bruch's membrane, the most prevalent of which is age-related macular degeneration. Numerous studies in mouse models have helped to elucidate the molecular pathogenesis underlying retinal, subretinal, and choroidal NV. There is considerable overlap because the precipitating event in each is stabilization of hypoxia inducible factor-1 (HIF-1) which leads to upregulation of several hypoxia-regulated gene products, including vascular endothelial growth factor (VEGF), angiopoietin 2, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and several others. Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal, subretinal, and choroidal NV, with perturbation of Bruch's membrane also needed for the latter. Additional HIF-1-regulated gene products cause further stimulation of the NV. It is difficult to model macular edema in animals and therefore proof-of-concept clinical trials were done and demonstrated that VEGF plays a central role and that suppression of Tie2 is also important. Neutralization of VEGF is currently the first line therapy for all of the above disease processes, but new treatments directed at some of the other molecular targets, particularly stabilization of Tie2, are likely to provide additional benefit for subretinal/choroidal NV and macular edema. In addition, the chronicity of these diseases as well as the implication of VEGF as a cause of retinal nonperfusion and progression of background diabetic retinopathy make sustained delivery approaches for VEGF

  9. Molecular Pathogenesis of Retinal and Choroidal Vascular Diseases

    Science.gov (United States)

    Campochiaro, Peter A.

    2015-01-01

    There are two major types of ocular neovascularization that affect the retina, retinal neovascularization (NV) and subretinal or choroidal NV. Retinal NV occurs in a group of diseases referred to as ischemic retinopathies in which damage to retinal vessels results in retinal ischemia. Most prevalent of these are diabetic retinopathy and retinal vein occlusions. Subretinal and choroidal NV occur in diseases of the outer retina and Bruch’s membrane, the most prevalent of which is age-related macular degeneration. Numerous studies in mouse models have helped to elucidate the molecular pathogenesis underlying retinal, subretinal, and choroidal NV. There is considerable overlap because the precipitating event in each is stabilization of hypoxia inducible factor-1 (HIF-1) which leads to upregulation of several hypoxia-regulated gene products, including vascular endothelial growth factor (VEGF), angiopoietin 2, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and several others. Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal, subretinal, and choroidal NV, with perturbation of Bruch’s membrane also needed for the latter. Additional HIF-1-regulated gene products cause further stimulation of the NV. It is difficult to model macular edema in animals and therefore proof-of-concept clinical trials were done and demonstrated that VEGF plays a central role and that suppression of Tie2 is also important. Neutralization of VEGF is currently the first line therapy for all of the above disease processes, but new treatments directed at some of the other molecular targets, particularly stabilization of Tie2, are likely to provide additional benefit for subretinal/choroidal NV and macular edema. In addition, the chronicity of these diseases as well as the implication of VEGF as a cause of retinal nonperfusion and progression of background diabetic retinopathy make sustained delivery approaches for

  10. Photovoltaic Retinal Prosthesis for Restoring Sight to Patients Blinded by Retinal Injury or Degeneration

    Science.gov (United States)

    2016-02-01

    measuring electrical waveforms produced by the implant using corneal electrodes. The same animals with the subretinal implants will be used here, as the...guidelines and the Statement for the Use of Animals in Ophthalmic and Vision Research. After a period of time (from 4 months to 1 year), implants were...densities on return electrodes equalize within 2 ms ( exponential time constant = 0.8 ms), and remain constant for the rest of the pulse. If the

  11. A novel form of progressive retinal atrophy in Swedish vallhund dogs.

    Directory of Open Access Journals (Sweden)

    Ann E Cooper

    Full Text Available Inherited retinal degenerations, such as retinitis pigmentosa (RP and age-related macular degeneration (AMD, represent leading causes of incurable blindness in humans. This is also true in dogs, where the term progressive retinal atrophy (PRA is used to describe inherited photoreceptor degeneration resulting in progressive vision loss. Because of the similarities in ocular anatomy, including the presence of a cone photoreceptor-rich central retinal region, and the close genotype-phenotype correlation, canine models contribute significantly to the understanding of retinal disease mechanisms and the development of new therapies. The screening of the pure-bred dog population for new forms of PRA represents an important strategy to establish new large animal models. By examining 324 dogs of the Swedish vallhund breed in seven countries and across three continents, we were able to describe a new and unique form of PRA characterized by the multifocal appearance of red and brown discoloration of the tapetal fundus followed over time by thinning of the retina. We propose three stages of the disease based on the appearance of the ocular fundus and associated visual deficits. Electroretinography revealed a gradual loss of both rod and cone photoreceptor-mediated function in Stages 2 and 3 of the disease. In the few dogs that suffered from pronounced vision loss, night-blindness occurred first in late Stage 2, followed by decreased day-vision in Stage 3. Histologic examinations confirmed the loss of photoreceptor cells at Stage 3, which was associated with the accumulation of autofluorescent material in the adjacent retinal pigment epithelium. Pedigree analysis was suggestive of an autosomal-recessive mode of inheritance. Mutations in six known canine retinal degeneration genes as well as hypovitaminosis E were excluded as causes of the disease. The observed variability in the age of disease onset and rate of progression suggest the presence of genetic and

  12. AAV delivery of wild-type rhodopsin preserves retinal function in a mouse model of autosomal dominant retinitis pigmentosa.

    Science.gov (United States)

    Mao, Haoyu; James, Thomas; Schwein, Alison; Shabashvili, Arseniy E; Hauswirth, William W; Gorbatyuk, Marina S; Lewin, Alfred S

    2011-05-01

    Autosomal dominant retinitis pigmentosa (ADRP) is frequently caused by mutations in RHO, the gene for rod photoreceptor opsin. Earlier, a study on mice carrying mutated rhodopsin transgenes on either RHO + / +  or RHO + /- backgrounds suggested that the amount of wild-type rhodopsin affected survival of photoreceptors. Therefore, we treated P23H RHO transgenic mice with adeno-associated virus serotype 5 (AAV5) expressing a cDNA clone of the rhodopsin gene (RHO301) that expressed normal opsin from the mouse opsin promoter. Analysis of the electroretinogram (ERG) demonstrated that increased expression of RHO301 slowed the rate of retinal degeneration in P23H mice: at 6 months, a-wave amplitudes were increased by 100% and b-wave amplitudes by 79%. In contrast, nontransgenic mice injected with AAV5 RHO301 demonstrated a decrease in the ERG, confirming the damaging effect of rhodopsin overproduction in normal photoreceptors. In P23H mice, the increase in the ERG amplitudes was correlated with improvement of retinal structure: the thickness of the outer nuclear layer in RHO301-treated eyes was increased by 80% compared with control eyes. These findings suggest that the wild-type RHO gene can be delivered to rescue retinal degeneration in mice carrying a RHO mutation and that increased production of normal rhodopsin can suppress the effect of the mutated protein. These findings make it possible to treat ADRP caused by different mutations of RHO with the expression of wild-type RHO.

  13. Laenderyggens degeneration og radiologi

    DEFF Research Database (Denmark)

    Jacobsen, Steffen; Gosvig, Kasper Kjaerulf; Sonne-Holm, Stig

    2006-01-01

    Low back pain (LBP) is one of the most common conditions, and at the same time one of the most complex nosological entities. The lifetime prevalence is approximately 80%, and radiological features of lumbar degeneration are almost universal in adults. The individual risk factors for LBP and signi......Low back pain (LBP) is one of the most common conditions, and at the same time one of the most complex nosological entities. The lifetime prevalence is approximately 80%, and radiological features of lumbar degeneration are almost universal in adults. The individual risk factors for LBP...... and significant relationships between radiological findings and subjective symptoms have both been notoriously difficult to identify. The lack of consensus on clinical criteria and radiological definitions has hampered the undertaking of properly executed epidemiological studies. The natural history of LBP...

  14. Quantum degenerate systems

    Energy Technology Data Exchange (ETDEWEB)

    Micheli, Fiorenza de [Centro de Estudios Cientificos, Arturo Prat 514, Valdivia (Chile); Instituto de Fisica, Pontificia Universidad Catolica de Valparaiso, Casilla 4059, Valparaiso (Chile); Zanelli, Jorge [Centro de Estudios Cientificos, Arturo Prat 514, Valdivia (Chile); Universidad Andres Bello, Av. Republica 440, Santiago (Chile)

    2012-10-15

    A degenerate dynamical system is characterized by a symplectic structure whose rank is not constant throughout phase space. Its phase space is divided into causally disconnected, nonoverlapping regions in each of which the rank of the symplectic matrix is constant, and there are no classical orbits connecting two different regions. Here the question of whether this classical disconnectedness survives quantization is addressed. Our conclusion is that in irreducible degenerate systems-in which the degeneracy cannot be eliminated by redefining variables in the action-the disconnectedness is maintained in the quantum theory: there is no quantum tunnelling across degeneracy surfaces. This shows that the degeneracy surfaces are boundaries separating distinct physical systems, not only classically, but in the quantum realm as well. The relevance of this feature for gravitation and Chern-Simons theories in higher dimensions cannot be overstated.

  15. Cataracts and macular degeneration.

    Science.gov (United States)

    Shoch, D

    1979-09-01

    The intraocular lens restores general vision and some degree of independence and mobility to patients with dense cataracts and macular degeneration. The patient, however, must be repeatedly warned that fine central vision, particularly reading, will not be possible after the surgery. An aphakic spectacle leaves such patients a narrow band of vision when superimposed over the macular lesion, and contact lenses are too small for the patient to manage insertion without help.

  16. Interconnection between brain and retinal neurodegenerations.

    Science.gov (United States)

    Jindal, Vishal

    2015-01-01

    The eye is a special sensory organ, which is basically an extension of the brain. Both are derived from neural tube and consist of neurons. Therefore, diseases of both the brain and eye should have some similarity. Neurodegenerative disorders like Alzheimer's disease (AD) is the major cause of dementia in the world. Amyloid deposition in the cerebral cortex and hippocampal region is the basic pathology in AD. But along with it, there are various changes that take place in the eye, i.e., abnormal pupillary reaction, decreased vision, decreased contrast sensitivity, visual field changes, loss of retinal ganglionic cells and retinal fiber layer, peripapillary atrophy, increased cup-disk ratio, retinal thinning, tortuosity of blood vessels, and deposition of Aβ-like substance in the retina. And these changes are present in the early part of the disease when only mild cognitive impairment is there. As the brain is covered by a hard bony skull which makes it difficult to directly visualize the changes occurring in the brain at molecular levels, finer details of disease progression are not available with us. But the eye is the window of the brain; with advanced modern techniques, we can directly visualize the changes in the retina at a very fine level. Therefore, by depicting neurodegenerative changes in the eye, we can diagnose and manage AD at very early stages. Along with it, retinal neurodegenerations like glaucoma and age-related macular degeneration (ARMD) are the major cause of loss of vision, and still, there are no effective treatment modalities for these blinding conditions. So if we can understand its pathogenesis and progression by correlating with brain neurodegenerations, we can come up with a better therapy for glaucoma and ARMD.

  17. Arap1 Deficiency Causes Photoreceptor Degeneration in Mice

    Science.gov (United States)

    Moshiri, Ala; Humpal, Devin; Leonard, Brian C.; Imai, Denise M.; Tham, Addy; Bower, Lynette; Clary, Dave; Glaser, Thomas M.; Lloyd, K. C. Kent; Murphy, Christopher J.

    2017-01-01

    Purpose Small guanosine triphosphatase (GTPase) ADP-ribosylation factors (Arfs) regulate membrane traffic and actin reorganization under the control of GTPase-activating proteins (GAPs). Arap1 is an Arf-directed GAP that inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome, but the diversity of its functions is incompletely understood. The aim of this study was to determine the role of Arap1 in the mammalian retina. Methods Genetically engineered Arap1 knockout mice were screened for ocular abnormalities in the National Institutes of Health Knockout Mouse Production and Phenotyping (KOMP2) Project. Arap1 knockout and wild-type eyes were imaged using optical coherence tomography and fundus photography, and analyzed by immunohistochemistry. Results Arap1−/− mice develop a normal appearing retina, but undergo photoreceptor degeneration starting at 4 weeks postnatal age. The fundus appearance of mutants is notable for pigmentary changes, optic nerve pallor, vascular attenuation, and outer retinal thinning, reminiscent of retinitis pigmentosa in humans. Immunohistochemical studies suggest the cell death is predominantly in the outer nuclear layer. Functional evaluation of the retina by electroretinography reveals amplitudes are reduced. Arap1 is detected most notably in Müller glia, and not in photoreceptors, implicating a role for Müller glia in photoreceptor survival. Conclusions Arap1 is necessary for normal photoreceptor survival in mice, and may be a novel gene relevant to human retinal degenerative processes, although its mechanism is unknown. Further studies in this mouse model of retinal degeneration will give insights into the cellular functions and signaling pathways in which Arap1 participates. PMID:28324111

  18. Imaging geographic atrophy in age-related macular degeneration.

    Science.gov (United States)

    Göbel, Arno P; Fleckenstein, Monika; Schmitz-Valckenberg, Steffen; Brinkmann, Christian K; Holz, Frank G

    2011-01-01

    Advances in retinal imaging technology have largely contributed to the understanding of the natural history, prognostic markers and disease mechanisms of geographic atrophy (GA) due to age-related macular degeneration. There is still no therapy available to halt or slow the disease process. In order to evaluate potential therapeutic effects in interventional trials, there is a need for precise quantification of the GA progression rate. Fundus autofluorescence imaging allows for accurate identification and segmentation of atrophic areas and currently represents the gold standard for evaluating progressive GA enlargement. By means of high-resolution spectral-domain optical coherence tomography, distinct microstructural alterations related to GA can be visualized.

  19. Geometric phases for non-degenerate and degenerate mixed states

    CERN Document Server

    Singh, K; Basu, K; Chen, J L; Du Jiang Feng

    2003-01-01

    This paper focuses on the geometric phase of general mixed states under unitary evolution. Here we analyze both non-degenerate as well as degenerate states. Starting with the non-degenerate case, we show that the usual procedure of subtracting the dynamical phase from the total phase to yield the geometric phase for pure states, does not hold for mixed states. To this end, we furnish an expression for the geometric phase that is gauge invariant. The parallelity conditions are shown to be easily derivable from this expression. We also extend our formalism to states that exhibit degeneracies. Here with the holonomy taking on a non-abelian character, we provide an expression for the geometric phase that is manifestly gauge invariant. As in the case of the non-degenerate case, the form also displays the parallelity conditions clearly. Finally, we furnish explicit examples of the geometric phases for both the non-degenerate as well as degenerate mixed states.

  20. A CMOS active pixel sensor for retinal stimulation

    Science.gov (United States)

    Prydderch, Mark L.; French, Marcus J.; Mathieson, Keith; Adams, Christopher; Gunning, Deborah; Laudanski, Jonathan; Morrison, James D.; Moodie, Alan R.; Sinclair, James

    2006-02-01

    Degenerative photoreceptor diseases, such as age-related macular degeneration and retinitis pigmentosa, are the most common causes of blindness in the western world. A potential cure is to use a microelectronic retinal prosthesis to provide electrical stimulation to the remaining healthy retinal cells. We describe a prototype CMOS Active Pixel Sensor capable of detecting a visual scene and translating it into a train of electrical pulses for stimulation of the retina. The sensor consists of a 10 x 10 array of 100 micron square pixels fabricated on a 0.35 micron CMOS process. Light incident upon each pixel is converted into output current pulse trains with a frequency related to the light intensity. These outputs are connected to a biocompatible microelectrode array for contact to the retinal cells. The flexible design allows experimentation with signal amplitudes and frequencies in order to determine the most appropriate stimulus for the retina. Neural processing in the retina can be studied by using the sensor in conjunction with a Field Programmable Gate Array (FPGA) programmed to behave as a neural network. The sensor has been integrated into a test system designed for studying retinal response. We present the most recent results obtained from this sensor.

  1. Biophysical mechanism of transient retinal phototropism in rod photoreceptors

    Science.gov (United States)

    Zhao, Xiaohui; Thapa, Damber; Wang, Benquan; Gai, Shaoyan; Yao, Xincheng

    2016-03-01

    Oblique light stimulation evoked transient retinal phototropism (TRP) has been recently detected in frog and mouse retinas. High resolution microscopy of freshly isolated retinas indicated that the TRP is predominated by rod photoreceptors. Comparative confocal microscopy and optical coherence tomography (OCT) revealed that the TRP predominantly occurred from the photoreceptor outer segment (OS). However, biophysical mechanism of rod OS change is still unknown. In this study, frog retinal slices, which open a cross section of retinal photoreceptor and other functional layers, were used to test the effect of light stimulation on rod OS. Near infrared light microscopy was employed to monitor photoreceptor changes in retinal slices stimulated by a rectangular-shaped visible light flash. Rapid rod OS length change was observed after the stimulation delivery. The magnitude and direction of the rod OS change varied with the position of the rods within the stimulated area. In the center of stimulated region the length of the rod OS shrunk, while in the peripheral region the rod OS tip swung towards center region in the plane perpendicular to the incident stimulus light. Our experimental result and theoretical analysis suggest that the observed TRP may reflect unbalanced disc-shape change due to localized pigment bleaching. Further investigation is required to understand biochemical mechanism of the observed rod OS kinetics. Better study of the TRP may provide a noninvasive biomarker to enable early detection of age-related macular degeneration (AMD) and other diseases that are known to produce retinal photoreceptor dysfunctions.

  2. New approaches and potential treatments for dry age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Francisco Max Damico

    2012-02-01

    Full Text Available Emerging treatments for dry age-related macular degeneration (AMD and geographi c atrophy focus on two strategies that target components involved in physiopathological pathways: prevention of photoreceptors and retinal pigment epithelium loss (neuroprotection induction, oxidative damage prevention, and visual cycle modification and suppression of inflammation. Neuroprotective drugs, such as ciliary neurotrophic factor, brimonidine tartrate, tandospirone, and anti-amyloid β antibodies, aim to prevent apoptosis of retinal cells. Oxidative stress and depletion of essential micronutrients are targeted by the Age-Related Eye Disease Study (AREDS formulation. Visual cycle modulators reduce the activity of the photoreceptors and retinal accumulation of toxic fluorophores and lipofuscin. Eyes with dry age-related macular degeneration present chronic inflammation and potential treatments include corticosteroid and complement inhibition. We review the current concepts and rationale of dry age-related macular degeneration treatment that will most likely include a combination of drugs targeting different pathways involved in the development and progression of age-related macular degeneration.

  3. Modifier genes as therapeutics: the nuclear hormone receptor Rev Erb alpha (Nr1d1 rescues Nr2e3 associated retinal disease.

    Directory of Open Access Journals (Sweden)

    Nelly M Cruz

    Full Text Available Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.

  4. Post-cataract surgery visual disturbance in a retinitis pigmentosa patient with asteroid hyalosis.

    Science.gov (United States)

    Jingami, Yoko; Otani, Atsushi; Kojima, Hiroshi; Makiyama, Yukiko; Yoshimura, Nagahisa

    2011-05-01

    A patient with retinitis pigmentosa showed visual disturbances following successful cataract surgery. He had a dense asteroid hyalosis in the eye before cataract surgery. After the surgery he noticed that his vision became worse. The visual disturbance was explained as being caused by the progression of retinal degeneration. Although the electroretinogram was non-recordable, the degeneration of macular area appeared relatively small. We considered that dense asteroid hyalosis was responsible for his visual disturbances, and pars plana vitrectomy (PPV) was performed to remove the asteroid hyalosis. After the PPV, rapid improvement of his visual acuity was observed. Cataract surgery may affect the status of asteroid hyalosis and cause rapid visual loss. PPV should be considered for retinitis pigmentosa patients with dense asteroid hyalosis, especially when a large decrease in visual acuity is noted shortly after cataract surgery.

  5. Post-Cataract Surgery Visual Disturbance in a Retinitis Pigmentosa Patient with Asteroid Hyalosis

    Directory of Open Access Journals (Sweden)

    Yoko Jingami

    2011-08-01

    Full Text Available A patient with retinitis pigmentosa showed visual disturbances following successful cataract surgery. He had a dense asteroid hyalosis in the eye before cataract surgery. After the surgery he noticed that his vision became worse. The visual disturbance was explained as being caused by the progression of retinal degeneration. Although the electroretinogram was non-recordable, the degeneration of macular area appeared relatively small. We considered that dense asteroid hyalosis was responsible for his visual disturbances, and pars plana vitrectomy (PPV was performed to remove the asteroid hyalosis. After the PPV, rapid improvement of his visual acuity was observed. Cataract surgery may affect the status of asteroid hyalosis and cause rapid visual loss. PPV should be considered for retinitis pigmentosa patients with dense asteroid hyalosis, especially when a large decrease in visual acuity is noted shortly after cataract surgery.

  6. Up-regulation of tumor necrosis factor superfamily genes in early phases of photoreceptor degeneration.

    Directory of Open Access Journals (Sweden)

    Sem Genini

    Full Text Available We used quantitative real-time PCR to examine the expression of 112 genes related to retinal function and/or belonging to known pro-apoptotic, cell survival, and autophagy pathways during photoreceptor degeneration in three early-onset canine models of human photoreceptor degeneration, rod cone dysplasia 1 (rcd1, X-linked progressive retinal atrophy 2 (xlpra2, and early retinal degeneration (erd, caused respectively, by mutations in PDE6B, RPGRORF15, and STK38L. Notably, we found that expression and timing of differentially expressed (DE genes correlated with the cell death kinetics. Gene expression profiles of rcd1 and xlpra2 were similar; however rcd1 was more severe as demonstrated by the results of the TUNEL and ONL thickness analyses, a greater number of genes that were DE, and the identification of altered expression that occurred at earlier time points. Both diseases differed from erd, where a smaller number of genes were DE. Our studies did not highlight the potential involvement of mitochondrial or autophagy pathways, but all three diseases were accompanied by the down-regulation of photoreceptor genes, and up-regulation of several genes that belong to the TNF superfamily, the extrinsic apoptotic pathway, and pro-survival pathways. These proteins were expressed by different retinal cells, including horizontal, amacrine, ON bipolar, and Müller cells, and suggest an interplay between the dying photoreceptors and inner retinal cells. Western blot and immunohistochemistry results supported the transcriptional regulation for selected proteins. This study highlights a potential role for signaling through the extrinsic apoptotic pathway in early cell death events and suggests that retinal cells other than photoreceptors might play a primary or bystander role in the degenerative process.

  7. Progressive outer retinal necrosis-like retinitis in immunocompetent hosts.

    Science.gov (United States)

    Chawla, Rohan; Tripathy, Koushik; Gogia, Varun; Venkatesh, Pradeep

    2016-08-10

    We describe two young immunocompetent women presenting with bilateral retinitis with outer retinal necrosis involving posterior pole with centrifugal spread and multifocal lesions simulating progressive outer retinal necrosis (PORN) like retinitis. Serology was negative for HIV and CD4 counts were normal; however, both women were on oral steroids at presentation for suspected autoimmune chorioretinitis. The retinitis in both eyes responded well to oral valaciclovir therapy. However, the eye with the more fulminant involvement developed retinal detachment with a loss of vision. Retinal atrophy was seen in the less involved eye with preservation of vision. Through these cases, we aim to describe a unique evolution of PORN-like retinitis in immunocompetent women, which was probably aggravated by a short-term immunosuppression secondary to oral steroids.

  8. KR-31378, a potassium-channel opener, induces the protection of retinal ganglion cells in rat retinal ischemic models.

    Science.gov (United States)

    Choi, Anho; Choi, Jun-Sub; Yoon, Yone-Jung; Kim, Kyung-A; Joo, Choun-Ki

    2009-04-01

    KR-31378 is a newly developed K(ATP)-channel opener. To investigate the ability of KR-31378 to protect retinal ganglion cells (RGC), experiments were conducted using two retinal ischemia models. Retinal ischemia was induced by transient high intraocular pressure (IOP) for acute ischemia and by three episcleral vein occlusion for chronic retinal ischemia. KR-31378 was injected intraperitoneally and administered orally in the acute and chronic ischemia models, respectively. Under the condition of chronic ischemia, RGC density in the KR-31378-treated group was statistically higher than that in the non-treated group, and IOP was reduced. In the acute retinal ischemia model, 90% of RGC were degenerated after one week in non-treated retina, but, RGC in KR-31378-treated retina were protected from ischemic damage in a dose-dependent manner and showed inhibited glial fibrillary acidic protein (GFAP) expression. Furthermore, the KR-31378 protective effect was inhibited by glibenclamide treatment in acute ischemia. These findings indicate that systemic KR-31378 treatment may protect against ischemic injury-induced ganglion cell loss in glaucoma.

  9. Neuropilin 1 Involvement in Choroidal and Retinal Neovascularisation

    Science.gov (United States)

    Fernández-Robredo, Patricia; Sim, Dawn A.; Fruttiger, Marcus

    2017-01-01

    Purpose Inhibiting VEGF is the gold standard treatment for neovascular age-related macular degeneration (AMD). It is also effective in preventing retinal oedema and neovascularisation (NV) in diabetic retinopathy (DR) and retinal vein occlusions (RVO). Neuropilin 1 (Nrp1) is a co-receptor for VEGF and many other growth factors, and therefore a possible alternative drug target in intra ocular neovascular disease. Here we assessed choroidal and retinal NV in an inducible, endothelial specific knock out model for Nrp1. Methods Crossing Nrp1 floxed mice with Pdgfb-CreERT2 mice produced tamoxifen-inducible, endothelial specific Nrp1 knock out mice (Nrp1ΔEC) and Cre-negative, control littermates. Cre-recombinase activity was confirmed in the Ai3(RCL-EYFP) reporter strain. Animals were subjected to laser-induced CNV (532 nm) and spectral domain-optical coherence tomography (SD-OCT) was performed immediately after laser and at day 7. Fluorescein angiography (FA) evaluated leakage and postmortem lectin staining in flat mounted RPE/choroid complexes was also used to measure CNV. Furthermore, retinal neovascularisation in the oxygen induced retinopathy (OIR) model was assessed by immunohistochemistry in retinal flatmounts. Results In vivo FA, OCT and post-mortem lectin staining showed a statistically significant reduction in leakage (p<0.05), CNV volume (p<0.05) and CNV area (p<0.05) in the Nrp1ΔEC mice compared to their Cre-negative littermates. Also the OIR model showed reduced retinal NV in the mutant animals compared to wild types (p<0.001). Conclusion We have demonstrated reduced choroidal and retinal NV in animals that lack endothelial Nrp1, confirming a role of Nrp1 in those processes. Therefore, Nrp1 may be a promising drug target for neovascular diseases in the eye. PMID:28107458

  10. Noninvasive, in vivo assessment of mouse retinal structure using optical coherence tomography.

    Directory of Open Access Journals (Sweden)

    M Dominik Fischer

    Full Text Available BACKGROUND: Optical coherence tomography (OCT is a novel method of retinal in vivo imaging. In this study, we assessed the potential of OCT to yield histology-analogue sections in mouse models of retinal degeneration. METHODOLOGY/PRINCIPAL FINDINGS: We achieved to adapt a commercial 3(rd generation OCT system to obtain and quantify high-resolution morphological sections of the mouse retina which so far required in vitro histology. OCT and histology were compared in models with developmental defects, light damage, and inherited retinal degenerations. In conditional knockout mice deficient in retinal retinoblastoma protein Rb, the gradient of Cre expression from center to periphery, leading to a gradual reduction of retinal thickness, was clearly visible and well topographically quantifiable. In Nrl knockout mice, the layer involvement in the formation of rosette-like structures was similarly clear as in histology. OCT examination of focal light damage, well demarcated by the autofluorescence pattern, revealed a practically complete loss of photoreceptors with preservation of inner retinal layers, but also more subtle changes like edema formation. In Crb1 knockout mice (a model for Leber's congenital amaurosis, retinal vessels slipping through the outer nuclear layer towards the retinal pigment epithelium (RPE due to the lack of adhesion in the subapical region of the photoreceptor inner segments could be well identified. CONCLUSIONS/SIGNIFICANCE: We found that with the OCT we were able to detect and analyze a wide range of mouse retinal pathology, and the results compared well to histological sections. In addition, the technique allows to follow individual animals over time, thereby reducing the numbers of study animals needed, and to assess dynamic processes like edema formation. The results clearly indicate that OCT has the potential to revolutionize the future design of respective short- and long-term studies, as well as the preclinical

  11. Automated retinal fovea type distinction in spectral-domain optical coherence tomography of retinal vein occlusion

    Science.gov (United States)

    Wu, Jing; Waldstein, Sebastian M.; Gerendas, Bianca S.; Langs, Georg; Simader, Christian; Schmidt-Erfurth, Ursula

    2015-03-01

    Spectral-domain Optical Coherence Tomography (SD-OCT) is a non-invasive modality for acquiring high- resolution, three-dimensional (3D) cross-sectional volumetric images of the retina and the subretinal layers. SD-OCT also allows the detailed imaging of retinal pathology, aiding clinicians in the diagnosis of sight degrading diseases such as age-related macular degeneration (AMD), glaucoma and retinal vein occlusion (RVO). Disease diagnosis, assessment, and treatment will require a patient to undergo multiple OCT scans, possibly using multiple scanners, to accurately and precisely gauge disease activity, progression and treatment success. However, cross-vendor imaging and patient movement may result in poor scan spatial correlation potentially leading to incorrect diagnosis or treatment analysis. The retinal fovea is the location of the highest visual acuity and is present in all patients, thus it is critical to vision and highly suitable for use as a primary landmark for cross-vendor/cross-patient registration for precise comparison of disease states. However, the location of the fovea in diseased eyes is extremely challenging to locate due to varying appearance and the presence of retinal layer destroying pathology. Thus categorising and detecting the fovea type is an important prior stage to automatically computing the fovea position. Presented here is an automated cross-vendor method for fovea distinction in 3D SD-OCT scans of patients suffering from RVO, categorising scans into three distinct types. OCT scans are preprocessed by motion correction and noise filing followed by segmentation using a kernel graph-cut approach. A statistically derived mask is applied to the resulting scan creating an ROI around the probable fovea location from which the uppermost retinal surface is delineated. For a normal appearance retina, minimisation to zero thickness is computed using the top two retinal surfaces. 3D local minima detection and layer thickness analysis are used

  12. Detection of Hydroxychloroquine Retinal Toxicity by Automated Perimetry in 60 Rheumatoid Arthritis Patients With Normal Fundoscopic Findings

    OpenAIRE

    Motarjemizadeh, Qader; Aidenloo, Naser Samadi; Abbaszadeh, Mohammad

    2015-01-01

    Hydroxychloroquine (HCQ) is an antimalarial drug used extensively in treatment of autoimmune diseases such as rheumatoid arthritis. Retinal toxicity is the most important side effects of this drug. Even after the drug is discontinued, retinal degeneration from HCQ can continue to progress. Consequently, multiple ophthalmic screening tests have been developed to detect early retinopathy. The aim of the current study was to evaluate the value of central 2-10 perimetry method in early detection ...

  13. Functional and Molecular Characterization of Rod-like Cells from Retinal Stem Cells Derived from the Adult Ciliary Epithelium

    OpenAIRE

    Gian Carlo Demontis; Claudia Aruta; Antonella Comitato; Anna De Marzo; Valeria Marigo

    2012-01-01

    In vitro generation of photoreceptors from stem cells is of great interest for the development of regenerative medicine approaches for patients affected by retinal degeneration and for high throughput drug screens for these diseases. In this study, we show unprecedented high percentages of rod-fated cells from retinal stem cells of the adult ciliary epithelium. Molecular characterization of rod-like cells demonstrates that they lose ciliary epithelial characteristics but acquire photoreceptor...

  14. Imaging polarimetry in patients with neovascular age-related macular degeneration

    Science.gov (United States)

    Elsner, Ann E.; Weber, Anke; Cheney, Michael C.; VanNasdale, Dean A.; Miura, Masahiro

    2007-01-01

    Imaging polarimetry was used to examine different components of neovascular membranes in age-related macular degeneration. Retinal images were acquired with a scanning laser polarimeter. An innovative pseudo-color scale, based on cardinal directions of color, displayed two types of image information: relative phases and magnitudes of birefringence. Membranes had relative phase changes that did not correspond to anatomical structures in reflectance images. Further, membrane borders in depolarized light images had significantly higher contrasts than those in reflectance images. The retinal birefringence in neovascular membranes indicates optical activity consistent with molecular changes rather than merely geometrical changes. PMID:17429494

  15. Transplanting Retinal Cells using Bucky Paper for Support

    Science.gov (United States)

    Loftus, David J.; Cinke, Martin; Meyyappan, Meyya; Fishman, Harvey; Leng, Ted; Huie, Philip; Bilbao, Kalayaan

    2004-01-01

    A novel treatment for retinal degenerative disorders involving transplantation of cells into the eye is currently under development at NASA Ames Research Center and Stanford University School of Medicine. The technique uses bucky paper as a support material for retinal pigment epithelial (RPE) cells, iris pigment epithelial (IPE) cells, and/or stem cells. This technology is envisioned as a treatment for age-related macular degeneration, which is the leading cause of blindness in persons over age 65 in Western nations. Additionally, patients with other retinal degenerative disorders, such as retinitis pigmentosa, may be treated by this strategy. Bucky paper is a mesh of carbon nanotubes (CNTs), as shown in Figure 1, that can be made from any of the commercial sources of CNTs. Bucky paper is biocompatible and capable of supporting the growth of biological cells. Because bucky paper is highly porous, nutrients, oxygen, carbon dioxide, and waste can readily diffuse through it. The thickness, density, and porosity of bucky paper can be tailored in manufacturing. For transplantation of cells into the retina, bucky paper serves simultaneously as a substrate for cell growth and as a barrier for new blood vessel formation, which can be a problem in the exudative type of macular degeneration. Bucky paper is easily handled during surgical implantation into the eye. Through appropriate choice of manufacturing processes, bucky paper can be made relatively rigid yet able to conform to the retina when the bucky paper is implanted. Bucky paper offers a distinct advantage over other materials that have been investigated for retinal cell transplantation - lens capsule and Descemet's membrane - which are difficult to handle during surgery because they are flimsy and do not stay flat.

  16. Image Compression and Resizing for Retinal Implant in Bionic Eye

    Directory of Open Access Journals (Sweden)

    N.Sharmili

    2011-06-01

    Full Text Available One field where computer-related Image processing technology shows great promise for the future isbionic implants such as Cochlear implants, Retinal implants etc.. Retinal implants are being developedaround the world in hopes of restoring useful vision for patients suffering from certain types of diseaseslike Age-related Macular Degeneration (AMD and Retinitis Pigmentosa (RP. In these diseases thephotoreceptor cells slowly degenerated, leading to blindness. However, many of the inner retinalneurons that transmit signals from the photoreceptors to the brain are preserved to a large extent for aprolonged period of time. The Retinal Prosthesis aims to provide partial vision by electricallyactivating the remaining cells of the retina. The Epi retinal prosthesis system is composed of twounits, extra ocular unit and intraocular implant. The two units are connected by a telemetric inductivelink. The Extraocular unit consists of a CCD camera, an image processor, an encoder, and a transmitterbuilt on the eyeglass. High-resolution image from a CCD camera is reduced to lower resolutionmatching the array of electrodes by image processor, which is then encoded into bit stream. Eachelectrode in an implant corresponds to one pixel in an image. The bit stream is modulated on a 22 MHzcarrier and then transmitted wirelessly to the inside implant. This paper mainly discusses twoapproaches in image processing which reduces the size of the image without loss of the object detectionrate to that of the original image. One is about the related image processing algorithms include imageresizing, color erasing, edge enhancement and edge detection. Second one is to generate the saliencymap for an image.

  17. Muller cell reactivity in response to photoreceptor degeneration in rats with defective polycystin-2.

    Directory of Open Access Journals (Sweden)

    Stefanie Vogler

    Full Text Available BACKGROUND: Retinal degeneration in transgenic rats that express a mutant cilia gene polycystin-2 (CMV-PKD2(1/703HA is characterized by initial photoreceptor degeneration and glial activation, followed by vasoregression and neuronal degeneration (Feng et al., 2009, PLoS One 4: e7328. It is unknown whether glial activation contributes to neurovascular degeneration after photoreceptor degeneration. We characterized the reactivity of Müller glial cells in retinas of rats that express defective polycystin-2. METHODS: Age-matched Sprague-Dawley rats served as control. Retinal slices were immunostained for intermediate filaments, the potassium channel Kir4.1, and aquaporins 1 and 4. The potassium conductance of isolated Müller cells was recorded by whole-cell patch clamping. The osmotic swelling characteristics of Müller cells were determined by superfusion of retinal slices with a hypoosmotic solution. FINDINGS: Müller cells in retinas of transgenic rats displayed upregulation of GFAP and nestin which was not observed in control cells. Whereas aquaporin-1 labeling of photoreceptor cells disappeared along with the degeneration of the cells, aquaporin-1 emerged in glial cells in the inner retina of transgenic rats. Aquaporin-4 was upregulated around degenerating photoreceptor cells. There was an age-dependent redistribution of Kir4.1 in retinas of transgenic rats, with a more even distribution along glial membranes and a downregulation of perivascular Kir4.1. Müller cells of transgenic rats displayed a slight decrease in their Kir conductance as compared to control. Müller cells in retinal tissues from transgenic rats swelled immediately under hypoosmotic stress; this was not observed in control cells. Osmotic swelling was induced by oxidative-nitrosative stress, mitochondrial dysfunction, and inflammatory lipid mediators. INTERPRETATION: Cellular swelling suggests that the rapid water transport through Müller cells in response to osmotic stress

  18. EYS Mutations Causing Autosomal Recessive Retinitis Pigmentosa: Changes of Retinal Structure and Function with Disease Progression

    Directory of Open Access Journals (Sweden)

    David B. McGuigan

    2017-07-01

    Full Text Available Mutations in the EYS (eyes shut homolog gene are a common cause of autosomal recessive (ar retinitis pigmentosa (RP. Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal degeneration. We studied clinically and with chromatic static perimetry, spectral-domain optical coherence tomography (OCT, and en face autofluoresence imaging, a cohort of 15 patients (ages 12–51 at first visit, some of whom had longitudinal data of function and structure. Rod sensitivity was able to be measured by chromatic perimetry in most patients at their earliest visits and some patients retained patchy rod function into the fifth decade of life. As expected from RP, cone sensitivity persisted after rod function was no longer measurable. The photoreceptor nuclear layer of the central retina was abnormal except at the fovea in most patients at first visit. Perifoveal disease measured over a period of years indicated that photoreceptor structural loss was followed by dysmorphology of the inner retina and loss of retinal pigment epithelial integrity. Although there could be variability in severity, preliminary analyses of the rates of vision loss suggested that EYS is a more rapidly progressive disease than other ciliopathies causing arRP, such as USH2A and MAK.

  19. [Retinal regeneration with iPS cells ‒ Clinical trials for retinal degenerative disorders].

    Science.gov (United States)

    Sugita, Sunao

    2015-01-01

    Potential for re-programming cells has become widely accepted as a tool for obtaining transplantation materials. There has been great interest in cell-based therapies, including retinal transplants, because there is a reduced risk of immune rejection. Stem cells have the capacity for self-renewal plus the capacity to generate several differentiated cells. They are derived from many sources including human adult-derived induced pluripotent stem (iPS) cells and have found early application in the context of ocular disease. In results, our established iPS-retinal pigment epithelial (RPE) cells are high-quality RPE cells. iPS cells-derived RPE cells clearly showed polygonal morphology (mostly hexagonal) and contained melanin. Moreover, RPE cells derived from iPS cells had many characteristics of mature RPE cells in vivo, but no characteristics of pluripotent stem cells. Recently, we transplanted RPE cell sheets to treat a patient with wet age-related macular degeneration (September, 2014). In addition, we are now conducting experiments to determine whether allogeneic T cells can recognize iPS-RPE cells from HLA-A, B, DRB1 locus homozygote donors. iPS bank might be useful as allografts in retinal disorders, if the recipient T cells cannot respond to allogeneic RPE cells because of match to some of main HLA antigens.

  20. Retinal Detachment in Preeclampsia

    Directory of Open Access Journals (Sweden)

    Prado Renata Silva do

    2002-01-01

    Full Text Available Preeclampsia is an obstetric disease of unknown cause that affects approximately 5% of pregnant women. The visual system may be affected with variable intensity, being the retinal detachment a rare complication. The retinal detachment in preeclampsia is usually bilateral and serous, and its pathogenesis is related to the choroidal ischemia secondary to an intense arteriolar vasospasm. The majority of patients have complete recovery of vision with clinical management, and surgery is unnecessary. This is a case report of a 27 year old patient who developed the severe form of preeclampsia on her first pregnancy. She had progressive blurred vision, until she could see only shadows. Ophthalmic examination diagnosed spread and bilateral retinal detachment. With blood pressure control at postpartum, the patient had her retina reattached, and recovery of vision.

  1. Probabilistic retinal vessel segmentation

    Science.gov (United States)

    Wu, Chang-Hua; Agam, Gady

    2007-03-01

    Optic fundus assessment is widely used for diagnosing vascular and non-vascular pathology. Inspection of the retinal vasculature may reveal hypertension, diabetes, arteriosclerosis, cardiovascular disease and stroke. Due to various imaging conditions retinal images may be degraded. Consequently, the enhancement of such images and vessels in them is an important task with direct clinical applications. We propose a novel technique for vessel enhancement in retinal images that is capable of enhancing vessel junctions in addition to linear vessel segments. This is an extension of vessel filters we have previously developed for vessel enhancement in thoracic CT scans. The proposed approach is based on probabilistic models which can discern vessels and junctions. Evaluation shows the proposed filter is better than several known techniques and is comparable to the state of the art when evaluated on a standard dataset. A ridge-based vessel tracking process is applied on the enhanced image to demonstrate the effectiveness of the enhancement filter.

  2. Retinal flow cytometer.

    Science.gov (United States)

    Alt, C; Veilleux, I; Lee, H; Pitsillides, C M; Côté, D; Lin, C P

    2007-12-01

    The in vivo flow cytometer is an instrument capable of continuous, real-time monitoring of fluorescently labeled cells in the circulation without the need to draw blood samples. However, the original system probes a single vessel in the mouse ear; the small sample volume limits the sensitivity of the technique. We describe an in vivo retinal flow cytometer that simultaneously probes five artery-vein pairs in the mouse eye by circularly scanning a small laser spot rapidly around the optic nerve head. We demonstrate that the retinal flow cytometer detects about five times more cells per minute than the original in vivo flow cytometer does in the ear.

  3. [Retinal pneumopexy in the treatment of rhegmatogenous retinal detachment].

    Science.gov (United States)

    Levai, L; Gavriş, Monica; Gábor, Radó; Bagosi, P

    2014-01-01

    To evaluate the efficiency of retinal pneumopexy in patients with rhegmatogenous retinal detachment. This clinical prospective study unrolled between november 2010-june 2012 in the Ophthalmology Department of the Military Hospital in Cluj-Napoca and Satu Mare Emergency Hospital included 20 patients (20 eyes) with rhegmatogenous retinal detachment. Patients were treated with retinal pneumopexy followed by laser photocoagulation. Anatomical and functional results were evaluated 1, 3, 6, 12 and 19 months after treatment. In 17 eyes out of 20, we achieved retinal reattachment and visual recovery. Three cases yelded no success, these being further treated with posterior vitrectomy. Retinal pneumopexy is a minimally invasive treatment method of rhegmatogenous retinal detachment with very good results in well selected cases.

  4. Intervertebral disc degeneration in dogs

    NARCIS (Netherlands)

    Bergknut, Niklas

    2011-01-01

    Back pain is common in both dogs and humans, and is often associated with intervertebral disc (IVD) degeneration. The IVDs are essential structures of the spine and degeneration can ultimately result in diseases such as IVD herniation or spinal instability. In order to design new treatments halting

  5. Cav1.4 L-Type Calcium Channels Contribute to Calpain Activation in Degenerating Photoreceptors of rd1 Mice.

    Directory of Open Access Journals (Sweden)

    Christian Schön

    Full Text Available Retinitis pigmentosa is an inherited blinding disorder characterized by progressive degeneration and loss of photoreceptors. The exact mechanism of degeneration and cell death of photoreceptors is not known, but is thought to involve disturbed Ca2+-signaling. Ca2+ can enter the photoreceptor cell via outer segment cyclic nucleotide-gated (CNG channels or synaptic Cav1.4 L-type voltage-gated calcium channels (VGCC. Previously, we have shown that genetic ablation of the Cngb1 gene encoding the B subunit of the rod CNG channel delays the fast progressing degeneration in the rd1 mutant mouse model of retinitis pigmentosa. In this study, we crossbred rd1 mice with the Cacna1f-deficient mouse lacking the Cav1.4 α1 subunit of the L-type VGCC. Longitudinal in vivo examinations of photoreceptor layer thickness by optical coherence tomography revealed a significant, but not sustained delay of retinal degeneration in Cacna1f x rd1 double mutant mice compared to rd1 mice. This was accompanied by a reduction of TUNEL positive cells in the early phase of rod degeneration. Remarkably, Cacna1f x rd1 double mutant mice displayed a strong decrease in the activation of the Ca2+-dependent protease calpain during photoreceptor loss. Our results show that genetic deletion of the synaptic Cav1.4 L-type VGCCs impairs calpain activation and leads to a short-term preservation of photoreceptors in the rd1 mouse.

  6. Double Degenerate Stars

    Institute of Scientific and Technical Information of China (English)

    LUO Xin-Lian; BAI Hua; ZHAO Lei

    2008-01-01

    Regardless of the formation mechanism, an exotic object, the double degenerate star (DDS), is introduced and investigated, which is composed of baryonic matter and some unknown fermion dark matter. Different from the simple white dwarfs (WDs), there is additional gravitational force provided by the unknown fermion component inside DDSs, which may strongly affect the structure and the stability of such kind of objects. Many possible and strange observational phenomena connecting with them are concisely discussed. Similar to the normal WD, this object can also experience thermonuclear explosion as type Ia supernova explosion when DDS's mass exceeds the maximum mass that can be supported by electron degeneracy pressure. However, since the total mass of baryonic matter can be much lower than that of WD at Chandrasekhar mass limit, the peak luminosity should be much dimmer than what we expect before, which may throw a slight shadow on the standard candle of SN Ia in the research of cosmology.

  7. Overexpression of Pax6 results in microphthalmia, retinal dysplasia and defective retinal ganglion cell axon guidance

    Directory of Open Access Journals (Sweden)

    Jeffery Glen

    2008-05-01

    Full Text Available Abstract Background The transcription factor Pax6 is expressed by many cell types in the developing eye. Eyes do not form in homozygous loss-of-function mouse mutants (Pax6Sey/Sey and are abnormally small in Pax6Sey/+ mutants. Eyes are also abnormally small in PAX77 mice expressing multiple copies of human PAX6 in addition to endogenous Pax6; protein sequences are identical in the two species. The developmental events that lead to microphthalmia in PAX77 mice are not well-characterised, so it is not clear whether over- and under-expression of Pax6/PAX6 cause microphthalmia through similar mechanisms. Here, we examined the consequences of over-expression for the eye and its axonal connections. Results Eyes form in PAX77+/+ embryos but subsequently degenerate. At E12.5, we found no abnormalities in ocular morphology, retinal cell cycle parameters and the incidence of retinal cell death. From E14.5 on, we observed malformations of the optic disc. From E16.5 into postnatal life there is progressively more severe retinal dysplasia and microphthalmia. Analyses of patterns of gene expression indicated that PAX77+/+ retinae produce a normal range of cell types, including retinal ganglion cells (RGCs. At E14.5 and E16.5, quantitative RT-PCR with probes for a range of molecules associated with retinal development showed only one significant change: a slight reduction in levels of mRNA encoding the secreted morphogen Shh at E16.5. At E16.5, tract-tracing with carbocyanine dyes in PAX77+/+ embryos revealed errors in intraretinal navigation by RGC axons, a decrease in the number of RGC axons reaching the thalamus and an increase in the proportion of ipsilateral projections among those RGC axons that do reach the thalamus. A survey of embryos with different Pax6/PAX6 gene dosage (Pax6Sey/+, Pax6+/+, PAX77+ and PAX77+/+ showed that (1 the total number of RGC axons projected by the retina and (2 the proportions that are sorted into the ipsilateral and

  8. In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa.

    Science.gov (United States)

    Bakondi, Benjamin; Lv, Wenjian; Lu, Bin; Jones, Melissa K; Tsai, Yuchun; Kim, Kevin J; Levy, Rachelle; Akhtar, Aslam Abbasi; Breunig, Joshua J; Svendsen, Clive N; Wang, Shaomei

    2016-03-01

    Reliable genome editing via Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 may provide a means to correct inherited diseases in patients. As proof of principle, we show that CRISPR/Cas9 can be used in vivo to selectively ablate the rhodopsin gene carrying the dominant S334ter mutation (Rho(S334)) in rats that model severe autosomal dominant retinitis pigmentosa. A single subretinal injection of guide RNA/Cas9 plasmid in combination with electroporation generated allele-specific disruption of Rho(S334), which prevented retinal degeneration and improved visual function.

  9. Synthetic Polymer Scaffolds for Stem Cell Transplantation in Retinal Tissue Engineering

    Directory of Open Access Journals (Sweden)

    Michael J. Young

    2011-05-01

    Full Text Available Age-related macular degeneration and retinitis pigmentosa are two leading causes of irreversible blindness characterized by photoreceptor loss. Cell transplantation may be one of the most promising approaches of retinal repair. However, several problems hinder the success of retinal regeneration, including cell delivery and survival, limited cell integration and incomplete cell differentiation. Recent studies show that polymer scaffolds can address these three problems. This article reviews the current literature on synthetic polymer scaffolds used for stem cell transplantation, especially retinal progenitor cells. The advantages and disadvantages of different polymer scaffolds, the role of different surface modifications on cell attachment and differentiation, and controlled drug delivery are discussed. The development of material and surface modification techniques is vital in making cell transplantation a clinical success.

  10. Induced pluripotent stem cells for retinal degenerative diseases: a new perspective on the challenges

    Indian Academy of Sciences (India)

    Zi-Bing Jin; Satoshi Okamoto; Michiko Mandai; Masayo Takahashi

    2009-12-01

    Retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, are the prodominant causes of human blindness in the world; however, these diseases are difficult to treat. Currently, knowledge on the mechanisms of these diseases is still very limited and no radical drugs are available. Induced pluripotent stem (iPS) cells are an innovative technology that turns somatic cells into embryonic stem (ES)-like cells with pluripotent potential via the exogenous expression of several key genes. It can be used as an unlimited source for cell differentiation or tissue engineering, either of which is a promising therapy for human degenerative diseases. Induced pluripotent cells are both an unlimited source for retinal regeneration and an expectant tool for pharmaprojects and developmental or disease modelling. In this review, we try to summarize the advancement of iPS-based technologies and the potential utility for retinal degenerative diseases. We also discuss the challenges of using this technology in the retinology field.

  11. Ultra-high photosensitivity silicon nanophotonics for retinal prosthesis: electrical characteristics.

    Science.gov (United States)

    Khraiche, Massoud L; Lo, Yuhwa; Wang, Deli; Cauwenberghs, Gert; Freeman, William; Silva, Gabriel A

    2011-01-01

    Retinal degenerative diseases such as age related macular degeneration (AMD) and retinitis pigmentosa (RP), lead to the loss of the photoreceptor cells rendering the retina incapable of detecting light. Several engineering approaches have aimed at replacing the function of the photoreceptors by detecting light via an external camera or photodiodes and electrically stimulating the remaining retinal tissue to restore vision. These devices rely heavily on off-device processing to solve the computational challenge of matching the performance of the PRs. In this work, we present a unique ultra-high sensitivity photodetector technology with light sensitivity, signal amplification, light adaptation that shows signal transduction performance approaching those of the rods and cones in the mammalian retina. In addition, the technology offers nanoscale control over photodetectors topography with the potential to reproduce the visual acuity of the natural retina. This technology promises to drastically reduce the foot print, power consumption and computational needs of the current retinal prothesis, while reproducing high resolution vision.

  12. iPS Cells for Modelling and Treatment of Retinal Diseases

    Directory of Open Access Journals (Sweden)

    Fred K. Chen

    2014-12-01

    Full Text Available For many decades, we have relied on immortalised retinal cell lines, histology of enucleated human eyes, animal models, clinical observation, genetic studies and human clinical trials to learn more about the pathogenesis of retinal diseases and explore treatment options. The recent availability of patient-specific induced pluripotent stem cells (iPSC for deriving retinal lineages has added a powerful alternative tool for discovering new disease-causing mutations, studying genotype-phenotype relationships, performing therapeutics-toxicity screening and developing personalised cell therapy. This review article provides a clinical perspective on the current and potential benefits of iPSC for managing the most common blinding diseases of the eye: inherited retinal diseases and age-related macular degeneration.

  13. Nanotechnology-based drug delivery treatments and specific targeting therapy for age-related macular degeneration.

    Science.gov (United States)

    Lin, Tai-Chi; Hung, Kuo-Hsuan; Peng, Chi-Hsien; Liu, Jorn-Hon; Woung, Lin-Chung; Tsai, Ching-Yao; Chen, Shih-Jen; Chen, Yan-Ting; Hsu, Chih-Chien

    2015-11-01

    Nanoparticles combined with cells, drugs, and specially designed genes provide improved therapeutic efficacy in studies and clinical setting, demonstrating a new era of treatment strategy, especially in retinal diseases. Nanotechnology-based drugs can provide an essential platform for sustaining, releasing and a specific targeting design to treat retinal diseases. Poly-lactic-co-glycolic acid is the most widely used biocompatible and biodegradable polymer approved by the Food and Drug Administration. Many studies have attempted to develop special devices for delivering small-molecule drugs, proteins, and other macromolecules consistently and slowly. In this article, we first review current progress in the treatment of age-related macular degeneration. Then, we discuss the function of vascular endothelial growth factor (VEGF) and the pharmacological effects of anti-VEGF-A antibodies and soluble or modified VEGF receptors. Lastly, we summarize the combination of antiangiogenic therapy and nanomedicines, and review current potential targeting therapy in age-related macular degeneration.

  14. Nanotechnology-based drug delivery treatments and specific targeting therapy for age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Tai-Chi Lin

    2015-11-01

    Full Text Available Nanoparticles combined with cells, drugs, and specially designed genes provide improved therapeutic efficacy in studies and clinical setting, demonstrating a new era of treatment strategy, especially in retinal diseases. Nanotechnology-based drugs can provide an essential platform for sustaining, releasing and a specific targeting design to treat retinal diseases. Poly-lactic-co-glycolic acid is the most widely used biocompatible and biodegradable polymer approved by the Food and Drug Administration. Many studies have attempted to develop special devices for delivering small-molecule drugs, proteins, and other macromolecules consistently and slowly. In this article, we first review current progress in the treatment of age-related macular degeneration. Then, we discuss the function of vascular endothelial growth factor (VEGF and the pharmacological effects of anti-VEGF-A antibodies and soluble or modified VEGF receptors. Lastly, we summarize the combination of antiangiogenic therapy and nanomedicines, and review current potential targeting therapy in age-related macular degeneration.

  15. Estrogen signalling in the pathogenesis of age-related macular degeneration.

    Science.gov (United States)

    Kaarniranta, Kai; Machalińska, Anna; Veréb, Zoltán; Salminen, Antero; Petrovski, Goran; Kauppinen, Anu

    2015-02-01

    Age-related macular degeneration (AMD) is a multifactorial eye disease that is associated with aging, family history, smoking, obesity, cataract surgery, arteriosclerosis, hypertension, hypercholesterolemia and unhealthy diet. Gender has commonly been classified as a weak or inconsistent risk factor for AMD. This disease is characterized by degeneration of retinal pigment epithelial (RPE) cells, Bruch's membrane, and choriocapillaris, which secondarily lead to damage and death of photoreceptor cells and central visual loss. Pathogenesis of AMD involves constant oxidative stress, chronic inflammation, and increased accumulation of lipofuscin and drusen. Estrogen has both anti-oxidative and anti-inflammatory capacity and it regulates signaling pathways that are involved in the pathogenesis of AMD. In this review, we discuss potential cellular signaling targets of estrogen in retinal cells and AMD pathology.

  16. Facts about Age-Related Macular Degeneration

    Science.gov (United States)

    ... Degeneration (AMD) > Facts About Age-Related Macular Degeneration Facts About Age-Related Macular Degeneration This information was ... an Eye Care Professional Last Reviewed: September 2015 Fact Sheet Blurb The National Eye Institute (NEI) is ...

  17. Influence of microglia on retinal progenitor cell turnover and cell replacement.

    Science.gov (United States)

    Dick, A D

    2009-10-01

    Microglia within the retina are continually replaced from the bone marrow and are the resident myeloid-derived cells within the retina. Throughout life, microglial function is conditioned by the microenvironment affording immunomodulation to control inflammation as well as functioning to enable normal development and, during adulthood, maintain normal retinal function. In adulthood, recent evidence supports the concept that the retina continues to replace cells to maintain optimal function. Although in some cases after injury, degeneration, or inflammation there remains an inextricable decline in visual function inferring a deficit in cell replacement, the deficit could be explained by microglial cell activation influencing the ability of either retinal progenitor cells or recruited progenitor cells to integrate and differentiate appropriately. Myeloid cell response differs depending on insult: it is evident that during inflammation microglia and the infiltrating myeloid cell function are conditioned by the cytokine environment. Indeed, modulating myeloid cell function therapeutically suppresses disease in experimental models of autoimmunity, whereas in non-inflammatory models microglia have little or no effect on the course of degeneration. The extent of myeloid activation can help determine retinal progenitor cell turnover. Retinal progenitor cells may be isolated from adult human retina, which, albeit limited, display mitotic activity and can differentiate. Microglial activation secreting IL-6 limits progenitor cell turnover and the extent to which differentiation to post-mitotic retinal cells occurs. Such experimental data illustrate the need to develop methods to replenish normal retinal myeloid cell function facilitating integration, either by cell transplantation or by encouraging retinal progenitor cells to recover retinal function.

  18. Congenital scalp defects and vitreoretinal degeneration: redefining the Knobloch syndrome.

    Science.gov (United States)

    Seaver, L H; Joffe, L; Spark, R P; Smith, B L; Hoyme, H E

    1993-04-15

    An apparently autosomal recessive syndrome of hereditary vitreoretinal degeneration (VRD) with retinal detachment, high myopia, and congenital encephalocele was described in 1971 by Knobloch and Layer [J Pediatr Ophthalmol 8:181-184]. Clinical confirmation of the presence of encephaloceles was lacking, and no neuropathologic studies were reported. We have evaluated a similarly affected family with 2 sibs with high myopia, VRD, and occipital scalp defects. Histologic examination of the scalp defects showed heterotopic neuronal tissue in both instances. The older girl has had a unilateral retinal detachment. Her other eye and both eyes of the younger sib have so far been treated successfully with prophylactic retinal cryotherapy. Both children have normal to above normal intelligence. The family reported by Knobloch and Layer [1971] and the sibship herein described appear to represent a distinct autosomal recessive trait. Analysis of the associated defects suggests an underlying defect in early cephalic neuroectodermal morphogenesis. Data from these families imply that congenital occipital scalp defects rather than true encephaloceles may, as is true in some cases of Meckel syndrome, accompany Knobloch syndrome. The presence of a congenital midline scalp defect should alert the clinician to possible underlying central nervous system and/or ocular pathology and should lead to consideration of further diagnostic evaluations and prophylactic measures.

  19. Learning about Retinitis Pigmentosa

    Science.gov (United States)

    ... that detect light). Photoreceptor cells capture and process light helping us to see. As these cells breakdown and die, patients experience progressive vision loss. The most common feature of all forms of RP is a ... cells that detect dim light) and cones (retinal cells that detect light and ...

  20. Nanomaterials and Retinal Toxicity

    Science.gov (United States)

    The neuroretina should be considered as a potential site of nanomaterial toxicity. Engineered nanomaterials may reach the retina through three potential routes of exposure including; intra­ vitreal injection of therapeutics; blood-borne delivery in the retinal vasculature an...

  1. Retinal vein occlusion

    Science.gov (United States)

    ... decrease the risk of retinal vein occlusion. These measures include: Eating a low-fat diet Getting regular exercise Maintaining an ideal weight Not smoking Aspirin or other blood thinners may help prevent blockages in the other eye. Controlling diabetes may ...

  2. Retinal imaging with smartphone.

    Science.gov (United States)

    Ademola-Popoola, D S; Olatunji, V A

    2017-03-01

    The use of smartphones for various purposes among health professionals is increasing, especially with the availability of different applications. On account of cost, fundus cameras are not readily available in ophthalmic practice in developing countries. Since smartphones are readily available, easy to use and portable, they may present a cheap alternative in a resource-limited economy. to explore the use of smartphone (Blackberry Z-10) for retinal imaging in a resource-limited economy. A smartphone (Blackberry Z-10) was used to acquire retinal images with the use of +20D lens in patients with dilated pupils by activating the video mode of the camera. Clear retinal images were obtained in different clinical conditions in adults and children including branch retinal vein occlusion with fibrovascular proliferation, chorioretinal scarring from laser photocoagulation, presumed ocular toxoplasmosis, diabetic retinopathy, retinoblastoma, ocular albinism with fundus hypopigmentation. The ability to have low cost fundus imaging from readily available smartphones in an eye clinic in Nigeria presents a major boost to patient care and also offers an innovative role in research, education, and information sharing.

  3. Nanomaterials and Retinal Toxicity

    Science.gov (United States)

    The neuroretina should be considered as a potential site of nanomaterial toxicity. Engineered nanomaterials may reach the retina through three potential routes of exposure including; intra­ vitreal injection of therapeutics; blood-borne delivery in the retinal vasculature an...

  4. Retinal Imaging with Smartphone

    African Journals Online (AJOL)

    2017-03-06

    Mar 6, 2017 ... Aim and Objectives: to explore the use of smartphone (Blackberry. Z-10) for retinal imaging in ... Samsung phones with additional apps/software such as the Filmic pro to ... in Nigeria also compared the iPhone with the Android.

  5. Optical modulation of transgene expression in retinal pigment epithelium

    Science.gov (United States)

    Palanker, D.; Lavinsky, D.; Chalberg, T.; Mandel, Y.; Huie, P.; Dalal, R.; Marmor, M.

    2013-03-01

    Over a million people in US alone are visually impaired due to the neovascular form of age-related macular degeneration (AMD). The current treatment is monthly intravitreal injections of a protein which inhibits Vascular Endothelial Growth Factor, thereby slowing progression of the disease. The immense financial and logistical burden of millions of intravitreal injections signifies an urgent need to develop more long-lasting and cost-effective treatments for this and other retinal diseases. Viral transfection of ocular cells allows creation of a "biofactory" that secretes therapeutic proteins. This technique has been proven successful in non-human primates, and is now being evaluated in clinical trials for wet AMD. However, there is a critical need to down-regulate gene expression in the case of total resolution of retinal condition, or if patient has adverse reaction to the trans-gene products. The site for genetic therapy of AMD and many other retinal diseases is the retinal pigment epithelium (RPE). We developed and tested in pigmented rabbits, an optical method to down-regulate transgene expression in RPE following vector delivery, without retinal damage. Microsecond exposures produced by a rapidly scanning laser vaporize melanosomes and destroy a predetermined fraction of the RPE cells selectively. RPE continuity is restored within days by migration and proliferation of adjacent RPE, but since the transgene is not integrated into the nucleus it is not replicated. Thus, the decrease in transgene expression can be precisely determined by the laser pattern density and further reduced by repeated treatment without affecting retinal structure and function.

  6. Characterization of a spontaneous retinal neovascular mouse model.

    Directory of Open Access Journals (Sweden)

    Eiichi Hasegawa

    Full Text Available BACKGROUND: Vision loss due to vascular disease of the retina is a leading cause of blindness in the world. Retinal angiomatous proliferation (RAP is a subgroup of neovascular age-related macular degeneration (AMD, whereby abnormal blood vessels develop in the retina leading to debilitating vision loss and eventual blindness. The novel mouse strain, neoretinal vascularization 2 (NRV2, shows spontaneous fundus changes associated with abnormal neovascularization. The purpose of this study is to characterize the induction of pathologic angiogenesis in this mouse model. METHODS: The NRV2 mice were examined from postnatal day 12 (p12 to 3 months. The phenotypic changes within the retina were evaluated by fundus photography, fluorescein angiography, optical coherence tomography, and immunohistochemical and electron microscopic analysis. The pathological neovascularization was imaged by confocal microscopy and reconstructed using three-dimensional image analysis software. RESULTS: We found that NRV2 mice develop multifocal retinal depigmentation in the posterior fundus. Depigmented lesions developed vascular leakage observed by fluorescein angiography. The spontaneous angiogenesis arose from the retinal vascular plexus at postnatal day (p15 and extended toward retinal pigment epithelium (RPE. By three months of age, histological analysis revealed encapsulation of the neovascular lesion by the RPE in the photoreceptor cell layer and subretinal space. CONCLUSIONS: The NRV2 mouse strain develops early neovascular lesions within the retina, which grow downward towards the RPE beginning at p15. This retinal neovascularization model mimics early stages of human retinal angiomatous proliferation (RAP and will likely be a useful in elucidating targeted therapeutics for patients with ocular neovascular disease.

  7. Overexpressed or intraperitoneally injected human transferrin prevents photoreceptor degeneration in rd10 mice.

    Science.gov (United States)

    Picard, Emilie; Jonet, Laurent; Sergeant, Claire; Vesvres, Marie-Hélène; Behar-Cohen, Francine; Courtois, Yves; Jeanny, Jean-Claude

    2010-12-08

    Retinal degeneration has been associated with iron accumulation in age-related macular degeneration (AMD), and in several rodent models that had one or several iron regulating protein impairments. We investigated the iron concentration and the protective role of human transferrin (hTf) in rd10 mice, a model of retinal degeneration. The proton-induced X-ray emission (PIXE) method was used to quantify iron in rd10 mice 2, 3, and 4 weeks after birth. We generated mice with the β-phosphodiesterase mutation and hTf expression by crossbreeding rd10 mice with TghTf mice (rd10/hTf mice). The photoreceptor loss and apoptosis were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling in 3-week-old rd10/hTf mice and compared with 3-week-old rd10 mice. The neuroprotective effect of hTf was analyzed in 5-day-old rd10 mice treated by intraperitoneal administration with hTf for up to 25 days. The retinal hTf concentrations and the thickness of the outer nuclear layer were quantified in all treated mice at 25 days postnatally. PIXE analysis demonstrated an age-dependent iron accumulation in the photoreceptors of rd10 mice. The rd10/hTf mice had the rd10 mutation, expressed high levels of hTf, and showed a significant decrease in photoreceptor death. In addition, rd10 mice intraperitoneally treated with hTf resulted in the retinal presence of hTf and a dose-dependent reduction in photoreceptor degeneration. Our results suggest that iron accumulation in the retinas of rd10 mutant mice is associated with photoreceptor degeneration. For the first time, the enhanced survival of cones and rods in the retina of this model has been demonstrated through overexpression or systemic administration of hTf. This study highlights the therapeutic potential of Tf to inhibit iron-induced photoreceptor cell death observed in degenerative diseases such as retinitis pigmentosa and age-related macular degeneration.

  8. Relationship between macular pigment and visual function in subjects with early age-related macular degeneration

    OpenAIRE

    Akuffo, Kwadwo Owusu; Nolan, John M.; Peto, Tunde; Stack, Jim; Leung, Irene; Corcoran, Laura; Beatty, Stephen

    2016-01-01

    Purpose To investigate the relationship between macular pigment (MP) and visual function in subjects with early age-related macular degeneration (AMD). Methods 121 subjects with early AMD enrolled as part of the Central Retinal Enrichment Supplementation Trial (CREST; ISRCTN13894787) were assessed using a range of psychophysical measures of visual function, including best corrected visual acuity (BCVA), letter contrast sensitivity (CS), mesopic and photopic CS, mesopic and photopic glare disa...

  9. Aging Is Not a Disease: Distinguishing Age-Related Macular Degeneration from Aging

    OpenAIRE

    Ardeljan, Daniel; Chan, Chi-Chao

    2013-01-01

    Age-related macular degeneration (AMD) is a disease of the outer retina, characterized most significantly by atrophy of photoreceptors and retinal pigment epithelium accompanied with or without choroidal neovascularization. Development of AMD has been recognized as contingent on environmental and genetic risk factors, the strongest being advanced age. In this review, we highlight pathogenic changes that destabilize ocular homeostasis and promote AMD development. With normal aging, photorecept...

  10. Cellular and Molecular Pathology of Age-Related Macular Degeneration: Potential Role for Proteoglycans

    OpenAIRE

    Othman Al Gwairi; Lyna Thach; Wenhua Zheng; Narin Osman; Little, Peter J

    2016-01-01

    Age-related macular degeneration (AMD) is a retinal disease evident after the age of 50 that damages the macula in the centre of retina. It leads to a loss of central vision with retained peripheral vision but eventual blindness occurs in many cases. The initiation site of AMD development is Bruch’s membrane (BM) where multiple changes occur including the deposition of plasma derived lipids, accumulation of extracellular debris, changes in cell morphology, and viability and the formation of d...

  11. Combined treatment of exudative age related macular degeneration with photodynamic therapy and intravitreal triamcinolone

    OpenAIRE

    Ruiz-Moreno , Jose

    2008-01-01

    José Mª Ruiz-Moreno1,2, Javier A Montero21Department of Ophthalmology, Miguel Hernández University School of Medicine, Alicante, Spain; 2Vitreo-Retinal Unit, Alicante Institute of Ophthalmology, Alicante, SpainAbstract: Choroidal neovascularization (CNV) secondary to age related macular degeneration is among the leading causes of legal blindness in developed countries. Photodynamic therapy (PDT) with verteporfin induces CNV closure causing little damage to healt...

  12. Protection of retinal function by sulforaphane following retinal ischemic injury.

    Science.gov (United States)

    Ambrecht, Lindsay A; Perlman, Jay I; McDonnell, James F; Zhai, Yougang; Qiao, Liang; Bu, Ping

    2015-09-01

    Sulforaphane, a precursor of glucosinolate in cruciferous vegetables such as broccoli and cauliflower, has been shown to protect brain ischemic injury. In this study, we examined the effect of systemic administration of sulforaphane on retinal ischemic reperfusion injury. Intraocular pressure was elevated in two groups of C57BL/6 mice (n = 8 per group) for 45 min to induce retinal ischemic reperfusion injury. Following retinal ischemic reperfusion injury, vehicle (1% DMSO saline) or sulforaphane (25 mg/kg/day) was administered intraperitoneally daily for 5 days. Scotopic electroretinography (ERG) was used to quantify retinal function prior to and one-week after retinal ischemic insult. Retinal morphology was examined one week after ischemic insult. Following ischemic reperfusion injury, ERG a- and b-wave amplitudes were significantly reduced in the control mice. Sulforaphane treatment significantly attenuated ischemic-induced loss of retinal function as compared to vehicle treated mice. In vehicle treated mice, ischemic reperfusion injury produced marked thinning of the inner retinal layers, but the thinning of the inner retinal layers appeared significantly less with sulforaphane treatment. Thus, sulforaphane may be beneficial in the treatment of retinal disorders with ischemic reperfusion injury. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Progressive retinal nonperfusion in ischemic central retinal vein occlusion.

    Science.gov (United States)

    Wykoff, Charles C; Brown, David M; Croft, Daniel E; Major, James C; Wong, Tien P

    2015-01-01

    Serial wide-field fluorescein angiography was performed on eyes with preproliferative (ischemic) central retinal vein occlusion to evaluate retinal perfusion. Serial wide-field fluorescein angiography was performed on 12 preproliferative central retinal vein occlusion eyes in the 3-year Rubeosis Anti-VEGF (RAVE) trial using the Staurenghi lens (Ocular Staurenghi 230SLO Retina Lens) with a scanning laser ophthalmoscope (Heidelberg HRA Spectralis). "Disk area" was defined anatomically for each eye. Mean total field of gradable retina was 290 disk areas (range, 178-452). All eyes demonstrated extensive areas of retinal nonperfusion; at baseline, mean area of retinal perfusion was 106 disk areas (range, 37-129), correlating with a mean of 46.5% perfused retinal area (range, 19.1-56.4%). The area of retinal nonperfusion increased in all eyes with a mean loss of approximately 8.1% of perfused retinal area per year (range, 4.3-12.4%), which corresponded to a mean 15-disk areas (range, 12-35) of retina evolving from perfused to nonperfused annually. The extent of baseline and final nonperfusion was not significantly different between eyes that developed neovascularization and eyes that did not. In this population of severe central retinal vein occlusion eyes, profound retinal nonperfusion was observed with wide-field fluorescein angiography at baseline and the extent of nonperfusion progressed while undergoing anti-vascular endothelial growth factor therapy.

  14. Prevalence of comorbid retinal disease in patients with glaucoma at an academic medical center

    Directory of Open Access Journals (Sweden)

    Griffith JF

    2015-07-01

    Full Text Available Joseph F Griffith,1 Jeffrey L Goldberg2 1Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, 2Shiley Eye Center, University of California San Diego, La Jolla, CA, USA Background: Patients with various retinal diseases and patients who have undergone retinal procedures and surgeries have an increased risk of developing ocular hypertension and glaucoma. Little is known about the epidemiology of comorbid retinal diseases in glaucoma patients. This study evaluated the prevalence of retinal comorbidities in a population of patients with five types of glaucoma.Methods: A longitudinal, retrospective study was conducted using International Classification of Disease (ICD-9 billing records from 2003 to 2010 at an academic medical center. Patients were classified as having primary open-angle glaucoma (POAG, low tension open-angle glaucoma (NTG, pigmentary open-angle glaucoma, chronic-angle closure glaucoma (CACG, or pseudoexfoliation glaucoma (PXG if they had at least three clinic visits with the same ICD-9 code. Patients were classified as having a retinal comorbidity if they had two visits with the same code. Variables were analyzed with the independent t-test, χ2 test, analysis of variance, or Fisher’s exact test.Results: A total of 5,154 patients had glaucoma, and 14.8% of these had a retinal comorbidity. The prevalence of comorbid retinal disease was higher in patients with POAG (15.7% than in those with NTG (10.7%, PXG (10.1%, or pigmentary open-angle glaucoma (3.7%; P<0.05. Two hundred and two patients had diabetic retinopathy, with POAG patients (4.5% having a higher prevalence than those with CACG (1.4% or PXG (0.6%; P<0.001. There were 297 patients who had macular degeneration and both POAG (2.0% and PXG patients (2.9% had a higher prevalence of nonexudative macular degeneration than those with CACG (0%; P<0.01. Patients with comorbid retinal disease had a higher prevalence of blindness and low vision than those without comorbid

  15. Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation.

    Science.gov (United States)

    Tassoni, Alessia; Gutteridge, Alex; Barber, Amanda C; Osborne, Andrew; Martin, Keith R

    2015-10-01

    A variety of diseases lead to degeneration of retinal ganglion cells (RGCs) and their axons within the optic nerve resulting in loss of visual function. Although current therapies may delay RGC loss, they do not restore visual function or completely halt disease progression. Regenerative medicine has recently focused on stem cell therapy for both neuroprotective and regenerative purposes. However, significant problems remain to be addressed, such as the long-term impact of reactive gliosis occurring in the host retina in response to transplanted stem cells. The aim of this work was to investigate retinal glial responses to intravitreally transplanted bone marrow mesenchymal stem cells (BM-MSCs) to help identify factors able to modulate graft-induced reactive gliosis. We found in vivo that intravitreal BM-MSC transplantation is associated with gliosis-mediated retinal folding, upregulation of intermediate filaments, and recruitment of macrophages. These responses were accompanied by significant JAK/STAT3 and MAPK (ERK1/2 and JNK) cascade activation in retinal Muller glia. Lipocalin-2 (Lcn-2) was identified as a potential new indicator of graft-induced reactive gliosis. Pharmacological inhibition of STAT3 in BM-MSC cocultured retinal explants successfully reduced glial fibrillary acidic protein expression in retinal Muller glia and increased BM-MSC retinal engraftment. Inhibition of stem cell-induced reactive gliosis is critical for successful transplantation-based strategies for neuroprotection, replacement, and regeneration of the optic nerve.

  16. Concurrent OCT imaging of stimulus evoked retinal neural activation and hemodynamic responses

    Science.gov (United States)

    Son, Taeyoon; Wang, Benquan; Lu, Yiming; Chen, Yanjun; Cao, Dingcai; Yao, Xincheng

    2017-02-01

    It is well established that major retinal diseases involve distortions of the retinal neural physiology and blood vascular structures. However, the details of distortions in retinal neurovascular coupling associated with major eye diseases are not well understood. In this study, a multi-modal optical coherence tomography (OCT) imaging system was developed to enable concurrent imaging of retinal neural activity and vascular hemodynamics. Flicker light stimulation was applied to mouse retinas to evoke retinal neural responses and hemodynamic changes. The OCT images were acquired continuously during the pre-stimulation, light-stimulation, and post-stimulation phases. Stimulus-evoked intrinsic optical signals (IOSs) and hemodynamic changes were observed over time in blood-free and blood regions, respectively. Rapid IOSs change occurred almost immediately after stimulation. Both positive and negative signals were observed in adjacent retinal areas. The hemodynamic changes showed time delays after stimulation. The signal magnitudes induced by light stimulation were observed in blood regions and did not show significant changes in blood-free regions. These differences may arise from different mechanisms in blood vessels and neural tissues in response to light stimulation. These characteristics agreed well with our previous observations in mouse retinas. Further development of the multimodal OCT may provide a new imaging method for studying how retinal structures and metabolic and neural functions are affected by age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), and other diseases, which promises novel noninvasive biomarkers for early disease detection and reliable treatment evaluations of eye diseases.

  17. Gene Therapy in a Large Animal Model of PDE6A-Retinitis Pigmentosa

    Directory of Open Access Journals (Sweden)

    Freya M. Mowat

    2017-06-01

    Full Text Available Despite mutations in the rod phosphodiesterase 6-alpha (PDE6A gene being well-recognized as a cause of human retinitis pigmentosa, no definitive treatments have been developed to treat this blinding disease. We performed a trial of retinal gene augmentation in the Pde6a mutant dog using Pde6a delivery by capsid-mutant adeno-associated virus serotype 8, previously shown to have a rapid onset of transgene expression in the canine retina. Subretinal injections were performed in 10 dogs at 29–44 days of age, and electroretinography and vision testing were performed to assess functional outcome. Retinal structure was assessed using color fundus photography, spectral domain optical coherence tomography, and histology. Immunohistochemistry was performed to examine transgene expression and expression of other retinal genes. Treatment resulted in improvement in dim light vision and evidence of rod function on electroretinographic examination. Photoreceptor layer thickness in the treated area was preserved compared with the contralateral control vector treated or uninjected eye. Improved rod and cone photoreceptor survival, rhodopsin localization, cyclic GMP levels and bipolar cell dendrite distribution was observed in treated areas. Some adverse effects including foci of retinal separation, foci of retinal degeneration and rosette formation were identified in both AAV-Pde6a and control vector injected regions. This is the first description of successful gene augmentation for Pde6a retinitis pigmentosa in a large animal model. Further studies will be necessary to optimize visual outcomes and minimize complications before translation to human studies.

  18. Flavonoid allosteric modulation of mutated visual rhodopsin associated with retinitis pigmentosa.

    Science.gov (United States)

    Herrera-Hernández, María Guadalupe; Ramon, Eva; Lupala, Cecylia S; Tena-Campos, Mercè; Pérez, Juan J; Garriga, Pere

    2017-09-11

    Dietary flavonoids exhibit many biologically-relevant functions and can potentially have beneficial effects in the treatment of pathological conditions. In spite of its well known antioxidant properties, scarce structural information is available on the interaction of flavonoids with membrane receptors. Advances in the structural biology of a specific class of membrane receptors, the G protein-coupled receptors, have significantly increased our understanding of drug action and paved the way for developing improved therapeutic approaches. We have analyzed the effect of the flavonoid quercetin on the conformation, stability and function of the G protein-coupled receptor rhodopsin, and the G90V mutant associated with the retinal degenerative disease retinitis pigmentosa. By using a combination of experimental and computational methods, we suggest that quercetin can act as an allosteric modulator of opsin regenerated with 9-cis-retinal and more importantly, that this binding has a positive effect on the stability and conformational properties of the G90V mutant associated with retinitis pigmentosa. These results open new possibilities to use quercetin and other flavonoids, in combination with specific retinoids like 9-cis-retinal, for the treatment of retinal degeneration associated with retinitis pigmentosa. Moreover, the use of flavonoids as allosteric modulators may also be applicable to other members of the G protein-coupled receptors superfamily.

  19. OCT as a convenient tool to assess the quality and application of organotypic retinal samples

    Science.gov (United States)

    Gater, Rachel; Khoshnaw, Nicholas; Nguyen, Dan; El Haj, Alicia J.; Yang, Ying

    2016-03-01

    Eye diseases such as macular degeneration and glaucoma have profound consequences on the quality of human life. Without treatment, these diseases can lead to loss of sight. To develop better treatments for retinal diseases, including cell therapies and drug intervention, establishment of an efficient and reproducible 3D native retinal tissue system, enabled over a prolonged culture duration, will be valuable. The retina is a complex tissue, consisting of ten layers with a different density and cellular composition to each. Uniquely, as a light transmitting tissue, retinal refraction of light differs among the layers, forming a good basis to use optical coherence tomography (OCT) in assessing the layered structure of the retina and its change during the culture and treatments. In this study, we develop a new methodology to generate retinal organotypic tissues and compare two substrates: filter paper and collagen hydrogel, to culture the organotypic tissue. Freshly slaughtered pig eyes have been obtained for use in this study. The layered morphology of intact organotypic retinal tissue cultured on two different substrates has been examined by spectral domain OCT. The viability of the tissues has been examined by live/dead fluorescence dye kit to cross validate the OCT images. For the first time, it is demonstrated that the use of a collagen hydrogel supports the viability of retinal organotypic tissue, capable of prolonged culture up to 2 weeks. OCT is a convenient tool for appraising the quality and application of organotypic retinal samples and is important in the development of current organotypic models.

  20. Scleral buckling procedure with chandelier illumination for pediatric rhegmatogenous retinal detachment

    Directory of Open Access Journals (Sweden)

    Yokoyama T

    2015-01-01

    Full Text Available Toshiyuki Yokoyama, Koki Kanbayashi, Tamaki YamaguchiDepartment of Ophthalmology, Juntendo University Nerima Hospital, Tokyo, JapanPurpose: To assess the treatment of pediatric patients with rhegmatogenous retinal detachment (RRD by scleral buckling with chandelier illumination.Methods: Three eyes were treated in three patients, healthy boys aged 7 years, 12 years, and 11 years, with RRD, macular involvement, and small retinal holes, of which two were preoperatively undetectable. Conventional scleral buckling with cryoretinopexy was performed under the contact lens for vitreous surgery or noncontact wide-angle viewing system using 27-gauge twin chandelier illumination.Results: The only known predisposing factor for retinal detachment was myopia stronger than 3 D with lattice retinal degeneration in two of the three patients. Retinal reattachment was achieved in all cases without intra- or postoperative complications. However, visual recovery was limited in one of the three patients.Conclusion: Scleral buckling with chandelier illumination is effective for pediatric RRD, especially if the retinal hole is difficult to detect preoperatively. However, visual recovery was sometimes limited because of macular involvement due to late diagnosis, which is one of the characteristic features of pediatric RRD.Keywords: pediatric rhegmatogenous retinal detachment, chandelier illumination, scleral buckling

  1. Photobiomodulation for the treatment of retinal diseases: a review.

    Science.gov (United States)

    Geneva, Ivayla I

    2016-01-01

    Photobiomodulation (PBM), also known as low level laser therapy, has recently risen to the attention of the ophthalmology community as a promising new approach to treat a variety of retinal conditions including age-related macular degeneration, retinopathy of prematurity, diabetic retinopathy, Leber's hereditary optic neuropathy, amblyopia, methanol-induced retinal damage, and possibly others. This review evaluates the existing research pertaining to PBM applications in the retina, with a focus on the mechanisms of action and clinical outcomes. All available literature until April 2015 was reviewed using PubMed and the following keywords: "photobiomodulation AND retina", "low level light therapy AND retina", "low level laser therapy AND retina", and "FR/NIR therapy AND retina". In addition, the relevant references listed within the papers identified through PubMed were incorporated. The literature supports the conclusion that the low-cost and non-invasive nature of PBM, coupled with the first promising clinical reports and the numerous preclinical-studies in animal models, make PBM well-poised to become an important player in the treatment of a wide range of retinal disorders. Nevertheless, large-scale clinical trials will be necessary to establish the PBM therapeutic ranges for the various retinal diseases, as well as to gain a deeper understanding of its mechanisms of action.

  2. Photobiomodulation for the treatment of retinal diseases: a review

    Science.gov (United States)

    Geneva, Ivayla I.

    2016-01-01

    Photobiomodulation (PBM), also known as low level laser therapy, has recently risen to the attention of the ophthalmology community as a promising new approach to treat a variety of retinal conditions including age-related macular degeneration, retinopathy of prematurity, diabetic retinopathy, Leber's hereditary optic neuropathy, amblyopia, methanol-induced retinal damage, and possibly others. This review evaluates the existing research pertaining to PBM applications in the retina, with a focus on the mechanisms of action and clinical outcomes. All available literature until April 2015 was reviewed using PubMed and the following keywords: “photobiomodulation AND retina”, “low level light therapy AND retina”, “low level laser therapy AND retina”, and “FR/NIR therapy AND retina”. In addition, the relevant references listed within the papers identified through PubMed were incorporated. The literature supports the conclusion that the low-cost and non-invasive nature of PBM, coupled with the first promising clinical reports and the numerous preclinical-studies in animal models, make PBM well-poised to become an important player in the treatment of a wide range of retinal disorders. Nevertheless, large-scale clinical trials will be necessary to establish the PBM therapeutic ranges for the various retinal diseases, as well as to gain a deeper understanding of its mechanisms of action. PMID:26949625

  3. Druse-Induced Morphology Evolution in Retinal Pigment Epithelium

    CERN Document Server

    Mazzitello, K I; Chrenek, M A; Family, F; Grossniklaus, H E; Nickerson, J M; Jiang, Y

    2016-01-01

    The retinal pigment epithelium (RPE) is a key site of pathogenesis for many retina diseases. The formation of drusen in the retina is characteristic of retinal degeneration. We investigate morphological changes in the RPE in the presence of soft drusen using an integrated experimental and modeling approach. We collect RPE flat mount images from donated human eyes and develop 1) statistical tools to quantify the images and 2) a cell-based model to simulate the morphology evolution. We compare three different mechanisms of RPE repair evolution, cell apoptosis, cell fusion, and expansion, and Simulations of our RPE morphogenesis model quantitatively reproduce deformations of human RPE morphology due to drusen, suggesting that a purse-string mechanism is sufficient to explain how RPE heals cell loss caused by drusen-damage. We found that drusen beneath tissue promote cell death in a number that far exceeds the cell numbers covering the drusen. Tissue deformations are studied using area distributions, Voronoi doma...

  4. Acetazolamide for cystoid macular oedema in Bietti crystalline retinal dystrophy.

    Science.gov (United States)

    Broadhead, Geoffrey K; Chang, Andrew A

    2014-04-01

    Bietti crystalline retinal dystrophy is a rare, inherited disorder whose hallmark is the presence of retinal crystal deposits associated with later chorioretinal degeneration. This condition may rarely be complicated by the development of cystoid macular oedema leading to rapid visual decline. Currently, treatment options for this complication of Bietti dystrophy are limited and the visual prognosis is poor. Here, we present a case of cystoid macular oedema associated with Bietti dystrophy that was successfully diagnosed using multimodal imaging techniques including optical coherence tomography and fluorescein angiography. These modalities confirmed the diagnosis of macular oedema and excluded other possible causes of oedema such as choroidal neovascularisation. In this patient, cystoid macular oedema was resolved with oral acetazolamide therapy, a treatment that has not been previously reported in this context. Acetazolamide treatment resulted in oedema resolution and improvement in visual function, and can be considered a therapeutic option for other patients with Bietti dystrophy who develop cystoid macular oedema.

  5. Corneal Confocal Microscopy: An Imaging Endpoint for Axonal Degeneration in Multiple Sclerosis.

    Science.gov (United States)

    Petropoulos, Ioannis N; Kamran, Saadat; Li, Yi; Khan, Adnan; Ponirakis, Georgios; Akhtar, Naveed; Deleu, Dirk; Shuaib, Ashfaq; Malik, Rayaz A

    2017-07-01

    To evaluate whether corneal confocal microscopy (CCM) detects axonal degeneration and whether this is associated with retinal nerve fiber degeneration and clinical disability in patients with multiple sclerosis (MS). Twenty-five patients with MS and 25 healthy control subjects underwent CCM, optical coherence tomography (OCT), and assessment of neurological disability using the expanded disability status scale (EDSS) and MS severity score (MSSS). In patients with MS compared with controls, there was a significant reduction in corneal nerve fiber density (CNFD), branch density (CNBD), and length (CNFL). There was no significant difference in CCM parameters between patients with optic neuritis (MS-ON) and without (MS-NON), or between relapsing-remitting (RRMS) and secondary-progressive MS (SPMS). There was significant thinning of the retinal nerve fiber layer (RNFL) in the global, temporal, temporal superior, and temporal inferior quadrants, with no difference between MS-ON and MS-NON. Patients with SPMS compared with RRMS had a significantly lower global, temporal superior, temporal inferior, nasal, and nasal superior RNFL. The EDSS and MSSS correlated significantly with CNBD, nasal, nasal superior, and nasal inferior RNFL and with CNBD and nasal inferior RNFL, respectively. CCM and OCT detect significant corneal and retinal nerve degeneration which relates to the severity of neurological deficits in patients with mild MS.

  6. Peripapillary retinal thermal coagulation following electrical injury

    Directory of Open Access Journals (Sweden)

    Manjari Tandon

    2013-01-01

    Full Text Available In this study, we have presented the case report of a 20 year old boy who suffered an electric injury shock, following which he showed peripapillary retinal opacification and increased retinal thickening that subsequently progressed to retinal atrophy. The fluorescein angiogram revealed normal retinal circulation, thus indicating thermal damage to retina without any compromise to retinal circulation.

  7. [Age related macular degeneration].

    Science.gov (United States)

    Sayen, Alexandra; Hubert, Isabelle; Berrod, Jean-Paul

    2011-02-01

    Age-related macular degeneration (ARMD) is a multifactorial disease caused by a combination of genetic and environmental factors. It is the first cause of blindness in patients over 50 in the western world. The disease has been traditionally classified into early and late stages with dry (atrophic) and wet (neovascular) forms: neovascular form is characterized by new blood vessels development under the macula (choroidal neovascularisation) which lead to a rapid decline of vision associated with metamorphopsia and requiring an urgent ophtalmological examination. Optical coherence tomography is now one of the most important part of the examination for diagnosis and treatment. Patient with age related maculopathy should consider taking a dietary supplement such that used in AREDS. The treatment of the wet ARMD has largely beneficied since year 2006 of anti-VEGF (vascular endothelial growth factor) molecules such as ranibizumab or bevacizumab given as repeated intravitreal injections. A systematic follow up each 4 to 8 week in required for several years. There is no effective treatment at the moment for dry AMD. For patients with binocular visual acuity under 60/200 rehabilitation includes low vision specialist, vision aids and psychological support.

  8. Clinical research of retinal laser photocoagulation and Ranibizumab on the treatment of neovascular glaucoma

    Directory of Open Access Journals (Sweden)

    Wei-Peng Jiang

    2015-10-01

    Full Text Available AIM: To explore the improvement of visual function and the adverse reactions of retinal laser photocoagulation combined with ranibizumab for the treatment of neovascular glaucoma(NVG, to provide the basis for clinical treatment.METHODS: One hundred patients with 129 eyes in our hospital from January 2012 to June 2014 were selected. They were randomly divided into the observation group and the control group, 50 cases in each one. Patients in the control group(67 eyeswere treated with retinal laser photocoagulation, and those in the observation group(62 eyeswere given retinal laser photocoagulation combined with ranibizumab treatment. After the treatment, the degeneration of iris neovascularization, visual acuity, intraocular pressure, ocular fundus and the adverse reactions were evaluated. Optical coherence tomography(OCTwas used to detect retinal nerve fiber layer(RNFLthickness and visual field defect. RESULTS: The degeneration rate of the iris neovascularization in the observation group was 95.2%(59/62, higher than that of the control group 83.6%(56/67(PPPPPP>0.05.CONCLUSION: The treatment of NVG with laser photocoagulation combined with ranibizumab has good clinical efficacy, and can significantly improve the vision and retinal structure and function of the patients, and is safer.

  9. Functional annotation of the human retinal pigment epithelium transcriptome

    Directory of Open Access Journals (Sweden)

    Gorgels Theo GMF

    2009-04-01

    Full Text Available Abstract Background To determine level, variability and functional annotation of gene expression of the human retinal pigment epithelium (RPE, the key tissue involved in retinal diseases like age-related macular degeneration and retinitis pigmentosa. Macular RPE cells from six selected healthy human donor eyes (aged 63–78 years were laser dissected and used for 22k microarray studies (Agilent technologies. Data were analyzed with Rosetta Resolver, the web tool DAVID and Ingenuity software. Results In total, we identified 19,746 array entries with significant expression in the RPE. Gene expression was analyzed according to expression levels, interindividual variability and functionality. A group of highly (n = 2,194 expressed RPE genes showed an overrepresentation of genes of the oxidative phosphorylation, ATP synthesis and ribosome pathways. In the group of moderately expressed genes (n = 8,776 genes of the phosphatidylinositol signaling system and aminosugars metabolism were overrepresented. As expected, the top 10 percent (n = 2,194 of genes with the highest interindividual differences in expression showed functional overrepresentation of the complement cascade, essential in inflammation in age-related macular degeneration, and other signaling pathways. Surprisingly, this same category also includes the genes involved in Bruch's membrane (BM composition. Among the top 10 percent of genes with low interindividual differences, there was an overrepresentation of genes involved in local glycosaminoglycan turnover. Conclusion Our study expands current knowledge of the RPE transcriptome by assigning new genes, and adding data about expression level and interindividual variation. Functional annotation suggests that the RPE has high levels of protein synthesis, strong energy demands, and is exposed to high levels of oxidative stress and a variable degree of inflammation. Our data sheds new light on the molecular composition of BM, adjacent to the

  10. A CNGB1 frameshift mutation in Papillon and Phalene dogs with progressive retinal atrophy.

    Directory of Open Access Journals (Sweden)

    Saija J Ahonen

    Full Text Available Progressive retinal degenerations are the most common causes of complete blindness both in human and in dogs. Canine progressive retinal atrophy (PRA or degeneration resembles human retinitis pigmentosa (RP and is characterized by a progressive loss of rod photoreceptor cells followed by a loss of cone function. The primary clinical signs are detected as vision impairment in a dim light. Although several genes have been associated with PRAs, there are still PRAs of unknown genetic cause in many breeds, including Papillons and Phalènes. We have performed a genome wide association and linkage studies in cohort of 6 affected Papillons and Phalènes and 14 healthy control dogs to map a novel PRA locus on canine chromosome 2, with a 1.9 Mb shared homozygous region in the affected dogs. Parallel exome sequencing of a trio identified an indel mutation, including a 1-bp deletion, followed by a 6-bp insertion in the CNGB1 gene. This mutation causes a frameshift and premature stop codon leading to probable nonsense mediated decay (NMD of the CNGB1 mRNA. The mutation segregated with the disease and was confirmed in a larger cohort of 145 Papillons and Phalènes (PFisher = 1.4×10(-8 with a carrier frequency of 17.2 %. This breed specific mutation was not present in 334 healthy dogs from 10 other breeds or 121 PRA affected dogs from 44 other breeds. CNGB1 is important for the photoreceptor cell function its defects have been previously associated with retinal degeneration in both human and mouse. Our study indicates that a frameshift mutation in CNGB1 is a cause of PRA in Papillons and Phalènes and establishes the breed as a large functional animal model for further characterization of retinal CNGB1 biology and possible retinal gene therapy trials. This study enables also the development of a genetic test for breeding purposes.

  11. Treatment of neovascular age-related macular degeneration in patients with diabetes

    Directory of Open Access Journals (Sweden)

    Michael Cummings

    2008-06-01

    Full Text Available Michael Cummings1, José Cunha-Vaz21Academic Department of Diabetes and Endocrinology, Queen Alexandra Hospital, Portsmouth, UK; 2Department of Ophthalmology, University Hospital of Coimbra, Centre of Ophthalmology, Institute of Biomedical Research on Light and Image, Faculty of Medicine, University of Coimbra, and Association for Innovation and Biomedical Research on Light and Image, Coimbra, PortugalAbstract: The number of patients with type 2 diabetes continues to rise; an anticipated 300 million people will be affected by 2025. The immense social and economic burden of the condition is exacerbated by the initial asymptomatic nature of type 2 diabetes, resulting in a high prevalence of micro- and macrovascular complications at presentation. Diabetic retinopathy, one of the potential microvascular complications associated with diabetes, and neovascular age-related macular degeneration (AMD are the two most frequent retinal degenerative diseases, and are responsible for the majority of blindness due to retinal disease. Both conditions predominantly affect the central macula, and are associated with the presence of retinal edema and an aggressive inflammatory repair process that accelerates disease progression. The associated retinal edema and the inflammatory repair process are directly involved in the breakdown of the blood-retinal barrier (BRB. Yet, the underlying alterations to the BRB caused by the diseases are very different. The coexistence of the two conditions appears to be relatively uncommon, suggesting that diabetes may even protect patients from developing neovascular AMD. However, it is thought that the inflammatory repair responses associated with diabetic retinopathy and neovascular AMD may be cumulative and, in patients affected by both, could result in chronic diffuse cystoid edema. Treatment considerations in such patients should, therefore, include the role of retinal edema and the increased susceptibility of patients with

  12. Degenerate pseudo-Riemannian metrics

    CERN Document Server

    Hervik, Sigbjorn; Yamamoto, Kei

    2014-01-01

    In this paper we study pseudo-Riemannian spaces with a degenerate curvature structure i.e. there exists a continuous family of metrics having identical polynomial curvature invariants. We approach this problem by utilising an idea coming from invariant theory. This involves the existence of a boost, the existence of this boost is assumed to extend to a neighbourhood. This approach proves to be very fruitful: It produces a class of metrics containing all known examples of degenerate metrics. To date, only Kundt and Walker metrics have been given, however, our study gives a plethora of examples showing that degenerate metrics extend beyond the Kundt and Walker examples. The approach also gives a useful criterion for a metric to be degenerate. Specifically, we use this to study the subclass of VSI and CSI metrics (i.e., spaces where polynomial curvature invariants are all vanishing or constants, respectively).

  13. Age-Related Macular Degeneration

    Science.gov (United States)

    ... version of this page please turn Javascript on. Age-related Macular Degeneration About AMD Click for more ... a leading cause of vision loss among people age 60 and older. It causes damage to the ...

  14. Sirtuins Expression and Their Role in Retinal Diseases

    Science.gov (United States)

    2017-01-01

    Sirtuins have received considerable attention since the discovery that silent information regulator 2 (Sir2) extends the lifespan of yeast. Sir2, a nicotinamide adenine dinucleotide- (NAD-) dependent histone deacetylase, serves as both a transcriptional effector and energy sensor. Oxidative stress and apoptosis are implicated in the pathogenesis of neurodegenerative eye diseases. Sirtuins confer protection against oxidative stress and retinal degeneration. In mammals, the sirtuin (SIRT) family consists of seven proteins (SIRT1–SIRT7). These vary in tissue specificity, subcellular localization, and enzymatic activity and targets. In this review, we present the current knowledge of the sirtuin family and discuss their structure, cellular location, and biological function with a primary focus on their role in different neuroophthalmic diseases including glaucoma, optic neuritis, and age-related macular degeneration. The potential role of certain therapeutic targets is also described. PMID:28197299

  15. Sirtuins Expression and Their Role in Retinal Diseases

    Directory of Open Access Journals (Sweden)

    Sankarathi Balaiya

    2017-01-01

    Full Text Available Sirtuins have received considerable attention since the discovery that silent information regulator 2 (Sir2 extends the lifespan of yeast. Sir2, a nicotinamide adenine dinucleotide- (NAD- dependent histone deacetylase, serves as both a transcriptional effector and energy sensor. Oxidative stress and apoptosis are implicated in the pathogenesis of neurodegenerative eye diseases. Sirtuins confer protection against oxidative stress and retinal degeneration. In mammals, the sirtuin (SIRT family consists of seven proteins (SIRT1–SIRT7. These vary in tissue specificity, subcellular localization, and enzymatic activity and targets. In this review, we present the current knowledge of the sirtuin family and discuss their structure, cellular location, and biological function with a primary focus on their role in different neuroophthalmic diseases including glaucoma, optic neuritis, and age-related macular degeneration. The potential role of certain therapeutic targets is also described.

  16. On the degenerate phase boundaries

    CERN Document Server

    Ma, Y; Kuang, Z; Ma, Yongge; Liang, Canbin; Kuang, Zhiquan

    1999-01-01

    The structure of the phase boundary between degenerate and non-degenerate regions in Ashtekar's gravity has been studied by Bengtsson and Jacobson who conjectured that the "phase boundary" should always be null. In this paper, we reformulate the reparametrization procedure in the mapping language and distinguish a phase boundary from its image. It is shown that the image has to be null, while the nullness of the phase boundary requries more suitable criterion.

  17. Functional ectopic neuritogenesis by retinal rod bipolar cells is regulated by miR-125b-5p during retinal remodeling in RCS rats.

    Science.gov (United States)

    Fu, Yan; Hou, Baoke; Weng, Chuanhuang; Liu, Weiping; Dai, Jiaman; Zhao, Congjian; Yin, Zheng Qin

    2017-04-21

    Following retinal degeneration, retinal remodeling can cause neuronal microcircuits to undergo structural alterations, which particularly affect the dendrites of bipolar cells. However, the mechanisms and functional consequences of such changes remain unclear. Here, we used Royal College of Surgeon (RCS) rats as a model of retinal degeneration, to study structural changes in rod bipolar cells (RBCs) and the underlying mechanisms of these changes. We found that, with retinal degeneration, RBC dendrites extended into the outer nuclear layer (ONL) of the retina, and the ectopic dendrites formed synapses with the remaining photoreceptors. This ectopic neuritogenesis was associated with brain-derived neurotrophic factor (BDNF) - expression of which was negatively regulated by miR-125b-5p. Overexpression of miR-125b-5p in the retinae of RCS rats diminished RBC ectopic dendrites, and compromised the b-wave of the flash electroretinogram (ERG). In contrast, down-regulation of miR-125b-5p (or exogenous BDNF treatment) increased RBC ectopic dendrites, and improved b-wave. Furthermore, we showed that the regulation of ectopic neuritogenesis by BDNF occurred via the downstream modulation of the TrkB-CREB signaling pathway. Based on these findings, we conclude that ectopic dendrites are likely to be providing functional benefits and that, in RCS rats, miR-125b-5p regulates ectopic neuritogenesis by RBCs through modulation of the BDNF-TrkB-CREB pathway. This suggests that therapies that reduce miR-125b-5p expression could be beneficial in human retinal degenerative disease.

  18. Effects of multiple intravitreal anti-VEGF injections on retinal nerve fiber layer and intraocular pressure: a comparative clinical study

    Institute of Scientific and Technical Information of China (English)

    Franck; Amouyal; Danièle; Denis; Frédéric; Matonti

    2014-01-01

    Dear Sir,Ifound the article by Sobac1etal[1]very interesting.The authors concluded that repeated intravitreal injection(IVI)of ranibizumab or bevacizumab didn’t seem have adverse effects on retinal nerve fiber layer(RNFL)thickness in wet age-related macular degeneration(AMD)patients.

  19. Retinal flow cytometer

    OpenAIRE

    Alt, C.; Veilleux, I.; H. Lee; Pitsillides, C. M.; Côté, D.; Lin, C.P.

    2007-01-01

    The in vivo flow cytometer is an instrument capable of continuous, real-time monitoring of fluorescently labeled cells in the circulation without the need to draw blood samples. However, the original system probes a single vessel in the mouse ear; the small sample volume limits the sensitivity of the technique. We describe an in vivo retinal flow cytometer that simultaneously probes five artery–vein pairs in the mouse eye by circularly scanning a small laser spot rapidly around the optic nerv...

  20. Retinal Thickening and Photoreceptor Loss in HIV Eyes without Retinitis.

    Directory of Open Access Journals (Sweden)

    Cheryl A Arcinue

    Full Text Available To determine the presence of structural changes in HIV retinae (i.e., photoreceptor density and retinal thickness in the macula compared with age-matched HIV-negative controls.Cohort of patients with known HIV under CART (combination Antiretroviral Therapy treatment were examined with a flood-illuminated retinal AO camera to assess the cone photoreceptor mosaic and spectral-domain optical coherence tomography (SD-OCT to assess retinal layers and retinal thickness.Twenty-four eyes of 12 patients (n = 6 HIV-positive and 6 HIV-negative were imaged with the adaptive optics camera. In each of the regions of interest studied (nasal, temporal, superior, inferior, the HIV group had significantly less mean cone photoreceptor density compared with age-matched controls (difference range, 4,308-6,872 cones/mm2. A different subset of forty eyes of 20 patients (n = 10 HIV-positive and 10 HIV-negative was included in the retinal thickness measurements and retinal layer segmentation with the SD-OCT. We observed significant thickening in HIV positive eyes in the total retinal thickness at the foveal center, and in each of the three horizontal B-scans (through the macular center, superior, and inferior to the fovea. We also noted that the inner retina (combined thickness from ILM through RNFL to GCL layer was also significantly thickened in all the different locations scanned compared with HIV-negative controls.Our present study shows that the cone photoreceptor density is significantly reduced in HIV retinae compared with age-matched controls. HIV retinae also have increased macular retinal thickness that may be caused by inner retinal edema secondary to retinovascular disease in HIV. The interaction of photoreceptors with the aging RPE, as well as possible low-grade ocular inflammation causing diffuse inner retinal edema, may be the key to the progressive vision changes in HIV-positive patients without overt retinitis.

  1. Current and future potential of retinal optical coherence tomography in multiple sclerosis with and without optic neuritis.

    Science.gov (United States)

    Balk, Lisanne J; Petzold, Axel

    2014-01-01

    Multiple sclerosis (MS) is a disorder characterized by inflammation and neuroaxonal degeneration. The latter is held responsible for the irreversible disability in patients with MS. The eye is a unique window into the brain. With the advent of optical coherence tomography, accurate quantification of retinal layer thickness has become feasible. Neuroaxonal degeneration affecting the retinal layers is structurally and functionally related to pathology in the visual pathways, which is most severe following MS optic neuritis. This is relevant to recognize because MS optic neuritis may mask the subtle thinning of retinal layers associated with global CNS atrophy, which is also related to more global loss of neurological function. Taken together, optical coherence tomography stands at the brink of becoming a validated imaging biomarker for monitoring neurodegeneration in MS and to provide end points for clinical trials.

  2. Delivery of antioxidant enzyme genes to protect against ischemia/reperfusion-induced injury to retinal microvasculature.

    Science.gov (United States)

    Chen, Baihua; Caballero, Sergio; Seo, Soojung; Grant, Maria B; Lewin, Alfred S

    2009-12-01

    Retinal ischemia/reperfusion (I/R) injury results in the generation of reactive oxygen species (ROS). The aim of this study was to investigate whether delivery of the manganese superoxide dismutase gene (SOD2) or the catalase gene (CAT) could rescue the retinal vascular damage induced by I/R in mice. I/R injury to the retina was induced in mice by elevating intraocular pressure for 2 hours, and reperfusion was established immediately afterward. One eye of each mouse was pretreated with plasmids encoding manganese superoxide dismutase or catalase complexed with cationic liposomes and delivered by intravitreous injection 48 hours before initiation of the procedure. Superoxide ion, hydrogen peroxide, and 4-hydroxynonenal (4-HNE) protein modifications were measured by fluorescence staining, immunohistochemistry, and Western blot analysis 1 day after the I/R injury. At 7 days after injury, retinal vascular cell apoptosis and acellular capillaries were quantitated. Superoxide ion, hydrogen peroxide, and 4-HNE protein modifications increased at 24 hours after I/R injury. Administration of plasmids encoding SOD2 or CAT significantly reduced levels of superoxide ion, hydrogen peroxide, and 4-HNE. Retinal vascular cell apoptosis and acellular capillary numbers increased greatly by 7 days after the injury. Delivery of SOD2 or CAT inhibited the I/R-induced apoptosis of retinal vascular cell and retinal capillary degeneration. Delivery of antioxidant genes inhibited I/R-induced retinal capillary degeneration, apoptosis of vascular cells, and ROS production, suggesting that antioxidant gene therapy might be a treatment for I/R-related disease.

  3. Retinal Morphology and Sensitivity Are Primarily Impaired in Eyes with Neuromyelitis Optica Spectrum Disorder (NMOSD)

    Science.gov (United States)

    Akiba, Ryutaro; Yokouchi, Hirotaka; Mori, Masahiro; Oshitari, Toshiyuki; Baba, Takayuki; Sawai, Setsu; Kuwabara, Satoshi; Yamamoto, Shuichi

    2016-01-01

    Background Previous studies of neuromyelitis optica spectrum disorder (NMOSD) using spectral domain optical coherence tomography (SD-OCT) showed that the outer nuclear layer (ONL) in eyes without a history of optic neuritis (ON) was thinner than that of healthy controls. It remains unclear whether the ONL thinning is caused by a direct attack on the retina by an autoantibody or a retrograde degeneration. Objective To determine the mechanisms involved in the retinal damage in eyes with NMOSD without ON. Methods SD-OCT was used to determine the thicknesses of the different retinal layers of 21 eyes of 12 NMOSD patients without prior ON and 19 eyes of 10 healthy controls. Eyes with peripapillary retinal nerve fiber layer (RNFL) thinning were excluded to eliminate the confounding effects of retrograde degeneration. Microperimetry was used to determine the central retinal sensitivity. The data of the two groups were compared using generalized estimated equation models to account for inter-eye dependencies. Results The ganglion cell plus inner plexiform layer and the inner nuclear layer plus outer plexiform layer thicknesses of the NMOSD eyes were not significantly different from that of the control eyes (P = 0.28, P = 0.78). However, the ONL and average macular thickness (AMT) in the NMOSD eyes were significantly thinner than that of the control eyes (P = 0.022, P = 0.036). The retinal sensitivity in the central 10°, 10° to 2°, and 2° sectors were significantly lower in the NMOSD eyes than in the control eyes (P = 0.013, P = 0.022, P = 0.002). Conclusions The ONL thinning, AMT thinning, and reduced retinal sensitivity in eyes with NMOSD without significant peripapillary RNFL thinning are most likely due to direct retinal pathology. PMID:27936154

  4. Progress and perspectives on the role of RPE cell inflammatory responses in the development of age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Suofu Qin

    2008-12-01

    Full Text Available Suofu Qin, Gerard A RodriguesRetinal Disease Research, Department of Biological Sciences, Allergan, Inc., Irvine, CA, USAAbstract: Age-related macular degeneration (AMD is the leading cause of blindness in developed countries. The etiology of AMD remains poorly understood and no treatment is currently available for the atrophic form of AMD. Atrophic AMD has been proposed to involve abnormalities of the retinal pigment epithelium (RPE, which lies beneath the photoreceptor cells and normally provides critical metabolic support to these light-sensing cells. Cumulative oxidative stress and local inflammation are thought to represent pathological processes involved in the etiology of atrophic AMD. Studies of tissue culture and animal models reveal that oxidative stress-induced injury to the RPE results in a chronic inflammatory response, drusen formation, and RPE atrophy. RPE degeneration in turn causes a progressive degeneration of photoreceptors, leading to the irreversible loss of vision. This review describes some of the potential major molecular and cellular events contributing to RPE death and inflammatory responses. In addition, potential target areas for therapeutic intervention will be discussed and new experimental therapeutic strategies for atrophic AMD will be presented.Keywords: age-related macular degeneration, danger signals, complement, inflammation, retinal pigment epithelial cells

  5. [Application of retinal oximeter in ophthalmology].

    Science.gov (United States)

    Li, Jing; Ma, Jianmin; Wang, Ningli

    2015-11-01

    Retinal oximeter is a new machine which has been used in the diagnose, treatment and research of several ophthalmic diseases for recent years. It allows ophthalmologists to gain retinal oxygen saturation directly. Therefore, retinal oximeter might be useful for ophthalmologists to understand ophthalmic diseases more deeper and clarify the impact of ischemia on retinal function. It has been reported in the literatures that retinal oximeter has potentially useful diagnostic and therapeutic indications in various eye diseases such as diabetic retinopathy, central retinal vein and artery occlusion, retinitis pigmentosa, glaucomatous optic neuropathy, et al. In this thesis, the application of retinal oximeter in ophthalmology is reviewed.

  6. Wilson's disease (hepatolenticular degeneration).

    Science.gov (United States)

    Herron, B E

    1976-01-01

    Wilson's disease, or hepatolenticular degeneration, is a rare inherited disorder of copper metabolism which usually affects young people. Excess copper accumulates in the tissues, primarily in the liver, brain, and cornea. This copper deposition results in a wide range of hepatic and neurological symptoms, and may produce psychiatric illness. Hepatic involvement often occurs in childhood, while neurological deficits generally are detected at a later age. The disease is inherited in an autosomal recessive fashion. Ocular findings are of particular importance because the corneal copper deposition, forming the Kayser-Fleischer ring,is the only pathognomonic sign of the disease. The structure of the ring and the presence of copper have been well established. An anterior capsular deposition of copper in the lens results in a characteristic sunflower cataract in some of these patients. Other ocular abnormalities have been described but are much less common. The pathogenesis of the disease and the basic genetic defect remain obscure. It is clear that there is excess copper in the tissues, but the mechanism of its deposition is unknown. It is in some way associated with a failure to synthesize the serum copper protein ceruloplasmin normally. Another theory suggests that an abnormal protein with a high affinity for copper may bind the metal in the tissues. The diagnosis may be suggested by the clinical manifestations and confirmed by the presence of a Kayser-Fleischer ring. In the absence of these findings biochemical determinations are necessary. The most important of these are the serum ceruloplasmin, the urinary copper, and the hepatic copper concentration on biopsy. Treatment consists in the administration of the copper chelating agent, penicillamine, and the avoidance of a high copper intake. This usually results in marked clinical improvement if irreversible tissue damage has not occurred. Maintenance therapy for life is necessary in order to continue the negative

  7. Retinal oximetry in patients with ischaemic retinal diseases

    DEFF Research Database (Denmark)

    Rilvén, Sandra; Torp, Thomas Lee; Grauslund, Jakob

    2017-01-01

    increased retinal arterial oxygen saturation (raSatO2 ) in patients with DR. In patients with central retinal vein occlusion (CRVO), all studies found that rvSatO2 was reduced, but raSatO2 remained unchanged. Branch retinal vein occlusion was not associated with changes in retinal oxygen saturation......, but this was based on a single study. In conclusion, DR is associated with increased rvSatO2 and might also be related to increased raSatO2 . Central retinal vein occlusion (CRVO) is correlated with increased rvSatO2 but unrelated to raSatO2 . Prospective studies are needed to expand these findings. These would tell...... retinopathy (DR) and four about retinal vein occlusion. No studies about retinal artery occlusion were included. In diabetes, all studies found that increases in retinal venous oxygen saturation (rvSatO2 ) were associated with present as well as increasing levels of DR. Four of six studies also found...

  8. Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia.

    Science.gov (United States)

    Schön, Christian; Asteriti, Sabrina; Koch, Susanne; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Herms, Jochen; Seeliger, Mathias W; Cangiano, Lorenzo; Biel, Martin; Michalakis, Stylianos

    2016-03-15

    Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Melanopsin retinal ganglion cell loss in Alzheimer disease

    Science.gov (United States)

    Ross‐Cisneros, Fred N.; Koronyo, Yosef; Hannibal, Jens; Gallassi, Roberto; Cantalupo, Gaetano; Sambati, Luisa; Pan, Billy X.; Tozer, Kevin R.; Barboni, Piero; Provini, Federica; Avanzini, Pietro; Carbonelli, Michele; Pelosi, Annalisa; Chui, Helena; Liguori, Rocco; Baruzzi, Agostino; Koronyo‐Hamaoui, Maya; Sadun, Alfredo A.; Carelli, Valerio

    2015-01-01

    Objective Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction. Methods We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild‐moderate AD patients, and in a subgroup of 16 we evaluated rest–activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross‐sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid β (Aβ) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age‐matched controls. Results We demonstrated an age‐related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat‐mounted AD retinas, Aβ accumulation was remarkably evident inside and around mRGCs. Interpretation We show variable degrees of rest–activity circadian dysfunction in AD patients. We also demonstrate age‐related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aβ deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD. ANN NEUROL 2016;79:90–109 PMID:26505992

  10. Retinal detachment surgery without cryotherapy.

    OpenAIRE

    Chignell, A H; Markham, R H

    1981-01-01

    A series of cases of retinal detachment treated without the application of cryotherapy at the time of surgery has been studied. The omission of cryotherapy while not interfering with retinal reattachment, carries the risk of redetachment at a later date. Macular pucker may still occur in spite of the absence of cryotherapy.

  11. Perceptual Fading without Retinal Adaptation

    Science.gov (United States)

    Hsieh, Po-Jang; Colas, Jaron T.

    2012-01-01

    A retinally stabilized object readily undergoes perceptual fading and disappears from consciousness. This startling phenomenon is commonly believed to arise from local bottom-up sensory adaptation to edge information that occurs early in the visual pathway, such as in the lateral geniculate nucleus of the thalamus or retinal ganglion cells. Here…

  12. Retinal Mueller glial cells trigger the hallmark inflammatory process in autoimmune uveitis.

    Science.gov (United States)

    Hauck, Stefanie M; Schoeffmann, Stephanie; Amann, Barbara; Stangassinger, Manfred; Gerhards, Hartmut; Ueffing, Marius; Deeg, Cornelia A

    2007-06-01

    Spontaneous equine recurrent uveitis (ERU) is an incurable autoimmune disease affecting the eye. Although retinal-autoantigen specific T-helper 1 cells have been demonstrated to trigger disease progression and relapses, the molecular processes leading to retinal degeneration and consequent blindness remain unknown. To elucidate such processes, we studied changes in the total retinal proteome of ERU-diseased horses compared to healthy controls. Severe changes in the retinal proteome were found for several markers for blood-retinal barrier breakdown and whose emergence depended upon disease severity. Additionally, uveitic changes in the retina were accompanied by upregulation of aldose 1-epimerase, selenium-binding protein 1, alpha crystallin A chain, phosphatase 2A inhibitor (SET), and glial fibrillary acidic protein (GFAP), the latter indicating an involvement of retinal Mueller glial cells (RMG) in disease process. To confirm this, we screened for additional RMG-specific markers and could demonstrate that, in uveitic retinas, RMG concomitantly upregulate vimentin and GFAP and downregulate glutamine synthetase. These expression patterns suggest for an activated state of RMG, which further downregulate the expression of pigment epithelium-derived factor (PEDF) and begin expressing interferon-gamma, a pro-inflammatory cytokine typical for T-helper 1 cells. We thus propose that RMG may play a fatal role in uveitic disease progression by directly triggering inflammatory processes through the expression and secretion of interferon-gamma.

  13. Laser speckle imaging of rat retinal blood flow with hybrid temporal and spatial analysis method

    Science.gov (United States)

    Cheng, Haiying; Yan, Yumei; Duong, Timothy Q.

    2009-02-01

    Noninvasive monitoring of blood flow in retinal circulation will reveal the progression and treatment of ocular disorders, such as diabetic retinopathy, age-related macular degeneration and glaucoma. A non-invasive and direct BF measurement technique with high spatial-temporal resolution is needed for retinal imaging. Laser speckle imaging (LSI) is such a method. Currently, there are two analysis methods for LSI: spatial statistics LSI (SS-LSI) and temporal statistical LSI (TS-LSI). Comparing these two analysis methods, SS-LSI has higher signal to noise ratio (SNR) and TSLSI is less susceptible to artifacts from stationary speckle. We proposed a hybrid temporal and spatial analysis method (HTS-LSI) to measure the retinal blood flow. Gas challenge experiment was performed and images were analyzed by HTS-LSI. Results showed that HTS-LSI can not only remove the stationary speckle but also increase the SNR. Under 100% O2, retinal BF decreased by 20-30%. This was consistent with the results observed with laser Doppler technique. As retinal blood flow is a critical physiological parameter and its perturbation has been implicated in the early stages of many retinal diseases, HTS-LSI will be an efficient method in early detection of retina diseases.

  14. Saffron reduces ATP-induced retinal cytotoxicity by targeting P2X7 receptors.

    Science.gov (United States)

    Corso, Lucia; Cavallero, Anna; Baroni, Debora; Garbati, Patrizia; Prestipino, Gianfranco; Bisti, Silvia; Nobile, Mario; Picco, Cristiana

    2016-03-01

    P2X7-type purinergic receptors are distributed throughout the nervous system where they contribute to physiological and pathological functions. In the retina, this receptor is found in both inner and outer cells including microglia modulating signaling and health of retinal cells. It is involved in retinal neurodegenerative disorders such as retinitis pigmentosa and age-related macular degeneration (AMD). Experimental studies demonstrated that saffron protects photoreceptors from light-induced damage preserving both retinal morphology and visual function and improves retinal flicker sensitivity in AMD patients. To evaluate a possible interaction between saffron and P2X7 receptors (P2X7Rs), different cellular models and experimental approaches were used. We found that saffron positively influences the viability of mouse primary retinal cells and photoreceptor-derived 661W cells exposed to ATP, and reduced the ATP-induced intracellular calcium increase in 661W cells. Similar results were obtained on HEK cells transfected with recombinant rat P2X7R but not on cells transfected with rat P2X2R. Finally, patch-clamp experiments showed that saffron inhibited cationic currents in HEK-P2X7R cells. These results point out a novel mechanism through which saffron may exert its protective role in neurodegeneration and support the idea that P2X7-mediated calcium signaling may be a crucial therapeutic target in the treatment of neurodegenerative diseases.

  15. Preclinical studies on specific gene therapy for recessive retinal degenerative diseases.

    Science.gov (United States)

    Stieger, Knut; Chauveau, Christine; Rolling, Fabienne

    2010-10-01

    Inherited retinal diseases are non-lethal and have a wide level of genetic heterogeneity. Many of the genes involved have now been identified and their function elucidated, providing a major step towards the development of gene-based treatments. The most widely used vectors for ocular gene delivery are based on adeno-associated virus (AAV) because they mediate long-term transgene expression in a variety of retinal cell types and elicit minimal immune responses. Extensive preclinical evaluation of gene transfer strategies in small and large animal models is key to the development of successful gene-based therapies for the retina. These preclinical studies have already allowed the field to reach the point where gene therapy to treat inherited blindness has been brought to clinical trial. In this manuscript, we focus on recombinant AAV-mediated specific gene therapy for recessive retinal degenerative diseases we describe the preclinical studies for the treatment of retinal degeneration caused by retinal pigmented epithelium (RPE) cells or photoreceptor defects and the immune response induced by retinal rAAV gene transfer.

  16. Neuroprotective effects of citicoline in in vitro models of retinal neurodegeneration.

    Science.gov (United States)

    Matteucci, Andrea; Varano, Monica; Gaddini, Lucia; Mallozzi, Cinzia; Villa, Marika; Pricci, Flavia; Malchiodi-Albedi, Fiorella

    2014-04-14

    In recent years, citicoline has been the object of remarkable interest as a possible neuroprotectant. The aim of this study was to investigate if citicoline affected cell survival in primary retinal cultures and if it exerted neuroprotective activity in conditions modeling retinal neurodegeneration. Primary retinal cultures, obtained from rat embryos, were first treated with increasing concentrations of citicoline (up to 1000 µM) and analyzed in terms of apoptosis and caspase activation and characterized by immunocytochemistry to identify neuronal and glial cells. Subsequently, excitotoxic concentration of glutamate or High Glucose-containing cell culture medium (HG) was administered as well-known conditions modeling neurodegeneration. Glutamate or HG treatments were performed in the presence or not of citicoline. Neuronal degeneration was evaluated in terms of apoptosis and loss of synapses. The results showed that citicoline did not cause any damage to the retinal neuroglial population up to 1000 µM. At the concentration of 100 µM, it was able to counteract neuronal cell damage both in glutamate- and HG-treated retinal cultures by decreasing proapoptotic effects and contrasting synapse loss. These data confirm that citicoline can efficiently exert a neuroprotective activity. In addition, the results suggest that primary retinal cultures, under conditions inducing neurodegeneration, may represent a useful system to investigate citicoline neuroprotective mechanisms.

  17. Neuroprotective Effects of Citicoline in in Vitro Models of Retinal Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Andrea Matteucci

    2014-04-01

    Full Text Available In recent years, citicoline has been the object of remarkable interest as a possible neuroprotectant. The aim of this study was to investigate if citicoline affected cell survival in primary retinal cultures and if it exerted neuroprotective activity in conditions modeling retinal neurodegeneration. Primary retinal cultures, obtained from rat embryos, were first treated with increasing concentrations of citicoline (up to 1000 µM and analyzed in terms of apoptosis and caspase activation and characterized by immunocytochemistry to identify neuronal and glial cells. Subsequently, excitotoxic concentration of glutamate or High Glucose-containing cell culture medium (HG was administered as well-known conditions modeling neurodegeneration. Glutamate or HG treatments were performed in the presence or not of citicoline. Neuronal degeneration was evaluated in terms of apoptosis and loss of synapses. The results showed that citicoline did not cause any damage to the retinal neuroglial population up to 1000 µM. At the concentration of 100 µM, it was able to counteract neuronal cell damage both in glutamate- and HG-treated retinal cultures by decreasing proapoptotic effects and contrasting synapse loss. These data confirm that citicoline can efficiently exert a neuroprotective activity. In addition, the results suggest that primary retinal cultures, under conditions inducing neurodegeneration, may represent a useful system to investigate citicoline neuroprotective mechanisms.

  18. Preservation of cone photoreceptors after a rapid yet transient degeneration and remodeling in cone-only Nrl−/− mouse retina

    Science.gov (United States)

    Roger, Jerome E; Ranganath, Keerthi; Zhao, Lian; Cojocaru, Radu I; Brooks, Matthew; Gotoh, Norimoto; Veleri, Shobi; Hiriyanna, Avinash; Rachel, Rivka A; Campos, Maria Mercedes; Fariss, Robert N; Wong, Wai T; Swaroop, Anand

    2012-01-01

    Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss in many retinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor NRL. The loss of Nrl (Nrl−/−) in mice results in a retina with predominantly S-opsin containing cones that exhibit molecular and functional characteristics of WT cones. Here we report that Nrl−/− retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by four months of age, resulting in a thinner but intact outer nuclear layer with residual cones expressing S- and M-opsins and a preserved photopic ERG. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of genes related to stress response and inflammation, implying their involvement in cone death. The Nrl−/− mouse illustrates the long-term viability of cones in the absence of rods and RPE defects in a rodless retina. We propose that Nrl−/− retina may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone-dominant human macula. PMID:22238088

  19. Spectrophotometric retinal oximetry in pigs

    DEFF Research Database (Denmark)

    Traustason, Sindri; Kiilgaard, Jens Folke; Karlsson, Robert

    2013-01-01

    PURPOSE: To assess the validity of spectrophotometric retinal oximetry, by comparison to blood gas analysis and intra-vitreal measurements of partial pressure of oxygen (pO2). METHODS: Female domestic pigs were used for all experiments (n=8). Oxygen fraction in inspired air was changed using...... a mixture of room air, pure oxygen and pure nitrogen, ranging from 5% to 100% oxygen. Femoral arterial blood gas analysis and retinal oximetry was performed at each level of inspiratory oxygen fraction. Retinal oximetry was performed using a commercial instrument, the Oxymap Retinal Oximeter T1 (Oxymap ehf......, Reykjavik, Iceland). The device simultaneously acquires images at two wavelengths (570 nm and 600 nm) and specialized software automatically detects retinal blood vessels. In three pigs, invasive pO2-measurements were performed after the initial non-invasive measurements. RESULTS: Comparison of femoral...

  20. Bilateral retinitis following typhoid fever.

    Science.gov (United States)

    Prabhushanker, M; Topiwalla, Tasneem T; Ganesan, Geetha; Appandaraj, Sripal

    2017-01-01

    Post typhoid fever immune related reactions affecting the eye is a rare finding which can have various presentations in which typhoid retinopathy is not a well recognized sequelae. Here we present a case of 59 year old male who presented with right eye sudden painless loss of vision 4 weeks after typhoid fever which was diagnosed and treated successfully. His BCVA was 2/60 in right eye and 6/6 in left eye. Fundus examination showed retinitis along with macular serous detachment in right eye and retinitis in left eye. Significant improvement in BCVA in right eye was observed after treatment with oral steroid with resolving retinitis lesions. Diagnosis of post typhoid immune mediated retinitis was made with good resolution following treatment. Immune mediated retinitis is a rare sequelae to typhoid infection which can be successfully treated with systemic steroids with good resolution of the lesions.

  1. [Future methods of treatment in age related macular degeneration].

    Science.gov (United States)

    Turlea, C

    2012-01-01

    In the present time the treatment of Age Related Macular Degeneration (ARMD) begins to develop. Many medical therapies are presently tested in the two types of ARMD, geographic atrophy and exudative ARMD. In atrophic ARMD, new drugs are aimed to spare photoreceptors and the retinal pigment epithelium, to prevent oxidative damage on the retina and to suppress the inflammation process. In exudative ARMD, new therapies are already in use and in progress, especially the anti-VEGF factors, and others try to improve visual prognosis in targeting other mechanism or cells involved in the angiogenesis process. This article reviews and summarizes the available data, presented in several scientific meetings, congresses or given directly by the companies involved.

  2. Progress in measurement of ocular blood flow and relevance to our understanding of glaucoma and age-related macular degeneration.

    Science.gov (United States)

    Harris, A; Chung, H S; Ciulla, T A; Kagemann, L

    1999-09-01

    New technologies have facilitated the study of the ocular circulation. These modalities and analysis techniques facilitate very precise and comprehensive study of retinal, choroidal, and retrobulbar circulations. These techniques include: 1. Vessel caliber assessment; 2. Scanning laser ophthalmoscopic fluorescein angiography and indocyanine green angiography to image and evaluate the retinal circulation and choroidal circulation respectively; 3. Laser Doppler flowmetry and confocal scanning laser Doppler flowmetry to measure blood flow in the optic nerve head and retinal capillary beds; 4. Ocular pulse measurement; and 5. color Doppler imaging to measure blood flow velocities in the central retinal artery, the ciliary arteries and the ophthalmic artery. These technique have greatly enhanced the ability to quantify ocular perfusion defects in many disorders, including glaucoma and age-related macular degeneration, two of the most prevalent causes of blindness in the industrialized world. Recently it has become clear, in animal models of glaucoma, that retinal ganglion cells die via apoptosis. The factors that initiate apoptosis in these cells remain obscure, but ischemia may play a central role. Patients with either primary open-angle glaucoma or normal-tension glaucoma experience various ocular blood flow deficits. With regard to age-related macular degeneration, the etiology remains unknown although some theories include primary retinal pigment epithelial senescence, genetic defects such as those found in the ABCR gene which is also defective in Stargardt's disease and ocular perfusion abnormalities. As the choriocapillaris supplies the metabolic needs of the retinal pigment epithelium and the outer retina, perfusion defect in the choriocapillaris could account for some of the physiologic and pathologic changes in AMD. Vascular defects have been identified in both nonexudative and exudative AMD patients using new technologies. This paper is a comprehensive update

  3. Observation of Human Retinal Remodeling in Octogenarians with a Resveratrol Based Nutritional Supplement

    OpenAIRE

    Donn Carroll; Carla Podella; Lawrence Ulanski; William Stiles; Stuart Richer

    2013-01-01

    Purpose: Rare spontaneous remissions from age-related macular degeneration (AMD) suggest the human retina has large regenerative capacity, even in advanced age. We present examples of robust improvement of retinal structure and function using an OTC oral resveratrol (RV) based nutritional supplement called Longevinex® or L/RV (circa 2004, Resveratrol Partners, LLC, Las Vegas, NV, USA). RV, a polyphenolic phytoalexin caloric-restriction mimic, induces hormesis at low doses with widespread bene...

  4. Retinal pigment epithelial acid lipase activity and lipoprotein receptors: effects of dietary omega-3 fatty acids.

    OpenAIRE

    2002-01-01

    PURPOSE: To show that fish oil-derived omega-3 polyunsaturated fatty acids, delivered to the retinal pigment epithelium (RPE) by circulating low-density lipoproteins (LDL), enhance already considerable RPE lysosomal acid lipase activity, providing for more efficient hydrolysis of intralysosomal RPE lipids, an effect that may help prevent development of age-related macular degeneration (ARMD). METHODS: Colorimetric biochemical and histochemical techniques were used to demonstrate RPE acid lipa...

  5. Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

    OpenAIRE

    2015-01-01

    abstract A variety of diseases lead to degeneration of retinal ganglion cells (RGCs) and their axons within the optic nerve resulting in loss of visual function. Although current therapies may delay RGC loss, they do not restore visual function or completely halt disease progression. Regenerative medicine has recently focused on stem cell therapy for both neuroprotective and regenerative purposes. However, significant problems remain to be addressed, such as the long‐term impact of reactive g...

  6. Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells

    OpenAIRE

    2007-01-01

    Usher syndrome type IIA (USH2A), characterized by progressive photoreceptor degeneration and congenital moderate hearing loss, is the most common subtype of Usher syndrome. In this article, we show that the USH2A protein, also known as usherin, is an exceptionally large (≈600-kDa) matrix protein expressed specifically in retinal photoreceptors and developing cochlear hair cells. In mammalian photoreceptors, usherin is localized to a spatially restricted membrane microdomain at the apical inne...

  7. Perceptual learning in patients with macular degeneration

    Directory of Open Access Journals (Sweden)

    Tina ePlank

    2014-10-01

    Full Text Available Patients with age-related macular degeneration (AMD or hereditary macular dystrophies (JMD rely on an efficient use of their peripheral visual field. We trained eight AMD and five JMD patients to perform a texture-discrimination task (TDT at their preferred retinal locus (PRL used for fixation. Six training sessions of approximately one hour duration were conducted over a period of approximately 3 weeks. Before, during and after training twelve patients and twelve age-matched controls (the data from two controls had to be discarded later took part in three functional magnetic resonance imaging (fMRI sessions to assess training-related changes in the BOLD response in early visual cortex. Patients benefited from the training measurements as indexed by significant decrease (p=.001 in the stimulus onset asynchrony (SOA between the presentation of the texture target on background and the visual mask, and in a significant location specific effect of the PRL with respect to hit rate (p=.014. The following trends were observed: (i Improvement in Vernier acuity for an eccentric line-bisection task; (ii positive correlation between the development of BOLD signals in early visual cortex and initial fixation stability (r=0.531; (iii positive correlation between the increase in task performance and initial fixation stability (r=0.730. The first two trends were non-significant, whereas the third trend was significant at p=.014, Bonferroni corrected. Consequently, our exploratory study suggests that training on the TDT can enhance eccentric vision in patients with central vision loss. This enhancement is accompanied by a modest alteration in the BOLD response in early visual cortex.

  8. Gene expression changes within Müller glial cells in retinitis pigmentosa.

    Science.gov (United States)

    Roesch, Karin; Stadler, Michael B; Cepko, Constance L

    2012-01-01

    Retinitis pigmentosa (RP) is a progressive retinal degeneration in which the retina loses nearly all of its photoreceptor cells and undergoes major structural changes. Little is known regarding the role the resident glia, the Müller glia, play in the progression of the disease. In this article, we define gene expression changes in Müller glial cells (MGCs) from two different mouse models of RP, the retinal degeneration 1 (rd1) and rhodopsin knockout (Rhod-ko) models. The RNA repertoire of single MGCs was comprehensively profiled, and a comparison was made between MGCs from wild-type (WT) and mutant retinas. Two time points were chosen for analysis, one at the peak of rod photoreceptor death and one during the period of cone photoreceptor death. Retinas were dissociated, and single MGCs were chosen under a dissecting microscope using a micropipette. Single cell cDNAs were generated and genome-wide profiles were obtained by hybridization to Affymetrix arrays. A comparison was made among all samples to discover the changes in gene expression during the periods of rod and cone photoreceptor death. MGCs respond to retinal degeneration by undergoing gliosis, a process marked by the upregulation of glial fibrillary acidic protein (Gfap). Many additional transcripts were found to change. These can be placed into functional clusters, such as retinal remodeling, stress response, and immune-related response. A high degree of heterogeneity among the individual cells was observed, possibly due to their different spatial proximities to dying cells and/or inherent heterogeneity among MGCs.

  9. Topographic prominence discriminator for the detection of short-latency spikes of retinal ganglion cells

    Science.gov (United States)

    Choi, Myoung-Hwan; Ahn, Jungryul; Park, Dae Jin; Lee, Sang Min; Kim, Kwangsoo; Cho, Dong-il Dan; Senok, Solomon S.; Koo, Kyo-in; Goo, Yong Sook

    2017-02-01

    Objective. Direct stimulation of retinal ganglion cells in degenerate retinas by implanting epi-retinal prostheses is a recognized strategy for restoration of visual perception in patients with retinitis pigmentosa or age-related macular degeneration. Elucidating the best stimulus-response paradigms in the laboratory using multielectrode arrays (MEA) is complicated by the fact that the short-latency spikes (within 10 ms) elicited by direct retinal ganglion cell (RGC) stimulation are obscured by the stimulus artifact which is generated by the electrical stimulator. Approach. We developed an artifact subtraction algorithm based on topographic prominence discrimination, wherein the duration of prominences within the stimulus artifact is used as a strategy for identifying the artifact for subtraction and clarifying the obfuscated spikes which are then quantified using standard thresholding. Main results. We found that the prominence discrimination based filters perform creditably in simulation conditions by successfully isolating randomly inserted spikes in the presence of simple and even complex residual artifacts. We also show that the algorithm successfully isolated short-latency spikes in an MEA-based recording from degenerate mouse retinas, where the amplitude and frequency characteristics of the stimulus artifact vary according to the distance of the recording electrode from the stimulating electrode. By ROC analysis of false positive and false negative first spike detection rates in a dataset of one hundred and eight RGCs from four retinal patches, we found that the performance of our algorithm is comparable to that of a generally-used artifact subtraction filter algorithm which uses a strategy of local polynomial approximation (SALPA). Significance. We conclude that the application of topographic prominence discrimination is a valid and useful method for subtraction of stimulation artifacts with variable amplitudes and shapes. We propose that our algorithm

  10. Noninvasive two-photon microscopy imaging of mouse retina and retinal pigment epithelium through the pupil of the eye.

    Science.gov (United States)

    Palczewska, Grazyna; Dong, Zhiqian; Golczak, Marcin; Hunter, Jennifer J; Williams, David R; Alexander, Nathan S; Palczewski, Krzysztof

    2014-07-01

    Two-photon excitation microscopy can image retinal molecular processes in vivo. Intrinsically fluorescent retinyl esters in subcellular structures called retinosomes are an integral part of the visual chromophore regeneration pathway. Fluorescent condensation products of all-trans-retinal accumulate in the eye with age and are also associated with age-related macular degeneration (AMD). Here, we report repetitive, dynamic imaging of these compounds in live mice through the pupil of the eye. By leveraging advanced adaptive optics, we developed a data acquisition algorithm that permitted the identification of retinosomes and condensation products in the retinal pigment epithelium by their characteristic localization, spectral properties and absence in genetically modified or drug-treated mice. This imaging approach has the potential to detect early molecular changes in retinoid metabolism that trigger light- and AMD-induced retinal defects and to assess the effectiveness of treatments for these conditions.

  11. Inflammation and its role in age-related macular degeneration.

    Science.gov (United States)

    Kauppinen, Anu; Paterno, Jussi J; Blasiak, Janusz; Salminen, Antero; Kaarniranta, Kai

    2016-05-01

    Inflammation is a cellular response to factors that challenge the homeostasis of cells and tissues. Cell-associated and soluble pattern-recognition receptors, e.g. Toll-like receptors, inf