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  1. 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.

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

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    Ueki, Yumi; Ramirez, Grisela; Salcedo, Ernesto; Stabio, Maureen E; Lefcort, Frances

    2016-01-01

    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.

  3. Early Events in Retinal Degeneration Caused by Rhodopsin Mutation or Pigment Epithelium Malfunction: Differences and Similarities

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    Di Pierdomenico, Johnny; García-Ayuso, Diego; Pinilla, Isabel; Cuenca, Nicolás; Vidal-Sanz, Manuel; Agudo-Barriuso, Marta; Villegas-Pérez, María P.

    2017-01-01

    To study the course of photoreceptor cell death and macro and microglial reactivity in two rat models of retinal degeneration with different etiologies. Retinas from P23H-1 (rhodopsin mutation) and Royal College of Surgeon (RCS, pigment epithelium malfunction) rats and age-matched control animals (Sprague-Dawley and Pievald Viro Glaxo, respectively) were cross-sectioned at different postnatal ages (from P10 to P60) and rhodopsin, L/M- and S-opsin, ionized calcium-binding adapter molecule 1 (Iba1), glial fibrillary acid protein (GFAP), and proliferating cell nuclear antigen (PCNA) proteins were immunodetected. Photoreceptor nuclei rows and microglial cells in the different retinal layers were quantified. Photoreceptor degeneration starts earlier and progresses quicker in P23H-1 than in RCS rats. In both models, microglial cell activation occurs simultaneously with the initiation of photoreceptor death while GFAP over-expression starts later. As degeneration progresses, the numbers of microglial cells increase in the retina, but decreasing in the inner retina and increasing in the outer retina, more markedly in RCS rats. Interestingly, and in contrast with healthy animals, microglial cells reach the outer nuclei and outer segment layers. The higher number of microglial cells in dystrophic retinas cannot be fully accounted by intraretinal migration and PCNA immunodetection revealed microglial proliferation in both models but more importantly in RCS rats. The etiology of retinal degeneration determines the initiation and pattern of photoreceptor cell death and simultaneously there is microglial activation and migration, while the macroglial response is delayed. The actions of microglial cells in the degeneration cannot be explained only in the basis of photoreceptor death because they participate more actively in the RCS model. Thus, the retinal degeneration caused by pigment epithelium malfunction is more inflammatory and would probably respond better to interventions

  4. Loss of Arf4 causes severe degeneration of the exocrine pancreas but not cystic kidney disease or retinal degeneration.

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    Jillian N Pearring

    2017-04-01

    Full Text Available Arf4 is proposed to be a critical regulator of membrane protein trafficking in early secretory pathway. More recently, Arf4 was also implicated in regulating ciliary trafficking, however, this has not been comprehensively tested in vivo. To directly address Arf4's role in ciliary transport, we deleted Arf4 specifically in either rod photoreceptor cells, kidney, or globally during the early postnatal period. Arf4 deletion in photoreceptors did not cause protein mislocalization or retinal degeneration, as expected if Arf4 played a role in protein transport to the ciliary outer segment. Likewise, Arf4 deletion in kidney did not cause cystic disease, as expected if Arf4 were involved in general ciliary trafficking. In contrast, global Arf4 deletion in the early postnatal period resulted in growth restriction, severe pancreatic degeneration and early death. These findings are consistent with Arf4 playing a critical role in endomembrane trafficking, particularly in the pancreas, but not in ciliary function.

  5. Round atrophic holes in lattice degeneration--an important cause of phakic retinal detachment.

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    Tillery, W V; Lucier, A C

    1976-01-01

    Round atrophic holes in lattice degeneration are an important cause of phakic retinal detachment. Detachments due solely to round holes in lattice accounted for almost 2.8% of all retinal detachments treated at Wills Eye Hospital from January 1970 to August 1973. These detachments had the following important characteristics: 1. One of the patients were under the age of 30 years. 2. Over 75% of the patients had refractive errors more myopic than -3 D spherical equivalent. 3. Inferior detachments were slightly more common than superior detachments. When located inferiorly, there was a tendency for slow progression as indicated by the frequent presence of pigmented demarcation lines. 4. Surgical repair with standard scleral buckling techniques was successful in 98% of these detachments. Young, moderate to highly myopic patients with round holes in areas of lattice degeneration seem to have a greater risk of developing this type of detachment. Patients with the triad of youth, myopia, and round holes in lattice degeneration deserve close observation.

  6. Gene Therapy for the Retinal Degeneration of Usher Syndrome Caused by Mutations in MYO7A.

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    Lopes, Vanda S; Williams, David S

    2015-01-20

    Usher syndrome is a deaf-blindness disorder. One of the subtypes, Usher 1B, is caused by loss of function of the gene encoding the unconventional myosin, MYO7A. A variety of different viral-based delivery approaches have been tested for retinal gene therapy to prevent the blindness of Usher 1B, and a clinical trial based on one of these approaches has begun. This review evaluates the different approaches. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  7. Light and inherited retinal degeneration

    OpenAIRE

    Paskowitz, D M; LaVail, M M; Duncan, J L

    2006-01-01

    Light deprivation has long been considered a potential treatment for patients with inherited retinal degenerative diseases, but no therapeutic benefit has been demonstrated to date. In the few clinical studies that have addressed this issue, the underlying mutations were unknown. Our rapidly expanding knowledge of the genes and mechanisms involved in retinal degeneration have made it possible to reconsider the potential value of light restriction in specific genetic contexts. This review summ...

  8. Progress toward the maintenance and repair of degenerating retinal circuitry.

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    Vugler, Anthony A

    2010-01-01

    Retinal diseases such as age-related macular degeneration and retinitis pigmentosa remain major causes of severe vision loss in humans. Clinical trials for treatment of retinal degenerations are underway and advancements in our understanding of retinal biology in health/disease have implications for novel therapies. A review of retinal biology is used to inform a discussion of current strategies to maintain/repair neural circuitry in age-related macular degeneration, retinitis pigmentosa, and Type 2 Leber congenital amaurosis. In age-related macular degeneration/retinitis pigmentosa, a progressive loss of rods/cones results in corruption of bipolar cell circuitry, although retinal output neurons/photoreceptive melanopsin cells survive. Visual function can be stabilized/enhanced after treatment in age-related macular degeneration, but in advanced degenerations, reorganization of retinal circuitry may preclude attempts to restore cone function. In Type 2 Leber congenital amaurosis, useful vision can be restored by gene therapy where central cones survive. Remarkable progress has been made in restoring vision to rodents using light-responsive ion channels inserted into bipolar cells/retinal ganglion cells. Advances in genetic, cellular, and prosthetic therapies show varying degrees of promise for treating retinal degenerations. While functional benefits can be obtained after early therapeutic interventions, efforts should be made to minimize circuitry changes as soon as possible after rod/cone loss. Advances in retinal anatomy/physiology and genetic technologies should allow refinement of future reparative strategies.

  9. 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.

  10. The prognosis of retinal detachment due to lattice degeneration.

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    Benson, W E; Morse, P H

    1978-09-01

    In a series of 553 consecutive retinal detachments, 29% (120) were due to lattice degeneration. Forty-five percent of these were due to atrophic holes in the lattice degeneration and 55% were due to tears caused by traction posterior to or at the end of a patch of lattice. In phakic patients, retinal detachments due to atrophic holes were most common in young myopes. Detachments due to traction tears were seen in older, less myopic patients. The incidence of massive periretinal proliferation was less (5%) in detachments due to lattice degeneration than in detachments not due to lattice degeneration (6.5%).

  11. [Peripheral retinal degenerations--treatment recommendations].

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    Joussen, A M; Kirchhof, B

    2004-10-01

    This report reviews the clinical appearance of degenerative diseases of the peripheral retina in relationship to the risk of developing a rhegmatogenous retinal detachment. We present recommendations for preventive treatment in eyes at increased risk of developing retinal detachment. Retinal degenerations are common lesions involving the peripheral retina but most of them are clinically insignificant. Lattice degeneration, degenerative retinoschisis, cystic retinal tufts, and very rarely zonular traction tufts can result in rhegmatogenous retinal detachment. Therefore, these lesions have been considered for prophylactic treatment; however, adequate studies have not been performed to date. Most of the peripheral retinal degenerations may not require treatment except in rare, high-risk situations. According to current knowledge there is no higher incidence of secondary pucker or other side effects after laser coagulation. Therefore, generous laser indication is recommended if risk factors apply.

  12. Peripheral retinal degenerations and the risk of retinal detachment.

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    Lewis, Hilel

    2003-07-01

    To review the degenerative diseases of the peripheral retina in relationship with the risk to develop a rhegmatogenous retinal detachment and to present recommendations for use in eyes at increased risk of developing a retinal detachment. Focused literature review and author's clinical experience. Retinal degenerations are common lesions involving the peripheral retina, and most of them are clinically insignificant. Lattice degeneration, degenerative retinoschisis, cystic retinal tufts, and, rarely, zonular traction tufts, can result in a rhegmatogenous retinal detachment. Therefore, these lesions have been considered for prophylactic therapy; however, adequate studies have not been performed to date. Well-designed, prospective, randomized clinical studies are necessary to determine the benefit-risk ratio of prophylactic treatment. In the meantime, the evidence available suggests that most of the peripheral retinal degenerations should not be treated except in rare, high-risk situations.

  13. Retinal Cell Degeneration in Animal Models

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    Masayuki Niwa

    2016-01-01

    Full Text Available 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 insight into the underlying mechanisms of the disease, and will facilitate the development of novel effective therapeutic drugs to treat retinal cell damage.

  14. An Unusual Case of Extensive Lattice Degeneration and Retinal Detachment

    OpenAIRE

    Mathew, David J.; Sarma, Saurabh Kumar; Basaiawmoit, Jennifer V.

    2016-01-01

    Lattice degeneration of the retina is not infrequently encountered on a dilated retinal examination and many of them do not need any intervention. We report a case of atypical lattice degeneration variant with peripheral retinal detachment. An asymptomatic 35-year-old lady with minimal refractive error was found to have extensive lattice degeneration, peripheral retinal detachment and fibrotic changes peripherally with elevation of retinal vessels on dilated retinal examination. There were al...

  15. Lattice degeneration of the retina and retinal detachment.

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    Semes, L P

    1992-01-01

    Lattice retinal degeneration is considered the most significant peripheral retinal disorder potentially predisposing to retinal breaks and retinal detachment. Lattice degeneration affects the vitreous and inner retinal layers with secondary changes as deep as the retinal pigment epithelium and perhaps the choriocapillaris. Variations in clinical appearance are the rule; geographically, lattice lesions favor the vertical meridians between the equator and the ora serrata. Lattice degeneration begins early in life and has been reported in sequential generations of the same family. Along with its customary bilateral occurrence, lattice shares other characteristics of a dystrophy. The association between the vitreous and retina in lattice lesions may be responsible for the majority of lattice-induced retinal detachments. The tumultuous event of posterior vitreous separation in the presence of abnormally strong vitreoretinal adherence is the trigger for a retinal tear that, in turn, may lead to retinal detachment. Although retinal holes in young patients with lattice degeneration may play a role in the evolution of retinal detachment, the clinical course of lattice degeneration seems to be one of dormancy rather than of progressive change. This discussion outlines the pathophysiology of lattice retinal degeneration and the relationship of pathophysiology to clinical presentation. The epidemiology of lattice degeneration is summarized, as are the possible precursors to retinal detachment. A clinical characterization of the natural history of lattice degeneration is offered, and interventions for complications are described. To conclude, management strategies from a primary-care standpoint are reviewed.

  16. Prescreening whole exome sequencing results from patients with retinal degeneration for variants in genes associated with retinal degeneration

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    Bryant L

    2017-12-01

    Full Text Available Laura Bryant,1 Olga Lozynska,1 Albert M Maguire,1–3 Tomas S Aleman,1–3 Jean Bennett1–3 1Center for Advanced Retinal and Ocular Therapeutics (CAROT, FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Ophthalmology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 3Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Background: Accurate clinical diagnosis and prognosis of retinal degeneration can be aided by the identification of the disease-causing genetic variant. It can confirm the clinical diagnosis as well as inform the clinician of the risk for potential involvement of other organs such as kidneys. It also aids in genetic counseling for affected individuals who want to have a child. Finally, knowledge of disease-causing variants informs laboratory investigators involved in translational research. With the advent of next-generation sequencing, identifying pathogenic mutations is becoming easier, especially the identification of novel pathogenic variants.Methods: We used whole exome sequencing on a cohort of 69 patients with various forms of retinal degeneration and in whom screens for previously identified disease-causing variants had been inconclusive. All potential pathogenic variants were verified by Sanger sequencing and, when possible, segregation analysis of immediate relatives. Potential variants were identified by using a semi-masked approach in which rare variants in candidate genes were identified without knowledge of the clinical diagnosis (beyond “retinal degeneration” or inheritance pattern. After the initial list of genes was prioritized, genetic diagnosis and inheritance pattern were taken into account.Results: We identified the likely pathogenic variants in 64% of the subjects. Seven percent had a single

  17. Negative electroretinograms in pericentral pigmentary retinal degeneration.

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    Hotta, Kazuki; Kondo, Mineo; Nakamura, Makoto; Hotta, Junko; Terasaki, Hiroko; Miyake, Yozo; Hida, Tetsuo

    2006-01-01

    The clinical presentation and electrophysiological findings are described of three consecutive cases with pericentral pigmentary retinal degeneration. The responses to bright flashes after dark adaptation showed negative waveform shape in all cases. Rod responses were strongly reduced compared with cone responses. Cone electroretinograms elicited by long-duration stimuli showed greater loss of the on-response than the off-response. The ratio of the on-response amplitude to off-response amplitude of these patients (0.52 +/- 0.12; mean +/- SD, n = 6) was significantly smaller than that of normal subject (0.83 +/- 0.21; mean +/- SD, n = 8) (Mann-Whitney U-test, P retinal function, especially in transmission between photoreceptors and depolarizing bipolar cells.

  18. An Unusual Case of Extensive Lattice Degeneration and Retinal Detachment.

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    Mathew, David J; Sarma, Saurabh Kumar; Basaiawmoit, Jennifer V

    2016-07-01

    Lattice degeneration of the retina is not infrequently encountered on a dilated retinal examination and many of them do not need any intervention. We report a case of atypical lattice degeneration variant with peripheral retinal detachment. An asymptomatic 35-year-old lady with minimal refractive error was found to have extensive lattice degeneration, peripheral retinal detachment and fibrotic changes peripherally with elevation of retinal vessels on dilated retinal examination. There were also areas of white without pressure, chorioretinal scarring and retinal breaks. All the changes were limited to beyond the equator but were found to span 360 degrees. She was treated with barrage laser all around to prevent extension of the retinal detachment posteriorly. She remained stable till her latest follow-up two years after the barrage laser. This case is reported for its rarity with a discussion of the probable differential diagnoses. To the best of our knowledge, this is the first report of such findings in lattice degeneration.

  19. Frequency of lattice degeneration and retinal breaks in the fellow eye in retinal detachment.

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    Lorentzen, S E

    1988-04-01

    The fellow eye of 100 consecutively admitted cases of retinal detachment was studied with three-mirror examination for the presence of lattice degeneration and retinal breaks. Lattice degeneration was found in 18% and retinal breaks in 20% of fellow eyes.

  20. Transplantation of retinal pigment epithelial cells - a possible future treatment for age-related macular degeneration

    DEFF Research Database (Denmark)

    Wiencke, Anne Katrine

    2001-01-01

    ophthalmology, age-related macular degeneration, transplantation, retinal pigment epithelial cells, treatment......ophthalmology, age-related macular degeneration, transplantation, retinal pigment epithelial cells, treatment...

  1. Transplantation of retinal pigment epithelial cells - a possible future treatment for age-related macular degeneration

    DEFF Research Database (Denmark)

    Wiencke, Anne Katrine

    2001-01-01

    ophthalmology, age-related macular degeneration, retinal pigment epithelial cells, transplantation, treatment......ophthalmology, age-related macular degeneration, retinal pigment epithelial cells, transplantation, treatment...

  2. Prolonged Prevention of Retinal Degeneration with Retinylamine Loaded Nanoparticles

    OpenAIRE

    Puntel, Anthony; Maeda, Akiko; Golczak, Marcin; Gao, Song-Qi; Yu, Guanping; Palczewski, Krzysztof; Lu, Zheng-Rong

    2015-01-01

    Retinal degeneration impairs the vision of millions in all age groups worldwide. Increasing evidence suggests that the etiology of many retinal degenerative diseases is associated with impairment in biochemical reactions involved in the visual cycle, a metabolic pathway responsible for regeneration of the visual chromophore (11-cis-retinal). Inefficient clearance of toxic retinoid metabolites, especially all-trans-retinal, is considered responsible for photoreceptor cytotoxicity. Primary amin...

  3. Progression of transsynaptic retinal degeneration with spectral-domain optical coherence tomography

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    Stephen G. Schwartz

    2017-04-01

    Conclusions and importance: Retrograde transsynaptic retinal degeneration may occur in patients with homonymous visual field loss caused by post-geniculate neurologic disease. This is best detected as homonymous thinning of the retina, corresponding to the pattern of visual field loss, using SD-OCT of the GCC and macula. The retinal changes occur at a variable time following the onset of neurologic disease.

  4. The hormone prolactin is a novel, endogenous trophic factor able to regulate reactive glia and to limit retinal degeneration.

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    Arnold, Edith; Thebault, Stéphanie; Baeza-Cruz, German; Arredondo Zamarripa, David; Adán, Norma; Quintanar-Stéphano, Andrés; Condés-Lara, Miguel; Rojas-Piloni, Gerardo; Binart, Nadine; Martínez de la Escalera, Gonzalo; Clapp, Carmen

    2014-01-29

    Retinal degeneration is characterized by the progressive destruction of retinal cells, causing the deterioration and eventual loss of vision. We explored whether the hormone prolactin provides trophic support to retinal cells, thus protecting the retina from degenerative pressure. Inducing hyperprolactinemia limited photoreceptor apoptosis, gliosis, and changes in neurotrophin expression, and it preserved the photoresponse in the phototoxicity model of retinal degeneration, in which continuous exposure of rats to bright light leads to retinal cell death and retinal dysfunction. In this model, the expression levels of prolactin receptors in the retina were upregulated. Moreover, retinas from prolactin receptor-deficient mice exhibited photoresponsive dysfunction and gliosis that correlated with decreased levels of retinal bFGF, GDNF, and BDNF. Collectively, these data unveiled prolactin as a retinal trophic factor that may regulate glial-neuronal cell interactions and is a potential therapeutic molecule against retinal degeneration.

  5. Calcium channel blockers inhibit retinal degeneration in the retinal-degeneration-B mutant of Drosophila.

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    Sahly, I; Bar Nachum, S; Suss-Toby, E; Rom, A; Peretz, A; Kleiman, J; Byk, T; Selinger, Z; Minke, B

    1992-01-01

    Light accelerates degeneration of photoreceptor cells of the retinal degeneration B (rdgB) mutant of Drosophila. During early stages of degeneration, light stimuli evoke spikes from photoreceptors of the mutant fly; no spikes can be recorded from photoreceptors of the wild-type fly. Production of spike potentials from mutant photoreceptors was blocked by diltiazem, verapamil hydrochloride, and cadmium. Little, if any, effect of the (-)-cis isomer or (+)-cis isomer of diltiazem on the light response was seen. Further, the (+)-cis isomer was approximately 50 times more effective than the (-)-cis isomer in blocking the Ca2+ spikes, indicating that diltiazem action on the rdgB eye is mediated by means of blocking voltage-sensitive Ca2+ channels, rather than by blocking the light-sensitive channels. Application of the Ca(2+)-channel blockers (+)-cis-diltiazem and verapamil hydrochloride to the eyes of rdgB flies over a 7-day period largely inhibited light-dependent degeneration of the photoreceptor cells. Pulse labeling with [32P]phosphate showed much greater incorporation into eye proteins of [32P]phosphate in rdgB flies than in wild-type flies. Retarding the light-induced photoreceptor degeneration in the mutant by Ca(2+)-channel blockers, thus, suggests that toxic increase in intracellular Ca2+ by means of voltage-gated Ca2+ channels, possibly secondary to excessive phosphorylation, leads to photoreceptor degeneration in the rdgB mutant. Images PMID:1309615

  6. Phakic retinal detachment associated with atrophic hole of lattice degeneration of the retina.

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    Murakami-Nagasako, F; Ohba, N

    1983-01-01

    Forty patients with phakic nontraumatic retinal detachment caused by atrophic retinal hole of lattice degeneration were reviewed. The condition was characterized by insidious, slowly developing shallow detachment, with frequent formation of demarcation lines. Often, the patients did not recognize their visual problems until the detachment had extended to the macular region. Young patients under 40 years of age were more common than older patients. Myopic refractive errors were frequently associated. The results of surgical repair were favorable. The risk of retinal detachment in lattice degeneration with atrophic holes was estimated to be about 1 in 90 patients, and prophylactic treatment for this common anomaly is not readily recommended.

  7. LONGITUDINAL STRUCTURAL CHANGES IN LATE-ONSET RETINAL DEGENERATION.

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    Cukras, Catherine; Flamendorf, Jason; Wong, Wai T; Ayyagari, Radha; Cunningham, Denise; Sieving, Paul A

    2016-12-01

    To characterize longitudinal structural changes in early stages of late-onset retinal degeneration to investigate pathogenic mechanisms. Two affected siblings, both with a S163R missense mutation in the causative gene C1QTNF5, were followed for 8+ years. Color fundus photos, fundus autofluorescence images, near-infrared reflectance fundus images, and spectral domain optical coherence tomography scans were acquired during follow-up. Both patients, aged 45 and 50 years, had good visual acuities (>20/20) in the context of prolonged dark adaptation. Baseline color fundus photography demonstrated yellow-white, punctate lesions in the temporal macula that correlated with a reticular pattern on fundus autofluorescence and near-infrared reflectance imaging. Baseline spectral domain optical coherence tomography imaging revealed subretinal deposits that resemble reticular pseudodrusen described in age-related macular degeneration. During follow-up, these affected areas developed confluent thickening of the retinal pigment epithelial layer and disruption of the ellipsoid zone of photoreceptors before progressing to overt retinal pigment epithelium and outer retinal atrophy. Structural changes in early stages of late-onset retinal degeneration, revealed by multimodal imaging, resemble those of reticular pseudodrusen observed in age-related macular degeneration and other retinal diseases. Longitudinal follow-up of these lesions helps elucidate their progression to frank atrophy and may lend insight into the pathogenic mechanisms underlying diverse retinal degenerations.

  8. Risk of retinal detachment in patients with lattice degeneration.

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    Sasaki, K; Ideta, H; Yonemoto, J; Tanaka, S; Hirose, A; Oka, C

    1998-01-01

    To determine the risk of retinal detachment in patients with lattice degeneration of the retina, we statistically analyzed the incidence of retinal detachment in these patients. The data of hospital patients with retinal detachment associated with lattice degeneration in Kumamoto Prefecture, Japan, in 1990 were collected. The prevalence of lattice degeneration in Kumamoto was reported to be 9.5% in 1980. Based on population data from the 1990 census, the cumulative incidence of retinal detachment associated with lattice degeneration was calculated in this study. Among 1,840,000 residents in Kumamoto, there were 110 patients with retinal detachment associated with lattice degeneration; 72 with detachment resulting from tractional tears (tears), and 38 with detachment from atrophic holes. The cumulative incidence of retinal detachment from atrophic holes was 1.5% at the age of 40 years; from tears it was 3.6% at the age of 80 years. The cumulative incidence of detachment from both atrophic holes and tears was 5.3% at the age of 80 years. The results of this study are useful for clarifying the natural course of lattice degeneration.

  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. Effect of substance P on recovery from laser-induced retinal degeneration.

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    Hong, Hyun Sook; Kim, Suna; Nam, Seungwoo; Um, Jihyun; Kim, Yeong Hoon; Son, Youngsook

    2015-01-01

    Retinal degeneration is caused by neovascularization and persistent inflammation in the retinal pigment epithelium (RPE) and choroid, and causes serious eye disease including age-related macular degeneration (AMD). Thus, inhibiting inflammation and neovascularization may be a primary approach to protect the retina from degeneration. The purpose of this study was to determine whether substance P (SP), which can suppress inflammation and mobilize stem cells, can protect the RPE from degeneration. The effect of SP was evaluated by analyzing systemic inflammation, cell survival, and neovascularization within the argon laser-injured retina of mice. At 1 week postinjury, the SP-treated group had lower tumor necrosis factor-alpha and higher interleukin-10 serum concentrations, and a more intact retinal structure compared to the vehicle-treated group. In mice administered SP repeatedly for 4 weeks, the retinal structure appeared normal and showed sparse neovascularization, whereas the vehicle-treated group showed severe retinal destruction and dense neovascularization. Moreover, the efficacy of SP was identical to that of mesenchymal stem cells that were transplanted into the vitreous after retinal injury. This study highlights the potential for the endogenous neuropeptide SP as a treatment for retinal damage to prevent conditions such as AMD. © 2015 by the Wound Healing Society.

  11. Primary amines protect against retinal degeneration in mouse models of retinopathies.

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    Maeda, Akiko; Golczak, Marcin; Chen, Yu; Okano, Kiichiro; Kohno, Hideo; Shiose, Satomi; Ishikawa, Kaede; Harte, William; Palczewska, Grazyna; Maeda, Tadao; Palczewski, Krzysztof

    2011-12-25

    Vertebrate vision is initiated by photoisomerization of the visual pigment chromophore 11-cis-retinal and is maintained by continuous regeneration of this retinoid through a series of reactions termed the retinoid cycle. However, toxic side reaction products, especially those involving reactive aldehyde groups of the photoisomerized product, all-trans-retinal, can cause severe retinal pathology. Here we lowered peak concentrations of free all-trans-retinal with primary amine-containing Food and Drug Administration (FDA)-approved drugs that did not inhibit chromophore regeneration in mouse models of retinal degeneration. Schiff base adducts between all-trans-retinal and these amines were identified by MS. Adducts were observed in mouse eyes only when an experimental drug protected the retina from degeneration in both short-term and long-term treatment experiments. This study demonstrates a molecular basis of all-trans-retinal-induced retinal pathology and identifies an assemblage of FDA-approved compounds with protective effects against this pathology in a mouse model that shows features of Stargardt's disease and age-related retinal degeneration.

  12. Relationship between retinal lattice degeneration and open angle glaucoma.

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    Rahimi, Mansour

    2005-01-01

    Patients with retinal disorders may develop glaucoma of both a primary and secondary type. Pigment may contribute to trabecular obstruction in some patients with open-angle glaucoma. Lattice degeneration of the retina in its typical form is a sharply demarcated, circumferentially oriented, degenerative process with significant alterations of retinal pigmentation. The association between myopia, open angle glaucoma and pigment dispersion is striking. Therefore, it could be postulated that there is significant prevalence of open angle glaucoma in patients with retinal lattice degeneration, especially in combination with myopia.

  13. [Clinical features and prognosis of retinal lattice degeneration].

    Science.gov (United States)

    Guo, X R

    1990-07-01

    110 cases (110 eyes) of retinal lattice degeneration were clinically observed and followed up for 3-8 years. Most lesions were located in the superotemporal quadrant, band-shaped, and parallel to the ora serrata. 80.9% of the lesions presented various degrees of pigmentation, 67.1% yellowish white spots, and 83.6% white lines. 32.9% of the eyes developed retinal holes. Most lattice degenerations were accompanied by vitreous degeneration and vitreoretinal traction. The disease progressed only slowly, though in a few cases it tended to expand.

  14. Urocortin 2 treatment is protective in excitotoxic retinal degeneration.

    Science.gov (United States)

    Szabadfi, K; Kiss, P; Reglodi, D; Fekete, E M; Tamas, A; Danyadi, B; Atlasz, T; Gabriel, R

    2014-03-01

    Urocortin 2 (Ucn 2) is a corticotrop releasing factor paralog peptide with many physiological functions and it has widespread distribution. There are some data on the cytoprotective effects of Ucn 2, but less is known about its neuro- and retinoprotective actions. We have previously shown that Ucn 2 is protective in ischemia-induced retinal degeneration. The aim of the present study was to examine the protective potential of Ucn 2 in monosodium-glutamate (MSG)-induced retinal degeneration by routine histology and to investigate cell-type specific effects by immunohistochemistry. Rat pups received MSG applied on postnatal days 1, 5 and 9 and Ucn 2 was injected intravitreally into one eye. Retinas were processed for histology and immunocytochemistry after 3 weeks. Immunolabeling was determined for glial fibrillary acidic protein, vesicular glutamate transporter 1, protein kinase Cα, calbindin, parvalbumin and calretinin. Retinal tissue from animals treated with MSG showed severe degeneration compared to normal retinas, but intravitreal Ucn 2 treatment resulted in a retained retinal structure both at histological and neurochemical levels: distinct inner retinal layers and rescued inner retinal cells (different types of amacrine and rod bipolar cells) could be observed. These findings support the neuroprotective function of Ucn 2 in MSG-induced retinal degeneration.

  15. Clinical Characteristics and Current Therapies for Inherited Retinal Degenerations

    Science.gov (United States)

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

    2015-01-01

    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. PMID:25324231

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

    OpenAIRE

    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.

    2013-01-01

    The first retinal gene therapy in human blindness from RPE65 mutations has focused on safety and efficacy, as defined by improved vision. The disease component not studied, however, has been the fate of photoreceptors in this progressive retinal degeneration. We show that gene therapy improves vision for at least 3 y, but photoreceptor degeneration progresses unabated in humans. In the canine model, the same result occurs when treatment is at the disease stage equivalent to humans. The study ...

  17. Automated imaging dark adaptometer for investigating hereditary retinal degenerations

    Science.gov (United States)

    Azevedo, Dario F. G.; Cideciyan, Artur V.; Regunath, Gopalakrishnan; Jacobson, Samuel G.

    1995-05-01

    We designed and built an automated imaging dark adaptometer (AIDA) to increase accuracy, reliability, versatility and speed of dark adaptation testing in patients with hereditary retinal degenerations. AIDA increases test accuracy by imaging the ocular fundus for precise positioning of bleaching and stimulus lights. It improves test reliability by permitting continuous monitoring of patient fixation. Software control of stimulus presentation provides broad testing versatility without sacrificing speed. AIDA promises to facilitate the measurement of dark adaptation in studies of the pathophysiology of retinal degenerations and in future treatment trials of these diseases.

  18. The surface morphology of retinal breaks and lattice retinal degeneration. A scanning electron microscopic study.

    Science.gov (United States)

    Robinson, M R; Streeten, B W

    1986-02-01

    In 14 of 110 eye bank eyes, lesions characteristic of peripheral retinal surface pathology were examined by scanning electron microscopy (SEM). These included operculated and flap tears, trophic round holes, lattice degeneration with holes, and paravascular retinal "pitting" degeneration. By SEM, the edges of the retinal breaks were covered by smooth cellular membranes, merging peripherally with a meshwork of vitreous fibrils. The membrane cells had poorly defined borders, a pitted surface, and variable numbers of microvilli consistent with glia. Lattice surfaces and foci of paravascular retinal degeneration were covered by similar membrane, but showed characteristic differences. It appears that breaks in the internal limiting membrane always stimulate proliferation of preretinal glial membranes. Similar cellular morphology of the membranes associated with breaks is consistent with a common cell of origin. Limited proliferation of these membranes suggests that surface gliosis is normally inhibited when the cells contact either intact basement membrane or vitreous.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. [Outcome of cataract surgery in patients with pigmentary retinal degeneration].

    Science.gov (United States)

    Grześk, Magdalena; Kałuzny, Józef; Malukiewicz-Wiśniewska, Grazyna

    2007-01-01

    To evaluate the results of cataract surgery in patients with RP because retinitis pigmentosa is one of the disease entities that belongs to tapeto-retinal degenerations. The occurrence of RP appearance is 1:4000 to 1:3000. Twenty patients with RP (7 women and 13 men, 33 eyes), who underwent cataract surgery were examined retrospectively. Average age in our group was 46.6 years. Visual acuity, intraocular pressure, slip lamp examination, fundus examination, cataract morphology, visual field were taken before surgery and on discharge, on the basis of medical documentation. Control examination was taken, on average, eighty one months after cataract surgery. Nine eyes were operated by phacoemulsification, 24 eyes by means of extracapsular cataract extraction. In the same way control group of 18 patients who underwent cataract surgery without RP (33 eyes) was examined. In RP group in 63.6% patients on discharge from the hospital and in 60.6% patients during the control examination, improvement of visual acuity was revealed. Deterioration was noted in 18.2% of patients on discharge from hospital and in 24.2% of patients during the control examination. In the control group improvement of visual acuity was revealed in 90.9% of patients on discharge and in 97% patients during the control examination, whereas deterioration of visual acuity occurred in 6.1% patients on discharge and in 3% patients during the check examination. In patients with retinitis pigmentosa cataract occurs earlier then in the control group. Cataract surgery for relatively minor opacities is beneficial in patients with RP, and causes improvement of visual acuity in most of eyes undergoing surgery.

  1. Iron in hereditary retinal degeneration: PIXE microanalysis Preliminary results

    International Nuclear Information System (INIS)

    Sergeant, C.; Gouget, B.; Llabador, Y.; Simonoff, M.; Yefimova, M.; Courtois, Y.; Jeanny, J.C.

    1999-01-01

    Several types of hereditary retinal degeneration with progressive alteration of photoreceptors exist in men and animals. Recent immunohistochemical results have shown strong degradation of transferrin, the protein responsible for iron transport, in retinas of rats with hereditary retinal degeneration. Freeze-dried thin sections of rat retinas from different stages of the disease, and respective coeval control sections, have been analyzed using nuclear microprobe. In this first part of the study, the rat retinas at post-natal stages of 35 and 45 days have been analyzed. The sample preparation and the post-irradiation staining to determine precisely the retinal layers involved are described. Preliminary results of element distributions (K, Ca, Fe) in the rat retina layers are discussed. A very high content of calcium in the choriocapillaris of dystrophic rat retinas was observed. Preliminary results on iron distribution in the rat retina layers are presented

  2. Molecular pharmacodynamics of emixustat in protection against retinal degeneration.

    Science.gov (United States)

    Zhang, Jianye; Kiser, Philip D; Badiee, Mohsen; Palczewska, Grazyna; Dong, Zhiqian; Golczak, Marcin; Tochtrop, Gregory P; Palczewski, Krzysztof

    2015-07-01

    Emixustat is a visual cycle modulator that has entered clinical trials as a treatment for age-related macular degeneration (AMD). This molecule has been proposed to inhibit the visual cycle isomerase RPE65, thereby slowing regeneration of 11-cis-retinal and reducing production of retinaldehyde condensation byproducts that may be involved in AMD pathology. Previously, we reported that all-trans-retinal (atRAL) is directly cytotoxic and that certain primary amine compounds that transiently sequester atRAL via Schiff base formation ameliorate retinal degeneration. Here, we have shown that emixustat stereoselectively inhibits RPE65 by direct active site binding. However, we detected the presence of emixustat-atRAL Schiff base conjugates, indicating that emixustat also acts as a retinal scavenger, which may contribute to its therapeutic effects. Using agents that lack either RPE65 inhibitory activity or the capacity to sequester atRAL, we assessed the relative importance of these 2 modes of action in protection against retinal phototoxicity in mice. The atRAL sequestrant QEA-B-001-NH2 conferred protection against phototoxicity without inhibiting RPE65, whereas an emixustat derivative incapable of atRAL sequestration was minimally protective, despite direct inhibition of RPE65. These data indicate that atRAL sequestration is an essential mechanism underlying the protective effects of emixustat and related compounds against retinal phototoxicity. Moreover, atRAL sequestration should be considered in the design of next-generation visual cycle modulators.

  3. Taurine Provides Neuroprotection against Retinal Ganglion Cell Degeneration

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Therapeutic Approaches to Histone Reprogramming in Retinal Degeneration.

    Science.gov (United States)

    Berner, Andre K; Kleinman, Mark E

    2016-01-01

    Recent data have revealed epigenetic derangements and subsequent chromatin remodeling as a potent biologic switch for chronic inflammation and cell survival which are important therapeutic targets in the pathogenesis of several retinal degenerations. Histone deacetylases (HDACs) are a major component of this system and serve as a unique control of the chromatin remodeling process. With a multitude of targeted HDAC inhibitors now available, their use in both basic science and clinical studies has widened substantially. In the field of ocular biology, there are data to suggest that HDAC inhibition may suppress neovascularization and may be a possible treatment for retinitis pigmentosa and dry age-related macular degeneration (AMD). However, the effects of these inhibitors on cell survival and chemokine expression in the chorioretinal tissues remain very unclear. Here, we review the multifaceted biology of HDAC activity and pharmacologic inhibition while offering further insight into the importance of this epigenetic pathway in retinal degenerations. Our laboratory investigations aim to open translational avenues to advance dry AMD therapeutics while exploring the role of acetylation on inflammatory gene expression in the aging and degenerating retina.

  6. Interventions for asymptomatic retinal breaks and lattice degeneration for preventing retinal detachment.

    Science.gov (United States)

    Wilkinson, Charles P

    2014-09-05

    Asymptomatic retinal breaks and lattice degeneration are visible lesions that are risk factors for later retinal detachment. Retinal detachments occur when fluid in the vitreous cavity passes through tears or holes in the retina and separates the retina from the underlying retinal pigment epithelium. Creation of an adhesion surrounding retinal breaks and lattice degeneration, with laser photocoagulation or cryotherapy, has been recommended as an effective means of preventing retinal detachment. This therapy is of value in the management of retinal tears associated with the symptoms of flashes and floaters and persistent vitreous traction upon the retina in the region of the retinal break, because such symptomatic retinal tears are associated with a high rate of progression to retinal detachment. Retinal tears and holes unassociated with acute symptoms and lattice degeneration are significantly less likely to be the sites of retinal breaks that are responsible for later retinal detachment. Nevertheless, treatment of these lesions frequently is recommended, in spite of the fact that the effectiveness of this therapy is unproven. The objective of this review was to assess the effectiveness and safety of techniques used to treat asymptomatic retinal breaks and lattice degeneration for the prevention of retinal detachment. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 2), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to February 2014), EMBASE (January 1980 to February 2014), PubMed (January 1948 to February 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials

  7. Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

    OpenAIRE

    Ma, Hongwei; Thapa, Arjun; Morris, Lynsie; Redmond, T. Michael; Baehr, Wolfgang; Ding, Xi-Qin

    2014-01-01

    Photoreceptors degenerate in a wide array of hereditary retinal diseases and age-related macular degeneration. There is currently no treatment available for retinal degenerations. While outnumbered roughly 20:1 by rods in the human retina, it is the cones that mediate color vision and visual acuity, and their survival is critical for vision. In this communication, we investigate whether thyroid hormone (TH) signaling affects cone viability in retinal degeneration mouse models. TH signaling is...

  8. Evidence-based analysis of prophylactic treatment of asymptomatic retinal breaks and lattice degeneration.

    Science.gov (United States)

    Wilkinson, C P

    2000-01-01

    To assess the quality of information in the literature regarding the benefits of prophylactic treatment of asymptomatic retinal tears and lattice degeneration. Asymptomatic retinal breaks occur in approximately 7% of patients over age 40, and lattice degeneration is present in approximately 8% of the general population. Because retinal breaks cause retinal detachment and lattice degeneration is associated with approximately 30% of retinal detachments, prophylactic treatment of these lesions has sometimes been recommended. A panel of vitreoretinal experts performed a literature review of all publications regarding prevention of retinal detachment that have been published in English. These articles were then used to prepare recommendations for patient care in an American Academy of Ophthalmology Preferred Practice Pattern (PPP). Each recommendation was rated according to: (1) its importance in the care process and (2) the strength of evidence supporting the given recommendation. Most recommendations were rated as A (most important to patient care). Only a single publication was graded as I (providing strong evidence in support of a recommendation), and this was not a prospective trial. Of the few publications rated as II (substantial evidence), most were studies documenting a lack of treatment benefit. Because of an absence of level I and level II studies in the literature, level III (consensus of expert opinion) was the basis for most recommendations in the PPP. The current literature regarding prevention of retinal detachment does not provide sufficient information to support strongly prophylactic treatment of lesions other than symptomatic flap tears. Prospective randomized trials of prophylactic therapy are indicated. Eyes highly predisposed to retinal detachment should be considered for such studies.

  9. Sudden acquired retinal degeneration syndrome in western Canada: 93 cases.

    Science.gov (United States)

    Leis, Marina L; Lucyshyn, Danica; Bauer, Bianca S; Grahn, Bruce H; Sandmeyer, Lynne S

    2017-11-01

    This study reviewed clinical data from dogs diagnosed with sudden acquired retinal degeneration syndrome (SARDS) in western Canada. Medical records from the Western College of Veterinary Medicine from 2002 to 2016 showed that 93 cases of SARDS were diagnosed based on presentation for sudden blindness and a bilaterally extinguished electroretinogram. The most common pure breeds were the miniature schnauzer, dachshund, and pug. The mean age at diagnosis was 8.1 years and males and females were equally affected. Most of the dogs were presented with normal non-chromatic, but abnormal chromatic pupillary light reflexes. The incidence of retinal degeneration as detected via ophthalmoscopy increased over time after SARDS diagnosis. Polyuria, polydipsia, polyphagia, weight gain, elevated liver enzyme values, isosthenuria, and proteinuria were common clinical and laboratory findings. Chromatic pupillary light reflex testing may be more valuable than non-chromatic pupillary light testing in detecting pupil response abnormalities in dogs with SARDS, although electroretinography remains the definitive diagnostic test.

  10. Sudden acquired retinal degeneration syndrome in western Canada: 93 cases

    Science.gov (United States)

    Leis, Marina L.; Lucyshyn, Danica; Bauer, Bianca S.; Grahn, Bruce H.; Sandmeyer, Lynne S.

    2017-01-01

    This study reviewed clinical data from dogs diagnosed with sudden acquired retinal degeneration syndrome (SARDS) in western Canada. Medical records from the Western College of Veterinary Medicine from 2002 to 2016 showed that 93 cases of SARDS were diagnosed based on presentation for sudden blindness and a bilaterally extinguished electroretinogram. The most common pure breeds were the miniature schnauzer, dachshund, and pug. The mean age at diagnosis was 8.1 years and males and females were equally affected. Most of the dogs were presented with normal non-chromatic, but abnormal chromatic pupillary light reflexes. The incidence of retinal degeneration as detected via ophthalmoscopy increased over time after SARDS diagnosis. Polyuria, polydipsia, polyphagia, weight gain, elevated liver enzyme values, isosthenuria, and proteinuria were common clinical and laboratory findings. Chromatic pupillary light reflex testing may be more valuable than non-chromatic pupillary light testing in detecting pupil response abnormalities in dogs with SARDS, although electroretinography remains the definitive diagnostic test. PMID:29089658

  11. Effect of pharmacologically induced retinal degeneration on retinal autofluorescence lifetimes in mice.

    Science.gov (United States)

    Dysli, Chantal; Dysli, Muriel; Zinkernagel, Martin S; Enzmann, Volker

    2016-12-01

    Fluorescence lifetime imaging ophthalmoscopy (FLIO) was used to investigate retinal autofluorescence lifetimes in mouse models of pharmacologically induced retinal degeneration over time. Sodium iodate (NaIO 3 , 35 mg/kg intravenously) was used to induce retinal pigment epithelium (RPE) degeneration with subsequent loss of photoreceptors (PR) whereas N-methyl-N-nitrosourea (MNU, 45 mg/kg intraperitoneally) was employed for degeneration of the photoreceptor cell layer alone. All mice were measured at day 3, 7, 14, and 28 after the respective injection of NaIO 3 , MNU or NaCl (control). Fluorescence lifetime imaging was performed using a fluorescence lifetime imaging ophthalmoscope (Heidelberg Engineering, Heidelberg, Germany). Fluorescence was excited at 473 nm and fluorescence lifetimes were measured in a short and a long spectral channel (498-560 nm and 560-720 nm). Corresponding optical coherence tomography (OCT) images were consecutively acquired and histology was performed at the end of the experiments. Segmentation of OCT images and histology verified the cell type-specific degeneration process over time. Retinal autofluorescence lifetimes increased from day 3 to day 28 in mice after NaIO 3 treatment. Finally, at day 28, fluorescence lifetimes were prolonged by 8% in the short and 61% in the long spectral channel compared to control animals (p = 0.21 and p = 0.004, respectively). In mice after MNU treatment, the mean retinal autofluorescence lifetimes were already decreased at day 3 and retinal lifetimes were finally shortened by 27% in the short and 51% in the long spectral channel at day 28 (p = 0.0028). In conclusion, degeneration of the RPE with subsequent photoreceptor degeneration by NaIO 3 lead to longer mean fluorescence lifetimes of the retina compared to control mice, whereas during specific degeneration of the photoreceptor layer induced by MNU shorter lifetimes were measured. Therefore, short retinal fluorescence lifetimes may originate

  12. Oxygen-induced retinopathy in mice with retinal photoreceptor cell degeneration.

    Science.gov (United States)

    Zhang, Qian; Zhang, Zuo-Ming

    2014-04-25

    It is reported that retinal neovascularization seems to rarely co-exist with retinitis pigmentosa in patients and in some mouse models; however, it is not widely acknowledged as a universal phenomenon in all strains of all animal species. We aimed to further explore this phenomenon with an oxygen-induced retinopathy model in mice with retinal photoreceptor cell degeneration. Oxygen-induced retinopathy of colored and albino mice with rapid retinal degeneration were compared to homologous wild-type mice. The retinas were analyzed using high-molecular-weight FITC-dextran stained flat-mount preparation, hematoxylin and eosin (H&E) stained cross-sections, an immunohistochemical test for vascular endothelial growth factor (VEGF) distribution and Western blotting for VEGF expression after exposure to hyperoxia between postnatal days 17 (P17) and 21. Leakage and areas of non-perfusion of the retinal blood vessels were alleviated in the retinal degeneration mice. The number of preretinal vascular endothelial cell nuclei in the retinal degeneration mice was smaller than that in the homologous wild-type mice after exposure to hyperoxia (Poxygen-induced retinopathy was positively correlated with the VEGF expression level. However, the VEGF expression level was lower in the retinal degeneration mice. Proliferative retinopathy occurred in mice with rapid retinal degeneration, but retinal photoreceptor cell degeneration could partially restrain the retinal neovascularization in this rapid retinal degeneration mouse model. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Digoxin-induced retinal degeneration depends on rhodopsin.

    Science.gov (United States)

    Landfried, Britta; Samardzija, Marijana; Barben, Maya; Schori, Christian; Klee, Katrin; Storti, Federica; Grimm, Christian

    2017-03-16

    Na,K-ATPases are energy consuming ion pumps that are required for maintaining ion homeostasis in most cells. In the retina, Na,K-ATPases are especially important to sustain the dark current in photoreceptor cells needed for rapid hyperpolarization of rods and cones in light. Cardiac glycosides like digoxin inhibit the activity of Na,K-ATPases by targeting their catalytic alpha subunits. This leads to a disturbed ion balance, which can affect cellular function and survival. Here we show that the treatment of wild-type mice with digoxin leads to severe retinal degeneration and loss of vision. Digoxin induced cell death specifically in photoreceptor cells with no or only minor effects in other retinal cell types. Photoreceptor-specific cytotoxicity depended on the presence of bleachable rhodopsin. Photoreceptors of Rpe65 knockouts, which have no measurable rhodopsin and photoreceptors of Rpe65 R91W mice that have treatment. Similarly, cones in the all-cone retina of Nrl knockout mice were also not affected. Digoxin induced expression of several genes involved in stress signaling and inflammation. It also activated proteins such as ERK1/2, AKT, STAT1, STAT3 and CASP1 during a period of up to 10 days after treatment. Activation of signaling genes and proteins, as well as the dependency on bleachable rhodopsin resembles mechanisms of light-induced photoreceptor degeneration. Digoxin-mediated photoreceptor cell death may thus be used as an inducible model system to study molecular mechanisms of retinal degeneration.

  14. Target 5000: Target Capture Sequencing for Inherited Retinal Degenerations

    Directory of Open Access Journals (Sweden)

    Adrian Dockery

    2017-11-01

    Full Text Available There are an estimated 5000 people in Ireland who currently have an inherited retinal degeneration (IRD. It is the goal of this study, through genetic diagnosis, to better enable these 5000 individuals to obtain a clearer understanding of their condition and improved access to potentially applicable therapies. Here we show the current findings of a target capture next-generation sequencing study of over 750 patients from over 520 pedigrees currently situated in Ireland. We also demonstrate how processes can be implemented to retrospectively analyse patient datasets for the detection of structural variants in previously obtained sequencing reads. Pathogenic or likely pathogenic mutations were detected in 68% of pedigrees tested. We report nearly 30 novel mutations including three large structural variants. The population statistics related to our findings are presented by condition and credited to their respective candidate gene mutations. Rediagnosis rates of clinical phenotypes after genotyping are discussed. Possible causes of failure to detect a candidate mutation are evaluated. Future elements of this project, with a specific emphasis on structural variants and non-coding pathogenic variants, are expected to increase detection rates further and thereby produce an even more comprehensive representation of the genetic landscape of IRDs in Ireland.

  15. Retinal Structure Measurements as Inclusion Criteria for Stem Cell-Based Therapies of Retinal Degenerations.

    Science.gov (United States)

    Jacobson, Samuel G; Matsui, Rodrigo; Sumaroka, Alexander; Cideciyan, Artur V

    2016-04-01

    We reviewed and illustrated the most optimal retinal structural measurements to make in stem cell clinical trials. Optical coherence tomography (OCT) and autofluorescence (AF) imaging were used to evaluate patients with severe visual loss from nonsyndromic and syndromic retinitis pigmentosa (RP), ABCA4-Stargardt disease, and nonneovascular age-related macular degeneration (AMD). Outer nuclear layer (ONL), rod outer segment (ROS) layer, inner retina, ganglion cell layer (GCL), and nerve fiber layer (NFL) thicknesses were quantified. All patients had severely reduced visual acuities. Retinitis pigmentosa patients had limited visual fields; maculopathy patients had central scotomas with retained peripheral function. For the forms of RP illustrated, there was detectable albeit severely reduced ONL across the scanned retina, and normal or hyperthick GCL and NFL. Maculopathy patients had no measurable ONL centrally; it became detectable with eccentricity. Some maculopathy patients showed unexpected GCL losses. Autofluorescence imaging illustrated central losses of RPE integrity. A hypothetical scheme to relate patient data with different phases of retinal remodeling in animal models of retinal degeneration was presented. Stem cell science is advancing, but it is not too early to open the discussion of criteria for patient selection and monitoring. Available clinical tools, such as OCT and AF imaging, can provide inclusion/exclusion criteria and robust objective outcomes. Accepting that early trials may not lead to miraculous cures, we should be prepared to know why-scientifically and clinically-so we can improve subsequent trials. We also must determine if retinal remodeling is an impediment to efficacy.

  16. Stem cells in clinical trials for treatment of retinal degeneration.

    Science.gov (United States)

    Klassen, Henry

    2016-01-01

    After decades of basic science research involving the testing of regenerative strategies in animal models of retinal degenerative diseases, a number of clinical trials are now underway, with additional trials set to begin shortly. These efforts will evaluate the safety and preliminary efficacy of cell-based products in the eyes of patients with a number of retinal conditions, notably including age-related macular degeneration, retinitis pigmentosa and Stargardt's disease. This review considers the scientific work and early trials with fetal cells and tissues that set the stage for the current clinical investigatory work, as well the trials themselves, specifically those either now completed, underway or close to initiation. The cells of interest include retinal pigment epithelial cells derived from embryonic stem or induced pluripotent stem cells, undifferentiated neural or retinal progenitors or cells from the vascular/bone marrow compartment or umbilical cord tissue. Degenerative diseases of the retina represent a popular target for emerging cell-based therapeutics and initial data from early stage clinical trials suggest that short-term safety objectives can be met in at least some cases. The question of efficacy will require additional time and testing to be adequately resolved.

  17. Aag-initiated base excision repair drives alkylation-induced retinal degeneration in mice.

    Science.gov (United States)

    Meira, Lisiane B; Moroski-Erkul, Catherine A; Green, Stephanie L; Calvo, Jennifer A; Bronson, Roderick T; Shah, Dharini; Samson, Leona D

    2009-01-20

    Vision loss affects >3 million Americans and many more people worldwide. Although predisposing genes have been identified their link to known environmental factors is unclear. In wild-type animals DNA alkylating agents induce photoreceptor apoptosis and severe retinal degeneration. Alkylation-induced retinal degeneration is totally suppressed in the absence of the DNA repair protein alkyladenine DNA glycosylase (Aag) in both differentiating and postmitotic retinas. Moreover, transgenic expression of Aag activity restores the alkylation sensitivity of photoreceptors in Aag null animals. Aag heterozygotes display an intermediate level of retinal degeneration, demonstrating haploinsufficiency and underscoring that Aag expression confers a dominant retinal degeneration phenotype.

  18. Decreased Expression of DREAM Promotes the Degeneration of Retinal Neurons

    Science.gov (United States)

    Chintala, Shravan; Cheng, Mei; Zhang, Xiao

    2015-01-01

    The intrinsic mechanisms that promote the degeneration of retinal ganglion cells (RGCs) following the activation of N-Methyl-D-aspartic acid-type glutamate receptors (NMDARs) are unclear. In this study, we have investigated the role of downstream regulatory element antagonist modulator (DREAM) in NMDA-mediated degeneration of the retina. NMDA, phosphate-buffered saline (PBS), and MK801 were injected into the vitreous humor of C57BL/6 mice. At 12, 24, and 48 hours after injection, expression of DREAM in the retina was determined by immunohistochemistry, western blot analysis, and electrophoretic mobility-shift assay (EMSA). Apoptotic death of cells in the retina was determined by terminal deoxynucleotidyl transferace dUTP nick end labeling (TUNEL) assays. Degeneration of RGCs in cross sections and in whole mount retinas was determined by using antibodies against Tuj1 and Brn3a respectively. Degeneration of amacrine cells and bipolar cells was determined by using antibodies against calretinin and protein kinase C (PKC)-alpha respectively. DREAM was expressed constitutively in RGCs, amacrine cells, bipolar cells, as well as in the inner plexiform layer (IPL). NMDA promoted a progressive decrease in DREAM levels in all three cell types over time, and at 48 h after NMDA-treatment very low DREAM levels were evident in the IPL only. DREAM expression in retinal nuclear proteins was decreased progressively after NMDA-treatment, and correlated with its decreased binding to the c-fos-DRE oligonucleotides. A decrease in DREAM expression correlated significantly with apoptotic death of RGCs, amacrine cells and bipolar cells. Treatment of eyes with NMDA antagonist MK801, restored DREAM expression to almost normal levels in the retina, and significantly decreased NMDA-mediated apoptotic death of RGCs, amacrine cells, and bipolar cells. Results presented in this study show for the first time that down-regulation of DREAM promotes the degeneration of RGCs, amacrine cells, and

  19. Novel Animal Model of Crumbs-Dependent Progressive Retinal Degeneration That Targets Specific Cone Subtypes.

    Science.gov (United States)

    Fu, Jinling; Nagashima, Mikiko; Guo, Chuanyu; Raymond, Pamela A; Wei, Xiangyun

    2018-01-01

    Human Crb1 is implicated in some forms of retinal degeneration, suggesting a role in photoreceptor maintenance. Multiple Crumbs (Crb) polarity genes are expressed in vertebrate retina, although their functional roles are not well understood. To gain further insight into Crb and photoreceptor maintenance, we compared retinal cell densities between wild-type and Tg(RH2-2:Crb2b-sfEX/RH2-2:GFP)pt108b transgenic zebrafish, in which the extracellular domain of Crb2b-short form (Crb2b-sfEX) is expressed in the retina as a secreted protein, which disrupts the planar organization of RGB cones (red, green, and blue) by interfering with Crb2a/2b-based cone-cone adhesion. We used standard morphometric techniques to assess age-related changes in retinal cell densities in adult zebrafish (3 to 27 months old), and to assess effects of the Crb2b-sfEX transgene on retinal structure and photoreceptor densities. Linear cell densities were measured in all retinal layers in radial sections with JB4-Feulgen histology. Planar (surface) densities of cones were determined in retinal flat-mounts. Cell counts from wild-type and pt108b transgenic fish were compared with both a "photoreceptor maintenance index" and statistical analysis of cell counts. Age-related changes in retinal cell linear densities and cone photoreceptor planar densities in wild-type adult zebrafish provided a baseline for analysis. Expression of Crb2b-sfEX caused progressive and selective degeneration of RGB cones, but had no effect on ultraviolet-sensitive (UV) cones, and increased numbers of rod photoreceptors. These differential responses of RGB cones, UV cones, and rods to sustained exposure to Crb2b-sfEX suggest that Crb-based photoreceptor maintenance mechanisms are highly selective.

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

    NARCIS (Netherlands)

    Slijkerman, R.W.N.; Vache, C.; Dona, M.; Garcia-Garcia, G.; Claustres, M.; Hetterschijt, L.; Peters, T.A.; Hartel, B.P.; Pennings, R.J.E.; Millan, J.M.; Aller, E.; Garanto, A.; Collin, R.W.J.; Kremer, H.; Roux, A.F.; WIjk, E. van

    2016-01-01

    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

  1. PAR-Complex and Crumbs Function During Photoreceptor Morphogenesis and Retinal Degeneration.

    Science.gov (United States)

    Pichaud, Franck

    2018-01-01

    The fly photoreceptor has long been used as a model to study sensory neuron morphogenesis and retinal degeneration. In particular, elucidating how these cells are built continues to help further our understanding of the mechanisms of polarized cell morphogenesis, intracellular trafficking and the causes of human retinal pathologies. The conserved PAR complex, which in flies consists of Cdc42-PAR6-aPKC-Bazooka, and the transmembrane protein Crumbs (Crb) are key players during photoreceptor morphogenesis. While the PAR complex regulates polarity in many cell types, Crb function in polarity is relatively specific to epithelial cells. Together Cdc42-PAR6-aPKC-Bazooka and Crb orchestrate the differentiation of the photoreceptor apical membrane (AM) and zonula adherens (ZA) , thus allowing these cells to assemble into a neuro-epithelial lattice. In addition to its function in epithelial polarity, Crb has also been shown to protect fly photoreceptors from light-induced degeneration, a process linked to Rhodopsin expression and trafficking. Remarkably, mutations in the human Crumbs1 (CRB1) gene lead to retinal degeneration, making the fly photoreceptor a powerful disease model system.

  2. PAR-Complex and Crumbs Function During Photoreceptor Morphogenesis and Retinal Degeneration

    Directory of Open Access Journals (Sweden)

    Franck Pichaud

    2018-03-01

    Full Text Available The fly photoreceptor has long been used as a model to study sensory neuron morphogenesis and retinal degeneration. In particular, elucidating how these cells are built continues to help further our understanding of the mechanisms of polarized cell morphogenesis, intracellular trafficking and the causes of human retinal pathologies. The conserved PAR complex, which in flies consists of Cdc42-PAR6-aPKC-Bazooka, and the transmembrane protein Crumbs (Crb are key players during photoreceptor morphogenesis. While the PAR complex regulates polarity in many cell types, Crb function in polarity is relatively specific to epithelial cells. Together Cdc42-PAR6-aPKC-Bazooka and Crb orchestrate the differentiation of the photoreceptor apical membrane (AM and zonula adherens (ZA, thus allowing these cells to assemble into a neuro-epithelial lattice. In addition to its function in epithelial polarity, Crb has also been shown to protect fly photoreceptors from light-induced degeneration, a process linked to Rhodopsin expression and trafficking. Remarkably, mutations in the human Crumbs1 (CRB1 gene lead to retinal degeneration, making the fly photoreceptor a powerful disease model system.

  3. The Rate of Vitamin A Dimerization in Lipofuscinogenesis, Fundus Autofluorescence, Retinal Senescence and Degeneration.

    Science.gov (United States)

    Washington, Ilyas; Saad, Leonide

    2016-01-01

    One of the earliest events preceding several forms of retinal degeneration is the formation and accumulation of vitamin A dimers in the retinal pigment epithelium (RPE) and underlying Bruch's membrane (BM). Such degenerations include Stargardt disease, Best disease, forms of retinitis pigmentosa, and age-related macular degeneration (AMD). Since their discovery in the 1990's, dimers of vitamin A, have been postulated as chemical triggers driving retinal senescence and degeneration. There is evidence to suggest that the rate at which vitamin A dimerizes and the eye's response to the dimerization products may dictate the retina's lifespan. Here, we present outstanding questions, finding the answers to which may help to elucidate the role of vitamin A dimerization in retinal degeneration.

  4. An activated unfolded protein response promotes retinal degeneration and triggers an inflammatory response in the mouse retina.

    Science.gov (United States)

    Rana, T; Shinde, V M; Starr, C R; Kruglov, A A; Boitet, E R; Kotla, P; Zolotukhin, S; Gross, A K; Gorbatyuk, M S

    2014-12-18

    Recent studies on the endoplasmic reticulum stress have shown that the unfolded protein response (UPR) is involved in the pathogenesis of inherited retinal degeneration caused by mutant rhodopsin. However, the main question of whether UPR activation actually triggers retinal degeneration remains to be addressed. Thus, in this study, we created a mouse model for retinal degeneration caused by a persistently activated UPR to assess the physiological and morphological parameters associated with this disease state and to highlight a potential mechanism by which the UPR can promote retinal degeneration. We performed an intraocular injection in C57BL6 mice with a known unfolded protein response (UPR) inducer, tunicamycin (Tn) and examined animals by electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT) and histological analyses. We detected a significant loss of photoreceptor function (over 60%) and retinal structure (35%) 30 days post treatment. Analysis of retinal protein extracts demonstrated a significant upregulation of inflammatory markers including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and IBA1. Similarly, we detected a strong inflammatory response in mice expressing either Ter349Glu or T17M rhodopsin (RHO). These mutant rhodopsin species induce severe retinal degeneration and T17M rhodopsin elicits UPR activation when expressed in mice. RNA and protein analysis revealed a significant upregulation of pro- and anti-inflammatory markers such as IL-1β, IL-6, p65 nuclear factor kappa B (NF-kB) and MCP-1, as well as activation of F4/80 and IBA1 microglial markers in both the retinas expressing mutant rhodopsins. We then assessed if the Tn-induced inflammatory marker IL-1β was capable of inducing retinal degeneration by injecting C57BL6 mice with a recombinant IL-1β. We observed ~19% reduction in ERG a-wave amplitudes and a 29% loss of photoreceptor cells compared with

  5. Progress of stem/progenitor cell-based therapy for retinal degeneration.

    Science.gov (United States)

    Tang, Zhimin; Zhang, Yi; Wang, Yuyao; Zhang, Dandan; Shen, Bingqiao; Luo, Min; Gu, Ping

    2017-05-10

    Retinal degeneration (RD), such as age-related macular degeneration (AMD) and retinitis pigmentosa, is one of the leading causes of blindness. Presently, no satisfactory therapeutic options are available for these diseases principally because the retina and retinal pigmented epithelium (RPE) do not regenerate, although wet AMD can be prevented from further progression by anti-vascular endothelial growth factor therapy. Nevertheless, stem/progenitor cell approaches exhibit enormous potential for RD treatment using strategies mainly aimed at the rescue and replacement of photoreceptors and RPE. The sources of stem/progenitor cells are classified into two broad categories in this review, which are (1) ocular-derived progenitor cells, such as retinal progenitor cells, and (2) non-ocular-derived stem cells, including embryonic stem cells, induced pluripotent stem cells, and mesenchymal stromal cells. Here, we discuss in detail the progress in the study of four predominant stem/progenitor cell types used in animal models of RD. A short overview of clinical trials involving the stem/progenitor cells is also presented. Currently, stem/progenitor cell therapies for RD still have some drawbacks such as inhibited proliferation and/or differentiation in vitro (with the exception of the RPE) and limited long-term survival and function of grafts in vivo. Despite these challenges, stem/progenitor cells represent the most promising strategy for RD treatment in the near future.

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

    Science.gov (United States)

    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

  7. Course of Sodium Iodate-Induced Retinal Degeneration in Albino and Pigmented Mice.

    Science.gov (United States)

    Chowers, Guy; Cohen, Matan; Marks-Ohana, Devora; Stika, Shelly; Eijzenberg, Ayala; Banin, Eyal; Obolensky, Alexey

    2017-04-01

    To characterize the course of sodium iodate (SI)-induced retinal degeneration in young adult albino and pigmented mice. Single intraperitoneal (IP) injections of SI (25, 50, and 100 mg/kg) were performed in 7- to 8-week-old BALB/c and C57Bl/6J mice. Retinal function and structure was assessed at baseline, 24 hours, 3 days, 1, 2, 3, and 4 weeks postinjection by optokinetic tracking response, ERG, optical coherence tomography (OCT), and histologic and immunohistochemical techniques. The 50 mg/kg SI dosage was selected after dose ranging due to consistent retinal effects and lack of systemic toxicity. Time-dependent deterioration in retinal function and morphology was consistently observed between 1 and 4 weeks in all measured parameters. These include reduction of ERG responses, thinning of retinal layers as observed by OCT and histology, and loss of RPE nuclei. Immunohistochemistry revealed rapid RPE disorganization with loss of tight junctions and markedly reduced expression of RPE65 and rod opsin, accompanied by mislocalization of cone opsins. Earlier time points displayed variable results, including partial recovery of visual acuity at 1 week and supranormal ERG cone responses at 24 hours, suggesting possible limitations of early intervention and assessment in the SI model. A single IP injection of 50 mg/kg SI leads to severe RPE injury followed by vision impairment, dysfunction, and loss of photoreceptors in both BALB/c and C57Bl/6J mice. This easily induced and reproducible noninherited model may serve as a useful tool for seeking and evaluating novel therapeutic modalities for the treatment of retinal degenerations caused by primary failure of the RPE.

  8. Characterization of cytochrome c as marker for retinal cell degeneration by uv/vis spectroscopic imaging

    Science.gov (United States)

    Hollmach, Julia; Schweizer, Julia; Steiner, Gerald; Knels, Lilla; Funk, Richard H. W.; Thalheim, Silko; Koch, Edmund

    2011-07-01

    Retinal diseases like age-related macular degeneration have become an important cause of visual loss depending on increasing life expectancy and lifestyle habits. Due to the fact that no satisfying treatment exists, early diagnosis and prevention are the only possibilities to stop the degeneration. The protein cytochrome c (cyt c) is a suitable marker for degeneration processes and apoptosis because it is a part of the respiratory chain and involved in the apoptotic pathway. The determination of the local distribution and oxidative state of cyt c in living cells allows the characterization of cell degeneration processes. Since cyt c exhibits characteristic absorption bands between 400 and 650 nm wavelength, uv/vis in situ spectroscopic imaging was used for its characterization in retinal ganglion cells. The large amount of data, consisting of spatial and spectral information, was processed by multivariate data analysis. The challenge consists in the identification of the molecular information of cyt c. Baseline correction, principle component analysis (PCA) and cluster analysis (CA) were performed in order to identify cyt c within the spectral dataset. The combination of PCA and CA reveals cyt c and its oxidative state. The results demonstrate that uv/vis spectroscopic imaging in conjunction with sophisticated multivariate methods is a suitable tool to characterize cyt c under in situ conditions.

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

    NARCIS (Netherlands)

    Novosel, J.; Wang, Ziyuan; De Jong, Henk; Vermeer, K.A.; van Vliet, L.J.; Styner, Martin A.; Angelini, Elsa D.

    2016-01-01

    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

  11. Comparison of Mouse and Human Retinal Pigment Epithelium Gene Expression Profiles: Potential Implications for Age-Related Macular Degeneration

    NARCIS (Netherlands)

    Bennis, A.; Gorgels, T.G.M.F.; ten Brink, J.B.; van der Spek, P.J.; Bossers, K.; Heine, V.M.; Bergen, A.A.

    2015-01-01

    Background The human retinal pigment epithelium (RPE) plays an important role in the pathogenesis of age related macular degeneration (AMD). AMD is the leading cause of blindness worldwide. There is currently no effective treatment available. Preclinical studies in AMD mouse models are essential to

  12. Comparison of Mouse and Human Retinal Pigment Epithelium Gene Expression Profiles : Potential Implications for Age-Related Macular Degeneration

    NARCIS (Netherlands)

    Bennis, Anna; Gorgels, Theo G M F; Ten Brink, Jacoline B; van der Spek, Peter J; Bossers, Koen; Heine, Vivi M; Bergen, Arthur A

    2015-01-01

    BACKGROUND: The human retinal pigment epithelium (RPE) plays an important role in the pathogenesis of age related macular degeneration (AMD). AMD is the leading cause of blindness worldwide. There is currently no effective treatment available. Preclinical studies in AMD mouse models are essential to

  13. Comparison of Mouse and Human Retinal Pigment Epithelium Gene Expression Profiles: Potential Implications for Age-Related Macular Degeneration

    NARCIS (Netherlands)

    Bennis, Anna; Gorgels, Theo G. M. F.; ten Brink, Jacoline B.; van der Spek, Peter J.; Bossers, Koen; Heine, Vivi M.; Bergen, Arthur A.

    2015-01-01

    The human retinal pigment epithelium (RPE) plays an important role in the pathogenesis of age related macular degeneration (AMD). AMD is the leading cause of blindness worldwide. There is currently no effective treatment available. Preclinical studies in AMD mouse models are essential to develop new

  14. Transplantation of rat embryonic stem cell-derived retinal progenitor cells preserves the retinal structure and function in rat retinal degeneration.

    Science.gov (United States)

    Qu, Zepeng; Guan, Yuan; Cui, Lu; Song, Jian; Gu, Junjie; Zhao, Hanzhi; Xu, Lei; Lu, Lixia; Jin, Ying; Xu, Guo-Tong

    2015-11-09

    Degenerative retinal diseases like age-related macular degeneration (AMD) are the leading cause of blindness. Cell transplantation showed promising therapeutic effect for such diseases, and embryonic stem cell (ESC) is one of the sources of such donor cells. Here, we aimed to generate retinal progenitor cells (RPCs) from rat ESCs (rESCs) and to test their therapeutic effects in rat model. The rESCs (DA8-16) were cultured in N2B27 medium with 2i, and differentiated to two types of RPCs following the SFEBq method with modifications. For rESC-RPC1, the cells were switched to adherent culture at D10, while for rESC-RPC2, the suspension culture was maintained to D14. Both RPCs were harvested at D16. Primary RPCs were obtained from P1 SD rats, and some of them were labeled with EGFP by infection with lentivirus. To generate Rax::EGFP knock-in rESC lines, TALENs were engineered to facilitate homologous recombination in rESCs, which were cotransfected with the targeting vector and TALEN vectors. The differentiated cells were analyzed with live image, immunofluorescence staining, flow cytometric analysis, gene expression microarray, etc. RCS rats were used to mimic the degeneration of retina and test the therapeutic effects of subretinally transplanted donor cells. The structure and function of retina were examined. We established two protocols through which two types of rESC-derived RPCs were obtained and both contained committed retina lineage cells and some neural progenitor cells (NPCs). These rESC-derived RPCs survived in the host retinas of RCS rats and protected the retinal structure and function in early stage following the transplantation. However, the glia enriched rESC-RPC1 obtained through early and longer adherent culture only increased the b-wave amplitude at 4 weeks, while the longer suspension culture gave rise to evidently neuronal differentiation in rESC-RPC2 which significantly improved the visual function of RCS rats. We have successfully differentiated

  15. Gene therapy for inherited retinal and optic nerve degenerations.

    Science.gov (United States)

    Moore, Nicholas A; Morral, Nuria; Ciulla, Thomas A; Bracha, Peter

    2018-01-01

    The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity. Areas covered: This review covers Leber's congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber's hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis. Expert opinion: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.

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

    Science.gov (United States)

    Carrigan, Matthew; Duignan, Emma; Humphries, Pete; Palfi, Arpad; Kenna, Paul F; Farrar, G Jane

    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. A panel of 182 retinopathy-associated genes was sequenced to locate disease-causing mutations in patients with inherited retinopathies. Sequencing revealed a novel homozygous truncating mutation in the GNAT1 gene in a patient with significant pigmentary disturbance and constriction of visual fields, a presentation consistent with retinitis pigmentosa. This is the first report of a patient homozygous for a complete loss-of-function GNAT1 mutation. The clinical data from this patient provide definitive evidence of retinitis pigmentosa with late onset in addition to the lifelong night-blindness that would be expected from a lack of transducin function. These data suggest that some truncating GNAT1 variants can indeed cause a recessive, mild, late-onset retinal degeneration in human beings rather than just stationary night-blindness as reported previously, with notable similarities to the phenotype of the Gnat1 knockout mouse. 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/

  17. Chemical Exacerbation of Light-induced Retinal Degeneration in F344/N Rats in National Toxicology Program Rodent Bioassays

    OpenAIRE

    Yamashita, Haruhiro; Hoenerhoff, Mark J.; Peddada, Shyamal D.; Sills, Robert C.; Pandiri, Arun R.

    2016-01-01

    Retinal degeneration due to chronic ambient light exposure is a common spontaneous age-related finding in albino rats, but it can also be related to exposures associated with environmental chemicals and drugs. Typically, light induced retinal degeneration has a central/hemispherical localization where as chemical induced retinal degeneration has a diffuse localization. This study was conducted to identify National Toxicology Program (NTP) rodent bioassays with treatment-related retinal degene...

  18. All-optical recording and stimulation of retinal neurons in vivo in retinal degeneration mice

    Science.gov (United States)

    Strazzeri, Jennifer M.; Williams, David R.; Merigan, William H.

    2018-01-01

    Here we demonstrate the application of a method that could accelerate the development of novel therapies by allowing direct and repeatable visualization of cellular function in the living eye, to study loss of vision in animal models of retinal disease, as well as evaluate the time course of retinal function following therapeutic intervention. We use high-resolution adaptive optics scanning light ophthalmoscopy to image fluorescence from the calcium sensor GCaMP6s. In mice with photoreceptor degeneration (rd10), we measured restored visual responses in ganglion cell layer neurons expressing the red-shifted channelrhodopsin ChrimsonR over a six-week period following significant loss of visual responses. Combining a fluorescent calcium sensor, a channelrhodopsin, and adaptive optics enables all-optical stimulation and recording of retinal neurons in the living eye. Because the retina is an accessible portal to the central nervous system, our method also provides a novel non-invasive method of dissecting neuronal processing in the brain. PMID:29596518

  19. 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.

  20. A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration.

    Science.gov (United States)

    Chavali, Venkata R M; Khan, Naheed W; Cukras, Catherine A; Bartsch, Dirk-Uwe; Jablonski, Monica M; Ayyagari, Radha

    2011-05-15

    Late-onset retinal macular degeneration (L-ORD) is an autosomal dominant inherited disorder caused by a single missense mutation (S163R) in the CTRP5/C1QTNF5 protein. Early phenotypic features of L-ORD include: dark adaptation abnormalities, nyctalopia, and drusen deposits in the peripheral macular region. Apart from posterior segment abnormalities, these patients also develop abnormally long anterior lens zonules. In the sixth decade of life the rod and cone function declines, accompanied by electroretinogram (ERG) abnormalities. Some patients also develop choroidal neovascularization and glaucoma. In order to understand the disease pathology and mechanisms involved in retinal dystrophy, we generated a knock-in (Ctrp5(+/-)) mouse model carrying the disease-associated mutation in the mouse Ctrp5/C1QTNF5 gene. These mice develop slower rod-b wave recovery consistent with early dark adaptation abnormalities, accumulation of hyperautofluorescence spots, retinal pigment epithelium abnormalities, drusen, Bruch's membrane abnormalities, loss of photoreceptors, and retinal vascular leakage. The Ctrp5(+/-) mice, which have most of the pathological features of age-related macular degeneration, are unique and may serve as a valuable model both to understand the molecular pathology of late-onset retinal degeneration and to evaluate therapies.

  1. Ethanol Exposure Causes Muscle Degeneration in Zebrafish

    Directory of Open Access Journals (Sweden)

    Elizabeth C. Coffey

    2018-03-01

    Full Text Available Alcoholic myopathies are characterized by neuromusculoskeletal symptoms such as compromised movement and weakness. Although these symptoms have been attributed to neurological damage, EtOH may also target skeletal muscle. EtOH exposure during zebrafish primary muscle development or adulthood results in smaller muscle fibers. However, the effects of EtOH exposure on skeletal muscle during the growth period that follows primary muscle development are not well understood. We determined the effects of EtOH exposure on muscle during this phase of development. Strikingly, muscle fibers at this stage are acutely sensitive to EtOH treatment: EtOH induces muscle degeneration. The severity of EtOH-induced muscle damage varies but muscle becomes more refractory to EtOH as muscle develops. NF-kB induction in muscle indicates that EtOH triggers a pro-inflammatory response. EtOH-induced muscle damage is p53-independent. Uptake of Evans blue dye shows that EtOH treatment causes sarcolemmal instability before muscle fiber detachment. Dystrophin-null sapje mutant zebrafish also exhibit sarcolemmal instability. We tested whether Trichostatin A (TSA, which reduces muscle degeneration in sapje mutants, would affect EtOH-treated zebrafish. We found that TSA and EtOH are a lethal combination. EtOH does, however, exacerbate muscle degeneration in sapje mutants. EtOH also disrupts adhesion of muscle fibers to their extracellular matrix at the myotendinous junction: some detached muscle fibers retain beta-Dystroglycan indicating failure of muscle end attachments. Overexpression of Paxillin, which reduces muscle degeneration in zebrafish deficient for beta-Dystroglycan, is not sufficient to rescue degeneration. Taken together, our results suggest that EtOH exposure has pleiotropic deleterious effects on skeletal muscle.

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

    Science.gov (United States)

    2016-07-01

    regulating drugs – currently not purposed to treat retinal damage – may serve to ameliorate retinal degeneration in mice who have experienced blast...to buy a set for for our experiments going forward). A parallel experiments of SNR experiments with red vs green dye (data not shown), moreover

  3. The reduction of retinal autofluorescence caused by light exposure.

    Science.gov (United States)

    Morgan, Jessica I W; Hunter, Jennifer J; Merigan, William H; Williams, David R

    2009-12-01

    A prior study showed that long exposure to 568-nm light at levels below the maximum permissible exposure safety limit produces retinal damage preceded by a transient reduction in the autofluorescence of retinal pigment epithelial (RPE) cells in vivo. The present study shows how the effects of exposure power and duration combine to produce this autofluorescence reduction and find the minimum exposure causing a detectable autofluorescence reduction. Macaque retinas were imaged using a fluorescence adaptive optics scanning laser ophthalmoscope to resolve individual RPE cells in vivo. The retina was exposed to 568-nm light over a square subtending 0.5 degrees with energies ranging from 1 to 788 J/cm(2), where power and duration were independently varied. In vivo exposures of 5 J/cm(2) and higher caused an immediate decrease in autofluorescence followed by either full autofluorescence recovery (exposures or= 247 J/cm(2)). No significant autofluorescence reduction was observed for exposures of 2 J/cm(2) and lower. Reciprocity of exposure power and duration held for the exposures tested, implying that the total energy delivered to the retina, rather than its distribution in time, determines the amount of autofluorescence reduction. That reciprocity held is consistent with a photochemical origin, which may or may not cause retinal degeneration. The implementation of safe methods for delivering light to the retina requires a better understanding of the mechanism causing autofluorescence reduction. Finally, RPE imaging was demonstrated using light levels that do not cause a detectable reduction in autofluorescence.

  4. 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.

  5. Expression pattern of Ccr2 and Cx3cr1 in inherited retinal degeneration.

    Science.gov (United States)

    Kohno, Hideo; Koso, Hideto; Okano, Kiichiro; Sundermeier, Thomas R; Saito, Saburo; Watanabe, Sumiko; Tsuneoka, Hiroshi; Sakai, Tsutomu

    2015-10-12

    Though accumulating evidence suggests that microglia, resident macrophages in the retina, and bone marrow-derived macrophages can cause retinal inflammation which accelerates photoreceptor cell death, the details of how these cells are activated during retinal degeneration (RD) remain uncertain. Therefore, it is important to clarify which cells play a dominant role in fueling retinal inflammation. However, distinguishing between microglia and macrophages is difficult using conventional techniques such as cell markers (e.g., Iba-1). Recently, two mouse models for visualizing chemokine receptors were established, Cx3cr1 (GFP/GFP) and Ccr2 (RFP/RFP) mice. As Cx3cr1 is expressed in microglia and Ccr2 is reportedly expressed in activated macrophages, these mice have the potential to distinguish microglia and macrophages, yielding novel information about the activation of these inflammatory cells and their individual roles in retinal inflammation. In this study, c-mer proto-oncogene tyrosine kinase (Mertk) (-/-) mice, which show photoreceptor cell death due to defective retinal pigment epithelium phagocytosis, were employed as an animal model of RD. Mertk (-/-) Cx3cr1 (GFP/+) Ccr2 (RFP/+) mice were established by breeding Mertk (-/-) , Cx3cr1 (GFP/GFP) , and Ccr2 (RFP/RFP) mice. The retinal morphology and pattern of inflammatory cell activation and invasion of Mertk (-/-) Cx3cr1 (GFP/+) Ccr2 (RFP/+) mice were evaluated using retina and retinal pigment epithelium (RPE) flat mounts, retinal sections, and flow cytometry. Four-week-old Mertk (-/-) Cx3cr1 (GFP/+) Ccr2 (RFP/+) mice showed Cx3cr1-GFP-positive microglia in the inner retina. Cx3cr1-GFP and Ccr2-RFP dual positive activated microglia were observed in the outer retina and subretinal space of 6- and 8-week-old animals. Ccr2-RFP single positive bone marrow-derived macrophages were observed to migrate into the retina of Mertk (-/-) Cx3cr1 (GFP/+) Ccr2 (RFP/+) mice. These invading cells were still observed in the

  6. The influence of refractive error and lattice degeneration on the incidence of retinal detachment.

    Science.gov (United States)

    Burton, T C

    1989-01-01

    This study indicates the feasibility of stratifying the general population into various risk pools for retinal detachment depending on a person's age, refractive status, and the presence of lattice degeneration. At first impression the risks seem at variance with the fine clinical studies of Byer, who has shown a very low detachment rate in the population with lattice degeneration. In all likelihood the vast majority of his patients were emmetropic or mildly myopic, so that very few would be expected to develop detachments during their entire lifetimes, let along during intervals of only 10 to 20 years. This study shows the futility of following, or treating prophylactically, young emmetropic individuals with lattice degeneration. Assuming that prophylaxis is actually effective, one would have to treat 1000 emmetropic lattice patients in the 30 to 39 year age group to prevent a single detachment over a 10-year period. Lattice patients with low to moderate degrees of myopia tend to develop detachments between 40 and 60 years of age caused by premature posterior vitreous separation and tractional tears. Clearly prophylaxis for this group is not warranted, since only 5% to 10% of these individuals will experience detachments in their lifetimes. On the other hand this study has verified the previous suspicions that persons with myopia exceeding -5.0 D accompanied by lattice degeneration have an extraordinarily high risk of detachment during their lifetimes. Detachments in this group tend to cluster in the second, third, and fourth decades, are typically caused by atrophic holes, are slowly progressive, and are often simultaneously bilateral. Enhanced vigilance is certainly appropriate during this time and perhaps consideration should be given to prophylactically treating this group. This would be no small task, since within a population of 1 million persons there would be about 1150 aged 10 to 39 years with myopia exceeding -5.0 D and lattice degeneration. Only 4

  7. An anti-angiogenic state in mice and humans with retinal photoreceptor cell degeneration

    NARCIS (Netherlands)

    Lahdenranta, J.; Pasqualini, R.; Schlingemann, R. O.; Hagedorn, M.; Stallcup, W. B.; Bucana, C. D.; Sidman, R. L.; Arap, W.

    2001-01-01

    Abnormal angiogenesis accompanies many pathological conditions including cancer, inflammation, and eye diseases. Proliferative retinopathy because of retinal neovascularization is a leading cause of blindness in developed countries. Another major cause of irreversible vision loss is retinitis

  8. 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.

  9. Retinal pigment epithelial detachments and tears, and progressive retinal degeneration in light chain deposition disease.

    Science.gov (United States)

    Spielberg, Leigh H; Heckenlively, John R; Leys, Anita M

    2013-05-01

    Light-chain deposition disease (LCDD) is a rare condition characterised by deposition of monoclonal immunoglobulin light chains (LCs) in tissues, resulting in varying degrees of organ dysfunction. This study reports the characteristic clinical ocular findings seen in advanced LCDD upon development of ocular fundus changes. This is the first report to describe this entity in vivo in a series of patients. A case series of ocular fundus changes in three patients with kidney biopsy-proven LCDD. All patients underwent best corrected visual acuity (BCVA) exam, perimetry, colour fundus photography and fluorescein angiography; two patients underwent indocyanine green angiography, optical coherence tomography, ultrasound and electroretinography; and one patient underwent fundus autofluorescence. Three patients, 53-60 years old at initial presentation, were studied. All three presented with night blindness, poor dark adaptation, metamorphopsia and visual loss. Examination revealed serous and serohaemorrhagic detachments, multiple retinal pigment epithelial (RPE) tears, diffuse RPE degeneration and progressive fibrotic changes. Neither choroidal neovascularisation nor other vascular abnormalities were present. Final best corrected visual acuity (BCVA) ranged from 20/40 to 20/300. Progressive LC deposition in the fundus seems to damage RPE pump function with flow disturbance between choroid and retina. This pathogenesis can explain the evolution to RPE detachments and subsequent rips and progressive retinal malfunction.

  10. 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.

  11. 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.

  12. Astrocytes and Müller Cell Alterations During Retinal Degeneration in a Transgenic Rat Model of Retinitis Pigmentosa

    Science.gov (United States)

    Fernández-Sánchez, Laura; Lax, Pedro; Campello, Laura; Pinilla, Isabel; Cuenca, Nicolás

    2015-01-01

    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 (GCL) of P23H vs. 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. PMID:26733810

  13. Prevalence of anti-retinal autoantibodies in different stages of Age-related macular degeneration.

    Science.gov (United States)

    Adamus, Grazyna; Chew, Emily Y; Ferris, Frederick L; Klein, Michael L

    2014-12-08

    Age-related macular degeneration (AMD) is the leading cause of central vision loss in older adults. Anti-retinal autoantibodies (AAbs) have been found in individuals with AMD. The goal of the study was to determine the AAb specificity in different stages of AMD, and determine whether there is a prevalent AAb signature. Sera of 134 participants in the Age-related Eye Disease Study were analyzed for anti-retinal AAbs by western blotting. The subjects were classified by diagnostic subgroups based upon their clinical classification: No AMD, Intermediate AMD, and Late AMD - geographic atrophy (GA) and Late AMD - neovascular (NV). The presence of anti-retinal AAb was detected in 58% patients with Intermediate and Late AMD, and 54% of those with no AMD. AAbs bound to fifteen different retinal antigens. Most individuals had 1 specific AAbs (67%), with the remainder having 2 to 4 different AAbs. Over 40% of patients with Intermediate AMD, and 46% of those with GA had anti-enolase AAbs, compared with 29% of individuals with NV and 29% with no AMD. Different AAbs signatures related to NV as compared to GA and/or Intermediate AMD were distinguished. Anti-40-kDa (10%) and 42-kDa (16%) autoantibodies were associated with Intermediate AMD, while anti-30-kDa AAbs (23%) were primarily present in GA. Anti-32-kDa (12%), 35-kDa (21%), and 60-kDa (8%) AAbs were more frequent in NV AMD. A unique AAb pattern for each of the disease subgroups was present when AMD progressed from the intermediate to the late forms of severity. Differences in the frequency of specific AAbs between AMD subgroups suggested that they may participate in pathogenicity of AMD. Further studies are necessary to confirm these observations in the larger cohort and individual AMD patients over time.

  14. Retinitis-pigmentosa-like tapetoretinal degeneration in a rabbit breed.

    Science.gov (United States)

    Reichenbach, A; Baar, U

    1985-08-15

    By chance, we found a rabbit strain with retinal dystrophy. The eyes of these rabbits were examined by ophthalmoscopy, electroretinography, histology, and cytology--the latter after retina dissociation with papaine. The results suggest this rabbit strain to be a possible animal model for human retinitis pigmentosa.

  15. The severity of retinal degeneration in Rp1h gene-targeted mice is dependent on genetic background.

    Science.gov (United States)

    Liu, Qin; Saveliev, Alexei; Pierce, Eric A

    2009-04-01

    The severity of disease in patients with retinitis pigmentosa (RP) can vary significantly, even among patients with the same primary mutations. It is hypothesized that modifier genes play important roles in determining the severity of RP, including the retinitis pigmentosa 1 (RP1) form of disease. To investigate the basis of variation in disease expression for RP1 disease, the authors generated congenic mice with a gene-targeted retinitis pigmentosa 1 homolog (Rp1h) allele (Rp1h(tm1Eap)) on several different genetic backgrounds and analyzed their retinal phenotypes. The Rp1h(tm1Eap) allele was placed onto the C57BL/6J, DBA1/J, and A/J backgrounds. Retinal function of the resultant congenic mice was evaluated using electroretinographic analyses. Retinal structure and ultrastructure were evaluated using light and electron microscopy. Rp1h protein location was determined with immunofluorescence microscopy. Analysis of the retinal phenotype of incipient congenic (N6) B6.129S-Rp1h(+/tm1Eap), DBA.129S(B6)-Rp1h(+/tm1Eap), and A.129S(B6)-Rp1h(+/tm1Eap) mice at 1 year of age showed retinal degeneration only in the A.129S(B6)-Rp1h(+/tm1Eap) mice. Further analyses revealed that the photoreceptors of the fully congenic A.129S(B6)-Rp1h(+/tm1Eap) mice show evidence of degeneration at 6 months of age and are almost completely lost by 18 months of age. In contrast, the photoreceptor cells in the fully congenic B6.129S-Rp1h(+/tm1Eap) mice remain healthy up to 18 months. The severity of the retinal degeneration caused by the Rp1h(tm1Eap) allele is notably dependent on genetic background. The development and characterization of the B6.129S-Rp1h(+/tm1Eap) and A.129S(B6)-Rp1h(+/tm1Eap) congenic mouse lines will facilitate identification of sequence alterations in genes that modify the severity of RP1 disease.

  16. Development and degeneration of cone bipolar cells are independent of cone photoreceptors in a mouse model of retinitis pigmentosa.

    Directory of Open Access Journals (Sweden)

    Miao Chen

    Full Text Available Retinal photoreceptors die during retinal synaptogenesis in a portion of retinal degeneration. Whether cone bipolar cells establish regular retinal mosaics and mature morphologies, and resist degeneration are not completely understood. To explore these issues, we backcrossed a transgenic mouse expressing enhanced green fluorescent protein (EGFP in one subset of cone bipolar cells (type 7 into rd1 mice, a classic mouse model of retinal degeneration, to examine the development and survival of cone bipolar cells in a background of retinal degeneration. Our data revealed that both the development and degeneration of cone bipolar cells are independent of the normal activity of cone photoreceptors. We found that type 7 cone bipolar cells achieved a uniform tiling of the retinal surface and developed normal dendritic and axonal arbors without the influence of cone photoreceptor innervation. On the other hand, degeneration of type 7 cone bipolar cells, contrary to our belief of central-to-peripheral progression, was spatially uniform across the retina independent of the spatiotemporal pattern of cone degeneration. The results have important implications for the design of more effective therapies to restore vision in retinal degeneration.

  17. 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.

  18. Prevalence and characteristics of peripheral retinal degeneration in Chinese adults with high myopia: a cross-sectional prevalence survey.

    Science.gov (United States)

    Lam, Dennis S C; Fan, Dorothy S P; Chan, Wai-Man; Tam, Barbara S M; Kwok, Alvin K H; Leung, Alfred T S; Parsons, Hugh

    2005-04-01

    The purpose of this study was to study the prevalence of peripheral retinal findings in adult Chinese patients with high myopia (refraction degeneration (51.2%), followed by lattice degeneration in 12.2% and retinal holes in 7.5% of eyes. A positive correlation was noted between axial length and the lesions of pigmentary degeneration and pavingstone degeneration. The prevalence of retinal holes was 6.4% and 30.0% in eyes with axial length of or = 30 mm, respectively (chi-squared test, p = 0.006). A high prevalence of peripheral retinal degenerations was found in adult Chinese high myopes. The presence of retinal holes was positively correlated with very high myopia of an axial length of > or = 30 mm.

  19. NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP).

    Science.gov (United States)

    Schorderet, Daniel F; Escher, Pascal

    2009-11-01

    NR2E3, also called photoreceptor-specific nuclear receptor (PNR), is a transcription factor of the nuclear hormone receptor superfamily whose expression is uniquely restricted to photoreceptors. There, its physiological activity is essential for proper rod and cone photoreceptor development and maintenance. Thirty-two different mutations in NR2E3 have been identified in either homozygous or compound heterozygous state in the recessively inherited enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD). The clinical phenotype common to all these patients is night blindness, rudimental or absent rod function, and hyperfunction of the "blue" S-cones. A single p.G56R mutation is inherited in a dominant manner and causes retinitis pigmentosa (RP). We have established a new locus-specific database for NR2E3 (www.LOVD.nl/eye), containing all reported mutations, polymorphisms, and unclassified sequence variants, including novel ones. A high proportion of mutations are located in the evolutionarily-conserved DNA-binding domains (DBDs) and ligand-binding domains (LBDs) of NR2E3. Based on homology modeling of these NR2E3 domains, we propose a structural localization of mutated residues. The high variability of clinical phenotypes observed in patients affected by NR2E3-linked retinal degenerations may be caused by different disease mechanisms, including absence of DNA-binding, altered interactions with transcriptional coregulators, and differential activity of modifier genes.

  20. Transgenic Mice Over-Expressing RBP4 Have RBP4-Dependent and Light-Independent Retinal Degeneration.

    Science.gov (United States)

    Du, Mei; Phelps, Eric; Balangue, Michael J; Dockins, Aaron; Moiseyev, Gennadiy; Shin, Younghwa; Kane, Shelley; Otalora, Laura; Ma, Jian-Xing; Farjo, Rafal; Farjo, Krysten M

    2017-08-01

    Transgenic mice overexpressing serum retinol-binding protein (RBP4-Tg) develop progressive retinal degeneration, characterized by microglia activation, yet the precise mechanisms underlying retinal degeneration are unclear. Previous studies showed RBP4-Tg mice have normal ocular retinoid levels, suggesting that degeneration is independent of the retinoid visual cycle or light exposure. The present study addresses whether retinal degeneration is light-dependent and RBP4-dependent by testing the effects of dark-rearing and pharmacological lowering of serum RBP4 levels, respectively. RBP4-Tg mice reared on normal mouse chow in normal cyclic light conditions were directly compared to RBP4-Tg mice exposed to chow supplemented with the RBP4-lowering compound A1120 or dark-rearing conditions. Quantitative retinal histological analysis was conducted to assess retinal degeneration, and electroretinography (ERG) and optokinetic tracking (OKT) tests were performed to assess retinal and visual function. Ocular retinoids and bis-retinoid A2E were quantified. Dark-rearing RBP4-Tg mice effectively reduced ocular bis-retinoid A2E levels, but had no significant effect on retinal degeneration or dysfunction in RBP4-Tg mice, demonstrating that retinal degeneration is light-independent. A1120 treatment lowered serum RBP4 levels similar to wild-type mice, and prevented structural retinal degeneration. However, A1120 treatment did not prevent retinal dysfunction in RBP4-Tg mice. Moreover, RBP4-Tg mice on A1120 diet had significant worsening of OKT response and loss of cone photoreceptors compared to RBP4-Tg mice on normal chow. This may be related to the very significant reduction in retinyl ester levels in the retina of mice on A1120-supplemented diet. Retinal degeneration in RBP4-Tg mice is RBP4-dependent and light-independent.

  1. Correlation between SD-OCT, immunocytochemistry and functional findings in a pigmented animal model of retinal degeneration

    Directory of Open Access Journals (Sweden)

    Nicolás eCuenca

    2014-12-01

    Full Text Available Purpose: The P23H rhodopsin mutation is an autosomal dominant cause of retinitis pigmentosa. The degeneration can be tracked using different anatomical and functional methods. In our case, we evaluated the anatomical changes using Spectral-Domain Optical Coherence Tomography (SD-OCT and correlated the findings with retinal thickness values determined by immunocytochemistry.Methods: Pigmented rats heterozygous for the P23H mutation, with ages between P18 and P180 were studied. Function was assessed by means of optomotor testing and ERGs. Retinal thicknesses measurements, autofluorescence and fluorescein angiography were performed using Spectralis OCT. Retinas were studied by means of immunohistochemistry. Results: Between P30 and P180, visual acuity decreased from 0.500 to 0.182 cycles per degree (cyc/deg and contrast sensitivity decreased from 54.56 to 2.98 for a spatial frequency of 0.089 cyc/deg. Only cone-driven b-wave responses reached developmental maturity. Flicker fusions were also comparable at P29 (42 Hz. Double flash-isolated rod-driven responses were already affected at P29. Photopic responses revealed deterioration after P29.A reduction in retinal thicknesses and morphological modifications were seen in OCT sections. Statistically significant differences were found in all evaluated thicknesses. Autofluorescence was seen in P23H rats as sparse dots. Immunocytochemistry showed a progressive decrease in the outer nuclear layer, and morphological changes. Although anatomical thickness measures were significantly lower than OCT values, there was a very strong correlation between the values measured by both techniques.Conclusions: In pigmented P23H rats, a progressive deterioration occurs in both retinal function and anatomy. Anatomical changes can be effectively evaluated using SD-OCT and immunocytochemistry, with a good correlation between their values, thus making SD-OCT an important tool for research in retinal degeneration.

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

    Science.gov (United States)

    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 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. PMID:25234724

  3. Protective effect of sulforaphane against retinal degeneration in the Pde6rd10 mouse model of retinitis pigmentosa.

    Science.gov (United States)

    Kang, Kai; Yu, Minzhong

    2017-12-01

    Retinitis pigmentosa (RP) is a group of inherited diseases characterized by the death of rod photoreceptors, followed by the death of cone photoreceptors, progressively leading to partial or complete blindness. Currently no specific treatment is available for RP patients. Sulforaphane (SFN) has been confirmed to be an effective antioxidant in the treatment of many diseases. In this study, we tested the therapeutic effects of SFN against photoreceptor degeneration in Pde6b rd10 mice. rd10 mice and C57/BL6 wild-type (WT) mice were treated with SFN and saline, respectively, from P6 to P20. Electroretinography (ERG), terminal deoxynucleotidyl transferase dUTP nick end labeling and western blot were tested, respectively, at P21 for the analysis of retinal function, retinal cell apoptosis or death and the protein express of GRP78/BiP (TUNEL) as a marker of endoplasmic reticulum (ER) stress. Compared with the saline group, the SFN-treated group showed significantly higher ERG a-wave and b-wave amplitudes, less photoreceptor death, and the downregulation of GRP78/BiP. Our data showed that SFN ameliorated the retinal degeneration of rd10 mice, which is possibly related to the downregulation of GRP78 expression.

  4. Mutation K42E in dehydrodolichol diphosphate synthase (DHDDS) causes recessive retinitis pigmentosa.

    Science.gov (United States)

    Lam, Byron L; Züchner, Stephan L; Dallman, Julia; Wen, Rong; Alfonso, Eduardo C; Vance, Jeffery M; Peričak-Vance, Margaret A

    2014-01-01

    A single-nucleotide mutation in the gene that encodes DHDDS has been identified by whole exome sequencing as the cause of the non-syndromic recessive retinitis pigmentosa (RP) in a family of Ashkenazi Jewish origin in which three of the four siblings have early onset retinal degeneration. The peripheral retinal degeneration in the affected siblings was evident in the initial examination in 1992 and only one had detectable electroretinogram (ERG) that suggested cone-rod dysfunction. The pigmentary retinal degeneration subsequently progressed rapidly. The identified mutation changes the highly conserved residue Lys42 to Glu, resulting in lower catalytic efficiency. Patterns of plasma transferrin isoelectric focusing gel were normal in all family members, indicating no significant abnormality in protein glycosylation. Dolichols have been shown to influence the fluidity and of the membrane and promote vesicle fusion. Considering that photoreceptor outer segments contain stacks of membrane discs, we believe that the mutation may lead to low dolichol levels in photoreceptor outer segments, resulting in unstable membrane structure that leads to photoreceptor degeneration.

  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. Nanosecond laser therapy reverses pathologic and molecular changes in age-related macular degeneration without retinal damage.

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    Jobling, A I; Guymer, R H; Vessey, K A; Greferath, U; Mills, S A; Brassington, K H; Luu, C D; Aung, K Z; Trogrlic, L; Plunkett, M; Fletcher, E L

    2015-02-01

    Age-related macular degeneration (AMD) is a leading cause of vision loss, characterized by drusen deposits and thickened Bruch's membrane (BM). This study details the capacity of nanosecond laser treatment to reduce drusen and thin BM while maintaining retinal structure. Fifty patients with AMD had a single nanosecond laser treatment session and after 2 yr, change in drusen area was compared with an untreated cohort of patients. The retinal effect of the laser was determined in human and mouse eyes using immunohistochemistry and compared with untreated eyes. In a mouse with thickened BM (ApoEnull), the effect of laser treatment was quantified using electron microscopy and quantitative PCR. In patients with AMD, nanosecond laser treatment reduced drusen load at 2 yr. Retinal structure was not compromised in human and mouse retina after laser treatment, with only a discrete retinal pigment epithelium (RPE) injury, and limited mononuclear cell response observed. BM was thinned in the ApoEnull mouse 3 mo after treatment (ApoEnull treated 683 ± 38 nm, ApoEnull untreated 890 ± 60 nm, C57Bl6J 606 ± 43 nm), with the expression of matrix metalloproteinase-2 and -3 increased (>260%). Nanosecond laser resolved drusen independent of retinal damage and improved BM structure, suggesting this treatment has the potential to reduce AMD progression. © FASEB.

  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. Cone function studied with flicker electroretinogram during progressive retinal degeneration in RCS rats.

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    Pinilla, I; Lund, R D; Sauvé, Y

    2005-01-01

    The Royal College of Surgeons (RCS) rat has a primary defect in retinal pigment epithelial cells that leads to the progressive loss of photoreceptors and central visual responsiveness. While most rods are lost by 90 days of age (P90), cones degenerate more slowly, and can be detected anatomically up to 2 years of age, despite massive neuronal death and retinal remodelling. To examine how this progressive degenerative process impacts on cone function, we recorded the electroretingram to white light flashes (1.37 log cd s m(-2)) presented at frequencies ranging from 3 to 50 Hz, under light adapted conditions (29.8 cd m(-2)). Pigmented dystrophic and congenic non-dystrophic RCS rats aged from 18 to 300 days were studied. In all responsive animals at all ages, maximal amplitudes were obtained at 3 Hz. In both non-dystrophic and dystrophic rats, there was an increase from P18 to P21 in response amplitude and critical fusion frequency. After P21, these two parameters declined progressively with age in dystrophic rats. Other changes included prolongation in latency, which was first detected prior to the initiation of amplitude reduction. While phase shifts were also detected in dystrophic RCS rats, they appeared at later degenerative stages. The latest age at which responses could be elicited in dystrophic rats was at P200, with positive waves being replaced by negative deflections. The effect of increments in the intensity of background illumination was tested at P50 in both groups. This caused a diminution in flicker response amplitude and critical fusion frequencies in non-dystrophics, while in dystrophic animals, response amplitudes were reduced only at low frequencies and critical fusion frequencies were unaltered. In conclusion, although dystrophic RCS rats undergo a progressive decline in cone function with age, the flicker responsiveness at P21 is comparable to that of non-dystrophic congenic rats, suggesting normal developmental maturation of the cone system in

  9. A Proinflammatory Function of Toll-Like Receptor 2 in the Retinal Pigment Epithelium as a Novel Target for Reducing Choroidal Neovascularization in Age-Related Macular Degeneration.

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    Feng, Lili; Ju, Meihua; Lee, Kei Ying V; Mackey, Ashley; Evangelista, Mariasilvia; Iwata, Daiju; Adamson, Peter; Lashkari, Kameran; Foxton, Richard; Shima, David; Ng, Yin Shan

    2017-10-01

    Current treatments for choroidal neovascularization, a major cause of blindness for patients with age-related macular degeneration, treat symptoms but not the underlying causes of the disease. Inflammation has been strongly implicated in the pathogenesis of choroidal neovascularization. We examined the inflammatory role of Toll-like receptor 2 (TLR2) in age-related macular degeneration. TLR2 was robustly expressed by the retinal pigment epithelium in mouse and human eyes, both normal and with macular degeneration/choroidal neovascularization. Nuclear localization of NF-κB, a major downstream target of TLR2 signaling, was detected in the retinal pigment epithelium of human eyes, particularly in eyes with advanced stages of age-related macular degeneration. TLR2 antagonism effectively suppressed initiation and growth of spontaneous choroidal neovascularization in a mouse model, and the combination of anti-TLR2 and antivascular endothelial growth factor receptor 2 yielded an additive therapeutic effect on both area and number of spontaneous choroidal neovascularization lesions. Finally, in primary human fetal retinal pigment epithelium cells, ligand binding to TLR2 induced robust expression of proinflammatory cytokines, and end products of lipid oxidation had a synergistic effect on TLR2 activation. Our data illustrate a functional role for TLR2 in the pathogenesis of choroidal neovascularization, likely by promoting inflammation of the retinal pigment epithelium, and validate TLR2 as a novel therapeutic target for reducing choroidal neovascularization. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  10. Effects of Subretinal Gene Transfer at Different Time Points in a Mouse Model of Retinal Degeneration.

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    Dai, Xufeng; Zhang, Hua; Han, Juanjuan; He, Ying; Zhang, Yangyang; Qi, Yan; Pang, Ji-Jing

    2016-01-01

    Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is necessary for photoreceptors to generate an important lipid component of their membranes. The absence of LPCAT1 results in early and rapid rod and cone degeneration. Retinal degeneration 11 (rd11) mice carry a mutation in the Lpcat1 gene, and are an excellent model of early-onset rapid retinal degeneration (RD). To date, no reports have documented gene therapy administration in the rd11 mouse model at different ages. In this study, the AAV8 (Y733F)-smCBA-Lpcat1 vector was subretinally injected at postnatal day (P) 10, 14, 18, or 22. Four months after injection, immunohistochemistry and analysis of retinal morphology showed that treatment at P10 rescued about 82% of the wild-type retinal thickness. However, the diffusion of the vector and the resulting rescue were limited to an area around the injection site that was only 31% of the total retinal area. Injection at P14 resulted in vector diffusion that covered approximately 84% of the retina, and we found that gene therapy was more effective against RD when exposure to light was limited before and after treatment. We observed long-term preservation of electroretinogram (ERG) responses, and preservation of retinal structure, indicating that early treatment followed by limited light exposure can improve gene therapy effectiveness for the eyes of rd11 mice. Importantly, delayed treatment still partially preserved M-cones, but not S-cones, and M-cones in the rd11 retina appeared to have a longer window of opportunity for effective preservation with gene therapy. These results provide important information regarding the effects of subretinal gene therapy in the mouse model of LPCAT1-deficiency.

  11. Outcomes of macular hole surgery in patients treated intraoperatively for retinal breaks and/or lattice degeneration.

    Science.gov (United States)

    Hwang, John; Escariao, Paulo; Iranmanesh, Reza; Tosi, Gian Marco; Chang, Stanley

    2007-01-01

    To assess the outcome of macular hole surgery in patients treated intraoperatively for retinal breaks and/or lattice degeneration. Retrospective review of patients who underwent macular hole surgery from September 1998 to August 2005. Outcomes in eyes that received intraoperative endolaser photocoagulation for retinal breaks and/or lattice degeneration were compared to outcomes in a case-matched control group without retinal breaks or lattice degeneration. A total of 235 consecutive macular hole surgery cases were reviewed. Twenty-four eyes from 24 patients received intraoperative endolaser photocoagulation for retinal breaks and/or lattice degeneration. Macular hole closure occurred in all case and control eyes without any incidence of postoperative retinal detachment. Best-corrected visual acuity improvement of at least three Snellen lines occurred in 100% of case eyes and 92% of control eyes. Outcomes of macular hole surgery in patients with retinal breaks and/or lattice degeneration are similar to outcomes in the overall population when these conditions are treated with intraoperative endolaser photocoagulation. Postoperative retinal detachment does not appear to be correlated with treated retinal tears and greater attention should focus on detecting and managing intraoperative breaks. In our hands, routine use panoramic viewing has replaced indirect ophthalmoscopy, by saving time, and reducing the risk of contamination.

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

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    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.

  13. Relationship between full-thickness macular hole and retinal break/lattice degeneration.

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    Zhang, Jinglin; Li, Yonghao; Zhao, Xiujuan; Cai, Yu; Yu, Xiling; Lu, Lin

    2015-12-01

    The purpose is to investigate the relationship between full-thickness macular hole (MH) and retinal break (RB) and/or lattice degeneration. Patients diagnosed as full-thickness MH and referred to Dr. Lin Lu from January 2009 to December 2013 were evaluated. All patients underwent general ophthalmologic examinations, fundus examination and optical coherence tomography (OCT). The RB and/or lattice degeneration were recorded. Totally 183 eyes of 167 patients were included. The sex ratio of men to women was 1:2.88. A total of 17 eyes were pseudophakic and 166 eyes were phakic. RB and/or lattice degeneration were found in 62 eyes (33.88%). The prevalence of RB and/or lattice degeneration was similar between men and women (P = 0.344 > 0.05). There was no statistical difference between the pseudophakic eyes and phakic eyes (P = 0.138 > 0.05). All of the RB and/or lattice degeneration were located near or anterior to the equator. The inferior quadrants and the vertical meridian were affected more often than the superior quadrants and the horizontal meridian. We identified a high incidence of RB/lattice degeneration in cases of full-thickness MH. Carefully examination of the peripheral retina and prophylactic treatment of RB and/or lattice degeneration are critical.

  14. [Tapeto-retinal degeneration combined with incomplete general albinism (author's transl)].

    Science.gov (United States)

    Ivandić, T

    1975-05-01

    Report on a family, which presented the rare autosomal dominant transmitted, incomplete general albinism associated with autosomal recessive inherited, diffuse tapeto-retinal degeneration "sine pigmento". hypopigmentation of skin, eyebrows and hair, blue iris and fundus albinoticus with hypoplasia of the macula. In 3 cases additionally appeared: waxy pallor of optic disc, vascular narrowing, reflexless hypoplastic macula, pigmentless periphery, acquired blue-yellow blindness, concentric limitation of the visual field, reduced darkadaptation, abolished electroretinogram and myopic astigmatism.

  15. Imaging retinal degeneration in mice by combining Fourier domain optical coherence tomography and fluorescent scanning laser ophthalmoscopy

    Science.gov (United States)

    Hossein-Javaheri, Nima; Molday, Laurie L.; Xu, Jing; Molday, Robert S.; Sarunic, Marinko V.

    2009-02-01

    Visualization of the internal structures of the retina is critical for clinical diagnosis and monitoring of pathology as well as for medical research investigating the root causes of retinal degeneration. Optical Coherence Tomography (OCT) is emerging as the preferred technique for non-contact sub-surface depth-resolved imaging of the retina. The high resolution cross sectional images acquired in vivo by OCT can be compared to histology to visually delineate the retinal layers. The recent demonstration of the significant sensitivity increase obtained through use of Fourier domain (FD) detection with OCT has been used to facilitate high speed scanning for volumetric reconstruction of the retina in software. The images acquired by OCT are purely structural, relying on refractive index differences in the tissue for contrast, and do not provide information on the molecular content of the sample. We have constructed a FDOCT prototype and combined it with a fluorescent Scanning Laser Ophthalmoscope (fSLO) to permit real time alignment of the field of view on the retina. The alignment of the FDOCT system to the specimen is crucial for the registration of measurements taken throughout longitudinal studies. In addition, fluorescence detection has been integrated with the SLO to enable the en face localization of a molecular contrast signal, which is important for retinal angiography, and also for detection of autofluorescence associated with some forms of retinal degeneration, for example autofluorescence lipofuscin accumulations are associated with Stargardt's Macular Dystrophy. The integrated FD OCT/fSLO system was investigated for imaging the retina of the mice in vivo.

  16. Corneal and Retinal Neuronal Degeneration in Early Stages of Diabetic Retinopathy.

    Science.gov (United States)

    Srinivasan, Sangeetha; Dehghani, Cirous; Pritchard, Nicola; Edwards, Katie; Russell, Anthony W; Malik, Rayaz A; Efron, Nathan

    2017-12-01

    To examine the neuronal structural integrity of cornea and retina as markers for neuronal degeneration in nonproliferative diabetic retinopathy (NPDR). Participants were recruited from the broader Brisbane community, Queensland, Australia. Two hundred forty-one participants (187 with diabetes and 54 nondiabetic controls) were examined. Diabetic retinopathy (DR) was graded according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), corneal nerve fiber tortuosity (CNFT), full retinal thickness, retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), focal (FLV) and global loss volumes (GLV), hemoglobin A1c (HbA1c), nephropathy, neuropathy, and cardiovascular measures were examined. The central zone (P = 0.174), parafoveal thickness (P = 0.090), perifovea (P = 0.592), RNFL (P = 0.866), GCC (P = 0.798), and GCC GLV (P = 0.338) did not differ significantly between the groups. In comparison to the control group, those with very mild NPDR and those with mild NPDR had significantly higher focal loss in GCC volume (P = 0.036). CNFL was significantly lower in those with mild NPDR (P = 0.004) in comparison to the control group and those with no DR. The CNBD (P = 0.094) and CNFT (P = 0.458) did not differ between the groups. Both corneal and retinal neuronal degeneration may occur in early stages of diabetic retinopathy. Further studies are required to examine these potential markers for neuronal degeneration in the absence of clinical signs of DR.

  17. Curcumin Delays Retinal Degeneration by Regulating Microglia Activation in the Retina of rd1 Mice.

    Science.gov (United States)

    Wang, Yanhe; Yin, Zhiyuan; Gao, Lixiong; Sun, Dayu; Hu, Xisu; Xue, Langyue; Dai, Jiaman; Zeng, YuXiao; Chen, Siyu; Pan, Boju; Chen, Min; Xie, Jing; Xu, Haiwei

    2017-01-01

    Retinitis pigmentosa (RP) is characterized by degeneration of photoreceptors, and there are currently no effective treatments for this disease. However, curcumin has shown neuroprotectant efficacy in a RP rat and swine model, and thus, may have neuroprotective effects in this disease. Immunofluorescence staining, electroretinogram recordings, and behavioral tests were used to analyze the effects of curcumin and the underlying mechanism in retinal degeneration 1 (rd1) mice. The number of apoptotic cells in the retina of rd1 mice at postnatal day 14 significantly decreased with curcumin treatment and visual function was improved. The activation of microglia and secretion of chemokines and matrix metalloproteinases in the retina were inhibited by curcumin. These effects were also observed in a co-culture of BV2 microglial cells and retina-derived 661W cells. Curcumin delayed retinal degeneration by suppressing microglia activation in the retina of rd1 mice. Thus, it may be an effective treatment for neurodegenerative disorders such as RP. © 2017 The Author(s). Published by S. Karger AG, Basel.

  18. Curcumin Delays Retinal Degeneration by Regulating Microglia Activation in the Retina of rd1 Mice

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    Yanhe Wang

    2017-11-01

    Full Text Available Background/Aims: Retinitis pigmentosa (RP is characterized by degeneration of photoreceptors, and there are currently no effective treatments for this disease. However, curcumin has shown neuroprotectant efficacy in a RP rat and swine model, and thus, may have neuroprotective effects in this disease. Methods: Immunofluorescence staining, electroretinogram recordings, and behavioral tests were used to analyze the effects of curcumin and the underlying mechanism in retinal degeneration 1 (rd1 mice. Results: The number of apoptotic cells in the retina of rd1 mice at postnatal day 14 significantly decreased with curcumin treatment and visual function was improved. The activation of microglia and secretion of chemokines and matrix metalloproteinases in the retina were inhibited by curcumin. These effects were also observed in a co-culture of BV2 microglial cells and retina-derived 661W cells. Conclusions: Curcumin delayed retinal degeneration by suppressing microglia activation in the retina of rd1 mice. Thus, it may be an effective treatment for neurodegenerative disorders such as RP.

  19. Lipoic Acid and Progesterone Alone or in Combination Ameliorate Retinal Degeneration in an Experimental Model of Hereditary Retinal Degeneration

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    Dolores T. Ramírez-Lamelas

    2018-05-01

    Full Text Available Retinitis pigmentosa (RP is a group of inherited retinopathies characterized by photoreceptors death. Our group has shown the positive progesterone (P4 actions on cell death progression in an experimental model of RP. In an effort to enhance the beneficial effects of P4, the aim of this study was to combine P4 treatment with an antioxidant [lipoic acid (LA] in the rd1 mice. rd1 and control mice were treated with 100 mg/kg body weight of P4, LA, or a combination of both on postnatal day 7 (PN7, 9, and 11, and were sacrificed at PN11. The administration of LA and/or P4 diminishes cell death in rd1 retinas. The effect obtained after the combined administration of LA and P4 is higher than the one obtained with LA or P4 alone. The three treatments decreased GFAP staining, however, in the far peripheral retina, and the two treatments that offered better results were LA and LA plus P4. LA or LA plus P4 increased retinal glutathione (GSH concentration in the rd1 mice. Although LA and P4 are able to protect photoreceptors from death in rd1 mice retinas, a better effectiveness is achieved when administering LA and P4 at the same time.

  20. The role of whiskers in compensation of visual deficit in a mouse model of retinal degeneration.

    Science.gov (United States)

    Voller, Jaroslav; Potužáková, Barbora; Šimeček, Vojtěch; Vožeh, František

    2014-01-13

    Sensory deprivation in one modality can enhance the development of the remaining modalities via mechanisms of synaptic plasticity. Mice of the C3H strain suffer from RD1 retinal degeneration that leads to visual impairment at weaning age. We examined a role of whiskers in compensation of the visual deficit. In order to differentiate the contribution of the whiskers from other mechanisms that can take part in the compensation, we investigated the effect of both chronic and acute tactile deprivation. Three-month-old mice were used. We examined motor skills (rotarod, beam walking test), gait control (CatWalk system), spontaneous motor activity (open field) and CNS excitability to an acoustic stimulus for assessment of compensatory changes in auditory system (audiogenic epilepsy). In the sighted mice, the only effect was a decline in their rotarod test performance after acute whisker removal. In the blind animals, chronic tactile deprivation caused changes in their gait and impaired the performance in motor tests. Some other compensatory mechanisms were involved but the whiskers are essential for the compensation as it emerged from more marked change of gait and the worsening of the motor performance after the acute whisker removal. Both chronic and acute tactile deprivation induced anxiety-like behaviour. Only a combination of blindness and chronic tactile deprivation led to an increased sense of hearing. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  1. Retinal pigment epithelium, age-related macular degeneration and neurotrophic keratouveitis.

    Science.gov (United States)

    Bianchi, Enrica; Scarinci, Fabio; Ripandelli, Guido; Feher, Janos; Pacella, Elena; Magliulo, Giuseppe; Gabrieli, Corrado Balacco; Plateroti, Rocco; Plateroti, Pasquale; Mignini, Fiorenzo; Artico, Marco

    2013-01-01

    Age-related macular degeneration (AMD) is the leading cause of impaired vision and blindness in the aging population. The aims of our studies were to identify qualitative and quantitative alterations in mitochondria in human retinal pigment epithelium (RPE) from AMD patients and controls and to test the protective effects of pigment epithelium-derived factor (PEDF), a known neurotrophic and antiangiogenic substance, against neurotrophic keratouveitis. Histopathological alterations were studied by means of morphometry, light and electron microscopy. Unexpectedly, morphometric data showed that the RPE alterations noted in AMD may also develop in normal aging, 10-15 years later than appearing in AMD patients. Reduced tear secretion, corneal ulceration and leukocytic infiltration were found in capsaicin (CAP)-treated rats, but this effect was significantly attenuated by PEDF. These findings suggest that PEDF accelerated the recovery of tear secretion and also prevented neurotrophic keratouveitis and vitreoretinal inflammation. PEDF may have a clinical application in inflammatory and neovascular diseases of the eye.

  2. Risk factors for progressive axonal degeneration of the retinal nerve fibre layer in multiple sclerosis patients.

    Science.gov (United States)

    Garcia-Martin, Elena; Pueyo, Victoria; Almarcegui, Carmen; Martin, Jesus; Ara, Jose R; Sancho, Eva; Pablo, Luis E; Dolz, Isabel; Fernandez, Javier

    2011-11-01

    To quantify structural and functional degeneration in the retinal nerve fibre layer (RNFL) of patients with multiple sclerosis (MS) over a 2-year time period, and to analyse the effect of prior optic neuritis (ON) as well as the duration and incidence of MS relapses. 166 MS patients and 120 healthy controls underwent assessment of visual acuity and colour vision, visual field examination, optical coherence tomography, scanning laser polarimetry and visual evoked potentials (VEPs). All subjects were re-evaluated after a period of 12 and 24 months. Changes in the optic nerve were detected by structural measurements but not by functional assessments. Changes registered in MS patients were greater than changes in healthy controls (p<0.05). Eyes with previous ON showed a greater reduction of parameters in the baseline evaluation, but RNFL atrophy was not significantly greater in the longitudinal study. Patients with MS relapses showed a greater reduction of RNFL thickness and VEP amplitude compared with non-relapsing cases. Patients with and without treatment showed similar measurement reduction, but the non-treated group had a significantly higher increase in Expanded Disability Status Scale (p=0.029). MS causes progressive axonal loss in the optic nerve, regardless of a history of ON. This ganglion cell atrophy occurs in all eyes but is more marked in MS eyes than in healthy eyes.

  3. 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.

  4. 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.

  5. Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration.

    Science.gov (United States)

    Ma, Hongwei; Yang, Fan; Butler, Michael R; Belcher, Joshua; Redmond, T Michael; Placzek, Andrew T; Scanlan, Thomas S; Ding, Xi-Qin

    2017-08-01

    Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have implicated TH signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we demonstrated that antithyroid drug treatment and targeting iodothyronine deiodinases (DIOs) to suppress cellular tri-iodothyronine (T3) production or increase T3 degradation preserves cones. In this work, we investigated the effectiveness of inhibition of the TH receptor (TR). Two genes, THRA and THRB , encode TRs; THRB 2 has been associated with cone viability. Using TR antagonists and Thrb2 deletion, we examined the effects of TR inhibition. Systemic and ocular treatment with the TR antagonists NH-3 and 1-850 increased cone density by 30-40% in the Rpe65 -/- mouse model of Leber congenital amaurosis and reduced the number of TUNEL + cells. Cone survival was significantly improved in Rpe65 -/- and Cpfl1 (a model of achromatopsia with Pde6c defect) mice with Thrb2 deletion. Ventral cone density in Cpfl1/Thrb2 -/- and Rpe65 -/- / Thrb2 -/- mice was increased by 1- to 4-fold, compared with age-matched controls. Moreover, the expression levels of TR were significantly higher in the cone-degeneration retinas, suggesting locally elevated TR signaling. This work shows that the effects of antithyroid treatment or targeting DIOs were likely mediated by TRs and that suppressing TR protects cones. Our findings support the view that inhibition of TR locally in the retina is a therapeutic strategy for retinal degeneration management.-Ma, H., Yang, F., Butler, M. R., Belcher, J., Redmond, T. M., Placzek, A. T., Scanlan, T. S., Ding, X.-Q. Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

  6. Repair mechanism of retinal pigment epithelial tears in age-related macular degeneration.

    Science.gov (United States)

    Mukai, Ryo; Sato, Taku; Kishi, Shoji

    2015-03-01

    To investigate repair mechanisms of retinal pigment epithelial (RPE) tears in age-related macular degeneration. The authors retrospectively studied 10 eyes with age-related macular degeneration that developed RPE tears during follow-up or after treatment with an anti-vascular endothelial growth factor drug or photodynamic therapy combined with ranibizumab. After development of the RPE tears, all follow-ups exceeded 13 months. Spectral domain or swept-source optical coherence tomography have been used to examine consecutive retinal changes where the RPE tears developed and attempted to determine the repair mechanisms. Retinal pigment epithelial tears developed during the natural course (n = 4) after ranibizumab treatment (n = 2) and after photodynamic therapy and ranibizumab (n = 4). Subretinal fluid persisted for more than 6 months after the RPE tears developed (n = 4), with the area where the RPE was lost found to be covered with thickened proliferative tissue. In 6 eyes where the subretinal fluid was absorbed within 2 months, optical coherence tomography showed the outer retina appeared to be directly attached to Bruch membrane, and there was attenuation of the normal hyperreflective band attributable to normal RPE during follow-up. Results suggest that two repair processes may be present in the area where RPE tears developed. Persistent subretinal fluid may lead to repair with thick proliferative tissue, while the outer retina appears to attach to Bruch membrane when there is early subretinal fluid resolution after RPE tear development.

  7. 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.

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

    Science.gov (United States)

    2016-02-01

    We explored two boundary conditions for the stimulating and return electrodes: (1) When surface of each electrode was assumed equipotential , the...Stanford Nanofabrication Facility (SNF) using Surface Technology Systems (STS) PECVD. The precursors were SiH4 and NH3 (40:33.5 ratio of SiH4/NH3) at a... surface coating of retinal prostheses by PECVD at SNF (Plasma- Therm Shuttlelock SLR-730-PECVD). This tool used a capacitive-coupled plasma with

  9. Understanding the Function of Genes Involved in Inherited Retinal Degeneration-Insights into the Pathogenesis and Function of C8ORF37

    Science.gov (United States)

    Sharif, Ali Sakawa

    Inherited retinal degenerative diseases (IRD) are a group of disorders that lead to progressive deterioration of mainly the photoreceptors. Retinitis pigmentosa (RP) and cone-rod dystrophy (CRD) are two forms of IRDs. RP is the most common form of IRD and is due to rod photoreceptor degeneration followed by cone photoreceptor loss. CRD, on the other hand, is characterized by the loss of cones or the concurrent degeneration of both cones and rods. Both RP and CRD are presently incurable. More than 200 genes have been identified to cause IRDs and the functions of many of these genes remain unclear. Mutations in a novel gene, C8ORF37, were identified to cause recessive, severe, and early-onset RP and CRD. I, therefore, pioneered in characterizing the role of C8ORF37 in the retina. This dissertation is comprised of four chapters that is organized as follows: (1) summary of an ocular disorder (2) a genetic model of a retinal disorder (3) biochemical/proteomic analysis of C8ORF37 (4) potential clinical applications. A summary of ocular disorders is discussed in Chapter 1, with an emphasis on CRD. Chapter 2 focuses on the generation and characterization of C8orf37 mutant mouse models that recapitulate the retinal pathologies observed in human patients. In C8orf37 knockout retinas, the outer segment (OS) was nonuniform, swollen, and wider in width when compared to the controls. Moreover, many OS membrane proteins were reduced in the retina of C8orf37 knockout, including CNGB1 and RDS, proteins essential for OS disc morphogenesis and alignment. Our findings shed new light on the pathogenesis underlying retinal dysfunction and degeneration in C8ORF37-deficient patients. To determine the function of a novel protein, a powerful approach is by identifying its binding partners. In Chapter 3, I discuss GST pull-down using bovine retinal lysates, yeast-two-hybrid, and immunoprecipitation with mouse retinal lysate in order to identify C8ORF37-interacting proteins. Our pull

  10. Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

    OpenAIRE

    Mathur, Pranav; Yang, Jun

    2015-01-01

    Usher syndrome (USH), clinically and genetically heterogeneous, is the leading genetic cause of combined hearing and vision loss. USH is classified into three types, based on the hearing and vestibular symptoms observed in patients. Sixteen loci have been reported to be involved in the occurrence of USH and atypical USH. Among them, twelve have been identified as causative genes and one as a modifier gene. Studies on the proteins encoded by these USH genes suggest that USH proteins interact a...

  11. Edaravone Prevents Retinal Degeneration in Adult Mice Following Optic Nerve Injury.

    Science.gov (United States)

    Akiyama, Goichi; Azuchi, Yuriko; Guo, Xiaoli; Noro, Takahiko; Kimura, Atsuko; Harada, Chikako; Namekata, Kazuhiko; Harada, Takayuki

    2017-09-01

    To assess the therapeutic potential of edaravone, a free radical scavenger that is used for the treatment of acute brain infarction and amyotrophic lateral sclerosis, in a mouse model of optic nerve injury (ONI). Two microliters of edaravone (7.2 mM) or vehicle were injected intraocularly 3 minutes after ONI. Optical coherence tomography, retrograde labeling of retinal ganglion cells (RGCs), histopathology, and immunohistochemical analyses of phosphorylated apoptosis signal-regulating kinase-1 (ASK1) and p38 mitogen-activated protein kinase (MAPK) in the retina were performed after ONI. Reactive oxygen species (ROS) levels were assessed with a CellROX Green Reagent. Edaravone ameliorated ONI-induced ROS production, RGC death, and inner retinal degeneration. Also, activation of the ASK1-p38 MAPK pathway that induces RGC death following ONI was suppressed with edaravone treatment. The results of this study suggest that intraocular administration of edaravone may be a useful treatment for posttraumatic complications.

  12. CLRN1 mutations cause nonsyndromic retinitis pigmentosa

    NARCIS (Netherlands)

    Khan, M.I.; Kersten, F.F.J.; Azam, M.; Collin, R.W.J.; Hussain, A.; Shah, S.T.; Keunen, J.E.E.; Kremer, J.M.J.; Cremers, F.P.M.; Qamar, R.; Hollander, A.I. den

    2011-01-01

    OBJECTIVE: To describe the mutations in the CLRN1 gene in patients from 2 consanguineous Pakistani families diagnosed with autosomal recessive retinitis pigmentosa (arRP). DESIGN: Case-series study. PARTICIPANTS: Affected and unaffected individuals of 2 consanguineous Pakistani families and 90

  13. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.

    Science.gov (United States)

    Yang, Fan; Ma, Hongwei; Belcher, Joshua; Butler, Michael R; Redmond, T Michael; Boye, Sanford L; Hauswirth, William W; Ding, Xi-Qin

    2016-12-01

    Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65 -/- mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

  14. Enhancing the efficacy of AREDS antioxidants in light-induced retinal degeneration.

    Science.gov (United States)

    Wong, Paul; Markey, M; Rapp, C M; Darrow, R M; Ziesel, A; Organisciak, D T

    2017-01-01

    Light-induced photoreceptor cell degeneration and disease progression in age-related macular degeneration (AMD) involve oxidative stress and visual cell loss, which can be prevented, or slowed, by antioxidants. Our goal was to test the protective efficacy of a traditional Age-related Eye Disease Study antioxidant formulation (AREDS) and AREDS combined with non-traditional antioxidants in a preclinical animal model of photooxidative retinal damage. Male Sprague-Dawley rats were reared in a low-intensity (20 lux) or high-intensity (200 lux) cyclic light environment for 6 weeks. Some animals received a daily dietary supplement consisting of a small cracker infused with an AREDS antioxidant mineral mixture, AREDS antioxidants minus zinc, or zinc oxide alone. Other rats received AREDS combined with a detergent extract of the common herb rosemary, AREDS plus carnosic acid, zinc oxide plus rosemary, or rosemary alone. Antioxidant efficacy was determined by measuring retinal DNA levels 2 weeks after 6 h of intense exposure to white light (9,000 lux). Western blotting was used to determine visual cell opsin and arrestin levels following intense light treatment. Rhodopsin regeneration was determined after 1 h of exposure to light. Gene array analysis was used to determine changes in the expression of retinal genes resulting from light rearing environment or from antioxidant supplementation. Chronic high-intensity cyclic light rearing resulted in lower levels of rod and cone opsins, retinal S-antigen (S-ag), and medium wavelength cone arrestin (mCAR) than found for rats maintained in low cyclic light. However, as determined by retinal DNA, and by residual opsin and arrestin levels, 2 weeks after acute photooxidative damage, visual cell loss was greater in rats reared in low cyclic light. Retinal damage decreased with AREDS plus rosemary, or with zinc oxide plus rosemary whereas AREDS alone and zinc oxide alone (at their daily recommended levels) were both ineffective. One

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

    Directory of Open Access Journals (Sweden)

    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. Gene therapy for inherited retinal degenerations: initial successes and future challenges

    Science.gov (United States)

    Gupta, Priya R.; Huckfeldt, Rachel M.

    2017-10-01

    Inherited retinal degenerations are a clinically and genetically heterogeneous group of conditions that have historically shared an untreatable course. In recent years, however, a wide range of therapeutic strategies have demonstrated efficacy in preclinical studies and entered clinical trials with a common goal of improving visual function for patients affected with these conditions. Gene therapy offers a particularly elegant and precise opportunity to target the causative genetic mutations underlying these monogenic diseases. The present review will provide an overview of gene therapy with particular emphasis on key clinical results to date and challenges for the future.

  17. Platelet-derived growth factor (PDGF)-C inhibits neuroretinal apoptosis in a murine model of focal retinal degeneration.

    Science.gov (United States)

    Wang, Yujuan; Abu-Asab, Mones S; Yu, Cheng-Rong; Tang, Zhongshu; Shen, Defen; Tuo, Jingsheng; Li, Xuri; Chan, Chi-Chao

    2014-06-01

    Platelet-derived growth factor (PDGF)-C is a member of the PDGF family and is critical for neuronal survival in the central nervous system. We studied the possible survival and antiapoptotic effects of PDGF-C on focal retinal lesions in Ccl2(-/-)/Cx3cr1(-/-) on C57BL/6N [Crb1(rd8)] (DKO rd8) background mice, a model for progressive and focal retinal degeneration. We found no difference in transcript and protein expression of PDGF-C in the retina between DKO rd8 mice and wild type (WT, C57BL/6N). Recombinant PDGF-CC protein (500 ng/eye) was injected intravitreally into the right eye of DKO rd8 mice with phosphate-buffered saline as controls into the left eye. The retinal effects of PDGF-C were assessed by fundoscopy, ocular histopathology, A2E levels, apoptotic molecule analysis, and direct flat mount retinal vascular labeling. We found that the PDGF-CC-treated eyes showed slower progression or attenuation of the focal retinal lesions, lesser photoreceptor and retinal pigment epithelial degeneration resulting in better-preserved photoreceptor structure. Lower expression of apoptotic molecules was detected in the PDGF-CC-treated eyes than in controls. In addition, no retinal neovascularization was observed after PDGF-CC treatment. Our results demonstrate that PDGF-C potently ameliorates photoreceptor degeneration via the suppression of apoptotic pathways without inducing retinal angiogenesis. The protective effects of PDGF-C suggest a novel alternative approach for potential age-related retinal degeneration treatment.

  18. Usher syndrome: hearing loss, retinal degeneration and associated abnormalities

    Science.gov (United States)

    Mathur, Pranav; Yang, Jun

    2014-01-01

    Usher syndrome (USH), clinically and genetically heterogeneous, is the leading genetic cause of combined hearing and vision loss. USH is classified into three types, based on the hearing and vestibular symptoms observed in patients. Sixteen loci have been reported to be involved in the occurrence of USH and atypical USH. Among them, twelve have been identified as causative genes and one as a modifier gene. Studies on the proteins encoded by these USH genes suggest that USH proteins interact among one another and function in multiprotein complexes in vivo. Although their exact functions remain enigmatic in the retina, USH proteins are required for the development, maintenance and function of hair bundles, which are the primary mechanosensitive structure of inner ear hair cells. Despite the unavailability of a cure, progress has been made to develop effective treatments for this disease. In this review, we focus on the most recent discoveries in the field with an emphasis on USH genes, protein complexes and functions in various tissues as well as progress toward therapeutic development for USH. PMID:25481835

  19. Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities.

    Science.gov (United States)

    Mathur, Pranav; Yang, Jun

    2015-03-01

    Usher syndrome (USH), clinically and genetically heterogeneous, is the leading genetic cause of combined hearing and vision loss. USH is classified into three types, based on the hearing and vestibular symptoms observed in patients. Sixteen loci have been reported to be involved in the occurrence of USH and atypical USH. Among them, twelve have been identified as causative genes and one as a modifier gene. Studies on the proteins encoded by these USH genes suggest that USH proteins interact among one another and function in multiprotein complexes in vivo. Although their exact functions remain enigmatic in the retina, USH proteins are required for the development, maintenance and function of hair bundles, which are the primary mechanosensitive structure of inner ear hair cells. Despite the unavailability of a cure, progress has been made to develop effective treatments for this disease. In this review, we focus on the most recent discoveries in the field with an emphasis on USH genes, protein complexes and functions in various tissues as well as progress toward therapeutic development for USH. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Acquired retinal pigmentary degeneration in a child with 13q deletion syndrome.

    Science.gov (United States)

    Aguilera, Zenia P; Belin, Peter J; Cavuoto, Kara M; Jayakar, Parul; McKeown, Craig A

    2015-10-01

    Orbeli syndrome, or 13q deletion syndrome, is a rare condition caused by a distal deletion in the long arm of chromosome 13. The syndrome is characterized by severe physical malformations and developmental delays and has been associated with numerous ocular manifestations. We report the case of a 10-year-old boy with 13q deletion syndrome, who was evaluated for impaired vision and found to have bilateral retinal pigmentary changes resembling those seen in retinitis pigmentosa. There has only been one other case of retinal pigment variation in association with 13q deletion syndrome; however, this represents the first case of bilateral symmetric retinal pigmentary changes with corresponding rod and cone dysfunction on electroretinography. Copyright © 2015 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

  1. [Lattice degeneration of the retina].

    Science.gov (United States)

    Boĭko, E V; Suetov, A A; Mal'tsev, D S

    2014-01-01

    Lattice degeneration of the retina is a clinically important type of peripheral retinal dystrophies due to its participation in the pathogenesis of rhegmatogenous retinal detachment. In spite of extensive epidemiological, morphological, and clinical data, the question on causes of this particular type of retinal dystrophies currently remains debatable. Existing hypotheses on pathogenesis of retinal structural changes in lattice degeneration explain it to a certain extent. In clinical ophthalmology it is necessary to pay close attention to this kind of degenerations and distinguish between cases requiring preventive treatment and those requiring monitoring.

  2. Propofol causes neuronal degeneration in neonatal mice and long ...

    African Journals Online (AJOL)

    Propofol causes neuronal degeneration in neonatal mice and long-term ... of 2.5 and 5.0 mg/kg (treatment group) or normal saline (control) on postnatal day 7. ... PO2, glucose and lactate), among which decreased blood glucose might be ...

  3. Measurement of Retinal Sensitivity on Tablet Devices in Age-Related Macular Degeneration.

    Science.gov (United States)

    Wu, Zhichao; Guymer, Robyn H; Jung, Chang J; Goh, Jonathan K; Ayton, Lauren N; Luu, Chi D; Lawson, David J; Turpin, Andrew; McKendrick, Allison M

    2015-06-01

    We compared measurements of central retinal sensitivity on a portable, low-cost tablet device to the established method of microperimetry in age-related macular degeneration (AMD). A customized test designed to measure central retinal sensitivity (within the central 1° radius) on a tablet device was developed using an open-source platform called PsyPad. A total of 30 participants with AMD were included in this study, and all participants performed a practice test on PsyPad, followed by four tests of one eye and one test of the other eye. Participants then underwent standardized microperimetry examinations in both eyes. The average test duration on PsyPad was 53.9 ± 7.5 seconds, and no significant learning effect was observed over the examinations performed ( P = 1.000). The coefficient of repeatability of central retinal sensitivity between the first two examinations on PsyPad was ±1.76 dB. The mean central retinal sensitivity was not significantly different between PsyPad (25.7 ± 0.4 dB) and microperimetry (26.1 ± 0.4 dB, P = 0.094), and the 95% limits of agreement between the two measures were between -4.12 and 4.92 dB. The measurements of central retinal sensitivity can be performed effectively using a tablet device, displaying reasonably good agreement with those obtained using the established method of microperimetry. These findings highlight the potential of tablet devices as low-cost and portable tools for developing and performing visual function measures that can be easily and widely implemented.

  4. The Time Course of Deafness and Retinal Degeneration in a Kunming Mouse Model for Usher Syndrome.

    Science.gov (United States)

    Yao, Lu; Zhang, Lei; Qi, Lin-Song; Liu, Wei; An, Jing; Wang, Bin; Xue, Jun-Hui; Zhang, Zuo-Ming

    2016-01-01

    Usher syndrome is a group of autosomal recessive diseases characterized by congenital deafness and retinitis pigmentosa. In a mouse model for Usher syndrome, KMush/ush, discovered in our laboratory, we measured the phenotypes, characterized the architecture and morphology of the retina, and quantified the level of expression of pde6b and ush2a between postnatal (P) days 7, and 56. Electroretinograms and auditory brainstem response were used to measure visual and auditory phenotypes. Fundus photography and light microscopy were used to measure the architecture and morphology of the retina. Quantitative real-time PCR was used to measure the expression levels of mRNA. KMush/ush mice had low amplitudes and no obvious waveforms of Electroretinograms after P14 compared with controls. Thresholds of auditory brainstem response in our model were higher than those of controls after P14. By P21, the retinal vessels of KMush/ush mice were attenuated and their optic discs had a waxy pallor. The retinas of KMush/ush mice atrophied and the choroidal vessels were clearly visible. Notably, the architecture of each retinal layer was not different as compared with control mice at P7, while the outer nuclear layer (ONL) and other retinal layers of KMush/ush mice were attenuated significantly between P14 and P21. ONL cells were barely seen in KMush/ush mice at P56. As compared with control mice, the expression of pde6b and ush2a in KMush/ush mice declined significantly after P7. This study is a first step toward characterizing the progression of disease in our mouse model. Future studies using this model may provide insights about the etiology of the disease and the relationships between genotypes and phenotypes providing a valuable resource that could contribute to the foundation of knowledge necessary to develop therapies to prevent the retinal degeneration in patients with Usher Syndrome.

  5. The Time Course of Deafness and Retinal Degeneration in a Kunming Mouse Model for Usher Syndrome.

    Directory of Open Access Journals (Sweden)

    Lu Yao

    Full Text Available Usher syndrome is a group of autosomal recessive diseases characterized by congenital deafness and retinitis pigmentosa. In a mouse model for Usher syndrome, KMush/ush, discovered in our laboratory, we measured the phenotypes, characterized the architecture and morphology of the retina, and quantified the level of expression of pde6b and ush2a between postnatal (P days 7, and 56. Electroretinograms and auditory brainstem response were used to measure visual and auditory phenotypes. Fundus photography and light microscopy were used to measure the architecture and morphology of the retina. Quantitative real-time PCR was used to measure the expression levels of mRNA. KMush/ush mice had low amplitudes and no obvious waveforms of Electroretinograms after P14 compared with controls. Thresholds of auditory brainstem response in our model were higher than those of controls after P14. By P21, the retinal vessels of KMush/ush mice were attenuated and their optic discs had a waxy pallor. The retinas of KMush/ush mice atrophied and the choroidal vessels were clearly visible. Notably, the architecture of each retinal layer was not different as compared with control mice at P7, while the outer nuclear layer (ONL and other retinal layers of KMush/ush mice were attenuated significantly between P14 and P21. ONL cells were barely seen in KMush/ush mice at P56. As compared with control mice, the expression of pde6b and ush2a in KMush/ush mice declined significantly after P7. This study is a first step toward characterizing the progression of disease in our mouse model. Future studies using this model may provide insights about the etiology of the disease and the relationships between genotypes and phenotypes providing a valuable resource that could contribute to the foundation of knowledge necessary to develop therapies to prevent the retinal degeneration in patients with Usher Syndrome.

  6. Alterations of sodium and potassium channels of RGCs in RCS rat with the development of retinal degeneration.

    Science.gov (United States)

    Chen, Zhongshan; Song, Yanping; Yao, Junping; Weng, Chuanhuang; Yin, Zheng Qin

    2013-11-01

    All know that retinitis pigmentosa (RP) is a group of hereditary retinal degenerative diseases characterized by progressive dysfunction of photoreceptors and associated with progressive cells loss; nevertheless, little is known about how rods and cones loss affects the surviving inner retinal neurons and networks. Retinal ganglion cells (RGCs) process and convey visual information from retina to visual centers in the brain. The healthy various ion channels determine the normal reception and projection of visual signals from RGCs. Previous work on the Royal College of Surgeons (RCS) rat, as a kind of classical RP animal model, indicated that, at late stages of retinal degeneration in RCS rat, RGCs were also morphologically and functionally affected. Here, retrograde labeling for RGCs with Fluorogold was performed to investigate the distribution, density, and morphological changes of RGCs during retinal degeneration. Then, patch clamp recording, western blot, and immunofluorescence staining were performed to study the channels of sodium and potassium properties of RGCs, so as to explore the molecular and proteinic basis for understanding the alterations of RGCs membrane properties and firing functions. We found that the resting membrane potential, input resistance, and capacitance of RGCs changed significantly at the late stage of retinal degeneration. Action potential could not be evoked in a part of RGCs. Inward sodium current and outward potassium current recording showed that sodium current was impaired severely but only slightly in potassium current. Expressions of sodium channel protein were impaired dramatically at the late stage of retinal degeneration. The results suggested that the density of RGCs decreased, process ramification impaired, and sodium ion channel proteins destructed, which led to the impairment of electrophysiological functions of RGCs and eventually resulted in the loss of visual function.

  7. Rimonabant, a selective cannabinoid1 receptor antagonist, protects against light-induced retinal degeneration in vitro and in vivo.

    Science.gov (United States)

    Imamura, Tomoyo; Tsuruma, Kazuhiro; Inoue, Yuki; Otsuka, Tomohiro; Ohno, Yuta; Ogami, Shiho; Yamane, Shinsaku; Shimazawa, Masamitsu; Hara, Hideaki

    2017-05-15

    The endocannabinoid system is involved in some neurodegenerative diseases such as Alzheimer's disease. An endogenous constellation of proteins related to cannabinoid 1 receptor signaling, including free fatty acids, diacylglycerol lipase, and N-acylethanolamine-hydrolyzing acid amidase, are localized in the murine retina. Moreover, the expression levels of endogenous agonists of cannabinoid receptors are changed in the vitreous fluid. However, the role of the endocannabinoid system in the retina, particularly in the light-induced photoreceptor degeneration, remains unknown. Therefore, we investigated involvement of the cannabinoid 1 receptor in light-induced retinal degeneration using in vitro and in vivo models. To evaluate the effect of cannabinoid 1 receptors in light irradiation-induced cell death, the mouse retinal cone-cell line (661W) was treated with a cannabinoid 1 receptor antagonist, rimonabant. Time-dependent changes of expression and localization of retinal cannabinoid 1 receptors were measured using Western blot and immunostaining. Retinal damage was induced in mice by exposure to light, followed by intravitreal injection of rimonabant. Electroretinograms and histologic analyses were performed. Rimonabant suppressed light-induced photoreceptor cell death. Cannabinoid 1 receptor expression was upregulated by light exposure. Treatment with rimonabant improved both a- and b-wave amplitudes and the thickness of the outer nuclear layer. These results suggest that the cannabinoid 1 receptor is involved in light-induced retinal degeneration and it may represent a therapeutic target in the light-induced photoreceptor degeneration related diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Chemically-induced photoreceptor degeneration and protection in mouse iPSC-derived three-dimensional retinal organoids

    Directory of Open Access Journals (Sweden)

    Shin-ichiro Ito

    2017-10-01

    Full Text Available Induced pluripotent stem cells (iPSCs, which can be differentiated into various tissues and cell types, have been used for clinical research and disease modeling. Self-organizing three-dimensional (3D tissue engineering has been established within the past decade and enables researchers to obtain tissues and cells that almost mimic in vivo development. However, there are no reports of practical experimental procedures that reproduce photoreceptor degeneration. In this study, we induced photoreceptor cell death in mouse iPSC-derived 3D retinal organoids (3D-retinas by 4-hydroxytamoxifen (4-OHT, which induces photoreceptor degeneration in mouse retinal explants, and then established a live-cell imaging system to measure degeneration-related properties. Furthermore, we quantified the protective effects of representative ophthalmic supplements for treating the photoreceptor degeneration. This drug evaluation system enables us to monitor drug effects in photoreceptor cells and could be useful for drug screening.

  9. Non-invasive stem cell therapy in a rat model for retinal degeneration and vascular pathology.

    Directory of Open Access Journals (Sweden)

    Shaomei Wang

    Full Text Available BACKGROUND: Retinitis pigmentosa (RP is characterized by progressive night blindness, visual field loss, altered vascular permeability and loss of central vision. Currently there is no effective treatment available except gene replacement therapy has shown promise in a few patients with specific gene defects. There is an urgent need to develop therapies that offer generic neuro-and vascular-protective effects with non-invasive intervention. Here we explored the potential of systemic administration of pluripotent bone marrow-derived mesenchymal stem cells (MSCs to rescue vision and associated vascular pathology in the Royal College Surgeons (RCS rat, a well-established animal model for RP. METHODOLOGY/PRINCIPAL FINDINGS: Animals received syngeneic MSCs (1x10(6 cells by tail vein at an age before major photoreceptor loss. PRINCIPAL RESULTS: both rod and cone photoreceptors were preserved (5-6 cells thick at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs. CONCLUSIONS/SIGNIFICANCE: These results underscore the potential application of MSCs in treating retinal degeneration. The advantages of this non-invasive cell-based therapy are: cells are easily isolated and can be expanded in large quantity for autologous graft; hypoimmunogenic nature as allogeneic donors; less controversial in nature than other stem cells; can be readministered with minor discomfort

  10. Alterations in NMDA receptor expression during retinal degeneration in the RCS rat.

    Science.gov (United States)

    Gründer, T; Kohler, K; Guenther, E

    2001-01-01

    To determine how a progressive loss of photoreceptor cells and the concomitant loss of glutamatergic input to second-order neurons can affect inner-retinal signaling, glutamate receptor expression was analyzed in the Royal College of Surgeons (RCS) rat, an animal model of retinitis pigmentosa. Immunohistochemistry was performed on retinal sections of RCS rats and congenic controls between postnatal (P) day 3 and the aged adult (up to P350) using specific antibodies against N-methyl-D-aspartate (NMDA) subunits. All NMDA subunits (NR1, NR2A-2D) were expressed in control and dystrophic retinas at all ages, and distinct patterns of labeling were found in horizontal cells, subpopulations of amacrine cells and ganglion cells, as well as in the outer and inner plexiform layer (IPL). NRI immunoreactivity in the inner plexiform layer of adult control retinas was concentrated in two distinct bands, indicating a synaptic localization of NMDA receptors in the OFF and ON signal pathways. In the RCS retina, these bands of NRI immunoreactivity in the IPL were much weaker in animals older than P40. In parallel, NR2B immunoreactivity in the outer plexiform layer (OPL) of RCS rats was always reduced compared to controls and vanished between P40 and P120. The most striking alteration observed in the degenerating retina, however, was a strong expression of NRI immunoreactivity in Müller cell processes in the inner retina which was not observed in control animals and which was present prior to any visible sign of photoreceptor degeneration. The results suggest functional changes in glutamatergic receptor signaling in the dystrophic retina and a possible involvement of Müller cells in early processes of this disease.

  11. Valproic acid prevents retinal degeneration in a murine model of normal tension glaucoma.

    Science.gov (United States)

    Kimura, Atsuko; Guo, Xiaoli; Noro, Takahiko; Harada, Chikako; Tanaka, Kohichi; Namekata, Kazuhiko; Harada, Takayuki

    2015-02-19

    Valproic acid (VPA) is widely used for treatment of epilepsy, mood disorders, migraines and neuropathic pain. It exerts its therapeutic benefits through modulation of multiple mechanisms including regulation of gamma-aminobutyric acid and glutamate neurotransmissions, activation of pro-survival protein kinases and inhibition of histone deacetylase. The evidence for neuroprotective properties associated with VPA is emerging. Herein, we investigated the therapeutic potential of VPA in a mouse model of normal tension glaucoma (NTG). Mice with glutamate/aspartate transporter gene deletion (GLAST KO mice) demonstrate progressive retinal ganglion cell (RGC) loss and optic nerve degeneration without elevated intraocular pressure, and exhibit glaucomatous pathology including glutamate neurotoxicity and oxidative stress in the retina. VPA (300mg/kg) or vehicle (PBS) was administered via intraperitoneal injection in GLAST KO mice daily for 2 weeks from the age of 3 weeks, which coincides with the onset of glaucomatous retinal degeneration. Following completion of the treatment period, the vehicle-treated GLAST KO mouse retina showed significant RGC death. Meanwhile, VPA treatment prevented RGC death and thinning of the inner retinal layer in GLAST KO mice. In addition, in vivo electrophysiological analyses demonstrated that visual impairment observed in vehicle-treated GLAST KO mice was ameliorated with VPA treatment, clearly establishing that VPA beneficially affects both histological and functional aspects of the glaucomatous retina. We found that VPA reduces oxidative stress induced in the GLAST KO retina and stimulates the cell survival signalling pathway associated with extracellular-signal-regulated kinases (ERK). This is the first study to report the neuroprotective effects of VPA in an animal model of NTG. Our findings raise intriguing possibilities that the widely prescribed drug VPA may be a novel candidate for treatment of glaucoma. Copyright © 2015 Elsevier

  12. X-linked dominant cone-rod degeneration: linkage mapping of a new locus for retinitis pigmentosa (RP 15) to Xp22.13-p22.11.

    OpenAIRE

    McGuire, R E; Sullivan, L S; Blanton, S H; Church, M W; Heckenlively, J R; Daiger, S P

    1995-01-01

    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 excluded all mapped autosomal loci. However, a marker from ...

  13. 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.

  14. The fellow eye of patients with phakic rhegmatogenous retinal detachment from atrophic holes of lattice degeneration without posterior vitreous detachment.

    Science.gov (United States)

    Gonzales, C R; Gupta, A; Schwartz, S D; Kreiger, A E

    2004-11-01

    Primary phakic rhegmatogenous retinal detachment (RRD) without posterior vitreous detachment (PVD) represents a unique clinical entity that behaves differently from RRD associated with PVD. While previous studies have reported the long term findings in the fellow eye of patients with RRD and PVD, the outcome of the fellow eye of patients with RRD without PVD is not known. Consecutive patients with RRD not associated with PVD were studied retrospectively. The authors evaluated the fellow eye for retinal detachment or other vision threatening pathology. 27 patients (mean age 32 years) were studied with follow up of between 9 and 326 months (mean 111 months). 24 (89%) were myopic. Bilateral retinal detachment occurred in eight patients (30%). On initial examination, 17 patients (63%) had retinal findings (including lattice degeneration, atrophic holes, and/or cystic retinal tufts) in the fellow eye that might predispose them to retinal detachment. 14 vision threatening events or diagnoses occurred (nine of which were rhegmatogenous in nature) in the fellow eye including eight retinal detachments, one traumatic PVD without retinal tears, one retinal tear after PVD, one diagnosis of pigmentary glaucoma needing trabeculectomy, two visually significant cataracts, and one diagnosis of chorioretinitis. 23 patients (85%) maintained visual acuity better than 20/50, with most retaining 20/20 vision in the fellow eye. Patients who experience RRD without PVD are at risk of developing vision threatening events in the contralateral eye and, as such, the fellow eye should be followed carefully.

  15. Long-Term Protection of Genetically Ablated Rabbit Retinal Degeneration by Sustained Transscleral Unoprostone Delivery.

    Science.gov (United States)

    Nagai, Nobuhiro; Koyanagi, Eri; Izumida, Yasuko; Liu, Junjun; Katsuyama, Aya; Kaji, Hirokazu; Nishizawa, Matsuhiko; Osumi, Noriko; Kondo, Mineo; Terasaki, Hiroko; Mashima, Yukihiko; Nakazawa, Toru; Abe, Toshiaki

    2016-12-01

    To evaluate the long-term protective effects of transscleral unoprostone (UNO) against retinal degeneration in transgenic (Tg) rabbits (Pro347Leu rhodopsin mutation). The UNO release devices (URDs) were implanted into the sclerae of Tg rabbits and ERG, optical coherence tomography (OCT), and ophthalmic examinations were conducted for 40 weeks. Unoprostone metabolites in retina, choroid/RPE, aqueous humor, and plasma from wild-type (Wt) rabbits were measured using liquid chromatography-tandem mass spectrometry. In situ hybridization and immunohistochemistry evaluated the retinal distribution of big potassium (BK) channels, and RT-PCR evaluated the expressions of BK channels and m-opsin at 1 week after URD treatment. The URD released UNO at a rate of 10.2 ±1.0 μg/d, and the release rate and amount of UNO decreased during 32 weeks. Higher ERG amplitudes were observed in the URD-treated Tg rabbits compared with the placebo-URD, or nontreated controls. At 24 weeks after implantation into the URD-treated Tg rabbits, OCT images showed preservation of retinal thickness, and histologic examinations (44 weeks) showed greater thickness of outer nuclear layers. Unoprostone was detected in the retina, choroid, and plasma of Wt rabbits. Retina/plasma ratio of UNO levels were 38.0 vs. 0.68 ng UNO*hour/mL in the URD-treated group versus control (topical UNO), respectively. Big potassium channels were observed in cone, cone ON-bipolar, and rod bipolar cells. Reverse-transcriptase PCR demonstrated BK channels and m-opsins increased in URD-treated eyes. In Tg rabbits, URD use slowed the decline of retinal function for more than 32 weeks, and therefore provides a promising tool for long-term treatment of RP.

  16. Incidence and causes of iatrogenic retinal breaks in idiopathic macular hole and epiretinal membrane.

    Science.gov (United States)

    Yagi, Fumihiko; Takagi, Seiji; Tomita, Goji

    2014-03-01

    To evaluate the incidence and cause of iatrogenic retinal breaks (RBs) and postoperative retinal detachment (RD) in cases of idiopathic macular hole (MH) and epiretinal membrane (ERM). We analyzed 79 eyes with MH and 41 eyes with ERM, the relationship between the incidence of RBs and RD, and the frequency of posterior vitreous detachment (PVD) and lattice degeneration (LD). The incidence of RBs related to the operation was significantly higher in eyes with MH. The frequency of PVD was significantly higher in eyes with ERM. The frequency of LD did not differ between groups. In the MH group, the incidence of RBs related to the operation was high in eyes without PVD, but with LD. We observed four cases of RD in the MH group. The MH group had higher incidence of RBs related to the operation, especially in eyes without PVD or with LD.

  17. 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.

  18. Clinically undetected retinal breaks causing retinal detachment: A review of options for management.

    Science.gov (United States)

    Gupta, Deepak; Ching, Jared; Tornambe, Paul E

    2017-08-12

    The successful detection of retinal breaks is a critical step in rhegmatogenous retinal detachment surgery in order to prevent persistent/recurrent retinal detachments. Not all retinal breaks causing retinal detachments are obvious. Retinal breaks may be obscured by opacities that are either anterior segment related, lens related, or posterior segment related. Rules to identify breaks based on subretinal fluid configuration are more difficult to apply in pseudophakic, aphakic, and scleral buckle encircled eyes-and in eyes with repeat detachments and those with proliferative vitreoretinopathy. Exudative detachments exhibit characteristic features and must be ruled out. A thorough clinical examination preoperatively is important even if a vitrectomy is planned. We review the incidence and causes of undetected breaks, along with preoperative/clinical issues that may hinder break detection. We review the literature with respect to investigative approaches and techniques that are available to the vitreoretinal surgeon when primary breaks remain clinically undetected during the preoperative examination. We broadly divide the surgical approaches into ones where the surgeon utilizes techniques to pursue actively a search for breaks versus adopting a purely speculative approach. Advantages and disadvantages of various techniques are appraised. Intuitively one might argue that an encircling scleral buckle combined with vitrectomy would give higher single operation success than pars plana vitrectomy alone because "undetected" retinal breaks would be addressed by a 360° plombage. We could not confirm this concept. Newer techniques, such as pars plana vitrectomy augmented with dye extrusion or endoscopic-assisted pars plana vitrectomy, show encouraging results. Technological advances such as intraoperative optical coherence tomography will also help to broaden the vitreoretinal surgeon's armamentarium. At this time, there is no gold standard in terms of the recommended

  19. Activation of muscarinic receptors protects against retinal neurons damage and optic nerve degeneration in vitro and in vivo models.

    Science.gov (United States)

    Tan, Pan-Pan; Yuan, Hai-Hong; Zhu, Xu; Cui, Yong-Yao; Li, Hui; Feng, Xue-Mei; Qiu, Yu; Chen, Hong-Zhuan; Zhou, Wei

    2014-03-01

    Muscarinic acetylcholine receptor agonist pilocarpine reduces intraocular pressure (IOP) of glaucoma mainly by stimulating ciliary muscle contraction and then increasing aqueous outflow. It is of our great interest to know whether pilocarpine has the additional properties of retinal neuroprotection independent of IOP lowering in vitro and in vivo models. In rat primary retinal cultures, cell viability was measured using an MTT assay and the trypan blue exclusion method, respectively. Retinal ganglion cells (RGCs) were identified by immunofluorescence and quantified by flow cytometry. For the in vivo study, the retinal damage after retinal ischemia/reperfusion injury in rats was evaluated by histopathological study using hematoxylin and eosin staining, transmission electron microscopy, and immunohistochemical study on cleaved caspase-3, caspase-3, and ChAT. Pretreatment of pilocarpine attenuated glutamate-induced neurotoxicity of primary retinal neurons in a dose-dependent manner. Protection of pilocarpine in both retinal neurons and RGCs was largely abolished by the nonselective muscarinic receptor antagonist atropine and the M1-selective muscarinic receptor antagonist pirenzepine. After ischemia/reperfusion injury in retina, the inner retinal degeneration occurred including ganglion cell layer thinning and neuron lost, and the optic nerve underwent vacuolar changes. These degenerative changes were significantly lessened by topical application of 2% pilocarpine. In addition, the protective effect of pilocarpine on the ischemic rat retina was favorably reflected by downregulating the expression of activated apoptosis marker cleaved caspase-3 and caspase-3 and upregulating the expression of cholinergic cell marker ChAT. Taken together, this highlights pilocarpine through the activation of muscarinic receptors appear to afford significant protection against retinal neurons damage and optic nerve degeneration at clinically relevant concentrations. These data also

  20. 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.

  1. Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa.

    Science.gov (United States)

    Arno, Gavin; Agrawal, Smriti A; Eblimit, Aiden; Bellingham, James; Xu, Mingchu; Wang, Feng; Chakarova, Christina; Parfitt, David A; Lane, Amelia; Burgoyne, Thomas; Hull, Sarah; Carss, Keren J; Fiorentino, Alessia; Hayes, Matthew J; Munro, Peter M; Nicols, Ralph; Pontikos, Nikolas; Holder, Graham E; Asomugha, Chinwe; Raymond, F Lucy; Moore, Anthony T; Plagnol, Vincent; Michaelides, Michel; Hardcastle, Alison J; Li, Yumei; Cukras, Catherine; Webster, Andrew R; Cheetham, Michael E; Chen, Rui

    2016-12-01

    Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2016-06-21

    Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridine-phosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimer-phosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4(-/-) mice reared in cyclic light compared with darkness. In albino Abca4(-/-) mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic light-reared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Pigment epithelium-derived factor reduces apoptosis and pro-inflammatory cytokine gene expression in a murine model of focal retinal degeneration.

    Science.gov (United States)

    Wang, Yujuan; Subramanian, Preeti; Shen, Defen; Tuo, Jingsheng; Becerra, S Patricia; Chan, Chi-Chao

    2013-11-26

    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 [Crb1(rd8)]) 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. A novel homozygous truncating GNAT1 mutation implicated in retinal degeneration

    OpenAIRE

    Carrigan, Matthew; Duignan, Emma; Humphries, Pete; Palfi, Arpad; Kenna, Paul F; Farrar, G Jane

    2015-01-01

    Background The GNAT1 gene encodes the ? 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. Methods A panel of 182 retinopathy-associated genes was sequenced to locate disease-causing mutations in patients with inherited retinopathies. Results Sequencing revealed a ...

  7. 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. Copyright © 2015. Published by Elsevier B.V.

  8. Optical Coherence Tomography of Retinal Degeneration in Royal College of Surgeons Rats and Its Correlation with Morphology and Electroretinography

    Science.gov (United States)

    Yamauchi, Kodai; Mounai, Natsuki; Tanabu, Reiko; Nakazawa, Mitsuru

    2016-01-01

    Purpose To evaluate the correlation between optical coherence tomography (OCT) and the histological, ultrastructural and electroretinography (ERG) findings of retinal degeneration in Royal College of Surgeons (RCS-/-) rats. Materials and Methods Using OCT, we qualitatively and quantitatively observed the continual retinal degeneration in RCS-/- rats, from postnatal (PN) day 17 until PN day 111. These findings were compared with the corresponding histological, electron microscopic, and ERG findings. We also compared them to OCT findings in wild type RCS+/+ rats, which were used as controls. Results After PN day 17, the hyperreflective band at the apical side of the photoreceptor layer became blurred. The inner segment (IS) ellipsoid zone then became obscured, and the photoreceptor IS and outer segment (OS) layers became diffusely hyperreflective after PN day 21. These changes correlated with histological and electron microscopic findings showing extracellular lamellar material that accumulated in the photoreceptor OS layer. After PN day 26, the outer nuclear layer became significantly thinner (P RCS-/- and RCS+/+ rats. Conclusion Our results suggest that OCT demonstrates histologically validated photoreceptor degeneration in RCS rats, and that OCT findings partly correlate with ERG findings. We propose that OCT is a less invasive and useful method for evaluating photoreceptor degeneration in animal models of retinitis pigmentosa. PMID:27644042

  9. Optical Coherence Tomography of Retinal Degeneration in Royal College of Surgeons Rats and Its Correlation with Morphology and Electroretinography.

    Directory of Open Access Journals (Sweden)

    Kobu Adachi

    Full Text Available To evaluate the correlation between optical coherence tomography (OCT and the histological, ultrastructural and electroretinography (ERG findings of retinal degeneration in Royal College of Surgeons (RCS-/- rats.Using OCT, we qualitatively and quantitatively observed the continual retinal degeneration in RCS-/- rats, from postnatal (PN day 17 until PN day 111. These findings were compared with the corresponding histological, electron microscopic, and ERG findings. We also compared them to OCT findings in wild type RCS+/+ rats, which were used as controls.After PN day 17, the hyperreflective band at the apical side of the photoreceptor layer became blurred. The inner segment (IS ellipsoid zone then became obscured, and the photoreceptor IS and outer segment (OS layers became diffusely hyperreflective after PN day 21. These changes correlated with histological and electron microscopic findings showing extracellular lamellar material that accumulated in the photoreceptor OS layer. After PN day 26, the outer nuclear layer became significantly thinner (P < 0.01 and hyperreflective compared with that in the controls; conversely, the photoreceptor IS and OS layers, as well as the inner retinal layers, became significantly thicker (P < 0.001 and P = 0.05, respectively. The apical hyperreflective band, as well as the IS ellipsoid zone, gradually disappeared between PN day 20 and PN day 30; concurrently, the ERG a- and b-wave amplitudes deteriorated. In contrast, the thicknesses of the combined retinal pigment epithelium and choroid did not differ significantly between RCS-/- and RCS+/+ rats.Our results suggest that OCT demonstrates histologically validated photoreceptor degeneration in RCS rats, and that OCT findings partly correlate with ERG findings. We propose that OCT is a less invasive and useful method for evaluating photoreceptor degeneration in animal models of retinitis pigmentosa.

  10. Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice

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    Shanshan Huang

    2015-10-01

    Full Text Available In polyglutamine (polyQ diseases, large polyQ repeats cause juvenile cases with different symptoms than those of adult-onset patients, who carry smaller expanded polyQ repeats. The mechanisms behind the differential pathology mediated by different polyQ repeat lengths remain unknown. By studying knockin mouse models of spinal cerebellar ataxia-17 (SCA17, we found that a large polyQ (105 glutamines in the TATA-box-binding protein (TBP preferentially causes muscle degeneration and reduces the expression of muscle-specific genes. Direct expression of TBP with different polyQ repeats in mouse muscle revealed that muscle degeneration is mediated only by the large polyQ repeats. Different polyQ repeats differentially alter TBP’s interaction with neuronal and muscle-specific transcription factors. As a result, the large polyQ repeat decreases the association of MyoD with TBP and DNA promoters. Our findings suggest that specific alterations in protein interactions by large polyQ repeats may account for the unique pathology in juvenile polyQ diseases.

  11. Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice

    Science.gov (United States)

    Huang, Shanshan; Yang, Su; Guo, Jifeng; Yan, Sen; Gaertig, Marta A.; Li, Shihua; Li, Xiao-Jiang

    2015-01-01

    SUMMARY In polyglutamine (polyQ) diseases, large polyQ repeats cause juvenile cases with different symptoms than adult-onset patients, who carry smaller expanded polyQ repeats. The mechanisms behind the differential pathology mediated by different polyQ repeat lengths remain unknown. By studying knock-in mouse models of spinal cerebellar ataxia-17 (SCA17), we found that a large polyQ (105 glutamines) in the TATA box-binding protein (TBP) preferentially causes muscle degeneration and reduces the expression of muscle-specific genes. Direct expression of TBP with different polyQ repeats in mouse muscle revealed that muscle degeneration is mediated only by the large polyQ repeats. Different polyQ repeats differentially alter TBP’s interaction with neuronal and muscle-specific transcription factors. As a result, the large polyQ repeat decreases the association of MyoD with TBP and DNA promoters. Our findings suggest that specific alterations in protein interactions by large polyQ repeats may account for the unique pathology in juvenile polyQ diseases. PMID:26387956

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

    Directory of Open Access Journals (Sweden)

    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.

  13. 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...... previously treatment-naïve patients with neovascular age-related macular degeneration receiving intravitreal injections with 1.25 mg bevacizumab. Patients were examined with multifocal electroretinography, full-field electroretinography, optical coherence tomography, and visual acuity. Follow...

  14. Subpopulations of Bone Marrow Mesenchymal Stem Cells Exhibit Differential Effects in Delaying Retinal Degeneration.

    Science.gov (United States)

    Li, P; Tian, H; Li, Z; Wang, L; Gao, F; Ou, Q; Lian, C; Li, W; Jin, C; Zhang, J; Xu, J-Y; Wang, J; Zhang, J; Wang, F; Lu, L; Xu, G-T

    2016-01-01

    Bone marrow mesenchymal stem cells (BMSCs) have a therapeutic role in retinal degeneration (RD). However, heterogeneity of BMSCs may be associated with differential therapeutic effects in RD. In order to confirm this hypothesis, two subsets of rat BMSCs, termed rBMSC1 and rBMSC2, were obtained, characterized and functionally evaluated in the treatment of RD of Royal College of Surgeons (RCS) rats. Both subpopulations expressed mesenchymal stem cells (MSC) markers CD29 and CD90, but were negative for hemacyte antigen CD11b and CD45 expression. In comparison with rBMSC2, rBMSC1 showed higher rate of proliferation, stronger colony formation, and increased adipogenic potential, whereas rBMSC2 exhibited higher osteogenic potential. Microarray analysis showed differential gene expression patterns between rBMSC1 and rBMSC2, including functions related to proliferation, differentiation, immunoregulation, stem cell maintenance and division, survival and antiapoptosis. After subretinal transplantation in RCS rats, rBMSC1 showed stronger rescue effect than rBMSC2, including increased b-wave amplitude, restored retinal nuclear layer thickness, and decreased number of apoptotic photoreceptors, whereas the rescue function of rBMSC2 was essentially not better than the control. Histological analysis also demonstrated that rBMSC1 possessed a higher survival rate than rBMSC2 in subretinal space. In addition, treatment of basic fibroblast growth factor, an accompanying event in subretinal injection, triggered more robust increase in secretion of growth factors by rBMSC1 as compared to rBMSC2. Taken together, these results have suggested that the different therapeutic functions of BMSC subpopulations are attributed to their distinct survival capabilities and paracrine functions. The underlying mechanisms responsible for the different functions of BMSC subpopulation may lead to a new strategy for the treatment of RD.

  15. RETINAL PIGMENT EPITHELIAL TEAR AFTER INTRAVITREAL RANIBIZUMAB TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

    Science.gov (United States)

    Cho, Han Joo; Kim, Hyoung Seok; Yoo, Seul Gi; Han, Jung Il; Lew, Young Ju; Cho, Sung Won; Lee, Tae Gon; Kim, Jong Woo

    2016-10-01

    To evaluate the risk factors for retinal pigment epithelium (RPE) tears after intravitreal ranibizumab injections in neovascular age-related macular degeneration (nAMD) and to determine the efficacy of continued ranibizumab treatment after RPE tears. A total of 407 treatment-naïve eyes (377 patients) with nAMD were retrospectively included. All patients were treated with an initial series of 3 monthly loading injections, followed by further injections as required. Baseline characteristics and pigment epithelial detachment (PED) lesion features were evaluated as potential risk factors for RPE tear. The visual and anatomical outcomes after treatment during 12 months were also evaluated. By 12 months, RPE tears developed in 32 eyes (7.9%). Pigment epithelial detachment height was associated with a higher risk of RPE tear (odds ratio [OR], 1.318; 95% confidence interval [CI], 1.217-2.031, P = 0.018). Fibrovascular PED compared with serous PED had a higher risk of developing tears (OR, 9.129; 95% CI, 6.228-32.124, P = 0.039), and typical nAMD (OR, 4.166; 95% CI, 2.030-14.913, P = 0.031) and retinal angiomatous proliferation (OR, 3.778; 95% CI, 2.185-9.277, P = 0.040) had a higher risk of developing tears compared with polypoidal choroidal vasculopathy. Mean best-corrected visual acuity (BCVA) of RPE tear patients showed no significant improvement after treatment at 12 months; however, patients with RPE tears without foveal involvement (19 eyes) showed significant BCVA improvement at 12 months (P = 0.034). PED type and nAMD subtype are associated with the development of RPE tears after intravitreal ranibizumab injections. Continued ranibizumab therapy after RPE tear development can maintain visual acuity when the fovea is not involved.

  16. Sirtuin 1 participates in the process of age-related retinal degeneration.

    Science.gov (United States)

    Zeng, Ying; Yang, Ke

    The process of aging involves retinal cell damage that leads to visual dysfunction. Sirtuin (Sirt) 1 can prevent oxidative stress, DNA damage, and apoptosis. In the present study, we measured the expression of Sirt1 as a functional regulator in the retina during the aging process. The visual function and Sirt1 expression in young (1 month) and old (19 months) Sprague-Dawley (SD) rats. Electroretinogram (ERG) and real-time polymerase chain reaction (PCR) or Western blotting were performed. Resveratrol, an activator of Sirt1, was orally administered to SD rats at a dose of 5 mg/kg/day for 19 months. The expression of Sirt1, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) was evaluated in the retinas of mice that did and did not receive resveratrol treatment. Apoptosis was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. With decreasing b-wave amplitude, the expression level of Sirt1 was significantly reduced in aged retinas compared to that in young retinas. After 19 months of treatment with resveratrol, the Sirt1 expression level and b-wave amplitude increased. In old rats treated with resveratrol, the expression levels of BDNF and TrkB were up-regulated. Compared to young retinas, the aged retinas exhibited higher apoptosis, but resveratrol delayed this process. Our data demonstrated a reduction of Sirt1 expression during the aging process of the retina, but enhancing Sirt1 expression reversed the degeneration of the retina. These results suggested that increasing Sirt1 expression may protect retinal neurons and visual function via regulating neurotrophin and its receptor. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Retinal and Optic Nerve Degeneration in Patients with Multiple Sclerosis Followed up for 5 Years.

    Science.gov (United States)

    Garcia-Martin, Elena; Ara, Jose R; Martin, Jesus; Almarcegui, Carmen; Dolz, Isabel; Vilades, Elisa; Gil-Arribas, Laura; Fernandez, Francisco J; Polo, Vicente; Larrosa, Jose M; Pablo, Luis E; Satue, Maria

    2017-05-01

    To quantify retinal nerve fiber layer (RNFL) changes in patients with multiple sclerosis (MS) and healthy controls with a 5-year follow-up and to analyze correlations between disability progression and RNFL degeneration. Observational and longitudinal study. One hundred patients with relapsing-remitting MS and 50 healthy controls. All participants underwent a complete ophthalmic and electrophysiologic exploration and were re-evaluated annually for 5 years. Visual acuity (Snellen chart), color vision (Ishihara pseudoisochromatic plates), visual field examination, optical coherence tomography (OCT), scanning laser polarimetry (SLP), and visual evoked potentials. Expanded Disability Status Scale (EDSS) scores, disease duration, treatments, prior optic neuritis episodes, and quality of life (QOL; based on the 54-item Multiple Sclerosis Quality of Life Scale score). Optical coherence tomography (OCT) revealed changes in all RNFL thicknesses in both groups. In the MS group, changes were detected in average thickness and in the mean deviation using the GDx-VCC nerve fiber analyzer (Laser Diagnostic Technologies, San Diego, CA) and in the P100 latency of visual evoked potentials; no changes were detected in visual acuity, color vision, or visual fields. Optical coherence tomography showed greater differences in the inferior and temporal RNFL thicknesses in both groups. In MS patients only, OCT revealed a moderate correlation between the increase in EDSS and temporal and superior RNFL thinning. Temporal RNFL thinning based on OCT results was correlated moderately with decreased QOL. Multiple sclerosis patients exhibit a progressive axonal loss in the optic nerve fiber layer. Retinal nerve fiber layer thinning based on OCT results is a useful marker for assessing MS progression and correlates with increased disability and reduced QOL. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  18. Encephalopathy with intracerebral calcification, white matter lesions, growth hormone deficiency, microcephaly, and retinal degeneration: two sibs confirming a probably distinct entity.

    OpenAIRE

    Bönnemann, C G; Meinecke, P; Reich, H

    1991-01-01

    Two sibs with an encephalopathy, including intracerebral calcification and white matter lesions, dwarfism owing to growth hormone deficiency, and retinal degeneration are reported. The onset of the disease in both patients occurred with retardation of motor development during the first year of life. Later, dwarfism, mental retardation, spasticity, ataxia, and retinal degeneration became apparent. These cases probably represent some form of connatal leucodystrophy. The differential diagnosis i...

  19. Reduced-illuminance autofluorescence imaging in ABCA4-associated retinal degenerations

    Science.gov (United States)

    Cideciyan, Artur V.; Swider, Malgorzata; Aleman, Tomas S.; Roman, Marisa I.; Sumaroka, Alexander; Schwartz, Sharon B.; Stone, Edwin M.; Jacobson, Samuel G.

    2007-05-01

    The health of the retinal pigment epithelium (RPE) can be estimated with autofluorescence (AF) imaging of lipofuscin, which accumulates as a byproduct of retinal exposure to light. Lipofuscin may be toxic to the RPE, and its toxicity may be enhanced by short-wavelength (SW) illumination. The high-intensity and SW excitation light used in conventional AF imaging could, at least in principle, increase the rate of lipofuscin accumulation and/or increase its toxicity. We considered two reduced-illuminance AF imaging (RAFI) methods as alternatives to conventional AF imaging. RAFI methods use either near-infrared (NIR) light or reduced-radiance SW illumination for excitation of fluorophores. We quantified the distribution of RAFI signals in relation to retinal structure and function in patients with the prototypical lipofuscin accumulation disease caused by mutations in ABCA4. There was evidence for two subclinical stages of macular ABCA4 disease involving hyperautofluorescence of both SW- and NIR-RAFI with and without associated loss of visual function. Use of RAFI methods and microperimetry in future clinical trials involving lipofuscinopathies should allow quantification of subclinical disease expression and progression without subjecting the diseased retina/RPE to undue light exposure.

  20. Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa

    Science.gov (United States)

    Daiger, Stephen P.; Bowne, Sara J.; Sullivan, Lori S.

    2015-01-01

    Retinitis pigmentosa (RP) has a prevalence of approximately one in 4000; 25%–30% of these cases are autosomal dominant retinitis pigmentosa (adRP). Like other forms of inherited retinal disease, adRP is exceptionally heterogeneous. Mutations in more than 25 genes are known to cause adRP, more than 1000 mutations have been reported in these genes, clinical findings are highly variable, and there is considerable overlap with other types of inherited disease. Currently, it is possible to detect disease-causing mutations in 50%–75% of adRP families in select populations. Genetic diagnosis of adRP has advantages over other forms of RP because segregation of disease in families is a useful tool for identifying and confirming potentially pathogenic variants, but there are disadvantages too. In addition to identifying the cause of disease in the remaining 25% of adRP families, a central challenge is reconciling clinical diagnosis, family history, and molecular findings in patients and families. PMID:25304133

  1. Hydrostatic Pressure Does Not Cause Detectable Changes in Survival of Human Retinal Ganglion Cells

    Science.gov (United States)

    Osborne, Andrew; Aldarwesh, Amal; Rhodes, Jeremy D.; Broadway, David C.; Everitt, Claire; Sanderson, Julie

    2015-01-01

    Purpose Elevated intraocular pressure (IOP) is a major risk factor for glaucoma. One consequence of raised IOP is that ocular tissues are subjected to increased hydrostatic pressure (HP). The effect of raised HP on stress pathway signaling and retinal ganglion cell (RGC) survival in the human retina was investigated. Methods A chamber was designed to expose cells to increased HP (constant and fluctuating). Accurate pressure control (10-100mmHg) was achieved using mass flow controllers. Human organotypic retinal cultures (HORCs) from donor eyes (pressure for 24 or 48h caused no loss of structural integrity, LDH release, decrease in RGC marker expression (THY-1) or loss of RGCs compared with controls. In addition, there was no increase in TUNEL-positive NeuN-labelled cells at either time-point indicating no increase in apoptosis of RGCs. OGD increased apoptosis, reduced RGC marker expression and RGC number and caused elevated LDH release at 24h. p38 and JNK phosphorylation remained unchanged in HORCs exposed to fluctuating pressure (10-100mmHg; 1 cycle/min) for 15, 30, 60 and 90min durations, whereas OGD (3h) increased activation of p38 and JNK, remaining elevated for 90min post-OGD. Conclusions Directly applied HP had no detectable impact on RGC survival and stress-signalling in HORCs. Simulated ischemia, however, activated stress pathways and caused RGC death. These results show that direct HP does not cause degeneration of RGCs in the ex vivo human retina. PMID:25635827

  2. 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.

  3. Preventive and therapeutic effects of SkQ1-containing Visomitin eye drops against light-induced retinal degeneration.

    Science.gov (United States)

    Novikova, Yu P; Gancharova, O S; Eichler, O V; Philippov, P P; Grigoryan, E N

    2014-10-01

    The human retina is constantly affected by light of varying intensity, this being especially true for photoreceptor cells and retinal pigment epithelium. Traditionally, photoinduced damages of the retina are induced by visible light of high intensity in albino rats using the LIRD (light-induced retinal degeneration) model. This model allows study of pathological processes in the retina and the search for retinoprotectors preventing retinal photodamage. In addition, the etiology and mechanisms of retina damage in the LIRD model have much in common with the mechanisms of the development of age-related retinal disorders, in particular, with age-related macular degeneration (AMD). We have studied preventive and therapeutic effects of Visomitin eye drops (based on the mitochondria-targeted antioxidant SkQ1) on albino rat retinas damaged by bright light. In the first series of experiments, rats receiving Visomitin for two weeks prior to illumination demonstrated significantly less expressed atrophic and degenerative changes in the retina compared to animals receiving similar drops with no SkQ1. In the second series, the illuminated rats were treated for two weeks with Visomitin or similar drops without SkQ1. The damaged retinas of the experimental animals were repaired much more effectively than those of the control animals. Therefore, we conclude that Visomitin SkQ1-containing eye drops have pronounced preventive and therapeutic effects on the photodamaged retina and might be recommended as a photoprotector and a pharmaceutical preparation for the treatment of AMD in combination with conventional medicines.

  4. Manganese-Enhanced MRI for Preclinical Evaluation of Retinal Degeneration Treatments.

    Science.gov (United States)

    Schur, Rebecca M; Sheng, Li; Sahu, Bhubanananda; Yu, Guanping; Gao, Songqi; Yu, Xin; Maeda, Akiko; Palczewski, Krzysztof; Lu, Zheng-Rong

    2015-07-01

    Apply manganese-enhanced magnetic resonance imaging (MEMRI) to assess ion channel activity and structure of retinas from mice subject to light-induced retinal degeneration treated with prophylactic agents. Abca4(-/-)Rdh8(-/-) double knockout mice with and without prophylactic retinylamine (Ret-NH2) treatment were illuminated with strong light. Manganese-enhanced MRI was used to image the retina 2 hours after intravitreous injection of MnCl2 into one eye. Contrast-enhanced MRIs of the retina and vitreous humor in each experimental group were assessed and correlated with the treatment. Findings were compared with standard structural and functional assessments of the retina by optical coherence tomography (OCT), histology, and electroretinography (ERG). Manganese-enhanced MRI contrast in the retina was high in nonilluminated and illuminated Ret-NH2-treated mice, whereas no enhancement was evident in the retina of the light-illuminated mice without Ret-NH2 treatment (P treatment based on the measurement of ion channel activity. This approach could be used as a complementary tool in preclinical development of new prophylactic therapies for retinopathies.

  5. Outcomes in Eyes with Retinal Angiomatous Proliferation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).

    Science.gov (United States)

    Daniel, Ebenezer; Shaffer, James; Ying, Gui-shuang; Grunwald, Juan E; Martin, Daniel F; Jaffe, Glenn J; Maguire, Maureen G

    2016-03-01

    To compare baseline characteristics, visual acuity (VA), and morphologic outcomes between eyes with retinal angiomatous proliferation (RAP) and all other eyes among patients with neovascular age-related macular degeneration (NVAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Prospective cohort study within the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). Patients with NVAMD. Reading center staff evaluated digital color fundus photographs, fluorescein angiography (FA) images, and optical coherence tomography (OCT) scans of eyes with NVAMD treated with either ranibizumab or bevacizumab over a 2-year period. Retinal angiomatous proliferation was identified by the intense intra-retinal leakage of fluorescein in combination with other associated features. Visual acuity; fluorescein leakage; scar; geographic atrophy (GA) on FA; retinal thickness, fluid, and subretinal hyperreflective material (SHRM) on OCT; and the number of intravitreal anti-VEGF injections at 1 and 2 years. Retinal angiomatous proliferation was present in 126 of 1183 (10.7%) study eyes at baseline. Mean VA improvement from baseline was greater (10.6 vs. 6.9 letters; P = 0.01) at 1 year, but similar at 2 years (7.8 vs. 6.2 letters; P = 0.34). At 1 year, eyes with RAP were more likely to have no fluid (46% vs. 26%; P treatment in CATT, eyes with RAP were less likely to have fluid, FA leakage, scar, and SHRM and more likely to have GA than eyes without RAP. Mean improvement in VA was similar at 2 years. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  6. Conditional ablation of the choroideremia gene causes age-related changes in mouse retinal pigment epithelium.

    Science.gov (United States)

    Wavre-Shapton, Silène T; Tolmachova, Tanya; Lopes da Silva, Mafalda; da Silva, Mafalda Lopes; Futter, Clare E; Seabra, Miguel C

    2013-01-01

    The retinal pigment epithelium (RPE) is a pigmented monolayer of cells lying between the photoreceptors and a layer of fenestrated capillaries, the choriocapillaris. Choroideremia (CHM) is an X-linked progressive degeneration of these three layers caused by the loss of function of Rab Escort protein-1 (REP1). REP1 is involved in the prenylation of Rab proteins, key regulators of membrane trafficking. To study the pathological consequences of chronic disruption of membrane traffic in the RPE we used a cell type-specific knock-out mouse model of the disease, where the Chm/Rep1 gene is deleted only in pigmented cells (Chm(Flox), Tyr-Cre+). Transmission electron microscopy (TEM) was used to quantitate the melanosome distribution in the RPE and immunofluorescent staining of rhodopsin was used to quantitate phagocytosed rod outer segments in retinal sections. The ultrastructure of the RPE and Bruch's membrane at different ages was characterised by TEM to analyse age-related changes occurring as a result of defects in membrane traffic pathways. Chm/Rep1 gene knockout in RPE cells resulted in reduced numbers of melanosomes in the apical processes and delayed phagosome degradation. In addition, the RPE accumulated pathological changes at 5-6 months of age similar to those observed in 2-year old controls. These included the intracellular accumulation of lipofuscin-containing deposits, disorganised basal infoldings and the extracellular accumulation of basal laminar and basal linear deposits. The phenotype of the Chm(Flox), Tyr-Cre+ mice suggests that loss of the Chm/Rep1 gene causes premature accumulation of features of aging in the RPE. Furthermore, the striking similarities between the present observations and some of the phenotypes reported in age-related macular degeneration (AMD) suggest that membrane traffic defects may contribute to the pathogenesis of AMD.

  7. Conditional ablation of the choroideremia gene causes age-related changes in mouse retinal pigment epithelium.

    Directory of Open Access Journals (Sweden)

    Silène T Wavre-Shapton

    Full Text Available The retinal pigment epithelium (RPE is a pigmented monolayer of cells lying between the photoreceptors and a layer of fenestrated capillaries, the choriocapillaris. Choroideremia (CHM is an X-linked progressive degeneration of these three layers caused by the loss of function of Rab Escort protein-1 (REP1. REP1 is involved in the prenylation of Rab proteins, key regulators of membrane trafficking. To study the pathological consequences of chronic disruption of membrane traffic in the RPE we used a cell type-specific knock-out mouse model of the disease, where the Chm/Rep1 gene is deleted only in pigmented cells (Chm(Flox, Tyr-Cre+. Transmission electron microscopy (TEM was used to quantitate the melanosome distribution in the RPE and immunofluorescent staining of rhodopsin was used to quantitate phagocytosed rod outer segments in retinal sections. The ultrastructure of the RPE and Bruch's membrane at different ages was characterised by TEM to analyse age-related changes occurring as a result of defects in membrane traffic pathways. Chm/Rep1 gene knockout in RPE cells resulted in reduced numbers of melanosomes in the apical processes and delayed phagosome degradation. In addition, the RPE accumulated pathological changes at 5-6 months of age similar to those observed in 2-year old controls. These included the intracellular accumulation of lipofuscin-containing deposits, disorganised basal infoldings and the extracellular accumulation of basal laminar and basal linear deposits. The phenotype of the Chm(Flox, Tyr-Cre+ mice suggests that loss of the Chm/Rep1 gene causes premature accumulation of features of aging in the RPE. Furthermore, the striking similarities between the present observations and some of the phenotypes reported in age-related macular degeneration (AMD suggest that membrane traffic defects may contribute to the pathogenesis of AMD.

  8. Sudden acquired retinal degeneration in dogs: breed distribution of 495 canines.

    Science.gov (United States)

    Heller, Amanda R; van der Woerdt, Alexandra; Gaarder, James E; Sapienza, John S; Hernandez-Merino, Elena; Abrams, Kenneth; Church, Melanie L; La Croix, Noelle

    2017-03-01

    The purpose of this study was to describe breed, age, gender, and weight distribution of dogs affected with sudden acquired retinal degeneration (SARD) and to investigate whether SARD is more common in small breed dogs. Medical records of dogs diagnosed with SARD confirmed by an electroretinogram were reviewed. Breed, age, gender, and weight were recorded when available. The same data were obtained for dogs with SARD described in the veterinary literature. Three hundred and two dogs were included from the ophthalmology practices and 193 dogs from the veterinary literature. Sixty breeds were present in the study. Mixed-breed dogs were the most common at 108 dogs (21.8%), followed by the Dachshund (68, 13.7%), Chinese Pug (44, 8.9%), Miniature Schnauzer (39, 7.9%), Maltese (23, 4.6%), Cocker Spaniel (22, 4.4%), Bichon Frise (18, 3.6%), Beagle (16, 3.2%), Brittany (15, 3.0%), and Pomeranian (10, 2.0%). Fifty other breeds were represented by 1-9 dogs each. The median age was 9 years (range = 10 months-16 years). The weight was known for 197 dogs. About 60.9% of dogs were less than 25 pounds, 31.5% were between 25 and 50 pounds, and 7.6% were greater than 50 pounds. Gender was recorded in 393 dogs: 217 female dogs and 176 male dogs. As previously reported, SARD is most common in middle-aged to older dogs. Smaller dogs of less than 25 pounds appear overrepresented, while large/giant breed dogs of greater than 50 pounds are infrequently diagnosed. In this study, there was no statistical significance between female and male dogs. © 2016 American College of Veterinary Ophthalmologists.

  9. Cofactors associated with Sudden Acquired Retinal Degeneration Syndrome: 151 dogs within a reference population.

    Science.gov (United States)

    Auten, Candace R; Thomasy, Sara M; Kass, Philip H; Good, Kathryn L; Hollingsworth, Steven R; Maggs, David J

    2018-05-01

    To determine factors associated with sudden acquired retinal degeneration syndrome (SARDS) diagnosed within one referral population. 151 dogs diagnosed with SARDS. Breed, age, sex, and body weight were compared between dogs with electroretinogram-confirmed SARDS and dogs presented to the UC Davis Veterinary Medical Teaching Hospital (UCD-VMTH) from 1991 to 2014. SARDS was diagnosed in 151 dogs, representing 1.3% of dogs presented to the UCD-VMTH for ophthalmic disease. Although dogs of 36 breeds were affected, the Dachshund (n = 31, 21%), Schnauzer (16, 11%), Pug (11, 7%), and Brittany (5, 3%) were significantly overrepresented, and the Labrador Retriever (3, 2%) was significantly underrepresented vs. the reference population (P < 0.001). Median (range) age and body weight of affected vs. reference dogs were 8.9 (3-20) vs. 6.8 (0.1-26) years and 12.4 (2.8-52.7) vs. 22.3 (0.1-60) kg, respectively. Dogs 6-10 years of age and between 10-20 kg in body weight were significantly overrepresented in the SARDS population, while dogs <6 years of age were significantly underrepresented (P < 0.01). Spayed females (59% of affected dogs) were significantly overrepresented compared to the reference population, whereas intact females (1% of affected dogs) were significantly underrepresented. Consistent with previous studies, smaller, middle-aged, spayed female dogs may be at increased risk of developing SARDS. Unlike previous studies, this is the first study comparing a variety of SARDS-affected breeds to a reference population. Potentially increased risk of SARDS in several breeds, particularly Dachshunds, suggests a familial factor that warrants further investigation using genetic techniques. © 2017 American College of Veterinary Ophthalmologists.

  10. Progression of retinal pigment epithelial atrophy in antiangiogenic therapy of neovascular age-related macular degeneration.

    Science.gov (United States)

    Schütze, Christopher; Wedl, Manuela; Baumann, Bernhard; Pircher, Michael; Hitzenberger, Christoph K; Schmidt-Erfurth, Ursula

    2015-06-01

    To monitor retinal pigment epithelial (RPE) atrophy progression during antiangiogenic therapy of neovascular age-related macular degeneration (AMD) over 2 years using polarization-sensitive optical coherence tomography (OCT). Prospective interventional case series. setting: Clinical practice. Thirty patients (31 eyes) with treatment-naïve neovascular AMD. Standard intravitreal therapy (0.5 mg ranibizumab) was administered monthly during the first year and pro re nata (PRN; as-needed) during the second year. Spectral-domain (SD) OCT and polarization-sensitive OCT (selectively imaging the RPE) examinations were performed at baseline and at 1, 3, 6, 12, and 24 months using a standardized protocol. RPE-related changes were evaluated using a semi-automated polarization-sensitive OCT segmentation algorithm and correlated with SD OCT and fundus autofluorescence (FAF) findings. RPE response, geographic atrophy (GA) progression. Atrophic RPE changes included RPE thinning, RPE porosity, focal RPE atrophy, and development of GA. Early RPE loss (ie, RPE porosity, focal atrophy) increased progressively during initial monthly treatment and remained stable during subsequent PRN-based therapy. GA developed in 61% of eyes at month 24. Mean GA area increased from 0.77 mm(2) at 12 months to 1.10 mm(2) (standard deviation = 1.09 mm(2)) at 24 months. Reactive accumulation of RPE-related material at the lesion borders increased until month 3 and subsequently decreased. Progressive RPE atrophy and GA developed in the majority of eyes. RPE migration signifies certain RPE plasticity. Polarization-sensitive OCT specifically images RPE-related changes in neovascular AMD, contrary to conventional imaging methods. Polarization-sensitive OCT allows for precisely monitoring the sequence of RPE-related morphologic changes. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Prevalence and laterality of lattice retinal degeneration within a primary eye care population.

    Science.gov (United States)

    Semes, L P; Holland, W C; Likens, E G

    2001-04-01

    The purpose of this study was to determine the prevalence of lattice retinal degeneration (LRD) in a primary eye care population and to compare this prevalence to that of other studies reported from selected populations. In addition, the percentage of unilateral and bilateral cases was to be determined. A prospective study design was conceived to examine 600 consecutive patients presenting to the UABSO Primary Care Clinics. Each patient had been appointed for general eye examination. The following data were collected contemporaneously over six months from September 1993 to March 1994: demographics, medical and ocular history; refractive correction (calculated and recorded as spherical equivalent, SE); best-corrected visual acuity; and the presence and features of all ocular fundus findings, as evaluated through a dilated pupil. Of the 600 patients examined, 31 (5.2%) had LRD. Subjects ranged in age from 14 to 78 years (mean, 37.4 +/- 17.9 yrs.). Seventeen (55%) of the patients were white and 14 (45%) were black; 21 patients (68%) were female and 14 (32%) were male. The mean refractive correction (SE) was -1.77 D (range, +2.25 to -8.00 D). The lesions were bilateral in 19 (61.3%) of the patients; unilateral in 12 (38.7%). LRD lesions were observed in the vertical meridian (within 30 degrees of 6 or 12 o'clock) in all patients. The prevalence of LRD in a primary eye care population is comparable to that reported from other, selected populations. The proportion of bilateral cases in our material was greater than that from some other studies. Another item of note from the present data was exclusively vertical geographic location. We attribute the greater prevalence of bilateral cases in this material to the nature of the eye care delivery system.

  12. Different effects of valproic acid on photoreceptor loss in Rd1 and Rd10 retinal degeneration mice.

    Science.gov (United States)

    Mitton, Kenneth P; Guzman, Alvaro E; Deshpande, Mrinalini; Byrd, David; DeLooff, Camryn; Mkoyan, Kristina; Zlojutro, Paul; Wallace, Adrianne; Metcalf, Brandon; Laux, Kirsten; Sotzen, Jason; Tran, Trung

    2014-01-01

    injections with VPA (P9-P21) dramatically slowed the loss of rod photoreceptors in Pde6b(rd1/rd1) mice. At age P21, VPA-treated mice had several extra rows of rod photoreceptor nuclei compared to PBS-injected littermates. Dosing started later (P14) or dosing every second day also rescued photoreceptors. In contrast, systemic VPA treatment of Pde6b(rd10/rd10) mice (P17-P28) reduced visual function that correlated with a slight increase in photoreceptor loss. Treating Pde6b(rd10/rd10) mice earlier (P9-P21) also failed to rescue photoreceptors. Treating wild-type mice earlier (P9-P21) reduced the number of photoreceptors in VPA-treated mice by 20% compared to PBS-treated animals. A single systemic dose of VPA can change retinal neurotrophic factor and rod-specific gene expression in the immature retina. Daily VPA treatment from P17 to P28 can also alter gene expression in the mature neural retina. While daily treatment with VPA could significantly reduce photoreceptor loss in the rd1 model, VPA treatment slightly accelerated photoreceptor loss in the rd10 model. The apparent rescue of photoreceptors in the rd1 model was not the result of producing more photoreceptors before degeneration. In fact, daily systemic VPA was toxic to wild-type photoreceptors when started at P9. However, the effective treatment period for Pde6b(rd1/rd1) mice (P9-P21) has significant overlap with the photoreceptor maturation period, which complicates the use of the rd1 model for testing of VPA's efficacy. In contrast, VPA treatment started after P17 did not cause photoreceptor loss in wild-type mice. Thus, the acceleration of photoreceptor loss in the rd10 model may be more relevant where both photoreceptor loss and VPA treatment (P17-P28) started when the central retina was mature.

  13. Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration.

    Science.gov (United States)

    Pyakurel, Aswin; Balmer, Delphine; Saba-El-Leil, Marc K; Kizilyaprak, Caroline; Daraspe, Jean; Humbel, Bruno M; Voisin, Laure; Le, Yun Z; von Lintig, Johannes; Meloche, Sylvain; Roduit, Raphaël

    2017-12-15

    Recent work suggested that the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is increased in the retinal pigment epithelium (RPE) of age-related macular degeneration (ARMD) patients and therefore could be an attractive therapeutic target. Notably, ERK1/2 pathway inhibitors are used in cancer therapy, with severe and noncharacterized ocular side effects. To decipher the role of ERK1/2 in RPE cells, we conditionally disrupted the Erk1 and Erk2 genes in mouse RPE. The loss of ERK1/2 activity resulted in a significant decrease in the level of RPE65 expression, a decrease in ocular retinoid levels concomitant with low visual function, and a rapid disorganization of RPE cells, ultimately leading to retinal degeneration. Our results identify the ERK1/2 pathway as a direct regulator of the visual cycle and a critical component of the viability of RPE and photoreceptor cells. Moreover, our results caution about the need for a very fine adjustment of kinase inhibition in cancer or ARMD treatment in order to avoid ocular side effects. Copyright © 2017 Pyakurel et al.

  14. Progranulin, a major secreted protein of mouse adipose-derived stem cells, inhibits light-induced retinal degeneration.

    Science.gov (United States)

    Tsuruma, Kazuhiro; Yamauchi, Mika; Sugitani, Sou; Otsuka, Tomohiro; Ohno, Yuta; Nagahara, Yuki; Ikegame, Yuka; Shimazawa, Masamitsu; Yoshimura, Shinichi; Iwama, Toru; Hara, Hideaki

    2014-01-01

    Adipose tissue stromal vascular fraction contains mesenchymal stem cells, which show protective effects when administered to damaged tissues, mainly through secreted trophic factors. We examined the protective effects of adipose-derived stem cells (ASCs) and ASC-conditioned medium (ASC-CM) against retinal damage and identified the neuroprotective factors in ASC-CM. ASCs and mature adipocytes were isolated from mouse subcutaneous tissue. ASCs were injected intravitreally in a mouse model of light-induced retinal damage, and ASC injection recovered retinal function as measured by electroretinogram and inhibited outer nuclear layer, thinning, without engraftment of ASCs. ASC-CM and mature adipocyte-conditioned medium were collected after 72 hours of culture. In vitro, H2O2- and light-induced cell death was reduced in a photoreceptor cell line with ASC-CM but not with mature adipocyte-conditioned medium. In vivo, light-induced photoreceptor damage was evaluated by measurement of outer nuclear layer thickness at 5 days after light exposure and by electroretinogram recording. ASC-CM significantly inhibited photoreceptor degeneration and retinal dysfunction after light exposure. Progranulin was identified as a major secreted protein of ASCs that showed protective effects against retinal damage in vitro and in vivo. Furthermore, progranulin phosphorylated extracellular signal-regulated kinase, cAMP response element binding protein, and hepatocyte growth factor receptor, and protein kinase C signaling pathways were involved in the protective effects of progranulin. These findings suggest that ASC-CM and progranulin have neuroprotective effects in the light-induced retinal-damage model. Progranulin may be a potential target for the treatment of the degenerative diseases of the retina.

  15. 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.

  16. Retinal vascular caliber, iris color, and age-related macular degeneration in the Irish Nun Eye Study.

    Science.gov (United States)

    McGowan, Amy; Silvestri, Giuliana; Moore, Evelyn; Silvestri, Vittorio; Patterson, Christopher C; Maxwell, Alexander P; McKay, Gareth J

    2014-12-18

    To evaluate the relationship between retinal vascular caliber (RVC), iris color, and age-related macular degeneration (AMD) in elderly Irish nuns. Data from 1233 participants in the cross-sectional observational Irish Nun Eye Study were assessed from digital photographs with a standardized protocol using computer-assisted software. Macular images were graded according to the modified Wisconsin Age-related Maculopathy Grading System. Regression models were used to assess associations, adjusting for age, mean arterial blood pressure, body mass index, refraction, and fellow RVC. In total, 1122 (91%) participants had gradable retinal images of sufficient quality for vessel assessment (mean age: 76.3 years [range, 56-100 years]). In an unadjusted analysis, we found some support for a previous finding that individuals with blue iris color had narrower retinal venules compared to those with brown iris color (P < 0.05), but this was no longer significant after adjustment. Age-related macular degeneration status was categorized as no AMD, any AMD, and late AMD only. Individuals with any AMD (early or late AMD) had significantly narrower arterioles and venules compared to those with no AMD in an unadjusted analysis, but this was no longer significant after adjustment. A nonsignificant reduced risk of any AMD or late AMD only was observed in association with brown compared to blue iris color, in both unadjusted and adjusted analyses. Retinal vascular caliber was not significantly associated with iris color or early/late AMD after adjustment for confounders. A lower but nonsignificant AMD risk was observed in those with brown compared to blue iris color. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

  17. Vision deficits precede structural losses in a mouse model of mitochondrial dysfunction and progressive retinal degeneration.

    Science.gov (United States)

    Laliberté, Alex M; MacPherson, Thomas C; Micks, Taft; Yan, Alex; Hill, Kathleen A

    2011-12-01

    Current animal models of retinal disease often involve the rapid development of a retinal disease phenotype; however, this is at odds with age-related diseases that take many years to manifest clinical symptoms. The present study was performed to examine an apoptosis-inducing factor (Aif)-deficient model, the harlequin carrier mouse (X(hq)X), and determine how mitochondrial dysfunction and subsequent accelerated aging affect the function and structure of the mouse retina. Vision and eye structure for cohorts of 6 X(hq)X and 6 wild type mice at 3, 11, and 15 months of age were studied using in vivo electroretinography (ERG), and optical coherence tomography (OCT). Retinal superoxide levels were determined in situ using dihydroethidium (DHE) histochemistry. Retinal cell counts were quantified post mortem using hematoxylin and eosin (H&E) staining. ERG analysis of X(hq)X retinal function indicated a reduction in b-wave amplitude significant at 3 months of age (p retina (p retina may account for the early and significant reduction in retinal function. This remodeling of retinal neurochemistry in response to stress may be a relevant mechanism in the progression of normal retinal aging and early stages of some retinal degenerative diseases. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. Non-syndromic retinitis pigmentosa

    NARCIS (Netherlands)

    Verbakel, S.K. (Sanne K.); R.A.C. van Huet (Ramon A. C.); C.J.F. Boon (Camiel); A.I. Hollander (Anneke); R.W.J. Collin (Rob); C.C.W. Klaver (Caroline); C. Hoyng (Carel); R. Roepman (Ronald); B.J. Klevering (Jeroen)

    2018-01-01

    textabstractRetinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic,

  19. 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.

  20. Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations.

    Science.gov (United States)

    Nagel-Wolfrum, Kerstin; Möller, Fabian; Penner, Inessa; Wolfrum, Uwe

    2014-09-01

    The eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30-50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the

  1. Retinitis Pigmentosa

    Science.gov (United States)

    ... Linked Retinoschisis (XLRS) X-Linked Retinitis Pigmentosa (XLRP) Usher Syndrome Other Retinal Diseases Glossary News & Research News & Research ... degenerate. Forms of RP and related diseases include Usher syndrome, Leber congenital amaurosis, and Bardet-Biedl syndrome, among ...

  2. Expression and regulation of enzymes in the ceramide metabolic pathway in human retinal pigment epithelial cells and their relevance to retinal degeneration.

    Science.gov (United States)

    Zhu, DanHong; Sreekumar, Parameswaran G; Hinton, David R; Kannan, Ram

    2010-03-31

    Ceramide and its metabolic derivatives are important modulators of cellular apoptosis and proliferation. Dysregulation or imbalance of their metabolic pathways may promote the development of retinal degeneration. The aim of this study was to identify the expression and regulation of key enzymes of the ceramide pathway in retinal pigment epithelial (RPE) cells. RT-PCR was used to screen the enzymes involved in ceramide metabolism that are expressed in RPE. Over-expression of neutral sphingomyelinase-2 (SMPD3) or sphingosine kinase 1 (Sphk1) in ARPE-19 cells was achieved by transient transfection of SMPD3 or Sphk1 cDNA subcloned into an expression vector. The number of apoptotic or proliferating cells was determined using TUNEL and BrdU assays, respectively. Neutral sphingomyelinase-1, neutral sphingomyelinase-2, acidic ceramidase, ceramide kinase, SphK1 and Sphk2 were expressed in both ARPE-19 and early passage human fetal RPE (fRPE) cells, while alkaline ceramidase 2 was only expressed in fRPE cells. Over-expression of SMPD3 decreased RPE cell proliferation and increased cell apoptosis. The percentage of apoptotic cells increased proportionally with the amount of transfected SMPD3 DNA. Over-expression of SphK1 promoted cell proliferation and protected ARPE-19 cells from ceramide-induced apoptosis. The effect of C(2) ceramide on induction of apoptosis was evaluated in polarized vs. non-polarized RPE cultures; polarization of RPE was associated with much reduced apoptosis in response to ceramide. In conclusion, RPE cells possess the synthetic machinery for the production of ceramide, sphingosine, ceramide-1-phosphate (C1P), and sphingosine-1-phosphate (S1P). Over-expression of SMPD3 may increase cellular ceramide levels, leading to enhanced cell death and arrested cell proliferation. The selective induction of apoptosis in non-polarized RPE cultures by C(2) ceramide suggests that increased ceramide levels will preferentially affect non-polarized RPE, as are found in

  3. 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.

  4. 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.

  5. Pigment epithelial detachment followed by retinal cystoid degeneration leads to vision loss in treatment of neovascular age-related macular degeneration.

    Science.gov (United States)

    Schmidt-Erfurth, Ursula; Waldstein, Sebastian M; Deak, Gabor-Gyoergy; Kundi, Michael; Simader, Christian

    2015-04-01

    Intravitreal antiangiogenic therapy is the major therapeutic breakthrough in neovascular age-related macular degeneration (AMD). Optical coherence tomography (OCT) is the leading diagnostic tool, but solid criteria for optimal therapeutic outcomes are lacking. A comprehensive analysis of structure/function correlations using Food and Drug Administration- and European Medicines Agency-approved substances and fixed and flexible regimens was performed. Post hoc analysis of a prospective, randomized multicenter clinical trial including 189 study sites. A total of 1240 patients with active neovascular AMD. Participants received intravitreal ranibizumab or aflibercept. A fixed regimen was used for 48 weeks followed by a flexible regimen until week 96. At monthly intervals, best-corrected visual acuity (BCVA) was measured and retinal morphology was assessed by standardized OCT, including intraretinal cysts (IRCs), subretinal fluid (SRF), and pigment epithelial detachment (PED), presenting with a width ≥400 μm or a height of ≥200 μm. Results were correlated for each regimen, feature, and time. The BCVA outcomes in relation to retinal pathomorphology based on noninferiority for all treatment arms. In neovascular AMD, only IRC at baseline and persistent through week 12 had a negative impact on BCVA. With therapeutic intervention, exudative features such as IRC and SRF resolved rapidly in 74% of eyes, whereas PED responded only slowly with 38%. Independent of the type of regimen, fixed or flexible, retinal morphology correlated tightly with visual function. Intraretinal cysts consistently showed the lowest BCVA gains with either regimen or substance. With the switch from a fixed to a flexible pro re nata (PRN) regimen, progressive visual loss occurred exclusively in the group with primary PED presenting as the hallmark of neovascular activity and was induced by secondary formation of IRC in the neurosensory retina. The efficacy of antiangiogenic therapy in neovascular

  6. Gene expression changes in the retina following subretinal injection of human neural progenitor cells into a rodent model for retinal degeneration.

    Science.gov (United States)

    Jones, Melissa K; Lu, Bin; Saghizadeh, Mehrnoosh; Wang, Shaomei

    2016-01-01

    Retinal degenerative diseases (RDDs) affect millions of people and are the leading cause of vision loss. Although treatment options for RDDs are limited, stem and progenitor cell-based therapies have great potential to halt or slow the progression of vision loss. Our previous studies have shown that a single subretinal injection of human forebrain derived neural progenitor cells (hNPCs) into the Royal College of Surgeons (RCS) retinal degenerate rat offers long-term preservation of photoreceptors and visual function. Furthermore, neural progenitor cells are currently in clinical trials for treating age-related macular degeneration; however, the molecular mechanisms of stem cell-based therapies are largely unknown. This is the first study to analyze gene expression changes in the retina of RCS rats following subretinal injection of hNPCs using high-throughput sequencing. RNA-seq data of retinas from RCS rats injected with hNPCs (RCS(hNPCs)) were compared to sham surgery in RCS (RCS(sham)) and wild-type Long Evans (LE(sham)) rats. Differential gene expression patterns were determined with in silico analysis and confirmed with qRT-PCR. Function, biologic, cellular component, and pathway analyses were performed on differentially expressed genes and investigated with immunofluorescent staining experiments. Analysis of the gene expression data sets identified 1,215 genes that were differentially expressed between RCS(sham) and LE(sham) samples. Additionally, 283 genes were differentially expressed between the RCS(hNPCs) and RCS(sham) samples. Comparison of these two gene sets identified 68 genes with inverse expression (termed rescue genes), including Pdc, Rp1, and Cdc42ep5. Functional, biologic, and cellular component analyses indicate that the immune response is enhanced in RCS(sham). Pathway analysis of the differential expression gene sets identified three affected pathways in RCS(hNPCs), which all play roles in phagocytosis signaling. Immunofluorescent staining

  7. Performance of photovoltaic arrays in-vivo and characteristics of prosthetic vision in animals with retinal degeneration

    Science.gov (United States)

    Lorach, Henri; Goetz, Georges; Mandel, Yossi; Lei, Xin; Kamins, Theodore I.; Mathieson, Keith; Huie, Philip; Dalal, Roopa; Harris, James S.; Palanker, Daniel

    2014-01-01

    Summary Loss of photoreceptors during retinal degeneration leads to blindness, but information can be reintroduced into the visual system using electrical stimulation of the remaining retinal neurons. Subretinal photovoltaic arrays convert pulsed illumination into pulsed electric current to stimulate the inner retinal neurons. Since required irradiance exceeds the natural luminance levels, an invisible near-infrared (915nm) light is used to avoid photophobic effects. We characterized the thresholds and dynamic range of cortical responses to prosthetic stimulation with arrays of various pixel sizes and with different number of photodiodes. Stimulation thresholds for devices with 140µm pixels were approximately half those of 70µm pixels, and with both pixel sizes, thresholds were lower with 2 diodes than with 3 diodes per pixel. In all cases these thresholds were more than two orders of magnitude below the ocular safety limit. At high stimulation frequencies (>20Hz), the cortical response exhibited flicker fusion. Over one order of magnitude of dynamic range could be achieved by varying either pulse duration or irradiance. However, contrast sensitivity was very limited. Cortical responses could be detected even with only a few illuminated pixels. Finally, we demonstrate that recording of the corneal electric potential in response to patterned illumination of the subretinal arrays allows monitoring the current produced by each pixel, and thereby assessing the changes in the implant performance over time. PMID:25255990

  8. 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 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. RESULTS: 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...

  9. Relationship of retinal morphology and retinal sensitivity in the treatment of neovascular age-related macular degeneration using aflibercept.

    Science.gov (United States)

    Sulzbacher, Florian; Roberts, Philipp; Munk, Marion R; Kaider, Alexandra; Kroh, Maria Elisabeth; Sacu, Stefan; Schmidt-Erfurth, Ursula

    2014-12-11

    To relate the functional response to distinct morphological features of the retina during aflibercept treatment for neovascular AMD (nAMD). A total of 726 retinal locations in 22 consecutive eyes presenting with treatment-naive nAMD underwent a standardized examination with spectral-domain optical coherence tomography (SD-OCT) and topographic microperimetry (MP) at baseline, after 3 and 12 months of continuous intravitreal aflibercept therapy. The retinal sensitivity at each stimulus location was registered to the corresponding location on SD-OCT morphology. Subsequently, the microperimetric responses were evaluated with respect to the following underlying SD-OCT features: neovascular complex (NVC), subretinal fluid (SRF), intraretinal fluid (IRF), intraretinal cystoid space (IRC), serous pigment epithelium detachment (sPED), and fibrovascular pigment epithelium detachment (fPED). Baseline sensitivity was reduced to mean values of 1.8 dB in NVC, 2.2 dB in IRC, 2.8 dB in IRF, 2.6 dB in sPED, 3.6 dB in SRF, and 4.6 dB in fPED. Improvements in retinal sensitivity were most pronounced during the initial 3-month interval, when significant recovery was documented for SRF and sPED with +4.0/5.5 dB (P 0.05 for each category). Significant functional benefits following intravitreal aflibercept treatment could be detected over all defined morphological pathologies. The level of improvement varied dependent on the associated feature with the best prognosis for visual improvement in SRF and sPED and least with intraretinal fluid and particularly intraretinal cysts. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

  10. [Retinal pigmentary degeneration--clinical features, diagnostics and possibilities of treatment].

    Science.gov (United States)

    Grześk, Magdalena; Malukiewicz-Wiśniewska, Grazyna

    2007-01-01

    The purpose of this study was to evaluate clinical course of retinitis pigmentosa taking into consideration models of inheritance and possible treatment. Retinitis pigmentosa belongs to heterogeneous group of hereditary disorders, which are connected with gradual loss of the photoreceptor function, firstly rod cells subsequently cones, which is accompanied by the retinal pigmentary epithelium disorder. Retinitis pigmentosa connected with X chromosome is one of the most severe form of this disease that in polish population takes place with frequency at average 10-15% which is similar to ADRP--10-20%. Course of RP, despite many similarities may differ from each other and prognosis depends on model of inheritance. Unfortunately, in spite of many efforts, nowadays medicine do not have successful treatment for patients with RP.

  11. 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.

  12. Spectral analysis of fundus autofluorescence pattern as a tool to detect early stages of degeneration in the retina and retinal pigment epithelium.

    Science.gov (United States)

    Feldman, Tatiana B; Yakovleva, Marina A; Larichev, Andrey V; Arbukhanova, Patimat M; Radchenko, Alexandra Sh; Borzenok, Sergey A; Kuzmin, Vladimir A; Ostrovsky, Mikhail A

    2018-05-22

    The aim of this work is the determination of quantitative diagnostic criteria based on the spectral characteristics of fundus autofluorescence to detect early stages of degeneration in the retina and retinal pigment epithelium (RPE). RPE cell suspension samples were obtained from the cadaver eyes with and without signs of age-related macular degeneration (AMD). Fluorescence analysis at an excitation wavelength of 488 nm was performed. The fluorescence lifetimes of lipofuscin-granule fluorophores were measured by counting time-correlated photon method. Comparative analysis of fluorescence spectra of RPE cell suspensions from the cadaver eyes with and without signs of AMD showed a significant difference in fluorescence intensity at 530-580 nm in response to fluorescence excitation at 488 nm. It was notably higher in eyes with visual pathology than in normal eyes regardless of the age of the eye donor. Measurements of fluorescence lifetimes of lipofuscin fluorophores showed that the contribution of photooxidation and photodegradation products of bisretinoids to the total fluorescence at 530-580 nm of RPE cell suspensions was greater in eyes with visual pathology than in normal eyes. Because photooxidation and photodegradation products of bisretinoids are markers of photodestructive processes, which can cause RPE cell death and initiate degenerative processes in the retina, quantitative determination of increases in these bisretinoid products in lipofuscin granules may be used to establish quantitative diagnostic criteria for degenerative processes in the retina and RPE.

  13. Retinal genes are differentially expressed in areas of primary versus secondary degeneration following partial optic nerve injury.

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    Wissam Chiha

    Full Text Available Partial transection (PT of the optic nerve is an established experimental model of secondary degeneration in the central nervous system. After a dorsal transection, retinal ganglion cells (RGCs with axons in ventral optic nerve are intact but vulnerable to secondary degeneration, whereas RGCs in dorsal retina with dorsal axons are affected by primary and secondary injuries. Using microarray, we quantified gene expression changes in dorsal and ventral retina at 1 and 7 days post PT, to characterize pathogenic pathways linked to primary and secondary degeneration.In comparison to uninjured retina Cryba1, Cryba2 and Crygs, were significantly downregulated in injured dorsal retina at days 1 and 7. While Ecel1, Timp1, Mt2A and CD74, which are associated with reducing excitotoxicity, oxidative stress and inflammation, were significantly upregulated. Genes associated with oxygen binding pathways, immune responses, cytokine receptor activity and apoptosis were enriched in dorsal retina at day 1 after PT. Oxygen binding and apoptosis remained enriched at day 7, as were pathways involved in extracellular matrix modification. Fewer changes were observed in ventral retina at day 1 after PT, most associated with the regulation of protein homodimerization activity. By day 7, apoptosis, matrix organization and signal transduction pathways were enriched. Discriminant analysis was also performed for specific functional gene groups to compare expression intensities at each time point. Altered expression of selected genes (ATF3, GFAP, Ecel1, TIMP1, Tp53 and proteins (GFAP, ECEL1 and ATF3 were semi-quantitatively assessed by qRT-PCR and immunohistochemistry respectively.There was an acute and complex primary injury response in dorsal retina indicative of a dynamic interaction between neuroprotective and neurodegenerative events; ventral retina vulnerable to secondary degeneration showed a delayed injury response. Both primary and secondary injury resulted in the

  14. Sirtuin1 Over-Expression Does Not Impact Retinal Vascular and Neuronal Degeneration in a Mouse Model of Oxygen-Induced Retinopathy

    Science.gov (United States)

    Michan, Shaday; Juan, Aimee M.; Hurst, Christian G.; Cui, Zhenghao; Evans, Lucy P.; Hatton, Colman J.; Pei, Dorothy T.; Ju, Meihua; Sinclair, David A.; Smith, Lois E. H.; Chen, Jing

    2014-01-01

    Proliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. Retinopathy is characterized by an initial phase of vessel loss, leading to tissue ischemia and hypoxia, followed by sight threatening pathologic neovascularization in the second phase. Previously we found that Sirtuin1 (Sirt1), a metabolically dependent protein deacetylase, regulates vascular regeneration in a mouse model of oxygen-induced proliferative retinopathy (OIR), as neuronal depletion of Sirt1 in retina worsens retinopathy. In this study we assessed whether over-expression of Sirtuin1 in retinal neurons and vessels achieved by crossing Sirt1 over-expressing flox mice with Nestin-Cre mice or Tie2-Cre mice, respectively, may protect against retinopathy. We found that over-expression of Sirt1 in Nestin expressing retinal neurons does not impact vaso-obliteration or pathologic neovascularization in OIR, nor does it influence neuronal degeneration in OIR. Similarly, increased expression of Sirt1 in Tie2 expressing vascular endothelial cells and monocytes/macrophages does not protect retinal vessels in OIR. In addition to the genetic approaches, dietary supplement with Sirt1 activators, resveratrol or SRT1720, were fed to wild type mice with OIR. Neither treatment showed significant vaso-protective effects in retinopathy. Together these results indicate that although endogenous Sirt1 is important as a stress-induced protector in retinopathy, over-expression of Sirt1 or treatment with small molecule activators at the examined doses do not provide additional protection against retinopathy in mice. Further studies are needed to examine in depth whether increasing levels of Sirt1 may serve as a potential therapeutic approach to treat or prevent retinopathy. PMID:24416337

  15. Sirtuin1 over-expression does not impact retinal vascular and neuronal degeneration in a mouse model of oxygen-induced retinopathy.

    Science.gov (United States)

    Michan, Shaday; Juan, Aimee M; Hurst, Christian G; Cui, Zhenghao; Evans, Lucy P; Hatton, Colman J; Pei, Dorothy T; Ju, Meihua; Sinclair, David A; Smith, Lois E H; Chen, Jing

    2014-01-01

    Proliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. Retinopathy is characterized by an initial phase of vessel loss, leading to tissue ischemia and hypoxia, followed by sight threatening pathologic neovascularization in the second phase. Previously we found that Sirtuin1 (Sirt1), a metabolically dependent protein deacetylase, regulates vascular regeneration in a mouse model of oxygen-induced proliferative retinopathy (OIR), as neuronal depletion of Sirt1 in retina worsens retinopathy. In this study we assessed whether over-expression of Sirtuin1 in retinal neurons and vessels achieved by crossing Sirt1 over-expressing flox mice with Nestin-Cre mice or Tie2-Cre mice, respectively, may protect against retinopathy. We found that over-expression of Sirt1 in Nestin expressing retinal neurons does not impact vaso-obliteration or pathologic neovascularization in OIR, nor does it influence neuronal degeneration in OIR. Similarly, increased expression of Sirt1 in Tie2 expressing vascular endothelial cells and monocytes/macrophages does not protect retinal vessels in OIR. In addition to the genetic approaches, dietary supplement with Sirt1 activators, resveratrol or SRT1720, were fed to wild type mice with OIR. Neither treatment showed significant vaso-protective effects in retinopathy. Together these results indicate that although endogenous Sirt1 is important as a stress-induced protector in retinopathy, over-expression of Sirt1 or treatment with small molecule activators at the examined doses do not provide additional protection against retinopathy in mice. Further studies are needed to examine in depth whether increasing levels of Sirt1 may serve as a potential therapeutic approach to treat or prevent retinopathy.

  16. Subsurface femtosecond tissue alteration: selectively photobleaching macular degeneration pigments in near retinal contact.

    Science.gov (United States)

    Manevitch, Zakhariya; Lewis, Aaron; Levy, Carol; Zeira, Evelyne; Banin, Eyal; Manevitch, Alexandra; Khatchatouriants, Artium; Pe'er, Jacob; Galun, Eithan; Hemo, Itzhak

    2012-06-14

    This paper uses advances in the ultrafast manipulation of light to address a general need in medicine for a clinical approach that can provide a solution to a variety of disorders requiring subsurface tissue manipulation with ultralow collateral damage. Examples are age-related macular degeneration (AMD), fungal infections, tumors surrounded by overlying tissue, cataracts, etc. Although lasers have revolutionized the use of light in clinical settings, most lasers employed in medicine cannot address such problems of depth-selective tissue manipulation. This arises from the fact that they are mostly based on one photon based laser tissue interactions that provide a cone of excitation where the energy density is sufficiently high to excite heat or fluorescence in the entire cone. Thus, it is difficult to excite a specific depth of a tissue without affecting the overlying surface. However, the advent of femtosecond (fs) lasers has caused a revolution in multiphoton microscopy (Zipfel et al. Nat. Biotechnol. 2003, 21, 1369-1377; Denk et al. Science 1990, 248, 73-76) and fabrication (Kawata et al. Nature 2001, 412, 697-698). With such lasers, the photon energy density is only high enough for multiphoton processes in the focal volume, and this opens a new direction to address subsurface tissue manipulation. Here we show in an AMD animal model, Ccr2 KO knockout mutant mice, noninvasive, selective fs two-photon photobleaching of pigments associated with AMD that accumulate under and in ultraclose proximity to the overlying retina. Pathological evidence is presented that indicates the lack of collateral damage to the overlying retina or other surrounding tissue.

  17. 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

  18. 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.

  19. 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.

  20. Progressive retinal degeneration in a girl with Knobloch syndrome who presented with signs of ocular albinism.

    Science.gov (United States)

    Gradstein, Libe; Hansen, Ronald M; Cox, Gerald F; Altschwager, Pablo; Fulton, Anne B

    2017-04-01

    We report for the first time electroretinographic (ERG) evidence of progressive retinal abnormalities in a girl who presented in infancy with ocular features of albinism and gradually developed choroidal sclerosis and patchy retinal atrophy leading to a diagnosis of Knobloch syndrome (KS, OMIM 267750, COL18A1). At age 2 months, nystagmus and esotropia prompted ophthalmic evaluation. The appearance of choroidal sclerosis and atrophic retinal patches led to further evaluation at age 8 years. Genetics consultation was obtained in infancy and again at age 8 years as retinal findings evolved. Full field ERG responses in both scotopic and photopic conditions were recorded at both ages and compared to those in healthy control subjects. At age 2 months ERG response parameters were within normal limits for age and tyrosinase (TYR) gene sequencing revealed one novel mutation, p.S466F, and the temperature-sensitive polymorphism, p.R402Q, suggesting the diagnosis of oculocutaneous albinism type 1 (OCA1). At age 8 years, there was significant attenuation of both scotopic and photopic ERG responses. Genetic re-analysis led to the identification of a homozygous mutation, c.3213dupC, in the COL18A1 gene, thus confirming the diagnosis of Knobloch syndrome. Our patient with Knobloch syndrome developed abnormal ERG responses similar to those found in col18a1 knockout mice. Thus, we have documented progressive attenuation of the scotopic and photopic responses in KS.

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

    Science.gov (United States)

    Fernández-Sánchez, Laura; Lax, Pedro; Noailles, Agustina; Angulo, Antonia; Maneu, Victoria; Cuenca, Nicolás

    2015-07-31

    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.

  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. 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.

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

    Science.gov (United States)

    Leow, S N; Luu, Chi D; Hairul Nizam, M H; Mok, P L; Ruhaslizan, R; Wong, H S; Wan Abdul Halim, Wan Haslina; Ng, M H; Ruszymah, B H I; Chowdhury, S R; Bastion, M L C; Then, K Y

    2015-01-01

    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.

  5. Using CRISPR-Cas9 to Generate Gene-Corrected Autologous iPSCs for the Treatment of Inherited Retinal Degeneration.

    Science.gov (United States)

    Burnight, Erin R; Gupta, Manav; Wiley, Luke A; Anfinson, Kristin R; Tran, Audrey; Triboulet, Robinson; Hoffmann, Jeremy M; Klaahsen, Darcey L; Andorf, Jeaneen L; Jiao, Chunhua; Sohn, Elliott H; Adur, Malavika K; Ross, Jason W; Mullins, Robert F; Daley, George Q; Schlaeger, Thorsten M; Stone, Edwin M; Tucker, Budd A

    2017-09-06

    Patient-derived induced pluripotent stem cells (iPSCs) hold great promise for autologous cell replacement. However, for many inherited diseases, treatment will likely require genetic repair pre-transplantation. Genome editing technologies are useful for this application. The purpose of this study was to develop CRISPR-Cas9-mediated genome editing strategies to target and correct the three most common types of disease-causing variants in patient-derived iPSCs: (1) exonic, (2) deep intronic, and (3) dominant gain of function. We developed a homology-directed repair strategy targeting a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) and demonstrated restoration of the retinal transcript and protein in patient cells. We generated a CRISPR-Cas9-mediated non-homologous end joining (NHEJ) approach to excise a major contributor to Leber congenital amaurosis, the IVS26 cryptic-splice mutation in CEP290, and demonstrated correction of the transcript and protein in patient iPSCs. Lastly, we designed allele-specific CRISPR guides that selectively target the mutant Pro23His rhodopsin (RHO) allele, which, following delivery to both patient iPSCs in vitro and pig retina in vivo, created a frameshift and premature stop that would prevent transcription of the disease-causing variant. The strategies developed in this study will prove useful for correcting a wide range of genetic variants in genes that cause inherited retinal degeneration. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  6. Missed retinal breaks in rhegmatogenous retinal detachment

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    Brijesh Takkar

    2016-12-01

    Full Text Available AIM: To evaluate the causes and associations of missed retinal breaks (MRBs and posterior vitreous detachment (PVD in patients with rhegmatogenous retinal detachment (RRD. METHODS: Case sheets of patients undergoing vitreo retinal surgery for RRD at a tertiary eye care centre were evaluated retrospectively. Out of the 378 records screened, 253 were included for analysis of MRBs and 191 patients were included for analysis of PVD, depending on the inclusion criteria. Features of RRD and retinal breaks noted on examination were compared to the status of MRBs and PVD detected during surgery for possible associations. RESULTS: Overall, 27% patients had MRBs. Retinal holes were commonly missed in patients with lattice degeneration while missed retinal tears were associated with presence of complete PVD. Patients operated for cataract surgery were significantly associated with MRBs (P=0.033 with the odds of missing a retinal break being 1.91 as compared to patients with natural lens. Advanced proliferative vitreo retinopathy (PVR and retinal bullae were the most common reasons for missing a retinal break during examination. PVD was present in 52% of the cases and was wrongly assessed in 16%. Retinal bullae, pseudophakia/aphakia, myopia, and horse shoe retinal tears were strongly associated with presence of PVD. Traumatic RRDs were rarely associated with PVD. CONCLUSION: Pseudophakic patients, and patients with retinal bullae or advanced PVR should be carefully screened for MRBs. Though Weiss ring is a good indicator of PVD, it may still be over diagnosed in some cases. PVD is associated with retinal bullae and pseudophakia, and inversely with traumatic RRD.

  7. Hydrostatic pressure does not cause detectable changes in survival of human retinal ganglion cells.

    Directory of Open Access Journals (Sweden)

    Andrew Osborne

    Full Text Available Elevated intraocular pressure (IOP is a major risk factor for glaucoma. One consequence of raised IOP is that ocular tissues are subjected to increased hydrostatic pressure (HP. The effect of raised HP on stress pathway signaling and retinal ganglion cell (RGC survival in the human retina was investigated.A chamber was designed to expose cells to increased HP (constant and fluctuating. Accurate pressure control (10-100 mmHg was achieved using mass flow controllers. Human organotypic retinal cultures (HORCs from donor eyes (<24 h post mortem were cultured in serum-free DMEM/HamF12. Increased HP was compared to simulated ischemia (oxygen glucose deprivation, OGD. Cell death and apoptosis were measured by LDH and TUNEL assays, RGC marker expression by qRT-PCR (THY-1 and RGC number by immunohistochemistry (NeuN. Activated p38 and JNK were detected by Western blot.Exposure of HORCs to constant (60 mmHg or fluctuating (10-100 mmHg; 1 cycle/min pressure for 24 or 48 h caused no loss of structural integrity, LDH release, decrease in RGC marker expression (THY-1 or loss of RGCs compared with controls. In addition, there was no increase in TUNEL-positive NeuN-labelled cells at either time-point indicating no increase in apoptosis of RGCs. OGD increased apoptosis, reduced RGC marker expression and RGC number and caused elevated LDH release at 24 h. p38 and JNK phosphorylation remained unchanged in HORCs exposed to fluctuating pressure (10-100 mmHg; 1 cycle/min for 15, 30, 60 and 90 min durations, whereas OGD (3 h increased activation of p38 and JNK, remaining elevated for 90 min post-OGD.Directly applied HP had no detectable impact on RGC survival and stress-signalling in HORCs. Simulated ischemia, however, activated stress pathways and caused RGC death. These results show that direct HP does not cause degeneration of RGCs in the ex vivo human retina.

  8. 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.

  9. Apigenin-7-diglucuronide protects retinas against bright light-induced photoreceptor degeneration through the inhibition of retinal oxidative stress and inflammation.

    Science.gov (United States)

    Bian, Minjuan; Zhang, Yong; Du, Xiaoye; Xu, Jing; Cui, Jingang; Gu, Jiangping; Zhu, Weiliang; Zhang, Teng; Chen, Yu

    2017-05-15

    Vision impairment in retinal degenerative diseases such as age-related macular degeneration is primarily associated with photoreceptor degeneration, in which oxidative stress and inflammatory responses are mechanistically involved as central players. Therapies with photoreceptor protective properties remain to be developed. Apigenin-7-diglucuronide (A7DG), a flavonoid glycoside, is present in an assortment of medicinal plants with anti-inflammatory or ant-oxidant activities. However, the pharmacological significance of A7DG remains unknown in vivo. The current study isolated A7DG from Glechoma longituba (Nakai) Kuprian and investigated the retinal protective effect A7DG in mice characterized by bright light-induced photoreceptor degeneration. The results showed that A7DG treatment led to remarkable photoreceptor protection in bright light-exposed BALB/c mice. Moreover, A7DG treatment alleviated photoreceptor apoptosis, mitigated oxidative stress, suppressed reactive gliosis and microglial activation and attenuated the expression of proinflammatory genes in bright light-exposed retinas. The results demonstrated for the first time remarkable photoreceptor protective activities of A7DG in vivo. Inhibition of bright light-induced retinal oxidative stress and retinal inflammatory responses was associated with the retinal protection conferred by A7DG. The work here warrants further evaluation of A7DG as a pharmacological candidate for the treatment of vision-threatening retinal degenerative disorders. Moreover, given the general implication of oxidative stress and inflammation in the pathogenesis of neurodegeneration, A7DG could be further tested for the treatment of other neurodegenerative disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. A Homozygous Frameshift Mutation in LRAT Causes Retinitis Punctata Albescens

    NARCIS (Netherlands)

    Littink, Karin W.; van Genderen, Maria M.; van Schooneveld, Mary J.; Visser, Linda; Riemslag, Frans C. C.; Keunen, Jan E. E.; Bakker, Bjorn; Zonneveld, Marijke N.; den Hollander, Anneke I.; Cremers, Frans P. M.; van den Born, L. Ingeborgh

    2012-01-01

    Purpose: To determine the genetic defect and to describe the clinical characteristics in patients with retinitis punctata albescens (RPA) and fundus albipunctatus (FAP). Design: Case series/observational study. Participants: We included 13 patients affected by RPA or FAP. Methods: Thirteen patients

  11. A Homozygous Frameshift Mutation in LRAT Causes Retinitis Punctata Albescens.

    NARCIS (Netherlands)

    Littink, K.W.; Genderen, M.M. van; Schooneveld, M.J. van; Visser, L.; Riemslag, F.C.; Keunen, J.E.E.; Bakker, B.; Zonneveld, M.N.; Hollander, A.I. den; Cremers, F.P.M.; Born, L.I. van den

    2012-01-01

    PURPOSE: To determine the genetic defect and to describe the clinical characteristics in patients with retinitis punctata albescens (RPA) and fundus albipunctatus (FAP). DESIGN: Case series/observational study. PARTICIPANTS: We included 13 patients affected by RPA or FAP. METHODS: Thirteen patients

  12. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy.

    Science.gov (United States)

    Alavi, Marcel V; Mao, Mao; Pawlikowski, Bradley T; Kvezereli, Manana; Duncan, Jacque L; Libby, Richard T; John, Simon W M; Gould, Douglas B

    2016-01-27

    Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of basement membranes, cause multisystem disorders in humans and mice. In the eye, these include anterior segment dysgenesis, optic nerve hypoplasia and retinal vascular tortuosity. Here we investigate the retinal pathology in mice carrying dominant-negative Col4a1 mutations. To this end, we examined retinas longitudinally in vivo using fluorescein angiography, funduscopy and optical coherence tomography. We assessed retinal function by electroretinography and studied the retinal ultrastructural pathology. Retinal examinations revealed serous chorioretinopathy, retinal hemorrhages, fibrosis or signs of pathogenic angiogenesis with chorioretinal anastomosis in up to approximately 90% of Col4a1 mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional Col4a1 mutation and determined that primary vascular defects underlie Col4a1-associated retinopathy. We also found focal activation of Müller cells and increased expression of pro-angiogenic factors in retinas from Col4a1(+/Δex41)mice. Together, our findings suggest that patients with COL4A1 and COL4A2 mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with COL4A1 and COL4A2 mutations who are also at elevated risk of hemorrhagic strokes.

  13. Automated Segmentation Methods of Drusen to Diagnose Age-Related Macular Degeneration Screening in Retinal Images

    OpenAIRE

    Kim, Young Jae; Kim, Kwang Gi

    2018-01-01

    Existing drusen measurement is difficult to use in clinic because it requires a lot of time and effort for visual inspection. In order to resolve this problem, we propose an automatic drusen detection method to help clinical diagnosis of age-related macular degeneration. First, we changed the fundus image to a green channel and extracted the ROI of the macular area based on the optic disk. Next, we detected the candidate group using the difference image of the median filter within the ROI. We...

  14. Circulating anti-retinal antibodies in response to anti-angiogenic therapy in exudative age-related macular degeneration.

    Science.gov (United States)

    Kubicka-Trząska, Agnieszka; Wilańska, Joanna; Romanowska-Dixon, Bożena; Sanak, Marek

    2014-12-01

    To determine changes in anti-retinal antibodies (ARAs) during anti-VEGF therapy in patients with exudative age-related macular degeneration (AMD) and to assess the correlations between ARAs and disease activity. The study comprised 98 patients treated with intravitreal bevacizumab. The ophthalmic examination included best corrected visual acuity (BCVA), slit lamp biomicroscopy, fundoscopy, fluorescein angiography (FA), and optical coherence tomography (OCT). Serum ARAs levels were assessed by indirect immunofluorescence (IIF) on normal monkey retina substrate. These studies were repeated at 4 week intervals within 8 months of a follow-up. The sera of 50 sex- and age-matched healthy subjects were used as controls. At baseline examination, 94 (95.5%) of the 98 patients were positive for ARAs. The ARAs titres were significantly higher (p = 0.0000) than in controls. A positive correlation was found between titres of ARAs and the diameter of choroidal neovascularization (CNV) as measured by FA (p = 0.0000), and central retinal thickness (CRT) assessed by OCT (p = 0.0000). A positive correlation was also found between the diameter of CNV, CRT and the complexity of circulating ARAs. Following treatment all patients demonstrated significant decrease in ARAs levels as well as improvement of BCVA, reduction of subretinal fluid on OCT and decreased leakage on FA. Changes in serum ARAs levels occurred in parallel with clinical outcomes of anti-VEGF therapy. Treatment reduced serum levels of ARAs, with the greatest reduction occurring during the 'loading' phase. This study demonstrated that ARAs may act as a serum biomarker of the efficacy of anti-VEGF therapy. © 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  15. Age-Related Macular Degeneration.

    Science.gov (United States)

    Mehta, Sonia

    2015-09-01

    Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. AMD is diagnosed based on characteristic retinal findings in individuals older than 50. Early detection and treatment are critical in increasing the likelihood of retaining good and functional vision. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. The synthetic progestin norgestrel modulates Nrf2 signaling and acts as an antioxidant in a model of retinal degeneration

    Directory of Open Access Journals (Sweden)

    Ashleigh M. Byrne

    2016-12-01

    Full Text Available Retinitis pigmentosa (RP is one of the most common retinal degenerative conditions affecting people worldwide, and is currently incurable. It is characterized by the progressive loss of photoreceptors, in which the death of rod cells leads to the secondary death of cone cells; the cause of eventual blindness. As rod cells die, retinal-oxygen metabolism becomes perturbed, leading to increased levels of reactive oxygen species (ROS and thus oxidative stress; a key factor in the secondary death of cones. In this study, norgestrel, an FDA-approved synthetic analog of progesterone, was found to be a powerful neuroprotective antioxidant, preventing light-induced ROS in photoreceptor cells, and subsequent cell death. Norgestrel also prevented light-induced photoreceptor morphological changes that were associated with ROS production, and that are characteristic of RP. Further investigation showed that norgestrel acts via post-translational modulation of the major antioxidant transcription factor Nrf2; bringing about its phosphorylation, subsequent nuclear translocation, and increased levels of its effector protein superoxide dismutase 2 (SOD2. In summary, these results demonstrate significant protection of photoreceptor cells from oxidative stress, and underscore the potential of norgestrel as a therapeutic option for RP.

  17. Branch Retinal Artery Occlusion Caused by Toxoplasmosis in an Adolescent

    Directory of Open Access Journals (Sweden)

    Elizabeth Chiang

    2012-10-01

    Full Text Available Purpose: Branch retinal artery occlusion (BRAO, while not uncommon in elderly patient populations, is rare in children and adolescents. We report a case of a BRAO secondary to toxoplasmosis in this demographic. Case: A previously healthy 17-year-old male developed a unilateral BRAO in conjunction with inflammation and increased intraocular pressure. Family history was positive for cerebrovascular accidents in multiple family members at relatively young ages. The patient had a hypercoagulable workup as well as a cardiovascular workup which were both normal. A rheumatologic workup was unremarkable. By 3 weeks, a patch of retinitis was more easily distinguished from the BRAO and the diagnosis of ocular toxoplasmosis was made. Treatment was started with prednisone and azithromycin with subsequent improvement in vision. Toxoplasma antibody levels were elevated for IgG and negative for IgM, IgA, and IgE. The etiology of the BRAO was attributed to ocular toxoplasmosis. Conclusions: Vascular occlusions are rare in toxoplasmosis. This is the third case report of a BRAO in a patient in the pediatric population. The diagnosis of ocular toxoplasmosis should be considered in young patients with retinal artery occlusions associated with inflammation.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. 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

    2017-01-05

    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, p75 NTR , 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 p75 NTR enhancement. In contrast, ONC-induced reduction of TrkA, and increased proNGF were observed only at 7 and 14 dac. We propose that proNGF and p75 NTR 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.

  1. 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

    2018-01-01

    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 treatment. This information could be clinically helpful to evaluate early non-response. © 2017 S. Karger AG, Basel.

  2. Glucocorticoid-Induced Leucine Zipper Protects the Retina From Light-Induced Retinal Degeneration by Inducing Bcl-xL in Rats.

    Science.gov (United States)

    Gu, Ruiping; Tang, Wenyi; Lei, Boya; Ding, Xinyi; Jiang, Cheng; Xu, Gezhi

    2017-07-01

    The aim of the present study was to investigate the neuroprotective effects of glucocorticoid-induced leucine zipper (GILZ) in a light-induced retinal degeneration model and to explore the underlying mechanisms. Intravitreal injection of recombinant GILZ-overexpressing lentivirus (OE-GILZ-rLV) and short hairpin RNA targeting GILZ recombinant lentivirus (shRNA-GILZ-rLV) was performed to up- and downregulate retinal GILZ, respectively. Three days after stable transduction, rats were exposed to continuous bright light (5000 lux) for 2 days. Retinal function was assessed by full-field electroretinography (ERG), and the retinal structure was examined for photoreceptor survival and death in rats kept under a 12-hour light:2-hour dark cycle following light exposure. The expression levels of retinal Bcl-xL, caspase-9, and caspase-3 were examined by Western blotting or real-time PCR at 1, 3, 5, and 7 days after light exposure. Exposure to bright light downregulated retinal GILZ in parallel with the downregulation of Bcl-xL and the upregulation of active caspase-3. Overexpression of retinal GILZ attenuated the decrease of Bcl-xL and the activation of caspase-9 and caspase-3 at 1, 3, 5, and 7 days after bright light exposure, respectively. GILZ silencing aggravated the downregulation of Bcl-xL induced by bright light exposure. Bright light exposure reduced the amplitude of ERG, increased the number of apoptotic photoreceptor cells, and decreased retinal thickness; and GILZ overexpression could attenuate all these effects. Overexpression of GILZ by OE-GILZ-rLV transduction protected the retina from light-induced cellular damage by activating antiapoptotic pathways.

  3. 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.

  4. Differentiation and Transplantation of Embryonic Stem Cell-Derived Cone Photoreceptors into a Mouse Model of End-Stage Retinal Degeneration

    Directory of Open Access Journals (Sweden)

    Kamil Kruczek

    2017-06-01

    Full Text Available The loss of cone photoreceptors that mediate daylight vision represents a leading cause of blindness, for which cell replacement by transplantation offers a promising treatment strategy. Here, we characterize cone differentiation in retinas derived from mouse embryonic stem cells (mESCs. Similar to in vivo development, a temporal pattern of progenitor marker expression is followed by the differentiation of early thyroid hormone receptor β2-positive precursors and, subsequently, photoreceptors exhibiting cone-specific phototransduction-related proteins. We establish that stage-specific inhibition of the Notch pathway increases cone cell differentiation, while retinoic acid signaling regulates cone maturation, comparable with their actions in vivo. MESC-derived cones can be isolated in large numbers and transplanted into adult mouse eyes, showing capacity to survive and mature in the subretinal space of Aipl1−/− mice, a model of end-stage retinal degeneration. Together, this work identifies a robust, renewable cell source for cone replacement by purified cell suspension transplantation.

  5. HYPERSPECTRAL AUTOFLUORESCENCE IMAGING OF DRUSEN AND RETINAL PIGMENT EPITHELIUM IN DONOR EYES WITH AGE-RELATED MACULAR DEGENERATION.

    Science.gov (United States)

    Tong, Yuehong; Ben Ami, Tal; Hong, Sungmin; Heintzmann, Rainer; Gerig, Guido; Ablonczy, Zsolt; Curcio, Christine A; Ach, Thomas; Smith, R Theodore

    2016-12-01

    To elucidate the molecular pathogenesis of age-related macular degeneration (AMD) and interpretation of fundus autofluorescence imaging, the authors identified spectral autofluorescence characteristics of drusen and retinal pigment epithelium (RPE) in donor eyes with AMD. Macular RPE/Bruch membrane flat mounts were prepared from 5 donor eyes with AMD. In 12 locations (1-3 per eye), hyperspectral autofluorescence images in 10-nm-wavelength steps were acquired at 2 excitation wavelengths (λex 436, 480 nm). A nonnegative tensor factorization algorithm was used to recover 5 abundant emission spectra and their corresponding spatial localizations. At λex 436 nm, the authors consistently localized a novel spectrum (SDr) with a peak emission near 510 nm in drusen and sub-RPE deposits. Abundant emission spectra seen previously (S0 in Bruch membrane and S1, S2, and S3 in RPE lipofuscin/melanolipofuscin, respectively) also appeared in AMD eyes, with the same shapes and peak wavelengths as in normal tissue. Lipofuscin/melanolipofuscin spectra localizations in AMD eyes varied widely in their overlap with drusen, ranging from none to complete. An emission spectrum peaking at ∼510 nm (λex 436 nm) appears to be sensitive and specific for drusen and sub-RPE deposits. One or more abundant spectra from RPE organelles exhibit characteristic relationships with drusen.

  6. Progranulin deficiency causes the retinal ganglion cell loss during development.

    Science.gov (United States)

    Kuse, Yoshiki; Tsuruma, Kazuhiro; Mizoguchi, Takahiro; Shimazawa, Masamitsu; Hara, Hideaki

    2017-05-10

    Astrocytes are glial cells that support and protect neurons in the central nervous systems including the retina. Retinal ganglion cells (RGCs) are in contact with the astrocytes and our earlier findings showed the reduction of the number of cells in the ganglion cell layer in adult progranulin deficient mice. In the present study, we focused on the time of activation of the astrocytes and the alterations in the number of RGCs in the retina and optic nerve in progranulin deficient mice. Our findings showed that the number of Brn3a-positive cells was reduced and the expression of glial fibrillary acidic protein (GFAP) was increased in progranulin deficient mice. The progranulin deficient mice had a high expression of GFAP on postnatal day 9 (P9) but not on postnatal day 1. These mice also had a decrease in the number of the Brn3a-positive cells on P9. Taken together, these findings indicate that the absence of progranulin can affect the survival of RGCs subsequent the activation of astrocytes during retinal development.

  7. Automated Segmentation Methods of Drusen to Diagnose Age-Related Macular Degeneration Screening in Retinal Images

    Directory of Open Access Journals (Sweden)

    Young Jae Kim

    2018-01-01

    Full Text Available Existing drusen measurement is difficult to use in clinic because it requires a lot of time and effort for visual inspection. In order to resolve this problem, we propose an automatic drusen detection method to help clinical diagnosis of age-related macular degeneration. First, we changed the fundus image to a green channel and extracted the ROI of the macular area based on the optic disk. Next, we detected the candidate group using the difference image of the median filter within the ROI. We also segmented vessels and removed them from the image. Finally, we detected the drusen through Renyi’s entropy threshold algorithm. We performed comparisons and statistical analysis between the manual detection results and automatic detection results for 30 cases in order to verify validity. As a result, the average sensitivity was 93.37% (80.95%~100% and the average DSC was 0.73 (0.3~0.98. In addition, the value of the ICC was 0.984 (CI: 0.967~0.993, p<0.01, showing the high reliability of the proposed automatic method. We expect that the automatic drusen detection helps clinicians to improve the diagnostic performance in the detection of drusen on fundus image.

  8. 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.

  9. Human Umbilical Cord Mesenchymal Stem Cells: Subpopulations and Their Difference in Cell Biology and Effects on Retinal Degeneration in RCS Rats.

    Science.gov (United States)

    Wang, L; Li, P; Tian, Y; Li, Z; Lian, C; Ou, Q; Jin, C; Gao, F; Xu, J-Y; Wang, J; Wang, F; Zhang, J; Zhang, J; Li, W; Tian, H; Lu, L; Xu, G-T

    2017-01-01

    Human umbilical cord mesenchymal stem cells (hUC-MSCs) are potential candidates for treating retinal degeneration (RD). To further study the biology and therapeutic effects of the hUC-MSCs on retinal degeneration. Two hUC-MSC subpopulations, termed hUC-MSC1 and hUC-MSC2, were isolated by single-cell cloning method and their therapeutic functions were compared in RCS rat, a RD model. Although both subsets satisfied the basic requirements for hUC-MSCs, they were significantly different in morphology, proliferation rate, differentiation capacity, phenotype and gene expression. Furthermore, only the smaller, fibroblast-like, faster growing subset hUC-MSC1 displayed stronger colony forming potential as well as adipogenic and osteogenic differentiation capacities. When the two subsets were respectively transplanted into the subretinal spaces of RCS rats, both subsets survived, but only hUC-MSC1 expressed RPE cell markers Bestrophin and RPE65. More importantly, hUC-MSC1 showed stronger rescue effect on the retinal function as indicated by the higher b-wave amplitude on ERG examination, thicker retinal nuclear layer, and decreased apoptotic photoreceptors. When both subsets were treated with interleukin-6, mimicking the inflammatory environment when the cells were transplanted into the eyes with degenerated retina, hUC-MSC1 expressed much higher levels of trophic factors in comparison with hUC-MSC2. The data here, in addition to prove the heterogeneity of hUC-MSCs, confirmed that the stronger therapeutic effects of hUC-MSC1 were attributed to its stronger anti-apoptotic effect, paracrine of trophic factors and potential RPE cell differentiation capacity. Thus, the subset hUC-MSC1, not the other subset or the ungrouped hUC-MSCs should be used for effective treatment of RD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Occlusion of retinal capillaries caused by glial cell proliferation in chronic ocular inflammation.

    Science.gov (United States)

    Bianchi, E; Ripandelli, G; Feher, J; Plateroti, A M; Plateroti, R; Kovacs, I; Plateroti, P; Taurone, S; Artico, M

    2015-01-01

    The inner blood-retinal barrier is a gliovascular unit in which glial cells surround capillary endothelial cells and regulate retinal capillaries by paracrine interactions. During chronic ocular inflammation, microvascular complications can give rise to vascular proliferative lesions, which compromise visual acuity. This pathologic remodelling caused by proliferating Müller cells determines occlusion of retinal capillaries. The aim of the present study was to identify qualitative and quantitative alterations in the retinal capillaries in patients with post-traumatic chronic ocular inflammation or post-thrombotic vascular glaucoma. Moreover, we investigated the potential role of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines in retinal inflammation. Our electron microscopy findings demonstrated that during chronic ocular inflammation, thickening of the basement membrane, loss of pericytes and endothelial cells and proliferation of Müller cells occur with irreversible occlusion of retinal capillaries. Angiogenesis takes place as part of a regenerative reaction that results in fibrosis. We believe that VEGF and pro-inflammatory cytokines may be potential therapeutic targets in the treatment of this disease although further studies are required to confirm these findings.

  11. Clinical Features of Pregnancy-associated Retinal and Choroidal Diseases Causing Acute Visual Disturbance.

    Science.gov (United States)

    Park, Young Joo; Park, Kyu Hyung; Woo, Se Joon

    2017-08-01

    To report clinical features of patients with retinal and choroidal diseases presenting with acute visual disturbance during pregnancy. In this retrospective case series, patients who developed acute visual loss during pregnancy (including puerperium) and visited a tertiary hospital from July 2007 to June 2015, were recruited by searching electronic medical records. Patients were categorized according to the cause of visual loss. Clinical features and required diagnostic modalities were analyzed in the retinal and choroidal disease group. Acute visual loss occurred in 147 patients; 49 (38.9%) were classified into the retinal and choroidal group. The diagnoses included central serous chorioretinopathy (22.4%), hypertensive retinopathy with or without pre-eclampsia (22.4%), retinal tear with or without retinal detachment (18.4%), diabetic retinopathy progression (10.2%), Vogt-Koyanagi-Harada disease (4.1%), retinal artery occlusion (4.1%), multiple evanescent white dot syndrome (4.1%), and others (14.3%). Visual symptoms first appeared at gestational age 25.9 ± 10.3 weeks. The initial best-corrected visual acuity (BCVA) was 0.27 ± 0.39 logarithm of the minimum angle of resolution (logMAR); the final BCVA after delivery improved to 0.13 ± 0.35 logMAR. Serious visual deterioration (BCVA worth than 20 / 200) developed in two patients. Differential diagnoses were established with characteristic fundus and spectral-domain optical coherence tomography findings in all cases. In pregnant women with acute visual loss, retinal and choroidal diseases are common and could be vision threatening. Physicians should be aware of pregnancy-associated retinal and choroidal diseases and their clinical features. The differential diagnosis can be established with non-invasive techniques. © 2017 The Korean Ophthalmological Society

  12. Activated Retinal Pigment Epithelium, an Optical Coherence Tomography Biomarker for Progression in Age-Related Macular Degeneration

    Science.gov (United States)

    Curcio, Christine A.; Zanzottera, Emma C.; Ach, Thomas; Balaratnasingam, Chandrakumar; Freund, K. Bailey

    2017-01-01

    Purpose To summarize and contextualize recent histology and clinical imaging publications on retinal pigment epithelium (RPE) fate in advanced age-related macular degeneration (AMD); to support RPE activation and migration as important precursors to atrophy, manifest as intraretinal hyperreflective foci in spectral-domain optical coherence tomography (SDOCT). Methods The Project MACULA online resource for AMD histopathology was surveyed systematically to form a catalog of 15 phenotypes of RPE and RPE-derived cells and layer thicknesses in advanced disease. Phenotypes were also sought in correlations with clinical longitudinal eye-tracked SDOCT and with ex vivo imaging–histopathology correlations in geographic atrophy (GA) and pigment epithelium detachments (PED). Results The morphology catalog suggested two main pathways of RPE fate: basolateral shedding of intracellular organelles (apparent apoptosis in situ) and activation with anterior migration. Acquired vitelliform lesions may represent a third pathway. Migrated cells are packed with RPE organelles and confirmed as hyperreflective on SDOCT. RPE layer thickening due to cellular dysmorphia and thick basal laminar deposit is observed near the border of GA. Drusenoid PED show a life cycle of slow growth and rapid collapse preceded by RPE layer disruption and anterior migration. Conclusions RPE activation and migration comprise an important precursor to atrophy that can be observed at the cellular level in vivo via validated SDOCT. Collapse of large drusen and drusenoid PED appears to occur when RPE death and migration prevent continued production of druse components. Data implicate excessive diffusion distance from choriocapillaris in RPE death as well as support a potential benefit in targeting drusen in GA. PMID:28785769

  13. Macular ganglion cell complex and retinal nerve fiber layer comparison in different stages of age-related macular degeneration.

    Science.gov (United States)

    Zucchiatti, Ilaria; Parodi, Maurizio Battaglia; Pierro, Luisa; Cicinelli, Maria Vittoria; Gagliardi, Marco; Castellino, Niccolò; Bandello, Francesco

    2015-09-01

    To employ optical coherence tomography (OCT) to analyze the morphologic changes in the inner retina in different categories of age-related macular degeneration (AMD). Observational cross-sectional study. Single-center study. Inclusion criteria were age over 50, diagnosis of Age-Related Eye Disease Study (AREDS) category 2 and 3, naïve neovascular AMD, and atrophic AMD. Healthy patients of similar age acted as a control group. Primary outcome measures were the changes in ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL). Secondary outcomes included modifications of rim area and cup-to-disc ratio. One hundred and thirty eyes of 130 patients were recruited: 26 eyes for AREDS category 2, 26 for AREDS category 3, 26 for neovascular AMD, 26 with atrophic AMD, and 26 controls. Mean peripapillary RNFL thickness was significantly lower in neovascular AMD, compared to controls (P = .004); peripapillary RNFL did not significantly vary among AREDS category 2 and 3 and atrophic AMD groups, compared to controls. Mean GCC thickness was higher in the control group, becoming progressively thinner up to neovascular and atrophic AMD groups (P < .0001). Rim area was significantly thinner in the neovascular AMD group compared with controls (P = .047); cup-to-disc ratio was higher in the neovascular AMD group compared with the control group (P = .047). This study demonstrates that eyes with neovascular AMD display reduced RNFL and GCC thickness. RNFL is partially spared in atrophic advanced AMD. The identification of alteration in RNFL and GCC thickness may reveal useful for future therapeutic implications. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Peripapillary Retinal Nerve Fiber Measurement with Spectral-Domain Optical Coherence Tomography in Age-Related Macular Degeneration

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    Simon K. Law

    2017-12-01

    Full Text Available Purpose: To evaluate the relationship between the peripapillary retinal nerve fiber layer (RNFL measurements with Spectral-domain Optical Coherence Tomography (OCT and Age-related macular degeneration (AMD. Methods: Patients >60 years of age without glaucoma or record of intraocular pressure >21 mmHg and no systemic or intraocular diseases or treatment or surgical intervention that affected the RNFL underwent OCT measurement of the RNFL. The severity of AMD was staged with the Clinical Age-Related Maculopathy Staging System. The relationship between RNFL measurements and AMD stages of one eye per patient was analyzed. Results: Eighty-six eyes (46 patients with AMD and no glaucoma or other exclusion criteria received OCT RNFL measurements. Nine eyes (10.5% were excluded because of distorted peripapillary anatomy from exudative AMD (7 eyes or failure of the RNFL segmentation algorithm (2 eyes. Mean age ± S.D. of the 43 patients analyzed was 81.2 ± 7.3 years. The mean stage ± S.D. of AMD of the 77 eyes was 3.77 ± 1.05. Higher stages of AMD were statistically significantly associated with lower average RNFL and inferior sector RNFL (p = 0.049, 0 0015, respectively. The association of inferior sector RNFL and AMD stage remained statistically significant after adjusting for age. Conclusions: Spectral domain OCT is generally useful in measuring the peripapillary RNFL in eyes with different stages of AMD. Higher stage of AMD is associated with thinner peripapillary RNFL, which may masquerade as early glaucomatous damage.

  15. Using Patient-Specific Induced Pluripotent Stem Cells and Wild-Type Mice to Develop a Gene Augmentation-Based Strategy to Treat CLN3-Associated Retinal Degeneration.

    Science.gov (United States)

    Wiley, Luke A; Burnight, Erin R; Drack, Arlene V; Banach, Bailey B; Ochoa, Dalyz; Cranston, Cathryn M; Madumba, Robert A; East, Jade S; Mullins, Robert F; Stone, Edwin M; Tucker, Budd A

    2016-10-01

    Juvenile neuronal ceroid lipofuscinosis (JNCL) is a childhood neurodegenerative disease with early-onset, severe central vision loss. Affected children develop seizures and CNS degeneration accompanied by severe motor and cognitive deficits. There is no cure for JNCL, and patients usually die during the second or third decade of life. In this study, independent lines of induced pluripotent stem cells (iPSCs) were generated from two patients with molecularly confirmed mutations in CLN3, the gene mutated in JNCL. Clinical-grade adeno-associated adenovirus serotype 2 (AAV2) carrying the full-length coding sequence of human CLN3 was generated in a U.S. Food and Drug Administration-registered cGMP facility. AAV2-CLN3 was efficacious in restoring full-length CLN3 transcript and protein in patient-specific fibroblasts and iPSC-derived retinal neurons. When injected into the subretinal space of wild-type mice, purified AAV2-CLN3 did not show any evidence of retinal toxicity. This study provides proof-of-principle for initiation of a clinical trial using AAV-mediated gene augmentation for the treatment of children with CLN3-associated retinal degeneration.

  16. Early Involvement of Immune/Inflammatory Response Genes in Retinal Degeneration in DBA/2J Mice

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    W. Fan

    2010-01-01

    Full Text Available Purpose The DBA/2J (D2 mouse carries mutations in two of its genes, Tyrp1 and Gpnmb. These alterations result in the development of an immune response in the iris, leading to iris atrophy and pigment dispersion. The development of elevated intraocular pressure (IOP in this model of glaucoma is considered to be a significant factor leading to the death of retinal ganglion cells (RGCs. Changes in gene expression in the retina have already been correlated with the appearance of elevated IOP in the D2 mouse. The purpose of the present study was to determine if any changes in gene expression occur prior to the development of IOP. Methods The IOP was measured monthly using a rebound tonometer in D2 and age-matched C57/BL6 (B6 mice (normal controls. D2 animals with normal IOP at 2 and 4 M were used. In addition, mice at the age of 6–7 M were included to look for any trends in gene expression that might develop during the progression of the disease. Separate RNA samples were prepared from each of three individual retinas for each age, and gene expression profiles were determined with the aid of mouse oligonucleotide arrays (Agilent. A subset of genes was examined with the aid of real-time PCR. Immunocytochemistry was used to visualize changes in the retina for some of the gene-products. Results Four hundred and thirteen oligonucleotide probes were differentially expressed in the retinas of 4 M versus 2 M old D2 mice. The most significantly up-regulated genes (181 were associated with immune responses including interferon signaling, the complement system and the antigen presentation pathway, whereas the down-regulated genes (232 were linked to pathways related to cell death and known neurological diseases/disorders. These particular changes were not revealed in the age-matched B6 mice. By 6 M, when IOP started to increase in many of the D2 mice, more robust changes of these same genes were observed. Changes in the levels of selected genes

  17. Early Involvement of Immune/Inflammatory Response Genes in Retinal Degeneration in DBA/2J Mice

    Directory of Open Access Journals (Sweden)

    W. Fan

    2010-03-01

    Full Text Available Purpose: The DBA/2J (D2 mouse carries mutations in two of its genes, Tyrp1 and Gpnmb. These alterations result in the development of an immune response in the iris, leading to iris atrophy and pigment dispersion. The development of elevated intraocular pressure (IOP in this model of glaucoma is considered to be a significant factor leading to the death of retinal ganglion cells (RGCs. Changes in gene expression in the retina have already been correlated with the appearance of elevated IOP in the D2 mouse. The purpose of the present study was to determine if any changes in gene expression occur prior to the development of IOP. Methods: The IOP was measured monthly using a rebound tonometer in D2 and age-matched C57/BL6 (B6 mice (normal controls. D2 animals with normal IOP at 2 and 4 M were used. In addition, mice at the age of 6–7 M were included to look for any trends in gene expression that might develop during the progression of the disease. Separate RNA samples were prepared from each of three individual retinas for each age, and gene expression profiles were determined with the aid of mouse oligonucleotide arrays (Agilent. A subset of genes was examined with the aid of real-time PCR. Immunocytochemistry was used to visualize changes in the retina for some of the gene-products. Results: Four hundred and thirteen oligonucleotide probes were differentially expressed in the retinas of 4 M versus 2 M old D2 mice. The most significantly up-regulated genes (181 were associated with immune responses including interferon signaling, the complement system and the antigen presentation pathway, whereas the down-regulated genes (232 were linked to pathways related to cell death and known neurological diseases/disorders. These particular changes were not revealed in the age-matched B6 mice. By 6 M, when IOP started to increase in many of the D2 mice, more robust changes of these same genes were observed. Changes in the levels of selected genes

  18. Altered bioenergetics and enhanced resistance to oxidative stress in human retinal pigment epithelial cells from donors with age-related macular degeneration

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    Deborah A. Ferrington

    2017-10-01

    Full Text Available Age-related macular degeneration (AMD is the leading cause of blindness among older adults. It has been suggested that mitochondrial defects in the retinal pigment epithelium (RPE underlies AMD pathology. To test this idea, we developed primary cultures of RPE to ask whether RPE from donors with AMD differ in their metabolic profile compared with healthy age-matched donors. Analysis of gene expression, protein content, and RPE function showed that these cultured cells replicated many of the cardinal features of RPE in vivo. Using the Seahorse Extracellular Flux Analyzer to measure bioenergetics, we observed RPE from donors with AMD exhibited reduced mitochondrial and glycolytic function compared with healthy donors. RPE from AMD donors were also more resistant to oxidative inactivation of these two energy-producing pathways and were less susceptible to oxidation-induced cell death compared with cells from healthy donors. Investigation of the potential mechanism responsible for differences in bioenergetics and resistance to oxidative stress showed RPE from AMD donors had increased PGC1α protein as well as differential expression of multiple genes in response to an oxidative challenge. Based on our data, we propose that cultured RPE from donors phenotyped for the presence or absence of AMD provides an excellent model system for studying “AMD in a dish”. Our results are consistent with the ideas that (i a bioenergetics crisis in the RPE contributes to AMD pathology, and (ii the diseased environment in vivo causes changes in the cellular profile that are retained in vitro.

  19. Retinal degeneration and ionizing radiation hypersensitivity in a mouse model for Cockayne syndrome

    NARCIS (Netherlands)

    Gorgels, Theo G. M. F.; van der Pluijm, Ingrid; Brandt, Renata M. C.; Garinis, George A.; van Steeg, Harry; van den Aardweg, Gerard; Jansen, Gerard H.; Ruijter, Jan M.; Bergen, Arthur A. B.; van Norren, Dirk; Hoeijmakers, Jan H. J.; van der Horst, Gijsbertus T. J.

    2007-01-01

    Mutations in the CSB gene cause Cockayne syndrome (CS), a DNA repair disorder characterized by UV sensitivity and severe physical and neurological impairment. CSB functions in the transcription-coupled repair subpathway of nucleotide excision repair. This function may explain the UV sensitivity but

  20. [Using exon combined target region capture sequencing chip to detect the disease-causing genes of retinitis pigmentosa].

    Science.gov (United States)

    Rong, Weining; Chen, Xuejuan; Li, Huiping; Liu, Yani; Sheng, Xunlun

    2014-06-01

    To detect the disease-causing genes of 10 retinitis pigmentosa pedigrees by using exon combined target region capture sequencing chip. Pedigree investigation study. From October 2010 to December 2013, 10 RP pedigrees were recruited for this study in Ningxia Eye Hospital. All the patients and family members received complete ophthalmic examinations. DNA was abstracted from patients, family members and controls. Using exon combined target region capture sequencing chip to screen the candidate disease-causing mutations. Polymerase chain reaction (PCR) and direct sequencing were used to confirm the disease-causing mutations. Seventy patients and 23 normal family members were recruited from 10 pedigrees. Among 10 RP pedigrees, 1 was autosomal dominant pedigrees and 9 were autosomal recessive pedigrees. 7 mutations related to 5 genes of 5 pedigrees were detected. A frameshift mutation on BBS7 gene was detected in No.2 pedigree, the patients of this pedigree combined with central obesity, polydactyly and mental handicap. No.2 pedigree was diagnosed as Bardet-Biedl syndrome finally. A missense mutation was detected in No.7 and No.10 pedigrees respectively. Because the patients suffered deafness meanwhile, the final diagnosis was Usher syndrome. A missense mutation on C3 gene related to age-related macular degeneration was also detected in No. 7 pedigrees. A nonsense mutation and a missense mutation on CRB1 gene were detected in No. 1 pedigree and a splicesite mutation on PROM1 gene was detected in No. 5 pedigree. Retinitis pigmentosa is a kind of genetic eye disease with diversity clinical phenotypes. Rapid and effective genetic diagnosis technology combined with clinical characteristics analysis is helpful to improve the level of clinical diagnosis of RP.

  1. 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

    Directory of Open Access Journals (Sweden)

    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.

  2. Fully Automated Robust System to Detect Retinal Edema, Central Serous Chorioretinopathy, and Age Related Macular Degeneration from Optical Coherence Tomography Images

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    Samina Khalid

    2017-01-01

    Full Text Available Maculopathy is the excessive damage to macula that leads to blindness. It mostly occurs due to retinal edema (RE, central serous chorioretinopathy (CSCR, or age related macular degeneration (ARMD. Optical coherence tomography (OCT imaging is the latest eye testing technique that can detect these syndromes in early stages. Many researchers have used OCT images to detect retinal abnormalities. However, to the best of our knowledge, no research that presents a fully automated system to detect all of these macular syndromes is reported. This paper presents the world’s first ever decision support system to automatically detect RE, CSCR, and ARMD retinal pathologies and healthy retina from OCT images. The automated disease diagnosis in our proposed system is based on multilayered support vector machines (SVM classifier trained on 40 labeled OCT scans (10 healthy, 10 RE, 10 CSCR, and 10 ARMD. After training, SVM forms an accurate decision about the type of retinal pathology using 9 extracted features. We have tested our proposed system on 2819 OCT scans (1437 healthy, 640 RE, and 742 CSCR of 502 patients from two different datasets and our proposed system correctly diagnosed 2817/2819 subjects with the accuracy, sensitivity, and specificity ratings of 99.92%, 100%, and 99.86%, respectively.

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

    Science.gov (United States)

    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.

  4. Late complications following cryotherapy of lattice degeneration.

    Science.gov (United States)

    Benson, W E; Morse, P H; Nantawan, P

    1977-10-01

    We observed 341 patients who had received cryotherapy for lattice degeneration in order to identify possible late complications. Sequelae such as retinal tears posterior to an operculum or flap tears within treated areas showed that treatment did not necessarily prevent subsequent vitreous traction. Moreover, the newly created flap tears may extend beyond the treated area and can cause retinal detachment. Even scleral buckling did not necesserily prevent further traction. Therefore, we concluded that when cryotherapy is used to treat lattice degeneration, an adequate margin of surrounding retina should be treated and the treatment should extend to the ora serrata.

  5. Grafted c-kit+/SSEA1- eye-wall progenitor cells delay retinal degeneration in mice by regulating neural plasticity and forming new graft-to-host synapses.

    Science.gov (United States)

    Chen, Xi; Chen, Zehua; Li, Zhengya; Zhao, Chen; Zeng, Yuxiao; Zou, Ting; Fu, Caiyun; Liu, Xiaoli; Xu, Haiwei; Yin, Zheng Qin

    2016-12-30

    Despite diverse pathogenesis, the common pathological change observed in age-related macular degeneration and in most hereditary retinal degeneration (RD) diseases is photoreceptor loss. Photoreceptor replacement by cell transplantation may be a feasible treatment for RD. The major obstacles to clinical translation of stem cell-based cell therapy in RD remain the difficulty of obtaining sufficient quantities of appropriate and safe donor cells and the poor integration of grafted stem cell-derived photoreceptors into the remaining retinal circuitry. Eye-wall c-kit + /stage-specific embryonic antigen 1 (SSEA1) - cells were isolated via fluorescence-activated cell sorting, and their self-renewal and differentiation potential were detected by immunochemistry and flow cytometry in vitro. After labeling with quantum nanocrystal dots and transplantation into the subretinal space of rd1 RD mice, differentiation and synapse formation by daughter cells of the eye-wall c-kit + /SSEA1 - cells were evaluated by immunochemistry and western blotting. Morphological changes of the inner retina of rd1 mice after cell transplantation were demonstrated by immunochemistry. Retinal function of rd1 mice that received cell grafts was tested via flash electroretinograms and the light/dark transition test. Eye-wall c-kit + /SSEA1 - cells were self-renewing and clonogenic, and they retained their proliferative potential through more than 20 passages. Additionally, eye-wall c-kit + /SSEA1 - cells were capable of differentiating into multiple retinal cell types including photoreceptors, bipolar cells, horizontal cells, amacrine cells, Müller cells, and retinal pigment epithelium cells and of transdifferentiating into smooth muscle cells and endothelial cells in vitro. The levels of synaptophysin and postsynaptic density-95 in the retinas of eye-wall c-kit + /SSEA1 - cell-transplanted rd1 mice were significantly increased at 4 weeks post transplantation. The c-kit + /SSEA1 - cells were

  6. Outer retinal tubulation as a predictor of the enlargement amount of geographic atrophy in age-related macular degeneration.

    Science.gov (United States)

    Hariri, Amirhossein; Nittala, Muneeswar G; Sadda, SriniVas R

    2015-02-01

    To determine the prognostic value of outer retinal tubulation (ORT) in the enlargement amount of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). Cohort study. One hundred eight fellow untreated eyes of 143 patients with GA resulting from AMD enrolled in the MAHALO study (clinicaltrials.gov identifier, NCT01229215) who completely satisfied the study term and had gradable spectral-domain optical coherence tomography (OCT) images obtained at both baseline and month 18 visits. The MAHALO study enrolled 143 subjects into a phase 1b/2 multicenter, randomized, single-masked, sham-injection controlled clinical trial of the safety, tolerability, and evidence of activity of lampalizumab in patients with GA associated with AMD. Spectral-domain optical coherence tomography images were obtained at multiple time points in both eyes, although only the baseline and month 18 data of the fellow (nonstudy) eyes were considered in this exploratory analysis. The Cirrus HD-OCT review software was used for automatic segmentation and measurement of GA areas, with manual correction of segmentation errors by certified OCT graders. Baseline OCT images also were assessed for the presence of ORT. The enlargement amount of GA in eyes with ORT was compared with that of eyes without ORT. Comparison of the enlargement amount of GA in eyes with and without ORT. Twenty-four of these 108 eyes demonstrated evidence of ORT. The amount of enlargement of GA in eyes with ORT was significantly slower than that of eyes without ORT (1.85±0.78 vs. 2.67±1.61; P = 0.001). This difference remained significant when considering subgroups with unifocal or multifocal GA lesions, because eyes with ORT in both subgroups had a slower enlargement amount of GA than eyes without ORT (2.91±1.70 vs. 2.08±0.88 [P = 0.01], in eyes with multifocal GA lesions; and 2.24±1.40 vs. 1.63±0.57 [P = 0.02], in eyes with unifocal GA lesions). In eyes with ORT, GA lesions seem to enlarge at a

  7. Drusen Volume and Retinal Pigment Epithelium Abnormal Thinning Volume Predict 2-Year Progression of Age-Related Macular Degeneration.

    Science.gov (United States)

    Folgar, Francisco A; Yuan, Eric L; Sevilla, Monica B; Chiu, Stephanie J; Farsiu, Sina; Chew, Emily Y; Toth, Cynthia A

    2016-01-01

    To analyze the value of novel measures of retinal pigment epithelium-drusen complex (RPEDC) volume to predict 2-year disease progression of intermediate age-related macular degeneration (AMD). Prospective, observational study. Three hundred forty-five AMD and 122 non-AMD participants enrolled in the Age Related Eye Disease Study 2 Ancillary Spectral-Domain (SD) Optical Coherence Tomography (OCT) study. High-density SD OCT macular volumes were obtained at yearly study visits. The RPEDC abnormal thickening (henceforth, OCT drusen) and RPEDC abnormal thinning (RAT) volumes were generated by semiautomated segmentation of total RPEDC within a 5-mm-diameter macular field. Volume change and odds ratio (OR) with 95% confidence intervals (CI) for progression to advanced AMD with choroidal neovascularization (CNV) or central geographic atrophy (GA). Complete volumes were obtained in 265 and 266 AMD eyes and in 115 and 97 control eyes at baseline and at year 2, respectively. In AMD eyes, mean (standard deviation) OCT drusen volume increased from 0.08 mm(3) (0.16 mm(3)) to 0.10 mm(3) (0.23 mm(3); P < 0.001), and RAT volume increased from 8.3 × 10(-4) mm(3) (20.8 × 10(-4) mm(3)) to 18.4 × 10(-4) mm(3) (46.6 × 10(-4) mm(3); P < 0.001). Greater baseline OCT drusen volume was associated with 2-year progression to CNV (P = 0.002). Odds of developing CNV increased by 31% for every 0.1-mm(3) increase in baseline OCT drusen volume (OR, 1.31; 95% CI, 1.06-1.63; P = 0.013). Greater baseline RAT volume was associated with significant 2-year increase in RAT volume (P < 0.001), noncentral GA (P < 0.001), and progression to central GA (P < 0.001). Odds of developing central GA increased by 32% for every 0.001-mm(3) increase in baseline RAT volume (OR, 1.32; 95% CI, 1.14-1.53; P < 0.001). In non-AMD eyes, all volumes were significantly lower than AMD eyes and showed no significant 2-year change. Macular OCT drusen and RAT volumes increased significantly in AMD eyes over 2 years

  8. Non-invasive retinal imaging in mice with fluorescent Scanning Laser Ophthalmoscopy and Fourier Domain Optical Coherence Tomography

    OpenAIRE

    Hossein-Javaheri, Nima

    2010-01-01

    Visualization of the internal structures of the retina is critical for clinical diagnosis and monitoring of pathology as well as for medical research investigating the root causes of retinal degeneration. The aim of this thesis is to develop multi-modal non-invasive imaging technology for studying retinal degeneration and gene therapy in mice. We have constructed a FD-OCT prototype and combined it with a Scanning Laser Ophthalmoscope (SLO) to permit real time alignment of the retinal field of...

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

    Science.gov (United States)

    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.

  10. Lahore general hospital protocol for treatment of neovascular glaucoma caused by retinal disease

    International Nuclear Information System (INIS)

    Khaqan, H.A.; Haider, S.A.

    2013-01-01

    To evaluate efficacy of LGH (Lahore General Hospital) protocol for treatment of neovascular glaucoma caused by retinal diseases. Material and Methods: This case series was performed on 9 consecutive eyes of nine patients with uncontrolled neovascular glaucoma at Department of Ophthalmology, Unit II, Lahore General Hospital/PGMI, Lahore. All nine patients completed six months follow up. Among them 6 patients were having PDR (proliferative diabetic retinopathy) and 3 patients having CRVO (central retinal vein occlusion). LGH protocol for treatment of neovascular glaucoma was: To give intravitreal injection of avastin and then PRP (Pan Retinal Photocoagulation) or Trabeculectomy with MMC (Mitomycin C), if PRP and intravitreal avastin fails to control the intra ocular-pressure (IOP). Results: Three patients had IOP control after intravitreal injection of avastin and PRP, 5 patients had uncontrolled IOP after intravitreal avastin and two sessions of PRP, so they under went trabeculectomy with MMC. One patient had uncontrolled IOP despite of full treatment protocol. All other 8 patients IOP remained stable for six months. Conclusion: Significant decrease in intraocular pressure was achieved after observing LGH protocol for treatment of NVG (Neovascular Glaucoma) caused by retinal diseases. (author)

  11. Role of fractalkine/CX3CR1 interaction in light-induced photoreceptor degeneration through regulating retinal microglial activation and migration.

    Directory of Open Access Journals (Sweden)

    Meng Zhang

    Full Text Available BACKGROUND: Excessive exposure to light enhances the progression and severity of some human retinal degenerative diseases. While retinal microglia are likely to be important in neuron damage associated with these diseases, the relationship between photoreceptor damage and microglial activation remains poorly understood. Some recent studies have indicated that the chemokine fractalkine is involved in the pathogenesis of many neurodegenerative diseases. The present study was performed to investigate the cross-talk between injured photoreceptors and activated retinal microglia, focusing on the role of fractalkine and its receptor CX3CR1 in light-induced photoreceptor degeneration. METHODOLOGY/PRINCIPAL FINDINGS: Both in vivo and in vitro experiments were involved in the research. In vivo, Sprague-Dawley rats were exposed to blue light for 24 hours. In vitro, the co-culture of primary retinal microglia and a photoreceptor cell line (661W cell was exposed to blue light for five hours. Some cultures were pretreated by the addition of anti-CX3CR1 neutralizing antibody or recombinant fractalkine. Expression of fractalkine/CX3CR1 and inflammatory cytokines was detected by immunofluorescence, real-time PCR, Western immunoblot analysis, and ELISA assay. TUNEL method was used to detect cell apoptosis. In addition, chemotaxis assay was performed to evaluate the impact of soluble fractalkine on microglial migration. Our results showed that the expression of fractalkine that was significantly upregulated after exposure to light, located mainly at the photoreceptors. The extent of photoreceptor degeneration and microglial migration paralleled the increased level of fractalkine/CX3CR1. Compared with the control, the expression of inflammatory cytokines was significantly downregulated in the anti-CX3CR1 neutralizing antibody-treated group, and the number of photoreceptors was also well preserved. The addition of recombinant full-length fractalkine or soluble

  12. Ubiquitin–Synaptobrevin Fusion Protein Causes Degeneration of Presynaptic Motor Terminals in Mice

    Science.gov (United States)

    Liu, Yun; Li, Hongqiao; Sugiura, Yoshie; Han, Weiping; Gallardo, Gilbert; Khvotchev, Mikhail; Zhang, Yinan; Kavalali, Ege T.; Südhof, Thomas C.

    2015-01-01

    terminals. SIGNIFICANCE STATEMENT Degeneration of motor nerve terminals occurs in amyotrophic lateral sclerosis (ALS) patients as well as in mouse models of ALS, leading to progressive paralysis. What causes a motor nerve terminal to degenerate remains unknown. Here we report on transgenic mice expressing a ubiquitinated synaptic vesicle protein (UbG76V-GFP-Syb2) that develop progressive degeneration of motor nerve terminals. These mice may serve as a model for further elucidating the underlying cellular and molecular mechanisms of presynaptic nerve terminal degeneration. PMID:26290230

  13. Human Adipose-Derived Stem Cells Delay Retinal Degeneration in Royal College of Surgeons Rats Through Anti-Apoptotic and VEGF-Mediated Neuroprotective Effects.

    Science.gov (United States)

    Li, Z; Wang, J; Gao, F; Zhang, J; Tian, H; Shi, X; Lian, C; Sun, Y; Li, W; Xu, J-Y; Li, P; Zhang, J; Gao, Z; Xu, J; Wang, F; Lu, L; Xu, G-T

    2016-01-01

    Stem cell therapy is a promising therapeutic approach for retinal degeneration (RD). Our study investigated the effects of human adipose derived stem cell (hADSCs) on Royal College of Surgeons (RCS) rats. Green fluorescent protein (GFP)-labeled hADSCs were transplanted subretinally into RCS rats at postnatal (PN) 21 days to explore potential therapeutic effects, while adeno-associated viral vector (AAV2)-vascular endothelial growth factor (VEGF) and siVEGF-hADSCs were used to aid the mechanistic dissections. Visual function was evaluated by Electroretinogram (ERG) recording. Potential transdifferentiations were examined by Immunofluorescence (IF) and gene expressions were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Apoptotic retinal cells were detected by Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) assay and the cytokines secreted by hADSCs were measured by Enzyme-linked Immunosorbent Assay (ELISA). The visual function of RCS rats began to decrease one week after their eyes opened at PN week 3 and almost lost in PN 5 weeks, accompanied by the loss of retinal outer nuclear layer (ONL). Subretinal transplantation of hADSCs significantly improved the visual function 2 weeks after the transplantation and such therapeutic effect persisted up to 8 weeks after the treatment (PN 11 weeks), with 3-4 rows of photoreceptors remained in the ONL and reduced apoptosis. Consistent with these phenotypic changes, the gene expression of rod photoreceptor markers Rhodopsin (Rho), Crx and Opsin (Opn1) in RCS rats showed obvious decreasing trends over time after PN 3 weeks, but were elevated with hADSC treatment. hADSC transplantation also repressed the expressions of Bax, Bak and Caspase 3, but not the expression of anti-apoptotic genes, including Bcl-2 and Bcl-XL. Finally, substantial VEGF, hepatocyte growth factor (HGF) and pigment epithelium-derived factor (PEDF) secretions from hADSCs were detected, while endogenous

  14. 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.

  15. Transplantation of CX3CL1-expressing mesenchymal stem cells provides neuroprotective and immunomodulatory effects in a rat model of retinal degeneration.

    Science.gov (United States)

    Huang, Libin; Xu, Wei; Xu, Guoxing

    2013-08-01

    To investigate the neuroprotective and immunomodulatory effects of mesenchymal stem cells (MSCs) engineered to secrete CX3CL1 on the light-injured retinal structure and function. Normal MSCs and CX3CL1-expressing MSCs (CX3CL1-MSCs) were transplanted into the subretinal space of light-injured rats. By ERG and TUNEL methods, their rescue effect of the host retina was compared with untreated light-injured and vehicle-injected rats. Activated microglia in the retina were stained by ED-1 antibody, and Western blot was performed to quantify cytokines secreted by the retina post-transplantation. ERG analysis showed better function in CX3CL1-MSC-injected group than other groups at 21 days after transplantation (p < 0.05). CX3CL1-MSCs inhibited apoptosis of the retinal cells and microglial activation. Neurotrophic factors expression in host retina that received CX3CL1-MSCs was stronger than in the retina that received normal MSCs. Conversely, the expression of proinflammatory factors was downregulated. CX3CL1-MSCs subretinal transplantation may enhance protective effect against light-induced retinal degeneration.

  16. EFFECT OF INTRAVITREAL RANIBIZUMAB ON GANGLION CELL COMPLEX AND PERIPAPILLARY RETINAL NERVE FIBER LAYER IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION USING SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY.

    Science.gov (United States)

    Zucchiatti, Ilaria; Cicinelli, Maria V; Parodi, Maurizio Battaglia; Pierro, Luisa; Gagliardi, Marco; Accardo, Agostino; Bandello, Francesco

    2017-07-01

    To analyze the changes in ganglion cell complex and peripapillary retinal nerve fiber layer thickness, in central macular thickness and choroidal thickness on spectral domain optical coherence tomography in patients with neovascular age-related macular degeneration treated with intravitreal ranibizumab injections. All consecutive patients with untreated neovascular age-related macular degeneration received loading phase of three monthly intravitreal ranibizumab, followed by retreatments on a pro re nata protocol for 12 months. changes in ganglion cell complex and retinal nerve fiber layer at the end of follow-up. Secondary outcome: changes in best-corrected visual acuity, central macular thickness, and choroidal thickness at the end of follow-up. Choroidal thickness was measured at 500 μm, 1000 μm, and 1,500 μm intervals nasally, temporally, superiorly, and inferiorly to the fovea, respectively, on horizontal and vertical line scans centered on the fovea. Twenty-four eyes were included. Ganglion cell complex and peripapillary retinal nerve fiber layer thickness did not show statistically significant changes through 12 months (55.6 ± 18.5 and 81.9 ± 9.9 μm at baseline, 52.7 ± 19.3 and 84.6 ± 15.5 μm at month 12, P > 0.05). Central macular thickness showed progressive decrease from baseline to month 12, with maximum reduction at month 3 (P macular thickness was significantly reduced at the end of treatment. Further studies, with larger sample, longer follow-up, and greater number of injections, are warranted.

  17. 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.

  18. RNA interference gene therapy in dominant retinitis pigmentosa and cone-rod dystrophy mouse models caused by GCAP1 mutations

    Directory of Open Access Journals (Sweden)

    Li eJiang

    2014-04-01

    Full Text Available RNA interference (RNAi knockdown is an efficacious therapeutic strategy for silencing genes causative for dominant retinal dystrophies. To test this, we used self-complementary (sc AAV2/8 vector to develop an RNAi-based therapy in two dominant retinal degeneration mouse models. The allele-specific model expresses transgenic bovine GCAP1(Y99C establishing a rapid RP-like phenotype, whereas the nonallele-specific model expresses mouse GCAP1(L151F producing a slowly progressing cone/rod dystrophy (CORD. The late onset GCAP1(L151F-CORD mimics the dystrophy observed in human GCAP1-CORD patients. Subretinal injection of scAAV2/8 carrying shRNA expression cassettes specific for bovine or mouse GCAP1 showed strong expression at one week post-injection. In both allele-specific (GCAP1(Y99C-RP and nonallele-specific (GCAP1(L151F-CORD models of dominant retinal dystrophy, RNAi-mediated gene silencing enhanced photoreceptor survival, delayed onset of degeneration and improved visual function. Such results provide a proof of concept toward effective RNAi-based gene therapy mediated by scAAV2/8 for dominant retinal disease based on GCAP1 mutation. Further, nonallele-specific RNAi knockdown of GCAP1 may prove generally applicable toward the rescue of any human GCAP1-based dominant cone-rod dystrophy.

  19. 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)

    Lambertus, Stanley; 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

    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. 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. These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in

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

    Directory of Open Access Journals (Sweden)

    Stanley Lambertus

    Full Text Available 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.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.These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease

  1. 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

  2. Retinal function in deaf-blind syndromes

    OpenAIRE

    Malm, Eva

    2011-01-01

    A variety of disorders can cause retinal degeneration and hearing impairment, and it is of great value to have an early diagnosis since there is a large variation in phenotype and prognosis both within and between the different disorders. The general aim of this thesis was to characterize the retinal function, to describe the phenotype, and – where appropriate – to relate the phenotype to genotype in patients with combined visual and hearing impairment. Alström syndrome is a rare auto...

  3. Loss of binocular vision as direct cause for misrouting of temporal retinal fibers in albinism.

    Science.gov (United States)

    Banihani, Saleh M

    2015-10-01

    In humans, the nasal retina projects to the contralateral hemisphere, whereas the temporal retina projects ipsilaterally. The nasotemporal line that divides the retina into crossed and uncrossed parts coincides with the vertical meridian through the fovea. This normal projection of the retina is severely altered in albinism, in which the nasotemporal line shifted into the temporal retina with temporal retinal fibers cross the midline at the optic chiasm. This study proposes the loss of binocular vision as direct cause for misrouting of temporal retinal fibers and shifting of the nasotemporal line temporally in albinism. It is supported by many observations that clearly indicate that loss of binocular vision causes uncrossed retinal fibers to cross the midline. This hypothesis may alert scientists and clinicians to find ways to prevent or minimize the loss of binocular vision that may occur in some diseases such as albinism and early squint. Hopefully, this will minimize the misrouting of temporal fibers and improve vision in such diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Scanning laser densitometry and color perimetry demonstrate reduced photopigment density and sensitivity in two patients with retinal degeneration.

    Science.gov (United States)

    Tornow, R P; Stilling, R; Zrenner, E

    1999-10-01

    To test the feasibility of scanning laser densitometry with a modified Rodenstock scanning laser ophthalmoscope (SLO) to measure the rod and cone photopigment distribution in patients with retinal diseases. Scanning laser densitometry was performed using a modified Rodenstock scanning laser ophthalmoscope. The distribution of the photopigments was calculated from dark adapted and bleached images taken with the 514 nm laser of the SLO. This wavelength is absorbed by rod and cone photopigments. Discrimination is possible due to their different spatial distribution. Additionally, to measure retinal sensitivity profiles, dark adapted two color static perimetry with a Tübinger manual perimeter was performed along the horizontal meridian with 1 degree spacing. A patient with retinitis pigmentosa had slightly reduced photopigment density within the central +/- 5 degrees but no detectable photopigment for eccentricities beyond 5 degrees. A patient with cone dystrophy had nearly normal pigment density beyond +/- 5 degrees, but considerably reduced photopigment density within the central +/- 5 degrees. Within the central +/- 5 degrees, the patient with retinitis pigmentosa had normal sensitivity for the red stimulus and reduced sensitivity for the green stimulus. There was no measurable function beyond 7 degrees. The patient with cone dystrophy had normal sensitivity for the green stimulus outside the foveal center and reduced sensitivity for the red stimulus at the foveal center. The results of color perimetry for this patient with a central scotoma were probably influenced by eccentric fixation. Scanning laser densitometry with a modified Rodenstock SLO is a useful method to assess the human photopigment distribution. Densitometry results were confirmed by dark adapted two color static perimetry. Photopigment distribution and retinal sensitivity profiles can be measured with high spatial resolution. This may help to measure exactly the temporal development of retinal

  5. 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

    : Enrolled patients underwent repeated SDOCT imaging using the Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany). A single technician certified for clinical trials took 3 macular volume scans. Retinal thicknesses were calculated for each of the 9 Early Treatment Diabetic Retinopathy Study (ETDRS...... 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...

  6. Retinal Imaging and Image Analysis

    Science.gov (United States)

    Abràmoff, Michael D.; Garvin, Mona K.; Sonka, Milan

    2011-01-01

    Many important eye diseases as well as systemic diseases manifest themselves in the retina. While a number of other anatomical structures contribute to the process of vision, this review focuses on retinal imaging and image analysis. Following a brief overview of the most prevalent causes of blindness in the industrialized world that includes age-related macular degeneration, diabetic retinopathy, and glaucoma, the review is devoted to retinal imaging and image analysis methods and their clinical implications. Methods for 2-D fundus imaging and techniques for 3-D optical coherence tomography (OCT) imaging are reviewed. Special attention is given to quantitative techniques for analysis of fundus photographs with a focus on clinically relevant assessment of retinal vasculature, identification of retinal lesions, assessment of optic nerve head (ONH) shape, building retinal atlases, and to automated methods for population screening for retinal diseases. A separate section is devoted to 3-D analysis of OCT images, describing methods for segmentation and analysis of retinal layers, retinal vasculature, and 2-D/3-D detection of symptomatic exudate-associated derangements, as well as to OCT-based analysis of ONH morphology and shape. Throughout the paper, aspects of image acquisition, image analysis, and clinical relevance are treated together considering their mutually interlinked relationships. PMID:22275207

  7. Autophagy and exosomes in the aged retinal pigment epithelium: possible relevance to drusen formation and 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 loss of central vision in the elderly. The formation of drusen, an extracellular, amorphous deposit of material on Bruch's membrane in the macula of the retina, occurs early in the course of the disease. Although some of the molecular components of drusen are known, there is no understanding of the cell biology that leads to the formation of drusen. We have previously demonstrated increased mitochondrial DNA (mtDNA damage and decreased DNA repair enzyme capabilities in the rodent RPE/choroid with age. In this study, we found that drusen in AMD donor eyes contain markers for autophagy and exosomes. Furthermore, these markers are also found in the region of Bruch's membrane in old mice. By in vitro modeling increased mtDNA damage induced by rotenone, an inhibitor of mitochondrial complex I, in the RPE, we found that the phagocytic activity was not altered but that there were: 1 increased autophagic markers, 2 decreased lysosomal activity, 3 increased exocytotic activity and 4 release of chemoattractants. Exosomes released by the stressed RPE are coated with complement and can bind complement factor H, mutations of which are associated with AMD. We speculate that increased autophagy and the release of intracellular proteins via exosomes by the aged RPE may contribute to the formation of drusen. Molecular and cellular changes in the old RPE may underlie susceptibility to genetic mutations that are found in AMD patients and may be associated with the pathogenesis of AMD in the elderly.

  8. Activation of liver X receptor delayed the retinal degeneration of rd1 mice through modulation of the immunological function of glia.

    Science.gov (United States)

    He, Xiao; Sun, Dayu; Chen, Siyu; Xu, Haiwei

    2017-05-09

    Retinal degeneration (RD), including retinitis pigmentosa (RP), is an inherited eye disease characterized by progressive degeneration of photoreceptors. Recently, immune cells, including microglia, Müller cells and astrocytes, in degenerative retina are demonstrated to play key roles in the development of RD and can be used as potential therapeutic targets. Liver X receptors (LXRs) are important immuno-inflammatory response transcription factors that have been reported to be a new potential therapeutic drug target for neurodegenerative diseases. However, the potential therapeutic utility of LXRs for RP has not been evaluated. In the present study, Pde6β (rd1) mice received intraperitoneal injections of T0901317 (T0, 50 mg/kg/d) or vehicle (2% DMSO) for 7 days with age-matched C57/BL6 mice as controls. The effect of T0 was examined by quantitating photoreceptor apoptosis, microglial density and the expression of inflammatory mediators; the underlying mechanisms were then explored with a microarray assay. T0 markedly delayed apoptosis of the photoreceptors, partially through suppressing the activation of microglia and the gliosis of Müller cells, and decreased the expression levels of IL-6, iNOS, COX-2 and ENG in rd1 mice; as a result, the visual function of T0-treated rd1 mice measured with electroretinograms (ERG) was preserved for a longer time than that of vehicle-treated rd1 mice. The microarray assay showed that the Janus kinase/Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway was significantly affected in the retina of rd1 mice with T0 treatment. Our data suggested that T0 modulated the immunologic function of glia cells in the degenerative retina through the JAK3/STAT pathway and delayed the apoptosis of photoreceptors.

  9. Pilot evaluation of short-term changes in macular pigment and retinal sensitivity in different phenotypes of early age-related macular degeneration after carotenoid supplementation.

    Science.gov (United States)

    Corvi, Federico; Souied, Eric H; Falfoul, Yousra; Georges, Anouk; Jung, Camille; Querques, Lea; Querques, Giuseppe

    2017-06-01

    To investigate the response of carotenoid supplementation in different phenotypes of early age-related macular degeneration (AMD) by measuring macular pigment optical density (MPOD) and retinal sensitivity. Consecutive patients with only medium/large drusen and only reticular pseudodrusen (RPD) and age-matched and sex-matched controls were enrolled. At baseline, participants underwent a complete ophthalmological examination including measurement of best-corrected visual acuity (BCVA), MPOD and retinal sensitivity. Patients were put on vitamin supplementation (lutein 10 mg/day, zeaxanthin 2 mg/day) and 3 months later underwent a repeated ophthalmological examination. Twenty patients with medium/large drusen, 19 with RPD and 15 control subjects were included. At baseline, in controls, mean MPOD and BCVA were significantly higher compared with RPD (p=0.001 and p=0.01) but similar to medium/large drusen (p=0.9 and p=0.4). Mean retinal sensitivity was significantly higher in controls compared with RPD and medium/large drusen (for all p<0.0001). After 3 months of carotenoid supplementation the mean MPOD significantly increased in RPD (p=0.002), thus showing no more difference compared with controls (p=0.3); no significant changes were found in mean retinal sensitivity and BCVA (p=0.3 and p=0.7). Medium/large drusen did not show significant changes on MPOD, retinal sensitivity and BCVA (p=0.5, p=0.7 and p=0.7, respectively). Patients with early AMD, especially RPD phenotype, show lower macular sensitivity and MPOD than controls. After supplementation, MPOD significantly increased in RPD. These results suggest different pathophysiology for RPD as compared with medium/large drusen and may open new ways to identifying further therapeutic targets in this phenotype of early AMD. 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/.

  10. The P2Y12 Receptor Antagonist Ticagrelor Reduces Lysosomal pH and Autofluorescence in Retinal Pigmented Epithelial Cells From the ABCA4-/- Mouse Model of Retinal Degeneration

    Directory of Open Access Journals (Sweden)

    Wennan Lu

    2018-04-01

    Full Text Available The accumulation of partially degraded lipid waste in lysosomal-related organelles may contribute to pathology in many aging diseases. The presence of these lipofuscin granules is particularly evident in the autofluorescent lysosome-associated organelles of the retinal pigmented epithelial (RPE cells, and may be related to early stages of age-related macular degeneration. While lysosomal enzymes degrade material optimally at acidic pH levels, lysosomal pH is elevated in RPE cells from the ABCA4-/- mouse model of Stargardt’s disease, an early onset retinal degeneration. Lowering lysosomal pH through cAMP-dependent pathways decreases accumulation of autofluorescent material in RPE cells in vitro, but identification of an appropriate receptor is crucial for manipulating this pathway in vivo. As the P2Y12 receptor for ADP is coupled to the inhibitory Gi protein, we asked whether blocking the P2Y12 receptor with ticagrelor could restore lysosomal acidity and reduce autofluorescence in compromised RPE cells from ABCA4-/- mice. Oral delivery of ticagrelor giving rise to clinically relevant exposure lowered lysosomal pH in these RPE cells. Ticagrelor also partially reduced autofluorescence in the RPE cells of ABCA4-/- mice. In vitro studies in ARPE-19 cells using more specific antagonists AR-C69931 and AR-C66096 confirmed the importance of the P2Y12 receptor for lowering lysosomal pH and reducing autofluorescence. These observations identify P2Y12 receptor blockade as a potential target to lower lysosomal pH and clear lysosomal waste in RPE cells.

  11. Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa.

    Science.gov (United States)

    Nguyen, Thanh-Minh T; Hull, Sarah; Roepman, Ronald; van den Born, L Ingeborgh; Oud, Machteld M; de Vrieze, Erik; Hetterschijt, Lisette; Letteboer, Stef J F; van Beersum, Sylvia E C; Blokland, Ellen A; Yntema, Helger G; Cremers, Frans P M; van der Zwaag, Paul A; Arno, Gavin; van Wijk, Erwin; Webster, Andrew R; Haer-Wigman, Lonneke

    2017-09-01

    Recent findings suggesting that Abelson helper integration site 1 ( AHI1 ) is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether AHI1 variants cause non-syndromic retinitis pigmentosa (RP). Exome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1 were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient's fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells. In the three patients with RP, three sets of compound heterozygous variants were detected in AHI1 (c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by AHI1 , with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base. This report confirms that mutations in AHI1 can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1 variants on protein function, thus proposing a new genotype-phenotype correlation for AHI1 mutation associated retinal ciliopathies. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  12. 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.

  13. 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.

  14. Repeatability of Retinal Sensitivity Measurements Using a Medmont Dark-Adapted Chromatic Perimeter in Healthy and Age-Related Macular Degeneration Cases.

    Science.gov (United States)

    Tan, Rose S; Guymer, Robyn H; Luu, Chi D

    2018-05-01

    To determine the intrasession and intersession test-retest repeatability of retinal sensitivity measurements using a dark-adapted chromatic perimeter (DACP). For intrasession testing, retinal sensitivity within the central 24° for the 505-nm stimulus was measured after 20, 30, and 40 minutes of dark adaptation (DA) and for the 625-nm stimulus was measured after the first and second 505-nm tests. For intersession testing, retinal sensitivity for both stimuli was measured after 30 minutes of DA at baseline and 1 month. The point-wise sensitivity (PWS) difference and coefficient of repeatability (CoR) of each stimulus and group were determined. For intrasession testing, 10 age-related macular degeneration (AMD) and eight control subjects were recruited. The overall CoR for the 505-nm stimulus was 8.4 dB for control subjects and 9.1 dB for AMD cases, and for the 625-nm stimulus was 6.7 dB for control subjects and 9.5 dB for AMD cases. For intersession testing, seven AMD cases and 13 control subjects returned an overall CoR for the 505-nm stimulus of 8.2 dB for the control and 11.7 dB for the AMD group. For the 625-nm stimulus the CoR was 6.2 dB for the control group and 8.4 dB for the AMD group. Approximately 80% of all test points had a PWS difference of ±5 dB between the two intrasession or intersession measurements for both stimuli. The CoR for the DACP is larger than that reported for scotopic perimeters; however, the majority of test points had a PWS difference of ±5 dB between tests. The DACP offers an opportunity to measure static and dynamic rod function at multiple locations with an acceptable reproducibility level.

  15. Interim Results of a Multicenter Trial with the New Electronic Subretinal Implant Alpha AMS in 15 Patients Blind from Inherited Retinal Degenerations.

    Science.gov (United States)

    Stingl, Katarina; Schippert, Ruth; Bartz-Schmidt, Karl U; Besch, Dorothea; Cottriall, Charles L; Edwards, Thomas L; Gekeler, Florian; Greppmaier, Udo; Kiel, Katja; Koitschev, Assen; Kühlewein, Laura; MacLaren, Robert E; Ramsden, James D; Roider, Johann; Rothermel, Albrecht; Sachs, Helmut; Schröder, Greta S; Tode, Jan; Troelenberg, Nicole; Zrenner, Eberhart

    2017-01-01

    Purpose: We assessed the safety and efficacy of a technically advanced subretinal electronic implant, RETINA IMPLANT Alpha AMS, in end stage retinal degeneration in an interim analysis of two ongoing prospective clinical trials. The purpose of this article is to describe the interim functional results (efficacy). Methods: The subretinal visual prosthesis RETINA IMPLANT Alpha AMS (Retina Implant AG, Reutlingen, Germany) was implanted in 15 blind patients with hereditary retinal degenerations at four study sites with a follow-up period of 12 months (www.clinicaltrials.gov NCT01024803 and NCT02720640). Functional outcome measures included (1) screen-based standardized 2- or 4-alternative forced-choice (AFC) tests of light perception, light localization, grating detection (basic grating acuity (BaGA) test), and Landolt C-rings; (2) gray level discrimination; (3) performance during activities of daily living (ADL-table tasks). Results: Implant-mediated light perception was observed in 13/15 patients. During the observation period implant mediated localization of visual targets was possible in 13/15 patients. Correct grating detection was achieved for spatial frequencies of 0.1 cpd (cycles per degree) in 4/15; 0.33 cpd in 3/15; 0.66 cpd in 2/15; 1.0 cpd in 2/15 and 3.3 cpd in 1/15 patients. In two patients visual acuity (VA) assessed with Landolt C- rings was 20/546 and 20/1111. Of 6 possible gray levels on average 4.6 ± 0.8 (mean ± SD, n = 10) were discerned. Improvements (power ON vs. OFF) of ADL table tasks were measured in 13/15 patients. Overall, results were stable during the observation period. Serious adverse events (SAEs) were reported in 4 patients: 2 movements of the implant, readjusted in a second surgery; 4 conjunctival erosion/dehiscence, successfully treated; 1 pain event around the coil, successfully treated; 1 partial reduction of silicone oil tamponade leading to distorted vision (silicon oil successfully refilled). The majority of adverse events (AEs

  16. Interim Results of a Multicenter Trial with the New Electronic Subretinal Implant Alpha AMS in 15 Patients Blind from Inherited Retinal Degenerations

    Directory of Open Access Journals (Sweden)

    Katarina Stingl

    2017-08-01

    Full Text Available Purpose: We assessed the safety and efficacy of a technically advanced subretinal electronic implant, RETINA IMPLANT Alpha AMS, in end stage retinal degeneration in an interim analysis of two ongoing prospective clinical trials. The purpose of this article is to describe the interim functional results (efficacy.Methods: The subretinal visual prosthesis RETINA IMPLANT Alpha AMS (Retina Implant AG, Reutlingen, Germany was implanted in 15 blind patients with hereditary retinal degenerations at four study sites with a follow-up period of 12 months (www.clinicaltrials.gov NCT01024803 and NCT02720640. Functional outcome measures included (1 screen-based standardized 2- or 4-alternative forced-choice (AFC tests of light perception, light localization, grating detection (basic grating acuity (BaGA test, and Landolt C-rings; (2 gray level discrimination; (3 performance during activities of daily living (ADL-table tasks.Results: Implant-mediated light perception was observed in 13/15 patients. During the observation period implant mediated localization of visual targets was possible in 13/15 patients. Correct grating detection was achieved for spatial frequencies of 0.1 cpd (cycles per degree in 4/15; 0.33 cpd in 3/15; 0.66 cpd in 2/15; 1.0 cpd in 2/15 and 3.3 cpd in 1/15 patients. In two patients visual acuity (VA assessed with Landolt C- rings was 20/546 and 20/1111. Of 6 possible gray levels on average 4.6 ± 0.8 (mean ± SD, n = 10 were discerned. Improvements (power ON vs. OFF of ADL table tasks were measured in 13/15 patients. Overall, results were stable during the observation period. Serious adverse events (SAEs were reported in 4 patients: 2 movements of the implant, readjusted in a second surgery; 4 conjunctival erosion/dehiscence, successfully treated; 1 pain event around the coil, successfully treated; 1 partial reduction of silicone oil tamponade leading to distorted vision (silicon oil successfully refilled. The majority of adverse events

  17. Controlled delivery of tauroursodeoxycholic acid from biodegradable microspheres slows retinal degeneration and vision loss in P23H rats.

    Directory of Open Access Journals (Sweden)

    Laura Fernández-Sánchez

    Full Text Available Successful drug therapies for treating ocular diseases require effective concentrations of neuroprotective compounds maintained over time at the site of action. The purpose of this work was to assess the efficacy of intravitreal controlled delivery of tauroursodeoxycholic acid (TUDCA encapsulated in poly(D,L-lactic-co-glycolic acid (PLGA microspheres for the treatment of the retina in a rat model of retinitis pigmentosa. PLGA microspheres (MSs containing TUDCA were produced by the O/W emulsion-solvent evaporation technique. Particle size and morphology were assessed by light scattering and scanning electronic microscopy, respectively. Homozygous P23H line 3 rats received a treatment of intravitreal injections of TUDCA-PLGA MSs. Retinal function was assessed by electroretinography at P30, P60, P90 and P120. The density, structure and synaptic contacts of retinal neurons were analyzed using immunofluorescence and confocal microscopy at P90 and P120. TUDCA-loaded PLGA MSs were spherical, with a smooth surface. The production yield was 78%, the MSs mean particle size was 23 μm and the drug loading resulted 12.5 ± 0.8 μg TUDCA/mg MSs. MSs were able to deliver the loaded active compound in a gradual and progressive manner over the 28-day in vitro release study. Scotopic electroretinografic responses showed increased ERG a- and b-wave amplitudes in TUDCA-PLGA-MSs-treated eyes as compared to those injected with unloaded PLGA particles. TUDCA-PLGA-MSs-treated eyes showed more photoreceptor rows than controls. The synaptic contacts of photoreceptors with bipolar and horizontal cells were also preserved in P23H rats treated with TUDCA-PLGA MSs. This work indicates that the slow and continuous delivery of TUDCA from PLGA-MSs has potential neuroprotective effects that could constitute a suitable therapy to prevent neurodegeneration and visual loss in retinitis pigmentosa.

  18. Stem Cell-Based Therapeutic Applications in Retinal Degenerative Diseases.

    OpenAIRE

    Huang Yiming; Enzmann Volker; Ildstad Suzanne T

    2011-01-01

    Retinal degenerative diseases that target photoreceptors or the adjacent retinal pigment epithelium (RPE) affect millions of people worldwide. Retinal degeneration (RD) is found in many different forms of retinal diseases including retinitis pigmentosa (RP), age-related macular degeneration (AMD), diabetic retinopathy, cataracts, and glaucoma. Effective treatment for retinal degeneration has been widely investigated. Gene-replacement therapy has been shown to improve visual function in inheri...

  19. Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress.

    Science.gov (United States)

    Bonilha, Vera L; Bell, Brent A; Rayborn, Mary E; Samuels, Ivy S; King, Anna; Hollyfield, Joe G; Xie, Chengsong; Cai, Huaibin

    2017-03-01

    NOS immunoreactivity were detected in retina/RPE lysates from both young and old DJ-1 KO mice. These results demonstrate that DJ-1 KO mice display progressive signs of retinal/RPE degeneration in association with higher levels of oxidative stress markers. Collectively this analysis indicates that DJ-1 plays an important role in protecting photoreceptors and RPE from oxidative damage during aging. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Chronic cigarette smoke causes oxidative damage and apoptosis to retinal pigmented epithelial cells in mice.

    Directory of Open Access Journals (Sweden)

    Masashi Fujihara

    2008-09-01

    Full Text Available The purpose of this study was to determine whether mice exposed to chronic cigarette smoke develop features of early age-related macular degeneration (AMD. Two month old C57Bl6 mice were exposed to either filtered air or cigarette smoke in a smoking chamber for 5 h/day, 5 days/week for 6 months. Eyes were fixed in 2.5% glutaraldehyde/2% paraformaldehyde and examined for ultrastructural changes by transmission electron microscopy. The contralateral eye was fixed in 2% paraformaldehyde and examined for oxidative injury to the retinal pigmented epithelium (RPE by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG immunolabeling and apoptosis by TUNEL labeling. Mice exposed to cigarette smoke had immunolabeling for 8-OHdG in 85+/-3.7% of RPE cells counted compared to 9.5+/-3.9% in controls (p<0.00001. Bruch membrane was thicker in mice exposed to smoke (1086+/-332 nm than those raised in air (543+/-132 nm; p = 0.0069. The two most pronounced ultrastructural changes (severity grading scale from 0-3 seen were a loss of basal infoldings (mean difference in grade = 1.98; p<0.0001, and an increase in intracellular vacuoles (mean difference in grade = 1.7; p<0.0001. Ultrastructural changes to Bruch membrane in cigarette-smoke exposed mice were smaller in magnitude but consistently demonstrated significantly higher grade injury in cigarette-exposed mice, including basal laminar deposits (mean difference in grade = 0.54; p<0.0001, increased outer collagenous layer deposits (mean difference in grade = 0.59; p = 0.002, and increased basal laminar deposit continuity (mean difference in grade = 0.4; p<0.0001. TUNEL assay showed a higher percentage of apoptotic RPE from mice exposed to cigarette smoke (average 8.0+/-1.1% than room air (average 0+/-0%; p = 0.043. Mice exposed to chronic cigarette smoke develop evidence of oxidative damage with ultrastructural degeneration to the RPE and Bruch membrane, and RPE cell apoptosis. This model could be useful for studying the

  1. Retinal Cell Death Caused by Sodium Iodate Involves Multiple Caspase-Dependent and Caspase-Independent Cell-Death Pathways

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    Jasmin Balmer

    2015-07-01

    Full Text Available Herein, we have investigated retinal cell-death pathways in response to the retina toxin sodium iodate (NaIO3 both in vivo and in vitro. C57/BL6 mice were treated with a single intravenous injection of NaIO3 (35 mg/kg. Morphological changes in the retina post NaIO3 injection in comparison to untreated controls were assessed using electron microscopy. Cell death was determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL staining. The activation of caspases and calpain was measured using immunohistochemistry. Additionally, cytotoxicity and apoptosis in retinal pigment epithelial (RPE cells, primary retinal cells, and the cone photoreceptor (PRC cell line 661W were assessed in vitro after NaIO3 treatment using the ApoToxGlo™ assay. The 7-AAD/Annexin-V staining was performed and necrostatin (Nec-1 was administered to the NaIO3-treated cells to confirm the results. In vivo, degenerating RPE cells displayed a rounded shape and retracted microvilli, whereas PRCs featured apoptotic nuclei. Caspase and calpain activity was significantly upregulated in retinal sections and protein samples from NaIO3-treated animals. In vitro, NaIO3 induced necrosis in RPE cells and apoptosis in PRCs. Furthermore, Nec-1 significantly decreased NaIO3-induced RPE cell death, but had no rescue effect on treated PRCs. In summary, several different cell-death pathways are activated in retinal cells as a result of NaIO3.

  2. Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family.

    Science.gov (United States)

    Zobor, Ditta; Balousha, Ghassan; Baumann, Britta; Wissinger, Bernd

    2014-01-01

    Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 45 genes. Recently, the FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. We performed a clinical and molecular genetic study of a consanguineous Palestinian family with two three siblings affected with retinitis pigmentosa. DNA samples were collected from the index patient, his father, his affected sister, and two non-affected brothers. DNA sample from the index was subjected to high resolution genome-wide SNP array. Assuming identity-by-descent in this consanguineous family we applied homozygosity mapping to identify disease causing genes. The index patient reported night blindness since the age of 20 years, followed by moderate disease progression with decrease of peripheral vision, the development of photophobia and later on reduced central vision. At the age of 40 his visual acuity was counting fingers (CF) for both eyes, color discrimination was not possible and his visual fields were severely constricted. Funduscopic examination revealed a typical appearance of advanced RP with optic disc pallor, narrowed retinal vessels, bone-spicule like pigmentary changes in the mid-periphery and atrophic changes in the macula. His younger affected brother (37 years) was reported with overall milder symptoms, while the youngest sister (21 years) reported problems only with night vision. Applying high-density SNP arrays we identified several homozygous genomic regions one of which included the recently identified FAM161A gene mutated in RP28-linked autosomal recessive RP. Sequencing analysis revealed the presence of a novel homozygous nonsense mutation, c.1003C>T/p.R335X in the index patient and the affected sister. We identified an RP28-linked RP family in the Palestinian population caused by a novel nonsense mutation in FAM161A. RP in this family shows a typical disease onset with moderate to rapid progression

  3. Role hmatových vousů v kompenzaci zrakového deficitu a vliv neurodegenerativního postižení na krosmodální plasticitu u myšího modelu retinální a olivocerebelární degenerace

    OpenAIRE

    Voller, Jaroslav

    2015-01-01

    Sensory deprivation in one modality can enhance the development of the remaining modalities via mechanisms of synaptic plasticity. Mice of C3H strain suffers from RD1 retinal degeneration that leads to visual impairment at weaning age. Independently on the retinal degeneration there is also present olivocerebellar degeneration caused by Lurcher mutation. This neurodegenerative disorder causes motor deficits, increased CNS excitability as well as changes in synaptic plasticity. The aim of this...

  4. Autosomal recessive retinitis pigmentosa caused by mutations in the MAK gene.

    Science.gov (United States)

    Stone, Edwin M; Luo, Xunda; Héon, Elise; Lam, Byron L; Weleber, Richard G; Halder, Jennifer A; Affatigato, Louisa M; Goldberg, Jacqueline B; Sumaroka, Alexander; Schwartz, Sharon B; Cideciyan, Artur V; Jacobson, Samuel G

    2011-12-28

    To determine the disease expression in autosomal recessive (ar) retinitis pigmentosa (RP) caused by mutations in the MAK (male germ cell-associated kinase) gene. Patients with RP and MAK gene mutations (n = 24; age, 32-77 years at first visit) were studied by ocular examination, perimetry, and optical coherence tomography (OCT). All but one MAK patient were homozygous for an identical truncating mutation in exon 9 and had Ashkenazi Jewish heritage. The carrier frequency of this mutation among 1207 unrelated Ashkenazi control subjects was 1 in 55, making it the most common cause of heritable retinal disease in this population and MAK-associated RP the sixth most common Mendelian disease overall in this group. Visual acuities could be normal into the eighth decade of life. Kinetic fields showed early loss in the superior-temporal quadrant. With more advanced disease, superior and midperipheral function was lost, but the nasal field remained. Only a central island was present at late stages. Pigmentary retinopathy was less prominent in the superior nasal quadrant. Rod-mediated vision was abnormal but detectable in the residual field; all patients had rod>cone dysfunction. Photoreceptor layer thickness was normal centrally but decreased with eccentricity. At the stages studied, there was no evidence of photoreceptor ciliary elongation. The patterns of disease expression in the MAK form of arRP showed some resemblance to patterns described in autosomal dominant RP, especially the form caused by RP1 mutations. The similarity in phenotypes is of interest, considering that there is experimental evidence of interaction between Mak and RP1 in the photoreceptor cilium.

  5. Moderate traumatic brain injury causes acute dendritic and synaptic degeneration in the hippocampal dentate gyrus.

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    Xiang Gao

    Full Text Available Hippocampal injury-associated learning and memory deficits are frequent hallmarks of brain trauma and are the most enduring and devastating consequences following traumatic brain injury (TBI. Several reports, including our recent paper, showed that TBI brought on by a moderate level of controlled cortical impact (CCI induces immature newborn neuron death in the hippocampal dentate gyrus. In contrast, the majority of mature neurons are spared. Less research has been focused on these spared neurons, which may also be injured or compromised by TBI. Here we examined the dendrite morphologies, dendritic spines, and synaptic structures using a genetic approach in combination with immunohistochemistry and Golgi staining. We found that although most of the mature granular neurons were spared following TBI at a moderate level of impact, they exhibited dramatic dendritic beading and fragmentation, decreased number of dendritic branches, and a lower density of dendritic spines, particularly the mushroom-shaped mature spines. Further studies showed that the density of synapses in the molecular layer of the hippocampal dentate gyrus was significantly reduced. The electrophysiological activity of neurons was impaired as well. These results indicate that TBI not only induces cell death in immature granular neurons, it also causes significant dendritic and synaptic degeneration in pathohistology. TBI also impairs the function of the spared mature granular neurons in the hippocampal dentate gyrus. These observations point to a potential anatomic substrate to explain, in part, the development of posttraumatic memory deficits. They also indicate that dendritic damage in the hippocampal dentate gyrus may serve as a therapeutic target following TBI.

  6. The search for mutations in the gene for the beta subunit of the cGMP phosphodiesterase (PDEB) in patients with autosomal recessive retinitis pigmentosa

    DEFF Research Database (Denmark)

    Riess, O; Noerremoelle, A; Weber, B

    1992-01-01

    The finding of a mutation in the beta subunit of the cyclic GMP (cGMP) phosphodiesterase gene causing retinal degeneration in mice (the Pdeb gene) prompted a search for disease-causing mutations in the human phosphodiesterase gene (PDEB gene) in patients with retinitis pigmentosa. All 22 exons...

  7. Generation of retinal pigmented epithelium from iPSCs derived from the conjunctiva of donors with and without age related macular degeneration.

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    Zhouhui Geng

    Full Text Available Fidelity in pluripotent stem cell differentiation protocols is necessary for the therapeutic and commercial use of cells derived from embryonic and induced pluripotent stem cells. Recent advances in stem cell technology, especially the widespread availability of a range of chemically defined media, substrates and differentiation components, now allow the design and implementation of fully defined derivation and differentiation protocols intended for replication across multiple research and manufacturing locations. In this report we present an application of these criteria to the generation of retinal pigmented epithelium from iPSCs derived from the conjunctiva of donors with and without age related macular degeneration. Primary conjunctival cells from human donors aged 70-85 years were reprogrammed to derive multiple iPSC lines that were differentiated into functional RPE using a rapid and defined differentiation protocol. The combination of defined iPSC derivation and culture with a defined RPE differentiation protocol, reproducibly generated functional RPE from each donor without requiring protocol adjustments for each individual. This successful validation of a standardized, iPSC derivation and RPE differentiation process demonstrates a practical approach for applications requiring the cost-effective generation of RPE from multiple individuals such as drug testing, population studies or for therapies requiring patient-specific RPE derivations. In addition, conjunctival cells are identified as a practical source of somatic cells for deriving iPSCs from elderly individuals.

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

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    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.

  9. Cell Fate of Müller Cells During Photoreceptor Regeneration in an N-Methyl-N-nitrosourea-Induced Retinal Degeneration Model of Zebrafish.

    Science.gov (United States)

    Ogai, Kazuhiro; Hisano, Suguru; Sugitani, Kayo; Koriyama, Yoshiki; Kato, Satoru

    2016-01-01

    Zebrafish can regenerate several organs such as the tail fin, heart, central nervous system, and photoreceptors. Very recently, a study has demonstrated the photoreceptor regeneration in the alkylating agent N-methyl-N-nitrosourea (MNU)-induced retinal degeneration (RD) zebrafish model, in which whole photoreceptors are lost within a week after MNU treatment and then regenerated within a month. The research has also shown massive proliferation of Müller cells within a week. To address the question of whether proliferating Müller cells are the source of regenerating photoreceptors, which remains unknown in the MNU-induced zebrafish RD model, we employed a BrdU pulse-chase technique to label the proliferating cells within a week after MNU treatment. As a result of the BrdU pulse-chase technique, a number of BrdU(+) cells were observed in the outer nuclear layer as well as the inner nuclear layer. This implies that regenerating photoreceptors are derived from proliferating Müller cells in the zebrafish MNU-induced RD model.

  10. Putative digenic inheritance of heterozygous RP1L1 and C2orf71 null mutations in syndromic retinal dystrophy

    DEFF Research Database (Denmark)

    Liu, Yangfan P.; Bosch, Daniëlle G.M.; Siemiatkowska, Anna M.

    2017-01-01

    Background: Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to ex...

  11. Adaptive Optics Technology for High-Resolution Retinal Imaging

    Science.gov (United States)

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

    2013-01-01

    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. PMID:23271600

  12. Contribution of microglia-mediated neuroinflammation to retinal degenerative diseases.

    Science.gov (United States)

    Madeira, Maria H; Boia, Raquel; Santos, Paulo F; Ambrósio, António F; Santiago, Ana R

    2015-01-01

    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.

  13. Three novel and the common Arg677Ter RP1 protein truncating mutations causing autosomal dominant retinitis pigmentosa in a Spanish population

    Directory of Open Access Journals (Sweden)

    Antiñolo Guillermo

    2006-04-01

    Full Text Available Abstract Background Retinitis pigmentosa (RP, a clinically and genetically heterogeneous group of retinal degeneration disorders affecting the photoreceptor cells, is one of the leading causes of genetic blindness. Mutations in the photoreceptor-specific gene RP1 account for 3–10% of cases of autosomal dominant RP (adRP. Most of these mutations are clustered in a 500 bp region of exon 4 of RP1. Methods Denaturing gradient gel electrophoresis (DGGE analysis and direct genomic sequencing were used to evaluate the 5' coding region of exon 4 of the RP1 gene for mutations in 150 unrelated index adRP patients. Ophthalmic and electrophysiological examination of RP patients and relatives according to pre-existing protocols were carried out. Results Three novel disease-causing mutations in RP1 were detected: Q686X, K705fsX712 and K722fsX737, predicting truncated proteins. One novel missense mutation, Thr752Met, was detected in one family but the mutation does not co-segregate in the family, thereby excluding this amino acid variation in the protein as a cause of the disease. We found the Arg677Ter mutation, previously reported in other populations, in two independent families, confirming that this mutation is also present in a Spanish population. Conclusion Most of the mutations reported in the RP1 gene associated with adRP are expected to encode mutant truncated proteins that are approximately one third or half of the size of wild type protein. Patients with mutations in RP1 showed mild RP with variability in phenotype severity. We also observed several cases of non-penetrant mutations.

  14. A high dietary intake of sodium glutamate as flavoring (ajinomoto) causes gross changes in retinal morphology and function.

    Science.gov (United States)

    Ohguro, Hiroshi; Katsushima, Harumi; Maruyama, Ikuyo; Maeda, Tadao; Yanagihashi, Satsuki; Metoki, Tomomi; Nakazawa, Mitsuru

    2002-09-01

    The purpose of this study was to investigate the effects of glutamate accumulation in vitreous on retinal structure and function, due to a diet high in sodium glutamate. Three different diet groups were created, consisting of rats fed on a regular diet (diet A), a moderate excess of sodium glutamate diet (diet B) and a large excess of sodium glutamate diet (diet C). After 1, 3 and 6 months of the administration of these diets, amino acids concentrations in vitreous were analyzed. In addition, retinal morphology and function by electroretinogram (ERG) of three different diet groups were studied. Significant accumulation of glutamate in vitreous was observed in rats following addition of sodium glutamate to the diet as compared to levels with a regular diet. In the retinal morphology, thickness of retinal neuronal layers was remarkably thinner in rats fed on sodium glutamate diets than in those on a regular diet. TdT-dUTP terminal nick-end labelling (TUNEL) staining revealed significant accumulation of the positive staining cells within the retinal ganglion cell layers in retinas from diets B and C as compared with that from diet A. Similar to this, immunohistochemistry demonstrated increased expression of glial fibrillary acidic protein (GFAP) within the retinal inner layers from diets B and C as compared with diet A. Functionally, ERG responses were reduced in rats fed on a sodium glutamate diets as compared with those on a regular diet. The present study suggests that a diet with excess sodium glutamate over a period of several years may increase glutamate concentrations in vitreous and may cause retinal cell destruction.

  15. Identification of a disease-causing mutation in a Chinese patient with retinitis pigmentosa by targeted next-generation sequencing

    DEFF Research Database (Denmark)

    Xiao, Jianping; Guo, Xueqin; Wang, Yong

    2017-01-01

    Purpose: To identify disease-causing mutations in a Chinese patient with retinitis pigmentosa (RP). Methods: A detailed clinical examination was performed on the proband. Targeted next-generation sequencing (NGS) combined with bioinformatics analysis was performed on the proband to detect candidate...

  16. Acquired Nonpigmented Vitreous Cyst Associated With Lattice Degeneration.

    Science.gov (United States)

    Lu, Jing; Mai, Guiying; Liu, Ruyuan; Luo, Yan; Lu, Lin

    2017-10-01

    A 63-year-old male presented with a round-shaped floater and visual obscuration in the right eye. Clinical evaluation showed a nonpigmented vitreous cyst connected to a lattice degeneration by a stalk. Immunostaining of the vitreous cyst obtained from vitrectomy showed its origin of retinal neuroepithelium. The cyst was formed by continuous vitreous traction, which might tear up the disrupted retina at the area of lattice degeneration. This report added the lattice degeneration to the list of causes for the acquired vitreous cyst. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:856-858.]. Copyright 2017, SLACK Incorporated.

  17. Identification of the mutation causing progressive retinal atrophy in Old Danish Pointing Dog.

    Science.gov (United States)

    Karlskov-Mortensen, P; Proschowsky, H F; Gao, F; Fredholm, M

    2018-04-06

    Progressive retinal atrophy (PRA) is a common cause of blindness in many dog breeds. It is most often inherited as a simple Mendelian trait, but great genetic heterogeneity has been demonstrated both within and between breeds. In many breeds the genetic cause of the disease is not known, and until now, the Old Danish Pointing Dog (ODP) has been one of those breeds. ODP is one of the oldest dog breeds in Europe. Seventy years ago the breed almost vanished, but today a population still exists, primarily in Denmark but with some dogs in Germany and Sweden. PRA has been diagnosed in ODP since the late 1990s. It resembles late onset PRA in other dog breeds, and it is inherited as an autosomal recessive trait. In the present study, we performed whole-genome sequencing and identified a single base insertion (c.3149_3150insC) in exon 1 of C17H2orf71. This is the same mutation previously found to cause PRA in Gordon Setters and Irish Setters, and it was later found in Tibetan Terrier, Standard Poodle and the Polski Owczarek Nizinny. The presence of the mutation in such a diverse range of breeds indicates an origin preceding creation of modern dog breeds. Hence, we screened 262 dogs from 44 different breeds plus four crossbred dogs, and can subsequently add Miniature Poodle and another polish sheepdog, the Polski Owczarek Podhalanski, to the list of affected breeds. © 2018 Stichting International Foundation for Animal Genetics.

  18. 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.

  19. 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.

  20. Mechanisms of Retinal Damage from Chronic Laser Radiation.

    Science.gov (United States)

    1981-07-01

    and the other by 15 a slower, partly reversible rod cell degeneration It appears that a normal light cycle protects the rat eye somewhat from the...lium, disturbing the metabolic support of the receptors. Gross separation as in retinal detachment is known to cause degeneration of receptors and...border by scatter and reflection. A particular kind of specialization in the retina is represented by the fovea and macula . In the center of the macula

  1. Pathways of load-induced cartilage damage causing cartilage degeneration in the knee after meniscectomy

    NARCIS (Netherlands)

    Wilson, W.; Rietbergen, van B.; Donkelaar, van C.C.; Huiskes, R.

    2003-01-01

    Results of both clinical and animal studies show that meniscectomy often leads to osteoarthritic degenerative changes in articular cartilage. It is generally assumed that this process of cartilage degeneration is due to changes in mechanical loading after meniscectomy. It is, however, not known why

  2. Transcorneal Electrical Stimulation Therapy for Retinal Disease

    Science.gov (United States)

    2012-05-03

    Retinitis Pigmentosa; Macula Off; Primary Open Angle Glaucoma; Hereditary Macular Degeneration; Treated Retina Detachment; Retinal Artery Occlusion; Retinal Vein Occlusion; Non-Arthritic-Anterior-Ischemic Optic-Neuropathy; Hereditary Autosomal Dominant Optic Atrophy; Dry Age Related Macular Degeneration; Ischemic Macula Edema

  3. [Paediatric retinal detachment and hereditary vitreoretinal disorders].

    Science.gov (United States)

    Meier, P

    2013-09-01

    The number of retinal detachments in children is very low in comparison to the number in adults. One predisposing factor for development of paediatric retinal detachment is suffering from hereditary vitreoretinal degeneration (e.g., Stickler syndrome, Wagner syndrome, Kniest dysplasia, familial exudative vitreoretinopathy, congenital X-linked retinoschisis, Knobloch syndrome, incontinentia pigmenti, Norrie disease). Hereditary vitreoretinopathies are characterised by an abnormal-appearing vitreous gel with associated retinal changes. In most of these eyes further ocular abnormalities can be diagnosed. A group of hereditary disorders is associated with characteristic systemic abnormalities. Allied conditions should be considered in the clinical diagnosis. Vitreoretinopathies are the most common cause of inherited retinal detachment. In most eyes primary vitrectomy is necessary, and disease-specific surgical treatment is discussed. Georg Thieme Verlag KG Stuttgart · New York.

  4. Hilar Mossy Cell Degeneration Causes Transient Dentate Granule Cell Hyperexcitability and Impaired Pattern Separation

    Science.gov (United States)

    Jinde, Seiichiro; Zsiros, Veronika; Jiang, Zhihong; Nakao, Kazuhito; Pickel, James; Kohno, Kenji; Belforte, Juan E.; Nakazawa, Kazu

    2012-01-01

    Summary Although excitatory mossy cells of the hippocampal hilar region are known to project both to dentate granule cells and to interneurons, it is as yet unclear whether mossy cell activity’s net effect on granule cells is excitatory or inhibitory. To explore their influence on dentate excitability and hippocampal function, we generated a conditional transgenic mouse line, using the Cre/loxP system, in which diphtheria toxin receptor was selectively expressed in mossy cells. One week after injecting toxin into this line, mossy cells throughout the longitudinal axis were degenerated extensively, theta wave power of dentate local field potentials increased during exploration, and deficits occurred in contextual discrimination. By contrast, we detected no epileptiform activity, spontaneous behavioral seizures, or mossy-fiber sprouting 5–6 weeks after mossy cell degeneration. These results indicate that the net effect of mossy cell excitation is to inhibit granule cell activity and enable dentate pattern separation. PMID:23259953

  5. Overexpression of retinal degeneration slow (RDS protein adversely affects rods in the rd7 model of enhanced S-cone syndrome.

    Directory of Open Access Journals (Sweden)

    Dibyendu Chakraborty

    Full Text Available The nuclear receptor NR2E3 promotes expression of rod photoreceptor genes while repressing cone genes. Mice lacking NR2E3 (Nr2e3(rd7/rd7 referred to here as rd7 are a model for enhanced S-cone syndrome, a disease associated with increased sensitivity to blue light and night blindness. Rd7 retinas have reduced levels of the outer segment (OS structural protein retinal degeneration slow (RDS. We test the hypothesis that increasing RDS levels would improve the Rd7 phenotype. Transgenic mice over-expressing normal mouse peripherin/RDS (NMP in rods and cones were crossed onto the rd7 background. Disease phenotypes were assessed in NMP/rd7 eyes and compared to wild-type (WT and rd7 eyes at postnatal day 30. NMP/rd7 retinas expressed total RDS (transgenic and endogenous message at WT levels, and NMP protein was correctly localized to the OS. NMP/rd7 retinas have shorter OSs compared to rd7 and WT and significantly reduced number of rosettes. NMP/rd7 mice also exhibited significant deficits in scotopic ERG amplitudes compared to rd7 while photopic amplitudes remained unaffected. Protein levels of rhodopsin, RDS, and the RDS homologue ROM-1 were significantly reduced in the NMP/rd7 retinas compared to rd7. We show that correcting the levels of RDS gene expression does not improve the phenotype of the rd7 suggesting that RDS deficiency is not responsible for the defect in this model. We suggest that the specific rod defect in the NMP/rd7 is likely associated with ongoing problems in the rd7 that are related to the expression of cone genes in rod cells, a characteristic of the model.

  6. Age, sex, and type of medication predict the effect of anti-VEGF treatment on central retinal thickness in wet age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Bek T

    2018-03-01

    Full Text Available Toke Bek, Sidsel Ehlers Klug Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark Purpose: Randomized clinical trials studying the effects of VEGF inhibition on wet age-related macular degeneration (wAMD are designed so that the effects of individually varying risk factors on the treatment response are eliminated. The influence of these risk factors can be studied in large data sets from real-life experience.Patients and methods: All 2,255 patients diagnosed with wAMD requiring anti-VEGF treatment in at least one eye over more than 9 years in a defined Danish population with 0.9 million inhabitants were studied. The predictive value of eye laterality, sex, current smoking status, type of anti-VEGF compound, membrane position, membrane type, leakage area, number of injections, number of visits, age, time to follow-up, visual acuity, and central retinal thickness (CRT at baseline on change in CRT after three monthly injections with anti-VEGF compound followed by treatment pro re nata for up to 12 months was assessed.Results: After 12 months, 67 patients had died, 903 had had stable CRT for at least 6 months, and 1,285 patients had not achieved stable CRT. The reduction in CRT was -84.8±118.3 µm, whereas the increase in visual acuity was 2.2±14.7 Early Treatment Diabetic Retinopathy Study letters. The risk factors included contributed to 64% of the variation in CRT reduction. High age and high CRT at baseline predicted high CRT reduction, whereas more injections, treatment with ranibizumab, and male sex predicted a low CRT reduction.Conclusion: Age, sex, and type of anti-VEGF medication can be used to plan treatment and inform patients about the expected response of anti-VEGF treatment in wAMD. Keywords: wet AMD, anti-VEGF treatment, risk factors, real-life experience 

  7. Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration.

    Science.gov (United States)

    Qi, Y; Liu, H; Daniels, M P; Zhang, G; Xu, H

    2016-02-01

    Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L(del)). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1L(del) flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1L(del) flies had reduced complex I (NADH/ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency.

  8. 2-ethylpyridine, a cigarette smoke component, causes mitochondrial damage in human retinal pigment epithelial cells in vitro

    Directory of Open Access Journals (Sweden)

    S Mansoor

    2014-01-01

    Full Text Available Purpose: Our goal was to identify the cellular and molecular effects of 2-ethylpyridine (2-EP, a component of cigarette smoke on human retinal pigment epithelial cells (ARPE-19 in vitro. Materials and Methods: ARPE-19 cells were exposed to varying concentrations of 2-EP. Cell viability (CV was measured by a trypan blue dye exclusion assay. Caspase-3/7 and caspase-9 activities were measured by fluorochrome assays. The production of reactive oxygen/nitrogen species (ROS/RNS was detected with a 2′,7′-dichlorodihydrofluorescein diacetate dye assay. The JC-1 assay was used to measure mitochondrial membrane potential (ΔΨm. Mitochondrial redox potential was measured using a RedoxSensor Red kit and mitochondria were evaluated with Mitotracker dye. Results: After 2-EP exposure, ARPE-19 cells showed significantly decreased CV, increased caspase-3/7 and caspase-9 activities, elevated ROS/RNS levels, decreased ΔΨm value and decreased redox fluorescence when compared with control samples. Conclusions: These results show that 2-EP treatment induced cell death by caspase-dependent apoptosis associated with an oxidative stress and mitochondrial dysfunction. These data represent a possible mechanism by which smoking contributes to age-related macular degeneration and other retinal diseases and identify mitochondria as a target for future therapeutic interventions.

  9. Retinal Diseases Caused by Mutations in Genes Not Specifically Associated with the Clinical Diagnosis.

    Directory of Open Access Journals (Sweden)

    Xia Wang

    Full Text Available When seeking a confirmed molecular diagnosis in the research setting, patients with one descriptive diagnosis of retinal disease could carry pathogenic variants in genes not specifically associated with that description. However, this event has not been evaluated systematically in clinical diagnostic laboratories that validate fully all target genes to minimize false negatives/positives.We performed targeted next-generation sequencing analysis on 207 ocular disease-related genes for 42 patients whose DNA had been tested negative for disease-specific panels of genes known to be associated with retinitis pigmentosa, Leber congenital amaurosis, or exudative vitreoretinopathy.Pathogenic variants, including single nucleotide variations and copy number variations, were identified in 9 patients, including 6 with variants in syndromic retinal disease genes and 3 whose molecular diagnosis could not be distinguished easily from their submitted clinical diagnosis, accounting for 21% (9/42 of the unsolved cases.Our study underscores the clinical and genetic heterogeneity of retinal disorders and provides valuable reference to estimate the fraction of clinical samples whose retinal disorders could be explained by genes not specifically associated with the corresponding clinical diagnosis. Our data suggest that sequencing a larger set of retinal disorder related genes can increase the molecular diagnostic yield, especially for clinically hard-to-distinguish cases.

  10. The Loss of Vacuolar Protein Sorting 11 (vps11) Causes Retinal Pathogenesis in a Vertebrate Model of Syndromic Albinism

    Science.gov (United States)

    Thomas, Jennifer L.; Vihtelic, Thomas S.; denDekker, Aaron D.; Willer, Gregory; Luo, Xixia; Murphy, Taylor R.; Gregg, Ronald G.; Hyde, David R.

    2011-01-01

    Purpose. To establish the zebrafish platinum mutant as a model for studying vision defects caused by syndromic albinism diseases such as Chediak-Higashi syndrome, Griscelli syndrome, and Hermansky-Pudlak syndrome (HPS). Methods. Bulked segregant analysis and candidate gene sequencing revealed that the zebrafish platinum mutation is a single-nucleotide insertion in the vps11 (vacuolar protein sorting 11) gene. Expression of vps11 was determined by RT-PCR and in situ hybridization. Mutants were analyzed for pigmentation defects and retinal disease by histology, immunohistochemistry, and transmission electron microscopy. Results. Phenocopy and rescue experiments determined that a loss of Vps11 results in the platinum phenotype. Expression of vps11 appeared ubiquitous during zebrafish development, with stronger expression in the developing retina and retinal pigmented epithelium (RPE). Zebrafish platinum mutants exhibited reduced pigmentation in the body and RPE; however, melanophore development, migration, and dispersion occurred normally. RPE, photoreceptors, and inner retinal neurons formed normally in zebrafish platinum mutants. However, a gradual loss of RPE, an absence of mature melanosomes, and the subsequent degradation of RPE/photoreceptor interdigitation was observed. Conclusions. These data show that Vps11 is not necessary for normal retinal development or initiation of melanin biosynthesis, but is essential for melanosome maturation and healthy maintenance of the RPE and photoreceptors. PMID:21330665

  11. Retinal pigmentary changes in chronic uveitis mimicking retinitis pigmentosa.

    Science.gov (United States)

    Sevgi, D Damla; Davoudi, Samaneh; Comander, Jason; Sobrin, Lucia

    2017-09-01

    To present retinal pigmentary changes mimicking retinitis pigmentosa (RP) as a finding of advanced uveitis. We retrospectively reviewed charts of patients without a family history of inherited retinal degenerations who presented with retinal pigment changes and signs of past or present intraocular inflammation. Comprehensive eye examination including best-corrected visual acuity, slit-lamp examination and dilated fundus examination was performed on all patients in addition to color fundus photography, optical coherence tomography, fluorescein angiography (FA), and full-field electroretinogram testing. We identified five patients with ages ranging from 33 to 66 years, who presented with RP-like retinal pigmentary changes which were eventually attributed to longstanding uveitis. The changes were bilateral in three cases and unilateral in two cases. Four of five cases presented with active inflammation, and the remaining case showed evidence of active intraocular inflammation during follow-up. This study highlights the overlapping features of advanced uveitis and RP including the extensive pigmentary changes. Careful review of possible past uveitis history, detailed examination of signs of past or present inflammation and ancillary testing, with FA often being most helpful, are required for the correct diagnosis. This is important, because intervention can prevent further damage if the cause of the pigmentary changes is destructive inflammation.

  12. THICKNESS OF THE MACULA, RETINAL NERVE FIBER LAYER, AND GANGLION CELL-INNER PLEXIFORM LAYER IN THE AGE-RELATED MACULAR DEGENERATION: The Repeatability Study of Spectral Domain Optical Coherence Tomography.

    Science.gov (United States)

    Shin, Il-Hwan; Lee, Woo-Hyuk; Lee, Jong-Joo; Jo, Young-Joon; Kim, Jung-Yeul

    2018-02-01

    To determine the repeatability of measuring the thickness of the central macula, retinal nerve fiber layer, and ganglion cell-inner plexiform layer (GC-IPL) using spectral domain optical coherence tomography (Cirrus HD-OCT) in eyes with age-related macular degeneration. One hundred and thirty-four eyes were included. The measurement repeatability was assessed by an experienced examiner who performed two consecutive measurements using a 512 × 128 macular cube scan and a 200 × 200 optic disk cube scan. To assess changes in macular morphology in patients with age-related macular degeneration, the patients were divided into the following three groups according to the central macular thickness (CMT): A group, CMT 300 μm. Measurement repeatability was assessed using test-retest variability, a coefficient of variation, and an intraclass correlation coefficient. The mean measurement repeatability for the central macular, retinal nerve fiber layer, and GC-IPL thickness was high in the B group. The mean measurement repeatability for both the central macula and retinal nerve fiber layer thickness was high in the A and C groups, but was lower for the GC-IPL thickness. The measurement repeatability for GC-IPL thickness was high in the B group, but low in the A group and in the C group. The automated measurement repeatability for GC-IPL thickness was significantly lower in patients with age-related macular degeneration with out of normal CMT range. The effect of changes in macular morphology should be considered when analyzing GC-IPL thicknesses in a variety of ocular diseases.

  13. 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.

  14. RETINAL PIGMENT EPITHELIAL TEAR AND ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY IN EXUDATIVE AGE-RELATED MACULAR DEGENERATION: Clinical Course and Long-Term Prognosis.

    Science.gov (United States)

    Heimes, Britta; Farecki, Marie-Louise; Bartels, Sina; Barrelmann, Anna; Gutfleisch, Matthias; Spital, Georg; Lommatzsch, Albrecht; Pauleikhoff, Daniel

    2016-05-01

    To document the long-term outcome in cases of retinal pigment epithelial (RPE) tears after treatment of vascularized pigment epithelial detachments with anti-vascular endothelial growth factor therapy. A retrospective analysis of the long-term outcome of a consecutive series of eyes with RPE tear developed during anti-vascular endothelial growth factor therapy for pigment epithelial detachment associated with choroidal neovascularization or retinal angiomatous proliferation (vascularized pigment epithelial detachment) was performed. Best-corrected visual acuity (BCVA), spectral domain optical coherence tomography, and autofluorescence images and also fluorescein angiograms were analyzed to determine the functional and morphologic development over time. The long-term outcome of 22 eyes (21 patients, 13 women and 8 men; 65-85 years; mean: 76 years) with RPE tear was performed with minimal follow-up of 3 years (range: 3-5 years, mean: 44 months) and re-treatment with different therapeutic strategies. The eyes were differentiated in 2 groups according to the course of BCVA after the first 2 years of follow-up: Group 1 (11 eyes) demonstrated a stabilized or improved BCVA after 2 years and Group 2 (11 eyes) demonstrated a decrease in BCVA after 2 years. The initial BCVA between both groups was comparable. Also the mean initial size of the RPE tear was the same between the 2 groups, the area of the RPE tear decreased continuously during follow-up in Group 1, whereas this was the case in Group 2 only at the beginning of treatment with a further increase of the size of the RPE tear with longer follow-up. This corresponded with a different morphologic development between the two groups. In Group 1, increasing recovery of autofluorescence at the RPE-free area was visible beginning from the outer border, whereas in Group 2, further growth of the neovascular complex in the area of the RPE tear was observed resulting in larger fibrovascular scars. In addition, in both groups

  15. Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies.

    Science.gov (United States)

    Rivera, José Carlos; Holm, Mari; Austeng, Dordi; Morken, Tora Sund; Zhou, Tianwei Ellen; Beaudry-Richard, Alexandra; Sierra, Estefania Marin; Dammann, Olaf; Chemtob, Sylvain

    2017-08-22

    Retinopathy of prematurity (ROP) is an important cause of childhood blindness globally, and the incidence is rising. The disease is characterized by initial arrested retinal vascularization followed by neovascularization and ensuing retinal detachment causing permanent visual loss. Although neovascularization can be effectively treated via retinal laser ablation, it is unknown which children are at risk of entering this vision-threatening phase of the disease. Laser ablation may itself induce visual field deficits, and there is therefore a need to identify targets for novel and less destructive treatments of ROP. Inflammation is considered a key contributor to the pathogenesis of ROP. A large proportion of preterm infants with ROP will have residual visual loss linked to loss of photoreceptor (PR) and the integrity of the retinal pigment epithelium (RPE) in the macular region. Recent studies using animal models of ROP suggest that choroidal degeneration may be associated with a loss of integrity of the outer retina, a phenomenon so far largely undescribed in ROP pathogenesis. In this review, we highlight inflammatory and neuron-derived factors related to ROP progression, as well, potential targets for new treatment strategies. We also introduce choroidal degeneration as a significant cause of residual visual loss following ROP. We propose that ROP should no longer be considered an inner retinal vasculopathy only, but also a disease of choroidal degeneration affecting both retinal pigment epithelium and photoreceptor integrity.

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

    Directory of Open Access Journals (Sweden)

    Pia E. Leon

    2014-08-01

    Full Text Available AIM:To evaluate the visual function evolution of retinal 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 follow-up 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: Mean follow-up was 24wk (SD±4wk. A total 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 13 cases (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.

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

    NARCIS (Netherlands)

    Lambertus, S.; Bax, N.M.; Fakin, A.; Groenewoud, J.M.M.; Klevering, B.J.; Moore, A.T.; Michaelides, M.; Webster, A.R.; Wilt, G.J. van der; Hoyng, C.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

  18. Arrestin gene mutations in autosomal recessive retinitis pigmentosa.

    Science.gov (United States)

    Nakazawa, M; Wada, Y; Tamai, M

    1998-04-01

    To assess the clinical and molecular genetic studies of patients with autosomal recessive retinitis pigmentosa associated with a mutation in the arrestin gene. Results of molecular genetic screening and case reports with DNA analysis and clinical features. University medical center. One hundred twenty anamnestically unrelated patients with autosomal recessive retinitis pigmentosa. DNA analysis was performed by single strand conformation polymorphism followed by nucleotide sequencing to search for a mutation in exon 11 of the arrestin gene. Clinical features were characterized by visual acuity slitlamp biomicroscopy, fundus examinations, fluorescein angiography, kinetic visual field testing, and electroretinography. We identified 3 unrelated patients with retinitis pigmentosa associated with a homozygous 1-base-pair deletion mutation in codon 309 of the arrestin gene designated as 1147delA. All 3 patients showed pigmentary retinal degeneration in the midperipheral area with or without macular involvement. Patient 1 had a sibling with Oguchi disease associated with the same mutation. Patient 2 demonstrated pigmentary retinal degeneration associated with a golden-yellow reflex in the peripheral fundus. Patients 1 and 3 showed features of retinitis pigmentosa without the golden-yellow fundus reflex. Although the arrestin 1147delA has been known as a frequent cause of Oguchi disease, this mutation also may be related to the pathogenesis of autosomal recessive retinitis pigmentosa. This phenomenon may provide evidence of variable expressivity of the mutation in the arrestin gene.

  19. Serum levels of lipid metabolites in age-related macular degeneration

    OpenAIRE

    Orban, Tivadar; Johnson, William M.; Dong, Zhiqian; Maeda, Tadao; Maeda, Akiko; Sakai, Tsutomu; Tsuneoka, Hiroshi; Mieyal, John J.; Palczewski, Krzysztof

    2015-01-01

    Age-related macular degeneration (AMD) is a neurodegenerative disease that causes adult-onset blindness. There are 2 forms of this progressive disease: wet and dry. Currently there is no cure for AMD, but several treatment options have started to emerge making early detection critical for therapeutic success. Analysis of the eyes of Abca4−/−Rdh8−/− mice that display light-induced retinal degeneration indicates that 11-cis-retinal and docosahexaenoic acid (DHA) levels were significantly decrea...

  20. Loss of Binocular Vision in Monocularly Blind Patients Causes Selective Degeneration of the Superior Lateral Occipital Cortices

    NARCIS (Netherlands)

    Prins, Doety D; Jansonius, Nomdo M.; Cornelissen, Frans W.

    2017-01-01

    PURPOSE. Chronic ocular pathology, such as glaucoma and macular degeneration, is associated with neuroanatomic changes in the visual pathways. It is a challenge to determine the mechanism responsible for these changes. This could be functional deprivation or transsynaptic degeneration. Acquired

  1. USH1G with unique retinal findings caused by a novel truncating mutation identified by genome-wide linkage analysis

    Science.gov (United States)

    Taibah, Khalid; Bin-Khamis, Ghada; Kennedy, Shelley; Hemidan, Amal; Al-Qahtani, Faisal; Tabbara, Khalid; Mubarak, Bashayer Al; Ramzan, Khushnooda; Meyer, Brian F.; Al-Owain, Mohammed

    2012-01-01

    Purpose Usher syndrome (USH) is an autosomal recessive disorder divided into three distinct clinical subtypes based on the severity of the hearing loss, manifestation of vestibular dysfunction, and the age of onset of retinitis pigmentosa and visual symptoms. To date, mutations in seven different genes have been reported to cause USH type 1 (USH1), the most severe form. Patients diagnosed with USH1 are known to be ideal candidates to benefit from cochlear implantation. Methods Genome-wide linkage analysis using Affymetrix GeneChip Human Mapping 10K arrays were performed in three cochlear implanted Saudi siblings born from a consanguineous marriage, clinically diagnosed with USH1 by comprehensive clinical, audiological, and ophthalmological examinations. From the linkage results, the USH1G gene was screened for mutations by direct sequencing of the coding exons. Results We report the identification of a novel p.S243X truncating mutation in USH1G that segregated with the disease phenotype and was not present in 300 ethnically matched normal controls. We also report on the novel retinal findings and the outcome of cochlear implantation in the affected individuals. Conclusions In addition to reporting a novel truncating mutation, this report expands the retinal phenotype in USH1G and presents the first report of successful cochlear implants in this disease. PMID:22876113

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

    OpenAIRE

    Lambertus, Stanley; 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 vari...

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

    OpenAIRE

    Lambertus, S.; Bax, N. M.; Fakin, A.; Groenewoud, J. M. M.; Klevering, B. J.; Moore, A. T.; Michaelides, M.; Webster, A. R.; van der Wilt, G. J.; Hoyng, C. 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 ...

  4. Wallerian degeneration slow mouse neurons are protected against cell death caused by mechanisms involving mitochondrial electron transport dysfunction.

    Science.gov (United States)

    Tokunaga, Shinji; Araki, Toshiyuki

    2012-03-01

    Ischemia elicits a variety of stress responses in neuronal cells, which result in cell death. wld(S) Mice bear a mutation that significantly delays Wallerian degeneration. This mutation also protects all neuronal cells against other types of stresses resulting in cell death, including ischemia. To clarify the types of stresses that neuronal cell bodies derived from wld(S) mice are protected from, we exposed primary cultured neurons derived from wld(S) mice to various components of hypoxic stress. We found that wld(S) mouse neurons are protected against cellular injury induced by reoxygenation following hypoxic stress. Furthermore, we found that wld(S) mouse neurons are protected against functional impairment of the mitochondrial electron transport chain. These data suggest that Wld(S) protein expression may provide protection against neuronal cell death caused by mechanisms involving mitochondrial electron transport dysfunction. Copyright © 2011 Wiley Periodicals, Inc.

  5. Circulating Reactive Oxidant Causes Apoptosis of Retinal Pigment Epithelium and Cone Photoreceptors in the Mouse Central Retina

    Directory of Open Access Journals (Sweden)

    Wei Wang

    2011-01-01

    Full Text Available Reactive oxidants damage the retinal pigment epithelium (RPE, which is required for viability of overlying photoreceptors. Smoking which leads to chronic accumulation of reactive oxidants in the circulation is linked to age-related macular degeneration (AMD where RPE death is seen along with photoreceptor loss in the central macular region of the retina. It is unclear why this damage is concentrated in the central retina. We asked whether circulating oxidant might specifically target the central retina. Mice were administered the classic reactive oxidant iodate through tail vein injection, and visual acuity was followed by optokinetic response. Histology and apoptosis was examined by H&E and immunostaining. Iodate indeed selectively damaged the central retina, and this damage was highlighted by early apoptosis of RPE in the central retina followed by apoptosis of photoreceptors adjacent to the region of RPE loss–-cones were lost preferentially. The pattern and extent of this damage was independent of exposure to light. We then conclude that circulating oxidant is sufficient to selectively damage the central retina highlighted by sequential apoptosis of RPE and photoreceptors, with cones being the most sensitivity to this RPE loss.

  6. 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...... protein SDCCAG8 as causing NPHP type 10 in humans. To study the role of Sdccag8 in disease pathogenesis, we generated a Sdccag8 gene-trap mouse line. Homozygous Sdccag8(gt/gt) mice lacked the wild-type Sdccag8 transcript and protein, and recapitulated the human phenotypes of NPHP and retinal degeneration....... These mice exhibited early onset retinal degeneration that was associated with rhodopsin mislocalization in the photoreceptors and reduced cone cell numbers, and led to progressive loss of vision. By contrast, renal histologic changes occurred later, and no global ciliary defects were observed in the kidneys...

  7. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits

    NARCIS (Netherlands)

    Koppers, Max; Blokhuis, Anna M.; Westeneng, Henk Jan; Terpstra, Margo L.; Zundel, Caroline A C; Baptista Vieira de Sá, Renata; Schellevis, Raymond D.; Waite, Adrian J.; Blake, Derek J.; Veldink, Jan H.; Van Den Berg, Leonard H.; Pasterkamp, R. Jeroen

    2015-01-01

    Objective: How hexanucleotide (GGGGCC) repeat expansions in C9ORF72 cause amyotrophic lateral sclerosis (ALS) remains poorly understood. Both gain- and loss-of-function mechanisms have been proposed. Evidence supporting these mechanisms in vivo is, however, incomplete. Here we determined the effect

  8. Retinal Detachment

    Directory of Open Access Journals (Sweden)

    Adnan Riaz, MD

    2018-04-01

    Full Text Available History of present illness: A 58-year-old female presented to the emergency department reporting six days of progressive, atraumatic left eye vision loss. Her symptoms started with the appearance of dark spots and “spider webs,” and then progressed to darkening of vision in her left eye. She reports mild pain since yesterday. Her review of symptoms was otherwise negative. Ocular physical examination revealed normal external appearance, intact extraocular movements, and visual acuities of 20/25 OD and light/dark sensitivity OS. Fluorescein uptake was negative and slit lamp exam was unremarkable. Significant findings: Bedside ocular ultrasound revealed a serpentine, hyperechoic membrane that appeared tethered to the optic disc posteriorly with hyperechoic material underneath. These findings are consistent with retinal detachment (RD and associated retinal hemorrhage. Discussion: The retina is a layer of organized neurons that line the posterior portion of the posterior chamber of the eye. RD occurs when this layer separates from the underlying epithelium, resulting in ischemia and progressive photoreceptor degeneration, with potentially rapid and permanent vision loss if left untreated.1 Risk factors include advanced age, male sex (60%, race (Asians and Jews, and myopia and lattice degeneration.2 Bedside ultrasound (US performed by emergency physicians provides a valuable tool that has been used by ophthalmologists for decades to evaluate intraocular disease.1,3 Findings on bedside ultrasound consistent with RD include a hyperechoic membrane floating in the posterior chamber. RD usuallyremain tethered to the optic disc posteriorly and do not cross midline, a feature distinguishing them from posterior vitreous detachments. Associated retinal hemorrhage, seen as hyperechoic material under the retinal flap, can often be seen.1,2 US can also distinguish between “mac-on” and “mac-off” detachments. If the retina is still attached to the

  9. Cytomegalovirus (CMV) Infection Causes Degeneration of Cochlear Vasculature and Hearing Loss in a Mouse Model.

    Science.gov (United States)

    Carraro, Mattia; Almishaal, Ali; Hillas, Elaine; Firpo, Matthew; Park, Albert; Harrison, Robert V

    2017-04-01

    Cytomegalovirus (CMV) infection is one of the most common causes of congenital hearing loss in children. We have used a murine model of CMV infection to reveal functional and structural cochlear pathogenesis. The cerebral cortex of Balb/c mice (Mus musculus) was inoculated with 2000 pfu (plaque forming units) of murine CMV on postnatal day 3. At 6 weeks of age, cochlear function was monitored using auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measures. Histological assessment of cochlear vasculature using a corrosion cast technique was made at 8 weeks. Vascular casts of mCMV-damaged cochleas, and those of untreated control animals, were examined using scanning electron microscopy. We find very large variations in the degree of vascular damage in animals given identical viral injections (2000 pfu). The primary lesion caused by CMV infection is to the stria vascularis and to the adjacent spiral limbus capillary network. Capillary beds of the spiral ligament are generally less affected. The initial vascular damage is found in the mid-apical turn and appears to progress to more basal cochlear regions. After viral migration to the inner ear, the stria vascularis is the primary affected structure. We suggest that initial auditory threshold losses may relate to the poor development or maintenance of the endocochlear potential caused by strial dysfunction. Our increased understanding of the pathogenesis of CMV-related hearing loss is important for defining methods for early detection and treatment.

  10. Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene.

    Science.gov (United States)

    Shaibani, Aziz; Wong, Lee-Jun; Wei Zhang, Victor; Lewis, Richard Alan; Shinawi, Marwan

    2015-01-01

    Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G > A (p.R516Q) and c.1593+5_+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy.

  11. Neurodevelopmental disruption of cortico-striatal function caused by degeneration of habenula neurons.

    Directory of Open Access Journals (Sweden)

    Young-A Lee

    2011-04-01

    Full Text Available The habenula plays an important role on cognitive and affective functions by regulating monoamines transmission such as the dopamine and serotonin, such that its dysfunction is thought to underlie a number of psychiatric conditions. Given that the monoamine systems are highly vulnerable to neurodevelopmental insults, damages in the habenula during early neurodevelopment may cause devastating effects on the wide-spread brain areas targeted by monoamine innervations.Using a battery of behavioral, anatomical, and biochemical assays, we examined the impacts of neonatal damage in the habenula on neurodevelopmental sequelae of the prefrontal cortex (PFC and nucleus accumbens (NAcc and associated behavioral deficits in rodents. Neonatal lesion of the medial and lateral habenula by ibotenic acid produced an assortment of behavioral manifestations consisting of hyper-locomotion, impulsivity, and attention deficit, with hyper-locomotion and impulsivity being observed only in the juvenile period, whereas attention deficit was sustained up until adulthood. Moreover, these behavioral alterations were also improved by amphetamine. Our study further revealed that impulsivity and attention deficit were associated with disruption of PFC volume and dopamine (DA receptor expression, respectively. In contrast, hyper-locomotion was associated with decreased DA transporter expression in the NAcc. We also found that neonatal administration of nicotine into the habenula of neonatal brains produced selective lesion of the medial habenula. Behavioral deficits with neonatal nicotine administration were similar to those caused by ibotenic acid lesion of both medial and lateral habenula during the juvenile period, whereas they were different in adulthood.Because of similarity between behavioral and brain alterations caused by neonatal insults in the habenula and the symptoms and suggested neuropathology in attention deficit/hyperactivity disorder (ADHD, these results

  12. [The incidence of retinal tears in patients with posterior vitreous detachment].

    Science.gov (United States)

    Karaman, Ksenija; Gverović-Antunica, Antonela; Bućan, Kajo; Znaor, Ljubo; Bulović, Dijana; Skelin, Sinia

    2006-01-01

    Posterior vitreous detachment (PVD) is a common finding in older patients, characterized by detachment of the posterior hyaloid membrane (PHM) from the retinal surface. The detachment of PHM normally occurs without complications, however, one has to be aware that retinal tear is its most common complication. The aim of the study was to determine the incidence of retinal tears in eyes with PVD. A series of 40 patients (70 eyes) with PVD were included in this retrospective study. Eyes with a history of ocular trauma, surgery or intraocular inflammation were excluded. Patient charts were reviewed to collect the following information: age, sex, profession, type and duration of symptoms, best corrected visual acuity, refractive status, prior ocular disease, coincidental retinal pathology-lattice degeneration, number, type and location of retinal tears and treatment. Statistical analysis was done with the SPSS 11.0.3 software (SPSS Inc., USA). Besides descriptive statistics, Student's t-test and chi2-test were used. Among all study eyes with PVD, 34 (48.6%) were myopic, 24 (34.3%) hypermetropic and 12 (17.1%) emetropic; statistical analysis showed a significant difference (chi2 = 10.40, df=2, p lattice malignant degeneration of peripheral retinal was diagnosed. Thorough examination of the fundus periphery revealed 16 (22.8%) eyes with PVD were found to have retinal tears, 11 (15.7%) had only one retinal tear and 5 (7.1%) two retinal tears. All retinal tears were treated with argon laser photocoagulation. Superotemporal eye quadrant was the most common localization of retinal tears (56.25%). These results indicate that thorough fundus periphery examination should be done in all patients with PVD because it can cause rather rarely though retinal tears that represent a potentially sight threatening condition.

  13. Retinal detachment in black South Africans

    African Journals Online (AJOL)

    low incidence of retinal detachment in black patients is not known. ... a retinal break. Predisposing factors include peripheral retinal degenerations, myopia, aphakia and trauma. Delay in presentation increases the difficulty in achieving adequate surgical ... On examination, note was taken of the visual acuity in both eyes, the ...

  14. Inherited Retinal Degenerative Disease Registry

    Science.gov (United States)

    2017-09-13

    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

  15. Superior cervical gangliectomy induces non-exudative age-related macular degeneration in mice

    Directory of Open Access Journals (Sweden)

    Hernán H. Dieguez

    2018-02-01

    Full Text Available Non-exudative age-related macular degeneration, a prevalent cause of blindness, is a progressive and degenerative disease characterized by alterations in Bruch's membrane, retinal pigment epithelium, and photoreceptors exclusively localized in the macula. Although experimental murine models exist, the vast majority take a long time to develop retinal alterations and, in general, these alterations are ubiquitous, with many resulting from non-eye-specific genetic manipulations; additionally, most do not always reproduce the hallmarks of human age-related macular degeneration. Choroid vessels receive sympathetic innervation from the superior cervical ganglion, which, together with the parasympathetic system, regulates blood flow into the choroid. Choroid blood flow changes have been involved in age-related macular degeneration development and progression. At present, no experimental models take this factor into account. The aim of this work was to analyze the effect of superior cervical gangliectomy (also known as ganglionectomy on the choroid, Bruch's membrane, retinal pigment epithelium and retina. Adult male C57BL/6J mice underwent unilateral superior cervical gangliectomy and a contralateral sham procedure. Although superior cervical gangliectomy induced ubiquitous choroid and choriocapillaris changes, it induced Bruch's membrane thickening, loss of retinal pigment epithelium melanin content and retinoid isomerohydrolase, the appearance of drusen-like deposits, and retinal pigment epithelium and photoreceptor atrophy, exclusively localized in the temporal side. Moreover, superior cervical gangliectomy provoked a localized increase in retinal pigment epithelium and photoreceptor apoptosis, and a decline in photoreceptor electroretinographic function. Therefore, superior cervical gangliectomy recapitulated the main features of human non-exudative age-related macular degeneration, and could become a new experimental model of dry age

  16. Superior cervical gangliectomy induces non-exudative age-related macular degeneration in mice.

    Science.gov (United States)

    Dieguez, Hernán H; Romeo, Horacio E; González Fleitas, María F; Aranda, Marcos L; Milne, Georgia A; Rosenstein, Ruth E; Dorfman, Damián

    2018-02-07

    Non-exudative age-related macular degeneration, a prevalent cause of blindness, is a progressive and degenerative disease characterized by alterations in Bruch's membrane, retinal pigment epithelium, and photoreceptors exclusively localized in the macula. Although experimental murine models exist, the vast majority take a long time to develop retinal alterations and, in general, these alterations are ubiquitous, with many resulting from non-eye-specific genetic manipulations; additionally, most do not always reproduce the hallmarks of human age-related macular degeneration. Choroid vessels receive sympathetic innervation from the superior cervical ganglion, which, together with the parasympathetic system, regulates blood flow into the choroid. Choroid blood flow changes have been involved in age-related macular degeneration development and progression. At present, no experimental models take this factor into account. The aim of this work was to analyze the effect of superior cervical gangliectomy (also known as ganglionectomy) on the choroid, Bruch's membrane, retinal pigment epithelium and retina. Adult male C57BL/6J mice underwent unilateral superior cervical gangliectomy and a contralateral sham procedure. Although superior cervical gangliectomy induced ubiquitous choroid and choriocapillaris changes, it induced Bruch's membrane thickening, loss of retinal pigment epithelium melanin content and retinoid isomerohydrolase, the appearance of drusen-like deposits, and retinal pigment epithelium and photoreceptor atrophy, exclusively localized in the temporal side. Moreover, superior cervical gangliectomy provoked a localized increase in retinal pigment epithelium and photoreceptor apoptosis, and a decline in photoreceptor electroretinographic function. Therefore, superior cervical gangliectomy recapitulated the main features of human non-exudative age-related macular degeneration, and could become a new experimental model of dry age-related macular degeneration, and

  17. Towards a Completely Implantable, Light-Sensitive Intraocular Retinal Prosthesis

    National Research Council Canada - National Science Library

    Humayun, M

    2001-01-01

    An electronic retinal prosthesis is under development to treat retinitis pigmentosa and age-related macular degeneration, two presently incurable diseases of the outer retina that afflict millions world-wide...

  18. The complement system in age-related macular degeneration: A review of rare genetic variants and implications for personalized treatment

    NARCIS (Netherlands)

    Geerlings, M.J.; Jong, E.K.; Hollander, A.I. den

    2017-01-01

    Age-related macular degeneration (AMD) is a progressive retinal disease and the major cause of irreversible vision loss in the elderly. Numerous studies have found both common and rare genetic variants in the complement pathway to play a role in the pathogenesis of AMD. In this review we provide an

  19. Involvement of a gut-retina axis in protection against dietary glycemia induced age-related macular degeneration

    Science.gov (United States)

    Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial cell (RPE) dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns on risk for AMD, but th...

  20. THE ORGANOPHOSPHOROUS INSECTICIDE FENTHION DOES NOT AFFECT PHAGOCYTOSIS OF ROD OUTER SEGMENTS BY RETINAL PIGMENT EPITHELIUM CELLS IN CULTURE.

    Science.gov (United States)

    :Exposure to the organophosphorous insecticide fenthion has been associated with retinal degeneration in occupational studies. It has also been associated with pigmentary changes of the retina. Because retinal degeneration and pigmentary changes may be due to dysfunction of t...

  1. Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations

    Directory of Open Access Journals (Sweden)

    Kocerha Jannet

    2011-10-01

    Full Text Available Abstract Background Frontotemporal lobar degeneration (FTLD is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP caused by genetic mutations in the progranulin (PGRN gene. Results Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P PGRN mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p were also significantly dysregulated (unadjusted P PGRN mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology. Conclusions Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by PGRN mutations and provides new insight into potential future therapeutic options.

  2. α-Synuclein deficiency and efferent nerve degeneration in the mouse cochlea: a possible cause of early-onset presbycusis.

    Science.gov (United States)

    Park, S N; Back, S A; Choung, Y H; Kim, H L; Akil, O; Lustig, L R; Park, K H; Yeo, S W

    2011-11-01

    Efferent nerves under the outer hair cells (OHCs) play a role in the protection of these cells from loud stimuli. Previously, we showed that cochlear α-synuclein expression is localized to efferent auditory synapses at the base of the OHCs. To prove our hypothesis that α-synuclein deficiency and efferent auditory deficit might be a cause of hearing loss, we compared the morphology of efferent nerve endings and α-synuclein expression within the cochleae of two mouse models of presbycusis. Comparative animal study of presbycusis. The C57BL/6J(C57) mouse strain, a well-known model of early-onset hearing loss, and the CBA mouse strain, a model of relatively late-onset hearing loss, were examined. Auditory brainstem responses and distortion product otoacoustic emissions were recorded, and cochlear morphology with efferent nerve ending was compared. Western blotting was used to examine α-synuclein expression in the cochlea. Compared with CBA mice, C57 mice showed earlier onset high-frequency hearing loss and decreased function in OHCs, especially within high-frequency regions. C57 mice demonstrated more severe pathologic changes within the cochlea, particularly within the basal turn, than CBA mice of the same age. Weaker α-synuclein and synaptophysin expression in the efferent nerve endings and cochlear homogenates in C57 mice was observed. Our results support the hypothesis that efferent nerve degeneration, possibly due to differential α-synuclein expression, is a potential cause of early-onset presbycusis. Further studies at the cellular level are necessary to verify our results. Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  3. Digital quantification of Goldmann visual fields (GVFs) as a means for genotype-phenotype comparisons and detection of progression in retinal degenerations.

    Science.gov (United States)

    Zahid, Sarwar; Peeler, Crandall; Khan, Naheed; Davis, Joy; Mahmood, Mahdi; Heckenlively, John R; Jayasundera, Thiran

    2014-01-01

    To develop a reliable and efficient digital method to quantify planimetric Goldmann visual field (GVF) data to monitor disease course and treatment responses in retinal degenerative diseases. A novel method to digitally quantify GVFs using Adobe Photoshop CS3 was developed for comparison to traditional digital planimetry (Placom 45C digital planimeter; Engineer Supply, Lynchburg, Virginia, USA). GVFs from 20 eyes from 10 patients with Stargardt disease were quantified to assess the difference between the two methods (a total of 230 measurements per method). This quantification approach was also applied to 13 patients with X-linked retinitis pigmentosa (XLRP) with mutations in RPGR. Overall, measurements using Adobe Photoshop were more rapidly performed than those using conventional planimetry. Photoshop measurements also exhibited less inter- and intraobserver variability. GVF areas for the I4e isopter in patients with the same mutation in RPGR who were nearby in age had similar qualitative and quantitative areas. Quantification of GVFs using Adobe Photoshop is quicker, more reliable, and less user dependent than conventional digital planimetry. It will be a useful tool for both retrospective and prospective studies of disease course as well as for monitoring treatment response in clinical trials for retinal degenerative diseases.

  4. Digital Quantification of Goldmann Visual Fields (GVF) as a Means for Genotype-Phenotype Comparisons and Detection of Progression in Retinal Degenerations

    Science.gov (United States)

    Zahid, Sarwar; Peeler, Crandall; Khan, Naheed; Davis, Joy; Mahmood, Mahdi; Heckenlively, John; Jayasundera, Thiran

    2015-01-01

    Purpose To develop a reliable and efficient digital method to quantify planimetric Goldmann visual field (GVF) data to monitor disease course and treatment responses in retinal degenerative diseases. Methods A novel method to digitally quantify GVF using Adobe Photoshop CS3 was developed for comparison to traditional digital planimetry (Placom 45C digital planimeter; EngineerSupply, Lynchburg, Virginia, USA). GVFs from 20 eyes from 10 patients with Stargardt disease were quantified to assess the difference between the two methods (a total of 230 measurements per method). This quantification approach was also applied to 13 patients with X-linked retinitis pigmentosa (XLRP) with mutations in RPGR. Results Overall, measurements using Adobe Photoshop were more rapidly performed than those using conventional planimetry. Photoshop measurements also exhibited less inter- and intra-observer variability. GVF areas for the I4e isopter in patients with the same mutation in RPGR who were nearby in age had similar qualitative and quantitative areas. Conclusions Quantification of GVF using Adobe Photoshop is quicker, more reliable, and less-user dependent than conventional digital planimetry. It will be a useful tool for both retrospective and prospective studies of disease course as well as for monitoring treatment response in clinical trials for retinal degenerative diseases. PMID:24664690

  5. 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

  6. Retinal stem cells and potential cell transplantation treatments

    Directory of Open Access Journals (Sweden)

    Tai-Chi Lin

    2014-11-01

    Full Text Available 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.

  7. Segmented inner plexiform layer thickness as a potential biomarker to evaluate open-angle glaucoma: Dendritic degeneration of retinal ganglion cell.

    Directory of Open Access Journals (Sweden)

    Eun Kyoung Kim

    Full Text Available To evaluate the changes of retinal nerve fiber layer (RNFL, ganglion cell layer (GCL, inner plexiform layer (IPL, and ganglion cell-inner plexiform layer (GCIPL thicknesses and compare structure-function relationships of 4 retinal layers using spectral-domain optical coherence tomography (SD-OCT in macular region of glaucoma patients.In cross-sectional study, a total of 85 eyes with pre-perimetric to advanced glaucoma and 26 normal controls were enrolled. The glaucomatous eyes were subdivided into three groups according to the severity of visual field defect: a preperimetric glaucoma group, an early glaucoma group, and a moderate to advanced glaucoma group. RNFL, GCL, IPL, and GCIPL thicknesses were measured at the level of the macula by the Spectralis (Heidelberg Engineering, Heidelberg, Germany SD-OCT with automated segmentation software. For functional evaluation, corresponding mean sensitivity (MS values were measured using 24-2 standard automated perimetry (SAP.RNFL, GCL, IPL, and GCIPL thicknesses were significantly different among 4 groups (P < .001. Macular structure losses were positively correlated with the MS values of the 24-2 SAP for RNFL, GCL, IPL, and GCIPL (R = 0.553, 0.636, 0.648 and 0.646, respectively, P < .001. In regression analysis, IPL and GCIPL thicknesses showed stronger association with the corresponding MS values of 24-2 SAP compared with RNFL and GCL thicknesses (R2 = 0.420, P < .001 for IPL; R2 = 0.417, P< .001 for GCIPL thickness.Segmented IPL thickness was significantly associated with the degree of glaucoma. Segmental analysis of the inner retinal layer including the IPL in macular region may provide valuable information for evaluating glaucoma.

  8. Segmented inner plexiform layer thickness as a potential biomarker to evaluate open-angle glaucoma: Dendritic degeneration of retinal ganglion cell.

    Science.gov (United States)

    Kim, Eun Kyoung; Park, Hae-Young Lopilly; Park, Chan Kee

    2017-01-01

    To evaluate the changes of retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), and ganglion cell-inner plexiform layer (GCIPL) thicknesses and compare structure-function relationships of 4 retinal layers using spectral-domain optical coherence tomography (SD-OCT) in macular region of glaucoma patients. In cross-sectional study, a total of 85 eyes with pre-perimetric to advanced glaucoma and 26 normal controls were enrolled. The glaucomatous eyes were subdivided into three groups according to the severity of visual field defect: a preperimetric glaucoma group, an early glaucoma group, and a moderate to advanced glaucoma group. RNFL, GCL, IPL, and GCIPL thicknesses were measured at the level of the macula by the Spectralis (Heidelberg Engineering, Heidelberg, Germany) SD-OCT with automated segmentation software. For functional evaluation, corresponding mean sensitivity (MS) values were measured using 24-2 standard automated perimetry (SAP). RNFL, GCL, IPL, and GCIPL thicknesses were significantly different among 4 groups (P < .001). Macular structure losses were positively correlated with the MS values of the 24-2 SAP for RNFL, GCL, IPL, and GCIPL (R = 0.553, 0.636, 0.648 and 0.646, respectively, P < .001). In regression analysis, IPL and GCIPL thicknesses showed stronger association with the corresponding MS values of 24-2 SAP compared with RNFL and GCL thicknesses (R2 = 0.420, P < .001 for IPL; R2 = 0.417, P< .001 for GCIPL thickness). Segmented IPL thickness was significantly associated with the degree of glaucoma. Segmental analysis of the inner retinal layer including the IPL in macular region may provide valuable information for evaluating glaucoma.

  9. [Clinical Characteristics of Rhegmatogenous Retinal Detachment in Highly Myopic and Phakic Eyes].

    Science.gov (United States)

    Orihara, Tadashi; Hirota, Kazunari; Yokota, Reiji; Kunita, Daisuke; Itoh, Yuji; Rii, Tosho; Koto, Takashi; Hiraoka, Tomoyuki; Inoue, Makoto; Hirakata, Akito

    2016-05-01

    To evaluate clinical characteristics of rhegmatogenous retinal detachment in high myopic and phakic eyes. The subjects were 1174 eyes of phakic rhegmatogenous retinal detachment detected in 1199 eyes that underwent initial vitreoretinal surgery between April 2006 and March 2011. Eyes with macular hole retinal detachment or secondary retinal detachment were excluded. The 486 eyes with high myopia (spherical equivalent ≤ -6.0 D or axial length ≥ 26.5 mm) and the 688 eyes with non-high myopia were compared. The mean age was significantly younger in the high myopia group (42.7 ± 14.2 years old, p lattice degeneration were more frequent (16.7%, 20.4%, respectively). The incidences of the retinal detachment in younger age and those caused by retinal holes were higher in the high myopia group. Higher incidence of retinal detachment and lattice degeneration in the fellow eyes of the high myopia group indicated that careful observation also in the fellow eyes was recommended.

  10. Interleukin-17 retinotoxicity is prevented by gene transfer of a soluble interleukin-17 receptor acting as a cytokine blocker: implications for age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Daniel Ardeljan

    Full Text Available Age-related macular degeneration (AMD is a common yet complex retinal degeneration that causes irreversible central blindness in the elderly. Pathology is widely believed to follow loss of retinal pigment epithelium (RPE and photoreceptor degeneration. Here we report aberrant expression of interleukin-17A (IL17A and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. IL17-dependent retinal degeneration in a mouse model of focal retinal degeneration can be prevented by gene therapy with adeno-associated virus vector encoding soluble IL17 receptor. This intervention rescues RPE and photoreceptors in a MAPK-dependent process. The IL17 pathway plays a key role in RPE and photoreceptor degeneration and could hold therapeutic potential in AMD.

  11. 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.

  12. Optico-cochleo-dentate degeneration associated with severe peripheral neuropathy and caused by peroxisomal D-bifunctional protein deficiency

    NARCIS (Netherlands)

    Schröder, J. M.; Hackel, V.; Wanders, R. J. A.; Göhlich-Ratmann, G.; Voit, T.

    2004-01-01

    The clinical, neuroradiological, neuropathological and biochemical findings in a patient with optico-cochleo-dentate degeneration (OCDD; OMIM 258700) are presented in a severe case succumbing at the age of 4 years. The electron microscopic and biochemical data showed for the first time that OCDD may

  13. Age-Related Macular Degeneration: Advances in Management and Diagnosis

    Directory of Open Access Journals (Sweden)

    Yoshihiro Yonekawa

    2015-02-01

    Full Text Available Age-related macular degeneration (AMD is the most common cause of irreversible visual impairment in older populations in industrialized nations. AMD is a late-onset deterioration of photoreceptors and retinal pigment epithelium in the central retina caused by various environmental and genetic factors. Great strides in our understanding of AMD pathogenesis have been made in the past several decades, which have translated into revolutionary therapeutic agents in recent years. In this review, we describe the clinical and pathologic features of AMD and present an overview of current diagnosis and treatment strategies.

  14. C-terminal truncations in human 3 '-5 ' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

    NARCIS (Netherlands)

    Richards, Anna; van den Maagdenberg, Arn M. J. M.; Jen, Joanna C.; Kavanagh, David; Bertram, Paula; Spitzer, Dirk; Liszewski, M. Kathryn; Barilla-LaBarca, Maria-Louise; Terwindt, Gisela M.; Kasai, Yumi; McLellan, Mike; Grand, Mark Gilbert; Vanmolkot, Kaate R. J.; de Vries, Boukje; Wan, Jijun; Kane, Michael J.; Mamsa, Hafsa; Schaefer, Ruth; Stam, Anine H.; Haan, Joost; Paulus, T. V. M. de Jong; Storimans, Caroline W.; van Schooneveld, Mary J.; Oosterhuis, Jendo A.; Gschwendter, Andreas; Dichgans, Martin; Kotschet, Katya E.; Hodgkinson, Suzanne; Hardy, Todd A.; Delatycki, Martin B.; Hajj-Ali, Rula A.; Kothari, Parul H.; Nelson, Stanley F.; Frants, Rune R.; Baloh, Robert W.; Ferrari, Michel D.; Atkinson, John P.

    Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease

  15. Retinal protective effects of topically administered agmatine on ischemic ocular injury caused by transient occlusion of the ophthalmic artery

    Directory of Open Access Journals (Sweden)

    S. Hong

    2012-03-01

    Full Text Available Agmatine, an endogenous polyamine and putative neuromodulator, is known to have neuroprotective effects on various neurons in the central nervous system. We determined whether or not topically administered agmatine could reduce ischemic retinal injury. Transient ocular ischemia was achieved by intraluminal occlusion of the middle cerebral artery of ddY mice (30-35 g for 2 h, which is known to also induce occlusion of the ophthalmic artery. In the agmatine group (N = 6, a 1.0 mM agmatine-containing ophthalmic solution was administered four times daily for 2 weeks before occlusion. In the control group (N = 6, a 0.1% hyaluronic acid ophthalmic solution was instilled at the same times. At 22 h after reperfusion, the eyeballs were enucleated and the retinal sections were stained by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL. Transient ocular ischemia induced apoptosis of retinal cells in the entire retinal layer, and topically administered agmatine can significantly reduce this ischemic retinal injury. The proportion of apoptotic cells was definitely decreased (P < 0.001; Kruskal-Wallis test. Overall, we determined that topical agmatine application effectively decreases retinal damage in an in vivo ocular ischemic injury model. This implies that agmatine is a good candidate as a direct neuroprotective agent for eyes with ocular ischemic diseases.

  16. Retinal protective effects of topically administered agmatine on ischemic ocular injury caused by transient occlusion of the ophthalmic artery

    Science.gov (United States)

    Hong, S.; Hara, H.; Shimazawa, M.; Hyakkoku, K.; Kim, C.Y.; Seong, G.J.

    2012-01-01

    Agmatine, an endogenous polyamine and putative neuromodulator, is known to have neuroprotective effects on various neurons in the central nervous system. We determined whether or not topically administered agmatine could reduce ischemic retinal injury. Transient ocular ischemia was achieved by intraluminal occlusion of the middle cerebral artery of ddY mice (30-35 g) for 2 h, which is known to also induce occlusion of the ophthalmic artery. In the agmatine group (N = 6), a 1.0 mM agmatine-containing ophthalmic solution was administered four times daily for 2 weeks before occlusion. In the control group (N = 6), a 0.1% hyaluronic acid ophthalmic solution was instilled at the same times. At 22 h after reperfusion, the eyeballs were enucleated and the retinal sections were stained by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Transient ocular ischemia induced apoptosis of retinal cells in the entire retinal layer, and topically administered agmatine can significantly reduce this ischemic retinal injury. The proportion of apoptotic cells was definitely decreased (P agmatine application effectively decreases retinal damage in an in vivo ocular ischemic injury model. This implies that agmatine is a good candidate as a direct neuroprotective agent for eyes with ocular ischemic diseases. PMID:22331138

  17. Retinitis pigmentosa: genes and disease mechanisms.

    Science.gov (United States)

    Ferrari, Stefano; Di Iorio, Enzo; Barbaro, Vanessa; Ponzin, Diego; Sorrentino, Francesco S; Parmeggiani, Francesco

    2011-06-01

    Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium of the retina which lead to progressive visual loss. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. While usually limited to the eye, RP may also occur as part of a syndrome as in the Usher syndrome and Bardet-Biedl syndrome. Over 40 genes have been associated with RP so far, with the majority of them expressed in either the photoreceptors or the retinal pigment epithelium. The tremendous heterogeneity of the disease makes the genetics of RP complicated, thus rendering genotype-phenotype correlations not fully applicable yet. In addition to the multiplicity of mutations, in fact, different mutations in the same gene may cause different diseases. We will here review which genes are involved in the genesis of RP and how mutations can lead to retinal degeneration. In the future, a more thorough analysis of genetic and clinical data together with a better understanding of the genotype-phenotype correlation might allow to reveal important information with respect to the likelihood of disease development and choices of therapy.

  18. Clinicopathological report of retinitis pigmentosa with vitamin E deficiency caused by mutation of the alpha-tocopherol transfer protein gene.

    Science.gov (United States)

    Pang, J; Kiyosawa, M; Seko, Y; Yokota, T; Harino, S; Suzuki, J

    2001-01-01

    To discuss the clinicopathological findings in a patient with retinitis pigmentosa (RP) accompanied by a vitamin E deficiency caused by an H101Q mutation in the alpha-tocopherol transfer protein (alpha-TTP) gene. The clinical course of this patient was followed by conventional ophthalmological examinations over a 3-year period. After the patient died from pancreatic cancer, the eyes were obtained, and examined by light and electron microscopy. The patient complained of night blindness subsequent to adult-onset ataxia, although the ataxia was very mild. His visual acuity was 0.6 OU, and ophthalmoscopy revealed RP sine pigmento. Ring scotomas were detected, and the electroretinography, electro-oculography, and dark-adaptation were altered. Fluorescein angiography showed granular hyperfluorescence around the macula. No progression of the visual and neurological symptoms was observed during the 10 years he was taking oral vitamin E. Histopathological examination revealed the loss of the outer and inner segments of the photoreceptors in the area corresponding to the ring scotoma, as well as a disorganization and shortening of the outer segments in the peripheral retina. We conclude that the clinical and pathological findings in the eyes of this patient having RP with vitamin E deficiency caused by an H101Q mutation are similar to those of common autosomal recessive RP. However, special attention is required in making a diagnosis of RP with vitamin E deficiency because RP with vitamin E deficiency is medically treatable. The mild Friedreich-type ataxia accompanying the RP may be helpful in identifying this disease.

  19. Advances in Bone Marrow Stem Cell Therapy for Retinal Dysfunction

    Science.gov (United States)

    Park, Susanna S.; Moisseiev, Elad; Bauer, Gerhard; Anderson, Johnathon D.; Grant, Maria B.; Zam, Azhar; Zawadzki, Robert J.; Werner, John S.; Nolta, Jan A.

    2016-01-01

    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 retina. These stem cells have primarily paracrine trophic effects although some cells can directly incorporate into damaged tissue. Since the paracrine trophic effects can have regenerative effects on multiple cells in the retina, the use of this cell therapy is not limited to a particular retinal condition. Autologous bone marrow-derived stem cells are being explored in early clinical trials as therapy for various retinal conditions. These bone marrow stem cells include mesenchymal stem cells, mononuclear cells and CD34+ cells. Autologous therapy requires no systemic immunosuppression or donor matching. Intravitreal delivery of CD34+ cells and mononuclear cells appears to be tolerated and is being explored since some of these cells can home into the damaged retina after intravitreal administration. The safety of intravitreal delivery of mesenchymal stem cells has not been well established. This review provides an update of the current evidence in support of the use of bone marrow stem cells as treatment for retinal dysfunction. The potential limitations and complications of using certain forms of bone marrow stem cells as therapy are discussed. Future directions of research include methods to optimize the therapeutic potential of these stem cells, non-cellular alternatives using extracellular vesicles, and in vivo high-resolution retinal imaging to detect cellular changes in the retina following cell therapy. PMID:27784628

  20. Compromised Integrity of Central Visual Pathways in Patients With Macular Degeneration.

    Science.gov (United States)

    Malania, Maka; Konrad, Julia; Jägle, Herbert; Werner, John S; Greenlee, Mark W

    2017-06-01

    Macular degeneration (MD) affects the central retina and leads to gradual loss of foveal vision. Although, photoreceptors are primarily affected in MD, the retinal nerve fiber layer (RNFL) and central visual pathways may also be altered subsequent to photoreceptor degeneration. Here we investigate whether retinal damage caused by MD alters microstructural properties of visual pathways using diffusion-weighted magnetic resonance imaging. Six MD patients and six healthy control subjects participated in the study. Retinal images were obtained by spectral-domain optical coherence tomography (SD-OCT). Diffusion tensor images (DTI) and high-resolution T1-weighted structural images were collected for each subject. We used diffusion-based tensor modeling and probabilistic fiber tractography to identify the optic tract (OT) and optic radiations (OR), as well as nonvisual pathways (corticospinal tract and anterior fibers of corpus callosum). Fractional anisotropy (FA) and axial and radial diffusivity values (AD, RD) were calculated along the nonvisual and visual pathways. Measurement of RNFL thickness reveals that the temporal circumpapillary retinal nerve fiber layer was significantly thinner in eyes with macular degeneration than normal. While we did not find significant differences in diffusion properties in nonvisual pathways, patients showed significant changes in diffusion scalars (FA, RD, and AD) both in OT and OR. The results indicate that the RNFL and the white matter of the visual pathways are significantly altered in MD patients. Damage to the photoreceptors in MD leads to atrophy of the ganglion cell axons and to corresponding changes in microstructural properties of central visual pathways.

  1. Perspectives of Stem Cell-Based Therapy for Age-Related Retinal Degenerative Diseases.

    Science.gov (United States)

    Holan, Vladimir; Hermankova, Barbora; Kossl, Jan

    2017-09-01

    Retinal degenerative diseases, which include age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and glaucoma, mostly affect the elderly population and are the most common cause of decreased quality of vision or even blindness. So far, there is no satisfactory treatment protocol to prevent, stop, or cure these disorders. A great hope and promise for patients suffering from retinal diseases is represented by stem cell-based therapy that could replace diseased or missing retinal cells and support regeneration. In this respect, mesenchymal stem cells (MSCs) that can be obtained from the particular patient and used as autologous cells have turned out to be a promising stem cell type for treatment. Here we show that MSCs can differentiate into cells expressing markers of retinal cells, inhibit production of pro-inflammatory cytokines by retinal tissue, and produce a number of growth and neuroprotective factors for retinal regeneration. All of these properties make MSCs a prospective cell type for cell-based therapy of age-related retinal degenerative diseases.

  2. Early rhegmatogenous retinal detachment following laser in situ keratomileusis for high myopia.

    Science.gov (United States)

    Farah, M E; Höfling-Lima, A L; Nascimento, E

    2000-01-01

    Four eyes had early rhegmatogenous retinal detachment within 3 months of laser in situ keratomileusis (LASIK) for correction of high myopia using the microkeratome, Clear Corneal Molder. In two eyes, retinal detachment resulted from horseshoe tears, one occurring in an otherwise normal region of the retina and the other at the margin of an area of lattice degeneration detected during preoperative examination. The first eye was treated with retinopexy using a 287 encircling scleral exoplant, drainage of subretinal fluid, and laser photocoagulation by indirect ophthalmoscopy. The other eye was treated with pneumatic retinopexy and cryotherapy. In the other eyes, retinal detachment was the result of giant tears with no evidence of prior retinal degeneration. These eyes were treated with pars plana vitrectomy, fluid-gas exchange with 15% perfluoropropane (C3F8), endolaser photocoagulation, and a 42 encircling scleral exoplant. After treatment, the first two eyes achieved spectacle-corrected visual acuity of 20/40. In the last two eyes, final spectacle-corrected visual acuity was 20/400 in one eye and light perception in the other. Although no cause-effect relationship between LASIK and retinal detachment can be stated, these cases suggest that LASIK may be associated with retinal detachment, particularly in highly myopic eyes. Further studies are necessary to determine high-risk patient characteristics.

  3. Host cell reactivation by fibroblasts from patients with pigmentary degeneration of the retina

    International Nuclear Information System (INIS)

    Lytle, C.D.; Tarone, R.E.; Barrett, S.F.; Robbins, J.H.; Wirtschafter, J.D.; Dupuy, J.-M.

    1983-01-01

    Cockayne syndrome (CS) is an autosomal recessive disease characterized by numerous clinical abnormalities including acute sun sensitivity and primary pigmentary degeneration of the retina. Cultured fibroblasts from CS patients are hypersensitive to ultraviolet radiation. Host cell reactivation of irradiated virus was studied in CS and in other diseases with retinal degeneration to evaluate repair. The survival of UV-irradiated Herpes simplex virus type 1 was determined in fibroblast lines from four normal donors, two patients with CS, one with both xeroderma pigmentosum (XP) and CS, and from several other patients with (Usher syndrome, olivopontocerebellar atrophy, retinitis pigmentosa) and without (XP, ataxia telangiectasia) primary pigmentary degeneration of the retina. The viral survival curves in all cell lines showed two components: a very sensitive initial component followed by an exponential, less sensitive component. The exponential component had greater sensitivity than normal in the case of the CS patients, the patient with both XP and CS, and the XP patient. It was proposed that patients with CS have defective repair of DNA which may be the cause of their retinal degeneration. (author)

  4. Host cell reactivation by fibroblasts from patients with pigmentary degeneration of the retina

    Energy Technology Data Exchange (ETDEWEB)

    Lytle, C.D. (Food and Drug Administration, Rockville, MD (USA)); Tarone, R.E.; Barrett, S.F.; Robbins, J.H. (National Cancer Inst., Bethesda, MD (USA)); Wirtschafter, J.D. (Minnesota Univ., Minneapolis (USA). Hospitals); Dupuy, J.M. (Quebec Univ., Laval-des-Rapides (Canada). Inst. Armand-Frappier)

    1983-05-01

    Cockayne syndrome (CS) is an autosomal recessive disease characterized by numerous clinical abnormalities including acute sun sensitivity and primary pigmentary degeneration of the retina. Cultured fibroblasts from CS patients are hypersensitive to ultraviolet radiation. Host cell reactivation of irradiated virus was studied in CS and in other diseases with retinal degeneration to evaluate repair. The survival of UV-irradiated Herpes simplex virus type 1 was determined in fibroblast lines from four normal donors, two patients with CS, one with both xeroderma pigmentosum (XP) and CS, and from several other patients with (Usher syndrome, olivopontocerebellar atrophy, retinitis pigmentosa) and without (XP, ataxia telangiectasia) primary pigmentary degeneration of the retina. The viral survival curves in all cell lines showed two components: a very sensitive initial component followed by an exponential, less sensitive component. The exponential component had greater sensitivity than normal in the case of the CS patients, the patient with both XP and CS, and the XP patient. It was proposed that patients with CS have defective repair of DNA which may be the cause of their retinal degeneration.

  5. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy.

    NARCIS (Netherlands)

    Otto, E.A.; Hurd, T.W.; Airik, R.; Chaki, M.; Zhou, W.; Stoetzel, C.; Patil, S.B.; Levy, S.; Ghosh, A.K.; Murga-Zamalloa, C.A.; Reeuwijk, J. van; Letteboer, S.J.F.; Sang, L.; Giles, R.H.; Liu, Q.; Coene, K.L.M.; Estrada-Cuzcano, A.; Collin, R.W.J.; McLaughlin, H.M.; Held, S.; Kasanuki, J.M.; Ramaswami, G.; Conte, J.; Lopez, I.; Washburn, J.; Macdonald, J.; Hu, J.; Yamashita, Y.; Maher, E.R.; Guay-Woodford, L.M.; Neumann, H.P.; Obermuller, N.; Koenekoop, R.K.; Bergmann, C.; Bei, X.; Lewis, R.A.; Katsanis, N.; Lopes, V.; Williams, D.S.; Lyons, R.H.; Dang, C.V.; Brito, D.A.; Dias, M.B.; Zhang, X.; Cavalcoli, J.D.; Nurnberg, G.; Nurnberg, P.; Pierce, E.A.; Jackson, P.K.; Antignac, C.; Saunier, S.; Roepman, R.; Dollfus, H.; Khanna, H.; Hildebrandt, F.

    2010-01-01

    Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed

  6. 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.

  7. Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Wenhu, E-mail: wenhu.huang@pfizer.com; Collette, Walter; Twamley, Michelle; Aguirre, Shirley A.; Sacaan, Aida

    2015-12-15

    Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at ≥ 10 μg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 μg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at ≥ 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 μg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements. - Highlights: • There were strong correlations of ERG readouts to in vivo ophthalmic exams, TUNEL assay, and histopathology. • ERG appears to be more sensitive and can detect retinal functional changes at a very early stage of pathogenesis. • ERG can be incorporated into routine exploratory toxicity study to identify compound ocular safety issues. • In drug discovery, ERG is a quick, non-invasive, sensitive and reliable tool in retinal toxicity de-risking.

  8. Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats

    International Nuclear Information System (INIS)

    Huang, Wenhu; Collette, Walter; Twamley, Michelle; Aguirre, Shirley A.; Sacaan, Aida

    2015-01-01

    Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at ≥ 10 μg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 μg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at ≥ 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 μg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements. - Highlights: • There were strong correlations of ERG readouts to in vivo ophthalmic exams, TUNEL assay, and histopathology. • ERG appears to be more sensitive and can detect retinal functional changes at a very early stage of pathogenesis. • ERG can be incorporated into routine exploratory toxicity study to identify compound ocular safety issues. • In drug discovery, ERG is a quick, non-invasive, sensitive and reliable tool in retinal toxicity de-risking.

  9. Premature Tapetum Degeneration: a Major Cause of Abortive Pollen Development in Photoperiod Sensitive Genic Male Sterility in Rice

    Institute of Scientific and Technical Information of China (English)

    Yinlian Shi; Sha Zhao; Jialing Yao

    2009-01-01

    Photoperiod-sensitive genic male-sterile (PSGMS) rice (Oryza sativa L.), a natural mutant found in the rice cultivar Nongken 58, is very useful for the development of hybrid rice cultivars. Despite its widespread use in breeding programs, the initial stage of the abortive development of PSGMS rice and the possible cytological mechanisms of pollen abortion have not been determined. In the present study, a systematic cytological comparison of the anther development of PSGMS rice with its normal fertile counterpart is conducted. The results show that pollen abortion in PSGMS rice first occurs before the pollen mother cell (PMC) stage, and continues during the entire process of pollen development until pollen degradation. The abortive process was closely associated with the abnormal behavior of the tapetum. Although tapetum degeneration in PSGMS rice initiates already at the PMC stage, it proceeds slowly and does not complete until the breakdown of the pollen. Such cytological observations were supported by the results of the TUNEL (TdT-mediated dUTP Nick End Labeling) assay, which detects DNA fragmentation resulting from programmed cell death (PCD), indicating that the premature tapetum degeneration is in the process of PCD.

  10. Acute retinal ischemia caused by controlled low ocular perfusion pressure in a porcine model. Electrophysiological and histological characterisation

    DEFF Research Database (Denmark)

    Kyhn, Maria Voss; Warfvinge, Karin; Scherfig, Erik

    2009-01-01

    The purpose of this study was to establish, and characterize a porcine model of acute, controlled retinal ischemia. The controlled retinal ischemia was produced by clamping the ocular perfusion pressure (OPP) in the left eye to 5 mm Hg for 2 h. The OPP was defined as mean arterial blood pressure...... of the amplitudes obtained in the experimental, left eye, and the control, right eye. Quantitative histology was performed to measure the survival of ganglion cells, amacrine cells and horizontal cells 2-6 weeks after the ischemic insult. An OPP of 5 mm Hg for 2h induced significant reductions in the amplitudes...... the ischemic insult. This model seems to be suitable for investigations of therapeutic initiatives in diseases involving acute retinal ischemia....

  11. Inherited Retinal Degenerative Clinical Trial Network. Addendum

    Science.gov (United States)

    2013-10-01

    inherited orphan retinal degenerative diseases and dry age-related macular degeneration (AMD) through the conduct of clinical trials and other...design and conduct of effective and efficient clinical trials for inherited orphan retinal degenerative diseases and dry AMD; • Limited number and...linica l trial in the NEER network for autosomal dominant retinitis pigmentosa, and the ProgSTAR studies for Stargardt disease ) . As new interventions b

  12. Retinal vascular abnormalities and dragged maculae in a carrier with a new NDP mutation (c.268delC) that caused severe Norrie disease in the proband.

    Science.gov (United States)

    Lin, Phoebe; Shankar, Suma P; Duncan, Jacque; Slavotinek, Anne; Stone, Edwin M; Rutar, Tina

    2010-02-01

    Norrie disease (ND) is caused by mutations in the ND pseudoglioma (NDP) gene (MIM 300658) located at chromosome Xp11.4-p11.3. ND is characterized by abnormal retinal vascular development and vitreoretinal disorganization presenting at birth. Systemic manifestations include sensorineural deafness, progressive mental disorder, behavioral and psychological problems, growth failure, and seizures. Other vitreoretinopathies that are associated with NDP gene mutations include X-linked familial exudative vitreoretinopathy, Coats disease, persistent fetal vasculature, and retinopathy of prematurity. Phenotypic variability associated with NDP gene mutations has been well documented in affected male patients. However, there are limited data on signs in female carriers, with mild peripheral retinal abnormalities reported in both carrier and noncarrier females of families with NDP gene mutations. Here, we report a family harboring a single base-pair deletion, c.268delC, in the NDP gene causing a severe ND phenotype in the male proband and peripheral retinal vascular abnormalities with dragged maculae similar to those observed in familial exudative vitreoretinopathy in his carrier mother. Copyright (c) 2010 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.

  13. Striatonigral Degeneration

    Science.gov (United States)

    ... See More About Research The NINDS supports and conducts research on disorders of the brain and nervous system such as striatonigral degeneration. This research ... Publications Definition Striatonigral ...

  14. 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.

  15. 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.

  16. 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.

  17. Enhanced Detection of Sub-Retinal Pigment Epithelial Cell Layer Deposits in Human and Murine Tissue: Imaging Zinc as a Biomarker for Age-Related Macular Degeneration (An American Ophthalmological Society Thesis).

    Science.gov (United States)

    van Kuijk, Frederik J G M; McPherson, Scott W; Roehrich, Heidi

    2017-08-01

    Understanding the apparent paradoxical role of zinc in the pathogenesis and prevention of age-related macular degeneration (AMD) has been limited by the lack of animal models for its detection in sub-retinal epithelial deposits (drusen), a definitive early hallmark of AMD. In-vitro studies using Zinpyr-1 showed drusen contained high levels of zinc, but the probe was not suitable for in-vivo studies. This study compares Zinpyr-1 to ZPP1, a new fluorescein-based probe for zinc, to assess the potential of ZPP1 for in-vivo detection of zinc in drusen. Flat mounts of human sub-RPE tissue using the probes were analyzed by fluorescence and confocal microscopy. Flat mounts of sub-RPE tissue from mice deficient in superoxide dismutase isoform-1 (CuZn-SOD-KO) or isoform-2 (Mn-SOD-RPE-KO) were analyzed with sub-RPE deposits confirmed by histology. Drusen are detected in greater numbers and intensity with ZPP1 compared to Zinpyr-1. Using ZPP1, drusen was detected in a sample from a 46-year old human donor without ocular history, suggesting that ZPP1 might be sensitive enough to detect drusen at an early stage. With CuZn-SOD KO mice, ZPP1 detected sub-RPE deposits at 10 months of age, whereas Zinpyr-1 required 14 months. Detection of sub-RPE deposits by ZPP1 was greatly enhanced compared to Zinpyr-1. This enhanced sensitivity will allow for more insightful analysis of zinc in AMD using human specimens and mouse models. This could result in the development of a sensitive in-vivo probe to enhance research on the role zinc in drusen formation and the early clinical diagnosis of AMD.

  18. Clinical and social characteristics associated with reduced visual acuity at presentation in Australian patients with neovascular age-related macular degeneration: a prospective study from a long-term observational data set. The Fight Retinal Blindness! Project.

    Science.gov (United States)

    Nguyen, Vuong; Daien, Vincent; Guymer, Robyn H; McAllister, Ian L; Morlet, Nigel; Barthelmes, Daniel; Gillies, Mark C

    2018-04-01

    Identifying variables that influence presenting visual acuity (VA) in patients with neovascular age-related macular degeneration (nAMD) is important because it is a strong predictor of long-term outcomes. To assess the clinical and social characteristics associated with low presenting VA in nAMD patients. The present study is a cross-sectional analysis from a prospective, observational database. We identified 3242 treatment-naïve patients from 54 Australian practices in the Fight Retinal Blindness! registry. Age, gender, ethnicity and VA were recorded at the baseline visit. Socio-economic status was determined using the Australian Bureau of Statistics socio-economic indexes for areas. Association between clinical and socio-economic characteristics with presenting VA was identified. Poor VA (≤35 letters) in the presenting eye was associated with older age (adjusted odds ratio [AOR]: 1.33 for patients aged ≥80 years vs. <80 years [95% confidence interval, CI: 1.04, 1.71]), treatment at a public practice (AOR: 1.91 for public vs. private practices [95% CI: 1.46, 2.50]) and intermediate (36-69 letters) VA in the fellow eye (AOR: 0.67 [95% CI: 0.47, 0.95] and 0.64 [95% CI: 0.48, 0.85] for poor [≤35 letters] and good [≥70 letters] VA vs. intermediate VA in the fellow eye). Gender, ethnicity and socio-economic status were not independently associated with VA at presentation. Poor presenting vision is detrimental to the long-term outcomes of nAMD. Poor presentation of nAMD in Australia may not be related to socio-economic circumstances, but due to systems of care. Further research is warranted to determine why patients at public practices present with worse vision compared with private practices in Australia. © 2017 Royal Australian and New Zealand College of Ophthalmologists.

  19. 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.

  20. [Preventive treatment of retinal detachment in aphakic eyes].

    Science.gov (United States)

    Regnault, F; Bregeat, P

    1977-01-01

    We have examined 243 cases with retinal detachment occurring within 6 months following cataract surgery. In 92 of them retinal tear was due to lattice degeneration, in 66 to snail track degeneration and in 17 to equatorial degeneration. 290 other patients had preventive treatments. In this group, there were only 10 cases of retinal detachment. 9 out of 22 patients who had no preventive treatment suffered retinal detachments. There are two reasons for the occurrence of this retinal detachment in the 6 months following cataract surgery in eyes where retinal degenerations are found: (1) surgical trauma even with cryoextraction is responsible for traction of the vitreous base, (2) rapid disappearance of the hyaluronic acid in the aphakic vitreous is responsible for the degradation of the vitreous with formation of large zones of liquid vitreous. When adhesion between the vitreous and the retinal degeneration area remains, the traction is responsible for retinal tear or retinal detachment. The importance of the preventive treatment of retinal lesions prior to cataract surgery should be stressed.

  1. Barriers to Setting up a Vitreo‑retinal Unit of Ophthalmology in ...

    African Journals Online (AJOL)

    Vitreo‑retinal equipment is expensive and may be beyond the reach of a ... retinopathy, age‑related macular degeneration, retinal detachment ... requiring treatment. Earlier, we ... the Prevention of Blindness visited our institution and initiated ...

  2. Concentric retinitis pigmentosa: clinicopathologic correlations.

    Science.gov (United States)

    Milam, A H; De Castro, E B; Smith, J E; Tang, W X; John, S K; Gorin, M B; Stone, E M; Aguirre, G D; Jacobson, S G

    2001-10-01

    Progressive concentric (centripetal) loss of vision is one pattern of visual field loss in retinitis pigmentosa. This study provides the first clinicopathologic correlations for this form of retinitis pigmentosa. A family with autosomal dominant concentric retinitis pigmentosa was examined clinically and with visual function tests. A post-mortem eye of an affected 94 year old family member was processed for histopathology and immunocytochemistry with retinal cell specific antibodies. Unrelated simplex/multiplex patients with concentric retinitis pigmentosa were also examined. Affected family members of the eye donor and patients from the other families had prominent peripheral pigmentary retinopathy with more normal appearing central retina, good visual acuity, concentric field loss, normal or near normal rod and cone sensitivity within the preserved visual field, and reduced rod and cone electroretinograms. The eye donor, at age 90, had good acuity and function in a central island. Grossly, the central region of the donor retina appeared thinned but otherwise normal, while the far periphery contained heavy bone spicule pigment. Microscopically the central retina showed photoreceptor outer segment shortening and some photoreceptor cell loss. The mid periphery had a sharp line of demarcation where more central photoreceptors were near normal except for very short outer segments and peripheral photoreceptors were absent. Rods and cones showed abrupt loss of outer segments and cell death at this interface. It is concluded that concentric retinitis pigmentosa is a rare but recognizable phenotype with slowly progressive photoreceptor death from the far periphery toward the central retina. The disease is retina-wide but shows regional variation in severity of degeneration; photoreceptor death is severe in the peripheral retina with an abrupt edge between viable and degenerate photoreceptors. Peripheral to central gradients of unknown retinal molecule(s) may be defective

  3. Diabetes and overexpression of proNGF cause retinal neurodegeneration via activation of RhoA pathway.

    Directory of Open Access Journals (Sweden)

    Mohammed M H Al-Gayyar

    Full Text Available Our previous studies showed positive correlation between accumulation of proNGF, activation of RhoA and neuronal death in diabetic models. Here, we examined the neuroprotective effects of selective inhibition of RhoA kinase in the diabetic rat retina and in a model that stably overexpressed the cleavage-resistance proNGF plasmid in the retina. Male Sprague-Dawley rats were rendered diabetic using streptozotocin or stably express cleavage-resistant proNGF plasmid. The neuroprotective effects of the intravitreal injection of RhoA kinase inhibitor Y27632 were examined in vivo. Effects of proNGF were examined in freshly isolated primary retinal ganglion cell (RGC cultures and RGC-5 cell line. Retinal neurodegeneration was assessed by counting TUNEL-positive and Brn-3a positive retinal ganglion cells. Expression of proNGF, p75(NTR, cleaved-PARP, caspase-3 and p38MAPK/JNK were examined by Western-blot. Activation of RhoA was assessed by pull-down assay and G-LISA. Diabetes and overexpression of proNGF resulted in retinal neurodegeneration as indicated by 9- and 6-fold increase in TUNEL-positive cells, respectively. In vitro, proNGF induced 5-fold cell death in RGC-5 cell line, and it induced >10-fold cell death in primary RGC cultures. These effects were associated with significant upregulation of p75(NTR and activation of RhoA. While proNGF induced TNF-α expression in vivo, it selectively activated RhoA in primary RGC cultures and RGC-5 cell line. Inhibiting RhoA kinase with Y27632 significantly reduced diabetes- and proNGF-induced activation of proapoptotic p38MAPK/JNK, expression of cleaved-PARP and caspase-3 and prevented retinal neurodegeneration in vivo and in vitro. Taken together, these results provide compelling evidence for a causal role of proNGF in diabetes-induced retinal neurodegeneration through enhancing p75(NTR expression and direct activation of RhoA and p38MAPK/JNK apoptotic pathways.

  4. Retinal image restoration by means of blind deconvolution

    Science.gov (United States)

    Marrugo, Andrés G.; Šorel, Michal; Šroubek, Filip; Millán, María S.

    2011-11-01

    Retinal imaging plays a key role in the diagnosis and management of ophthalmologic disorders, such as diabetic retinopathy, glaucoma, and age-related macular degeneration. Because of the acquisition process, retinal images often suffer from blurring and uneven illumination. This problem may seriously affect disease diagnosis and progression assessment. Here we present a method for color retinal image restoration by means of multichannel blind deconvolution. The method is applied to a pair of retinal images acquired within a lapse of time, ranging from several minutes to months. It consists of a series of preprocessing steps to adjust the images so they comply with the considered degradation model, followed by the estimation of the point-spread function and, ultimately, image deconvolution. The preprocessing is mainly composed of image registration, uneven illumination compensation, and segmentation of areas with structural changes. In addition, we have developed a procedure for the detection and visualization of structural changes. This enables the identification of subtle developments in the retina not caused by variation in illumination or blur. The method was tested on synthetic and real images. Encouraging experimental results show that the method is capable of significant restoration of degraded retinal images.

  5. The prevalence and causes of bilateral and unilateral blindness in an elderly urban Danish population. The Copenhagen City Eye Study

    DEFF Research Database (Denmark)

    Buch, Helena; Vinding, T; La Cour, M

    2001-01-01

    of bilateral blindness, accounting for 60% of all blind persons. Glaucoma, myopic macular degeneration, cataract and retinitis pigmentosa were jointly the second most common cause, each accounting for 10% of all bilaterally blind persons. Diabetic retinopathy was not a cause of bilateral blindness. Amblyopia...

  6. 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.

  7. Biology and therapy of inherited retinal degenerative disease: insights from mouse models

    Science.gov (United States)

    Veleri, Shobi; Lazar, Csilla H.; Chang, Bo; Sieving, Paul A.; Banin, Eyal; Swaroop, Anand

    2015-01-01

    Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases. PMID:25650393

  8. Biology and therapy of inherited retinal degenerative disease: insights from mouse models

    Directory of Open Access Journals (Sweden)

    Shobi Veleri

    2015-02-01

    Full Text Available Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases.

  9. [Prophylactic treatment of retinal detachment].

    Science.gov (United States)

    Binder, S; Riss, B

    1981-08-01

    The indications for and results of prophylactic treatment of retinal detachment during a period of five years are reported and compared with the results in the literature. Half of the cases (3 out of 6 eyes) which developed a retinal detachment had been horse-shoe tears combined with a vitreous hemorrhage. For this reason a small buckle operation is recommended in these cases, to prevent further traction. Lattice degeneration should rather be observed than treated, except in special cases: This includes eyes where the fellow eye had a detachment from a lattice degeneration, cases in which one eye is blind from an uncured detachment or has no useful visual acuity, and eyes whose fellow eye has giant tears. In aphakic eyes treatment of lattice degeneration is recommended, because the incidence of detachment from these areas is high, especially in young aphakic cases. In one aphakic eye which had been photocoagulated several times the formation of a preretinal membrane was observed.

  10. Cerebellar Degeneration

    Science.gov (United States)

    ... FARA) National Ataxia Foundation (NAF) National Multiple Sclerosis Society See all related organizations Publications Degeneración cerebelosa Order NINDS Publications Definition Cerebellar degeneration is a process in which neurons ( ...

  11. Macular degeneration

    Science.gov (United States)

    The macula is the part of the retina that distinguishes fine details at the center of the field of vision. Macular degeneration results from a partial breakdown of the insulating layer between the retina and the choroid layer of ...

  12. Mutations in the PFN1 gene are not a common cause in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration in France.

    Science.gov (United States)

    Lattante, Serena; Le Ber, Isabelle; Camuzat, Agnès; Brice, Alexis; Kabashi, Edor

    2013-06-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are 2 adult onset neurological disorders with overlapping symptoms and clinical characteristics. It is well established that they share a common pathologic and genetic background. Recently, mutations in profilin 1 gene (PFN1) have been identified in patients with familial ALS, suggesting a role for this gene in the pathogenesis of the disease. Based on this, we hypothesized that mutations in PFN1 might also contribute to FTLD disease. We studied a French cohort of 165 ALS/FTLD patients, without finding any variant. We conclude that mutations in PFN1 are not a common cause for ALS/FTLD in France. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Lattice degeneration of the retina and the pigment dispersion syndrome.

    Science.gov (United States)

    Weseley, P; Liebmann, J; Walsh, J B; Ritch, R

    1992-11-15

    Retinal detachment occurs more frequently in patients with pigment dispersion syndrome. We evaluated the incidence of peripheral retinal abnormalities known to predispose to rhegmatogenous retinal detachment in a consecutive series of 60 patients with pigment dispersion syndrome with or without glaucoma. Lattice degeneration was present in at least one eye of 12 patients (20%). Seven patients had bilateral lesions. Full-thickness retinal breaks were found in seven patients (11.7%) and two patients (3.3%) had asymptomatic rhegmatogenous retinal detachments that required scleral buckle procedures. The incidence of lattice degeneration and full-thickness retinal breaks appears to be increased in this group of patients, and may be responsible for the increased risk of rhegmatogenous detachment.

  14. Exome analysis identified a novel mutation in the RBP4 gene in a consanguineous pedigree with retinal dystrophy and developmental abnormalities.

    Directory of Open Access Journals (Sweden)

    Catherine Cukras

    Full Text Available Retinitis Pigmentosa (RP is a common form of retinal degeneration characterized by photoreceptor degeneration and retinal pigment epithelium (RPE atrophy causing loss of visual field and acuities. Exome sequencing identified a novel homozygous splice site variant (c.111+1G>A in the gene encoding retinol binding protein 4 (RBP4. This change segregated with early onset, progressive, and severe autosomal recessive retinitis pigmentosa (arRP in an eight member consanguineous pedigree of European ancestry. Additionally, one patient exhibited developmental abnormalities including patent ductus arteriosus and chorioretinal and iris colobomas. The second patient developed acne from young age and extending into the 5(th decade. Both patients had undetectable levels of RBP4 in the serum suggesting that this mutation led to either mRNA or protein instability resulting in a null phenotype. In addition, the patients exhibited severe vitamin A deficiency, and diminished serum retinol levels. Circulating transthyretin levels were normal. This study identifies the RBP4 splice site change as the cause of RP in this pedigree. The presence of developmental abnormalities and severe acne in patients with retinal degeneration may indicate the involvement of genes that regulate vitamin A absorption, transport and metabolism.

  15. Exome analysis identified a novel mutation in the RBP4 gene in a consanguineous pedigree with retinal dystrophy and developmental abnormalities.

    Science.gov (United States)

    Cukras, Catherine; Gaasterland, Terry; Lee, Pauline; Gudiseva, Harini V; Chavali, Venkata R M; Pullakhandam, Raghu; Maranhao, Bruno; Edsall, Lee; Soares, Sandra; Reddy, G Bhanuprakash; Sieving, Paul A; Ayyagari, Radha

    2012-01-01

    Retinitis Pigmentosa (RP) is a common form of retinal degeneration characterized by photoreceptor degeneration and retinal pigment epithelium (RPE) atrophy causing loss of visual field and acuities. Exome sequencing identified a novel homozygous splice site variant (c.111+1G>A) in the gene encoding retinol binding protein 4 (RBP4). This change segregated with early onset, progressive, and severe autosomal recessive retinitis pigmentosa (arRP) in an eight member consanguineous pedigree of European ancestry. Additionally, one patient exhibited developmental abnormalities including patent ductus arteriosus and chorioretinal and iris colobomas. The second patient developed acne from young age and extending into the 5(th) decade. Both patients had undetectable levels of RBP4 in the serum suggesting that this mutation led to either mRNA or protein instability resulting in a null phenotype. In addition, the patients exhibited severe vitamin A deficiency, and diminished serum retinol levels. Circulating transthyretin levels were normal. This study identifies the RBP4 splice site change as the cause of RP in this pedigree. The presence of developmental abnormalities and severe acne in patients with retinal degeneration may indicate the involvement of genes that regulate vitamin A absorption, transport and metabolism.

  16. Retinitis Pigmentosa.

    Science.gov (United States)

    Carr, Ronald E.

    1979-01-01

    The author describes the etiology of retinitis pigmentosa, a visual dysfunction which results from progressive loss of the retinal photoreceptors. Sections address signs and symptoms, ancillary findings, heredity, clinical diagnosis, therapy, and research. (SBH)

  17. Retinal Diseases

    Science.gov (United States)

    ... Linked Retinoschisis (XLRS) X-Linked Retinitis Pigmentosa (XLRP) Usher Syndrome Other Retinal Diseases Glossary News & Research News & Research ... central portion of the retina called the macula. Usher Syndrome Usher syndrome is an inherited condition characterized by ...

  18. Moderate Light-Induced Degeneration of Rod Photoreceptors with Delayed Transducin Translocation in shaker1 Mice

    Science.gov (United States)

    Zallocchi, Marisa; Wang, Wei-Min; Delimont, Duane; Cosgrove, Dominic

    2011-01-01

    Purpose. Usher syndrome is characterized by congenital deafness associated with retinitis pigmentosa (RP). Mutations in the myosin VIIa gene (MYO7A) cause a common and severe subtype of Usher syndrome (USH1B). Shaker1 mice have mutant MYO7A. They are deaf and have vestibular dysfunction but do not develop photoreceptor degeneration. The goal of this study was to investigate abnormalities of photoreceptors in shaker1 mice. Methods. Immunocytochemistry and hydroethidine-based detection of intracellular superoxide production were used. Photoreceptor cell densities under various conditions of light/dark exposures were evaluated. Results. In shaker1 mice, the rod transducin translocation is delayed because of a shift of its light activation threshold to a higher level. Even moderate light exposure can induce oxidative damage and significant rod degeneration in shaker1 mice. Shaker1 mice reared under a moderate light/dark cycle develop severe retinal degeneration in less than 6 months. Conclusions. These findings show that, contrary to earlier studies, shaker1 mice possess a robust retinal phenotype that may link to defective rod protein translocation. Importantly, USH1B animal models are likely vulnerable to light-induced photoreceptor damage, even under moderate light. PMID:21447681

  19. Treatment of dry age-related macular degeneration with dobesilate

    OpenAIRE

    Cuevas, P; Outeiriño, L A; Angulo, J; Giménez-Gallego, G

    2012-01-01

    The authors present anatomical and functional evidences of dry age-macular degeneration improvement, after intravitreal treatment with dobesilate. Main outcomes measures were normalisation of retinal structure and function, assessed by optical coherence tomography, fundus-monitored microperimetry, electrophysiology and visual acuity. The effect might be related to the normalisation of the outer retinal architecture.

  20. 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.

  1. Presumed hereditary retinal degenerations: Ibadan experience ...

    African Journals Online (AJOL)

    This study describes the clinical presentation of RP, the prevalence of associated treatable disorders and the characteristics of patients with severe visual impairment and blindness. Method: A retrospective review of 52 cases presumed and diagnosed to have RP was performed on patients who presented at the Eye Clinic, ...

  2. Total retinal detachment occurring after minor head trauma.

    Science.gov (United States)

    Mircea, Pienaru; Ramona, Serban; Mircea, Filip; Andrei, Filip

    2015-01-01

    The objective of this article is to present the case of a patient with a severe decrease of visual acuity that occurred after an apparently minor head injury. Following the investigations, the patient was diagnosed with rhegmatogenous retinal detachment that was triggered by a fall from the same level and which occurred on a background of lattice degeneration. In this case, a minor trauma caused a severe complication because the patient had a contributing factor for the complication. The patient was operated and the end result was satisfactory.

  3. Total resection of any segment of the lateral meniscus may cause early cartilage degeneration: Evaluation by magnetic resonance imaging using T2 mapping.

    Science.gov (United States)

    Murakami, Koji; Arai, Yuji; Ikoma, Kazuya; Kato, Kammei; Inoue, Hiroaki; Nakagawa, Shuji; Fujii, Yuta; Ueshima, Keiichiro; Fujiwara, Hiroyoshi; Kubo, Toshikazu

    2018-06-01

    The aim of this study was to perform quantitative evaluation of degeneration of joint cartilage using T2 mapping in magnetic resonance imaging (MRI) after arthroscopic partial resection of the lateral meniscus.The subjects were 21 patients (23 knees) treated with arthroscopic partial resection of the lateral meniscus. MRI was performed for all knees before surgery and 6 months after surgery to evaluate the center of the lateral condyle of the femur in sagittal images for T2 mapping. Ten regions of interest (ROIs) on the articular cartilage were established at 10-degree intervals, from the point at which the femur shaft crossed the lateral femoral condyle joint to the articular cartilage 90° relative to the femur shaft. Preoperative and postoperative T2 values were evaluated at each ROI. Age, sex, body mass index, femorotibial angle, Tegner score, and amount of meniscal resection were evaluated when the T2 value increased more than 6% at 30°.T2 values at approximately 10 °, 20 °, 30 °, 40 °, 50 °, and 60 ° degrees relative to the anatomical axis of the femur were significantly greater postoperatively (3.1, 3.6, 5.5, 4.4, 5.0, 6.4%, respectively) than preoperatively. A >6% increase at 30° was associated with total resection of any segment of the meniscus.Degeneration of the articular cartilage, as shown by the disorganization of collagen arrays at positions approximately 10 °, 20 °, 30 °, 40 °, 50 °, and 60 ° relative to the anatomical axis of the femur, may start soon after arthroscopic lateral meniscectomy. Total resection of any segment of the lateral meniscus may cause T2 elevation of articular cartilage of lateral femoral condyle.

  4. Association of age-related macular degeneration and reticular macular disease with cardiovascular disease.

    Science.gov (United States)

    Rastogi, Neelesh; Smith, R Theodore

    2016-01-01

    Age-related macular degeneration is the leading cause of adult blindness in the developed world. Thus, major endeavors to understand the risk factors and pathogenesis of this disease have been undertaken. Reticular macular disease is a proposed subtype of age-related macular degeneration correlating histologically with subretinal drusenoid deposits located between the retinal pigment epithelium and the inner segment ellipsoid zone. Reticular lesions are more prevalent in females and in older age groups and are associated with a higher mortality rate. Risk factors for developing age-related macular degeneration include hypertension, smoking, and angina. Several genes related to increased risk for age-related macular degeneration and reticular macular disease are also associated with cardiovascular disease. Better understanding of the clinical and genetic risk factors for age-related macular degeneration and reticular macular disease has led to the hypothesis that these eye diseases are systemic. A systemic origin may help to explain why reticular disease is diagnosed more frequently in females as males suffer cardiovascular mortality at an earlier age, before the age of diagnosis of reticular macular disease and age-related macular degeneration. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. [Factors related to intraoperative retinal breaks in macular hole surgery].

    Science.gov (United States)

    Kumagai, K; Ogino, N; Demizu, S; Atsumi, K; Kurihara, H; Iwaki, M; Ishigooka, H; Tachi, N

    2001-02-01

    To evaluate the factors of intraoperative retinal breaks in macular hole surgery. This study included 558 eyes of 506 patients who underwent idiopathic macular hole surgery by one surgeon. Multiple regression was performed using the variables of gender, age, affected eye, lens status, stage, duration of symptoms, hole size, axial length, and lattice degeneration. The rate of retinal breaks was higher in stage 3 (16.0%) than in stage 4 (8.2%) (p = 0.014). In eyes with lattice degeneration intraoperative retinal breaks occurred in about 40% of the cases. Major factors were as follows: lattice degeneration (r = 0.24, p lattice degeneration, and gender (r = -0.18, p = 0.035) in eyes of stage 4 without lattice degeneration. The factors of intraoperative retinal breaks in macular hole surgery were lattice degeneration in all eyes and stage 3 in eyes without lattice degeneration. The high incidence of intraoperative retinal breaks in stage 3 was mainly due to the occurrence of posterior vitreous detachment. Male gender was a significant factor associated with intraoperative retinal breaks.

  6. Outcomes in bullous retinal detachment

    Directory of Open Access Journals (Sweden)

    Sarah P. Read

    2017-06-01

    Conclusions and importance: GRTs are an uncommon cause of retinal detachment. While pars plana vitrectomy with tamponade is standard in GRT management, there is variability in the use of scleral buckling and PFO in these cases. This is in contrast to retinal dialysis where scleral buckle alone can yield favorable results. Though a baseball ocular trauma is common, retinal involvement is rare compared to other sports injuries such as those occurring with tennis, soccer and golf. Sports trauma remains an important cause of retinal injury and patients should be counseled on the need for eye protection.

  7. The 'Displacing Foods of Modern Commerce' Are the Primary and Proximate Cause of Age-Related Macular Degeneration: A Unifying Singular Hypothesis.

    Science.gov (United States)

    Knobbe, Chris A; Stojanoska, Marija

    2017-11-01

    Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss and blindness in developed nations. AMD is anticipated to affect 196 million people worldwide, by 2020. However, the etiology of this disease remains unknown. Aging, genetic, and environmental influences have generally been implicated as major etiologic factors. We sought to examine the hypothesis that consumption of the 'displacing foods of modern commerce,' which equate to processed, nutrient-deficient and potentially toxic foods, may be the primary and proximate cause of AMD. To evaluate this hypothesis, we ran correlative AMD prevalence data against well-known proxy markers of processed food consumption, namely, sugar and vegetable oils, in 25 nations. In twenty-one nations, published studies provided AMD prevalence data and in four Pacific Island nations, practicing ophthalmologists in the regions completed retrospective chart analyses to estimate AMD prevalence in their respective regions. To estimate AMD prevalence historically, an extensive review of published papers and ophthalmic literature was completed. This review indicates that, between the years 1851 and 1930, AMD was a medical rarity worldwide, which then rose modestly in prevalence in the 1930s in the U.S. and U.K, finally elevating to epidemic proportions by 1975 in the U.S. Numerous developed nations have followed suit in recent decades. Simultaneously, between approximately 1880 and 2009, processed, nutrient-deficient foods gradually supplanted and displaced whole, unprocessed, nutrient-dense foods in developed nations, such that by 2009, 63 percent of the American diet was made up of nutrient-deficient foods in the form of refined white flour, added sugars, vegetable oils, and artificially created trans fats. The correlative data in 25 nations shows that increasing sugar and polyunsaturated vegetable oil consumption is invariably associated with new onset or rising prevalence of AMD, generally within about

  8. Progressive irreversible hearing loss is caused by stria vascularis degeneration in an Slc26a4-insufficient mouse model of large vestibular aqueduct syndrome.

    Science.gov (United States)

    Ito, T; Nishio, A; Wangemann, P; Griffith, A J

    2015-12-03

    Hearing loss of patients with enlargement of the vestibular aqueduct (EVA) can fluctuate or progress, with overall downward progression. The most common detectable cause of EVA is mutations of SLC26A4. We previously described a transgenic Slc26a4-insufficient mouse model of EVA in which Slc26a4 expression is controlled by doxycycline administration. Mice that received doxycycline from conception until embryonic day 17.5 (DE17.5; doxycycline discontinued at embryonic day 17.5) had fluctuating hearing loss between 1 and 6 months of age with an overall downward progression after 6 months of age. In this study, we characterized the cochlear functional and structural changes underlying irreversible hearing loss in DE17.5 mice at 12 months of age. The endocochlear potential was decreased and inversely correlated with auditory brainstem response thresholds. The stria vascularis was thickened and edematous in ears with less severe hearing loss, and thinned and atrophic in ears with more severe hearing loss. There were pathologic changes in marginal cell morphology and gene expression that were not observed at 3 months. We conclude that strial dysfunction and degeneration are the primary causes of irreversible progressive hearing loss in our Slc26a4-insufficient mouse model of EVA. This model of primary strial atrophy may be used to explore the mechanisms of progressive hearing loss due to strial dysfunction. Published by Elsevier Ltd.

  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. 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.

  11. Posterior lattice degeneration characterized by spectral domain optical coherence tomography.

    Science.gov (United States)

    Manjunath, Varsha; Taha, Mohammed; Fujimoto, James G; Duker, Jay S

    2011-03-01

    The purpose of this study was to use high-resolution spectral domain optical coherence tomography in the characterization of retinal and vitreal morphological changes overlying posterior lattice degeneration. A cross-sectional retrospective analysis was performed on 13 eyes of 13 nonconsecutive subjects with posterior lattice degeneration seen at the New England Eye Center, Tufts Medical Center between October 2009 and January 2010. Spectral domain optical coherence tomography images taken through the region of lattice degeneration were qualitatively analyzed. Four characteristic changes of the retina and vitreous were seen in the 13 eyes with lattice degeneration: 1) anterior/posterior U-shaped vitreous traction; 2) retinal breaks; 3) focal retinal thinning; and 4) vitreous membrane formation. The morphologic appearance of vitreous traction and retinal breaks were found to be consistent with previous histologic reports. It is possible to image posterior lattice degeneration in many eyes using spectral domain optical coherence tomography and to visualize the spectrum of retinal and vitreous changes throughout the area of lattice degeneration.

  12. Towards a Completely Implantable, Light-Sensitive Intraocular Retinal Prosthesis

    National Research Council Canada - National Science Library

    Humayun, M

    2001-01-01

    .... Previous studies have established the feasibility of the retinal prosthesis. Short-term tests in blind humans have shown that degenerated retina will respond to light in a way that is consistent with form vision...

  13. Altered Antioxidant-Oxidant Status in the Aqueous Humor and Peripheral Blood of Patients with Retinitis Pigmentosa

    Science.gov (United States)

    Martínez-Fernández de la Cámara, Cristina; Salom, David; Sequedo, Ma Dolores; Hervás, David; Marín-Lambíes, Cristina; Aller, Elena; Jaijo, Teresa; Díaz-LLopis, Manuel; Millán, José María; Rodrigo, Regina

    2013-01-01

    Retinitis Pigmentosa is a common form of hereditary retinal degeneration constituting the largest Mendelian genetic cause of blindness in the developed world. It has been widely suggested that oxidative stress possibly contributes to its pathogenesis. We measured the levels of total antioxidant capacity, free nitrotyrosine, thiobarbituric acid reactive substances (TBARS) formation, extracellular superoxide dismutase (SOD3) activity, protein, metabolites of the nitric oxide/cyclic GMP pathway, heme oxygenase-I and inducible nitric oxide synthase expression in aqueous humor or/and peripheral blood from fifty-six patients with retinitis pigmentosa and sixty subjects without systemic or ocular oxidative stress-related disease. Multivariate analysis of covariance revealed that retinitis pigmentosa alters ocular antioxidant defence machinery and the redox status in blood. Patients with retinitis pigmentosa present low total antioxidant capacity including reduced SOD3 activity and protein concentration in aqueous humor. Patients also show reduced SOD3 activity, increased TBARS formation and upregulation of the nitric oxide/cyclic GMP pathway in peripheral blood. Together these findings confirmed the hypothesis that patients with retinitis pigmentosa present reduced ocular antioxidant status. Moreover, these patients show changes in some oxidative-nitrosative markers in the peripheral blood. Further studies are needed to clarify the relationship between these peripheral markers and retinitis pigmentosa. PMID:24069283

  14. Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

    NARCIS (Netherlands)

    Klevering, B.J.; Blankenagel, A.; Maugeri, A.; Cremers, F.P.M.; Hoyng, C.B.; Rohrschneider, K.

    2002-01-01

    PURPOSE: To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. METHODS: The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were

  15. Pharmacotherapy of retinal disease with visual cycle modulators.

    Science.gov (United States)

    Hussain, Rehan M; Gregori, Ninel Z; Ciulla, Thomas A; Lam, Byron L

    2018-04-01

    Pharmacotherapy with visual cycle modulators (VCMs) is under investigation for retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardt macular dystrophy (SMD) and nonexudative age-related macular degeneration (AMD), all blinding diseases that lack effective treatment options. Areas covered: The authors review investigational VCMs, including oral retinoids, 9-cis-retinyl-acetate (zuretinol) and 9-cis-β-carotene, which restore 11-cis-retinal levels in RP and LCA caused by LRAT and RPE65 gene mutations, and may improve visual acuity and visual fields. Therapies for SMD aiming to decrease accumulation of toxic Vitamin A dimers and lipofuscin in the retina and retinal pigment epithelium (RPE) include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Mouse models of SMD show promising data for these treatments, though proof of efficacy in humans is currently lacking. Fenretinide and emixustat are investigational VCMs for dry AMD, though neither has been shown to reduce geographic atrophy or improve vision in human trials. A1120 prevents retinol transport into the RPE and may spare the side effects typically seen in VCMs (nyctalopia and chromatopsia) per mouse studies. Expert opinion: Oral VCMs may be feasible treatment options for degenerative retinal diseases based on pre-clinical and some early clinical studies. Further trials are warranted to assess their efficacy and safety in humans.

  16. Aiding the Eye, Watching the Brain: James Weiland, IEEE Fellow, explores the unique challenges of retinal prostheses.

    Science.gov (United States)

    Grifantini, Kristina

    2017-01-01

    The retina is a sophisticated neural network that provides humans with high-resolution vision. And for those who suffer from retinal disease or deterioration, particularly age-related macular degeneration (the leading cause of blindness among people over the age of 50 in the United States), a better understanding of how to stimulate the retina or completely override its path to the area of the brain that processes vision may offer hope to restore sight.

  17. Long-term gene therapy causes transgene-specific changes in the morphology of regenerating retinal ganglion cells.

    Directory of Open Access Journals (Sweden)

    Jennifer Rodger

    Full Text Available Recombinant adeno-associated viral (rAAV vectors can be used to introduce neurotrophic genes into injured CNS neurons, promoting survival and axonal regeneration. Gene therapy holds much promise for the treatment of neurotrauma and neurodegenerative diseases; however, neurotrophic factors are known to alter dendritic architecture, and thus we set out to determine whether such transgenes also change the morphology of transduced neurons. We compared changes in dendritic morphology of regenerating adult rat retinal ganglion cells (RGCs after long-term transduction with rAAV2 encoding: (i green fluorescent protein (GFP, or (ii bi-cistronic vectors encoding GFP and ciliary neurotrophic factor (CNTF, brain-derived neurotrophic factor (BDNF or growth-associated protein-43 (GAP43. To enhance regeneration, rats received an autologous peripheral nerve graft onto the cut optic nerve of each rAAV2 injected eye. After 5-8 months, RGCs with regenerated axons were retrogradely labeled with fluorogold (FG. Live retinal wholemounts were prepared and GFP positive (transduced or GFP negative (non-transduced RGCs injected iontophoretically with 2% lucifer yellow. Dendritic morphology was analyzed using Neurolucida software. Significant changes in dendritic architecture were found, in both transduced and non-transduced populations. Multivariate analysis revealed that transgenic BDNF increased dendritic field area whereas GAP43 increased dendritic complexity. CNTF decreased complexity but only in a subset of RGCs. Sholl analysis showed changes in dendritic branching in rAAV2-BDNF-GFP and rAAV2-CNTF-GFP groups and the proportion of FG positive RGCs with aberrant morphology tripled in these groups compared to controls. RGCs in all transgene groups displayed abnormal stratification. Thus in addition to promoting cell survival and axonal regeneration, vector-mediated expression of neurotrophic factors has measurable, gene-specific effects on the morphology of injured

  18. Optical coherent tomography in diagnoses of peripheral retinal degenarations

    OpenAIRE

    O. G. Pozdeyeva; T. B. Shaimov; A. Yu. Galin; R. B. Shaimov; T. A. Shaimova; A. V. Zolotova; A. V. Fomin

    2014-01-01

    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 op...

  19. Retinal vasculitis.

    Science.gov (United States)

    Abu El-Asrar, Ahmed M; Herbort, Carl P; Tabbara, Khalid F

    2005-12-01

    Retinal vasculitis is a sight-threatening intraocular inflammation affecting the retinal vessels. It may occur as an isolated ocular condition, as a manifestation of infectious or neoplastic disorders, or in association with a systemic inflammatory disease. The search for an underlying etiology should be approached in a multidisciplinary fashion based on a thorough history, review of systems, physical examination, and laboratory evaluation. Discrimination between infectious and noninfectious etiologies of retinal vasculitis is important because their treatment is different. This review is based on recently published articles on retinal vasculitis and deals with its clinical diagnosis, its link with systemic diseases, and its laboratory investigation.

  20. Pattern of retinal morphological and functional decay in a light-inducible, rhodopsin mutant mouse.

    Science.gov (United States)

    Gargini, Claudia; Novelli, Elena; Piano, Ilaria; Biagioni, Martina; Strettoi, Enrica

    2017-07-18

    Hallmarks of Retinitis Pigmentosa (RP), a family of genetic diseases, are a typical rod-cone-degeneration with initial night blindness and loss of peripheral vision, followed by decreased daylight sight and progressive visual acuity loss up to legal blindness. Great heterogeneity in nature and function of mutated genes, variety of mutations for each of them, variability in phenotypic appearance and transmission modality contribute to make RP a still incurable disease. Translational research relies on appropriate animal models mimicking the genetic and phenotypic diversity of the human pathology. Here, we provide a systematic, morphological and functional analysis of Rho Tvrm4 /Rho + rhodopsin mutant mice, originally described in 2010 and portraying several features of common forms of autosomal dominant RP caused by gain-of-function mutations. These mice undergo photoreceptor degeneration only when exposed briefly to strong, white light and allow controlled timing of induction of rod and cone death, which therefore can be elicited in adult animals, as observed in human RP. The option to control severity and retinal extent of the phenotype by regulating intensity and duration of the inducing light opens possibilities to exploit this model for multiple experimental purposes. Altogether, the unique features of this mutant make it an excellent resource for retinal degeneration research.

  1. Visual Outcomes in Japanese Patients with Retinitis Pigmentosa and Usher Syndrome Caused by USH2A Mutations.

    Science.gov (United States)

    Nagase, Yasunori; Kurata, Kentaro; Hosono, Katsuhiro; Suto, Kimiko; Hikoya, Akiko; Nakanishi, Hiroshi; Mizuta, Kunihiro; Mineta, Hiroyuki; Minoshima, Shinsei; Hotta, Yoshihiro

    2017-07-05

    EYS and USH2A are the most common causative genes for retinitis pigmentosa (RP) in Japan. We determined the clinical outcomes for USH2A-related non-syndromic RP or Usher syndrome type II (USH2). Two non-syndromic RP and 11 USH2 patients with previously identified USH2A mutations were included. Their complete history and medical records were collected using standard procedures. Visual fields and acuity were compared with those of patients with EYS mutations. Clinical analyses were based on ophthalmic and otolaryngologic examinations. In all patients, the fundus displayed changes typical of RP. Most patients showed relatively well-preserved visual acuity in their thirties or forties, with rapid deterioration in their fifties. Concentric constriction started in the twenties or thirties, and no effective residual visual field was observed after the fifties. The visual outcome for non-syndromic RP or USH2 patients with USH2A mutations is consistent with that for RP patients with EYS mutations.

  2. [Early therapeutic trials for retinitis pigmentosa].

    Science.gov (United States)

    Dufier, Jean-Louis

    2003-01-01

    Non syndromic forms of Retinitis Pigmentosa (RP) constitute a collection of clinically and genetically heterogeneous inherited retinal degenerative diseases. They are characterized by a bilateral progressive visual loss susceptible to cause blindness. These diseases are transmitted through pedigrees according to all known modes of inheritance. They are bilateral and usually start during infancy. However, very early clinical presentations exist, such as those observed in children affected by Leber Congenital Amaurosis, as well as late onset autosomal dominant forms of retinitis pigmentosa. The characteristic clinical aspect of the rod-cone RP dystrophies is marked by alterations of the peripheral retina associated with a night blindness and a progressive narrowing of the visual field. The ophthalmoscopic examination of RP patients commonly reveals thin retinal arteries and scattered pigmentary accumulations. In contrast, there are cone rod retinal dystrophies whose onset is marked by a decreased visual acuity before the appearance of any visual field alteration. Some forms of RPs display an ocular fundus devoid of any pigmentary alteration. Syndromic forms of RPs are not uncommon. The association of deafness with RP is detected in nearly 30% of the patients. Other associations with RP can include mental deficiency, facial dysmorphy, microcephaly, obesity, kidney deficiency, immune deficiencies, metabolic disorders. The existence of such syndromic forms of RP localizes RPs at the crossroad of several medical specialties. A long lasting collaboration between our department of ophthalmology and the department of medical genetics of the Necker-Sick Children Hospital has allowed us to establish numerous genotype-phenotype correlations, especially in LCA and Stargardt's disease. ABCR gene mutations cause Stargardt disease. ABCR mutations may also cause some types of Ages Related Macular Degenerations (AMD). Nowadays, there is no known efficient therapy available for

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

    Science.gov (United States)

    Ding, Suet Lee Shirley; Kumar, Suresh; Mok, Pooi Ling

    2017-07-28

    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.

  4. [Stickler's syndrome (dystrophia vitreoretinalis hereditaria). Results of surgery for retinal detachment].

    Science.gov (United States)

    Karel, I; Dolezalová, J; Oudová, P

    2001-05-01

    Stickler's syndrome (SS) is an autosomal dominant hereditary disease of the collagenous connective tissue where impaired development of the vitreous body gel and peripheral retina and detachment of the retina are associated with general manifestations. The objective of the retrospective study was to evaluate the long-term results of surgery of retinal detachment in SS. The group of patients comprised 7 patients, 6 men and 1 woman aged 4 to 45 years, average age 16.8 years. Autosomal dominant heredity was obvious in 6 members (85.7%) of two families. General manifestations of SS included abnormalities of the facial skeleton (6 patients), cleft palate (4 patients), impaired hearing (2 patients), marfanoid habitus (2 patients) and hyperextensibility of the joints (4 patients). In the eyes with SS was manifested by myopia from -1 to -9 D and a liquid vitreous body. Multiple foci of lattice degeneration supplemented the finding in 6 patients (85.7%). Detachment of the retina was a manifestation of SS in 12 of 14 eyes (85.7%). It was manifested in 5 of 7 patients concurrently or within 12 years in both eyes. The causes of retinal detachment were multiple equatorial and postequatorial tears due to lattice degeneration in 8 eyes (66.7%) or a giant tear in 4 eyes (33.3%). Advanced proliferative vitreoretinopathy (PVR) was associated with retinal detachment in 8 eyes (66.7%) and in 6 eyes (50%) it was not possible to assess the beginning of retinal detachment. In 3 of 5 patients with bilateral retinal detachment the adverse course of retinal detachment on the first eye was followed 8 to 12 years previously in another department: two retinal detachments with giant tears were evaluated as inoperable and one inveterated detachment with advanced PVR was operated unsuccessfully. Retinal detachment was operated in 9 eyes of 7 patients, in two patients both eyes were operated simultaneously. The patients were followed up after surgery for 11 months to 15 years, on average for 65

  5. Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats☆

    Science.gov (United States)

    Li, Guang; Garza, Bryan De La; Shih, Yen-Yu I.; Muir, Eric R.; Duong, Timothy Q.

    2013-01-01

    The Royal College of Surgeons (RCS) rat is an established animal model of retinitis pigmentosa, a family of inherited retinal diseases which starts with loss of peripheral vision and progresses to eventual blindness. Blood flow (BF), an important physiological parameter, is intricately coupled to metabolic function under normal physiological conditions and is perturbed in many neurological and retinal diseases. This study reports non-invasive high-resolution MRI (44 × 44 × 600 μm) to image quantitative retinal and choroidal BF and layer-specific retinal thicknesses in RCS rat retinas at different stages of retinal degeneration compared with age-matched controls. The unique ability to separate retinal and choroidal BF was made possible by the depth-resolved MRI technique. RBF decreased with progressive retinal degeneration, but ChBF did not change in RCS rats up to post-natal day 90. We concluded that choroidal and retinal circulations have different susceptibility to progressive retinal degeneration in RCS rats. Layer-specific retinal thickness became progressively thinner and was corroborated by histological analysis in the same animals. MRI can detect progressive anatomical and BF changes during retinal degeneration with laminar resolution. PMID:22721720

  6. Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats.

    Science.gov (United States)

    Li, Guang; De La Garza, Bryan; Shih, Yen-Yu I; Muir, Eric R; Duong, Timothy Q

    2012-08-01

    The Royal College of Surgeons (RCS) rat is an established animal model of retinitis pigmentosa, a family of inherited retinal diseases which starts with loss of peripheral vision and progresses to eventual blindness. Blood flow (BF), an important physiological parameter, is intricately coupled to metabolic function under normal physiological conditions and is perturbed in many neurological and retinal diseases. This study reports non-invasive high-resolution MRI (44 × 44 × 600 μm) to image quantitative retinal and choroidal BF and layer-specific retinal thicknesses in RCS rat retinas at different stages of retinal degeneration compared with age-matched controls. The unique ability to separate retinal and choroidal BF was made possible by the depth-resolved MRI technique. RBF decreased with progressive retinal degeneration, but ChBF did not change in RCS rats up to post-natal day 90. We concluded that choroidal and retinal circulations have different susceptibility to progressive retinal degeneration in RCS rats. Layer-specific retinal thickness became progressively thinner and was corroborated by histological analysis in the same animals. MRI can detect progressive anatomical and BF changes during retinal degeneration with laminar resolution. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. [Lattice degeneration of the peripheral retina: ultrastructural study].

    Science.gov (United States)

    Bec, P; Malecaze, F; Arne, J L; Mathis, A

    1985-01-01

    The ultrastructural study of a case of snail track degeneration shows the presence of lipid inclusions in both the glial and the macrophage cells in every layer of the retina, and the existence of intraretinal fibers different from collagen fibers appearing to be glial filaments similar to those found in astrocytic gliomes and to the Rosenthal fibers observed in senile nervous cells. Other features were thinning of the retina and absence of blood vessels in the retina. There are no abnormalities of the vitreo-retinal juncture. All the lesions are in agreement with those observed by Daicker [Ophthalmologica, Basel 165: 360-365, 1972; Klin. Mbl. Augenheilk. 172: 581-583, 1978] with some differences, however. They are different from those found in lattice degeneration. They show that snail track degeneration is a specific form of peripheral retinal degeneration which is quite different from lattice degeneration and must not be considered similar.

  8. [Clinical findings in members of a Czech family with retinitis pigmentosa caused by the c.2426_2427delAG mutation in RPGR].

    Science.gov (United States)

    Kousal, B; Skalická, P; Diblík, P; Kuthan, P; Langrová, H; Lišková, P

    2013-03-01

    To describe the phenotype of members of the first Czech retinitis pigmentosa family with an identified molecular genetic cause (c.2426_2427delAG in RPGR), followed for more than 13 years. Medical records were reviewed and a detailed ophthalmic examination including spectral-domain optical coherence tomography and full-field and multifocal electroretinography (ERG) was performed in two affected males, three female carriers and one unaffected female. A 22-year-old male who denied suffering from nyctalopia had a best corrected visual acuity (BCVA) of 0.63 in both eyes. Moderate myopia and myopic astigmatism were present bilaterally. Color vision and contrast sensitivity were normal. There was an eccentric constriction of the visual fields that spared the central 20 degrees in both eyes. Fundus examination revealed bilateral pigmentary changes in the mid-periphery. Full-field ERG documented a 10% rod and 20% cone response. The phenotype of his cousin, also aged 22 years, was more severe. He complained of nyctalopia since 12 years of age. His BCVA was 0.3 in the right eye and 0.5 in the left eye. Myopia and astigmatism were present bilaterally. Contrast sensitivity and color vision were severely impaired. Full field ERG was extinct, but some activity on multifocal ERG was still detectable. The constriction of the visual fields reached 5 degrees in both eyes. Fundus examination showed the typical retinitis pigmentosa appearance. All carriers denied that they suffered from nyctalopia, but two of them had decreased BCVA in at least one eye. None exhibited typical bone spicules or a tapetal-like reflex. Significant refractive errors were present in all eyes of the carriers. The finding of moderate or high myopia and astigmatism in males with retinitis pigmentosa as well as refractive errors in female relatives indicates possible X-linked inheritance, which may be especially important in pedigrees where the transmission pattern can not be clearly established. Our study

  9. Overexpression of Pax6 results in microphthalmia, retinal dysplasia and defective retinal ganglion cell axon guidance

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    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

  10. Success Rates of Vitrectomy in Treatment of Rhegmatogenous Retinal Detachment

    OpenAIRE

    Mohamed, Yasser Helmy; Ono, Kozue; Kinoshita, Hirofumi; Uematsu, Masafumi; Tsuiki, Eiko; Fujikawa, Azusa; Kitaoka, Takashi

    2016-01-01

    Aim. To investigate the anatomical success rates of pars plana vitrectomy (PPV) after primary rhegmatogenous retinal detachment (RRD). Methods. This retrospective study was conducted between December 2008 and October 2014 at Nagasaki University Hospital. The preoperative data recorded included the lens status, location of the retinal tear, whether a tear was visualized, presence of multiple tears, macula status, presence of peripheral lattice retinal degeneration, and best-corrected visual ac...

  11. Lattice degeneration of the retina.

    Science.gov (United States)

    Byer, N E

    1979-01-01

    Lattice degeneration of the retina is the most important of all clinically distinct entities that effect the peripheral fundus and are related to retinal detachment. The purpose of this review is to survey the extensive literature, to evaluate the many diverse opinions on this subject, and to correlate and summarize all the known facts regarding this disease entity. The disease is fully defined and described, both clinically and histologically. Some aspects of the disease are still poorly understood, and some remain controversial, especially in the area of management. For this reason, the indications for treatment are discussed under eight subsections, with a view toward providing practical guidelines for recommendations in management.

  12. Photostress Testing Device for Diagnosing Retinal Disease

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    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.

  13. STRUCTURAL ASSESSMENT OF HYPERAUTOFLUORESCENT RING IN PATIENTS WITH RETINITIS PIGMENTOSA

    Science.gov (United States)

    LIMA, LUIZ H.; CELLA, WENER; GREENSTEIN, VIVIENNE C.; WANG, NAN-KAI; BUSUIOC, MIHAI; THEODORE SMITH, R.; YANNUZZI, LAWRENCE A.; TSANG, STEPHEN H.

    2009-01-01

    Purpose To analyze the retinal structure underlying the hyperautofluorescent ring visible on fundus autofluorescence in patients with retinitis pigmentosa. Methods Twenty-four eyes of 13 patients with retinitis pigmentosa, aged 13 years to 67 years, were studied. The integrity of the photoreceptor cilia, also known as the inner/outer segment junction of the photoreceptors, the outer nuclear layer, and retinal pigment epithelium, was evaluated outside, across, and inside the ring with spectral-domain optical coherence tomography (OCT). Results Inside the foveal area, fundus autofluorescence did not detect abnormalities. Outside the ring, fundus autofluorescence revealed hypoautofluorescence compatible with the photoreceptor/retinal pigment epithelium degeneration. Spectral-domain OCT inside the ring, in the area of normal foveal fundus autofluorescence, revealed an intact retinal structure in all eyes and total retinal thickness values that were within normal limits. Across the ring, inner/outer segment junction disruption was observed and the outer nuclear layer was decreased in thickness in a centrifugal direction in all eyes. Outside the hyperautofluorescent ring, the inner/outer segment junction and the outer nuclear layer appeared to be absent and there were signs of retinal pigment epithelium degeneration. Conclusion Disruption of the inner/outer segment junction and a decrease in outer retinal thickness were found across the central hyperautofluorescent ring seen in retinitis pigmentosa. Outer segment phagocytosis by retinal pigment epithelium is necessary for the formation of an hyperautofluorescent ring. PMID:19584660

  14. [To cognize retinitis pigmentosa with scientific view].

    Science.gov (United States)

    Li, Gen-lin

    2009-03-01

    Retinitis pigmentosa (RP) is the most common inherited eye disease that usually leads into blind, and is high simplex and clinical heterogeneity. Recent years, some new hereditary forms have been found, such as digenic RP, mitochondrial RP, incomplete dominant inheritance RP. The phenotype of RP is multiplicity. Incompatible phenomenon between genotype and phenotypes was shown in some genes such as peripherin/RDS, RHO, RP2 and RP3. The complicated phenotype was shown in the rare RP forms, such as centricity RP, stemma RP, retinitis pigmentosa sine pigmento, and retinal degeneration slow. Retinal transplantation, retinal implantation, drug and neurotrophic factor therapy, and gene therapy have been well studied worldwide and presented some hopeful efficacy. Ophthalmologists and practitioners should cognize the new advance and new knowledge on RP therapy with a scientific view for better serving the RP patients.

  15. Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families

    Science.gov (United States)

    Coppieters, Frauke; Roels, Dimitri; De Jaegere, Sarah; Flipts, Helena; De Zaeytijd, Julie; Walraedt, Sophie; Claes, Charlotte; Fransen, Erik; Van Camp, Guy; Depasse, Fanny; Casteels, Ingele; de Ravel, Thomy

    2017-01-01

    Purpose Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. Methods Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. Results Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5–30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). Conclusions Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular

  16. Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population.

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    Katsuhiro Hosono

    Full Text Available Retinitis pigmentosa (RP is a highly heterogeneous genetic disease including autosomal recessive (ar, autosomal dominant (ad, and X-linked inheritance. Recently, arRP has been associated with mutations in EYS (Eyes shut homolog, which is a major causative gene for this disease. This study was conducted to determine the spectrum and frequency of EYS mutations in 100 Japanese arRP patients. To determine the prevalence of EYS mutations, all EYS exons were screened for mutations by polymerase chain reaction amplification, and sequence analysis was performed. We detected 67 sequence alterations in EYS, of which 21 were novel. Of these, 7 were very likely pathogenic mutations, 6 were possible pathogenic mutations, and 54 were predicted non-pathogenic sequence alterations. The minimum observed prevalence of distinct EYS mutations in our study was 18% (18/100, comprising 9 patients with 2 very likely pathogenic mutations and the remaining 9 with only one such mutation. Among these mutations, 2 novel truncating mutations, c.4957_4958insA (p.S1653KfsX2 and c.8868C>A (p.Y2956X, were identified in 16 patients and accounted for 57.1% (20/35 alleles of the mutated alleles. Although these 2 truncating mutations were not detected in Japanese patients with adRP or Leber's congenital amaurosis, we detected them in Korean arRP patients. Similar to Japanese arRP results, the c.4957_4958insA mutation was more frequently detected than the c.8868C>A mutation. The 18% estimated prevalence of very likely pathogenic mutations in our study suggests a major involvement of EYS in the pathogenesis of arRP in the Japanese population. Mutation spectrum of EYS in 100 Japanese patients, including 13 distinct very likely and possible pathogenic mutations, was largely different from the previously reported spectrum in patients from non-Asian populations. Screening for c.4957_4958insA and c.8868C>A mutations in the EYS gene may therefore be very effective for the genetic testing

  17. Misdiagnosis of X-linked retinitis pigmentosa in a choroideremia patient with heavily pigmented fundi.

    Science.gov (United States)

    Nanda, A; Salvetti, A P; Martinez-Fernandez de la Camara, C; MacLaren, R E

    2018-06-01

    Inherited retinal diseases are thought to be the leading cause of sight loss in the working age population. Mutations found in the RPGR and CHM genes cause retinitis pigmentosa (RP) and choroideremia, respectively. In the first instance, an X-linked family history of visual field loss commonly raises the suspicion of one of these two genes. In choroideremia, the classic description of a white fundal reflex secondary to the widespread chorioretinal degeneration was made over a hundred years ago in Caucasians. But, it is not so obvious in heavily pigmented fundi. Hence, the clinical diagnosis of CHM in non-Caucasian patients may be challenging in the first stages of the disease. Here we report a case of a Southeast Asian gentleman who has a family history of X-linked retinal degeneration and was found to have a confirmed in-frame deletion of 12 DNA nucleotides in exon 15 of the RPGR gene. Later in life, however, his fundal appearance showed unusual areas of circular pigment hypertrophy and clumping. He was therefore tested for carrying a disease-causing mutation in the CHM gene and a null mutation was found. Since gene therapy trials are ongoing for both of these conditions, it has now become critically important to establish the correct genetic diagnosis in order to recruit suitable candidates. Moreover, this case demonstrates the necessity to remain vigilant in the interpretation of genetic results which are inconsistent with clinical features.

  18. ILDR1 deficiency causes degeneration of cochlear outer hair cells and disrupts the structure of the organ of Corti: a mouse model for human DFNB42

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    Qing Sang

    2015-03-01

    Full Text Available Immunoglobulin-like domain containing receptor 1 (ILDR1 is a poorly characterized gene that was first identified in lymphoma cells. Mutations in ILDR1 are responsible for DFNB42, but the pathogenesis of hearing loss caused by ILDR1 mutations remains to be elucidated. To explore the role of ILDR1 in hearing, we created Ildr1 knockout mice. In heterozygous mice, ILDR1 expression was found in outer hair cells (OHCs and inner hair cells (IHCs of the organ of Corti. ILDR1-deficient mice are profoundly deaf by postnatal day 21 (P21. No significant difference was observed in the supporting cells and IHCs of ILDR1-deficient mice, but progressive degeneration of OHCs occurred at P15 and disruption of the tunnel running through the organ of Corti was noticeable at P21. By P28, there were no OHCs visible in any of the turns of the organ of Corti, and the tunnel of the organ of Corti was entirely destroyed. ILDR1 deficiency affects expression of tricellulin in vivo, and this provides a possible explanation to hearing loss. To further elucidate the mechanism of deafness related to ILDR1 deficiency, we pursued a differential proteomic approach to comprehensively assess differential protein expression in the cochleae of Ildr1+/− and Ildr1−/− mice at P21. Altogether, 708 proteins were up-regulated (fold change >1.5 and 114 proteins were down-regulated (fold change <0.5 in the Ildr1−/− mice compared with Ildr1+/− mice. Gene ontology classification indicated that a number of differentially expressed proteins are involved in cell adhesion, protein and vesicle-mediated transport, cell death, membrane organization, and cellular homeostasis. A few of these proteins are closely related to hearing development. Taken together, our data suggest that ILDR1 is important for the survival of OHCs and provide novel insights into the pathogenesis of human deafness DFNB42 deafness.

  19. Retinal Thickening and Photoreceptor Loss in HIV Eyes without Retinitis.

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    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.

  20. LONG-TERM FOLLOW-UP OF PATIENTS WITH RETINITIS PIGMENTOSA TYPE 12 CAUSED BY CRB1 MUTATIONS : A Severe Phenotype With Considerable Interindividual Variability

    NARCIS (Netherlands)

    Mathijssen, Inge B; Florijn, Ralph J; van den Born, L Ingeborgh; Zekveld-Vroon, Renate C; Ten Brink, Jacoline B; Plomp, Astrid S; Baas, Frank; Meijers-Heijboer, Hanne; Bergen, Arthur A B; van Schooneveld, Mary J

    2017-01-0